Groningen, Netherlands
Groningen, Netherlands

The University of Groningen , located in the city of Groningen, was founded in 1614. It is one of the oldest universities in the Netherlands as well as one of its largest. Since its inception more than 200,000 students have graduated. It is a member of the distinguished international Coimbra Group of European universities.In April 2013, according to the results of the International Student Barometer, the University of Groningen, for the third time in a row, has been voted the best University of the Netherlands. In 2014 the university celebrates its 400th anniversary and has planned various activities in and around the city of Groningen. For one month, from 15 May till 15 June, Groningen is immersed in a festive program RUG400 around the theme "For Infinity" .The University of Groningen has ten faculties, nine graduate schools, 27 research centres and institutes, and more than 175 degree programmes. Wikipedia.


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Patent
University of Groningen | Date: 2016-12-02

The invention relates to a method for providing analogs of human milk oligosaccharides (HMO), in particular oligosaccharides containing terminal sialic acid. The method comprises the steps of: a) providing a source of non-digestible galactooligosaccharides (GOS) containing at least two terminally bonded -linked galactose residues; b) providing a sialic acid donor having (2-3)-sialylated O-glycans; c) contacting said GOS with said sialic acid donor in the presence of an enzyme having trans-sialidase activity in an enzyme reaction mixture; and d) isolating from said enzyme reaction mixture a fraction comprising at least 20 percent by weight of disialylated galactooligosaccharides (di-Sia-GOS) based on the dry matter.


OBJECTIVE: The aim of this study was to compare the stratification of sepsis patients in the emergency department (ED) for ICU admission and mortality using the Predisposition, Infection, Response and Organ dysfunction (PIRO) and quick Sequential Organ Failure Assessment (qSOFA) scores with clinical judgement assessed by the ED staff. PATIENTS AND METHODS: This was a prospective observational study in the ED of a tertiary care teaching hospital. Adult nontrauma patients with suspected infection and at least two Systemic Inflammatory Response Syndrome criteria were included. The primary outcome was direct ED to ICU admission. The secondary outcomes were in-hospital, 28-day and 6-month mortality, indirect ICU admission and length of stay. Clinical judgement was recorded using the Clinical Impression Scores (CIS), appraised by a nurse and the attending physician. The PIRO and qSOFA scores were calculated from medical records. RESULTS: We included 193 patients: 103 presented with sepsis, 81 with severe sepsis and nine with septic shock. Fifteen patients required direct ICU admission. The CIS scores of nurse [area under the curve (AUC)=0.896] and the attending physician (AUC=0.861), in conjunction with PIRO (AUC=0.876) and qSOFA scores (AUC=0.849), predicted direct ICU admission. The CIS scores did not predict any of the mortality endpoints. The PIRO predicted in-hospital (AUC=0.764), 28-day (AUC=0.784) and 6-month mortality (AUC=0.695). The qSOFA score also predicted in-hospital (AUC=0.823), 28-day (AUC=0.848) and 6-month mortality (AUC=0.620). CONCLUSION: Clinical judgement is a fast and reliable method to stratify between ICU and general ward admission in ED patients with sepsis. The PIRO and qSOFA scores do not add value to this stratification, but perform better on the prediction of mortality. In sepsis patients, therefore, the principle of ‘treat first what kills first’ can be supplemented with ‘judge first and calculate later’. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


STUDY DESIGN.: Validation study with cross sectional and longitudinal measurements OBJECTIVE.: To translate the US National Institute of Health (NIH)-minimal dataset for clinical research on chronic low back pain into the Dutch language and to test its validity and reliability among people with chronic low back pain. SUMMARY OF BACKGROUND DATA.: The NIH developed a minimal dataset to encourage more complete and consistent reporting of clinical research and to be able to compare studies across countries in patients with low back pain. In the Netherlands, the NIH-minimal dataset has not been translated before and measurement properties are unknown. METHODS.: Cross cultural validity was tested by a formal forward-backward translation. Structural validity was tested with exploratory factor analyses (Comparative Fit Index (CFI), Tucker Lewis Index (TLI) and Root mean Square Error of Approximation (RMSEA)). Hypothesis testing was performed to compare subscales of the NIH dataset with the Pain Disability Index and the EurQol-5D (Pearson Correlation Coefficients). Internal consistency was tested with Cronbachʼs α and test-retest reliability at 2 weeks was calculated in a sub-sample of patients with Intraclass Correlation Coefficients (ICC) and Weighted Kappaʼs (κω). RESULTS.: In total, 452 patients were included of which 52 were included for the test-retest study. Validity: Factor analysis for structural validity pointed into the direction of a 7-factor model (Cronbachʼs α=0.78). Factors and total score of the NIH-minimal dataset showed fair to good correlations with PDI (r?=?0.43 to 0.70) and EQ5D (r?=?−0.41 to −0.64). Reliability: test-retest reliability per item showed substantial agreement (κω=0.65). Test-retest reliability per factor was moderate to good (ICC?=?0.71). CONCLUSION.: The Dutch Language version measurement properties of the NIH-minimal were satisfactory.Level of Evidence: N/A Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Hesselink W.H.,University of Groningen
Formal Aspects of Computing | Year: 2017

Given a mutual exclusion algorithm MXd for (Formula presented.) threads, a mutual exclusion algorithm for (Formula presented.) threads can be built in a tree of degree d with N leaves, with the critical section at the root of the tree. This tournament solution seems obviously correct and efficient. The present note proves the correctness, and formalizes the efficiency in terms of concurrent complexity by means of Bounded Unity. If the tree is balanced, the throughput is logarithmic in N. If moreover MXd satisfies FCFS (first-come first-served), the worst case individual delay of the tournament algorithm is of order N. This is optimal. © 2017 The Author(s)


Buunk A.P.,University of Groningen
Behavioral and Brain Sciences | Year: 2017

It is emphasized that in organizational settings, the responses to same-sex attractive others are enhanced among individuals high in intrasexual competitiveness; that especially attractive rivals who are perceived as unfriendly will induce competition; that among males, physical dominance may induce more competition than physical attractiveness; and that especially males may prefer to associate with attractive same-sex others for intrasexual collaboration. © Cambridge University Press 2017.


Vanclay F.,University of Groningen
Impact Assessment and Project Appraisal | Year: 2017

While the World Bank safeguard policies and International Finance Corporation Performance Standards specify the requirements to be observed when project-induced displacement and resettlement occurs, these international standards are not always followed. Governments often invoke the power of eminent domain and implement expropriation procedures instead of building support for a public or private project by negotiating with project-affected peoples. Evaluations of projects reveal that people are usually made worse off by being resettled. This paper provides a general introduction to the topic of project-induced displacement and resettlement, raising the key issues facing resettlement practice: under what conditions should projects and associated resettlements proceed; what constitutes appropriate compensation; can livelihoods be restored or improved; what is the role of benefit sharing and shared value; and how resettlement practice can be improved. Although there is ongoing improvement in the discourse and practice of project-induced resettlement, being resettled is still likely to be an impoverishment risk and have an emotional toll. Hopefully, however, under the right conditions, resettlement has the potential to be an opportunity for development. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


Smyth E.,Intersocial Consulting | Vanclay F.,University of Groningen
Impact Assessment and Project Appraisal | Year: 2017

The Social Framework for Projects assists in understanding, assessing, planning and managing the social issues associated with big projects, such as those leading to the resettlement or displacement of people. The Framework was iteratively developed by assessing existing models (e.g. Sustainable Livelihoods Approach of the UK Department for International Development; the Impoverishment Risks and Reconstruction model of Michael Cernea; the Capability Approach of Amartya Sen; Asset Based Community Development and other capitals-based approaches), reflecting on our practical experience in large projects, and on the basis of input and feedback from a wide range of stakeholders. It was designed to be compatible with the International Finance Corporation’s environmental and social performance standards and international best practice. It consists of 8 key social and environmental categories which address all the issues that contribute to people’s well-being and the social sustainability of projects, namely: people’s capacities, abilities and freedoms to achieve their goals; community/social supports and political context; livelihood assets and activities; culture and religion; infrastructure and services; housing and business structures; land and natural resources; and the living environment. The Framework is a conceptual model, a practical methodology and a communications tool to ensure that the process of mitigating negative social impacts and enhancing the benefits of large projects is effective and accessible to all stakeholders. © 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


De Persis C.,University of Groningen | Postoyan R.,University of Lorraine
IEEE Transactions on Automatic Control | Year: 2017

We present an approach for the coordination of a network of agents in a cyber-physical environment. The agents's dynamics are nonlinear, of arbitrary dimensions and possibly heterogeneous. The objective is to design resource-Aware distributed control strategies to ensure a coordination task. In particular, we aim at ensuring the convergence of the differences between the agents' output variables to a prescribed compact set, hence covering rendez-vous and formation control as specific scenarios. We develop event-based sampling strategies for that purpose. Three scenarios are studied. We first focus on event-Triggered control, in which case the agents continuously measure the relative distances with their neighbours and only update their control input at some time instants. This set-up is relevant to limit changes in control signals and therefore to reduce the resources usage of the actuators. A triggering rule is defined for each edge using an auxiliary variable, whose dynamics only depends on the local variables. We then explain how to derive time-Triggered and self-Triggered distributed controllers. These control strategies collect measurements and update the control inputs only at some discrete time instants, which save communication and computation resources. The existence of a uniform minimum amount of times between any two edge events is guaranteed in all cases, thus ruling out Zeno phenomenon. The analysis is carried out within the framework of hybrid systems and an invariance principle is used to conclude about coordination. © 1963-2012 IEEE.


Xia W.,Dalian University of Technology | Cao M.,University of Groningen
Automatica | Year: 2017

In-depth understanding of the spectral properties of grounded Laplacian matrices is critical for the analysis of convergence speeds of dynamical processes over complex networks, such as opinion dynamics in social networks with stubborn agents. We focus on grounded Laplacian matrices for directed graphs and show that their eigenvalues with the smallest real part must be real. Lower and upper bounds for such eigenvalues are provided utilizing tools from nonnegative matrix theory. For those eigenvectors corresponding to such eigenvalues, we discuss two cases when we can identify the vertex that corresponds to the smallest eigenvector component. We then discuss an application in leader–follower social networks where the grounded Laplacian matrices arise naturally. With the knowledge of the vertex corresponding to the smallest eigenvector component for the smallest eigenvalue, we prove that by removing or weakening specific directed couplings pointing to the vertex having the smallest eigenvector component, all the states of the other vertices converge faster to that of the leading vertex. This result is in sharp contrast to the well-known fact that when the vertices are connected together through undirected links, removing or weakening links does not accelerate and in general decelerates the converging process. © 2017 Elsevier Ltd


Chandgude A.L.,University of Groningen | Domling A.,University of Groningen
Organic Letters | Year: 2017

The Ugi four-component reaction (U-4CR) with N-hydroxyimides as a novel carboxylic acid isostere has been reported. This reaction provides straightforward access to α-hydrazino amides. A broad range of aldehydes, amines, isocyanides and N-hydroxyimides were employed to give products in moderate to high yields. This reaction displays N-N bond formation by cyclic imide migration in the Ugi reaction. Thus, N-hydroxyimide is added as a new acid component in the Ugi reaction and broadens the scaffold diversity. © 2017 American Chemical Society.


Gruner R.L.,University of Western Australia | Power D.,University of Melbourne | Power D.,University of Groningen
Journal of Cleaner Production | Year: 2017

For most firms, the development of sustainable supply chain practices remains challenging. Using a theory-building approach, we develop a theory of socio-ecological intergradation to provide managers with guidance in mimicking natural ecosystems to develop more local and thus sustainable supply chains. Socio-ecological intergradation refers to the gradual merging of social (organizational) and ecological (environmental) systems to shift a firm's focus from global supply chain optimization to building more regionally bound, socio-ecologically connected operations. Drawing on the natural and industrial ecology literature, the paper identifies five principles that mimic natural ecosystems and increase the environmental sustainability of supply chains, including the ecological systems they ultimately depend on. The paper further illustrates what these principles mean in both an environmental and a supply chain context and how, in concert, they can lead toward more sustainably designed and managed supply chains. In building a theory of socio-ecological intergradation, this research is one of the first attempts to apply ecological principles to supply chains, creating synergy and dialogue between the sustainable supply chain management, business ethics, and industrial ecology disciplines. © 2017 Elsevier Ltd


Monshizadeh N.,University of Groningen | De Persis C.,University of Groningen
Automatica | Year: 2017

This paper considers a problem of output agreement in heterogeneous networks with dynamics on the nodes as well as on the edges. The control and disturbance signals entering the nodal dynamics are “unmatched” meaning that some nodes are only subject to disturbances and not to the actuating signals. To further enrich our model and motivated by synchronization problems in physical networks, we accommodate (solvable) algebraic constraints resulting in a fairly general and heterogeneous network. It is shown that appropriate dynamic feedback controllers achieve output agreement on a desired vector, in the presence of physical coupling and despite the influence of constant as well as time-varying disturbances. Furthermore, we address the case of an optimal steady-state deployment of the control effort over the network by suitable distributed controllers. As a case study, the proposed results are applied to a heterogeneous microgrid. © 2016 Elsevier Ltd


Haagsma H.,University of Groningen
54th Annual Meeting of the Association for Computational Linguistics, ACL 2016 - Student Research Workshop | Year: 2016

Singleton (or non-coreferential) mentions are a problem for coreference resolution systems, and identifying singletons before mentions are linked improves resolution performance. Here, a singleton detection system based on word embeddings and neural networks is presented, which achieves state-of-The-Art performance (79.6% accuracy) on the CoNLL- 2012 shared task development set. Extrinsic evaluation with the Stanford and Berkeley coreference resolution systems shows significant improvement for the first, but not for the latter. The results show the potential of using neural networks and word embeddings for improving both singleton detection and coreference resolution. © 2016 Association for Computational Linguistics.


Even J.,University of Groningen
EPJ Web of Conferences | Year: 2016

Studies of the superheavy elements bring several challenges through low production yields, short half-lives, and high background rates. This paper describes the possibilities of chemical separations as techniques to overcome the background problematic and to investigate the nuclear properties of the heaviest nuclides. © The Authors, published by EDP Sciences.


Liu Y.,University of Groningen | Lehn J.-M.,CNRS Institute of Science and Supramolecular Engineering | Hirsch A.K.H.,University of Groningen
Accounts of Chemical Research | Year: 2017

Conspectus Constitutional dynamic chemistry (CDC) features the use of reversible linkages at both molecular and supramolecular levels, including reversible covalent bonds (dynamic covalent chemistry, DCC) and noncovalent interactions (dynamic noncovalent chemistry, DNCC). Due to its inherent reversibility and stimuli-responsiveness, CDC has been widely utilized as a powerful tool for the screening of bioactive compounds, the exploitation of receptors or substrates driven by molecular recognition, and the fabrication of constitutionally dynamic materials. Implementation of CDC in biopolymer science leads to the generation of constitutionally dynamic analogues of biopolymers, biodynamers, at the molecular level (molecular biodynamers) through DCC or at the supramolecular level (supramolecular biodynamers) via DNCC. Therefore, biodynamers are prepared by reversible covalent polymerization or noncovalent polyassociation of biorelevant monomers. In particular, molecular biodynamers, biodynamers of the covalent type whose monomeric units are connected by reversible covalent bonds, are generated by reversible polymerization of bio-based monomers and can be seen as a combination of biopolymers with DCC. Owing to the reversible covalent bonds used in DCC, molecular biodynamers can undergo continuous and spontaneous constitutional modifications via incorporation/decorporation and exchange of biorelevant monomers in response to internal or external stimuli. As a result, they behave as adaptive materials with novel properties, such as self-healing, stimuli-responsiveness, and tunable mechanical and optical character. More specifically, molecular biodynamers combine the biorelevant characters (e.g., biocompatibility, biodegradability, biofunctionality) of bioactive monomers with the dynamic features of reversible covalent bonds (e.g., changeable, tunable, controllable, self-healing, and stimuli-responsive capacities), to realize synergistic properties in one system. In addition, molecular biodynamers are commonly produced in aqueous media under mild or even physiological conditions to suit their biorelated applications. In contrast to static biopolymers emphasizing structural stability and unity by using irreversible covalent bonds, molecular biodynamers are seeking relative structural adaptability and diversity through the formation of reversible covalent bonds. Based on these considerations, molecular biodynamers are capable of reorganizing their monomers, generating, identifying, and amplifying the fittest structures in response to environmental factors. Hence, molecular biodynamers have received considerable research attention over the past decades. Accordingly, the construction of molecular biodynamers through equilibrium polymerization of nucleobase-, carbohydrate- or amino-acid-based monomers can lead to the fabrication of dynamic analogues of nucleic acids (DyNAs), polysaccharides (glycodynamers), or proteins (dynamic proteoids), respectively. In this Account, we summarize recent advances in developing different types of molecular biodynamers as structural or functional biomimetics of biopolymers, including DyNAs, glycodynamers, and dynamic proteoids. We introduce how chemists utilize various reversible reactions to generate molecular biodynamers with specific sequences and well-ordered structures in aqueous medium. We also discuss and list their potential applications in various research fields, such as drug delivery, drug discovery, gene sensing, cancer diagnosis, and treatment. © 2017 American Chemical Society.


Lolkema J.S.,University of Groningen | Slotboom D.J.,University of Groningen
Current Opinion in Structural Biology | Year: 2017

The recently determined crystal structure of the bacterial Na+-citrate symporter CitS provides unexpected structural and mechanistic insights. The protein has a fold that has not been seen in other proteins, but the oligomeric state, domain organization and proposed transport mechanism strongly resemble those of the sodium-dicarboxylate symporter vcINDY, and the putative exporters YdaH and MtrF, thus hinting at convergence in structure and function. CitS and the related proteins are predicted to translocate their substrates by an elevator-like mechanism, in which a compact transport domain slides up and down through the membrane while the dimerization domain is stably anchored. Here we review the large body of available biochemical data on CitS in the light of the new crystal structure. We show that the biochemical data are fully consistent with the proposed elevator mechanism, but also demonstrate that the current structural data cannot explain how strict coupling of citrate and Na+ transport is achieved. We propose a testable model for the coupling mechanism. © 2016 Elsevier Ltd


Laugs G.A.H.,University of Groningen | Moll H.C.,University of Groningen
Renewable and Sustainable Energy Reviews | Year: 2017

Energy scenarios are often used to investigate various possible energy futures and reduce the uncertainty that surrounds energy transition. However, scenario construction lacks consistent and adequate methodological standards, resulting in limited insight into the actual bandwidth covered by current energy scenarios and whether various perspectives on future energy development pathways are all adequately represented. Our research deployed a non-mathematical clustering approach to identify general trends in future energy scenarios and assess the role of Cornucopian and Malthusian oriented world views therein. We found that the futures communicated in quantified future energy scenarios overlap to a large extent and represent only a narrow bandwidth of moderate world views. We argue that the underrepresentation of extreme representations of world views and environmental discourses in energy scenarios skews the overall outlook on possible energy futures. This implies that scenario-informed policy design and decision-making risks bias towards the status-quo. © 2016 Elsevier Ltd


Evidential reasoning is hard, and errors can lead to miscarriages of justice with serious consequences. Analytic methods for the correct handling of evidence come in different styles, typically focusing on one of three tools: arguments, scenarios or probabilities. Recent research used Bayesian networks for connecting arguments, scenarios, and probabilities. Well-known issues with Bayesian networks were encountered: More numbers are needed than are available, and there is a risk of misinterpretation of the graph underlying the Bayesian network, for instance as a causal model. The formalism presented here models presumptive arguments about coherent hypotheses that are compared in terms of their strength. No choice is needed between qualitative or quantitative analytic styles, since the formalism can be interpreted with and without numbers. The formalism is applied to key concepts in argumentative, scenario and probabilistic analyses of evidential reasoning, and is illustrated with a fictional crime investigation example based on Alfred Hitchcock’s film ‘To Catch A Thief’. © 2017, The Author(s).


Samplonius J.M.,University of Groningen | Both C.,University of Groningen
Journal of Animal Ecology | Year: 2017

Predicting habitat quality is a major challenge for animals selecting a breeding patch, because it affects reproductive success. Breeding site selection may be based on previous experience, or on social information from the density and success of competitors with an earlier phenology. Variation in animal breeding phenology is often correlated with variation in habitat quality. Generally, animals breed earlier in high-quality habitats that allow them to reach a nutritional threshold required for breeding earlier or avoid nest predation. In addition, habitat quality may affect phenological overlap between species and thereby interspecific competition. Therefore, we hypothesized that competitor breeding phenology can be used as social cue by settling migrants to locate high-quality breeding sites. To test this hypothesis, we experimentally advanced and delayed hatching phenology of two resident tit species on the level of study plots and studied male and female settlement patterns of migratory pied flycatchers Ficedula hypoleuca. The manipulations were assigned at random in two consecutive years, and treatments were swapped between years in sites that were used in both years. In both years, males settled in equal numbers across treatments, but later arriving females avoided pairing with males in delayed phenology plots. Moreover, male pairing probability declined strongly with arrival date on the breeding grounds. Our results demonstrate that competitor phenology may be used to assess habitat quality by settling migrants, but we cannot pinpoint the exact mechanism (e.g. resource quality, predation pressure or competition) that has given rise to this pattern. In addition, we show that opposing selection pressures for arrival timing may give rise to different social information availabilities between sexes. We discuss our findings in the context of climate warming, social information use and the evolution of protandry in migratory animals. © 2017 British Ecological Society.


Van Der Schaft A.,University of Groningen
2016 IEEE 55th Conference on Decision and Control, CDC 2016 | Year: 2016

Negative imaginary and counter-clockwise systems have attracted attention as an interesting class of systems, which is well-motivated by applications. In this paper first the formulation and extension of negative imaginary and counter-clockwise systems as (nonlinear) input-output Hamiltonian systems with dissipation is summarized. Next it is shown how by considering the time-derivative of the outputs a port-Hamiltonian system is obtained, and how this leads to the consideration of alternate passive outputs for port-Hamiltonian systems. Furthermore, a converse result to positive feedback interconnection of input-output Hamiltonian systems with dissipation is obtained, stating that the positive feedback interconnection of two linear systems is an input-output Hamiltonian system with dissipation if and only if the systems themselves are input-output Hamiltonian systems with dissipation. This implies that the Poisson and resistive structure matrices can be redefined in such a way that the interaction between the two systems only takes place via the coupling term in the Hamiltonian of the interconnected system. Subsequently, it is shown how the positive feedback interconnection of two nonlinear input-output Hamiltonian systems with dissipation can be extended to the network interconnection of such systems, and how this leads to a stability analysis of the interconnected system in terms of the Hamiltonians and output mappings of the component systems associated to the vertices, as well as of the network topology. © 2016 IEEE.


Iftime O.V.,University of Groningen
2016 IEEE 55th Conference on Decision and Control, CDC 2016 | Year: 2016

In this paper we present an overview/tutorial of the existing results and a constructive solution for the suboptimal Hankel norm approximation problem for the Wiener class of infinite-dimensional systems. The presented approach is based on frequency domain techniques. The construction of a solution uses a recent result on the continuity of the J-spectral factorization in the Wiener norm. The Wiener class of systems is large enough to include many infinite-dimensional matrix-valued transfer functions used in mathematical modeling of different areas applications such as optimal control, prediction, physics-based modeling (to mention only a few). Therefore we believe that our approach should be of interest not only for systems theorists but also for control engineers when dealing with applications using infinite-dimensional system models and their approximations. © 2016 IEEE.


This commentary to the recent article by Wade & Kazeck discusses the role of constraints as a key concept in the understanding of the limitations in DCD. The concept of constraints is linked to affordances and is useful in the understanding of changes due to development and learning and the limitations of DCD, irrespective of theoretical point of view. © 2017 Elsevier B.V.


Verheij B.,University of Groningen
Frontiers in Artificial Intelligence and Applications | Year: 2016

Today's AI applications are so successful that they inspire renewed concerns about AI systems becoming ever more powerful. Addressing these concerns requires AI systems that are designed as ethical systems, in the sense that their choices are context-dependent, value-guided and rule-following. It is shown how techniques connecting qualitative and quantitative primitives recently developed for evidential argumentation in the law can be used for the design of such ethical systems. In this way, AI and Law techniques are extended to the theoretical understanding of intelligent systems guided by embedded values. © 2016 The authors and IOS Press. All rights reserved.


Hulzebos C.V.,University of Groningen
Journal of Perinatology | Year: 2017

Objective:The objective of this study is to determine whether irradiance levels of phototherapy (PT) devices in Dutch neonatal intensive care units (NICUs) increased between 2008 and 2013.Study Design:Irradiance of all types of PT devices, used in combination with incubators, was measured with a Dale 40 Radiometer (Fluke Biomedical, Everett, WA, USA) in all 10 Dutch NICUs.Results:Irradiance increased in seven NICUs. Median (range) irradiance increased from 9.7 (4.3–32.6) to 16.4 (6.8–41) μW cm-2 nm-1 for 24 overhead devices (P=0.004) and from 6.8 (0.8–15.6) to 22.3 (1.1–36.3) μW cm-2 nm-1 for 12 underneath devices (P=0.014). Five light-emitting diode (LED)-based devices were used in 2013 and one in 2008. The mean distance between overhead PT device and infant decreased by ~9 cm (P<0.001). Significantly more devices delivered minimal (10 μW cm-2 nm-1) recommended irradiance levels (80 vs ~45%; P=0.002).Conclusion:Irradiance of PT devices still varies, but has markedly improved since 2008 due to shorter distances between PT device and infant, and introduction of better performing LED-based devices.Journal of Perinatology advance online publication, 2 March 2017; doi:10.1038/jp.2017.13. © 2017 Nature America, Inc., part of Springer Nature.


The gene that encodes N-acetyltransferase 2 (NAT2), an enzyme that plays a crucial role in the metabolism of many drugs and xenobiotics, is located on chromosome 8p22, one of the most convictive susceptibility loci of schizophrenia. NAT2 genetic polymorphisms lead to various enzyme acetylation phenotypes. In the present study, six selected NAT2 exonic single nucleotide polymorphisms were genotyped in an independent case–control sample of a Northern Chinese Han population to verify the possible association between NAT2 and schizophrenia. Three (rs1801280T/341C, rs1799930/G590A, and rs1208/A803G) of the six single nucleotide polymorphisms showed significant allele frequency differences between the case and the control groups after rigorous Bonferroni correction. One protective fast-acetylation haplotype (NAT2*4) and two risk slow acetylation haplotypes (NAT2*5B and NAT2*6A) were discovered to be associated with schizophrenia. Our results indicate that NAT2 may be a susceptibility gene for schizophrenia in this Chinese Han population, and the risk haplotypes might cause the impairment of NAT2 in metabolizing neurotoxic substances. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Iftime O.V.,University of Groningen
Automatica | Year: 2017

We consider the Newton–Kleinman method for strongly stabilizable infinite-dimensional systems. Under certain assumptions, the maximal self-adjoint solution to the associated control algebraic Riccati equation is constructed. The constructed solution is also the maximal solution to the corresponding control algebraic Riccati inequality. © 2017 Elsevier Ltd


Paalvast Y.,University of Groningen
Current Opinion in Lipidology | Year: 2017

PURPOSE OF REVIEW: To discuss recent advances in research focused on intestinal lipid handling. RECENT FINDINGS: An important strategy in reducing atherosclerosis and risk of cardiovascular events is to increase the rate of reverse cholesterol transport, including its final step; cholesterol excretion from the body. The rate of removal is determined by a complex interplay between the factors involved in regulation of intestinal cholesterol absorption. One of these factors is a process known as transintestinal cholesterol excretion. This pathway comprises transport of cholesterol directly from the blood, through the enterocyte, into the intestinal lumen. In humans, this pathway accounts for 35% of cholesterol excretion in the feces. Mechanistic studies in mice revealed that, activation of the bile acid receptor farnesoid X receptor increases cholesterol removal via the transintestinal cholesterol excretion pathway as well as decreases plasma cholesterol and triglyceride providing an interesting target for treatment of dyslipidemia in humans. The physical chemical properties of bile acids are under control of farnesoid X receptor and determine intestinal cholesterol and triglyceride solubilization as well as absorption, providing a direct link between these two important factors in the pathogenesis of cardiovascular disease. Besides bile acids, intestinal phospholipids are important for luminal lipid solubilization. Interestingly, phospholipid remodeling through LPCAT3 was shown to be pivotal for uptake of fatty acids by enterocytes, which may provide a mechanistic handle for therapeutic intervention. SUMMARY: The importance of the intestine in control of cholesterol and triglyceride homeostasis is increasingly recognized. Recently, novel factors involved in regulation of cholesterol excretion and intestinal triglyceride and fatty acid uptake have been reported and are discussed in this short review. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Loaiza N.,University of Groningen
Current Opinion in Lipidology | Year: 2017

PURPOSE OF REVIEW: To highlight very recent studies identifying novel regulatory molecules and mechanisms in plasma lipid metabolism. RECENT FINDINGS: Two novel regulatory mechanisms of LDL receptor (LDLR) intracellular trafficking have been described. The “COMMD/CCDC22/CCDC93” and “Wiskott–Aldrich syndrome protein and SCAR homologue” complexes were found to be involved in LDLR endosomal sorting and recycling, whereas the GRP94 was shown to protect LDLR from early degradation within the hepatocyte secretory pathway. Additionally, the transcription factors PHD1 and Bmal1 were identified to regulate LDL-C levels in mice by modulating cholesterol excretion. Important advances are reported on the relevance of two Genome Wide Association Studies hits: Reassessment of GALNT2 showed, in contrast to previous reports, that loss of GALNT2 reduces HDL-cholesterol in humans and other mammalian species, while phospholipid transfer protein was identified as an additional target of GALNT2. Tetratricopeptide repeat domain protein 39B was found to promote ubiquitination and degradation of Liver X receptor, and its deficiency increased HDL-cholesterol and cholesterol removal while also inhibiting lipogenesis in mice. SUMMARY: The unraveling of mechanisms how new factors modulate plasma lipid levels keep providing interesting opportunities to rationally design novel therapies to treat cardiovascular disease but also metabolic disorders. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.


Van Der Veen D.R.,University of Surrey | Gerkema M.P.,University of Groningen
FASEB Journal | Year: 2017

Biological oscillations with an ultradian time scale of 1 to several hours include cycles in behavioral arousal, episodic glucocorticoid release, and gene expression. Ultradian rhythms are thought to have an extrinsic origin because of a perceived absence of ultradian rhythmicity in vitro and a lack of known molecular ultradian oscillators. We designed a novel, non-spectral-analysis method of separating ultradian from circadian components and applied it to a published gene expression dataset with an ultradian sampling resolution. Ultradian rhythms in mouse hepatocytes in vivo have been published, andwe validated our approach using this control by confirming 175 of 323 ultradian genes identified in a prior study and found 862 additional ultradian genes. For the first time, we now report ultradian expression of >900 genes in vitro. Sixty genes exhibited ultradian transcriptional rhythmicity, both in vivo and in vitro, including 5 genes involved in the cell cycle. Within these 60 genes, we identified significant enrichment of specific DNA motifs in the 1000 bp proximal promotor, some of which associate with known transcriptional factors. These findings are in strong support of instrinsically driven ultradian rhythms and expose potentialmolecularmechanisms andfunctionsunderlying ultradian rhythmsthat remainunknown.-Vander Veen, D.R., Gerkema, M. P.Unmasking ultradian rhythms in gene expression. FASEBJ. 31, 743-750 (2017). www.fasebj.org. © The Author(s).


de Bruin B.,University of Groningen
Contemporary Social Science | Year: 2013

I examine and evaluate the ethical standards and arguments that Socially Responsible Investment (SRI) investors use when they deselect the alcohol industry and alcohol corporations. The alcohol industry was the first industry excluded by SRI investors and is, relative to fund size, the second most prominent negative screen (after tobacco). I discuss the role of shareholder democracy in the alcohol industry, review some evidence on the financial effects of SRI on sin stocks and investigate the motivations that SRI investors may have to eschew investment in the alcohol industry (almost no motivation can be found). I discuss a number of ethical issues that are salient in the alcohol industry and that ought to concern ethical investors. I draw attention to, in particular, the marketing of alcopops (flavoured alcoholic beverages or malternatives such as Smirnoff Ice and Bacardi Breezer), and strategies involving so-called beer girls. This prepares the way to a reconstruction of two kinds of arguments that SRI investors might implicitly adhere to when they put a negative screen on alcohol: a Public Goods Argument and a Religious Values Argument. I show that the Public Goods Argument is problematic because it risks democratic legitimacy and effectiveness, and that while the Religious Values Argument is a coherent defence for individual investors accepting particular religious views, it is unacceptable if used by institutional investors forcing religious values upon involuntary participants when no societal unanimity concerning these religious values exists. Pension funds and health-care plans are examples of such investors. Finally, I provide an alternative Ethical Issues Argument and defend the claim that there are no good moral reasons for institutional SRI investors to circumvent the alcohol industry; rather, they should use shareholder democracy to make alcohol corporations address the ethical issues lest these issues will never be addressed by the corporations themselves. © 2013 Copyright Academy of Social Sciences.


News Article | April 17, 2017
Site: www.eurekalert.org

Carbon nanotubes can be used to make very small electronic devices, but they are difficult to handle. University of Groningen scientists, together with colleagues from the University of Wuppertal and IBM Zurich, have developed a method to select semiconducting nanotubes from a solution and make them self-assemble on a circuit of gold electrodes. The results were published in the journal Advanced Materials on 5 April. The results look deceptively simple: a self-assembled transistor with nearly 100 percent purity and very high electron mobility. But it took ten years to get there. University of Groningen Professor of Photophysics and Optoelectronics Maria Antonietta Loi designed polymers which wrap themselves around specific carbon nanotubes in a solution of mixed tubes. Thiol side chains on the polymer bind the tubes to the gold electrodes, creating the resultant transistor. 'In our previous work, we learned a lot about how polymers attach to specific carbon nanotubes', Loi explains. These nanotubes can be depicted as a rolled sheet of graphene, the two-dimensional form of carbon. 'Depending on the way the sheets are rolled up, they have properties ranging from semiconductor to semi-metallic to metallic.' Only the semiconductor tubes can be used to fabricate transistors, but the production process always results in a mixture. 'We had the idea of using polymers with thiol side chains some time ago', says Loi. The idea was that as sulphur binds to metals, it will direct polymer-wrapped nanotubes towards gold electrodes. While Loi was working on the problem, IBM even patented the concept. 'But there was a big problem in the IBM work: the polymers with thiols also attached to metallic nanotubes and included them in the transistors, which ruined them.' Loi's solution was to reduce the thiol content of the polymers, with the assistance of polymer chemists from the University of Wuppertal. 'What we have now shown is that this concept of bottom-up assembly works: by using polymers with a low concentration of thiols, we can selectively bring semiconducting nanotubes from a solution onto a circuit.' The sulphur-gold bond is strong, so the nanotubes are firmly fixed: enough even to stay there after sonication of the transistor in organic solvents. The production process is simple: metallic patterns are deposited on a carrier , which is then dipped into a solution of carbon nanotubes. The electrodes are spaced to achieve proper alignment: 'The tubes are some 500 nanometres long, and we placed the electrodes for the transistors at intervals of 300 nanometres. The next transistor is over 500 nanometres away.' The spacing limits the density of the transistors, but Loi is confident that this could be increased with clever engineering. 'Over the last years, we have created a library of polymers that select semiconducting nanotubes and developed a better understanding of how the structure and composition of the polymers influences which carbon nanotubes they select', says Loi. The result is a cheap and scalable production method for nanotube electronics. So what is the future for this technology? Loi: 'It is difficult to predict whether the industry will develop this idea, but we are working on improvements, and this will eventually bring the idea closer to the market.' Reference: Vladimir Derenskyi, Widianta Gomulya, Wytse Talsma, Jorge Mario Salazar-Rios, Martin Fritsch, Peter Nirmalraj, Heike Riel, Sybille Allard, Ulrich Scherf, Maria A. Loi: On-chip chemical self-assembly of semiconducting Single-Walled Carbon Nanotubes (SWNTs): towards robust and scale invariant SWNTs transistors Advanced Materials, online 5 april 2017


News Article | April 18, 2017
Site: www.materialstoday.com

Carbon nanotubes can be used to make very small electronic devices, but they are difficult to handle. Scientists at the University of Groningen in the Netherlands, together with colleagues from the University of Wuppertal in Germany and IBM Zurich in Switzerland, have now developed a method to select semiconducting nanotubes from a solution and make them self-assemble on a circuit of gold electrodes. They report this work in a paper in Advanced Materials. The results look deceptively simple: a self-assembled transistor with nearly 100% purity and very high electron mobility. But it took 10 years to get there. Maria Antonietta Loi, professor of photophysics and optoelectronics at the University of Groningen, designed polymers that wrap themselves around specific carbon nanotubes in a solution of mixed tubes. Sulphur-containing thiol side chains on the polymer then bind the tubes to the gold electrodes, producing the resultant transistor. “In our previous work, we learned a lot about how polymers attach to specific carbon nanotubes,” Loi explains. Carbon nanotubes can be depicted as a rolled up sheet of graphene, the two-dimensional form of carbon. “Depending on the way the sheets are rolled up, they have properties ranging from semiconductor to semi-metallic to metallic.” Only the semiconductor nanotubes can be used to fabricate transistors, but current production processes always generate a mixture of all different types of carbon nanotubes. “We had the idea of using polymers with thiol side chains some time ago,” says Loi. The idea is that as sulphur naturally binds to metals, the thiol side-chains will direct the polymer-wrapped nanotubes towards the gold electrodes. While Loi was working on the problem, IBM even patented the concept. “But there was a big problem in the IBM work: the polymers with thiols also attached to metallic nanotubes and included them in the transistors, which ruined them.” Loi's solution was to reduce the thiol content of the polymers, with the assistance of polymer chemists from the University of Wuppertal. “What we have now shown is that this concept of bottom-up assembly works: by using polymers with a low concentration of thiols, we can selectively bring semiconducting nanotubes from a solution onto a circuit.” The sulphur-gold bond is strong, so the nanotubes are firmly fixed, staying put even after sonication in organic solvents. The production process is simple: metallic patterns are deposited on a carrier, which is then dipped into a solution of carbon nanotubes. The electrodes are spaced to achieve proper alignment. “The tubes are some 500nm long, and we placed the electrodes for the transistors at intervals of 300nm. The next transistor is over 500nm.” This spacing limits the density of the transistors, but Loi is confident this could be increased with clever engineering. “Over the last years, we have created a library of polymers that select semiconducting nanotubes and developed a better understanding of how the structure and composition of the polymers influences which carbon nanotubes they select,” says Loi. The result is a cheap and scalable production method for nanotube electronics. So what is the future for this technology? “It is difficult to predict whether the industry will develop this idea, but we are working on improvements, and this will eventually bring the idea closer to the market,” Loi declares. This story is adapted from material from the University of Groningen, with editorial changes made by Materials Today. The views expressed in this article do not necessarily represent those of Elsevier. Link to original source.


Schwander T.,University of Groningen
Current biology : CB | Year: 2012

An unusual reproductive system was discovered in desert ants, in which daughter queens are produced asexually via parthenogenesis, whereas workers develop from hybrid crosses between genetically divergent lineages. The system appears to be doomed to extinction. Copyright © 2012 Elsevier Ltd. All rights reserved.


Baskent D.,University of Groningen
JARO - Journal of the Association for Research in Otolaryngology | Year: 2012

The brain, using expectations, linguistic knowledge, and context, can perceptually restore inaudible portions of speech. Such top-down repair is thought to enhance speech intelligibility in noisy environments. Hearing-impaired listeners with cochlear implants commonly complain about not understanding speech in noise. We hypothesized that the degradations in the bottom-up speech signals due to the implant signal processing may have a negative effect on the top-down repair mechanisms, which could partially be responsible for this complaint. To test the hypothesis, phonemic restoration of interrupted sentences was measured with young normal-hearing listeners using a noise-band vocoder simulation of implant processing. Decreasing the spectral resolution (by reducing the number of vocoder processing channels from 32 to 4) systematically degraded the speech stimuli. Supporting the hypothesis, the size of the restoration benefit varied as a function of spectral resolution. A significant benefit was observed only at the highest spectral resolution of 32 channels. With eight channels, which resembles the resolution available to most implant users, there was no significant restoration effect. Combined electric-acoustic hearing has been previously shown to provide better intelligibility of speech in adverse listening environments. In a second configuration, combined electric-acoustic hearing was simulated by adding low-pass-filtered acoustic speech to the vocoder processing. There was a slight improvement in phonemic restoration compared to the first configuration; the restoration benefit was observed at spectral resolutions of both 16 and 32 channels. However, the restoration was not observed at lower spectral resolutions (four or eight channels). Overall, the findings imply that the degradations in the bottom-up signals alone (such as occurs in cochlear implants) may reduce the top-down restoration of speech. © 2012 Association for Research in Otolaryngology.


Matrix-valued functions in the Wiener class on the imaginary line are considered in this note. This class of functions is large enough to be suitable for many applications in systems and control of infinite-dimensional systems. For this class of functions three kinds of factorization are discussed: (right-)standard factorization, canonical factorization, and J-spectral factorization. In particular, we focus on an algorithmic procedure to find a (right-)standard factorization and a J-spectral factorization for matrix-valued functions in the Wiener class under the assumption that such factorizations exists. In practice, the J-spectral factors for irrational functions are usually calculated using rational approximations. We show that approximation using rational functions may be achieved in the Wiener norm. © 2015 Elsevier Ltd.


Schmidt A.,TU Munich | Casini A.,University of Groningen | Kuhn F.E.,TU Munich
Coordination Chemistry Reviews | Year: 2014

Metal-mediated self-assemblies of the general formula MxLy (M=metal ion, L=ligand) have emerged as a promising research area of supramolecular chemistry because of their applicability in various fields such as molecular recognition, catalysis and drug delivery. The focus of this review is on discrete coordination cages of the type M2L4 using square-planar, square-pyramidal or octahedral coordinated metal ions (e.g. Pd, Pt, Co, Cu, Ni or Zn) and bis(monodentate) N-ligands. The synthesis and characterization of these metallocages is discussed, and special attention is given to the molecular structures with well-defined internal cavities and the molecular recognition properties. The self-assembled M2L4 cages are capable to encapsulate anionic, neutral or cationic guest molecules within their cavity. Therefore, some of these M2L4 host-guest systems are certainly promising for application in medical diagnostic, drug delivery, catalytic reactions, environmental analytics, material science and chemosensing. © 2014 Elsevier B.V.


Filatov M.,University of Groningen
Physical Chemistry Chemical Physics | Year: 2011

The ground state electronic structure of the high-temperature (HT) and the low-temperature (LT) phases of (EDO-TTF)2PF6 is investigated using the embedded cluster approach in combination with the density functional method designed to describe the strong non-dynamic electron correlation. It is found that, in the HT phase, the unpaired electron spins located on pairs of neighbouring EDO-TTF molecules are antiferromagnetically coupled along the stacking direction with the Heisenberg exchange integral J = -655 cm-1. In the LT phase, the unpaired spins located on the cationic EDO-TTF molecules are coupled antiferromagnetically with J values strongly alternating along the stacking axis of the crystal thus rendering it diamagnetic. The parameters of the extended Hubbard model are evaluated and the conductance properties of the two phases are estimated using these parameters. It is suggested to investigate the charge and spin excitations in the two phases of (EDO-TTF)2PF6 with the use of angle-resolved photoemission spectroscopy. © 2011 the Owner Societies.


De Groote M.L.,University of Groningen | Verschure P.J.,University of Amsterdam | Rots M.G.,University of Groningen
Nucleic Acids Research | Year: 2012

Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined DNA sequences are uniquely suited to answer such questions and could provide potent (bio)medical tools. Toward the goal of gene-specific GEM by overwriting epigenetic marks (Epigenetic Editing, EGE), instructive epigenetic marks need to be identified and their writers/erasers should then be fused to gene-specific DNA binding domains. The appropriate epigenetic mark(s) to change in order to efficiently modulate gene expression might have to be validated for any given chromatin context and should be (mitotically) stable. Various insights in such issues have been obtained by sequence-specific targeting of epigenetic enzymes, as is presented in this review. Features of such studies provide critical aspects for further improving EGE. An example of this is the direct effect of the edited mark versus the indirect effect of recruited secondary proteins by targeting epigenetic enzymes (or their domains). Proof-of-concept of expression modulation of an endogenous target gene is emerging from the few EGE studies reported. Apart from its promise in correcting disease-associated epi-mutations, EGE represents a powerful tool to address fundamental epigenetic questions. © 2012 The Author(s).


Bijlsma R.,University of Groningen | Loeschcke V.,University of Aarhus
Evolutionary Applications | Year: 2012

Biodiversity is increasingly subjected to human-induced changes of the environment. To persist, populations continually have to adapt to these often stressful changes including pollution and climate change. Genetic erosion in small populations, owing to fragmentation of natural habitats, is expected to obstruct such adaptive responses: (i) genetic drift will cause a decrease in the level of adaptive genetic variation, thereby limiting evolutionary responses; (ii) inbreeding and the concomitant inbreeding depression will reduce individual fitness and, consequently, the tolerance of populations to environmental stress. Importantly, inbreeding generally increases the sensitivity of a population to stress, thereby increasing the amount of inbreeding depression. As adaptation to stress is most often accompanied by increased mortality (cost of selection), the increase in the 'cost of inbreeding' under stress is expected to severely hamper evolutionary adaptive processes. Inbreeding thus plays a pivotal role in this process and is expected to limit the probability of genetically eroded populations to successfully adapt to stressful environmental conditions. Consequently, the dynamics of small fragmented populations may differ considerably from large nonfragmented populations. The resilience of fragmented populations to changing and deteriorating environments is expected to be greatly decreased. Alleviating inbreeding depression, therefore, is crucial to ensure population persistence. © 2011 Blackwell Publishing Ltd.


Boonstra A.,University of Groningen | Broekhuis M.,University of Groningen
BMC Health Services Research | Year: 2010

Background. The main objective of this research is to identify, categorize, and analyze barriers perceived by physicians to the adoption of Electronic Medical Records (EMRs) in order to provide implementers with beneficial intervention options. Methods. A systematic literature review, based on research papers from 1998 to 2009, concerning barriers to the acceptance of EMRs by physicians was conducted. Four databases, "Science", "EBSCO", "PubMed" and "The Cochrane Library", were used in the literature search. Studies were included in the analysis if they reported on physicians' perceived barriers to implementing and using electronic medical records. Electronic medical records are defined as computerized medical information systems that collect, store and display patient information. Results. The study includes twenty-two articles that have considered barriers to EMR as perceived by physicians. Eight main categories of barriers, including a total of 31 sub-categories, were identified. These eight categories are: A) Financial, B) Technical, C) Time, D) Psychological, E) Social, F) Legal, G) Organizational, and H) Change Process. All these categories are interrelated with each other. In particular, Categories G (Organizational) and H (Change Process) seem to be mediating factors on other barriers. By adopting a change management perspective, we develop some barrier-related interventions that could overcome the identified barriers. Conclusions. Despite the positive effects of EMR usage in medical practices, the adoption rate of such systems is still low and meets resistance from physicians. This systematic review reveals that physicians may face a range of barriers when they approach EMR implementation. We conclude that the process of EMR implementation should be treated as a change project, and led by implementers or change managers, in medical practices. The quality of change management plays an important role in the success of EMR implementation. The barriers and suggested interventions highlighted in this study are intended to act as a reference for implementers of Electronic Medical Records. A careful diagnosis of the specific situation is required before relevant interventions can be determined. © 2010 Boonstra and Broekhuis; licensee BioMed Central Ltd.


Kemp D.,University of Queensland | Vanclay F.,University of Groningen
Impact Assessment and Project Appraisal | Year: 2013

Historically, impact assessment practice has not explicitly considered human rights. That human rights are relevant to business has been confirmed through the United Nations Human Rights Council's endorsement of the 'Guiding Principles on Business and Human Rights'. Special Representative to the Secretary-General on business and human rights, Professor John Ruggie, advocated awareness of 'rights-holders' and 'duty-bearers' and a shift from third parties "naming and shaming" companies as a way of addressing human rights harms to companies also "knowing and showing" how they are taking responsibility for their human rights impacts and managing their human rights risks. Consideration of human rights should therefore be central to impact assessment for private sector projects, especially those affecting livelihoods, environment, health, safety and security, land and property, culture and gender dynamics. We provide an introduction to the business and human rights debate, discuss the relevance of human rights to the field of impact assessment, and examine a range of challenges associated with integrating the fields of human rights and social impact assessment. © 2013 Copyright IAIA.


OBJECTIVES: To update cost effectiveness estimates for the four dose (3+1) schedule of the seven valent pneumococcal conjugated vaccine (PCV-7) in the Netherlands and to explore the impact on cost effectiveness of reduced dose schedules and implementation of 10 valent and 13 valent pneumococcal vaccines (PCV-10 and PCV-13). DESIGN: Economic evaluation comparing PCV-7, PCV-10, and PCV-13 with no vaccination using a decision tree analytic model built from data in previous studies. SETTING: The Netherlands. Population A cohort of 180,000 newborns followed until 5 years of age. MAIN OUTCOME MEASURES: Costs; gains in life years and quality adjusted life years (QALYs); and incremental cost effectiveness ratios. RESULTS: Under base case assumptions-that is, assuming a five year protective period of the vaccine and no assumed net indirect effects (herd protection minus serotype replacement) among children aged over 5 years-vaccination with PVC-7 in a four dose (3+1) schedule was estimated to prevent 71 and 5778 cases of invasive and non-invasive pneumococcal disease, respectively, in children aged up to 5 years. This corresponds with a total net gain of 173 life years or 277 QALYs. The incremental cost effectiveness ratio of PCV-7 was estimated at euro113,891 ( pound98,300; $145,000) per QALY, well over the ratio of euro50,000 per QALY required for PCV-7 to be regarded as potentially cost effective. A three dose (2+1) schedule of PCV-7 reduced the incremental cost effectiveness ratio to euro82,975 per QALY. For various assumptions and including 10% of the maximum net indirect effects among individuals aged 5 years and over, PCV-10 and PCV-13 had incremental cost effectiveness ratios ranging from euro31,250 to euro52,947 per QALY. CONCLUSIONS: The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or both.


To carry out a systematic review of randomized controlled trials (RCTs) to investigate in patients with arthralgia of the temporomandibular joint (TMJ) the effectiveness of TMJ lavage compared to nonsurgical treatment with regard to pain intensity and mandibular range of motion. The electronic databases Cochrane Controlled Trials Register (1960-2012), PubMed÷Medline (1966-2012), and Embase (1966-2012) were systematically searched for relevant RCTs. References of relevant articles were searched for additional studies, as well as citing reports. Two authors independently performed data extraction by using predefined quality indicators. Relevant outcome data included reduction in pain, as assessed by a visual analog scale (VAS) or a pain score, and maximal mouth opening (MMO) before and 6 months after treatment. Included trials were combined using fixed and random effects meta-analysis. Three RCTs (222 patients) were included for meta-analysis. The statistically significant overall standardized mean difference (SMD) (P < .001) with regard to pain intensity was -1.07 (95% CI = -1.38, - 0.76) in favor of TMJ lavage. The MMO did not change significantly (P > .05, SMD = .05 [95% CI = -0.33, 0.23]). The results suggest that lavage of the TMJ may be slightly more effective than nonsurgical treatment for pain reduction. However, this difference is not likely to be clinically relevant.


Allersma T.,University of Groningen
The Cochrane database of systematic reviews | Year: 2013

Subfertility affects 15% to 20% of couples trying to conceive. In vitro fertilisation (IVF) is one of the assisted reproduction techniques developed to improve chances of achieving pregnancy. In the standard IVF method with controlled ovarian hyperstimulation (COH), growth and development of multiple follicles are stimulated by using gonadotrophins, often combined with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Although it is an established method of conception for subfertile couples, the treatment is expensive and has a high risk of adverse effects. Studies have shown that IVF in a natural cycle (NC) or a modified natural cycle (MNC) might be a promising low risk and low cost alternative to the standard stimulated IVF treatment since the available dominant follicle of each cycle is used. In this review, we included available randomised controlled studies comparing natural cycle IVF (NC and MNC) with standard IVF. To compare the efficacy and safety of natural cycle IVF (including both NC-IVF and MNC-IVF) with controlled ovarian hyperstimulation IVF (COH-IVF) in subfertile couples. An extended search including of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, conference abstracts in the Web of Knowledge, the World Health Organization International Trials Registry Platform search portal, LILACS database, PubMed and the OpenSIGLE database was conducted according to Cochrane guidelines. The last search was on 31st July 2013. All randomised controlled trials (RCTs) comparing either natural cycle IVF or modified natural cycle IVF versus standard IVF in subfertile couples were included. Data selection and extraction and risk of bias assessment were carried out independently by two authors (TA and AC). The primary outcome measures were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate per randomised woman. We calculated Mantel-Haenszel odds ratios for each dichotomous outcome and either the mean difference or the standardised mean difference (SMD) for continuous outcomes, with 95% confidence intervals (CIs). A fixed effect model was used unless there was substantial heterogeneity, in which case a random effects model was used. Six randomised controlled trials with a total of 788 women were included. The largest of these trials included 396 women eligible for this review.No evidence of a statistically significant difference was found between natural cycle and standard IVF in live birth rates (OR 0.68, 95% CI 0.46 to 1.01, two studies, 425 women, I(2)= 0%, moderate quality evidence). The evidence suggests that for a woman with a 53% chance of live birth using standard IVF, the chance using natural cycle IVF would range from 34% to 53%. There was no evidence of a statistically significant difference between natural cycle and standard IVF in rates of OHSS (OR 0.19, 95% CI 0.01 to 4.06, one study, 60 women, very low quality evidence), clinical pregnancy (OR 0.52 95% CI 0.17 to 1.61, 4 studies, 351 women, I(2)=63%, low quality evidence), ongoing pregnancy (OR 0.72, 95% CI 0.50 to 1.05, three studies, 485 women, I(2)=0%, moderate quality evidence), multiple pregnancy (OR 0.76, 95% CI 0.25 to 2.31, 2 studies, 527 women, I(2)=0%, very low quality evidence), gestational abnormalities (OR 0.44 95% CI 0.03 to 5.93, 1 study, 18 women, very low quality evidence) or cycle cancellations (OR 8.98, 95% CI 0.20 to 393.66, 2 studies, 159 women, I(2)=83%, very low quality evidence). One trial reported that the oocyte retrieval rate was significantly lower in the natural cycle group (MD -4.40, 95% CI -7.87 to -0.93, 60 women, very low quality evidence). There were insufficient data to draw any conclusions about rates of treatment cancellation. Findings on treatment costs were inconsistent and more data are awaited. The evidence was limited by imprecision. Findings for pregnancy rate and for cycle cancellation were sensitive to the choice of statistical model: for these outcomes, use of a fixed effect model suggested a benefit for the standard IVF group. Moreover the largest trial has not yet completed follow up, though data have been reported for over 95% of women. Further evidence from well conducted large trials is awaited on natural cycle IVF treatment. Future trials should compare natural cycle IVF with standard IVF. Outcomes should include cumulative live birth and pregnancy rates, the number of treatment cycles necessary to reach live birth, treatment costs and adverse effects.


Van Haastert P.J.M.,University of Groningen
Biophysical Journal | Year: 2010

Many amoeboid cells move by extending pseudopods. Here I present a new stochastic model for chemotaxis that is based on pseudopod extensions by Dictyostelium cells. In the absence of external cues, pseudopod extension is highly ordered with two types of pseudopods: de novo formation of a pseudopod at the cell body in random directions, and alternating right/left splitting of an existing pseudopod that leads to a persistent zig-zag trajectory. We measured the directional probabilities of the extension of splitting and de novo pseudopods in chemoattractant gradients with different steepness. Very shallow cAMP gradients can bias the direction of splitting pseudopods, but the bias is not perfect. Orientation of de novo pseudopods require much steeper cAMP gradients and can be more precise. These measured probabilities of pseudopod directions were used to obtain an analytical model for chemotaxis of cell populations. Measured chemotaxis of wild-type cells and mutants with specific defects in these stochastic pseudopod properties are similar to predictions of the model. These results show that combining splitting and de novo pseudopods is a very effective way for cells to obtain very high sensitivity to stable gradient and still be responsive to changes in the direction of the gradient. © 2010 by the Biophysical Society.


Croce R.,University of Groningen | Van Amerongen H.,Wageningen University
Journal of Photochemistry and Photobiology B: Biology | Year: 2011

Photosystem II (PSII) is responsible for the water oxidation in photosynthesis and it consists of many proteins and pigment-protein complexes in a variable composition, depending on environmental conditions. Sunlight-induced charge separation lies at the basis of the photochemical reactions and it occurs in the reaction center (RC). The RC is located in the PSII core which also contains light-harvesting complexes CP43 and CP47. The PSII core of plants is surrounded by external light-harvesting complexes (lhcs) forming supercomplexes, which together with additional external lhcs, are located in the thylakoid membrane where they perform their functions. In this paper we provide an overview of the available information on the structure and organization of pigment-protein complexes in PSII and relate this to experimental and theoretical results on excitation energy transfer (EET) and charge separation (CS). This is done for different subcomplexes, supercomplexes, PSII membranes and thylakoid membranes. Differences in experimental and theoretical results are discussed and the question is addressed how results and models for individual complexes relate to the results on larger systems. It is shown that it is still very difficult to combine all available results into one comprehensive picture. © 2011 Elsevier B.V. All rights reserved.


Verhoeff B.,University of Groningen
History of Psychiatry | Year: 2013

In this paper, I argue that a new relation between past and present - a supposed historical continuity in the meaning of autism - is created by the histories written by the discipline itself. In histories of autism written by 'practitioner-historians', a sense of scientific progress and an essentialist understanding of autism legitimize and reinforce current understandings and research directions in the field of autism. Conceptual discontinuities and earlier complexities and disputes concerning classifying and delineating autism are usually left out of the positivist narrative of autism. In an alternative history of the concept of autism, I demonstrate that there have been major shifts in the type of symptoms, signs and impairments that were - and are - thought to be essential and specific for autism. © The Author(s) 2013.


Rao S.,University of Groningen
IEEE Transactions on Automatic Control | Year: 2012

In this paper, behaviors with equal input and output cardinalities and with lossless positive real transfer functions corresponding to certain input-output partitions are considered. Based on Cauer synthesis method, an algorithm to obtain a minimal state map of such behaviors starting from an observable image representation is given. This algorithm makes use of polynomial algebraic methods to arrive at a minimal state map. It is shown that the algorithm has application in synthesis and analysis of lossless electrical networks. © 2012 IEEE.


Lambers Heerspink H.J.,University of Groningen
Contributions to nephrology | Year: 2013

Blood pressure is a strong risk factor for ischemic and atherosclerotic events such as stroke. Blood pressure is often elevated in patients with chronic kidney disease. Consequently, chronic kidney disease patients are at high risk of developing cardiovascular and cerebrovascular damage. Blood pressure reduction by means of inhibiting the renin-angiotensin-aldosterone system (RAAS) reduces the risk of stroke. There is evidence available in the primary and secondary prevention of stroke that RAAS blockade exerts cerebrovascular protective effects independent of blood pressure lowering. This chapter discusses the role of RAAS blockade for the prevention and treatment of stroke in chronic kidney disease. The role of dual RAAS blockade will be reviewed and alternative strategies to enhance the effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers will be provided. Copyright © 2013 S. Karger AG, Basel.


Darvishian M.,University of Groningen | Bijlsma M.J.,Unit of PharmacoEpidemiology and PharmacoEconomics PE2 | Hak E.,University of Groningen | van den Heuvel E.R.,University of Groningen | van den Heuvel E.R.,TU Eindhoven
The Lancet Infectious Diseases | Year: 2014

Background: The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people. Methods: We searched the Cochrane library, Medline, and Embase up to July 13, 2014, for test-negative design case-control studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions. Findings: 35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0.69, 95% CI 0.48-0.99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0.42, 95% CI 0.30-0.60; mismatch: OR 0.57, 95% CI 0.41-0.79) and widespread (match: 0.54, 0.46-0.62; mismatch: OR 0.72, 95% CI 0.60-0.85) outbreaks. Interpretation: Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population. Funding: None. © 2014 Elsevier Ltd.


De Jong B.,University of Groningen
Journal of Head Trauma Rehabilitation | Year: 2013

The demonstration by Monti et al. (2010) of willful modulation of brain activity in persistent vegetative state implies the exceptional condition of a complete motor locked-in syndrome. As a consequence, the contradictory character of the diagnosis minimally conscious state should be recognized because behaviorally observed minimal cognitive responsiveness does not exclude a higher level of well-differentiated self-consciousness. Introduction of the descriptive entities complete motor locked-in syndrome and minimal cognitive responsiveness is therefore advocated in the service of diagnostic precision. Copyright © 2013 Lippincott Williams & Wilkins.


One of the central aims of autism research is to identify specific neurodevelopmental mechanisms that cause and explain the visible autistic signs and symptoms. In this short paper, I argue that the persistent search for autism-specific pathophysiologies has two fundamental difficulties. The first regards the growing gap between basic autism science and clinical practice. The second regards the difficulties with demarcating autism as a psychiatric condition. Instead of the unremitting search for the neurobiological basis of autism, I suggest that basic autism research should focus on experiences of impairment and distress, and on how these experiences relate to particular (autistic) behaviors in particular circumstances, regardless of whether we are dealing with an autism diagnosis or not. © 2015, Springer Science+Business Media Dordrecht.


Kampen K.R.,University of Groningen
Leukemia Research | Year: 2012

The early history of leukemia reaches back 200 years. In 1811, Peter Cullen defined a case of splenitis acutus with unexplainable milky blood. Alfred Velpeau defined the leukemia associated symptoms, and observed pus in the blood vessels (1825). Alfred Donné detected a maturation arrest of the white blood cells (1844). John Bennett named the disease leucocythemia, based on the microscopic accumulation of purulent leucocytes (1845). That same year, Rudolf Virchow defined a reversed white and red blood cell balance. He introduced the disease as leukämie in 1847. Henry Fuller performed the first microscopic diagnose of a leukemic patient during life (1846). This gradual process brought us towards our current understanding of this complex disease. © 2011 Elsevier Ltd.


Franks D.M.,University of Queensland | Vanclay F.,University of Groningen
Environmental Impact Assessment Review | Year: 2013

Social Impact Assessment (SIA) has traditionally been practiced as a predictive study for the regulatory approval of major projects, however, in recent years the drivers and domain of focus for SIA have shifted. This paper details the emergence of Social Impact Management Plans (SIMPs) and undertakes an analysis of innovations in corporate and public policy that have put in place ongoing processes - assessment, management and monitoring - to better identify the nature and scope of the social impacts that might occur during implementation and to proactively respond to change across the lifecycle of developments. Four leading practice examples are analyzed. The International Finance Corporation (IFC) Performance Standards require the preparation of Environmental and Social Management Plans for all projects financed by the IFC identified as having significant environmental and social risks. Anglo American, a major resources company, has introduced a Socio-Economic Assessment Toolbox, which requires mine sites to undertake regular assessments and link these assessments with their internal management systems, monitoring activities and a Social Management Plan. In South Africa, Social and Labour Plans are submitted with an application for a mining or production right. In Queensland, Australia, Social Impact Management Plans were developed as part of an Environmental Impact Statement, which included assessment of social impacts. Collectively these initiatives, and others, are a practical realization of theoretical conceptions of SIA that include management and monitoring as core components of SIA. The paper concludes with an analysis of the implications for the practice of impact assessment including a summary of key criteria for the design and implementation of effective SIMPs. © 2013 Elsevier Inc.


Recent advances in nano-biotechnology have made it possible to realize a great variety of enzyme electrodes suitable for sensing and energy applications. In coating miniaturized electrodes with enzymes, there is no doubt that most of the available deposition processes suffer from the difficulty in depositing uniform and reproducible coatings of the active enzyme on the miniature transducer element. This mini-review highlights the promising prospects of two techniques, electrochemical deposition (ECD) and electrophoretic deposition (EPD), in enzyme immobilization onto miniaturized electrodes and their use as biosensors and biofuel cells. The main differences between ECD and EPD are described and highlighted in the sense to make it clear to the reader that both techniques employ electric fields to deposit enzyme but the conditions from which each process is achieved and hence the mechanisms are quite different. Many aspects dealing with deposition of enzyme under ECD and EPD are considered including surface charge of enzyme, its migration under the applied electric field and its precipitation on the electrode. Still all issues discussed in this mini-review are generic and need to be followed in the future by extensive theoretical and experimental research analysis. Finally, the advantages of ECD and EPD in fabrication of miniature biosensor and biofuel cell electrodes are described and discussed. © 2014 Elsevier B.V.


De Vos P.,University of Groningen
Advances in Experimental Medicine and Biology | Year: 2010

Cell encapsulation has been proposed for the treatment of a wide variety of diseases since it allows for transplantation of cells in the absence of undesired immunosuppression. The technology has been proposed to be a solution for the treatment of diabetes since it potentially allows a mandatory minute-to-minute regulation of glucose levels without side-effects. Encapsulation is based on the principle that transplanted tissue is protected for the host immune system by a semipermeable capsule. Many different concepts of capsules have been tested. During the past two decades three major approaches of encapsulation have been studied. These include (i) intravascular macrocapsules, which are anastomosed to the vascular system as AV shunt, (ii) extravascular macrocapsules, which are mostly diffusion chambers transplanted at different sites and (iii) extravascular microcapsules transplanted in the peritoneal cavity. The advantages and pitfalls of the three approaches are discussed and compared in view of applicability in clinical islet transplantation. © 2010 Landes Bioscience and Springer Science+Business Media.


Tamiola K.,University of Groningen | Mulder F.A.A.,University of Aarhus
Biochemical Society Transactions | Year: 2012

NMR spectroscopy offers the unique possibility to relate the structural propensities of disordered proteins and loop segments of folded peptides to biological function and aggregation behaviour. Backbone chemical shifts are ideally suited for this task, provided that appropriate reference data are available and idiosyncratic sensitivity of backbone chemical shifts to structural information is treated in a sensible manner. In the present paper, we describe methods to detect structural protein changes from chemical shifts, and present an online tool [ncSPC (neighbour-corrected Structural Propensity Calculator)], which unites aspects of several current approaches. Examples of structural propensity calculations are given for two well-characterized systems, namely the binding of α-synuclein to micelles and light activation of photoactive yellow protein. These examples spotlight the great power of NMR chemical shift analysis for the quantitative assessment of protein disorder at the atomic level, and further our understanding of biologically important problems. ©The Authors Journal compilation ©2012 Biochemical Society.


Jonkman M.F.,University of Groningen | Pasmooij A.M.G.,University of Groningen
Journal of Investigative Dermatology | Year: 2012

In this issue, Lai-Cheong et al. report a patient with Kindler syndrome who showed revertant mosaicism: a patch of normal-looking skin attributable to a reverse mutation. The molecular basis of the reverted patch appeared to be the deletion of a duplicated cytosine, thus restoring the reading frame of FERMT1 transcripts. This finding further pushes the frontier of revertant mosaicism, a phenomenon of spontaneous gene repair, which can be seen with the naked eye in skin. © 2012 The Society for Investigative Dermatology.


Groeneveld M.,University of Groningen | Slotboom D.-J.,University of Groningen
Biochemistry | Year: 2010

The Na+ aspartate symporter GltPh from Pyrococcus horikoshii is the only member of the glutamate transporter family for which crystal structures have been determined. The cation:aspartate coupling stoichiometry is unknown, thus hampering the elucidation of the ion coupling mechanism. Here we measure transport of 22Na+ and [ 14C]aspartate in proteoliposomes containing purified GltPh and demonstrate that three Na+ ions are symported with aspartate. © 2010 American Chemical Society.


Gostynski A.,University of Groningen | Pasmooij A.M.G.,University of Groningen | Jonkman M.F.,University of Groningen
Journal of the American Academy of Dermatology | Year: 2014

Background Epidermolysis bullosa (EB) is a group of genetic blistering diseases. Despite many efforts, treatment for EB remains symptomatic. Revertant mosaicism, coexistence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous genetic event (revertant cells) in 1 individual, can be found in EB. The naturally corrected revertant keratinocytes provide an opportunity for autologous cell therapy. Objective We sought to locally treat EB by transplantation of revertant skin. Methods Persistent ulcers in a patient with non-Herlitz junctional EB caused by mutations in the LAMB3 gene were treated by transplantation of split-thickness biopsy specimens from one of his revertant patches. Results All transplanted biopsy specimens were accepted and complete re-epithelialization occurred within 14 days. During 18 months of follow-up, the patient never experienced blisters or wounds in the grafted area, nor in the healed donor site. Immunofluorescence and DNA sequencing showed that acceptor sites healed with transplanted revertant keratinocytes. Limitations Punch grafting allows only limited expansion of revertant skin. Conclusions We demonstrate that phenotypical and genotypical correction of skin in patients with revertant mosaicism by expansion of revertant skin might be a promising therapeutic option for cutaneous manifestations of EB. © 2013 by the American Academy of Dermatology, Inc.


Dekens W.,University of Groningen | Boer D.,University of Groningen
Nuclear Physics B | Year: 2014

We provide a systematic study of minimal left-right models that are invariant under P, C, and/or CP transformations. Due to the high amount of symmetry such models are quite predictive in the amount and pattern of CP violation they can produce or accommodate at lower energies. Using current experimental constraints some of the models can already be excluded. For this purpose we provide an overview of the experimental constraints on the different left-right symmetric models, considering bounds from colliders, meson-mixing and low-energy observables, such as beta decay and electric dipole moments. The features of the various Yukawa and Higgs sectors are discussed in detail. In particular, we give the Higgs potentials for each case, discuss the possible vacua and investigate the amount of fine-tuning present in these potentials. It turns out that all left-right models with P, C, and/or CP symmetry have a high degree of fine-tuning, unless supplemented with mechanisms to suppress certain parameters. The models that are symmetric under both P and C are not in accordance with present observations, whereas the models with either P, C, or CP symmetry cannot be excluded by data yet. To further constrain and discriminate between the models measurements of B-meson observables at LHCb and B-factories will be especially important, while measurements of the EDMs of light nuclei in particular could provide complementary tests of the LRMs. © 2014 The Authors.


Kazemi S.,University of Groningen | Yatawatta S.,ASTRON
Monthly Notices of the Royal Astronomical Society | Year: 2013

A major stage of radio interferometric data processing is calibration or the estimation of systematic errors in the data and the correction for such errors. A stochastic error (noise) model is assumed, and in most cases, this underlying model is assumed to be Gaussian. However, outliers in the data due to interference or due to errors in the sky model would have adverse effects on processing based on a Gaussian noise model. Most of the shortcomings of calibration such as the loss in flux or coherence, and the appearance of spurious sources, could be attributed to the deviations of the underlying noise model. In this paper, we propose to improve the robustness of calibration by using a noise model based on Student's t-distribution. Student's t-noise is a special case of Gaussian noise when the variance is unknown. Unlike Gaussian-noise-model-based calibration, traditional least-squares minimization would not directly extend to a case when we have a Student's t-noise model. Therefore, we use a variant of the expectation-maximization algorithm, called the expectation-conditional maximization either algorithm, when we have a Student's t-noise model and use the Levenberg-Marquardt algorithm in the maximization step. We give simulation results to show the robustness of the proposed calibration method as opposed to traditional Gaussian-noise-model-based calibration, especially in preserving the flux of weaker sources that are not included in the calibration model. © 2013 The Authors Published by Oxford University Press on behalf of the Royal Astronomical Society.


Fernandez E.R.,University of Groningen | Zaroubi S.,University of Groningen
Monthly Notices of the Royal Astronomical Society | Year: 2013

There are only a few ways to constrain the era of reionization and the properties of high-redshift (z ≳ 6) stars through observations. Here, we discuss one of these observables - the spectrum of the near-infrared background - and how it is potentially affected by the transition from Population III to Population II stars. The stronger Lyman α emission expected from massive Population III stars could result in a 'bump' in the spectrum of the near-infrared background (referred to in this work as the Lyman α bump). The strength and shape of this bump can reveal properties of Population III stars. The Lyman α bump is predicted to be higher if Population III stars are more massive and present at lower redshifts. The shape of the bump is governed by the star formation rate and the time it takes Population III stars to transition to Population II stars. If Population III stars are indeed massive, a bump is predicted as long as Population HI stars exist at z ≲ 15, even if their star formation rate is as low as 10-7 M ⊙ yr-1 Mpc-3. This means that there may be some observational signature in the near-infrared background of small pockets of metal-free gas forming Population III stars at z ∼ 6. even if they are quite rare. © 2013 The Authors.


Fananas-Mastral M.,University of Groningen | Feringa B.L.,University of Groningen
Journal of the American Chemical Society | Year: 2014

Copper-catalysis allows the direct oxygen-arylation of dialkyl phosphonates with diaryliodonium salts. This novel methodology proceeds with a wide range of phosphonates and phosphoramidates under mild conditions and gives straightforward access to valuable mixed alkyl aryl phosphonates in very good yields and near perfect selectivity. © 2014 American Chemical Society.


Hou L.,University of Groningen | Zhang X.,University of Groningen | Pijper T.C.,University of Groningen | Browne W.R.,University of Groningen | Feringa B.L.,University of Groningen
Journal of the American Chemical Society | Year: 2014

Reversible noninvasive control over the generation of singlet oxygen is demonstrated in a bicomponent system comprising a diarylethene photochromic switch and a porphyrin photosensitizer by selective irradiation at distinct wavelengths. The efficient generation of singlet oxygen by the photosensitizer is observed when the diarylethene unit is in the colorless open form. Singlet oxygen generation is not observed when the diarylethene is converted to the closed form. Irradiation of the closed form with visible light (>470 nm) leads to full recovery of the singlet oxygen generating ability of the porphyrin sensitizer. © 2014 American Chemical Society.


A climate response function is introduced that consists of six exponential (low-pass) filters with weights depending as a power law on their e-folding times. The response of this two-parameter function to the combined forcings of solar irradiance, greenhouse gases, and SO2-related aerosols is fitted simultaneously to reconstructed temperatures of the past millennium, the response to solar cycles, the response to the 1991 Pinatubo volcanic eruption, and the modern 1850-2010 temperature trend. Assuming strong long-term modulation of solar irradiance, the quite adequate fit produces a climate response function with a millennium-scale response to doubled CO2 concentration of 2.0 ± 0.3 °C (mean ± standard error), of which about 50 % is realized with e-folding times of 0.5 and 2 years, about 30 % with e-folding times of 8 and 32 years, and about 20 % with e-folding times of 128 and 512 years. The transient climate response (response after 70 years of 1 % yearly rise of CO2 concentration) is 1.5 ± 0.2 °C. The temperature rise from 1820 to 1950 can be attributed for about 70 % to increased solar irradiance, while the temperature changes after 1950 are almost completely produced by the interplay of anthropogenic greenhouse gases and aerosols. The SO2-related forcing produces a small temperature drop in the years 1950-1970 and an inflection of the temperature curve around the year 2000. Fitting with a tenfold smaller modulation of solar irradiance produces a less adequate fit with millennium-scale and transient climate responses of 2.5 ± 0.4 and 1.9 ± 0.3 °C, respectively. © 2012 The Author(s).


Steg L.,University of Groningen
Annual Review of Environment and Resources | Year: 2016

Environmental problems can be reduced if people more consistently engage in proenvironmental actions. In this article, I discuss factors that motivate or inhibit individuals to act proenvironmentally. Many people are intrinsically motivated to engage in proenvironmental actions, because protecting the environment makes them feel good about themselves. People are more likely to be intrinsically motivated to act proenvironmentally over and again when they strongly endorse biospheric values. However, people may be less likely to act on their biospheric values when these values are not supported by the context, or when competing values are activated by factors in a choice context. Next, I discuss strategies to encourage proenvironmental actions by strengthening biospheric values, or by empowering and motivating people to act on their biospheric values. Moreover, I discuss factors influencing the acceptability of environmental policies that aim to encourage proenvironmental behavior. Copyright ©2016 by Annual Reviews. All rights reserved.


Cautun M.,University of Groningen | Weygaert R.,University of Groningen | Jones B.J.T.,University of Groningen
Monthly Notices of the Royal Astronomical Society | Year: 2013

We introduce the NEXUS algorithm for the identification of cosmic web environments: clusters, filaments, walls and voids. This is a multiscale and automatic morphological analysis tool that identifies all the cosmic structures in a scale free way, without preference for a certain size or shape. We develop the NEXUS method to incorporate the density, tidal field, velocity divergence and velocity shear as tracers of the cosmic web. We also present the NEXUS+ procedure which, taking advantage of a novel filtering of the density in logarithmic space, is very successful at identifying the filament and wall environments in a robust and natural way. To assess the algorithms we apply them to an N-body simulation. We find that all methods correctly identify the most prominent filaments and walls, while there are differences in the detection of the more tenuous structures. In general, the structures traced by the density and tidal fields are clumpier and more rugged than those present in the velocity divergence and velocity shear fields. We find that the NEXUS+ method captures much better the filamentary and wall networks and is successful in detecting even the fainter structures. We also confirm the efficiency of our methods by examining the dark matter particle and halo distributions. © 2012 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.


Jonkers I.,University of Groningen | Lis J.T.,Cornell University
Nature Reviews Molecular Cell Biology | Year: 2015

Recent advances in sequencing techniques that measure nascent transcripts and that reveal the positioning of RNA polymerase II (Pol II) have shown that the pausing of Pol II in promoter-proximal regions and its release to initiate a phase of productive elongation are key steps in transcription regulation. Moreover, after the release of Pol II from the promoter-proximal region, elongation rates are highly dynamic throughout the transcription of a gene, and vary on a gene-by-gene basis. Interestingly, Pol II elongation rates affect co-transcriptional processes such as splicing, termination and genome stability. Increasing numbers of factors and regulatory mechanisms have been associated with the steps of transcription elongation by Pol II, revealing that elongation is a highly complex process. Elongation is thus now recognized as a key phase in the regulation of transcription by Pol II. © 2015 Macmillan Publishers Limited.


Roest D.,University of Groningen
Journal of Cosmology and Astroparticle Physics | Year: 2014

We investigate all single-field, slow-roll inflationary models whose slow-roll parameters scale as 1/N in the limit of a large number of e-folds N. We proof that all such models belong to two universality classes, characterised by a single parameter. One class contains small field models like hilltop inflation, while the other class consists of large field models like chaotic inflation. We give the leading expressions for the spectral index and tensor-to-scalar ratio r, which are universal for each class, plus subleading corrections for a number of models. This predicts r either to be unobservably small, r < 0.01, or close to the present observational limit, r 0.07. © 2014 IOP Publishing Ltd and Sissa Medialab srl.


Velema W.A.,University of Groningen | Szymanski W.,University of Groningen | Feringa B.L.,University of Groningen
Journal of the American Chemical Society | Year: 2014

Pharmacotherapy is often severely hindered by issues related to poor drug selectivity, including side effects, environmental toxicity, and the emergence of resistance. Lack of selectivity is caused by the inability to control drug activity in time and space. Photopharmacology aims at solving this issue by incorporating photoswitchable groups into the molecular structure of bioactive compounds. These switching units allow for the use of light as an external control element for pharmacological activity, which can be delivered with very high spatiotemporal precision. This Perspective presents the reader with the current state and outlook on photopharmacology. In particular, the principles behind photoregulation of bioactivity, the challenges of molecular design, and the possible therapeutic scenarios are discussed. © 2014 American Chemical Society.


Bos J.,University of Groningen | Roelfes G.,University of Groningen
Current Opinion in Chemical Biology | Year: 2014

Artificial metalloenzymes have emerged over the last decades as an attractive approach towards combining homogeneous catalysis and biocatalysis. A wide variety of catalytic transformations have been established by artificial metalloenzymes, thus establishing proof of concept. The field is now slowly transforming to take on new challenges. These include novel designs, novel catalytic reactions, some of which have no equivalent in both homogenous catalysis and biocatalysis and the incorporation of artificial metalloenzymes in chemoenzymatic cascades. Some of these developments represent promising steps towards integrating artificial metalloenzymes in biological systems. This review will focus on advances in this field and perspectives discussed. © 2014 Elsevier Ltd.


van Rijn H.,University of Groningen
Current Opinion in Behavioral Sciences | Year: 2016

Interval timing tasks can only be performed efficiently when the output of a clock system can be stored over a longer period of time, and be retrieved and reused during later trials. Although the importance of temporal reference memory for accurate timing has been acknowledged since the earliest theoretical work on interval timing, formal accounts of the role of memory in interval timing are fairly recent. An short overview is given of the first formal models in which memory effects were accounted for, followed by a review of the current theoretical approaches, which can be categorized on the basis of whether they assume a dynamic or static memory system. © 2016 Elsevier Ltd.


Morey C.C.,University of Groningen | Mall J.T.,University of Groningen
Quarterly Journal of Experimental Psychology | Year: 2012

Some evidence suggests that memory for serial order is domain-general. Evidence also points to asymmetries in interference between verbal and visual-spatial tasks. We confirm that concurrently remembering verbal and spatial serial lists provokes substantial interference compared with remembering a single list, but we further investigate the impact of this interference throughout the serial position curve, where asymmetries are indeed apparent. A concurrent verbal order memory task affects spatial memory performance throughout the serial positions of the list, but performing a spatial order task affects memory for the verbal serial list only for early list items; in the verbal task only, the final items are unaffected by a concurrent task. Adding suffixes eliminates this asymmetry, resulting in impairment throughout the list for both tasks. These results suggest that domain-general working memory resources may be supplemented with resources specific to the verbal domain, but perhaps not with equivalent spatial resources. © 2012 Copyright The Experimental Psychology Society.


Botero C.A.,North Carolina State University | Botero C.A.,Washington University in St. Louis | Weissing F.J.,University of Groningen | Wright J.,Norwegian University of Science and Technology | Rubenstein D.R.,Columbia University
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015

In an era of rapid climate change, there is a pressing need to understand how organisms will cope with faster and less predictable variation in environmental conditions. Here we develop a unifying model that predicts evolutionary responses to environmentally driven fluctuating selection and use this theoretical framework to explore the potential consequences of altered environmental cycles. We first show that the parameter space determined by different combinations of predictability and timescale of environmental variation is partitioned into distinct regions where a single mode of response (reversible phenotypic plasticity, irreversible phenotypic plasticity, bet-hedging, or adaptive tracking) has a clear selective advantage over all others. We then demonstrate that, although significant environmental changes within these regions can be accommodated by evolution, most changes that involve transitions between regions result in rapid population collapse and often extinction. Thus, the boundaries between response mode regions in our model correspond to evolutionary tipping points, where even minor changes in environmental parameters can have dramatic and disproportionate consequences on population viability. Finally, we discuss how different life histories and genetic architectures may influence the location of tipping points in parameter space and the likelihood of extinction during such transitions. These insights can help identify and address some of the cryptic threats to natural populations that are likely to result from any natural or human-induced change in environmental conditions. They also demonstrate the potential value of evolutionary thinking in the study of global climate change. © 2015, National Academy of Sciences. All rights reserved.


Shafeeq S.,University of Groningen | Kuipers O.P.,University of Groningen | Kloosterman T.G.,University of Groningen
Molecular Microbiology | Year: 2013

Recent studies on pathogenic streptococci have revealed that zinc is a pivotal metal ion in their interaction with the host. In these streptococci, systems exist that ensure optimal use of zinc from the surrounding milieu, as well as export of zinc when concentrations exceed tolerance levels. Zinc uptake is of crucial importance for the virulence of streptococci, whereas elevated zinc levels induced in the host during infection are detrimental for these pathogens. The expression or activity of a number of putative surface proteins and virulence factors depends on zinc. Moreover, several metal sensor proteins that mediate the transcriptional response to zinc in streptococci have recently been characterized. A number of components of zinc- and other metal ion-acquisition systems are suitable as protective antigens and may be future targets for the development of new vaccines, thus providing opportunities for the development of novel therapies. This review will discuss the recent advancements in the important field of metal ion biology in relation to the virulence of pathogenic streptococci, with a central focus on zinc homeostasis in Streptococcus pneumoniae. copy; 2013 John Wiley & Sons Ltd.


Meijer M.F.,University of Groningen
Clinical orthopaedics and related research | Year: 2014

Computer-assisted surgery (CAS) has been developed to enhance prosthetic alignment during primary TKAs. Imageless CAS improves coronal and sagittal alignment compared with conventional TKA. However, the effect of imageless CAS on rotational alignment remains unclear. We conducted a systematic and qualitative review of the current literature regarding the effectiveness of imageless CAS during TKA on (1) rotational alignment of the femoral and tibial components and tibiofemoral mismatch in terms of deviation from neutral rotation, and (2) the number of femoral and tibial rotational outliers. Data sources included PubMed, MEDLINE, and EMBASE. Study selection, data extraction, and methodologic quality assessment were conducted independently by two reviewers. Standardized mean difference with 95% CI was calculated for continuous variables (rotational alignment of the femoral or tibial component and tibiofemoral mismatch). To compare the number of outliers for femoral and tibial component rotation, the odds ratio and 95% CI were calculated. The literature search produced 657 potentially relevant studies, 17 of which met the inclusion criteria. One study was considered as having high methodologic quality, 15 studies had medium, and one study had low quality. Conflicting evidence was found for all outcome measures except for tibiofemoral mismatch. Moderate evidence was found that imageless CAS had no influence on postoperative tibiofemoral mismatch. The measurement protocol for measuring tibial rotation varied among the studies and in only one of the studies was the sample size calculation based on one of the outcome measures used in our systematic review. More studies of high methodologic quality and with a sample size calculation based on the outcome measures will be helpful to assess whether an imageless CAS TKA improves femoral and tibial rotational alignment and tibiofemoral mismatch or decreases the number of femoral and tibial rotational outliers. To statistically analyze the results of different studies, the same measurement protocol should be used among the studies.


Van Der Meer J.-Y.,University of Groningen | Hirsch A.K.H.,University of Groningen
Natural Product Reports | Year: 2012

Covering: up to March 2012 Due to the increase in resistance of Plasmodium spp. against available antimalarials, there is a need for new, effective and innovative drugs. The non-mevalonate pathway for the biosynthesis of the universal isoprenoid precursors, which is absent in humans, is suggested as an attractive source of targets for such drugs with a novel mode of action. The biological importance of this pathway to Plasmodium spp. is proven by the efficacy of the clinical candidate fosmidomycin, which inhibits the biosynthesis of isoprenoid precursors; it is, however, less clear which isoprenoid end products are essential for parasite survival. In this Highlight, we identify protein prenylation, isoprene-containing quinone production, N-linked glycosylation as well as carotenoid and vitamin-E biosynthesis as probably essential isoprenoid-dependent physiological processes in Plasmodium. Inhibition of any of these processes blocks parasite development. Furthermore, both protein prenylation of SNARE proteins and a protein tyrosine phosphatase as well as tRNA prenylation have been identified as isoprene-dependent processes for which the physiological role in Plasmodium remains unclear. Therefore, the biosynthetic route to the isoprenoid precursors presents attractive drug targets for the development of antimalarials with novel modes of action. This journal is © The Royal Society of Chemistry.


Connolly M.P.,University of Groningen | Hoorens S.,RAND Europe | Chambers G.M.,University of New South Wales
Human Reproduction Update | Year: 2010

Background: Despite the growing use of assisted reproductive technologies (ART) worldwide, there is only a limited understanding of the economics of ART to inform policy about effective, safe and equitable financing of ART treatment. Methods: A review was undertaken of key studies regarding the costs and consequences of ART treatment, specifically examining the direct and indirect costs of treatment, economic drivers of utilization and clinical practice and broader economic consequences of ART-conceived children. Results: The direct costs of ART treatment vary substantially between countries, with the USA standing out as the most expensive. The direct costs generally reflect the costliness of the underlying healthcare system. If unsubsidized, direct costs represent a significant economic burden to patients. The level of affordability of ART treatment is an important driver of utilization, treatment choices, embryo transfer practices and ultimately multiple birth rates. The costs associated with caring for multiple-birth ART infants and their mothers are substantial, reflecting the underlying morbidity associated with such pregnancies. Investment analysis of ART treatment and ART-conceived children indicates that appropriate funding of ART services appears to represent sound fiscal policy. Conclusions: The complex interaction between the cost of ART treatment and how treatments are subsidized in different healthcare settings and for different patient groups has far-reaching consequences for ART utilization, clinical practice and infant outcomes. A greater understanding of the economics of ART is needed to inform policy decisions and to ensure the best possible outcomes from ART treatment. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


Batstra L.,University of Groningen | Frances A.,Duke University
Journal of Nervous and Mental Disease | Year: 2012

There have been a striking diagnostic inflation and a corresponding increase in the use of psychotropic drugs during the past 30 years. DSM-5, scheduled to appear in May 2013, proposes another grand expansion of mental illness. In this article, we will review the causes of diagnostic exuberance and associated medical treatment. We will then suggest a method of stepped care combined with stepped diagnosis, which may reduce overdiagnosis without risking undertreatment of those who really need help. The goal is to control diagnostic inflation, to reduce the harms and costs of unnecessary treatment, and to save psychiatry from overdiagnosis and ridicule. Copyright © 2012 by Lippincott Williams & Wilkins.


Festen E.A.M.,University of Groningen | Weersma R.K.,University of Groningen
Best Practice and Research: Clinical Gastroenterology | Year: 2014

Inflammatory bowel disease, consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut, which arises through an excessive immune response to the normal gut flora in a genetically susceptible host. The disease affects predominantly young adults and due to its chronic and relapsing nature gives rise to a high disease burden both financially, physically and psychologically. Current therapy still cannot prevent the need for surgical intervention in more than half of IBD patients. Consequently, advances in IBD therapy are of high importance. Recently, several new forms of targeted therapy have been introduced, which should improve surgery-free prognosis of IBD patients. Recent identification of genetic risk variants for IBD has led to new insights into the biological mechanisms of the disease, which will, in the future, lead to new targeted therapy. In the meantime repositioning of drugs from biologically similar diseases towards IBD might lead to new IBD therapies. © 2014 Elsevier Ltd. All rights reserved.


Sibon O.C.M.,University of Groningen | Strauss E.,Stellenbosch University
Nature Reviews Molecular Cell Biology | Year: 2016

The consensus has been that intracellular coenzyme A (CoA) is obtained exclusively by de novo biosynthesis via a universal, conserved five-step pathway in the cell cytosol. However, old and new evidence suggest that cells (and some microorganisms) have several strategies to obtain CoA, with 4′-phosphopantetheine (P-PantSH; the fourth intermediate in the canonical CoA biosynthetic pathway) serving as a 'nexus' metabolite. © 2016 Macmillan Publishers Limited, part of Springer Nature.


Schwander T.,University of Groningen | Leimar O.,University of Stockholm
Trends in Ecology and Evolution | Year: 2011

A major question for the study of phenotypic evolution is whether intra- and interspecific diversity originates directly from genetic variation, or instead, as plastic responses to environmental influences initially, followed later by genetic change. In species with discrete alternative phenotypes, evolutionary sequences can be inferred from transitions between environmental and genetic phenotype control, and from losses of phenotypic alternatives. From the available evidence, sequences appear equally probable to start with genetic polymorphism as with polyphenism, with a possible dominance of one or the other for specific trait types. We argue in this review that to evaluate the prevalence of each route, an investigation of both genetic and environmental cues for phenotype determination in several related rather than in isolated species is required. © 2011 Elsevier Ltd.


Fu J.,University of Groningen | Festen E.A.M.,University of Groningen | Wijmenga C.,University of Groningen
Human Molecular Genetics | Year: 2011

The successes of genome-wide association (GWA) studies have mainly come from studies performed in populations of European descent. Since complex traits are characterized by marked genetic heterogeneity, the findings so far may provide an incomplete picture of the genetic architecture of complex traits. However, the recent GWA studies performed on East Asian populations now allow us to globally assess the heterogeneity of association signals between populations of European ancestry and East Asians, and the possible obstacles for multi-ethnic GWA studies. We focused on four different traits that represent a broad range of complex phenotypes, which have been studied in both Europeans and East Asians: type 2 diabetes, systemic lupus erythematosus, ulcerative colitis and height. For each trait, we observed that most of the risk loci identified in East Asians were shared with Europeans. However, we also observed that a significant part of the association signals at these shared loci seems to be independent between populations. This suggests that disease aetiology is common between populations, but that risk variants are often population specific. These variants could be truly population specific and result from natural selection, genetic drift and recent mutations, or they could be spurious, caused by the limitations of the method of analysis employed in the GWA studies. We therefore propose a three-stage framework for multi-ethnic GWA analyses, starting with the commonly used single-nucleotide polymorphism-based analysis, and followed by a genebased approach and a pathway-based analysis, which will take into account the heterogeneity of association between populations at different levels. © The Author 2011.


Golachowska M.R.,University of Groningen | Hoekstra D.,University of Groningen | van IJzendoorn S.C.D.,University of Groningen
Trends in Cell Biology | Year: 2010

Recycling endosomes have taken central stage in the intracellular sorting and polarized trafficking of apical and basolateral plasma membrane components. Molecular players in the underlying mechanisms are now emerging, including small GTPases, class V myosins and adaptor proteins. In particular, defects in the expression or function of these recycling endosome-associated and endosome-regulating proteins have been implicated in cell surface polarity defects and diseases, including microvillus inclusion disease, arthrogryposis-renal dysfunction-cholestasis syndrome, and virus susceptibility. Key findings are that recycling endosomes recruit and deliver core polarity proteins to lateral cell surfaces and initiate the biogenesis of apical plasma membrane domains and epithelial cell polarity. Here, we review recent data that implicate recycling endosomes in the establishment and maintenance of epithelial cell polarity. © 2010 Elsevier Ltd.


Postma D.S.,University of Groningen | Bush A.,Imperial College London | Van Den Berge M.,University of Groningen
The Lancet | Year: 2015

Summary Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40-50 years, its origins can begin very early in life. Different risk factors in very early life - ie, in utero and during early childhood - drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life. © 2015 Elsevier Ltd.


Lisman T.,University of Groningen | Ariens R.A.S.,University of Leeds
Seminars in Thrombosis and Hemostasis | Year: 2016

The hemostatic balance in patients with liver diseases is relatively well preserved due to concomitant alterations in pro- and antihemostatic pathways. Thrombin generation studies support the notion of hemostatic competence in liver diseases, but in such tests alterations in fibrinogen level and function are not taken into account. We have recently studied structural and functional properties of the fibrin clot in patients with liver diseases. Although we have confirmed previous findings that hypersialylation of the fibrinogen molecule in patients with liver diseases contributes to a defective fibrinogen-to-fibrin conversion, we have found that once the clot has been formed, it has a thrombogenic nature as assessed by permeability assays. These thrombogenic properties of the fibrin clot in cirrhosis relate to incompletely characterized intrinsic changes in the fibrinogen molecule, which may include oxidation and hypersialylation. In addition, in patients with nonalcoholic fatty liver disease thrombogenic properties of the fibrin clot are not only due to liver disease but also to obesity and the metabolic syndrome. During liver transplantation, the clot normalizes and becomes increasingly permeable, and the functional properties of the fibrin clot are markedly normalized by fibrinogen concentrate, when added to plasma samples in vitro. These new insights in the functional properties of the fibrin clot in patients with liver diseases facilitate a more rational approach to treatment and prevention of both bleeding and thrombotic complications. © 2016 by Thieme Medical Publishers, Inc.


ter Horst G.J.,University of Groningen
Vitamins and hormones | Year: 2010

Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2), the main representative of the group, is highly lipophylic and can easily pass the blood-brain barrier to modulate neuronal activity. Particularly the limbic system, a group of tightly interconnected forebrain areas controlling mood and emotion, is rich in estrogen receptors. To date two cytoplasmatic and/or nuclear estrogen receptors named ER-alpha (ERalpha) and ER-beta (ERbeta) have been identified. In the brain, ERalpha plays a critical role in regulating reproductive neuroendocrine behavior and function. ERbeta appears to play an important role in nonreproductive behaviors, such as learning and memory, anxiety, and mood. Five splice variants of ERbeta, named Erb1, Erb2, Erb1d3, Erb2d3, and Erb1d4, have been identified with possibly different biological activities. There is evidence of a thus far not definitely characterized membrane-linked ER receptor named mER-X. In this review, the anatomy of the limbic system and the distribution of estrogen receptors (ERs) are described in relation to coping with stress and the higher prevalence of stress-related psychiatric disorders in women. Effects of cyclic estrogen administration and chronic stress on recovery and neuronal plasticity are illustrated with own results. Copyright 2010 Elsevier Inc. All rights reserved.


Abbott D.W.,Agriculture and Agri Food Canada | van Bueren A.L.,University of Groningen
Current Opinion in Structural Biology | Year: 2014

Generally, non-catalytic carbohydrate binding module (CBM) specificity has been shown to parallel the catalytic activity of the carbohydrate active enzyme (CAZyme) module it is appended to. With the rapid expansion in metagenomic sequence space for the potential discovery of new CBMs in addition to the recent emergence of several new CBM families that display diverse binding profiles and novel functions, elucidating the function of these protein modules has become a much more challenging task. This review summarizes several approaches that have been reported for using primary structure to inform CBM specificity and streamlining their biophysical characterization. In addition we discuss general trends in binding site architecture and several newly identified functions for CBMs. Streams of investigation that will facilitate the development and refinement of sequence-based prediction tools are suggested. © 2014.


In this paper block circulant and block Toeplitz long strings of MIMO systems with finite length are compared with their corresponding infinite-dimensional spatially invariant systems. The focus is on the convergence of the sequence of solutions to the control Riccati equations and the convergence of the sequence of growth bounds of the closed-loop generators. We show that block circulant approximants of infinite-dimensional spatially invariant systems reflect well the LQR behavior of the infinite-dimensional systems. An example of an exponentially stabilizable and exponentially detectable infinite-dimensional system is also considered in this paper. This example shows that the growth bounds of the Toeplitz approximants, as the length of the string increases, and the growth bound of the corresponding infinite-dimensional model, can be significantly different. On the positive side, we give sufficient conditions for the convergence of the growth bounds. © 2012 Elsevier Ltd. All rights reserved.


Boer D.,University of Groningen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

The possibility of a node in the x dependence of the Sivers and Qiu-Sterman functions is discussed in light of its importance for the experimental check of the overall sign change of the Sivers effect between semi-inclusive DIS and the Drell-Yan process. An x-dependent version of the Ehrnsperger-Schäfer-Greiner-Mankiewicz relation between the Qiu-Sterman function and a twist-3 part of g2 is presented, which naturally suggests a node in the Qiu-Sterman function. This relation could be checked experimentally as well and could provide qualitative information on the gluonic field strength inside the proton. Satisfying the Burkardt sum rule by means of a node is briefly discussed and the importance of modelling the Sivers function including its full Wilson line is pointed out. © 2011 Elsevier B.V.


van der Molena T.,University of Groningen
Primary Care Respiratory Journal | Year: 2010

Introduction: In the Western world, chronic obstructive pulmonary disease (COPD) is predominantly caused by long-term smoking, which results in pulmonary inflammation that is often associated with systemic inflammation. A number of co-morbid conditions, such as cardiovascular disease, muscle wasting, type 2 diabetes and asthma, may coexist with COPD; these and other co-morbidities not directly related to COPD are major causes of excess morbidity and mortality. Aim: This review sets out to explore the most frequent co-morbidities in COPD and their implications for treatment. Method: Review of the literature on co-morbidities of COPD. Results: Co-morbidities are frequent, but often remain undiagnosed in the COPD patient. In order to provide the best possible care for people with COPD, the physician should be aware of all potential co-morbidities that may arise, and the critical role that effective management of these co-morbidities can play in improving patient outcomes. Conclusions: Increased awareness of the potential co-morbidities of COPD, although potentially adding to the general practitioner's work burden, may provide insights into this difficult disease state and possibly improve each individual's prospects for effective management. © 2010 Primary Care Respiratory Society UK. All rights reserved.


Parikh K.,University of Groningen | Peppelenbosch M.P.,University of Groningen
Cancer Research | Year: 2010

Over the past years novel technologies have emerged to enable the determination of the transeriptome and proteome of clinical samples. These data sets will prove to be of significant value to our elucidation of the mechanisms that govern pathophysiology and may provide biological markers for future guidance in person-alized medicine. However, an equally important goal is to define those proteins that participate in signaling pathways during the disease manifestation itself or those pathways that are made active during successful clinical treatment of the disease: the main challenge now is the generation of large-scale data sets that will allow us to define kinome profiles with predictive properties on the outcome-of-disease and to obtain insight into tissue-specific analysis of kinase activity. This review describes the current techniques available to gen-erate kinome profiles of clinical tissue samples and discusses the future strategies necessary to achieve new insights into disease mechanisms and treatment targets. © 2010 American Association for Cancer Research.


Klein T.,University of Groningen | Bischoff R.,University of Groningen
Amino Acids | Year: 2011

Matrix metalloproteases (MMPs) comprise a family of enzymes that cleave protein substrates based on a conserved mechanism involving activation of an active site-bound water molecule by a Zn2+ ion. Although the catalytic domain of MMPs is structurally highly similar, there are many differences with respect to substrate specificity, cellular and tissue localization, membrane binding and regulation that make this a very versatile family of enzymes with a multitude of physiological functions, many of which are still not fully understood. Essentially, all members of the MMP family have been linked to disease development, notably to cancer metastasis, chronic inflammation and the ensuing tissue damage as well as to neurological disorders. This has stimulated a flurry of studies into MMP inhibitors as therapeutic agents, as well as into measuring MMP levels as diagnostic or prognostic markers. As with most protein families, deciphering the function(s) of MMPs is difficult, as they can modify many proteins. Which of these reactions are physiologically or pathophysiologically relevant is often not clear, although studies on knockout animals, human genetic and epigenetic, as well as biochemical studies using natural or synthetic inhibitors have provided insight to a great extent. In this review, we will give an overview of 23 members of the human MMP family and describe functions, linkages to disease and structural and mechanistic features. MMPs can be grouped into soluble (including matrilysins) and membrane-anchored species. We adhere to the 'MMP nomenclature' and provide the reader with reference to the many, often diverse, names for this enzyme family in the introduction. © 2010 The Author(s).


Savenije O.E.M.,University of Groningen | Kerkhof M.,University of Groningen | Koppelman G.H.,University of Groningen | Postma D.S.,University of Groningen
Journal of Allergy and Clinical Immunology | Year: 2012

It is difficult to distinguish at preschool age whether a wheezing child will or will not have asthma at school age. A prediction rule for asthma in preschool children might help to determine a prognosis and to study improvements in treatment and prevention. This review discusses (1) the development and use of clinical prediction rules, (2) the European Respiratory Society Task Force classification of wheeze at preschool age, (3) published prediction rules developed to identify preschool children who will have asthma at school age, and (4) recommendations to improve asthma prediction. Prediction rules are currently created more frequently, yet their clinical use remains low. The classification of episodic wheeze and multiple-trigger wheeze in preschool children shows conflicting results as to whether episodic wheeze and multiple-trigger wheeze differ in clinical features and has limited value in predicting asthma at school age. Clearly, more studies are needed to confirm this. Currently available prediction rules aiming to identify preschool children having asthma at school age are of modest clinical value. Prediction can be improved by more precise definitions and measures and, ultimately, by more knowledge of pathophysiologic mechanisms. In the future, biomarkers and genomic risk profiles to develop personalized medicine might further improve asthma prediction, treatment, and prevention. © 2012 American Academy of Allergy, Asthma & Immunology.


van Rijn P.,University of Groningen
Polymers | Year: 2013

Protein aggregation and protein self-assembly is an important occurrence in natural systems, and is in some form or other dictated by biopolymers. Very obvious influences of biopolymers on protein assemblies are, e.g., virus particles. Viruses are a multi-protein assembly of which the morphology is dictated by poly-nucleotides namely RNA or DNA. This "biopolymer" directs the proteins and imposes limitations on the structure like the length or diameter of the particle. Not only do these bionanoparticles use polymer-directed self-assembly, also processes like amyloid formation are in a way a result of directed protein assembly by partial unfolded/misfolded biopolymers namely, polypeptides. The combination of proteins and synthetic polymers, inspired by the natural processes, are therefore regarded as a highly promising area of research. Directed protein assembly is versatile with respect to the possible interactions which brings together the protein and polymer, e.g., electrostatic, v.d. Waals forces or covalent conjugation, and possible combinations are numerous due to the large amounts of different polymers and proteins available. The protein-polymer interacting behavior and overall morphology is envisioned to aid in clarifying protein-protein interactions and are thought to entail some interesting new functions and properties which will ultimately lead to novel bio-hybrid materials. © 2013 by the authors.


Vos Y.J.,University of Groningen | Hofstra R.M.W.,University of Groningen
Human Mutation | Year: 2010

The L1 syndrome is an X-linked recessive disease caused by mutations in the L1CAM gene. To date more than 200 different mutations have been reported, scattered over the entire gene, about 35% being missense mutations. Although it is tempting to consider these missense mutations as being disease-causing, one should be careful in drawing any firm conclusions, unless there is additional supporting information. This is in contrast to truncating mutations, which are always considered to be disease-causing, unless they involve truncations close to the gene stop codon. In order to allow conclusions to be drawn on the disease-causing nature of L1CAM (missense) mutations, we have updated and upgraded our LICAM mutation database with more pathogenicity data and clinical information collected from the literature or generated by our own research. As a result, the renewed database offers condensed scientific information, allowing conclusions to be drawn on the pathogenicity and severity of LICAM mutations based on multiple factors. The L1CAM Mutation Database is at: www.l1cammutationdatabase.info. ©2009 Wiley-Liss, Inc.


Chen M.,Peking University | Kallenberg C.G.M.,University of Groningen
Nature Reviews Rheumatology | Year: 2010

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include Wegener granulomatosis, microscopic polyangiitis, Churgĝ€ "Strauss syndrome and renal-limited vasculitis. This Review highlights the progress that has been made in our understanding of AAV pathogenesis and discusses new developments in the treatment of these diseases. Evidence from clinical studies, and both in vitro and in vivo experiments, supports a pathogenic role for ANCAs in the development of AAV; evidence is stronger for myeloperoxidase-ANCAs than for proteinase-3-ANCAs. Neutrophils, complement and effector T cells are also involved in AAV pathogenesis. With respect to treatment of AAV, glucocorticoids, cyclophosphamide and other conventional therapies are commonly used to induce remission in generalized disease. Pulse intravenous cyclophosphamide is equivalent in efficacy to oral cyclophosphamide but seems to be associated with less adverse effects. Nevertheless, alternatives to cyclophosphamide therapy have been investigated, such as the use of methotrexate as a less-toxic alternative to cyclophosphamide to induce remission in non-organ-threatening or non-life-threatening AAV. Furthermore, rituximab is equally as effective as cyclophosphamide for induction of remission in AAV and might become the standard of therapy in the near future. Controlled trials in which specific immune effector cells and molecules are being therapeutically targeted have been initiated or are currently being planned. © 2010 AJA, SIMM & SJTU All rights reserved.


Rodenhuis-Zybert I.A.,University of Groningen | Wilschut J.,University of Groningen | Smit J.M.,University of Groningen
Cellular and Molecular Life Sciences | Year: 2010

Dengue virus (DENV 1-4) represents a major emerging arthropod-borne pathogen. All four DENV serotypes are prevalent in the (sub) tropical regions of the world and infect 50-100 million individuals annually. Whereas the majority of DENV infections proceed asymptomatically or result in self-limited dengue fever, an increasing number of patients present more severe manifestations, such as dengue hemorrhagic fever and dengue shock syndrome. In this review we will give an overview of the infectious life cycle of DENV and will discuss the viral and host factors that are important in controlling DENV infection. © 2010 Springer Basel AG.


Van Spronsen F.J.,University of Groningen
Nature Reviews Endocrinology | Year: 2010

Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future. © 2010 Macmillan Publishers Limited. All rights reserved.


Minh B.Q.,University of Vienna | Nguyen M.A.T.,University of Groningen | Von Haeseler A.,University of Vienna
Molecular Biology and Evolution | Year: 2013

Nonparametric bootstrap has been a widely used tool in phylogenetic analysis to assess the clade support of phylogenetic trees. However, with the rapidly growing amount of data, this task remains a computational bottleneck. Recently, approximation methods such as the RAxML rapid bootstrap (RBS) and the Shimodaira-Hasegawa-like approximate likelihood ratio test have been introduced to speed up the bootstrap. Here, we suggest an ultrafast bootstrap approximation approach (UFBoot) to compute the support of phylogenetic groups in maximum likelihood (ML) based trees. To achieve this, we combine the resampling estimated log-likelihood method with a simple but effective collection scheme of candidate trees. We also propose a stopping rule that assesses the convergence of branch support values to automatically determine when to stop collecting candidate trees. UFBoot achieves a median speed up of 3.1 (range: 0.66-33.3) to 10.2 (range: 1.32-41.4) compared with RAxML RBS for real DNA and amino acid alignments, respectively. Moreover, our extensive simulations show that UFBoot is robust against moderate model violations and the support values obtained appear to be relatively unbiased compared with the conservative standard bootstrap. This provides a more direct interpretation of the bootstrap support. We offer an efficient and easy-to-use software (available at http://www.cibiv.at/software/iqtree) to perform the UFBoot analysis with ML tree inference. © 2013 The Author.


Hoppentocht M.,University of Groningen | Hagedoorn P.,University of Groningen | Frijlink H.W.,University of Groningen | de Boer A.H.,University of Groningen
Advanced Drug Delivery Reviews | Year: 2014

In the 50 years following the introduction of the first dry powder inhaler to the market, several developments have occurred. Multiple-unit dose and multi-dose devices have been introduced, but first generation capsule inhalers are still widely used for new formulations. Many new particle engineering techniques have been developed and considerable effort has been put in understanding the mechanisms that control particle interaction and powder dispersion during inhalation. Yet, several misconceptions about optimal inhaler performance manage to survive in modern literature. It is, for example still widely believed that a flow rate independent fine particle fraction contributes to an inhalation performance independent therapy, that dry powder inhalers perform best at 4. kPa (or 60. L/min) and that a high resistance device cannot be operated correctly by patients with reduced lung function. Nevertheless, there seems to be a great future for dry powder inhalation. Many new areas of interest for dry powder inhalation are explored and with the assistance of new techniques like computational fluid dynamics and emerging particle engineering technologies, this is likely to result in a new generation of inhaler devices and formulations, that will enable the introduction of new therapies based on inhaled medicines. © 2014.


Kuivenhoven J.A.,University of Groningen | Hegele R.A.,Robarts Research Institute
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2014

Mining of the genome for lipid genes has since the early 1970s helped to shape our understanding of how triglycerides are packaged (in chylomicrons), repackaged (in very low density lipoproteins; VLDL), and hydrolyzed, and also how remnant and low-density lipoproteins (LDL) are cleared from the circulation. Gene discoveries have also provided insights into high-density lipoprotein (HDL) biogenesis and remodeling. Interestingly, at least half of these key molecular genetic studies were initiated with the benefit of prior knowledge of relevant proteins. In addition, multiple important findings originated from studies in mouse, and from other types of non-genetic approaches. Although it appears by now that the main lipid pathways have been uncovered, and that only modulators or adaptor proteins such as those encoded by LDLRAP1, APOA5, ANGPLT3/4, and PCSK9 are currently being discovered, genome wide association studies (GWAS) in particular have implicated many new loci based on statistical analyses; these may prove to have equally large impacts on lipoprotein traits as gene products that are already known. On the other hand, since 2004 - and particularly since 2010 when massively parallel sequencing has become de rigeur - no major new insights into genes governing lipid metabolism have been reported. This is probably because the etiologies of true Mendelian lipid disorders with overt clinical complications have been largely resolved. In the meantime, it has become clear that proving the importance of new candidate genes is challenging. This could be due to very low frequencies of large impact variants in the population. It must further be emphasized that functional genetic studies, while necessary, are often difficult to accomplish, making it hazardous to upgrade a variant that is simply associated to being definitively causative. Also, it is clear that applying a monogenic approach to dissect complex lipid traits that are mostly of polygenic origin is the wrong way to proceed. The hope is that large-scale data acquisition combined with sophisticated computerized analyses will help to prioritize and select the most promising candidate genes for future research. We suggest that at this point in time, investment in sequence technology driven candidate gene discovery could be recalibrated by refocusing efforts on direct functional analysis of the genes that have already been discovered. This article is part of a Special Issue entitled: From Genome to Function. © 2014 Elsevier B.V.


Baron W.,University of Groningen | Hoekstra D.,University of Groningen
FEBS Letters | Year: 2010

In the central nervous system, a multilayered membrane layer known as the myelin sheath enwraps axons, and is required for optimal saltatory signal conductance. The sheath develops from membrane processes that extend from the plasma membrane of oligodendrocytes and displays a unique lipid and protein composition. Myelin biogenesis is carefully regulated, and multiple transport pathways involving a variety of endosomal compartments are involved. Here we briefly summarize how the major myelin proteins proteolipid protein and myelin basic protein reach the sheath, and highlight potential mechanisms involved, including the role of myelin specific lipids and cell polarity related transport pathways. © 2009 Federation of European Biochemical Societie.


van Vliet M.J.,University of Groningen
PLoS pathogens | Year: 2010

Mucositis, also referred to as mucosal barrier injury, is one of the most debilitating side effects of radiotherapy and chemotherapy treatment. Clinically, mucositis is associated with pain, bacteremia, and malnutrition. Furthermore, mucositis is a frequent reason to postpone chemotherapy treatment, ultimately leading towards a higher mortality in cancer patients. According to the model introduced by Sonis, both inflammation and apoptosis of the mucosal barrier result in its discontinuity, thereby promoting bacterial translocation. According to this five-phase model, the intestinal microbiota plays no role in the pathophysiology of mucositis. However, research has implicated a prominent role for the commensal intestinal microbiota in the development of several inflammatory diseases like inflammatory bowel disease, pouchitis, and radiotherapy-induced diarrhea. Furthermore, chemotherapeutics have a detrimental effect on the intestinal microbial composition (strongly decreasing the numbers of anaerobic bacteria), coinciding in time with the development of chemotherapy-induced mucositis. We hypothesize that the commensal intestinal microbiota might play a pivotal role in chemotherapy-induced mucositis. In this review, we propose and discuss five pathways in the development of mucositis that are potentially influenced by the commensal intestinal microbiota: 1) the inflammatory process and oxidative stress, 2) intestinal permeability, 3) the composition of the mucus layer, 4) the resistance to harmful stimuli and epithelial repair mechanisms, and 5) the activation and release of immune effector molecules. Via these pathways, the commensal intestinal microbiota might influence all phases in the Sonis model of the pathogenesis of mucositis. Further research is needed to show the clinical relevance of restoring dysbiosis, thereby possibly decreasing the degree of intestinal mucositis.


Stoffels J.M.J.,University of Groningen | Zhao C.,University of Cambridge | Baron W.,University of Groningen
Cellular and Molecular Life Sciences | Year: 2013

Tissue injury initiates extracellular matrix molecule expression, including fibronectin production by local cells and fibronectin leakage from plasma. To benefit tissue regeneration, fibronectin promotes opsonization of tissue debris, migration, proliferation, and contraction of cells involved in the healing process, as well as angiogenesis. When regeneration proceeds, the fibronectin matrix is fully degraded. However, in a diseased environment, fibronectin clearance is often disturbed, allowing structural variants to persist and contribute to disease progression and failure of regeneration. Here, we discuss first how fibronectin helps tissue regeneration, with a focus on normal cutaneous wound healing as an example of complete tissue recovery. Then, we continue to argue that, although the fibronectin matrix generated following cartilage and central nervous system white matter (myelin) injury initially benefits regeneration, fibronectin clearance is incomplete in chronic wounds (skin), osteoarthritis (cartilage), and multiple sclerosis (myelin). Fibronectin fragments or aggregates persist, which impair tissue regeneration. The similarities in fibronectin-mediated mechanisms of frustrated regeneration indicate that complete fibronectin clearance is a prerequisite for recovery in any tissue. Also, they provide common targets for developing therapeutic strategies in regenerative medicine. © 2013 Springer Basel.


Kallenberg C.G.M.,University of Groningen
Annals of the Rheumatic Diseases | Year: 2011

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.


Harder S.,University of Groningen | Spielmann J.,Universitatsstrasse 5
Chemical Communications | Year: 2011

Reaction of DIPPnacnacAlH2 with DIPPNH2BH3 did not give the anticipated deprotonation but nucleophilic substitution at B was observed instead. The product DIPPnacnacAl(BH4)2 was isolated and structurally characterized. Nucleophilic displacement at B might play a role in mechanistic pathways related to metal amidoborane complexes. © 2011 The Royal Society of Chemistry.


Internationally, national risk assessment (NRA) is rapidly gaining government sympathy as a science-based approach toward prioritizing the management of national hazards and threats, with the Netherlands and the United Kingdom in leading positions since 2007. NRAs are proliferating in Europe; they are also conducted in Australia, Canada, New Zealand, and the United States, while regional RAs now exist for over 100 Dutch or British provinces or counties. Focused on the Dutch NRA (DNRA) and supported by specific examples, summaries and evaluations are given of its (1) scenario development, (2) impact assessment, (3) likelihood estimation, (4) risk diagram, and (5) capability analysis. Despite the DNRA's thorough elaboration, apparent weaknesses are lack of stakeholder involvement, possibility of false-positive risk scenarios, rigid multicriteria impact evaluation, hybrid methods for likelihood estimation, half-hearted use of a "probability × effect" definition of risk, forced comparison of divergent risk scenarios, and unclear decision rules for risk acceptance and safety enhancement. Such weaknesses are not unique for the DNRA. In line with a somewhat reserved encouragement by the OECD (Studies in Risk Management. Innovation in Country Risk Management. Paris: OECD, 2009), the scientific solidity of NRA results so far is questioned, and several improvements are suggested. One critical point is that expert-driven NRAs may preempt political judgments and decisions by national security authorities. External review and validation of major NRA components is recommended for strengthening overall results as a reliable basis for national and/or regional safety policies. Meanwhile, a broader, more transactional concept of risk may lead to better national and regional risk assessments. © 2013 Society for Risk Analysis.


Roest D.,University of Groningen | Rosseel J.,University of Groningen
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2010

We show that known de Sitter solutions in extended gauged supergravity theories are interrelated via a web of supersymmetry-breaking truncations. In particular, all N = 8 models reduce to a subset of the N = 4 possibilities. Furthermore, a different subset of the N = 4 models can be truncated to stable de Sitter vacua in N = 2 theories. In addition to relations between the known cases, we also find new (un)stable models. © 2010.


Glashouwer K.A.,University of Groningen | De Jong P.J.,University of Groningen
Psychological Medicine | Year: 2010

Background Cognitive theory points to the importance of negative self-schemas in the onset and maintenance of depression and anxiety disorders. Hereby, it is important to distinguish between automatic and explicit self-schemas, reflecting different cognitive-motivational systems. This study tested whether patients with a current major depression and/or anxiety disorder are characterized by automatic self-anxious and self-depressive associations and whether these associations are disorder specific.Method Patients (n=2329) and non-clinical controls (n=652) were tested as part of The Netherlands Study of Depression and Anxiety, a multi-center, longitudinal, cohort study with patients from different health care settings. Patient groups and non-clinical controls (18-65 years of age) were compared with regard to automatic self-anxious and self-depressive associations measured with the Implicit Association Test.Results Individuals with an anxiety disorder showed enhanced self-anxious associations, whereas individuals with a depression showed enhanced self-depressive associations. Individuals with co-morbid disorders scored high on both automatic self-associations. Although remitted individuals showed weaker automatic self-associations than people with a current disorder, their automatic self-anxious/depressed associations were still significantly stronger than those of the control group. Importantly, automatic self-associations showed predictive validity for the severity of anxious and depressive symptoms over and above explicit self-beliefs.Conclusions This study represents the first evidence that automatic self-anxious and self-depressive associations are differentially involved in anxiety disorders and depression. This may help to explain the refractoriness of these disorders and points to the potential importance of automatic self-associations in the development of psychopathological symptoms. © Cambridge University Press 2009.


The effect of urban expansion on transportation in growing megacities has become a key issue in the context of global climate change as motorized mobility is a major source of domestic greenhouse gas emissions. The management of forms of urban development on the city fringe in order to encourage a sustainable transport system is usually overlooked in China, although it is increasingly attracting attention in developed countries. Examining the case of Beijing, this paper aims to reveal the policy implications of urban growth management for sustainable transportation in China's megacities. The analysis shows that in the rapid urban expansion process there has been obvious urban sprawl on the fringe of Beijing, characterized by low density and dispersed development in its physical aspect and a low degree of local mixed land use in its functional aspect. Trip distance and car use for travel on the city fringe have increased greatly due to urban sprawl. The results of the analysis suggest that urban growth management designed to curb urban sprawl would contribute to containing the growth in vehicle miles travelled in the suburbs. In addition, since urban sprawl has been greatly fuelled by increasing local government autonomy and fiscal responsibility, the negative effects of sprawling development on transportation certainly reflect the government's failure to manage growth in the current transformation process. To achieve sustainable urban expansion, stronger metropolitan development management measures should be enforced to control local development on the city fringe and promote sustainable transportation. © 2009 Elsevier Ltd. All rights reserved.


Koster L.J.A.,Zernike Institute for Advanced Materials | Shaheen S.E.,University of Denver | Hummelen J.C.,Zernike Institute for Advanced Materials | Hummelen J.C.,University of Groningen
Advanced Energy Materials | Year: 2012

Three different theoretical approaches are presented to identify pathways to organic solar cells with power conversion effi ciencies in excess of 20%. A radiation limit for organic solar cells is introduced that elucidates the role of charge-transfer (CT) state absorption. Provided this CT action is suffi ciently weak, organic solar cells can be as effi cient as their inorganic counterparts. Next, a model based on Marcus theory of electronic transfer that also considers exciton generation in both the electron donor and electron acceptor is used to show how reduction of the reorganization energies can lead to substantial effi ciency gains. Finally, the dielectric constant is introduced as a central parameter for effi cient solar cells. By using a drift-diffusion model, it is found that effi ciencies of more than 20% are within reach. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Kohlwein S.D.,University of Graz | Veenhuis M.,University of Groningen | van der Klei I.J.,University of Groningen
Genetics | Year: 2013

Lipid droplets (LDs) and peroxisomes are central players in cellular lipid homeostasis: some of their main functions are to control the metabolic flux and availability of fatty acids (LDs and peroxisomes) as well as of sterols (LDs). Both fatty acids and sterols serve multiple functions in the cell-as membrane stabilizers affecting membrane fluidity, as crucial structural elements of membraneforming phospholipids and sphingolipids, as protein modifiers and signaling molecules, and last but not least, as a rich carbon and energy source. In addition, peroxisomes harbor enzymes of the malic acid shunt, which is indispensable to regenerate oxaloacetate for gluconeogenesis, thus allowing yeast cells to generate sugars from fatty acids or nonfermentable carbon sources. Therefore, failure of LD and peroxisome biogenesis and function are likely to lead to deregulated lipid fluxes and disrupted energy homeostasis with detrimental consequences for the cell. These pathological consequences of LD and peroxisome failure have indeed sparked great biomedical interest in understanding the biogenesis of these organelles, their functional roles in lipid homeostasis, interaction with cellular metabolism and other organelles, as well as their regulation, turnover, and inheritance. These questions are particularly burning in view of the pandemic development of lipid-associated disorders worldwide. © 2013 by the Genetics Society of America.


Brenninkmeijer J.,University of Groningen
History of the Human Sciences | Year: 2010

The increasing attention to the brain in science and the media, and people's continuing quest for a better life, have resulted in a successful self-help industry for brain enhancement. Apart from brain books, foods and games, there are several devices on the market that people can use to stimulate their brains and become happier, healthier or more successful. People can, for example, switch their brain state into relaxation or concentration with a light-and-sound machine, they can train their brainwaves to cure their Attention Deficit Hyperactivity Disorder (ADHD) or solve their sleeping problems with a neurofeedback device, or they can influence the firing of their neurons with electric or magnetic stimulation to overcome their depression and anxieties. Working on your self with a brain device can be seen as a contemporary form of Michel Foucault's 'technologies of the self'. Foucault described how since antiquity people had used techniques such as reading manuscripts, listening to teachers, or saying prayers to 'act on their selves' and control their own thoughts and behaviours. Different techniques, Foucault stated, are based on different precepts and constitute different selves. I follow Foucault by stating that using a brain device for self-improvement indeed constitutes a new self. Drawing on interviews with users of brain devices and observations of the practices in brain clinics, I analyse how a new self takes shape in the use of brain devices; not a monistic (neuroscientific) self, but a 'layered' self of all kinds of entities that exchange and control each other continuously. © The Author(s), 2010.


Schwander T.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

Environmental shifts and lifestyle changes may result in formerly adaptive traits becoming non-functional or maladaptive. The subsequent decay of such traits highlights the importance of natural selection for adaptations, yet its causes have rarely been investigated. To study the fate of formerly adaptive traits after lifestyle changes, we evaluated sexual traits in five independently derived asexual lineages, including traits that are specific to males and therefore not exposed to selection. At least four of the asexual lineages retained the capacity to produce males that display normal courtship behaviours and are able to fertilize eggs of females from related sexual species. The maintenance of male traits may stem from pleiotropy, or from these traits only regressing via drift, which may require millions of years to generate phenotypic effects. By contrast, we found parallel decay of sexual traits in females. Asexual females produced altered airborne and contact signals, had modified sperm storage organs, and lost the ability to fertilize their eggs, impeding reversals to sexual reproduction. Female sexual traits were decayed even in recently derived asexuals, suggesting that trait changes following the evolution of asexuality, when they occur, proceed rapidly and are driven by selective processes rather than drift.


Tiessen A.H.,University of Groningen
BMC family practice | Year: 2012

Lower social economic status (SES) is related to an elevated cardiovascular (CV) risk. A pro-active primary prevention CV screening approach in general practice (GP) might be effective in a region with a low mean SES. This approach, supported by a regional GP laboratory, was investigated on feasibility, attendance rate and proportion of persons identified with an elevated risk. In a region with a low mean SES, men and women aged ≥ 50/55 years, respectively, were invited for cardiovascular risk profiling, based on SCORE 10-year risk of fatal cardiovascular disease and additional risk factors (family history, weight and end organ damage). Screening was performed by laboratory personnel, at the GP practice. Treatment advice was based on Dutch GP guidelines for cardiovascular risk management. Response rates were compared to those in five other practices, using the same screening method. 521 persons received invitations, 354 (68%) were interested, 33 did not attend and 43 were not further analysed because of already known diabetes/cardiovascular disease. Eventually 278 risk profiles were analysed, of which 60% had a low cardiovascular risk (SCORE-risk <5%). From the 40% participants with a SCORE-risk ≥ 5%, 60% did not receive medication yet for hypertension/hypercholesterolemia. In the other five GPs response rates were comparable to the currently described GP. Screening in GP in a low SES area, performed by a laboratory service, was feasible, resulted in high attendance, and identification and treatment advice of many new persons at risk for cardiovascular disease.


Advanced glycation end products (AGEs) are increased in patients with heart failure (HF). We studied the predictive value of plasma AGEs N(ε)-(carboxymethyl)lysine (CML), pentosidine, and the soluble form of its receptor (sRAGE) in a large HF population. In 580 patients hospitalized with HF, plasma AGEs were measured before discharge when patients were clinically stable. Patients were followed for a period of 18 months. Primary end point was a composite of death and HF admissions. CML was determined by liquid chromatography mass spectrometry, pentosidine by high-performance liquid chromatography and sRAGE by sequential sandwich immunoassay. Mean age was 71 ± 11 years, 62% were men, and mean left ventricular ejection fraction was 0.32 ± 0.14. At baseline, mean CML level was 2.16 ± 0.73 μmol/L, median pentosidine was 0.043 (0.030-0.074) μmol/L, and median sRAGE level was 2.92 (1.90-4.59) ng/mL. CML and pentosidine levels were independently related to the composite end-point (HR, 1.20 per SD; 95% CI,1.05-1.37; P = .01 and HR, 1.15 per SD; 95% CI, 1.00-1.31; P = .045, respectively) and HF hospitalization (HR, 1.27 per SD; 95% CI, 1.10-1.48; P = .001 and HR, 1.27 per SD; 95% CI, 1.10-1.47; P = .001, respectively). Furthermore, CML levels were independently related to increased mortality (P = .006). Whereas sRAGE levels were univariately predictive for outcome, in multivariate models sRAGE did not reach statistical significance. In HF patients, both CML and pentosidine predict HF hospitalization and the combined primary end-point (mortality or HF-hospitalization), whereas sRAGE did not predict events. In addition, CML was significantly and independently associated with a higher risk for mortality. Copyright © 2012 Mosby, Inc. All rights reserved.


Harder S.,University of Groningen
Coordination Chemistry Reviews | Year: 2011

This review summarizes the rapid developments in the chemistry of phosphonium-stabilized group 1 and 2 methandiides, i.e. that of alkali and alkaline-earth metal bis(iminophosphorane)methandiide and bis(thiophosphorane)methandiide complexes. Apart from syntheses, structures and reactivities, also a critical discussion on bonding is given. The group 2 complexes of this type can truly be seen as polar metal carbene compounds with a formally polar double metal-carbon bond. © 2010 Elsevier B.V.


Georgiadis J.R.,University of Groningen | Kringelbach M.L.,University of Oxford | Kringelbach M.L.,University of Aarhus
Progress in Neurobiology | Year: 2012

Sexual behavior is critical to species survival, yet comparatively little is known about the neural mechanisms in the human brain. Here we systematically review the existing human brain imaging literature on sexual behavior and show that the functional neuroanatomy of sexual behavior is comparable to that involved in processing other rewarding stimuli. Sexual behavior clearly follows the established principles and phases for wanting, liking and satiety involved in the pleasure cycle of other rewards. The studies have uncovered the brain networks involved in sexual wanting or motivation/anticipation, as well as sexual liking or arousal/consummation, while there is very little data on sexual satiety or post-orgasmic refractory period. Human sexual behavior also interacts with other pleasures, most notably social interaction and high arousal states. We discuss the changes in the underlying brain networks supporting sexual behavior in the context of the pleasure cycle, the changes to this cycle over the individual's life-time and the interactions between them. Overall, it is clear from the data that the functional neuroanatomy of sex is very similar to that of other pleasures and that it is unlikely that there is anything special about the brain mechanisms and networks underlying sex. © 2012 Elsevier Ltd.


Megens R.P.,University of Groningen | Roelfes G.,University of Groningen
Chemical Communications | Year: 2012

Using the DNA-based catalysis concept, a novel Cu(ii) catalyzed enantioselective oxa-Michael addition of alcohols to enones is reported. Enantioselectivities of up to 86% were obtained. The presence of water is important for the reactivity, possibly by reverting unwanted side reactions such as 1,2-additions. © 2012 The Royal Society of Chemistry.


Kwakernaak A.J.,University of Groningen | Zelle D.M.,University of Groningen | Bakker S.J.L.,University of Groningen | Navis G.,University of Groningen
Journal of the American Society of Nephrology | Year: 2013

Central distribution of body fat is associated with a higher risk of renal disease, but whether it is the distribution pattern or the overall excess weight that underlies this association is not well understood. Here, we studied the association between waist-to-hip ratio (WHR), which reflects central adiposity, and renal hemodynamics in 315 healthy persons with a mean bodymass index (BMI) of 24.9 kg/m2 and a mean 125I-iothalamate GFR of 109 ml/min per 1.73 m2. In multivariate analyses, WHR was associated with lower GFR, lower effective renal plasma flow, and higher filtration fraction, even after adjustment for sex, age, mean arterial pressure, and BMI. Multivariate models produced similar results regardless of whether the hemodynamic measures were indexed to body surface area. Thus, these results suggest that central body fat distribution, independent of BMI, is associated with an unfavorable pattern of renal hemodynamic measures that could underlie the increased renal risk reported in observational studies. Copyright © 2013 by the American Society of Nephrology.


Johnson C.,University of North Carolina at Greensboro | Boersma T.,University of Groningen
Energy Policy | Year: 2013

The large scale extraction of natural gas from shale rock layers in North America using hydraulic fracturing, or "fracking", has prompted geologists, economists and politicians in various parts of the world to ask whether there are new reserves of this precious resource to be found under their soils. It has also raised a host of questions about the potential environmental impacts of extracting it. Drawing on research on both sides of the Atlantic, this paper assesses the most pressing issues for research and policy makers related to shale gas extraction. The paper first provides a survey of environmental and economic issues related to shale gas. It then turns to a case study of Poland, whose policy makers have been among the most fervent proponents of shale gas development in the European Union. We examine the status of shale gas extraction in that country and what the barriers are to overcome before commercial extraction can in fact take place, if at all. © 2012 Elsevier Ltd.


Mazo Jr. M.,University of Groningen | Tabuada P.,University of California at Los Angeles
Systems and Control Letters | Year: 2011

There is an increasing demand for controller design techniques capable of addressing the complex requirements of today's embedded applications. This demand has sparked the interest in symbolic control where lower complexity models of control systems are used to cater for complex specifications given by temporal logics, regular languages, or automata. These specification mechanisms can be regarded as qualitative since they divide the trajectories of the plant into bad trajectories (those that need to be avoided) and good trajectories. However, many applications require also the optimization of quantitative measures of the trajectories retained by the controller, as specified by a cost or utility function. As a first step towards the synthesis of controllers reconciling both qualitative and quantitative specifications, we investigate in this paper the use of symbolic models for time-optimal controller synthesis. We consider systems related by approximate (alternating) simulation relations and show how such relations enable the transfer of time-optimality information between the systems. We then use this insight to synthesize approximately time-optimal controllers for a control system by working with a lower complexity symbolic model. The resulting approximately time-optimal controllers are equipped with upper and lower bounds for the time to reach a target, describing the quality of the controller. The results described in this paper were implemented in the Matlab Toolbox Pessoa (Mazo et al., 2009 [12]) which we used to workout several illustrative examples reported in this paper. © 2011 Elsevier B.V. All rights reserved.


Stavenga D.G.,University of Groningen
Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology | Year: 2010

The absorbance spectra of visual pigments can be approximated with mathematical expressions using as single parameter the absorbance peak wavelength. A comparison of the formulae of Stavenga et al. in Vision Res 33:1011-1017 (1993) and Govardovskii et al. in Vis Neurosci 17:509-528 (2000) applied to a number of invertebrate rhodopsins reveals that both templates well describe the normalized α-band of rhodopsins with peak wavelength > 400 nm; the template spectra are virtually indistinguishable in an absorbance range of about three log units. The template formulae of Govardovskii et al. in Vis Neurosci 17:509-528 (2000) describe the rhodopsin spectra better for absorbances below 10-3. The template predicted spectra deviate in the ultraviolet wavelength range from each other as well as from measured spectra, preventing a definite conclusion about the spectral shape in the wavelength range <400 nm. The metarhodopsin spectra of blowfly and fruitfly R1-6 photoreceptors derived from measured data appear to be virtually identical. The established templates describe the spectral shape of fly metarhodopsin reasonably well. However, the best fitting template spectrum slightly deviates from the experimental spectra near the peak and in the long-wavelength tail. Improved formulae for fitting the fly metarhodopsin spectra are proposed. © 2010 The Author(s).


Koolhaas J.M.,University of Groningen
Journal of visualized experiments : JoVE | Year: 2013

This video publication explains in detail the experimental protocol of the resident-intruder paradigm in rats. This test is a standardized method to measure offensive aggression and defensive behavior in a semi natural setting. The most important behavioral elements performed by the resident and the intruder are demonstrated in the video and illustrated using artistic drawings. The use of the resident intruder paradigm for acute and chronic social stress experiments is explained as well. Finally, some brief tests and criteria are presented to distinguish aggression from its more violent and pathological forms.


Hazenberg B.P.C.,University of Groningen
Rheumatic Disease Clinics of North America | Year: 2013

Amyloidosis is the name for protein-folding diseases characterized by extracellular deposition of a specific soluble precursor protein that aggregates in the form of insoluble fibrils. The classification of amyloidosis is based on the chemical characterization of the precursor protein. Deposition of amyloid is localized or systemic. The 4 main types of systemic amyloidosis are AL, AA, ATTR, and Aβ 2M type. A schematic approach is proposed for the clinical management of systemic amyloidosis. The importance of typing amyloid with confidence, the usefulness of imaging techniques, the principles of treatment, and the need for well-planned treatment monitoring during follow-up are discussed. © 2013 Elsevier Inc.


Popping G.,University of Groningen | Somerville R.S.,Rutgers University | Trager S.C.,University of Groningen
Monthly Notices of the Royal Astronomical Society | Year: 2014

We study the evolution of atomic and molecular gas in galaxies in semi-analytic models of galaxy formation that include new modelling of the partitioning of cold gas in galactic discs into atomic, molecular, and ionized phases.We adopt two scenarios for the formation of molecules: one pressure based and one metallicity based.We find that both recipes successfully reproduce the gas fractions and gas-to-stellar mass ratios of HI and H2 in local galaxies, as well as the HI and H2 disc sizes up to z = 2. We reach good agreement with the locally observed HI and H2 mass function, although both recipes slightly overpredict the low-mass end of the HI mass function. Both of our models predict that the high-mass end of the HI mass function remains nearly constant at redshifts z < 2.0. The metallicity-based recipe yields a higher cosmic density of cold gas and much lower cosmic H2 fraction over the entire redshift range probed than the pressure-based recipe. These strong differences in HI mass function and cosmic density between the two recipes are driven by low-mass galaxies (log (M/M⊙)≤7) residing in low-mass haloes (log (Mvir/M⊙) ≤ 10). Both recipes predict that galaxy gas fractions remain high from z ~ 6to3 and drop rapidly at lower redshift. The galaxyH2 fractions show a similar trend, but drop even more rapidly.We provide predictions for the CO J = 1-0 luminosity of galaxies, which will be directly comparable with observations with sub-mm and radio instruments © 2014 The Authors.


Willems D.L.,University of Amsterdam | Verhagen A.A.,University of Groningen | van Wijlick E.,Royal Dutch Medical Association
Pediatrics | Year: 2014

BACKGROUND AND OBJECTIVES: Pediatric bioethics presumes that decisions should be taken in the child's best interest. If it's ambiguous whether a decision is in the child's interest, we defer to parents. Should parents be permitted to consider their own interests in making decisions for their child? In the Netherlands, where neonatal euthanasia is legal, such questions sometimes arise in deciding whether to hasten the death of a critically ill, suffering child. We describe the recommendations of a national Dutch committee. Our objectives were to analyze the role of competing child and family interests and to provide guidance on end-of-life decisions for doctors caring for severely ill newborns.METHODS: We undertook literature review, 7 consensus meetings in a multidisciplinary expert commission, and invited comments on draft report by specialists' associations.RESULTS: Initial treatment is mandatory for most ill newborns, to clarify the prognosis. Continuation of treatment is conditional on further diagnostic and prognostic data. Muscle relaxants can sometimes be continued after withdrawal of artificial respiration without aiming to shorten the child's life. When gasping causes suffering, or protracted dying is unbearable for the parents, muscle relaxants may be used to end a newborn's life. Whenever muscle relaxants are used, cases should be reported to the national review committee.CONCLUSIONS: New national recommendations in the Netherlands for end-of-life decisions in newborns suggest that treatment should generally be seen as conditional. If treatment fails, it should be abandoned. In those cases, palliative care should be directed at both infant and parental suffering. Sometimes, this may permit interventions that hasten death. Copyright © 2014 by the American Academy of Pediatrics.


Massy Z.A.,Charles University | De Zeeuw D.,University of Groningen
Kidney International | Year: 2013

In the majority of patients with chronic kidney disease (CKD) the total and low-density lipoprotein (LDL) cholesterol are usually normal, with the exception of patients with nephrotic-range proteinuria and in peritoneal dialysis patients. Moreover, epidemiological evidence shows that the link between serum total cholesterol or LDL cholesterol and cardiovascular disease (CVD) in CKD is not as straightforward as in the general population. In addition, atherosclerosis-related events are responsible for only ∼30% of CVD in these patients. Nevertheless, intervention trials, particularly the Study of Heart and Renal Protection, and meta-analyses showed a proportional reduction of cardiovascular risk associated with the absolute reduction in LDL cholesterol in patients with CKD similar to the general population, with apparent attenuation of this relationship in end-stage kidney disease. Therefore, the use of cholesterol-lowering agents appears to be indicated in early CKD stages to prevent atherosclerosis-related risk. However, uncertainty persists as to the optimal management of this risk in end-stage kidney disease patients. In the present review, we discuss these issues and end up with a practical plan aimed to help the nephrologist in managing atherosclerosis- related risk using cholesterol-lowering therapies in CKD patients. © 2013 International Society of Nephrology.


Sidorenkov G.,University of Groningen
PloS one | Year: 2013

Landmark clinical trials have led to optimal treatment recommendations for patients with diabetes. Whether optimal treatment is actually delivered in practice is even more important than the efficacy of the drugs tested in trials. To this end, treatment quality indicators have been developed and tested against intermediate outcomes. No studies have tested whether these treatment quality indicators also predict hard patient outcomes. A cohort study was conducted using data collected from >10.000 diabetes patients in the Groningen Initiative to Analyze Type 2 Treatment (GIANTT) database and Dutch Hospital Data register. Included quality indicators measured glucose-, lipid-, blood pressure- and albuminuria-lowering treatment status and treatment intensification. Hard patient outcome was the composite of cardiovascular events and all-cause death. Associations were tested using Cox regression adjusting for confounding, reporting hazard ratios (HR) with 95% confidence intervals. Lipid and albuminuria treatment status, but not blood pressure lowering treatment status, were associated with the composite outcome (HR = 0.77, 0.67-0.88; HR = 0.75, 0.59-0.94). Glucose lowering treatment status was associated with the composite outcome only in patients with an elevated HbA1c level (HR = 0.72, 0.56-0.93). Treatment intensification with glucose-lowering but not with lipid-, blood pressure- and albuminuria-lowering drugs was associated with the outcome (HR = 0.73, 0.60-0.89). Treatment quality indicators measuring lipid- and albuminuria-lowering treatment status are valid quality measures, since they predict a lower risk of cardiovascular events and mortality in patients with diabetes. The quality indicators for glucose-lowering treatment should only be used for restricted populations with elevated HbA1c levels. Intriguingly, the tested indicators for blood pressure-lowering treatment did not predict patient outcomes. These results question whether all treatment indicators are valid measures to judge quality of health care and its economics.


Garcia R.,Northeastern University | Jager W.,University of Groningen
Journal of Product Innovation Management | Year: 2011

Agent-based modeling (ABM), a tool for capturing micro-level individuals' underlying decision processes and mimicking dynamic social effects observed at the macro level in the marketplace, is studied. The value of agent-based simulation models for practitioners and for management science depends on their capacity to contribute to the understanding and management of real markets. Studies are devoted towards combining multiple theories from innovation economics and economic sociology in a single modeling framework (SKIN) to capture the relevant processes of knowledge diffusion in industry networks. Data from a conjoint analysis is used to parameterize consumer agents in conjunction with data from an engineering-based design model to parameterize manufacturer agents. ABMs are being designed for testing managerial strategies that influence the degree and speed of diffusion processes is not currently available.


van Haastert P.J.M.,University of Groningen
PLoS Computational Biology | Year: 2010

Cell migration in the absence of external cues is well described by a correlated random walk. Most single cells move by extending protrusions called pseudopodia. To deduce how cells walk, we have analyzed the formation of pseudopodia by Dictyostelium cells. We have observed that the formation of pseudopodia is highly ordered with two types of pseudopodia: First, de novo formation of pseudopodia at random positions on the cell body, and therefore in random directions. Second, pseudopod splitting near the tip of the current pseudopod in alternating right/left directions, leading to a persistent zig-zag trajectory. Here we analyzed the probability frequency distributions of the angles between pseudopodia and used this information to design a stochastic model for cell movement. Monte Carlo simulations show that the critical elements are the ratio of persistent splitting pseudopodia relative to random de novo pseudopodia, the Left/Right alternation, the angle between pseudopodia and the variance of this angle. Experiments confirm predictions of the model, showing reduced persistence in mutants that are defective in pseudopod splitting and in mutants with an irregular cell surface. © 2010 Peter J. M. Van Haastert.


Flipse J.,University of Groningen | Wilschut J.,University of Groningen | Smit J.M.,University of Groningen
Traffic | Year: 2013

Dengue is the most common arthropod-borne viral infection in humans with ~50 million cases annually worldwide. In recent decades, a steady increase in the number of severe dengue cases has been seen. Severe dengue disease ismost often observed in individuals that have pre-existing immunity against heterotypic dengue subtypes and in infants with low levels of maternal dengue antibodies. The generally accepted hypothesis explaining the immunopathogenesis of severe dengue is called antibody-dependent enhancement of dengue infection. Here, circulating antibodies bind to the newly infecting virus but do not neutralize infection. Rather, these antibodies increase the infected cell mass and virus production. Additionally, antiviral responses are diminished allowing massive virus particle production early in infection. The large infected cell mass and the high viral load are prelude for severe disease development. In this review, we discuss what is known about the trafficking of dengue virus in its human host cells, and the signalling pathways activated after virus detection, both in the absence and presence of antibodies against the virus. This review summarizes work that aims to better understand the complex immunopathogenesis of severe dengue disease. © 2012 John Wiley & Sons A/S.


Rutgers A.,University of Groningen | Kallenberg C.G.M.,University of Groningen
Current Opinion in Rheumatology | Year: 2012

Purpose of Review: Induction treatment of antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) is not always successful and nonresponding patients are considered refractory. Recent Findings: Refractory disease should be subdefined to the treatment that was received. Cyclophosphamide refractory AAV occurs in up to 5% of patients. Many more patients develop contraindications to cyclophosphamide or relapse frequently. The latter two patient groups might also benefit from treatment used for cyclophosphamide refractory AAV. Summary: The most promising drug for treating refractory AAV is rituximab. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lewis-Evans B.,University of Groningen
Journal of Safety Research | Year: 2010

Introduction: The New Zealand Graduated Driver Licensing System (GDLS) is designed to allow novice drivers to gain driving experience under conditions of reduced risk. Method: To examine the effectiveness of the GDLS, an analysis of how the crash involvement of novice drivers changes as drivers move through the GDLS was undertaken. Crash profiles were created by data matching the New Zealand license and crash databases, covering a time period from 1999-2006. Results: The crash profiles show that the initial learner period of the GDLS is relatively safe and the time at which novice drivers have the highest rate of crash involvement is during the first few months of solo driving. Analysis using logistic regression also showed an effect of age and gender, with higher crash involvement associated with younger drivers and males. In addition, individuals who gained a full license within 12-18 months of holding a restricted license, due to completion of a time-discount associated educational program, had a higher level of involvement in crashes than individuals who gained a full license after 18 months. Conclusions: The crash profiles provide an insight into the crash risk associated with different phases of the New Zealand GDLS. Impact on Industry: Increasing the age at which drivers first begin to solo drive and the removal of the time-discount associated with completion of an educational program should be considered. © 2010 Elsevier Ltd.


Wilhelm M.M.,University of Groningen
Journal of Operations Management | Year: 2011

A growing research stream has expanded the level of analysis beyond single buyer-supplier relations to the network, including supplier-supplier relations. These supplier-supplier relations may constitute a missing link between the traditional analysis of the dyadic and the network level of analysis that are often treated separately. This paper explores the interplay of the supplier-supplier and network of analysis by focusing on the inherent tension between cooperation and competition, using a multiple case study design in the Japanese and German automobile industries. It is argued that the buyer is able to exert influence not only on the coopetition level, so within "horizontal supply chain relations," but that the coopetitive tension in the overall network can in fact be managed through the active establishment and maintenance of such relations. © 2011 Elsevier B.V. All rights reserved.


Jansonius N.M.,University of Groningen
Journal of the Optical Society of America A: Optics and Image Science, and Vision | Year: 2010

Wave-front analysis data from the human eye are commonly presented using the aberration coefficient c40 (primary spherical aberration) together with an overall measure of all higher-order aberrations. If groups of subjects are compared, however, the relevance of an observed difference cannot easily be assessed from these summary aberration measures. A method was developed for estimating various optical variables relevant to visual perception from summary wave-front analysis data. These variables were the myopic shift (the difference in the optimal focus between high and low spatial frequencies, a threat to the simultaneous in-focus viewing of fine and coarse patterns), the depth-of-focus (at 8 cpd), and the modulation transfer at high (16 cpd; reading small print) and low (4 cpd; edge detection) spatial frequencies. The depth-of-focus was defined in two ways: using a relative measure (the full width at half-height of the through-focus curve) and an absolute measure (the range where the through-focus curve exceeds a predefined modulation transfer value). The method was shown to be accurate by using previously published contrast sensitivity data and wave-front analysis data. The applicability of the method was illustrated by applying the method to wave-front analysis measurements performed in pseudophakic patients with aspheric and spherical intraocular lenses. © 2010 Optical Society of America.


Douven I.,University of Groningen
Behavioral and Brain Sciences | Year: 2011

Elqayam & Evans (E&E) argue against prescriptive normativism and in favor of descriptivism. I challenge the assumption, implicit in their article, that there is a choice to be made between the two approaches. While descriptivism may be the right approach for some questions, others call for a normativist approach. To illustrate the point, I briefly discuss two questions of the latter sort. © 2011 Cambridge University Press.


Robertus J.,University of Groningen | Browne W.R.,University of Groningen | Feringa B.L.,University of Groningen
Chemical Society Reviews | Year: 2010

In complex organisms, cells are often dependent on their extracellular matrix (ECM) for structural integrity, the mechanical properties of tissues, and for signaled regulation of cellular processes including adhesion, migration, growth, secretion, gene expression and apoptosis. Achieving dynamic control, i.e. by using an external stimulus, over the interactions between cells and artificial interfaces holds considerable promise in tissue engineering, medicine, cell biology and immunology. For example, improved spatial control over cell-surface interaction is potentially useful in the design of cell-based screening devices. Dynamic control over SAMs for cell adhesion provides an additional handle to direct and study the attachment of cells to surfaces, e.g., in studying cell spreading from a predetermined pattern in order to screen the cytotoxicity of drug candidates. However, 'reversible' control of cell adhesion onto substrates is an area that is still in its infancy. In this critical review recent developments in cell adhesion of mammalian cells to SAM-modified surfaces, the physical properties of which can be controlled by an external stimulus, e.g. by light, electrochemistry, etc., are discussed (118 references). © 2010 The Royal Society of Chemistry.


Asselbergs F.W.,University of Groningen | Williams S.M.,Vanderbilt University
Bioinformatics | Year: 2010

Motivation: The sequencing of the human genome has made it possible to identify an informative set of >1 million single nucleotide polymorphisms (SNPs) across the genome that can be used to carry out genome-wide association studies (GWASs). The availability of massive amounts of GWAS data has necessitated the development of new biostatistical methods for quality control, imputation and analysis issues including multiple testing. This work has been successful and has enabled the discovery of new associations that have been replicated in multiple studies. However, it is now recognized that most SNPs discovered via GWAS have small effects on disease susceptibility and thus may not be suitable for improving health care through genetic testing. One likely explanation for the mixed results of GWAS is that the current biostatistical analysis paradigm is by design agnostic or unbiased in that it ignores all prior knowledge about disease pathobiology. Further, the linear modeling framework that is employed in GWAS often considers only one SNP at a time thus ignoring their genomic and environmental context. There is now a shift away from the biostatistical approach toward a more holistic approach that recognizes the complexity of the genotype-phenotype relationship that is characterized by significant heterogeneity and gene-gene and gene-environment interaction. We argue here that bioinformatics has an important role to play in addressing the complexity of the underlying genetic basis of common human diseases. The goal of this review is to identify and discuss those GWAS challenges that will require computational methods. Contact: jason.h.moore@dartmouth.edu © The Author(s) 2010. Published by Oxford University Press.


Novaes C.D.,University of Groningen
Behavioral and Brain Sciences | Year: 2011

Elqayam & Evans' (E&E's) critique of normativism is related to an inherently philosophical question: Is thinking a normative affair? Should thinking be held accountable towards certain norms? I present the historical and philosophical origins of the view that thinking belongs to the realm of normativity and has a tight connection with logic, stressing the pivotal role of Kant in these developments. © 2011 Cambridge University Press.


Bergshoeffa E.A.,University of Groningen | Riccionib F.,King's College London
Journal of High Energy Physics | Year: 2011

We construct for arbitrary dimensions a universal T-duality covariant expression for the Wess-Zumino terms of supersymmetric String Solitons in toroidally compactified string theories with 32 supercharges. The worldvolume fields occurring in the effective action of these String Solitons form either a vector or a tensor multiplet with 16 supercharges. We determine the dimensions of the conjugacy classes under T-duality to which these String Solitons belong. We do this in two steps. First, we determine the T-duality representations of the p-forms of maximal supergravities that contain the potentials that couple to these String Solitons. We find that these are p-forms, with D - 4 ≤ p ≤ 6 if D ≥ 6 and with D - 4 ≤ p ≤ D if D < 6, transforming in the antisymmetric representation of rank m = p + 4 - D ≤ 4 of the T-duality symmetry SO(10 - D, 10 - D). All branes support vector multiplets except when m = 10 - D. In that case the T-duality representation splits, for D < 10, into a selfdual and anti-selfdual part, corresponding to 5- branes supporting either a vector or a tensor multiplet. In a second step we show that only certain well-defined lightlike directions in the anti-symmetric tensor representations of the T-duality group correspond to supersymmetric String Solitons. These lightlike directions define the conjugacy classes. As a by-product we show how by a straightforward procedure all solitonic fields of maximal supergravity are derived using the Kac-Moody algebra E11. © SISSA 2011.


Megens R.P.,University of Groningen | Roelfes G.,University of Groningen
Organic and Biomolecular Chemistry | Year: 2010

Water-miscible organic co-solvents can be used in DNA-based catalytic asymmetric reactions at appreciable concentration without a negative effect on enantioselectivity. While the rate of the copper(ii) Diels-Alder reaction is affected negatively by the presence of organic co-solvents, the copper(ii) catalyzed Michael addition and Friedel-Crafts alkylation reaction are significantly faster. Additionally, the presence of organic co-solvents allows for reaction temperatures <0 °C, which results in higher ee's. This is used to perform enantioselective Michael additions and Friedel-Crafts alkylations at gram scale, using catalyst loadings as low as 0.75 mol%. These results are an important step towards application of the DNA-based catalysis concept in organic synthesis © 2010 The Royal Society of Chemistry.


Kruijff S.,University of Groningen | Hoekstra H.J.,University of Groningen
European Journal of Surgical Oncology | Year: 2012

Melanoma is the most malignant type of all skin cancer types. It causes over 75% of all skin cancer related mortality. In the Netherlands, the total number of new diagnosed melanoma patients is expected to increase from 2400 patients in 2000 to 4800 patients in 2015. After surgical treatment, 20-28% of melanoma patients present with loco-regional recurrence, 26-60% with regional recurrences, and 15-50% with distant metastases. Early detection of lymph node (micro) metastases by means of a sentinel lymph node biopsy (SLNB) is therefore of crucial importance since early lymph node dissection decrease treatment morbidity and improve overall survival. However when patients present with palpable nodes, given the heterogeneity in survival, the suspicion rises that numerous patients have a form of subclinical dissemination, which can remain undetected by current modern imaging methods. Biomarkers could illuminate on this matter, although there is very little understanding of their biological significance. It can be expected that the strongest biological markers are surrogates of key biological events. The protein S-100B seems to be the best analyzed biomarker in melanoma. It has the potential to identify high-risk stage III melanoma patients who may benefit from adjuvant systematic treatment. In the stratification of new adjuvant therapeutic trials in patients with loco-regional recurrences, we therefore recommend the use of S-100B in the stratification. Since an effective (adjuvant) therapy for loco-regional metastatic and disseminated melanoma is recently introduced, the use of S-100B seems to alter dramatically in the near future. © 2011 Elsevier Ltd. All rights reserved.


Kallenberg C.G.M.,University of Groningen
Clinical Reviews in Allergy and Immunology | Year: 2011

Clinical observations, including a report of neonatal vasculitis occurring in a child born from a mother with anti-neutrophil cytoplasmic antibody directed to myeloperoxidase (MPO-ANCA)-associated vasculitis, suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data showing that ANCA can activate primed neutrophils to the production of reactive oxygen species and lytic enzymes resulting in lysis of endothelial cells. An interplay between neutrophils, the alternative pathway of complement, and MPO-ANCA resulting in systemic vasculitis including necrotizing glomerulonephritis has clearly been demonstrated in animal models. An in vivo pathogenic role of ANCA directed to proteinase 3 (PR3-ANCA) has, however, not been substantiated. In PR3-ANCA-associated vasculitis, granulomatous inflammation points to involvement of cell-mediated immunity. In vitro studies, indeed, suggest that PR3-specific Th17 CD4-positive lymphocytes are operative in lesion development. The triggering role of microbial factors is becoming more clear. In particular Staphylococcus aureus carriage and infection with Gram-negative bacteria could contribute to induction and persistence of ANCA-associated vasculitis (AAV). Insight into the pathogenic pathways involved in AAV have opened and will further open new ways to targeted treatment. © 2011 Springer Science+Business Media, LLC.


Loonen A.J.,University of Groningen
CNS spectrums | Year: 2013

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/ or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson's disease,and it occurs spontaneously as a symptom of Huntington's disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the corticostriato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway,which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here,we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.


Khusainov R.,University of Groningen | Kuipers O.P.,University of Groningen
ChemBioChem | Year: 2012

The nisin leader is believed to be crucial for nisin biosynthesis. Here, by using a construct completely lacking the leader peptide, we show that an up to fivefold-dehydrated leaderless prenisin can be obtained, as judged by MALDI-TOF MS, and that some of these species are biologically active, thus suggesting that at least three lanthionine rings are present. Notably, by expressing the leader peptide in trans together with the leaderless prenisin, we were able to increase the dehydration/cyclization efficiency of both NisB and NisC, but still with limited efficiency until the fifth dehydratable residue (Thr13) was processed, thereby enabling three rings to form. This, for the first time, demonstrates that 1) the leader is not absolutely necessary for the dehydration reaction of class I lantibiotics to occur in vivo; 2) the leader acts in trans in vivo; 3) the leader increases the efficiency of modification. Based on previous work and our current study, a model for the interactions of NisB and NisC with prenisin is proposed, in which the leader induces a more active conformation and/or productive complex formation of the biosynthetic machinery, and, when covalently bound, is involved in increasing the efficiency of dehydration to the C-terminal end of the prenisin substrate molecule. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Objectives: There is no robust proof that the efficacy of lithium in the prevention of manic and depressive episodes in bipolar disorder depends on its plasma level. This analysis aimed to compare the effect of lithium within the presumed therapeutic range of 0.6-1.2mEq/L and below 0.6mEq/L with that of placebo. Methods: We carried out a post hoc analysis of a double-blind trial in which patients aged ≥18years with bipolar I disorder (DSM-IV) who had achieved stabilization from a manic, depressive, or mixed episode during open-label treatment with quetiapine were randomized to continue quetiapine or to switch to lithium or placebo for up to 104weeks. Of patients randomized to lithium, 201 obtained median lithium levels between 0.6 and 1.2mEq/L, and 137 obtained median lithium levels <0.6mEq/L. Their outcomes were compared with those of patients receiving placebo (n=404). The primary outcome was time to recurrence of any mood event; additional outcomes included time to recurrence of a manic or depressive event. Results: Times to recurrence of any mood event as well as a manic or depressive event were significantly longer for the lithium 0.6-1.2mEq/L group versus placebo and versus lithium <0.6mEq/L, with no differences between lithium <0.6mEq/L and placebo. Conclusions: The results support and expand previous findings that lithium should be dosed high enough to achieve plasma levels ≥0.6mEq/L in order to achieve an effect in the prevention of both manic and depressive recurrences of bipolar I disorder. A major limitation is that the composition of the two lithium groups was not based on randomization. © 2012 John Wiley and Sons A/S.


Tangerman A.,University of Groningen
Journal of breath research | Year: 2010

Halitosis can be subdivided into intra-oral and extra-oral halitosis, depending on the place where it originates. Most reports now agree that the most frequent sources of halitosis exist within the oral cavity and include bacterial reservoirs such as the dorsum of the tongue, saliva and periodontal pockets, where anaerobic bacteria degrade sulfur-containing amino acids to produce the foul smelling volatile sulfur compounds (VSCs), especially hydrogen sulfide (H(2)S) and methyl mercaptan (CH(3)SH). Tongue coating is considered to be the most important source of VSCs. Oral malodor can now be treated effectively. Special attention in this overview is given to extra-oral halitosis. Extra-oral halitosis can be subdivided into non-blood-borne halitosis, such as halitosis from the upper respiratory tract including the nose and from the lower respiratory tract, and blood-borne halitosis. The majority of patients with extra-oral halitosis have blood-borne halitosis. Blood-borne halitosis is also frequently caused by odorous VSCs, in particular dimethyl sulfide (CH3SCH3). Extra-oral halitosis, covering about 5-10% of all cases of halitosis, might be a manifestation of a serious disease for which treatment is much more complicated than for intra-oral halitosis. It is therefore of utmost importance to differentiate between intra-oral and extra-oral halitosis. Differences between intra-oral and extra-oral halitosis are discussed extensively. The importance of applying odor characterization of various odorants in halitosis research is also highlighted in this article. The use of the odor index, odor threshold values and simulation of bad breath samples is explained.


Hut R.A.,University of Groningen | Beersma D.G.M.,University of Groningen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

Virtually all species have developed cellular oscillations and mechanisms that synchronize these cellular oscillations to environmental cycles. Such environmental cycles in biotic (e.g. food availability and predation risk) or abiotic (e.g. temperature and light) factors may occur on a daily, annual or tidal time scale. Internal timing mechanisms may facilitate behavioural or physiological adaptation to such changes in environmental conditions. These timing mechanisms commonly involve an internal molecular oscillator (a 'clock') that is synchronized ('entrained') to the environmental cycle by receptor mechanisms responding to relevant environmental signals ('Zeitgeber', i.e. German for time-giver). To understand the evolution of such timing mechanisms, we have to understand the mechanisms leading to selective advantage. Although major advances have been made in our understanding of the physiological and molecular mechanisms driving internal cycles (proximate questions), studies identifying mechanisms of natural selection on clock systems (ultimate questions) are rather limited. Here, we discuss the selective advantage of a circadian system and how its adaptation to day length variation may have a functional role in optimizing seasonal timing. We discuss various cases where selective advantages of circadian timing mechanisms have been shown and cases where temporarily loss of circadian timing may cause selective advantage.We suggest an explanation for why a circadian timing system has emerged in primitive life forms like cyanobacteria and we evaluate a possible molecular mechanism that enabled these bacteria to adapt to seasonal variation in day length. We further discuss how the role of the circadian system in photoperiodic time measurement may explain differential selection pressures on circadian period when species are exposed to changing climatic conditions (e.g. global warming) or when they expand their geographical range to different latitudes or altitudes. © 2011 The Royal Society.


Zou W.,University of Groningen | Visser C.,University of Groningen | Maduro J.A.,University of Groningen | Pshenichnikov M.S.,Zernike Institute for Advanced Materials | And 2 more authors.
Nature Photonics | Year: 2012

Photon upconversion of near-infrared photons is a promising way to overcome the Shockley-Queisser efficiency limit of 32% of a single-junction solar cell. However, the practical applicability of the most efficient known upconversion materials at moderate light intensities is limited by their extremely weak and narrowband near-infrared absorption. Here, we introduce the concept of an upconversion material where an organic near-infrared dye is used as an antenna for the β-NaYF 4:Yb,Er nanoparticles in which the upconversion occurs. The overall upconversion by the dye-sensitized nanoparticles is dramatically enhanced (by a factor of ̃3,300) as a result of increased absorptivity and overall broadening of the absorption spectrum of the upconverter. The proposed concept can be extended to cover any part of the solar spectrum by using a set of dye molecules with overlapping absorption spectra acting as an extremely broadband antenna system, connected to suitable upconverters. © 2012 Macmillan Publishers Limited. All rights reserved.


Nerbonne J.,University of Groningen
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

We examine situations in which linguistic changes have probably been propagated via normal contact as opposed to via conquest, recent settlement and large-scale migration. We proceed then from two simplifying assumptions: first, that all linguistic variation is the result of either diffusion or independent innovation, and, second, that we may operationalize social contact as geographical distance. It is clear that both of these assumptions are imperfect, but they allow us to examine diffusion via the distribution of linguistic variation as a function of geographical distance. Several studies in quantitative linguistics have examined this relation, starting with Séguy (Séguy 1971 Rev. Linguist. Romane 35, 335-357), and virtually all report a sublinear growth in aggregate linguistic variation as a function of geographical distance. The literature from dialectology and historical linguistics has mostly traced the diffusion of individual features, however, so that it is sensible to ask what sort of dynamic in the diffusion of individual features is compatible with Séguy's curve. We examine some simulations of diffusion in an effort to shed light on this question. © 2010 The Royal Society.


Bhujbal S.V.,CRP Sante | Bhujbal S.V.,University of Groningen | de Vos P.,University of Groningen | Niclou S.P.,CRP Sante
Advanced Drug Delivery Reviews | Year: 2014

Malignant brain tumors including glioblastoma are incurable cancers. Over the last years a number of promising novel treatment approaches have been investigated including the application of inhibitors of receptor tyrosine kinases and downstream targets, immune-based therapies and anti-angiogenic agents. Unfortunately so far the major clinical trials in glioblastoma patients did not deliver clear clinical benefits. Systemic brain tumor therapy is seriously hampered by poor drug delivery to the brain. Although in glioblastoma, the blood brain barrier is disrupted in the tumor core, the major part of the tumor is largely protected by an intact blood brain barrier. Active cytotoxic compounds encapsulated into liposomes, micelles, and nanoparticles constitute novel treatment options because they can be designed to facilitate entry into the brain parenchyma. In the case of biological therapeutics, encapsulation of therapeutic cells and their implantation into the surgical cavity represents another promising approach. This technology provides long term release of the active compound at the tumor site and reduces side effects associated with systemic delivery. The proof of principle of encapsulated cell factories has been successfully demonstrated in experimental animal models and should pave the way for clinical application. Here we review the challenges associated with the treatment of brain tumors and the different encapsulation options available for drugs and living cells, with an emphasis on alginate based cell encapsulation technology. © 2014 Elsevier B.V.


De Vos P.,University of Groningen | Lazarjani H.A.,University of Groningen | Poncelet D.,French National Center for Scientific Research | Faas M.M.,University of Groningen
Advanced Drug Delivery Reviews | Year: 2014

In the past two decades, many polymers have been proposed for producing immunoprotective capsules. Examples include the natural polymers alginate, agarose, chitosan, cellulose, collagen, and xanthan and synthetic polymers poly(ethylene glycol), polyvinyl alcohol, polyurethane, poly(ether-sulfone), polypropylene, sodium polystyrene sulfate, and polyacrylate poly(acrylonitrile-sodium methallylsulfonate). The biocompatibility of these polymers is discussed in terms of tissue responses in both the host and matrix to accommodate the functional survival of the cells. Cells should grow and function in the polymer network as adequately as in their natural environment. This is critical when therapeutic cells from scarce cadaveric donors are considered, such as pancreatic islets. Additionally, the cell mass in capsules is discussed from the perspective of emerging new insights into the release of so-called danger-associated molecular pattern molecules by clumps of necrotic therapeutic cells. We conclude that despite two decades of intensive research, drawing conclusions about which polymer is most adequate for clinical application is still difficult. This is because of the lack of documentation on critical information, such as the composition of the polymer, the presence or absence of confounding factors that induce immune responses, toxicity to enveloped cells, and the permeability of the polymer network. Only alginate has been studied extensively and currently qualifies for application.This review also discusses critical issues that are not directly related to polymers and are not discussed in the other reviews in this issue, such as the functional performance of encapsulated cells in vivo. Physiological endocrine responses may indeed not be expected because of the many barriers that the metabolites encounter when traveling from the blood stream to the enveloped cells and back to circulation. However, despite these diffusion barriers, many studies have shown optimal regulation, allowing us to conclude that encapsulated grafts do not always follow nature's course but are still a possible solution for many endocrine disorders for which the minute-to-minute regulation of metabolites is mandatory. © 2013 Elsevier B.V.


Dekker F.J.,University of Groningen | Van Den Bosch T.,University of Groningen | Martin N.I.,University Utrecht
Drug Discovery Today | Year: 2014

Lysine acetylation is a reversible post-translational modification (PTM) of cellular proteins and represents an important regulatory switch in signal transduction. Lysine acetylation, in combination with other PTMs, directs the outcomes as well as the activation levels of important signal transduction pathways such as the nuclear factor (NF)-κB pathway. Small molecule modulators of the 'writers' (HATs) and 'erasers' (HDACs) can regulate the NF-κB pathway in a specific manner. This review focuses on the effects of frequently used HAT and HDAC inhibitors on the NF-κB signal transduction pathway and inflammatory responses, and their potential as novel therapeutics. © 2013 The Authors.


Gilsbach B.K.,University of Groningen | Kortholt A.,University of Groningen
Frontiers in Molecular Neuroscience | Year: 2014

Human leucine rich repeat kinase 2 (LRRK2) belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), and a kinase domain. Mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset Parkinson's disease (PD). Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function. Important progress in the structural understanding of LRRK2 has come from our work with related Roco proteins from lower organisms. Atomic structures of Roco proteins from prokaryotes revealed that Roco proteins belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization). As in LRRK2, PD-analogous mutations in Roco proteins from bacteria decrease the GTPase reaction. Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity. Furthermore, the structure of Dictyostelium Roco4 kinase in complex with the LRRK2 inhibitor H1152 showed that Roco4 and other Roco family proteins can be important for the optimization of the current, and identification of new, LRRK2 kinase inhibitors. In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2. © 2014 Gilsbach and Kortholt.


Engqvist L.,University of Groningen | Engqvist L.,University of Bonn
Behavioral Ecology | Year: 2011

In species with high male mating effort, there is a trade-off between mating effort spent in a current mating and resources left for future matings. Males are therefore expected to allocate resources prudently across successive matings. Attractive males that will have a high mating success might therefore be forced to decrease mating investment in comparison with less-attractive males. Furthermore, if there is genetic variation in attractiveness, one might expect to find a negative genetic correlation between attractiveness and mating investment. Here, this genetic prediction is tested using the scorpionfly Panorpa cognata (Insecta: Mecoptera). In this species, males offer costly salivary secretions as nuptial gifts to females. By producing large secretions, males increase copulation duration and sperm transfer, thus gaining an advantage in sperm competition. I used a full-sib breeding design and found that both attractiveness and mating investment showed considerable heritability. Most importantly, there was a significant negative genetic correlation between attractiveness and mating investment: In families with attractive individuals, males produced smaller salivary secretions than in those with less-attractive males. The results thus demonstrate an important evolutionary trade-off between mating success and sperm competition success. © 2011 The Author.


Werner K.,University of Nantes | De Vries K.D.,University of Groningen | Scholten O.,University of Groningen
Astroparticle Physics | Year: 2012

We present a macroscopic calculation of coherent electro-magnetic radiation from air showers initiated by ultra-high energy cosmic rays, based on currents obtained from three-dimensional Monte Carlo simulations of air showers in a realistic geo-magnetic field. We discuss the importance of a correct treatment of the index of refraction in air, given by the law of Gladstone and Dale, which affects the pulses enormously for certain configurations, compared to a simplified treatment using a constant index. We predict in particular a geomagnetic Cherenkov radiation, which provides strong signals at high frequencies (GHz), for certain geometries together with "normal radiation" from the shower maximum, leading to a double peak structure in the frequency spectrum. We also provide some information about the numerical procedures referred to as EVA 1.0. © 2012 Elsevier B.V. All rights reserved.


Simons M.J.P.,University of Groningen | Verhulst S.,University of Groningen
Behavioral Ecology | Year: 2011

Male zebra finches display multiple secondary sexual traits such as song and red bill coloration. This color is dependent on carotenoids, which enhance immune function and are antioxidants. A red bill may thus function as an indicator signal. The zebra finch is extensively used in the study of carotenoid-dependent signaling. However, studies of female mate preferences for redder bills show mixed results. Here, we report a meta-analysis of mate-choice studies that reveals that female zebra finches do prefer males with redder bills (r = 0.61), except when there was reduced opportunity for imprinting or when bill color was experimentally manipulated, which both reduced preference for red bills to approximately zero. The latter may either be due to aspects of the experimental design or due to bill color being correlated with another trait such as song rate as was previously suggested. We show, however, in a separate meta-analysis on a different set of studies that the correlation between bill coloration and song rate (r = 0.14) was significantly lower than the r = 0.61 between bill color and attractiveness. We conclude, therefore, that the role of bill coloration in mate choice cannot be solely due to an association with song rate. Thus, we conclude that females do prefer males with redder bills when there was sufficient opportunity for sexual imprinting, but to what extent this is causally related to the bill color remains to be established. © 2011 The Author.


Pasmooij A.M.,University of Groningen
Discovery medicine | Year: 2012

Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the revertant mutations occur? 4) How do you recognize revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The revertant skin could potentially be used to treat the patient's own affected skin.


Hettema E.H.,University of Sheffield | Erdmann R.,Ruhr University Bochum | van der Klei I.,University of Groningen | Veenhuis M.,University of Groningen
Current Opinion in Cell Biology | Year: 2014

Significant progress has been made towards our understanding of the mechanism of peroxisome formation, in particular concerning sorting of peroxisomal membrane proteins, matrix protein import and organelle multiplication. Here we evaluate the progress made in recent years. We focus mainly on progress made in yeasts. We indicate the gaps in our knowledge and discuss conflicting models. © 2014.


Caputi K.I.,University of Groningen
International Journal of Modern Physics D | Year: 2014

The remarkable progress made in infrared (IR) astronomical instruments over the last 10-15 years has radically changed our vision of the extragalactic IR sky, and overall understanding of galaxy evolution. In particular, this has been the case for the study of active galactic nuclei (AGN), for which IR observations provide a wealth of complementary information that cannot be derived from data in other wavelength regimes. In this review, I summarize the unique contribution that IR astronomy has recently made to our understanding of AGN and their role in galaxy evolution, including both physical studies of AGN at IR wavelengths, and the search for AGN among IR galaxies in general. Finally, I identify and discuss key open issues that should be possible to address with forthcoming IR telescopes. © 2014 World Scientific Publishing Company.


Aleman A.,University of Groningen
Clinical Psychopharmacology and Neuroscience | Year: 2013

The potential of noninvasive neurostimulation by repetitive transcranial magnetic stimulation (rTMS) for improving psychiatric disorders has been studied increasingly over the past two decades. This is especially the case for major depression and for auditory-verbal hallucinations in schizophrenia. The present review briefly describes the background of this novel treatment modality and summarizes evidence from clinical trials into the efficacy of rTMS for depression and hallucinations. Evidence for efficacy in depression is stronger than for hallucinations, although a number of studies have reported clinically relevant improvements for hallucinations too. Different stimulation parameters (frequency, duration, location of stimulation) are discussed. There is a paucity of research into other psychiatric disorders, but initial evidence suggests that rTMS may also hold promise for the treatment of negative symptoms in schizophrenia, obsessive compulsive disorder and post-traumatic stress disorder. It can be concluded that rTMS induces alterations in neural networks relevant for psychiatric disorders and that more research is needed to elucidate efficacy and underlying mechanisms of action. Copyright © 2013, Korean College of Neuropsychopharmacology.


Krabbendam L.,VU University Amsterdam | Hooker C.I.,Harvard University | Aleman A.,University of Groningen
Schizophrenia Bulletin | Year: 2014

Epidemiological studies have suggested that the association between city upbringing and minority status with risk for schizophrenia can be explained by social mechanisms. Neuroimaging approaches hold promise for investigating this claim. Recent studies have shown that in healthy individuals, city upbringing and minority status are associated with increased activity in brain circuits involved in emotion regulation during social evaluative processing. These findings support the hypothesis that changes in the ability to regulate social stress contribute to the mechanism of risk. This is in accordance with a body of evidence demonstrating the sensitivity of the human brain to social stress, based on observational studies investigating the neurological sequelae of interpersonal trauma and experimental studies manipulating exposure to interpersonal distress. In this report, we summarize these initial findings, discuss methodological and conceptual challenges of pursuing this line of inquiry in schizophrenia, and suggest an outline for future research. © 2014 The Author. Published by Oxford University Press.


Koornstra J.J.,University of Groningen
Best Practice and Research: Clinical Gastroenterology | Year: 2012

Patients with familial adenomatous polyposis (FAP) and patients with Lynch syndrome have an increased risk of developing small intestinal neoplasia. In both conditions, the lifetime risk to develop small bowel cancer is estimated to be around 5%. In FAP, this risk is associated with the degree of duodenal polyposis, classically assessed by the Spigelman classification. For this reason, gastroduodenal surveillance with forward-viewing and side-viewing endoscopy is generally recommended. Studies using video capsule endoscopy and balloon-assisted enteroscopy in FAP patients have revealed that jejunal and ileal polyps occur frequently in FAP, especially in those with extensive duodenal polyposis. Nevertheless, the clinical relevance of small bowel polyps beyond the duodenum appears to be limited. Compared to FAP, little is known about the prevalence and natural history of small bowel neoplasia in Lynch syndrome. Surveillance of the small bowel is not recommended in Lynch syndrome, although recent data using capsule endoscopy provided promising results. © 2012 Elsevier Ltd. All rights reserved.


van Winkelhoff A.J.,University of Groningen
European journal of oral implantology | Year: 2012

To review and discuss current literature on the use of systemically administered or locally delivered antibiotics in the treatment of peri-implantitis. A literature search was conducted using MEDLINE through the PubMed database of the US National Library of Medicine using studies up to 2011. Studies on the microbiology of peri-implantitis lesions were hand selected. Two studies on the use of systemically administered antibiotics in the treatment of peri-implantitis were identified. Both studies involved a case series without controls. Five studies on locally delivered antibiotics were found. In all cases, local antibiotics were used in conjunction with mechanical debridement and chemical disinfection with antimicrobial agents such as chlorhexidine digluconate or hydrogen peroxide. The additional effects of local antibiotics were noted in all studies but were in general moderate. This may in part be due to the selection of patients with advanced deep pockets and advanced bone loss. The current available scientific information on the use of locally or systemically administered antibiotics is insufficient to allow any firm specific recommendations for the use of these drugs. Local application of minocycline or doxycycline as an adjunct to mechanical debridement and irrigation with an antimicrobial agent may be effective in moderately deep lesions. Surgical access by full-thickness flap surgery in deeper lesions is probably necessary to halt the progression of bone loss. No sound scientific basis is available for the use of systemic antibiotics. There is an urgent need for randomised clinical trials on the use of antibiotics in the treatment of peri-implantitis. Proper periodontal infection control in dentate patients before implants are installed and frequent supportive implant care represent effective measures to reduce the risk of future infections and their complications around oral implants.


Dijk C.,University of Amsterdam | de Jong P.J.,University of Groningen
Behaviour Research and Therapy | Year: 2012

It has been proposed that blushing-fearful individuals overestimate both the probability and the interpersonal costs of blushing. To study these judgmental biases, we presented a treatment-seeking sample of blushing-fearful individuals a series of vignettes describing social events and tested whether this clinical sample would overestimate the costs and probability of blushing compared to non-fearful controls. To test if blushing-fearfuls overestimate and/or low-fearful individuals underestimate the cost of displaying a blush, a second experiment examined the effects of blushing in these situations on observers' judgments. Experiment 1 showed that blushing-fearfuls indeed have judgmental biases for the probability and costs of blushing. Experiment 2 showed that the observers' judgments were very similar to the judgments anticipated by the low-fear group in Experiment 1. Thus the judgmental biases that were evident in the high-fearfuls can be best interpreted as an overestimation of the social costs of displaying a blush. These findings help improving our understanding of the mechanisms that may drive blushing phobia and also point to the clinical implication that it might be worthwhile to challenge blushing-fearfuls' judgmental biases. © 2011 Elsevier Ltd.


Bergshoeff E.A.,University of Groningen | Riccioni F.,University of Rome La Sapienza
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We show that the branes of ten-dimensional IIA/IIB string theory must satisfy, upon toroidal compactification, specific wrapping rules in order to reproduce the number of supersymmetric branes that follows from a supergravity analysis. The realization of these wrapping rules suggests that IIA/IIB string theory contains a whole class of generalized Kaluza-Klein monopoles. © 2011 Elsevier B.V.


Fingleton B.,University of Cambridge | Garretsen H.,University of Groningen | Martin R.,University of Cambridge
Journal of Regional Science | Year: 2012

We analyze the resilience of U.K. regions to employment shocks. Two basic notions of resilience are distinguished. With engineering resilience, there is an underlying stable growth path to which a regional economy rebounds following a shock. With ecological resilience, shocks can permanently affect the growth path of the regional economy. Our data set consists of quarterly employment series for 12 U.K. regions (NUTS I) for the period 1971-2010. Using a seemingly unrelated regression (SUR) model specification, we test for the relevance of (engineering) resilience of U.K. regional employment to the four recessionary shocks in our sample. It turns out that U.K. regions do indeed differ in their resilience, but that these differences mainly concern the initial resistance to these shocks and not so much the recovery stage. The SUR model does not allow shocks to have permanent effects and it also does not take the possibility of time differentiated shock spillovers between the 12 regions into account. To this end, we also estimate a vector error-correction model (VECM) specification where employment shocks can have permanent effects and where also interregional employment linkages are included. We find that employment shocks typically have permanent effects when it concerns the own-region effects. Permanent effects can also be found for the impact on other regions but the interregional effects are typically only significant for nearby regions. © 2012, Wiley Periodicals, Inc.


Bergshoeff E.A.,University of Groningen | Riccioni F.,University of Rome La Sapienza
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

We probe doubled geometry with dual fundamental branes, i.e. solitons. Restricting ourselves first to solitonic branes with more than two transverse directions we find that the doubled geometry requires an effective wrapping rule for the solitonic branes which is dual to the wrapping rule for fundamental branes. This dual wrapping rule can be understood by the presence of Kaluza-Klein monopoles. Extending our analysis to supersymmetric solitonic branes with less than or equal to two transverse directions we show that such solitons are precisely obtained by applying the same dual wrapping rule to these cases as well. This extended wrapping rule cannot be explained by the standard Kaluza-Klein monopole alone. Instead, it suggests the existence of a class of generalized Kaluza-Klein monopoles in ten-dimensional string theory. © 2011 Elsevier B.V.


Verhoeff B.,University of Groningen
Studies in History and Philosophy of Science Part C :Studies in History and Philosophy of Biological and Biomedical Sciences | Year: 2014

Using the conceptual tools of philosopher of science Ludwik Fleck, I argue that the reframing of autism as a neurodevelopmental spectrum disorder is constrained by two governing 'styles of thought' of contemporary psychiatry. The first is the historically conditioned 'readiness for directed perception' of, and thinking in terms of, ontologically distinct diseases. The clinical gaze of mental health professionals, the bureaucratic needs of health administration, the clinical and scientific utility of disease categories, and the practices of autism-oriented advocacy groups all imply a bias toward thinking about autism and related disorders as ontologically distinct psychiatric and scientific entities. Second, within the 'neuromolecular style of thought', mental disorders are more and more located at the neurobiological levels of the brain. In autism research, one of the biggest challenges is the identification of autism's neurobiological singularity. However, at a moment when biological and categorical approaches toward autism face serious empirical difficulties, a balance is established that holds together these two styles of thought. With a need to account for some of the most persistent uncertainties and conflicts in autism research, namely ubiquitous heterogeneity and a failure to identify disease specific biomarkers, the reframing of autism as a neurodevelopmental spectrum disorder satisfies the scientific, institutional and socio-political needs for stability and homogenization. © 2014 Elsevier Ltd.


Johannes F.,University of Groningen | Colome-Tatche M.,University of Groningen | Colome-Tatche M.,Leibniz University of Hanover
Genetics | Year: 2011

Interindividual differences in chromatin states at a locus (epialleles) can result in gene expression changes that are sometimes transmitted across generations. In this way, they can contribute to heritable phenotypic variation in natural and experimental populations independent of DNA sequence. Recent molecular evidence shows that epialleles often display high levels of transgenerational instability. This property gives rise to a dynamic dimension in phenotypic inheritance. To be able to incorporate these non-Mendelian features into quantitative genetic models, it is necessary to study the induction and the transgenerational behavior of epialleles in controlled settings. Here we outline a general experimental approach for achieving this using crosses of epigenomically perturbed isogenic lines in mammalian and plant species. We develop a theoretical description of such crosses and model the relationship between epiallelic instability, recombination, parent-of-origin effects, as well as transgressive segregation and their joint impact on phenotypic variation across generations. In the limiting case of fully stable epialleles our approach reduces to the classical theory of experimental line crosses and thus illustrates a fundamental continuity between genetic and epigenetic inheritance. We consider data from a panel of Arabidopsis epigenetic recombinant inbred lines and explore estimates of the number of quantitative trait loci for plant height that resulted from a manipulation of DNA methylation levels in one of the two isogenic founder strains. © 2011 by the Genetics Society of America.


The vascular endothelial growth factor (VEGF) family has been proposed to be the most important signaling protein family in vessel formation and maturation. VEGF receptor-2 (VEGFR-2) plays an abundant role in the most common forms of cancer. The localization of VEGFR-2 expression is important in cancer pathogenesis; however, so far, little attention has been paid to this phenomenon. Induced cytoplasmic VEGFR-2 transition from the nucleus is associated with poor prognostic cancer stages. Current VEGFR-2-targeted therapy approaches are effective in inhibiting or arresting tumor growth. Moreover, VEGFR-2-targeted therapy was demonstrated to restore the abnormal vasculature in tumors, enhancing their susceptibility toward conventional therapy. Most effects can be found when VEGFR-2-targeted therapy inhibits not only the induced angiogenesis but also the cancer cells that sometimes overexpress VEGFR-2. Nevertheless, we still have little knowledge about the mechanisms that regulate VEGFR-2 expression and how its localization is exactly involved in cancer prognosis. Further research and evaluation of VEGFR-2 regulation and its nuclear transition is necessary to develop more accurate therapeutic strategies to improve the patients' quality of life and their survival. © 2012 Lippincott Williams & Wilkins, Inc.


Hopcraft J.G.C.,University of Groningen | Olff H.,University of Groningen | Sinclair A.R.E.,University of British Columbia
Trends in Ecology and Evolution | Year: 2010

Herbivores are regulated by predation under certain environmental conditions, whereas under others they are limited by forage abundance and nutritional quality. Whether top-down or bottom-up regulation prevails depends both on abiotic constraints on forage availability and body size, because size simultaneously affects the risk of predation of herbivores and their nutritional demands. Consequently, ecosystems composed of similar species can have different dynamics if they differ in resource supply. Here, we use large herbivore assemblages in African savanna ecosystems to develop a framework that connects environmental gradients and disturbance patterns with body size and trophic structure. This framework provides a model for understanding the functioning and diversity of ecosystems in general, and unifies how top-down and bottom-up mechanisms depend on common underlying environmental gradients. © 2009 Elsevier Ltd. All rights reserved.


Kumar S.,University of Groningen | Kawalek A.,University of Groningen | van der Klei I.J.,University of Groningen
Current Opinion in Microbiology | Year: 2014

Peroxisomes are ubiquitous organelles that harbor diverse metabolic pathways, which are essential for normal cell performance. Conserved functions of these organelles are hydrogen peroxide metabolism and β-oxidation. Cells employ multiple quality control mechanisms to ensure proper peroxisome function and to protect peroxisomes from damage. These involve the function of molecular chaperones, a peroxisomal Lon protease and autophagic removal of dysfunctional organelles. In addition, multiple mechanisms exist to combat peroxisomal oxidative stress. Here, we outline recent advances in our understanding of peroxisomal quality control, focussing on yeast and filamentous fungi. © 2014 Elsevier Ltd.


Etienne R.S.,University of Groningen | Haegeman B.,French Institute for Research in Computer Science and Automation
American Naturalist | Year: 2012

In this article we propose a new framework for studying adaptive radiations in the context of diversity-dependent diversification. Diversity dependence causes diversification to decelerate at the end of an adaptive radiation but also plays a key role in the initial pulse of diversification. In particular, key innovations (which in our definition include novel traits as well as new environments) may cause decoupling of the diversity-dependent dynamics of the innovative clade from the diversity-dependent dynamics of its ancestral clade. We present a likelihood-based inference method to test for decoupling of diversity dependence using molecular phylogenies. The method, which can handle incomplete phylogenies, identifies when the decoupling took place and which diversification parameters are affected. We illustrate our approach by applying it to the molecular phylogeny of the North American clade of the legume tribe Psoraleeae (47 extant species, of which 4 are missing). Two diversification rate shifts were previously identified for this clade; our analysis shows that the first, positive shift can be associated with decoupling of two Pediomelum subgenera from the other Psoraleeae lineages, while we argue that the second, negative shift can be attributed to speciation being protracted. The latter explanation yields nonzero extinction rates, in contrast to previous findings. Our framework offers a new perspective on macroevolution: new environments and novel traits (ecological opportunity) and diversity dependence (ecological limits) cannot be considered separately. © 2012 by The University of Chicago.


Both C.,Netherlands Institute of Ecology | Both C.,University of Groningen
Current Biology | Year: 2010

During the past decades, phenology of many organisms has advanced in response to climate change [1]. Earlier arrival of long-distance migrants has been reported frequently [2, 3], but advancements of arrival and breeding were not always sufficient to match phenology at other trophic levels [4]. This has led to increased selection for early breeding [5] and severe population declines [6, 7]. This inadequate response has been explained by an inflexible start of migration, governed by cues unrelated to climate change, such as photoperiod [8]. It has been suggested that evolution at the genetic level is required for a change in photoresponsiveness [9]. Recently, such an evolutionary change in migration timing was suggested [10]. Here I show that timing of spring migration of pied flycatchers (Ficedula hypoleuca) has responded flexibly to climate change. Recovery dates during spring migration in Northern Africa advanced by ten days between 1980 and 2002, which was explained by improving Sahel rainfall and a phenotypic effect of birth date. The lack of advance on the breeding grounds most likely was due to environmental constraints during migration. Adjustment of arrival date in migrants to climate change could thus be rapid, but only if circumstances favorably change for the whole journey. © 2010 Elsevier Ltd. All rights reserved.


Hoendermis E.S.,University of Groningen
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology | Year: 2012

Experience with transcatheter valve-in-valve implantation in a failing bioprosthetic tricuspid valve is very limited. Fewer than 30 cases have been reported, and in most of them the Melody valve (Medtronic, Inc., Minneapolis, MN, USA) was used. With this case report and review of literature we sought to evaluate the safety and feasibility of the Edwards SAPIEN transcatheter valve (Edwards Lifesciences, Irvine, CA, USA) in valve implantation in the tricuspid position and to compare this intervention with the more established Melody valve implantation. We describe one of the rarely reported Edwards SAPIEN valve implantations in a bioprosthetic tricuspid valve which is also the first in a patient with Ebstein's anomaly. A review is presented of all eight case reports on Edwards SAPIEN valve implantations in tricuspid position. The procedure was successful in all cases. Valve performance after implantation was good and no complications were described. In only one procedure pre-stenting was performed. Transatrial, transjugular and transfemoral approaches have been used. The results are comparable to those of the series about Melody valve-in-valve implantation in the tricuspid valve. Mid-term follow-up data are not yet available for both valves. Edwards SAPIEN valve implantation in tricuspid bioprosthetic valves is feasible and safe. Considering the available sizes of the Edwards SAPIEN valve, it may become the preferred prosthesis for valve-in-valve implantation in the tricuspid position in the future.


Borg C.,University of Groningen | de Jong P.J.,University of Groningen
PLoS ONE | Year: 2012

Background: Sex and disgust are basic, evolutionary relevant functions that are often construed as paradoxical. In general the stimuli involved in sexual encounters are, at least out of context strongly perceived to hold high disgust qualities. Saliva, sweat, semen and body odours are among the strongest disgust elicitors. This results in the intriguing question of how people succeed in having pleasurable sex at all. One possible explanation could be that sexual engagement temporarily reduces the disgust eliciting properties of particular stimuli or that sexual engagement might weaken the hesitation to actually approach these stimuli. Methodology: Participants were healthy women (n = 90) randomly allocated to one of three groups: the sexual arousal, the non-sexual positive arousal, or the neutral control group. Film clips were used to elicit the relevant mood state. Participants engaged in 16 behavioural tasks, involving sex related (e.g., lubricate the vibrator) and non-sex related (e.g., take a sip of juice with a large insect in the cup) stimuli, to measure the impact of sexual arousal on feelings of disgust and actual avoidance behaviour. Principal Findings: The sexual arousal group rated the sex related stimuli as less disgusting compared to the other groups. A similar tendency was evident for the non-sex disgusting stimuli. For both the sex and non-sex related behavioural tasks the sexual arousal group showed less avoidance behaviour (i.e., they conducted the highest percentage of tasks compared to the other groups). Significance: This study has investigated how sexual arousal interplays with disgust and disgust eliciting properties in women, and has demonstrated that this relationship goes beyond subjective report by affecting the actual approach to disgusting stimuli. Hence, this could explain how we still manage to engage in pleasurable sexual activity. Moreover, these findings suggest that low sexual arousal might be a key feature in the maintenance of particular sexual dysfunctions. © 2012 Borg, de Jong.


Buitenhuis J.,University of Groningen | De Jong P.J.,University of Groningen
Spine | Year: 2011

Study Design. A descriptive overview of the relevant literature and the introduction of a new psychological model.Objective. The fear-avoidance (FA) model and the potential importance of illness beliefs in post-traumatic neck pain are discussed. The causal beliefs-anxiety model is introduced as an adaptation of the FA model, emphasizing the critical role of illness beliefs.Summary of Background Data. Although the FA model is most thoroughly used to investigate chronic low back pain, it seems also highly relevant as a starting point for other chronic pain conditions like whiplash. Kinesophobia and pain catastrophizing form critical components of the FA model. It has been shown that breaking the FA cycle by affecting the critical components of the model may be an effective method to prevent the development of chronicity.Methods. By using the FA model as a starting point, we present the causal beliefs-anxiety model and argue how this might help explain chronic whiplash symptoms and might provide clues for preventive interventions.Results. On experiencing muscular neck pain, catastrophizing may give rise to dysfunctional illness beliefs regarding the cause of this pain. The illness identity and other beliefs feed symptom expectation and attribution, as well as expectations regarding the course of muscular neck pain. These negative expectations can contribute to a less favorable outcome or may even cause symptoms. Therefore, it seems important to integrate the alleged role of illness beliefs in an adapted FA model, the "causal beliefs-anxiety model.".Conclusion. In clinical practice, it seems important to have insight into the patient's illness beliefs about the cause of the experienced symptoms. Health care professionals should be aware of the possible detrimental influence of dysfunctional illness beliefs. In the early stage, adequate explanation and information about the probable course may be sufficient to prevent the generation of dysfunctional illness beliefs thereby preventing the development of a chronic course. At the population level, educational campaigns that inform people about probable causes and realistic expectations regarding post-traumatic neck pain could provide an effective strategy for preventing chronic whiplash symptoms. © 2011, Lippincott Williams & Wilkins.


Van De Vliert E.,University of Groningen | Van De Vliert E.,University of Bergen
Behavioral and Brain Sciences | Year: 2013

This paper examines why fundamental freedoms are so unevenly distributed across the earth. Climato-economic theorizing proposes that humans adapt needs, stresses, and choices of goals, means, and outcomes to the livability of their habitat. The evolutionary process at work is one of collectively meeting climatic demands of cold winters or hot summers by using monetary resources. Freedom is expected to be lowest in poor populations threatened by demanding thermal climates, intermediate in populations comforted by undemanding temperate climates irrespective of income per head, and highest in rich populations challenged by demanding thermal climates. This core hypothesis is supported with new survey data across 85 countries and 15 Chinese provinces and with a reinterpretative review of results of prior studies comprising 174 countries and the 50 states in the United States. Empirical support covers freedom from want, freedom from fear, freedom of expression and participation, freedom from discrimination, and freedom to develop and realize one's human potential. Applying the theory to projections of temperature and income for 104 countries by 2112 forecasts that (a) poor populations in Asia, perhaps except Afghans and Pakistanis, will move up the international ladder of freedom, (b) poor populations in Africa will lose, rather than gain, relative levels of freedom unless climate protection and poverty reduction prevent this from happening, and (c) several rich populations will be challenged to defend current levels of freedom against worsening climato-economic livability. Copyright © 2013 Cambridge University Press.


Barta K.,University of Groningen | Ford P.C.,University of California at Santa Barbara
Accounts of Chemical Research | Year: 2014

ConspectusThis Account outlines recent efforts in our laboratories addressing a fundamental challenge of sustainability chemistry, the effective utilization of biomass for production of chemicals and fuels. Efficient methods for converting renewable biomass solids to chemicals and liquid fuels would reduce society's dependence on nonrenewable petroleum resources while easing the atmospheric carbon dioxide burden. The major nonfood component of biomass is lignocellulose, a matrix of the biopolymers cellulose, hemicellulose, and lignin. New approaches are needed to effect facile conversion of lignocellulose solids to liquid fuels and to other chemical precursors without the formation of intractable side products and with sufficient specificity to give economically sustainable product streams.We have devised a novel catalytic system whereby the renewable feedstocks cellulose, organosolv lignin, and even lignocellulose composites such as sawdust are transformed into organic liquids. The reaction medium is supercritical methanol (sc-MeOH), while the catalyst is a copper-doped porous metal oxide (PMO) prepared from inexpensive, Earth-abundant starting materials. This transformation occurs in a single stage reactor operating at 300-320°C and 160-220 bar. The reducing equivalents for these transformations are derived by the reforming of MeOH (to H2 and CO), which thereby serves as a "liquid syngas" in the present case. Water generated by deoxygenation processes is quickly removed by the water-gas shift reaction. The Cu-doped PMO serves multiple purposes, catalyzing substrate hydrogenolysis and hydrogenation as well as the methanol reforming and shift reactions. This one-pot "UCSB process" is quantitative, giving little or no biochar residual.Provided is an overview of these catalysis studies beginning with reactions of the model compound dihydrobenzofuran that help define the key processes occurring. The initial step is phenyl-ether bond hydrogenolysis, and this is followed by aromatic ring hydrogenation. The complete catalytic disassembly of the more complex organosolv lignin to monomeric units, largely propyl-cyclohexanol derivatives is then described. Operational indices based on 1H NMR analysis are also presented that facilitate holistic evaluation of these product streams that within several hours consist largely of propyl-cyclohexanol derivatives. Lastly, we describe the application of this methodology with several types of wood (pine sawdust, etc.) and with cellulose fibers. The product distribution, albeit still complex, displays unprecedented selectivity toward the production of aliphatic alcohols and methylated derivatives thereof. These observations clearly indicate that the Cu-doped solid metal oxide catalyst combined with sc-MeOH is capable of breaking down the complex biomass derived substrates to markedly deoxygenated monomeric units with increased hydrogen content. Possible implementations of this promising system on a larger scale are discussed. © 2014 American Chemical Society.


Oxidative stress has been suggested to play a key role in the development of cardiovascular disease (CVD). The aim of our study was to investigate the associations of serum peroxiredoxin 4 (Prx4), a hydrogen peroxide-degrading peroxidase, with incident CVD and all-cause mortality. We subsequently examined the incremental value of Prx4 for the risk prediction of CVD compared with the Framingham risk score (FRS). We performed Cox regression analyses in 8141 participants without history of CVD (aged 28 to 75 years; women 52.6%) from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study in Groningen, The Netherlands. Serum Prx4 was measured by an immunoluminometric assay in baseline samples. Main outcomes were: (1) incident CVD events or CVD mortality and (2) all-cause mortality during a median follow-up of 10.5 years. In total, 708 participants (7.8%) developed CVD events or CVD mortality, and 517 participants (6.3%) died. Baseline serum Prx4 levels were significantly higher in participants with incident CVD events or CVD mortality and in those who died than in participants who remained free of outcomes (both P<0.001). In multivariable models with adjustment for Framingham risk factors, hazard ratios were 1.16 (95% CI 1.06 to 1.27, P<0.001) for incident CVD events or CVD mortality and 1.17 (95% CI 1.06 to 1.29, P=0.003) for all-cause mortality per doubling of Prx4 levels. After the addition of Prx4 to the FRS, the net reclassification improvement was 2.7% (P=0.01) using 10-year risk categories of CVD. Elevated serum Prx4 levels are associated with a significantly higher risk of incident CVD events or CVD mortality and all-cause mortality after adjustment for clinical risk factors. The addition of Prx4 to the FRS marginally improved risk prediction of future CVD.


Buiter H.D.,University of Groningen
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

Fetal echogenic bowel (FEB) is a soft marker found on second trimester sonography. Our main aim was to determine the outcome of infants who presented with FEB and secondarily to identify additional sonographic findings that might have clinical relevance for the prognosis. We reviewed all pregnancies in which the diagnosis FEB was made in our Fetal Medicine Unit during 2009-2010 (N=121). We divided all cases into five groups according to additional sonographic findings. Group 1 consisted of cases of isolated FEB, group 2 of FEB associated with dilated bowels, group 3 of FEB with one or two other soft markers, group 4 of FEB with major congenital anomalies or three or more other soft markers, and group 5 consisted of FEB with isolated intrauterine growth restriction (IUGR). Of 121 cases, five were lost to follow-up. Of the remaining 116 cases, 48 (41.4%) were assigned to group 1, 15 (12.9%) to group 2, 15 (12.9%) to group 3, 27 (23.2%) to group 4, and 11 (9.5%) to group 5. The outcome for group 1 was uneventful. In group 2 and 3, two anomalies, anorectal malformation and cystic fibrosis, were detected postnatally (6.7%). In group 4, mortality and morbidity were high (78% resp. 22%). Group 5 also had high mortality (82%) and major morbidity (18%). If FEB occurs in isolation, it is a benign condition carrying a favourable prognosis. If multiple additional anomalies or early IUGR are observed, the prognosis tends to be less favourable to extremely poor.


Bertrand B.,University of Groningen | Bertrand B.,CNRS Molecular Chemistry Institute of Burgundy University | Casini A.,University of Groningen
Dalton Transactions | Year: 2014

From wedding rings on fingers to stained glass windows, by way of Olympic medals, gold has been highly prized for millennia. Nowadays, organometallic gold compounds occupy an important place in the field of medicinal inorganic chemistry due to their unique chemical properties with respect to gold coordination compounds. In fact, several studies have proved that they can be used to develop highly efficient metal-based drugs with possible applications in the treatment of cancer. This Perspective summarizes the results obtained for different families of bioactive organometallic gold compounds including cyclometallated gold(iii) complexes with C,N-donor ligands, gold(i) and gold(i/iii) N-heterocyclic (NHC) carbene complexes, as well as gold(i) alkynyl complexes, with promising anticancer effects. Most importantly, we will focus on recent developments in the field and discuss the potential of this class of organometallic compounds in relation to their versatile chemistry and innovative mechanisms of action. © 2014 The Royal Society of Chemistry.


Boonekamp J.J.,University of Groningen | Simons M.J.P.,University of Groningen | Hemerik L.,Wageningen University | Verhulst S.,University of Groningen
Aging Cell | Year: 2013

Biomarkers of aging are essential to predict mortality and agingrelated diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging because their associations with mortality generally diminish with age. How this pattern arises is, however, not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging, we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging-related diseases. © 2013 The Authors. © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.


Rupak G.,Mississippi State University | Higa R.,University of Groningen
Physical Review Letters | Year: 2011

The radiative neutron capture on lithium-7 is calculated model independently using a low-energy halo effective field theory. The cross section is expressed in terms of scattering parameters directly related to the S-matrix elements. It depends on the poorly known p-wave effective range parameter r 1. This constitutes the largest uncertainty in traditional model calculations. It is explicitly demonstrated by comparing with potential model calculations. A single parameter fit describes the low-energy data extremely well and yields r1≈1.47fm-1. © 2011 American Physical Society.


Brouwer H.,University of Groningen | Fitz H.,Max Planck Institute for Psycholinguistics | Hoeks J.,University of Groningen
Brain Research | Year: 2012

In traditional theories of language comprehension, syntactic and semantic processing are inextricably linked. This assumption has been challenged by the 'Semantic Illusion Effect' found in studies using Event Related brain Potentials. Semantically anomalous sentences did not produce the expected increase in N400 amplitude but rather one in P600 amplitude. To explain these findings, complex models have been devised in which an independent semantic processing stream can arrive at a sentence interpretation that may differ from the interpretation prescribed by the syntactic structure of the sentence. We review five such multi-stream models and argue that they do not account for the full range of relevant results because they assume that the amplitude of the N400 indexes some form of semantic integration. Based on recent evidence we argue that N400 amplitude might reflect the retrieval of lexical information from memory. On this view, the absence of an N400-effect in Semantic Illusion sentences can be explained in terms of priming. Furthermore, we suggest that semantic integration, which has previously been linked to the N400 component, might be reflected in the P600 instead. When combined, these functional interpretations result in a single-stream account of language processing that can explain all of the Semantic Illusion data. © 2012 Elsevier B.V.


Hunt R.A.R.,University of Cambridge | Otto S.,University of Groningen
Chemical Communications | Year: 2011

Combinatorial chemistry is a tool for selecting molecules with special properties. Dynamic combinatorial chemistry started off aiming to be just that. However, unlike ordinary combinatorial chemistry, the interconnectedness of dynamic libraries gives them an extra dimension. An understanding of these molecular networks at systems level is essential for their use as a selection tool and creates exciting new opportunities in systems chemistry. In this feature article we discuss selected examples and considerations related to the advanced exploitation of dynamic combinatorial libraries for their originally conceived purpose of identifying strong binding interactions. Also reviewed are examples illustrating a trend towards increasing complexity in terms of network behaviour and reversible chemistry. Finally, new applications of dynamic combinatorial chemistry in self-assembly, transport and self-replication are discussed.


A recent study in the lepidopteran Ostrinia scapulalis shows that endosymbionts can actively manipulate the sex determination mechanism of their host. Wolbachia bacteria alter the sex-specific splicing of the doublesex master switch gene. In ZZ males of this female heterogametic system, the female isoform of doublesex is produced in the presence of the bacteria. The effect is a lethal feminization of genotypic males. Curing of ZW females leads to males that die, indicating that the bacteria have an obligate role in proper sex determination and development of their host. Microbial intervention with host sex determination may be a driving force behind the evolutionary turnover of sex determination mechanisms. © 2012 WILEY Periodicals, Inc.


Schreiter S.,University of Groningen | Pijnenborg G.H.M.,University of Groningen | Aan Het Rot M.,University of Groningen
Journal of Affective Disorders | Year: 2013

Background Depression is associated with problems in social functioning. Impaired empathic abilities might underlie this association. Empathy is a multidimensional construct and involves both affective and cognitive processes. We reviewed the literature to find out to what extent depression may be associated with abnormal levels of affective and cognitive empathy. We also explored potential gender differences in these associations. Methods We used PsycInfo and Medline to conduct a systematic review of all studies on empathy and depression conducted in individuals with a primary diagnosis of major depressive disorder (MDD; patient samples) or in individuals with primarily subclinical depressive symptoms (analog samples). Results Thirty-seven studies met the inclusion criteria. The results indicated that depression was related to one type of affective empathy. Specifically, depression was related to high levels of empathic stress but not to abnormal empathic concern. Further, depression was related to limited cognitive empathy, as indicated by poor perspective taking, theory of mind, and empathic accuracy. Limitations Few studies have considered the variable gender in their design and analyses. Between and within study variation in demographic and clinical variables limits the interpretation of results. Self-report measures of empathy are subjective and vulnerable to bias. Poor performance on the more objective laboratory tasks might partially be explained by the broader cognitive deficits commonly observed in depression. Lastly, because all studies used a cross-sectional design, causality is difficult to establish. Conclusions Empathic abilities may be impaired in depression. The relation between empathy, depression, and gender is unclear. Future studies could use implicit and more ecologically valid measures of empathy. Insight into impaired empathy in depression may not only help explain poor social functioning in MDD but also benefit clinician-patient interactions. © 2013 Elsevier B.V.


Koppelman G.H.,University of Groningen | Sayers I.,University of Nottingham
Journal of Allergy and Clinical Immunology | Year: 2011

There has been great progress in identifying new asthma susceptibility genes. In asthmatic subjects there is variable airway remodeling that includes features such as smooth muscle hypertrophy/hyperplasia, basement membrane thickening, and increased extracellular matrix deposition. Does airway remodeling have a genetic contribution in asthma? Data from different murine strains suggest there is a genetic contribution to the development and progression of airway remodeling. In human subjects it is important to consider what surrogate markers of remodeling have been used in genetic studies. Baseline FEV1 and airway hyperresponsiveness are determined by a complex interplay of factors, including nonremodeling mechanisms; however, we consider a decline in FEV1 as a robust marker of remodeling. To date, single nucleotide polymorphisms spanning ADAM33, ESR1, PLAUR, and VEGF have been associated with an excess decline in lung function in asthmatic subjects carrying the rare alleles (FEV1, -13.0 to 55.2 mL/y excess). Interestingly these genes have overlapping functions in proteolytic pathways in the airways. There is accumulating evidence that genetic factors are important in the development of airway remodeling in asthmatic subjects, and further longitudinal studies with additional remodeling phenotypes and genome-wide association studies will identify novel susceptibility genes, leading to new approaches to target remodeling in asthmatic subjects. © 2011 American Academy of Allergy, Asthma & Immunology.


Schuurhuis J.M.,University of Groningen
British Journal of Cancer | Year: 2016

Background:Leukaemic patients receiving intensive chemotherapy and patients undergoing autologous stem-cell transplantation (ASCT) are routinely screened for oral foci of infection to reduce infectious complications that could occur during therapy. In this prospective study we assessed the effect of leaving chronic oral foci of infection untreated on the development of infectious complications in intensively treated haematological patients.Methods:We included and prospectively evaluated all intensively treated leukaemic patients and patients undergoing ASCT who were referred to our medical centre between September 2012 and May 2014, and who matched the inclusion/exclusion criteria. Acute oral foci of infection were removed before chemotherapy or ASCT, whereas chronic oral foci were left untreated.Results:In total 28 leukaemic and 35 ASCT patients were included. Acute oral foci of infection were found in 2 leukaemic (7%) and 2 ASCT patients (6%), and chronic oral foci of infection in 24 leukaemic (86%) and 22 ASCT patients (63%). Positive blood cultures with microorganisms potentially originating from the oral cavity occurred in 7 patients during treatment, but were uneventful on development of infectious complications.Conclusions:Our prospective study supports the hypothesis that chronic oral foci of infection can be left untreated as this does not increase infectious complications during intensive chemotherapy.British Journal of Cancer advance online publication, 22 March 2016; doi:10.1038/bjc.2016.60 www.bjcancer.com. © 2016 Cancer Research UK


Mulder M.,University of Groningen
Energy Journal | Year: 2015

We assess the development of competition in the Dutch electricity wholesale market over 2006-2011. In this period domestic generation capacity, both centralized and decentralized, as well as the cross-border transmission capacity increased. Using hourly plant-level data of centralized units and engineering-costs estimates, we estimate the weighted average Lerner index. During super peak hours, the annual average value of this index decreased from 0.23 in 2006 to 0.03 in 2011, indicating more competition. We find indications that the increase in competition can be attributed to the extension of cross-border connections, a higher price elasticity of net demand and more Bertrand-like competition. Enhancing the role of decentralized generation as well as fostering integration of markets seem to be effective measures to promote competition. Copyright © 2015 by the IAEE. All rights reserved.


Stevanovic J.,University of Groningen
European journal of preventive cardiology | Year: 2012

Long-term trials on the effectiveness of pharmacological treatment for primary cardiovascular disease prevention are scant. For that reason risk prediction models are used as a tool to project changes in cardiovascular disease incidence due to changes in risk factor levels observed in short-term randomized clinical trials. In this article, we summarize the literature on the application of these risk models in pharmacoeconomic studies for primary cardiovascular disease prevention interventions in high-income countries. We systematically reviewed the available literature on the application of cardiovascular disease risk models in pharmacoeconomic studies and assessed the quality of incorporation of risk models in these studies. Quality assessment indicated the distance between the characteristics of populations of the risk model and the studies reviewed, the frequent disagreement between risk model and study time horizons and the lack of proper consideration of the uncertainty surrounding risk predictions. Given that utilizing a risk model to project the effect of a pharmacological intervention to cardiovascular events provides an estimate of the intervention's clinical and economical impact, consideration should be paid to the agreement between the study and risk model populations as well as the level of uncertainty that these predictions add to the outcome of a decision-analytic model. In the absence of hard endpoint trials, the value of risk models to model pharmacological efficacy in primary cardiovascular disease prevention remains high, although their limitations should beacknowledged


Madduri A.V.R.,University of Groningen | Harutyunyan S.R.,University of Groningen | Minnaard A.J.,University of Groningen
Angewandte Chemie - International Edition | Year: 2012

Chiral tertiary alcohols: A copper(I) catalyst with a chiral ferrocenyl diphosphine ligand facilitates the additive-free 1,2-addition of readily available Grignard reagents to aromatic ketones, thus providing access to chiral tertiary alcohols with excellent yields and enantioselectivities. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Hemelrijk C.K.,University of Groningen | Puga-Gonzalez I.,University of Groningen
PLoS ONE | Year: 2012

Complex social behaviour of primates has usually been attributed to the operation of complex cognition. Recently, models have shown that constraints imposed by the socio-spatial structuring of individuals in a group may result in an unexpectedly high number of patterns of complex social behaviour, resembling the dominance styles of egalitarian and despotic species of macaques and the differences between them. This includes affiliative patterns, such as reciprocation of grooming, grooming up the hierarchy, and reconciliation. In the present study, we show that the distribution of support in fights, which is the social behaviour that is potentially most sophisticated in terms of cognitive processes, may emerge in the same way. The model represents the spatial grouping of individuals and their social behaviour, such as their avoidance of risks during attacks, the self-reinforcing effects of winning and losing their fights, their tendency to join in fights of others that are close by (social facilitation), their tendency to groom when they are anxious, the reduction of their anxiety by grooming, and the increase of anxiety when involved in aggression. Further, we represent the difference in intensity of aggression apparent in egalitarian and despotic macaques. The model reproduces many aspects of support in fights, such as its different types, namely, conservative, bridging and revolutionary, patterns of choice of coalition partners attributed to triadic awareness, those of reciprocation of support and 'spiteful acts' and of exchange between support and grooming. This work is important because it suggests that behaviour that seems to result from sophisticated cognition may be a side-effect of spatial structure and dominance interactions and it shows that partial correlations fail to completely omit these effects of spatial structure. Further, the model is falsifiable, since it results in many patterns that can easily be tested in real primates by means of existing data. © 2012 Hemelrijk, Puga-Gonzalez.


Graham T.,University of Groningen
Journal of Information Technology and Politics | Year: 2012

Net-based public sphere researchers have examined online deliberation in numerous ways. However, most studies have focused exclusively on political discussion forums. This article moves beyond such spaces by analyzing political talk from an online forum dedicated to reality television. The purpose is to examine the democratic quality of political talk that emerges in this space in light of a set of normative criteria of the public sphere. The analysis also moved beyond an elite model of deliberation by investigating the use of expressives (humor, emotional comments, and acknowledgments). The findings reveal that participants engaged in political talk that was often deliberative. It was a space where the use of expressives played a significant role in enhancing such talk. © 2012 Copyright Taylor and Francis Group, LLC.


de Faria P.,University of Groningen | Sofka W.,University of Tilburg
Research Policy | Year: 2010

International knowledge spillovers, especially through multinational companies (MNCs), have recently been a major topic of discussion among academics and practitioners. Most research in this field focuses on knowledge sharing activities of MNC subsidiaries. Relatively little is known about their capabilities for protecting valuable knowledge from spilling over to host country competitors. We extend this stream of research by investigating both formal protection strategies (e.g. patenting) as well as strategic ones (secrecy, lead time, complex design). We conceptualize the breadth of firm's knowledge protection strategies and relate it to the particular situation of MNC subsidiaries. Moreover, we argue that their approaches differ with regard to host country challenges and opportunities. We address these issues empirically, based on a harmonized survey of innovation activities of more than 1800 firms located in Portugal and Germany. We find evidence that MNCs prefer broader sets of knowledge protection strategies in a host country with fewer opportunities for knowledge sourcing (Portugal). In Germany, though, they opt for narrower sets of knowledge protection strategies if they invest in innovation activities themselves. We deduce that these results are due to a need for reciprocity in knowledge exchanges to benefit fully from promising host country knowledge flows. © 2010 Elsevier B.V. All rights reserved.


Polyuga R.V.,University of Groningen | van der Schaft A.,University of Groningen
Automatica | Year: 2010

Model reduction of port-Hamiltonian systems by means of the Krylov methods is considered, aiming at port-Hamiltonian structure preservation. It is shown how to employ the Arnoldi method for model reduction in a particular coordinate system in order to preserve not only a specific number of the Markov parameters but also the port-Hamiltonian structure for the reduced order model. Furthermore it is shown how the Lanczos method can be applied in a structure preserving manner to a subclass of port-Hamiltonian systems which is characterized by an algebraic condition. In fact, for the same subclass of port-Hamiltonian systems the Arnoldi method and the Lanczos method turn out to be equivalent in the sense of producing reduced order port-Hamiltonian models with the same transfer function. © 2010 Elsevier Ltd. All rights reserved.


Lisman T.,University of Groningen | Porte R.J.,University of Groningen
Blood | Year: 2010

Patients with liver disease frequently acquire a complex disorder of hemostasis secondary to their disease. Routine laboratory tests such as the prothrombin time and the platelet count are frequently abnormal and point to a hypocoagulable state. With more sophisticated laboratory tests it has been shown that patients with liver disease may be in hemostatic balance as a result of concomitant changes in both pro- and antihemostatic pathways. Clinically, this rebalanced hemostatic system is reflected by the large proportion of patients with liver disease who can undergo major surgery without any requirement for blood product transfusion. However, the hemostatic balance in the patient with liver disease is relatively unstable as evidenced by the occurrence of both bleeding and thrombotic complications in a significant proportion of patients. Although it is still common practice to prophylactically correct hemostatic abnormalities in patients with liver disease before invasive procedures by administration of blood products guided by the prothrombin time and platelet count, we believe that this policy is not evidence-based. In this article, we will provide arguments against the traditional concept that patients with liver failure have a hemostasis-related bleeding tendency. Consequences of these new insights for hemostatic management will be discussed. © 2010 by The American Society of Hematology.


Riezebos J.,University of Groningen
International Journal of Production Research | Year: 2010

POLCA is a material control system designed for make-to-order or engineer-to-order companies. These firms have to cope with a high variety of customised products, and strong pressure to provide short throughput times. POLCA constrains the amount of work in progress on the shop floor in order to achieve a short average shop floor throughput time. Earlier work has shown that the POLCA system has the capability to reduce both the average shop floor throughput time and the average total throughput time, but it is only effective if the POLCA system has been appropriately designed. The design of the POLCA system is therefore being investigated and discussed in this paper. We give an extensive literature review and give attention to the authorisation mechanisms of POLCA, the design of control loops, the route-specific capacity signals (POLCA cards), and specific facilities needed to use the POLCA system in practice. Finally, we report on the design of a POLCA system in practice, the first complete implementation of POLCA in The Netherlands, and present the quick scan that was used in the design of the POLCA system for this SME.


Azadi H.,University of Groningen | Ho P.,University of Groningen
Biotechnology Advances | Year: 2010

Since two decades ago, when the first GM crops were introduced, there have increasingly been hot debates on the applications of gene manipulation. Currently, the development of GM crop varieties has raised a wide range of new legal, ethical and economic questions in agriculture. There is a growing body of literature reflecting the socio-economic and environmental impacts of GM crops which aims to criticize their value for farming systems. While organic crops are promoted as environmentally-friendly products in developed countries, they have provoked great controversy in developing countries facing food security and a low agricultural productivity. Discussion has been especially vigorous when organic farming was introduced as an alternative method. There are in fact, a few tradeoffs in developing countries. On the one hand, farmers are encouraged to accept and implement GM crops because of their higher productivity, while on the other hand, organic farming is encouraged because of socio-economic and environmental considerations. A crucial question facing such countries is therefore, whether GM crops can co-exist with organic farming. This paper aims to review the main considerations and tradeoffs. © 2009 Elsevier Inc. All rights reserved.


Gerkema M.P.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

In 1942, Walls described the concept of a 'nocturnal bottleneck' in placental mammals, where these species could survive only by avoiding daytime activity during times in which dinosaurs were the dominant taxon. Walls based this concept of a longer episode of nocturnality in early eutherian mammals by comparing the visual systems of reptiles, birds and all three extant taxa of the mammalian lineage, namely the monotremes, marsupials (now included in the metatherians) and placentals (included in the eutherians). This review describes the status of what has become known as the nocturnal bottleneck hypothesis, giving an overview of the chronobiological patterns of activity. We review the ecological plausibility that the activity patterns of (early) eutherian mammals were restricted to the night, based on arguments relating to endothermia, energy balance, foraging and predation, taking into account recent palaeontological information. We also assess genes, relating to light detection (visual and non-visual systems) and the photolyase DNA protection system that were lost in the eutherian mammalian lineage. Our conclusion presently is that arguments in favour of the nocturnal bottleneck hypothesis in eutherians prevail.


Hut R.A.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

Properties of the circadian and annual timing systems are expected to vary systematically with latitude on the basis of different annual light and temperature patterns at higher latitudes, creating specific selection pressures. We review literature with respect to latitudinal clines in circadian phenotypes as well as in polymorphisms of circadian clock genes and their possible association with annual timing. The use of latitudinal (and altitudinal) clines in identifying selective forces acting on biological rhythms is discussed, and we evaluate how these studies can reveal novel molecular and physiological components of these rhythms.


Der Zee D.-J.V.,University of Groningen
Decision Support Systems | Year: 2011

Petri Nets have essential strengths in capturing a system's static structure and dynamics, its mathematical underpinning, and providing a graphical representation. However, visual simulation models of realistic systems based on Petri Nets are often perceived as too large and too complex to be easily understood. This constrains stakeholders in participating in such modeling and solution finding, and limits acceptance. We address this issue by considering a structured approach for guiding the analyst in creating more insightful models. Key elements are a domain-related reference architecture that supports conceptual modeling coupled with uniform rules for mapping high-level concepts onto low-level Petri Net components. The proposed approach is implemented and illustrated in the manufacturing domain. © 2010 Elsevier B.V. All rights reserved.


Kocer A.,University of Groningen
Current Opinion in Chemical Biology | Year: 2015

Sensing and responding to mechanical stimuli is an ancient behavior and ubiquitous to all forms of life. One of its players 'mechanosensitive ion channels' are involved in processes from osmosensing in bacteria to pain in humans. However, the mechanism of mechanosensing is yet to be elucidated. This review describes recent developments in the understanding of a bacterial mechanosensitive channel. Force from the lipid principle of mechanosensation, new methods to understand protein-lipid interactions, the role of water in the gating, the use of engineered mechanosensitive channels in the understanding of the gating mechanism and application of the accumulated knowledge in the field of drug delivery, drug design and sensor technologies are discussed. © 2015 Elsevier Ltd.


Chaiyen P.,Mahidol University | Fraaije M.W.,University of Groningen | Mattevi A.,University of Pavia
Trends in Biochemical Sciences | Year: 2012

The reaction of flavoenzymes with oxygen remains a fascinating area of research because of its relevance for reactive oxygen species (ROS) generation. Several exciting recent studies provide consistent mechanistic clues about the specific functional and structural properties of the oxidase and monooxygenase flavoenzymatic systems. Specifically, the spatial arrangement of the reacting oxygen that is in direct contact with the flavin group is emerging as a crucial factor that differentiates between oxidase and monooxygenase enzymes. A challenge for the future will be to use these emerging concepts to rationally engineer flavoenzymes, paving the way to new research avenues with far-reaching implications for oxidative biocatalysis and metabolic engineering. © 2012 Elsevier Ltd.


Bos J.,University of Groningen | Fusetti F.,University of Groningen | Driessen A.J.M.,University of Groningen | Roelfes G.,University of Groningen
Angewandte Chemie - International Edition | Year: 2012

A game of two halves: Artificial metalloenzymes are generated by forming a novel active site on the dimer interface of the transcription factor LmrR. Two copper centers are incorporated by binding to ligands in each half of the dimer. With this system up to 97% ee was obtained in the benchmark Cu II catalyzed Diels-Alder reaction (see scheme). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Bos J.,University of Groningen | Garcia-Herraiz A.,University of Groningen | Roelfes G.,University of Groningen
Chemical Science | Year: 2013

Direct addition of water to alkenes to generate important chiral alcohols as key motif in a variety of natural products still remains a challenge in organic chemistry. Here, we report the first enantioselective artificial metallo-hydratase, based on the transcription factor LmrR, which catalyses the conjugate addition of water to generate chiral β-hydroxy ketones with enantioselectivities up to 84% ee. A mutagenesis study revealed that an aspartic acid and a phenylalanine located in the active site play a key role in achieving efficient catalysis and high enantioselectivities. © 2013 The Royal Society of Chemistry.


Xia W.,University of Groningen | Cao M.,University of Groningen
Automatica | Year: 2011

This paper shows how different mechanisms may lead to clustering behavior in connected networks consisting of diffusively coupled agents. In contrast to the widely studied synchronization processes, in which the states of all the coupled agents converge to the same value asymptotically, in the cluster synchronization problem studied in this paper, we require all the interconnected agents to evolve into several clusters and each agent only to synchronize within its cluster. The first mechanism is that agents have different self-dynamics, and those agents having the same self-dynamics may evolve into the same cluster. When the agents' self-dynamics are identical, we present two other mechanisms under which cluster synchronization might be achieved. One is the presence of delays and the other is the existence of both positive and negative couplings between the agents. Some sufficient and/or necessary conditions are constructed to guarantee n-cluster synchronization. Simulation results are presented to illustrate the effectiveness of the theoretical analysis. © 2011 Elsevier Ltd. All rights reserved.


Ongoing growth in health care expenditures and changing patterns in the demand for health care challenge societies worldwide. The Chronic Care Model (CCM), combined with classification for care needs based on Kaiser Permanente (KP) Triangle, may offer a suitable framework for change. The aim of the present study is to investigate the effectiveness of Embrace, a population-based model for integrated elderly care, regarding patient outcomes, service use, costs, and quality of care. The CCM and the KP Triangle were translated to the Dutch setting and adapted to the full elderly population living in the community. A randomized controlled trial with balanced allocation was designed to test the effectiveness of Embrace. Eligible elderly persons are 75 years and older and enrolled with one of the participating general practitioner practices. Based on scores on the INTERMED-Elderly Self-Assessment and Groningen Frailty Indicator, participants will be stratified into one of three strata: (A) robust; (B) frail; and (C) complex care needs. Next, participants will be randomized per stratum to Embrace or care as usual. Embrace encompasses an Elderly Care Team per general practitioner practice, an Electronic Elderly Record System, decision support instruments, and a self-management support and prevention program - combined with care and support intensity levels increasing from stratum A to stratum C. Primary outcome variables are patient outcomes, service use, costs, and quality of care. Data will be collected at baseline, twelve months after starting date, and during the intervention period. This study could provide evidence for the effectiveness of Embrace. The Netherlands National Trial Register NTR3039.


Papari G.,University of Groningen | Petkov N.,University of Groningen
Image and Vision Computing | Year: 2011

We present an overview of various edge and line oriented approaches to contour detection that have been proposed in the last two decades. By edge and line oriented we mean methods that do not rely on segmentation. Distinction is made between edges and contours. Contour detectors are divided in local and global operators. The former are mainly based on differential analysis, statistical approaches, phase congruency, rank order filters, and combinations thereof. The latter include computation of contour saliency, perceptual grouping, relaxation labeling and active contours. Important aspects are covered, such as preprocessing aimed to suppress texture and noise, multiresolution techniques, connections between computational models and properties of the human visual system, and use of shape priors. An overview of procedures and metrics for quantitative performance evaluation is also presented. Our main conclusion is that contour detection has reached high degree of sophistication, taking into account multimodal contour definition (by luminance, color or texture changes), mechanisms for reducing the contour masking influence of noise and texture, perceptual grouping, multiscale aspects and high-level vision information. © 2010 Elsevier B.V. All rights reserved.


Oelerich J.,University of Groningen | Roelfes G.,University of Groningen
Chemical Science | Year: 2013

Here, the first examples of DNA-based organometallic catalysis in water that give rise to high enantioselectivities are described. Copper complexes of strongly intercalating ligands were found to enable the asymmetric intramolecular cyclopropanation of α-diazo-β-keto sulfones in water. Up to 84% ee was achieved, in the presence of salmon testes DNA as the only source of chirality, using dipyrido[3,2-a:2′,3′-c]phenazine (dppz) derivatives as ligands. © 2013 The Royal Society of Chemistry.


Etienne R.S.,University of Groningen | Rosindell J.,University of Groningen | Rosindell J.,University of Leeds
Systematic Biology | Year: 2012

Phylogenetic trees show a remarkable slowdown in the increase of number of lineages towards the present, a phenomenon which cannot be explained by the standard birth-death model of diversification with constant speciation and extinction rates. The birth-death model instead predicts a constant or accelerating increase in the number of lineages, which has been called the pull of the present. The observed slowdown has been attributed to nonconstancy of the speciation and extinction rates due to some form of diversity dependence (i.e., species-level density dependence), but the mechanisms underlying this are still unclear. Here, we propose an alternative explanation based on the simple concept that speciation takes time to complete. We show that this idea of "protracted" speciation can be incorporated in the standard birth-death model of diversification. The protracted birth-death model predicts a realistic slowdown in the rate of increase of number of lineages in the phylogeny and provides a compelling fit to four bird phylogenies with realistic parameter values. Thus, the effect of recognizing the generally accepted fact that speciation is not an instantaneous event is significant; even if it cannot account for all the observed patterns, it certainly contributes substantially and should therefore be incorporated into future studies. © 2011 The Author(s).


de Joode A.A.E.,University of Groningen | Sanders J.S.F.,University of Groningen | Stegeman C.A.,University of Groningen
Clinical Journal of the American Society of Nephrology | Year: 2013

Background and objectives This study evaluated predictors for patient and renal survival in patients with ANCAassociated vasculitis (AAV) with and without renal involvement. Design, setting, participants, & measurements There were 273 consecutive AAV patients from January 1990 until December 2007 who were followed until death, loss to follow-up, or December 2010. Based on organ involvement, patients were divided into renal (n=212) and nonrenal groups (n=61). The primary end point was ESRD requiring renal replacement therapy (RRT) or renal transplantation or death. Results Patient survival was significantly better in the nonrenal group compared with the renal group (hazard ratio, 0.55; 95% confidence interval, 0.33 to 0.92; P=0.02). In the renal group, renal survival was significantly worse in MPO-ANCA-positive patients (n=65) compared with PR3-ANCA-positive patients (n=138) (hazard ratio, 2.1; 95% confidence interval, 1.11 to 3.8; P=0.01). Of 48 patients who needed RRT at diagnosis, 11 patients (23%) died within 6 months and 14 patients (29%) did not regain renal function. Of all 23 patients who regained renal function after RRT, 7 patients (30%) were temporarily dialysis independent and needed dialysis later (range, 13-63 months). Five patients had a renal relapse in the 6 months before restart of RRT. Of all 203 PR3-ANCA-positive and MPO-ANCA-positive patients with renal involvement, 12 patients (6%) developed ESRD during follow-up. These patients were classified as CKD stage 4 or 5 after initial treatment and eight patients had a renal relapse before becoming dialysis dependent. Conclusions AAV patients with renal involvement who needed RRT had the worst survival probability. In multivariate analysis, the only major determinants for long-term renal survival were renal function at 6 months and renal relapses. © 2013 by the American Society of Nephrology.


Vera-Ciro C.,University of Wisconsin - Madison | Vera-Ciro C.,University of Groningen | Helmi A.,University of Groningen
Astrophysical Journal Letters | Year: 2013

We propose a new model for the dark matter halo of the Milky Way that fits the properties of the stellar stream associated with the Sagittarius dwarf galaxy. Our dark halo is oblate with qz = 0.9 for r ≲ 10 kpc, and can be made to follow the Law & Majewski model at larger radii. However, we find that the dynamical perturbations induced by the Large Magellanic Cloud on the orbit of Sgr cannot be neglected when modeling its streams. When taken into account, this leads us to constrain the Galaxy's outer halo shape to have minor-to-major axis ratio >(c/a)Φ = 0.8 and intermediate-to-major axis ratio (b/a)Φ = 0.9, in good agreement with cosmological expectations. © 2013. The American Astronomical Society. All rights reserved.


Yesilkaya H.,University of Leicester | Andisi V.F.,University of Groningen | Andrew P.W.,University of Leicester | Bijlsma J.J.E.,University of Groningen
Trends in Microbiology | Year: 2013

Streptococcus pneumoniae, an aerotolerant anaerobe, is an important human pathogen that regularly encounters toxic oxygen radicals from the atmosphere and from the host metabolism and immune system. Additionally, S. pneumoniae produces large amounts of H2O2 as a byproduct of its metabolism, which contributes to its virulence but also has adverse effects on its biology. Understanding how S. pneumoniae defends against oxidative stress is far from complete, but it is apparent that it does not follow the current paradigm of having canonical enzymes to detoxify oxygen radicals or homologues of typical oxidative stress responsive global regulators. We will give an overview of how S. pneumoniae copes with oxygen radicals. Furthermore, we draw parallels with other pathogenic streptococcal species and provide future research perspectives. © 2013 Elsevier Ltd.


Nijboer T.C.W.,University Utrecht | Kollen B.J.,University of Groningen | Kwakkel G.,University Utrecht | Kwakkel G.,VU University Amsterdam
Cortex | Year: 2013

The aim of the current study was to investigate recovery of visuospatial neglect during the first year after stroke. Visuospatial neglect was measured using two frequently and widely used tests: the letter cancellation test (LCT) and the line bisection test (LBT). This was a prospective cohort study of 101 stroke patients. Of these 101 patients, 51 patients showed visuospatial neglect. All time-dependent measures were taken weekly, starting from within 14days after stroke onset. From week 10-20 biweekly measurements were obtained. Follow-up measurements were performed at weeks 26, 38, and finally 52. For the present study, number of misses in the LCT, split on contralesional versus ipsilesional side, as well as the deviation from the actual midpoint in mm in the LBT were used. The longitudinal relationship of (bi)weekly time on improvement in LBT and LCT were investigated using random coefficient analysis and joinpoint analyses. Results indicated that progress of time is an independent covariate that reflects neurological recovery of visuospatial neglect. Additionally, trend changes were obtained in between 12 and 14weeks post-stroke with respect to the neglected side. This is the first prospective cohort study in which the time course of neglect is investigated by using intensive serial measurements in the early months post-stroke. © 2012.


Brenninkmeijer J.,University of Groningen
BioSocieties | Year: 2013

Many psychologists and other practitioners have started to use neurofeedback, a biofeedback system that is designed to help people adapt to their brain waves, usually either as a treatment for disorders like ADHD, depression, or as a form of enhancement to achieve 'peak performance'. Although scientific approval of this therapy is lacking, commercial neurofeedback clinics are proliferating across Europe and the United States. In this article, ethnographic material gathered through interviews with practitioners and clients and observations during neurofeedback sessions provides the groundwork for a theoretical analysis of neurofeedback. This account demonstrates that although at first glance neurofeedback appears as a straightforward engagement between the two agents - practitioner and client - and a computer, it is in fact a complex entanglement of collaborating and competing actors. Human and non-human actors together perform a process in which it is unclear which actor is directing the 'treatment'. While it remains unclear if and how the client is cured, restored or enhanced, this article demonstrates that through the process of neurofeedback, a new kind of self - one that is extended with all kind of entities that have emerged during the process - has clearly been brought into being. © 2013 Macmillan Publishers Ltd.


Rabelink T.J.,Leiden University | De Zeeuw D.,University of Groningen
Nature Reviews Nephrology | Year: 2015

Albuminuria is commonly used as a marker of kidney disease progression, but some evidence suggests that albuminuria also contributes to disease progression by inducing renal injury in specific disease conditions. Studies have confirmed that in patients with cardiovascular risk factors, such as diabetes and hypertension, endothelial damage drives progression of kidney disease and cardiovascular disease. A key mechanism that contributes to this process is the loss of the glycocalyx - a polysaccharide gel that lines the luminal endothelial surface and that normally acts as a barrier against albumin filtration. Degradation of the glycocalyx in response to endothelial activation can lead to albuminuria and subsequent renal and vascular inflammation, thus providing a pathophysiological framework for the clinical association of albuminuria with renal and cardiovascular disease progression. In this Review, we examine the likely mechanisms by which glycocalyx dysfunction contributes to kidney injury and explains the link between cardiovascular disease and albuminuria. Evidence suggests that glycocalyx dysfunction is reversible, suggesting that these mechanisms could be considered as therapeutic targets to prevent the progression of renal and cardiovascular disease. This possibility enables the use of existing drugs in new ways, provides an opportunity to develop novel therapies, and indicates that albuminuria should be reconsidered as an end point in clinical trials.


van Leeuwen R.W.F.,Erasmus Medical Center | van Gelder T.,Erasmus Medical Center | Mathijssen R.H.J.,Erasmus Medical Center | Jansman F.G.A.,Deventer Hospital | Jansman F.G.A.,University of Groningen
The Lancet Oncology | Year: 2014

In the past decade, many tyrosine-kinase inhibitors have been introduced in oncology and haemato-oncology. Because this new class of drugs is extensively used, serious drug-drug interactions are an increasing risk. In this Review, we give a comprehensive overview of known or suspected drug-drug interactions between tyrosine-kinase inhibitors and other drugs. We discuss all haemato-oncological and oncological tyrosine-kinase inhibitors that had been approved by Aug 1, 2013, by the US Food and Drug Administration or the European Medicines Agency. Various clinically relevant drug interactions with tyrosine-kinase inhibitors have been identified. Most interactions concern altered bioavailability due to altered stomach pH, metabolism by cytochrome P450 isoenzymes, and prolongation of the QTc interval. To guarantee the safe use of tyrosine-kinase inhibitors, a drugs review for each patient is needed. This Review provides specific recommendations to guide haemato-oncologists, oncologists, and clinical pharmacists, through the process of managing drug-drug interactions during treatment with tyrosine-kinase inhibitors in daily clinical practice. © 2014 Elsevier Ltd.


Rioz-Martinez A.,University of Groningen | Roelfes G.,University of Groningen
Current Opinion in Chemical Biology | Year: 2015

In the past decade, DNA-based hybrid catalysis has merged as a promising novel approach to homogeneous (asymmetric) catalysis. A DNA hybrid catalysts comprises a transition metal complex that is covalently or supramolecularly bound to DNA. The chiral microenvironment and the second coordination sphere interactions provided by the DNA are key to achieve high enantioselectivities and, often, additional rate accelerations in catalysis. Nowadays, current efforts are focused on improved designs, understanding the origin of the enantioselectivity and DNA-induced rate accelerations, expanding the catalytic scope of the concept and further increasing the practicality of the method for applications in synthesis. Herein, the recent developments will be reviewed and the perspectives for the emerging field of DNA-based hybrid catalysis will be discussed. © 2015 Elsevier Ltd.


Molleman L.,University of Groningen
Proceedings. Biological sciences / The Royal Society | Year: 2013

There is ample evidence that human cooperative behaviour towards other individuals is often conditioned on information about previous interactions. This information derives both from personal experience (direct reciprocity) and from experience of others (i.e. reputation; indirect reciprocity). Direct and indirect reciprocity have been studied separately, but humans often have access to both types of information. Here, we experimentally investigate information use in a repeated helping game. When acting as donor, subjects can condition their decisions to help recipients with both types of information at a small cost to access such information. We find that information from direct interactions weighs more heavily in decisions to help, and participants tend to react less forgivingly to negative personal experience than to negative reputation. Moreover, effects of personal experience and reputation interact in decisions to help. If a recipient's reputation is positive, the personal experience of the donor has a weak effect on the decision to help, and vice versa. Yet if the two types of information indicate conflicting signatures of helpfulness, most decisions to help follow personal experience. To understand the roles of direct and indirect reciprocity in human cooperation, they should be studied in concert, not in isolation.


Identifying genes encoding bacteriocins and ribosomally synthesized and posttranslationally modified peptides (RiPPs) can be a challenging task. Especially those peptides that do not have strong homology to previously identified peptides can easily be overlooked. Extensive use of BAGEL2 and user feedback has led us to develop BAGEL3. BAGEL3 features genome mining of prokaryotes, which is largely independent of open reading frame (ORF) predictions and has been extended to cover more (novel) classes of posttranslationally modified peptides. BAGEL3 uses an identification approach that combines direct mining for the gene and indirect mining via context genes. Especially for heavily modified peptides like lanthipeptides, sactipeptides, glycocins and others, this genetic context harbors valuable information that is used for mining purposes. The bacteriocin and context protein databases have been updated and it is now easy for users to submit novel bacteriocins or RiPPs. The output has been simplified to allow user-friendly analysis of the results, in particular for large (meta-genomic) datasets. The genetic context of identified candidate genes is fully annotated. As input, BAGEL3 uses FASTA DNA sequences or folders containing multiple FASTA formatted files. BAGEL3 is freely accessible at http://bagel.molgenrug.nl.


Kallenberg C.G.M.,University of Groningen
Nature Reviews Rheumatology | Year: 2014

The updated nomenclature for vasculitis defines this varied group of disorders by aetiology, specific features of pathogenesis and clinical symptoms; diagnostic and classification criteria for clinical practice are in development. Here, I review some important advances in the management of vasculitis within the category of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), which encompasses microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The clinical approach to the management of the patient with AAV should include testing for ANCA specificity; proteinase 3 (PR3)-specific ANCAs are most often associated with GPA, whereas myeloperoxidase (MPO)-ANCAs are usually associated with MPA. Also important to the management of AAV is an assessment of the disease stage and severity, to enable tailored treatment based on an algorithm derived from controlled-trial data. Remaining questions pertain to the dosage and duration of corticosteroid treatment, the selection of patients for, and duration of, maintenance treatment after induction of remission, and the identification of safer and more effective therapies than are currently in use. Outcome measures should assess not only disease activity, but also damage and quality of life. Infections, cardiovascular events and malignancies also contribute to outcome, and their prevention should therefore be part of the clinical approach to managing patients with AAV. © 2014 Macmillan Publishers Limited.


Ursavas E.,University of Groningen
Decision Support Systems | Year: 2014

This paper proposes a decision support system for optimizing operations on the quayside of a container terminal. Due to the existence of multiple parties involved in the decision making processes within port operations, it is essential to pay attention to each parties' concerns and demands which by nature are frequently conflicting with each other. This calls for a DSS that offers the flexibility of adjusting the balance within conflicting objectives, guiding the decision maker towards the final decision. Consequently, this study provides a DSS that determines the berthing and crane allocations simultaneously. To show the practical application of the DSS presented, a real life case study at a container terminal has been conducted. Implementation of the model shows that improvements ranging from 10% to 25% on service time and costs can be attained. © 2014 Elsevier B.V. All rights reserved.


Pagani G.A.,University of Groningen | Aiello M.,University of Groningen
Physica A: Statistical Mechanics and its Applications | Year: 2013

The statistical tools of Complex Network Analysis are of useful to understand salient properties of complex systems, may these be natural or pertaining human engineered infrastructures. One of these that is receiving growing attention for its societal relevance is that of electricity distribution. In this paper, we present a survey of the most relevant scientific studies investigating the properties of different Power Grids infrastructures using Complex Network Analysis techniques and methodologies. We categorize and explore the most relevant literature works considering general topological properties, physical properties, and differences between the various graph-related indicators and reliability aspects. We also trace the evolution in such field of the approach of study during the years to see the improvement achieved in the analysis. © 2013 Published by Elsevier B.V.


Roest A.M.,University of Tilburg | Martens E.J.,University of Tilburg | de Jonge P.,University of Tilburg | de Jonge P.,University of Groningen | Denollet J.,University of Tilburg
Journal of the American College of Cardiology | Year: 2010

Objectives: The purpose of this study was to assess the association between anxiety and risk of coronary heart disease (CHD). Background: Less research has focused on the association of anxiety with incident CHD in contrast to other negative emotions, such as depression. Methods: A meta-analysis of references derived from PubMed, EMBASE, and PsycINFO (1980 to May 2009) was performed without language restrictions. End points were cardiac death, myocardial infarction (MI), and cardiac events. The authors selected prospective studies of (nonpsychiatric) cohorts of initially healthy persons in which anxiety was assessed at baseline. Results: Twenty studies reporting on incident CHD comprised 249,846 persons with a mean follow-up period of 11.2 years. Anxious persons were at risk of CHD (hazard ratio [HR] random: 1.26; 95% confidence interval [CI]: 1.15 to 1.38; p < 0.0001) and cardiac death (HR: 1.48; 95% CI: 1.14 to 1.92; p = 0.003), independent of demographic variables, biological risk factors, and health behaviors. There was a nonsignificant trend for an association between anxiety and nonfatal MI (HR: 1.43; 95% CI: 0.85 to 2.40; p = 0.180). Subgroup analyses did not show any significant differences regarding study characteristics, with significant associations for different types of anxiety, short- and long-term follow-up, and both men and women. Conclusions: Anxiety seemed to be an independent risk factor for incident CHD and cardiac mortality. Future research should examine the association between anxiety and CHD with valid and reliable anxiety measures and focus on the mechanisms through which anxiety might affect CHD. © 2010 American College of Cardiology Foundation.


Medema M.H.,University of Groningen
Bioengineered bugs | Year: 2011

Natural products derived from the secondary metabolism of microbes constitute a cornerstone of modern medicine. Engineering bugs to produce these products in high quantities is a major challenge for biotechnology, which has usually been tackled by either one of two strategies: iterative random mutagenesis or rational design. Recently, we analyzed the transcriptome of a Streptomyces clavuligerus strain optimized for production of the β-lactamase inhibitor clavulanic acid by multiple rounds of mutagenesis and selection, and discovered that the observed changes matched surprisingly well with simple changes that have been introduced into these strains by rational engineering. Here, we discuss how in the new field of synthetic biology, random mutagenesis and rational engineering can be implemented complementarily in ways which may enable one to go beyond the status quo that has now been reached by each method independently.


Lisman T.,University of Groningen | Kamphuisen P.W.,University of Groningen | Northup P.G.,University of Virginia | Porte R.J.,University of Groningen
Journal of Hepatology | Year: 2013

Summary Until recently, it was widely accepted that patients with cirrhosis have a bleeding tendency related to the changes in the hemostatic system that occur as a consequence of the disease. However, it has now been well established that patients with cirrhosis are at risk for both bleeding and thrombotic complications. These thrombotic complications include portal vein thrombosis, deep vein thrombosis and pulmonary embolism, and coronary or cerebrovascular infarctions. Antithrombotic drugs to prevent or treat thrombotic complications in patients with cirrhosis have been used only minimally in the past due to the perceived bleeding risk. As the thrombotic complications and the necessity of antithrombotic treatment in these patients are increasingly recognized, the use of antithrombotic drugs in this population is likely increasing. Moreover, given the rising incidence of fatty liver disease and generally longer survival times of patients with chronic liver diseases, it would be reasonable to presume that some of these thrombotic complications may be increasing in incidence over time. In this review, we will outline the indications for antithrombotic treatment in patients with cirrhosis. Furthermore, we will discuss the available antithrombotic drugs and indicate possible applications, advantages, and caveats. Since for many of these drugs very little experience in patients with cirrhosis exists, these data are essential in the design of future clinical and laboratory studies on mechanisms, efficacy, and safety of the various antithrombotic strategies in these patients. © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.


du Toit J.T.,Utah State University | Olff H.,University of Groningen
Oecologia | Year: 2014

In community ecology, broad-scale spatial replication can accommodate contingencies in patterns within species groups, but contingencies in processes across species groups remain problematic. Here, based on a focused review of grazing and browsing by large mammals, we use one trophic guild as a "control" for the other to identify generalities that are not contingent upon specific consumer-resource interactions. An example of such a generality is the Jarman-Bell principle, which explains how allometries of metabolism and digestion influence dietary tolerance and thereby enable resource partitioning within both guilds at multiple scales. By comparing the grazing succession with browsing stratification we show how competition from smaller herbivores, rather than facilitation from larger ones, is the underlying process structuring ungulate assemblages when shared resources become limiting. Also, grazing lawns and browsing hedges are functionally similar. In each case, plants expressing tolerance traits can withstand chronic grazing or browsing in sites where the nutritive value of the local food resource is enhanced in positive feedback to the actions of its consumers. The debate over whether ungulates accelerate or decelerate nutrient cycling can be resolved by comparing grazing and browsing effects in the same ecosystem type. Evidence from African savannas points to the rate of nutrient cycling being controlled by the mix of tolerance and resistance traits in plants; not the relative dominance of grazing or browsing by local herbivores. We recommend this across-guild comparative approach as a novel solution with widespread utility for resolving contingencies in community processes. © 2014 Springer-Verlag Berlin Heidelberg.


Gosens R.,University of Groningen | Grainge C.,Hunter Medical Research Institute
Chest | Year: 2015

Recent work has demonstrated that mechanical forces occurring in the airway as a consequence of bronchoconstriction are sufficient to not only induce symptoms but also influence airway biology. Animal and human in vitro and in vivo work demonstrates that the airways are structurally and functionally altered by mechanical stress induced by bronchoconstriction. Compression of the airway epithelium and mechanosensing by the airway smooth muscle trigger the activation and release of growth factors, causing cell proliferation, extracellular matrix protein accumulation, and goblet cell differentiation. These effects of bronchoconstriction are of major importance to asthma pathophysiology and appear sufficient to induce remodeling independent of the inflammatory response. We review these findings in detail and discuss previous studies in light of this new evidence regarding the influence of mechanical forces in the airways. Furthermore, we highlight potential impacts of therapies influencing mechanical forces on airway structure and function in asthma. © 2015 American College of Chest Physicians.


van Imhoff D.E.,University of Groningen
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

To evaluate phototherapy practices by measuring the irradiance levels of phototherapy (PT) devices. Prospective study. Tertiary neonatal intensive care units. None. Irradiance levels of PT devices used in the 10 Dutch Neonatal Intensive Care Units (NICUs) were measured according to the local PT practice patterns. The irradiance levels of all overhead and fibre-optic PT devices were measured with a radiometer using an infant silhouette model. Eight different PT devices were used in the 10 NICUs; five were overhead devices and three fibre-optic pads. The median (range) irradiance level for overhead PT devices was 9.7 (4.3-32.6) μW/cm(2)/nm and for fibre-optic pads 6.8 (0.8-15.6) μW/cm(2)/nm. Approximately 50% of PT devices failed to meet the minimal recommended irradiance level of 10 μW/cm(2)/nm. Maximal irradiance levels for overhead PT spot lights were inversely related to the distance between device and infant model (R2=0.33). The distances ranged from 37 cm to 65 cm. PT devices in the Dutch NICUs show considerable variability with often too low irradiance levels. These results indicate that suboptimal PT is frequently applied and may even be ineffective towards reducing total serum bilirubin levels. These results underline the need for greater awareness among all healthcare workers towards the requirements for effective PT including measurements of irradiance and distance.


Sips G.J.,University of Groningen | Wilschut J.,University of Groningen | Smit J.M.,University of Groningen
Reviews in Medical Virology | Year: 2012

Flaviviruses, including Dengue, West Nile, Japanese encephalitis, and Tick-borne encephalitis virus, are major emerging human pathogens, affecting millions of individuals worldwide. Many clinically important flaviviruses elicit CNS diseases in infected hosts, including traditional "hemorrhagic" viruses, such as Dengue. This review focuses on the epidemiology, symptomatology, neuropathology, and, specifically, neuropathogenesis of flavivirus-induced human CNS disease. A detailed insight into specific factors priming towards neuroinvasive disease is of clear clinical significance, as well as importance to the development of antiviral therapies and identification of key mechanisms involved in the (re)emergence of specific flaviviruses, including potentially novel or previously unrecognized ones, as neuroinvasive pathogens. © 2011 John Wiley & Sons, Ltd.


Van Harten A.E.,University of Groningen | Scheeren T.W.L.,University of Groningen | Absalom A.R.,University of Groningen
Anaesthesia | Year: 2012

Postoperative cognitive dysfunction is receiving increasing attention, particularly as it mainly affects the (growing) elderly population. Until recently, cognitive deficits after cardiac surgery were thought to be caused by physiological disturbances associated with the cardiopulmonary bypass technique. Although the technique of 'off-pump' coronary revascularisation may potentially be associated with improved outcome, long-term follow-up studies have failed to demonstrate a significant reduction in the incidence of postoperative cognitive dysfunction. The focus of research is thus shifting from cardiopulmonary bypass to other factors common to both techniques, such as surgery, anaesthesia and patient-related predisposing factors. Priming of the immune system by ageing and atherosclerosis may result in an exaggerated systemic and cerebral inflammatory response to cardiac surgery and anaesthesia, causing neuronal loss or dysfunction resulting in cognitive dysfunction. We briefly discuss the evidence for cardiopulmonary bypass-related neuronal injuries in adult cardiac surgery patients, and review the evidence that immune priming is a key factor in the pathogenesis of cognitive dysfunction after cardiac surgery. © 2012 The Association of Anaesthetists of Great Britain and Ireland.


Wieling M.B.,University of Groningen | Hofman W.H.A.,University of Groningen
Computers and Education | Year: 2010

To what extent a blended learning configuration of face-to-face lectures, online on-demand video recordings of the face-to-face lectures and the offering of online quizzes with appropriate feedback has an additional positive impact on the performance of these students compared to the traditional face-to-face course approach? In a between-subjects design in which students were randomly assigned to a group having access to the online lectures including multiple choice quizzes and appropriate feedback or to a group having access to the online lectures only, 474 students (161 men and 313 women) of a course on European Law agreed to participate in the experiment. By using regression analysis we found that the course grade of the students was predicted by their grade point average, their study discipline, their grade goal for the course, the expected difficulty-level of the course, the number of online lectures they viewed, the number of lectures the students attended in person and the interaction between the lectures they viewed online and attended in person. Students who attended few lectures had more benefit from viewing online lectures than students who attended many lectures. In contrast to our expectations, the regression analysis did not show a significant effect of automated feedback on student performance. Offering recordings of face-to-face lectures is an easy extension of a traditional course and is of practical importance, because it enables students who are often absent from the regular face-to-face lectures to be able to improve their course grade by viewing the lectures online. © 2009 Elsevier Ltd. All rights reserved.


Kallosh R.,Stanford University | Linde A.,Stanford University | Roest D.,University of Groningen
Physical Review Letters | Year: 2014

We introduce a novel nonminimal coupling between gravity and the inflaton sector. Remarkably, for large values of this coupling all models asymptote to a universal attractor. This behavior is independent of the original scalar potential and generalizes the attractor in the φ4 theory with nonminimal coupling to gravity. The attractor is located in the "sweet spot" of parameter values that are preferred by Planck's recent results. © 2014 American Physical Society.


Kjos M.,University of Groningen | Veening J.-W.,University of Groningen
Molecular Microbiology | Year: 2014

Chromosome segregation is an essential part of the bacterial cell cycle but is poorly characterized in oval-shaped streptococci. Using time-lapse fluorescence microscopy and total internal reflection fluorescence microscopy, we have tracked the dynamics of chromosome segregation in live cells of the human pathogen Streptococcus pneumoniae. Our observations show that the chromosome segregation process last for two-thirds of the total cell cycle; the origin region segregates rapidly in the early stages of the cell cycle while nucleoid segregation finishes just before cell division. Previously we have demonstrated that the DNA-binding protein ParB and the condensin SMC promote efficient chromosome segregation, likely by an active mechanism. We now show that in the absence of SMC, cell division can occur over the unsegregated chromosomes. However, neither smc nor parB are essential in S.pneumoniae, suggesting the importance of additional mechanisms. Here we have identified the process of transcription as one of these mechanisms important for chromosome segregation in S.pneumoniae. Transcription inhibitors rifampicin and streptolydigin as well as mutants affected in transcription elongation cause chromosome segregation defects. Together, our results highlight the importance of passive (or indirect) processes such as transcription for chromosome segregation in oval-shaped bacteria. © 2014 John Wiley & Sons Ltd.


Pieper P.G.,University of Groningen
Netherlands Heart Journal | Year: 2011

Pregnant women with heart disease often have an increased risk of maternal cardiovascular and offspring complications. The magnitude of these risks varies depending on the type and severity of the underlying disease. Therefore risk assessment should be performed before pregnancy. This can be accomplished by taking into account predictors and risk scores that have been developed in large populations of pregnant women with heart disease, as well as by consulting disease-specific pregnancy literature. A system that integrates all available knowledge about the risk of pregnancy is the adapted World Health Organisation risk classification. The safety of pregnancy for women with heart disease can be enhanced by adequate risk assessment and counselling. © The Author(s) 2011.


Koning R.H.,University of Groningen
Journal of Sports Sciences | Year: 2011

Home advantage is a pervasive phenomenon in sport. It has been established in team sports such as basketball, baseball, American football, and European soccer. Attention to home advantage in individual sports has so far been limited. The aim of this study was to examine home advantage in professional tennis. Match-level data are used to measure home advantage. The test used is based on logit models, and consistent specification is addressed explicitly. Depending on the interpretation of home advantage, restrictions on the specification of the model need to be imposed. We find that although significant home advantage exists for men, the performance of women tennis players appears to be unaffected by home advantage. © 2011 Taylor & Francis.


Hoendermis E.S.,University of Groningen
Netherlands Heart Journal | Year: 2011

Pulmonary arterial hypertension (PAH), defined as group 1 of the World Heart Organisation (WHO) classification of pulmonary hypertension, is an uncommon disorder of the pulmonary vascular system. It is characterised by an increased pulmonary artery pressure, increased pulmonary vascular resistance and specific histological changes. It is a progressive disease finally resulting in right heart failure and premature death. Typical symptoms are dyspnoea at exercise, chest pain and syncope; furthermore clinical signs of right heart failure develop with disease progression. Echocardiography is the key investigation when pulmonary hypertension is suspected, but a reliable diagnosis of PAH and associated conditions requires an intense work-up including invasive measurement by right heart catheterisation. Treatment includes general measures and drugs targeting the pulmonary artery tone and vascular remodelling. This advanced medical therapy has significantly improved morbidity and mortality in patients with PAH in the last decade. Combinations of these drugs are indicated when treatment goals of disease stabilisation are not met. In patients refractory to medical therapy lung transplantation should be considered an option. © The Author(s) 2011.


Maan M.E.,University of Groningen | Sefc K.M.,University of Graz
Seminars in Cell and Developmental Biology | Year: 2013

Cichlid fishes constitute one of the most species-rich families of vertebrates. In addition to complex social behaviour and morphological versatility, they are characterised by extensive diversity in colouration, both within and between species. Here, we review the cellular and molecular mechanisms underlying colour variation in this group and the selective pressures responsible for the observed variation. We specifically address the evidence for the hypothesis that divergence in colouration is associated with the evolution of reproductive isolation between lineages. While we conclude that cichlid colours are excellent models for understanding the role of animal communication in species divergence, we also identify taxonomic and methodological biases in the current research effort. We suggest that the integration of genomic approaches with ecological and behavioural studies, across the entire cichlid family and beyond it, will contribute to the utility of the cichlid model system for understanding the evolution of biological diversity. © 2013 The Authors.


Mulder F.A.A.,University of Groningen | Filatov M.,Zernike Institute for Advanced Materials
Chemical Society Reviews | Year: 2010

In this tutorial review, we discuss the utilization of chemical shift information as well as ab initio calculations of nuclear shieldings for protein structure determination. Both the empirical and computational aspects of the chemical shift are reviewed and the role of molecular dynamics and the accuracy of different computational methods are discussed. It is anticipated that incorporating theoretical information on chemical shifts will increase the accuracy of protein structures, in the solid and liquid state alike, and extend the applicability of NMR spectroscopy to ever larger systems. © 2010 The Royal Society of Chemistry.


Radulovic V.,University of Groningen | De Haan G.,University of Groningen | Klauke K.,University of Groningen
Leukemia | Year: 2013

The equilibrium between self-renewal and differentiation of hematopoietic stem cells is regulated by epigenetic mechanisms. In particular, Polycomb-group (PcG) proteins have been shown to be involved in this process by repressing genes involved in cell-cycle regulation and differentiation. PcGs are histone modifiers that reside in two multi-protein complexes: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). The existence of multiple orthologs for each Polycomb gene allows the formation of a multitude of distinct PRC1 and PRC2 sub-complexes. Changes in the expression of individual PcG genes are likely to cause perturbations in the composition of the PRC, which affect PRC enzymatic activity and target selectivity. An interesting recent development is that aberrant expression of, and mutations in, PcG genes have been shown to occur in hematopoietic neoplasms, where they display both tumor-suppressor and oncogenic activities. We therefore comprehensively reviewed the latest research on the role of PcG genes in normal and malignant blood cell development. We conclude that future research to elucidate the compositional changes of the PRCs and methods to intervene in PRC assembly will be of great therapeutic relevance to combat hematological malignancies. © 2013 Macmillan Publishers Limited All rights reserved.


Bulmer A.C.,Griffith University | Verkade H.J.,University of Groningen | Wagner K.-H.,Griffith University | Wagner K.-H.,University of Vienna
Progress in Lipid Research | Year: 2013

Gilbert's syndrome (GS) is characterized by a benign, mildly elevated bilirubin concentration in the blood. Recent reports show clear protection from cardiovascular disease in this population. Protection of lipids, proteins and other macromolecules from oxidation by bilirubin represents the most commonly accepted mechanism contributing to protection in this group. However, a recent meta-analysis estimated that bilirubin only accounts for ∼34% of the cardioprotective effects within analysed studies. To reveal the additional contributing variables we have explored circulating cholesterol and triacylglycerol concentrations, which appear to be decreased in hyperbilirubinemic individuals/animals, and are accompanied by lower body mass index in highly powered studies. These results suggest that bilirubin could be responsible for the development of a lean and hypolipidemic state in GS. Here we also discuss the possible contributing mechanisms that might reduce circulating cholesterol and triacylglycerol concentrations in individuals with syndromes affecting bilirubin metabolism/excretion, which we hope will stimulate future research in the area. In summary, this article is the first review of lipid status in animal and human studies of hyperbilirubinemia and explores possible mechanisms that could contribute to lowering circulating lipid parameters and further explain cardiovascular protection in Gilbert's syndrome. © 2013 Elsevier Ltd. All rights reserved.


Pringle S.,University of Groningen | Van Os R.,University of Groningen | Coppes R.P.,University of Groningen
Stem Cells | Year: 2013

The ability to speak, swallow, masticate, taste food, and maintain a healthy oral cavity is heavily reliant on the presence of saliva, the hugely important effect of which on our everyday lives is often unappreciated. Hyposalivation, frequently experienced by people receiving radiation therapy for head and neck cancers, results in a plethora of symptoms whose combined effect can drastically reduce quality of life. Although artificial lubricants and drugs stimulating residual function are available to ameliorate the consequences of hyposalivation, their effects are at best transient. Such management techniques do not address the source of the problem: a lack of functional saliva-producing acinar cells, resulting from radiation-induced stem cell sterilization. Post-radiotherapy stimulation of cell proliferation only results in improved saliva secretion when part of the tissue has been spared or when the dose to the salivary gland (SG) remains below a certain level. Therefore, stem cell replacement therapy may be a good option to treat radiation-induced hyposalivation. Substantial progress has been made lately in the understanding of cell turnover in the SG, and the recent identification of stem and progenitor cell populations in the SG provides a basis for studies toward development of a stem cell-based therapy for xerostomia. Here, we review the current state of knowledge of SG stem cells and their potential for use in a cell-based therapy that may provide a more durable cure for hyposalivation. © AlphaMed Press.


Ricano-Ponce I.,University of Groningen | Wijmenga C.,University of Groningen
Annual Review of Genomics and Human Genetics | Year: 2013

Genetic studies in immune-mediated diseases have yielded a large number of disease-associated loci. Here we review the progress being made in 12 such diseases, for which 199 independently associated non-HLA loci have been identified by genome-wide association studies since 2007. It is striking that many of the loci are not unique to a single disease but shared between different immune-mediated diseases. The challenge now is to understand how the unique and shared genetic factors can provide insight into the underlying disease biology. We annotated disease-associated variants using the Encyclopedia of DNA Elements (ENCODE) database and demonstrate that, of the predisposing disease variants, the majority have the potential to be regulatory. We also demonstrate that many of these variants affect the expression of nearby genes. Furthermore, we summarize results from the Immunochip, a custom array, which allows a detailed comparison between five of the diseases that have so far been analyzed using this platform. Copyright © 2013 by Annual Reviews. All rights reserved.


van de Meeberg E.K.,University of Groningen
European Journal of Emergency Medicine | Year: 2016

OBJECTIVE: To evaluate the effect of routine use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) on the diagnosis rate of delirium in elderly Emergency Department (ED) patients and the validity of the CAM-ICU in the ED setting. METHODS: This was a prospective observational study in a tertiary care academic ED. We compared the diagnosis rate of delirium before implementation of the CAM-ICU, without routine use of a screening tool, with the diagnosis rate after implementation of the CAM-ICU. All consecutive patients aged 70 years or older were enrolled. The diagnosis rate before implementation was based on chart review and after implementation on a positive CAM-ICU score. In a subsample, the presence of delirium was evaluated independently according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria to assess the validity of the CAM-ICU. RESULTS: The total study population included 968 patients: 490 before and 478 after implementation of the CAM-ICU. The two groups were not significantly different in patient characteristics. Before implementation of the CAM-ICU, delirium was diagnosed in 14 patients (3%) and after implementation in 48 patients (10%) (P<0.001). The sensitivity of the CAM-ICU for delirium in the ED setting was 100%, specificity was 98%, positive predictive value was 92%, and negative predictive value was 100%. CONCLUSION: The diagnosis rate of delirium after implementation of the CAM-ICU was three-fold higher than before. The CAM-ICU is a reliable screening tool in the ED, with high sensitivity, specificity, and positive and negative predictive value. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Schutte E.,University of Groningen
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016

OBJECTIVE—: Skin autofluorescence (SAF), a measure of advanced glycation end product accumulation, is associated with kidney function. We investigated the association of SAF with rate of kidney function decline in a cohort of patients with peripheral artery disease. APPROACH AND RESULTS—: We performed a post hoc analysis of an observational longitudinal cohort study. We included 471 patients with peripheral artery disease, and SAF was measured at baseline. Primary end point was rate of estimated glomerular filtration rate (eGFR) decline. Secondary end points were incidence of eGFR <60 and <45 mL/min/1.73 m and rapid eGFR decline, defined as a decrease in eGFR of >5 mL/min/1.73 m/y. During a median follow-up of 3 years, the mean change in eGFR per year was −1.8±4.4 mL/min/1.73 m/y. No significant difference in rate of eGFR decline was observed per 1 arbitrary unit increase in SAF (−0.1 mL/min/1.73 m/y; 95% confidence interval, −0.7 to 0.5; P=0.8). Analyses of the secondary end points showed that there was an association of SAF with incidence of eGFR <60 and <45 mL/min/1.73 m (hazard ratio, 1.54; 95% confidence interval, 1.13–2.10; P=0.006 and hazard ratio, 1.76; 95% confidence interval, 1.20–2.59; P=0.004, respectively), but after adjustment for age and sex, significance was lost. There was no association of SAF with rapid eGFR decline. CONCLUSIONS—: In conclusion, in this cohort of patients with peripheral artery disease, elevated SAF was associated with lower baseline eGFR. Although SAF has previously been established as a predictor for cardiovascular disease and mortality, it did not predict the rate of kidney function decline during follow-up in this study. © 2016 American Heart Association, Inc.


Noordmans J.P.,University of Groningen | Wilschut H.W.,University of Groningen | Timmermans R.G.E.,University of Groningen
Physical Review Letters | Year: 2013

Forbidden (slow) β decays offer new opportunities to test the invariance of the weak interaction under Lorentz transformations. Within a general effective field theory framework we analyze and reinterpret the only two relevant experiments, performed in the 1970s, dedicated to search for a preferred direction in space in first- and second-forbidden β decays. We show that the results of these experiments put strong and unique limits on Lorentz violation, and in particular on the presence of several interactions in the modern Lorentz-violating standard model extension. We discuss prospects to improve on these limits. © 2013 American Physical Society.


Dashty M.,University of Groningen
Clinical Biochemistry | Year: 2013

In mammals, there are different metabolic pathways in cells that break down fuel molecules to transfer their energy into high energy compounds such as adenosine-5'-triphosphate (ATP), guanosine-5'-triphosphate (GTP), reduced nicotinamide adenine dinucleotide (NADH2), reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide phosphate (NADPH2). This process is called cellular respiration. In carbohydrate metabolism, the breakdown starts from digestion of food in the gastrointestinal tract and is followed by absorption of carbohydrate components by the enterocytes in the form of monosaccharides. Monosaccharides are transferred to cells for aerobic and anaerobic respiration via glycolysis, citric acid cycle and pentose phosphate pathway to be used in the starvation state. In the normal state, the skeletal muscle and liver cells store monosaccharides in the form of glycogen. In the obesity state, the extra glucose is converted to triglycerides via lipogenesis and is stored in the lipid droplets of adipocytes. In the lipotoxicity state, the lipid droplets of other tissues such as the liver, skeletal muscle and pancreatic beta cells also accumulate triacylglycerol. This event is the axis of the pathogenesis of metabolic dysregulation in insulin resistance, metabolic syndrome and type 2 diabetes. In this paper a summary of the metabolism of carbohydrates is presented in a way that researchers can follow the biochemical processes easily. © 2013 The Canadian Society of Clinical Chemists.


Henry L.,University of Oxford | Schwander T.,University of Groningen | Crespi B.J.,Simon Fraser University
Molecular Biology and Evolution | Year: 2012

Sexual reproduction is extremely widespread in spite of its presumed costs relative to asexual reproduction, indicating that it must provide significant advantages. One postulated benefit of sex and recombination is that they facilitate the purging of mildly deleterious mutations, which would accumulate in asexual lineages and contribute to their short evolutionary life span. To test this prediction, we estimated the accumulation rate of coding (nonsynonymous) mutations, which are expected to be deleterious, in parts of one mitochondrial (COI) and two nuclear (Actin and Hsp70) genes in six independently derived asexual lineages and related sexual species of Timema stick insects. We found signatures of increased coding mutation accumulation in all six asexual Timema and for each of the three analyzed genes, with 3.6- to 13.4-fold higher rates in the asexuals as compared with the sexuals. In addition, because coding mutations in the asexuals often resulted in considerable hydrophobicity changes at the concerned amino acid positions, coding mutations in the asexuals are likely associated with more strongly deleterious effects than in the sexuals. Our results demonstrate that deleterious mutation accumulation can differentially affect sexual and asexual lineages and support the idea that deleterious mutation accumulation plays an important role in limiting the long-Term persistence of all-female lineages. © The Author 2011.


Vakis A.I.,University of Groningen
Journal of Applied Mechanics, Transactions ASME | Year: 2014

A method is proposed to account for asperity interaction and bulk substrate deformation in models that utilize statistical summation of asperity forces to characterize contact between rough surfaces. Interaction deformations of noncontacting asperities are calculated based on the probability that they have taller neighbors in their vicinity, whose deformation upon contact, in turn, induces local substrate deformations. The effect of the order of interaction on the total contact force is explored and a limit is proposed based on asperity density. The updated contact force accounting for asperity interaction is found to tend to a constant fraction of the nominal contact force at the mathematical limit of asperity contact independent of the order of interaction, roughness, or material properties. For contact in the vicinity of zero mean plane separation, rough surfaces are found to exhibit greater asperity interaction resulting in reduced contact forces. A simplified curve-fitted expression is introduced that can be used to account for asperity interaction by adjusting the nominal contact force predicted by other models. © 2014 by ASME.


Roenneberg T.,Ludwig Maximilians University of Munich | Allebrandt K.V.,Ludwig Maximilians University of Munich | Merrow M.,University of Groningen | Vetter C.,Ludwig Maximilians University of Munich
Current Biology | Year: 2012

Obesity has reached crisis proportions in industrialized societies [1]. Many factors converge to yield increased body mass index (BMI). Among these is sleep duration [2-10]. The circadian clock controls sleep timing through the process of entrainment. Chronotype describes individual differences in sleep timing, and it is determined by genetic background, age, sex, and environment (e.g., light exposure) [11-14]. Social jetlag quantifies the discrepancy that often arises between circadian and social clocks, which results in chronic sleep loss [11, 15]. The circadian clock also regulates energy homeostasis [16], and its disruption - as with social jetlag - may contribute to weight-related pathologies [17-19]. Here, we report the results from a large-scale epidemiological study, showing that, beyond sleep duration, social jetlag is associated with increased BMI. Our results demonstrate that living "against the clock" may be a factor contributing to the epidemic of obesity. This is of key importance in pending discussions on the implementation of Daylight Saving Time and on work or school times, which all contribute to the amount of social jetlag accrued by an individual. Our data suggest that improving the correspondence between biological and social clocks will contribute to the management of obesity. Video Abstract: © 2012 Elsevier Ltd.


Rosindell J.,University of Leeds | Cornell S.J.,University of Leeds | Hubbell S.P.,University of California at Los Angeles | Etienne R.S.,University of Groningen
Ecology Letters | Year: 2010

Understanding the maintenance and origin of biodiversity is a formidable task, yet many ubiquitous ecological patterns are predicted by a surprisingly simple and widely studied neutral model that ignores functional differences between species. However, this model assumes that new species arise instantaneously as singletons and consequently makes unrealistic predictions about species lifetimes, speciation rates and number of rare species. Here, we resolve these anomalies - without compromising any of the original model's existing achievements and retaining computational and analytical tractability - by modelling speciation as a gradual, protracted, process rather than an instantaneous event. Our model also makes new predictions about the diversity of 'incipient' species and rare species in the metacommunity. We show that it is both necessary and straightforward to incorporate protracted speciation in future studies of neutral models, and argue that non-neutral models should also model speciation as a gradual process rather than an instantaneous one. © 2010 Blackwell Publishing Ltd/CNRS.


Kallenberg C.G.M.,University of Groningen
Clinical and Experimental Rheumatology | Year: 2015

Recent studies have increased our insight into the pathogenesis of ANCA-associated vasculitis (AAV). Although many data from in vitro and in vivo experimental studies support the pathogenic role of the autoantibodies, cellular immunity seems involved as well. Besides, an amplification loop via the alternative pathway of complement is apparent. These new insights make a more targeted therapeutic approach possible. In particular, the B-cell depleting antibody rituximab has been shown non-inferior to cyclophosphamide for induction of remission, and even superior in patients with relapsing disease being positive for PR3-ANCA. Rituximab is also superior to cyclophosphamide for maintaining remission. Blocking the C5a-receptor seems promising as well as an alternative for high dose corticosteroids during induction of remission. © Clinical and Experimental Rheumatology 2015.


Synthetic Biology is in a critical phase of its development: it has finally reached the point where it can move from proof-of-principle studies to real-world applications. Secondary metabolite biosynthesis, especially the discovery and production of antibiotics, is a particularly relevant target area for such applications of synthetic biology. The first international conference to explore this subject was held in Spain in October 2011. In four sessions on General Synthetic Biology, Filamentous Fungal Systems, Actinomyces Systems, and Tools and Host Structures, scientists presented the most recent technological and scientific advances, and a final-day Forward Look Plenary Discussion identified future trends in the field. © 2012 Blackwell Publishing Ltd.


Bystrykh L.V.,University of Groningen
PLoS ONE | Year: 2012

The diversity and scope of multiplex parallel sequencing applications is steadily increasing. Critically, multiplex parallel sequencing applications methods rely on the use of barcoded primers for sample identification, and the quality of the barcodes directly impacts the quality of the resulting sequence data. Inspection of the recent publications reveals a surprisingly variable quality of the barcodes employed. Some barcodes are made in a semi empirical fashion, without quantitative consideration of error correction or minimal distance properties. After systematic comparison of published barcode sets, including commercially distributed barcoded primers from Illumina and Epicentre, methods for improved, Hamming code-based sequences are suggested and illustrated. Hamming barcodes can be employed for DNA tag designs in many different ways while preserving minimal distance and error-correcting properties. In addition, Hamming barcodes remain flexible with regard to essential biological parameters such as sequence redundancy and GC content. Wider adoption of improved Hamming barcodes is encouraged in multiplex parallel sequencing applications. © 2012 Leonid V. Bystrykh.


Eduard Verhagen A.A.,University of Groningen
Journal of Medical Ethics | Year: 2013

In The Netherlands, neonatal euthanasia has become a legal option and the Groningen Protocol contains an approach to identify situations in which neonatal euthanasia might be appropriate. In the 5 years following the publication of the protocol, neither the prediction that this would be the first step on a slippery slope, nor the prediction of complete transparency and legal control became true. Instead, we experienced a transformation of the healthcare system after antenatal screening policy became a part of antenatal care. This resulted in increased terminations of pregnancy and less euthanasia.


Koolhaas J.M.,University of Groningen | de Boer S.F.,University of Groningen | Coppens C.M.,University of Groningen | Buwalda B.,University of Groningen
Frontiers in Neuroendocrinology | Year: 2010

Individual variation in behavior and physiology is a widespread and ecologically functional phenomenon in nature in virtually all vertebrate species. Due to domestication of laboratory animals, studies may suffer from a strong selection bias. This paper summarizes behavioral, neuroendocrine and neurobiological studies using the natural individual variation in rats and mice. Individual behavioral characteristics appear to be consistent over time and across situations. The individual variation has at least two dimensions in which the quality of the response to a challenging condition (coping style) is independent from the quantity of that response (stress reactivity). The neurobiology reveals important differences in the homeostatic control of the serotonergic neuron and the neuropeptides vasopressin and oxytocin in relation to coping style. It is argued that a careful exploitation of the broad natural and biologically functional individual variation in behavior and physiology may help in developing better animal models for understanding individual disease vulnerability. © 2010 Elsevier Inc.


Schuringa J.J.,University of Groningen | Vellenga E.,University of Groningen
Current Opinion in Hematology | Year: 2010

Purpose of review: The polycomb group gene BMI1 fulfills essential roles in both normal and leukemic stem cells. The underlying molecular mechanisms are beginning to become unraveled and an overview of the current knowledge on BMI1 signaling in normal and leukemic stem cells will be presented here. Recent findings: In addition to a role in bypassing senescence and the orchestration of the symmetry of hematopoietic stem cell divisions, it has recently become clear that BMI1 also functions in the protection against oxidative stress. In the absence of BMI1, reactive oxygen species accumulate, associating with activation of DNA damage response pathways and increased apoptosis. BMI1-mediated control over reactive oxygen species levels might occur independently of the INK4a/ARF pathway, but rather involves impaired mitochondrial functions. In human hematopoietic malignancies, BMI1 is frequently overexpressed, which associates with poor prognosis. Downmodulation of BMI1 impairs self-renewal and long-term expansion of leukemic stem cells. Summary: Understanding molecular mechanisms by which BMI1 affects stem cell fate will increase our insights into the biology of hematopoietic stem cells and will also aid in understanding the process of leukemic transformation and ultimately in the identification of drugable targets that might facilitate the eradication of leukemic stem cells. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Rossing P.,Steno Diabetes Center | De Zeeuw D.,University of Groningen
Kidney International | Year: 2011

Diabetic nephropathy has become a worldwide epidemic accounting for approximately one-third of all cases of end-stage renal disease. The problem is expected to grow, as the prevalence of diabetes is expected to increase from 285 million patients at present to 438 million patients in the year 2030, with increasing prevalence of diabetes particularly in Asia, and a global prevalence of microalbuminuria of ∼40%. This will have a major societal impact because of the enormous financial burden of renal replacement therapy and the invalidating character of this disease. Improved management of diabetes is clearly required, including improved glycemic control to avoid initiation of diabetic nephropathy, particularly in high-risk patients. Recently, the benefits of strict glycemic control on micro- and macrovascular complications have been questioned despite the clear association in observational studies between hyperglycemia and complications. It has been suggested that the benefit of lowering glucose is partly offset by side effects to the glucose-lowering medications, such as hypoglycemia, weight gain, and fluid retention. New treatment strategies with fewer side effects are necessary. Such a treatment could be an incretin-based treatment with glucagon-like peptide 1 analogs, with dipeptidyl peptidase-4 inhibitors that have recently been marketed, or with sodium-glucose transporter 2 inhibitors that are being developed in phase III studies. However, studies with renal end points using these agents are lacking. © 2011 International Society of Nephrology.


Dijkstra T.K.,University of Groningen | Henseler J.,University of Twente | Henseler J.,New University of Lisbon
MIS Quarterly: Management Information Systems | Year: 2015

This paper resumes the discussion in information systems research on the use of partial least squares (PLS) path modeling and shows that the inconsistency of PLS path coefficient estimates in the case of reflective measurement can have adverse consequences for hypothesis testing. To remedy this, the study introduces a vital extension of PLS: consistent PLS (PLSc). PLSc provides a correction for estimates when PLS is applied to reflective constructs: The path coefficients, inter-construct correlations, and indicator loadings become consistent. The outcome of a Monte Carlo simulation reveals that the bias of PLSc parameter estimates is comparable to that of covariance-based structural equation modeling. Moreover, the outcome shows that PLSc has advantages when using non-normally distributed data. We discuss the implications for IS research and provide guidelines for choosing among structural equation modeling techniques. © 2015 The Authors.


Bile acids (BAs) are essential for fat absorption and appear to modulate glucose and energy metabolism. Colesevelam, a BA sequestrant, improves glycemic control in type 2 diabetes mellitus (T2DM). We aimed to characterize the alterations in BA metabolism associated with T2DM and colesevelam treatment and to establish whether metabolic consequences of T2DM and colesevelam are related to changes in BA metabolism. Male subjects with T2DM (n = 16) and controls (n = 12) were matched for age and body mass index. BA pool sizes and synthesis/input rates were determined before and after 2 and 8 weeks of colesevelam treatment. T2DM subjects had higher cholic acid (CA) synthesis rate, higher deoxycholic acid (DCA) input rate, and enlarged DCA pool size. Colesevelam resulted in a preferential increase in CA synthesis in both groups. CA pool size was increased whereas chenodeoxycholic acid and DCA pool sizes were decreased upon treatment. Fasting and postprandial fibroblast growth factor 19 (FGF19) levels did not differ between controls and diabetics, but were decreased by treatment in both groups. Colesevelam treatment reduced hemoglobin A1C by 0.7% (P < 0.01) in diabetics. Yet, no relationships between BA kinetic parameters and changes in glucose metabolism were found in T2DM or with colesevelam treatment. CONCLUSION: Our results reveal significant changes in BA metabolism in T2DM, particularly affecting CA and DCA. Colesevelam treatment reduced FGF19 signaling associated with increased BA synthesis, particularly of CA, and resulted in a more hydrophilic BA pool without altering total BA pool size. However, these changes could not be related to the improved glycemic control in T2DM.


Kahya N.,University of Groningen
Biochimica et Biophysica Acta - Biomembranes | Year: 2010

Giant Unilamellar Vesicles (GUVs) provide a key model membrane system to study lipid-lipid and lipid-protein interactions, which are relevant to vital cellular processes, by (single-molecule) optical microscopy. Here, we review the work on reconstitution techniques for membrane proteins and other preparation methods for developing GUVs towards most suitable close-to-native membrane systems. Next, we present a few applications of protein-containing GUVs to study domain assembly and protein partitioning into raft-like domains. © 2010 Elsevier B.V.


Nederhof E.,University of Groningen
Physiology & behavior | Year: 2012

This paper integrates the cumulative stress hypothesis with the mismatch hypothesis, taking into account individual differences in sensitivity to programming. According to the cumulative stress hypothesis, individuals are more likely to suffer from disease as adversity accumulates. According to the mismatch hypothesis, individuals are more likely to suffer from disease if a mismatch occurs between the early programming environment and the later adult environment. These seemingly contradicting hypotheses are integrated into a new model proposing that the cumulative stress hypothesis applies to individuals who were not or only to a small extent programmed by their early environment, while the mismatch hypothesis applies to individuals who experienced strong programming effects. Evidence for the main effects of adversity as well as evidence for the interaction between adversity in early and later life is presented from human observational studies and animal models. Next, convincing evidence for individual differences in sensitivity to programming is presented. We extensively discuss how our integrated model can be tested empirically in animal models and human studies, inviting researchers to test this model. Furthermore, this integrated model should tempt clinicians and other intervenors to interpret symptoms as possible adaptations from an evolutionary biology perspective. Copyright © 2011 Elsevier Inc. All rights reserved.


Lefrandt J.D.,University of Groningen
Current diabetes reviews | Year: 2010

In 1976, D.J. Ewing showed a clear survival disadvantage for diabetic patients that had 'diabetic autonomic neuropathy', as assessed by heart rate and blood pressure variations during a battery of bedside tests. However, these variations do not solely depend on autonomic nervous system function, but also and possibly to a more important extent on the integrity of cardiovascular autonomic reflex loops. Increased intima media thickness at the site of the baroreceptors, reduced vascular distensibility, endothelial dysfunction and impaired cardiac function contribute to the cardiovascular autonomic dysfunction. Interestingly, these abnormalities are closely associated with the presence of (micro-) albuminuria that is regarded as a reflection of endothelial dysfunction or vascular damage in diabetes mellitus. Modern techniques to assess cardiovascular autonomic, vascular and cardiac function have improved the ability to detect early abnormalities. Analysis of heart rate variability, baroreflex sensitivity, muscle sympathetic nervous activity, LNMAinfusions and advanced echocardiography have shown that it is the interplay between autonomic control and cardiac and vascular properties that determines cardiovascular autonomic function. Moreover, these modern techniques have improved power to predict survival in diabetic patients in comparison with the classical Ewing's bedside tests. In conclusion, cardiovascular damage may be more important in cardiovascular autonomic dysfunction than neural function.


Efstathiou K.,University of Groningen | Sadovskii D.A.,University of the Littoral Opal Coast
Reviews of Modern Physics | Year: 2010

The hydrogen atom perturbed by sufficiently small homogeneous static electric and magnetic fields of arbitrary mutual alignment is a specific perturbation of the Kepler system with three degrees of freedom and three parameters. Normalization of the Keplerian symmetry reveals that the parameter space is stratified into resonant zones of systems, each zone with an internal dynamical stratification of its own (Efstathiou, Sadovskií, and Zhilinskií, 2007, Proc. R. Soc. London, Ser. A 463, 177110.1098/rspa. 2007.1843). Based on the fully integrable approximation, the bundle of invariant tori of individual systems within zones is characterized globally and the qualitative dynamical stratification is uncovered. The techniques involved in this analysis are illustrated with the example of the 1:1 resonance zone (near orthogonal fields) whose structure is known at present. Applications in the corresponding quantum system are also described. © 2010 The American Physical Society.


Damman J.,University of Groningen | Seelen M.A.,University of Groningen
Kidney International | Year: 2013

Complement activation plays an important role in the pathogenesis of renal allograft injury after kidney transplantation. There are three known pathways of complement activation, namely, classical, alternative, and lectin pathways. In renal allograft injury, contradictory results were reported about the role of the lectin pathway activated via mannan binding lectin (MBL). This Commentary discusses the findings by Bay et al. (this issue), who demonstrated a protective role for circulating MBL in the recipient, particularly in non-HLA immunized recipients. © 2012 International Society of Nephrology.


Kallenberg C.G.M.,University of Groningen | Heeringa P.,University of Groningen
Kidney International | Year: 2013

Renal lesions in ANCA-associated vasculitis (AAV) show an absence or paucity of immune deposits. Therefore, complement was not considered a major pathogenic factor. Data from an animal model of AAV, however, suggest involvement of the alternative pathway of complement. The paper by Gou et al. demonstrates activation also of the alternative and final common pathways in patients with AAV. Thus, the complement system might be a target for treatment in human AAV. © 2012 International Society of Nephrology.


Voss T.,TU Eindhoven | Scherpen J.M.A.,University of Groningen
Automatica | Year: 2011

In this paper we show how to perform stabilization and shape control for a finite dimensional model that recasts the dynamics of an inflatable space reflector in port-Hamiltonian (pH) form. We show how to derive a decentralized passivity-based controller which can be used to stabilize a 1D piezoelectric Timoshenko beam around a desired shape. Furthermore, we present simulation results obtained for the proposed decentralized control approach. © 2011 Elsevier Ltd. All rights reserved.


Dijkman W.P.,University of Groningen | Fraaije M.W.,University of Groningen
Applied and Environmental Microbiology | Year: 2014

In the search for useful and renewable chemical building blocks, 5-hydroxymethylfurfural (HMF) has emerged as a very promising candidate, as it can be prepared from sugars. HMF can be oxidized to 2,5-furandicarboxylic acid (FDCA), which is used as a substitute for petroleum-based terephthalate in polymer production. On the basis of a recently identified bacterial degradation pathway for HMF, candidate genes responsible for selective HMF oxidation have been identified. Heterologous expression of a protein from Methylovorus sp. strain MP688 in Escherichia coli and subsequent enzyme characterization showed that the respective gene indeed encodes an efficient HMF oxidase (HMFO). HMFO is a flavin adenine dinucleotide-containing oxidase and belongs to the glucose-methanol-choline-type flavoprotein oxidase family. Intriguingly, the activity of HMFO is not restricted to HMF, as it is active with a wide range of aromatic primary alcohols and aldehydes. The enzyme was shown to be relatively thermostable and active over a broad pH range. This makes HMFO a promising oxidative biocatalyst that can be used for the production of FDCA from HMF, a reaction involving both alcohol and aldehyde oxidations. © 2014, American Society for Microbiology.


Bu S.-C.,University of Groningen
Retina | Year: 2014

BACKGROUND:: Idiopathic epiretinal membrane (iERM) is a fibrocellular membrane that proliferates on the inner surface of the retina at the macular area. Membrane contraction is an important sight-threatening event and is due to fibrotic remodeling.METHODS:: Analysis of the current literature regarding the epidemiology, clinical features, and pathogenesis of iERM and fibrotic tissue contraction.RESULTS:: Epidemiologic studies report a relationship between iERM prevalence, increasing age, and posterior vitreous detachment. Clinically, iERM progresses through different stages characterized by an increased thickness and wrinkling of the membrane. Pathophysiologically, iERM formation is a fibrotic process in which myofibroblast formation and the deposition of newly formed collagens play key roles. Anomalous posterior vitreous detachment may be a key event initiating the formation of iERM. The age-related accumulation of advanced glycation end products may contribute to anomalous posterior vitreous detachment formation and may also influence the mechanical properties of the iERM.CONCLUSION:: Remodeling of the extracellular matrix at the vitreoretinal interface by aging and fibrotic changes, plays a significant role in the pathogenesis of iERM. A better understanding of molecular mechanisms underlying this process may eventually lead to the development of effective and nonsurgical approaches to treat and prevent vitreoretinal fibrotic diseases. © 2014 by Ophthalmic Communications Society, Inc.


Pigot A.L.,University of Groningen | Pigot A.L.,University of Oxford | Etienne R.S.,University of Groningen
Ecology Letters | Year: 2015

Phylogenies are increasingly applied to identify the mechanisms structuring ecological communities but progress has been hindered by a reliance on statistical null models that ignore the historical process of community assembly. Here, we address this, and develop a dynamic null model of assembly by allopatric speciation, colonisation and local extinction. Incorporating these processes fundamentally alters the structure of communities expected due to chance, with speciation leading to phylogenetic overdispersion compared to a classical statistical null model assuming equal probabilities of community membership. Applying this method to bird and primate communities in South America we show that patterns of phylogenetic overdispersion - often attributed to negative biotic interactions - are instead consistent with a species neutral model of allopatric speciation, colonisation and local extinction. Our findings provide a new null expectation for phylogenetic community patterns and highlight the importance of explicitly accounting for the dynamic history of assembly when testing the mechanisms governing community structure. © 2015 The Authors. Ecology Letters published by John Wiley & Sons Ltd and CNRS.


OBJECTIVE:: The aim of the present study was to describe different presentations, diagnostic tools, and available treatments for melanoma metastasized to the intestines. BACKGROUND:: The intestine is a frequent site of metastases in melanoma patients. In the current era, with long-term survival after systemic treatment, there is a need for a timely diagnosis and optimal treatment of intestinal metastases. METHODS:: Patients diagnosed between 2011 and 2015 with intestinal metastases of melanoma were included. Diagnostic procedures, treatment strategies, and their outcome were analyzed for all patients. RESULTS:: A total of 22 patients were included. Twenty patients received systemic therapy for widely disseminated disease. Fourteen of these twenty patients received local treatment for symptomatic intestinal metastases. Median overall survival after detection of intestinal metastasis in patients receiving systemic treatment was 22 months. On the basis of this cohort, a treatment algorithm for treatment of patients with symptomatic intestinal melanoma metastases was constructed. CONCLUSIONS:: The treatment of intestinal melanoma metastases has changed due to the introduction of novel systemic treatments that can result in long-term survival of patients with widely metastatic melanoma. Surgeons and other clinicians should be aware of these changes in clinical practice as well as the diverse presentation of intestinal melanoma metastases and the diagnostic and therapeutic dilemmas involved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Heinemann M.,ETH Zurich | Heinemann M.,University of Groningen | Zenobi R.,ETH Zurich
Current Opinion in Biotechnology | Year: 2011

Recent discoveries suggest that cells of a clonal population often display multiple metabolic phenotypes at the same time. Motivated by the success of mass spectrometry (MS) in the investigation of population-level metabolomics, the analytical community has initiated efforts towards MS-based single cell metabolomics to investigate metabolic phenomena that are buried under the population average. Here, we review the current approaches and illustrate their advantages and disadvantages. Because of significant advances in the field, different technologies are now at the verge of generating data that are useful for exploring and investigating metabolic heterogeneity. © 2010 Elsevier Ltd.


Schnell U.,University of Groningen | Dijk F.,University of Groningen | Sjollema K.A.,University of Groningen | Giepmans B.N.G.,University of Groningen
Nature Methods | Year: 2012

Fluorescent fusion proteins have revolutionized examination of proteins in living cells. Still, studies using these proteins are met with criticism because proteins are modified and ectopically expressed, in contrast to immunofluorescence studies. However, introducing immunoreagents inside cells can cause protein extraction or relocalization, not reflecting the in vivo situation. Here we discuss pitfalls of immunofluorescence labeling that often receive little attention and argue that immunostaining experiments in dead, permeabilized cells should be complemented with live-cell imaging when scrutinizing protein localization. © 2012 Nature America, Inc. All rights reserved.


Kallenberg C.G.M.,University of Groningen
Annals of the Rheumatic Diseases | Year: 2013

Cyclophosphamide has greatly improved prognosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and proliferative lupus nephritis (LN). However, the side effects of long-term cyclophosphamide treatment are considerable prompting a search for alternatives to cyclophosphamide. For maintenance treatment in AAV, azathioprine is the preferred drug with methotrexate as an alternative in the case of intolerance to azathioprine. Data on mycophenolate mofetil (MMF) for the induction of remission in AAV are being awaited, but rituximab appears as effective as cyclophosphamide in newly diagnosed patients with AAV, and is probably even better for relapsing patients, while the possibility of maintenance treatment with intermittent low-dose infusions of rituximab is being explored. In LN, low-dose intravenous cyclophosphamide is as effective as highdose cyclophosphamide for the induction of remission, with azathioprine being used for maintenance treatment. MMF can be used in the case of intolerance to cyclophosphamide and might be the first choice in black and Hispanic patients. In the case of intolerance to both cyclophosphamide and MMF, azathioprine with pulses of methylprednisolone can be used. Here, the role of rituximab has not been established. In conclusion, alternatives are available for cyclophosphamide both in AAV and proliferative LN.


Kamphuisen P.W.,University of Groningen
Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program | Year: 2012

Central venous catheters (CVCs) are used extensively in cancer patients for the administration of therapy and phlebotomy. An important complication of CVCs is the development of catheter-related thrombosis (CRT), which becomes symptomatic in approximately 5% of the patients. Several factors, such as insertion location and position of the catheter tip, increase the risk of CRT. Prevention of CRT with systemic anticoagulant prophylaxis has largely been ineffective. In addition, the optimal diagnostic strategy and anticoagulant treatment are unclear due to the lack of well-designed studies. The most recent American College of Chest Physicians guidelines recommend (color) Doppler ultrasound more than venography as the initial diagnostic test in patients with suspected arm thrombosis. Only if the ultrasound is negative and clinical suspicion is high is further testing with D-dimer, serial ultrasound, or venography advocated. In case of CRT, removal of the catheter is not necessary if it is functional and needed for chemotherapy. Anticoagulant treatment of CRT consists of treatment with low-molecular-weight heparin (LMWH) followed by vitamin K antagonists for at least 3 months. Whether long-term treatment with LMWH is more effective than vitamin K antagonists in cancer patients with CRT is unknown, but LMWH may be advocated following the recommendations in lower limb thrombosis and cancer. In addition, the effect of new anticoagulants in CRT has not been studied.


Boesjes M.,University of Groningen | Brufau G.,University of Groningen
Current Medicinal Chemistry | Year: 2014

In the last decade, it became clear that bile acids, in addition to their role in intestinal absorption of lipids and fat-soluble vitamins, are major regulators of metabolism. They activate signal transduction pathways through binding to the specific bile acid receptors TGR5 and FXR. Indirectly, bile acids influence metabolism via modification of the gut microbiota ecosystem. The relation between bile acid metabolism and gut microbiota composition is very complex whereas gut microbiota modulates bile acid structure, creating a complex bile acid pool consisting of a mixture of differentially structured species, bile acids alter gut microbiota by disturbing bacterial membrane integrity. In addition, to the effects on glucose and energy homeostasis, recent literature ascribed a role for bile acid signaling in control of inflammation and regulation of the nervous system. In this review, we discuss a selection of recent published studies describing the effects of intestinal bile acid signaling on health and disease. © 2014 Bentham Science Publishers.


Hadders-Algra M.,University of Groningen
Frontiers in Neurology | Year: 2014

This paper reviews the opportunities and challenges for early diagnosis and early intervention in cerebral palsy (CP). CP describes a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to disturbances that occurred in the fetal or infant brain. Therefore the paper starts with a summary of relevant information from developmental neuroscience. Most lesions underlying CP occur in the second half of gestation, when developmental activity in the brain reaches its summit. Variations in timing of the damage not only result in different lesions, but also in different neuroplastic reactions and different associated neuropathologies. This turns CP into a heterogeneous entity. This may mean that the best early diagnostics and the best intervention methods may differ for various subgroups of children with CP. Next, the paper addresses possibilities for early diagnosis. It discusses the predictive value of neuromotor and neurological exams, neuro-imaging techniques and neurophysiological assessments. Prediction is best when complementary techniques are used in longitudinal series. Possibilities for early prediction of CP differ for infants admitted to neonatal intensive care and other infants. In the former group best prediction is achieved with the combination of neuro-imaging and the assessment of general movements, in the latter group best prediction is based on carefully documented milestones and neurological assessment. The last part reviews early intervention in infants developing CP. Most knowledge on early intervention is based on studies in high risk infants without CP. In these infants early intervention programs promote cognitive development until preschool age; motor development profits less. The few studies on early intervention in infants developing CP suggest that programs that stimulate all aspects of infant development by means of family coaching are most promising. More research is urgently needed. © 2014 Hadders-algra.


Soliveres S.,University of Bern | Smit C.,University of Groningen | Maestre F.T.,Rey Juan Carlos University
Biological Reviews | Year: 2014

Once seen as anomalous, facilitative interactions among plants and their importance for community structure and functioning are now widely recognized. The growing body of modelling, descriptive and experimental studies on facilitation covers a wide variety of terrestrial and aquatic systems throughout the globe. However, the lack of a general body of theory linking facilitation among different types of organisms and biomes and their responses to environmental changes prevents further advances in our knowledge regarding the evolutionary and ecological implications of facilitation in plant communities. Moreover, insights gathered from alternative lines of inquiry may substantially improve our understanding of facilitation, but these have been largely neglected thus far. Despite over 15years of research and debate on this topic, there is no consensus on the degree to which plant-plant interactions change predictably along environmental gradients (i.e. the stress-gradient hypothesis), and this hinders our ability to predict how plant-plant interactions may affect the response of plant communities to ongoing global environmental change. The existing controversies regarding the response of plant-plant interactions across environmental gradients can be reconciled when clearly considering and determining the species-specificity of the response, the functional or individual stress type, and the scale of interest (pairwise interactions or community-level response). Here, we introduce a theoretical framework to do this, supported by multiple lines of empirical evidence. We also discuss current gaps in our knowledge regarding how plant-plant interactions change along environmental gradients. These include the existence of thresholds in the amount of species-specific stress that a benefactor can alleviate, the linearity or non-linearity of the response of pairwise interactions across distance from the ecological optimum of the beneficiary, and the need to explore further how frequent interactions among multiple species are and how they change across different environments. We review the latest advances in these topics and provide new approaches to fill current gaps in our knowledge. We also apply our theoretical framework to advance our knowledge on the evolutionary aspects of plant facilitation, and the relative importance of facilitation, in comparison with other ecological processes, for maintaining ecosystem structure, functioning and dynamics. We build links between these topics and related fields, such as ecological restoration, woody encroachment, invasion ecology, ecological modelling and biodiversity-ecosystem-functioning relationships. By identifying commonalities and insights from alternative lines of research, we further advance our understanding of facilitation and provide testable hypotheses regarding the role of (positive) biotic interactions in the maintenance of biodiversity and the response of ecological communities to ongoing environmental changes. © 2014 Cambridge Philosophical Society.


Van Beek H.L.,University of Groningen | Gonzalo G.D.,University of Groningen | Fraaije M.W.,University of Groningen
Chemical Communications | Year: 2012

The thermostable Baeyer-Villiger monooxygenase (BVMO) phenylacetone monooxygenase (PAMO) is used as a scaffold to introduce novel selectivities from other BVMOs or the metagenome by structure-inspired subdomain exchanges. This yields biocatalysts with new preferences in the oxidation of sulfides and the Baeyer-Villiger oxidation of ketones, all while maintaining most of the original thermostability. © The Royal Society of Chemistry 2012.


Madduri A.V.R.,University of Groningen | Minnaard A.J.,University of Groningen | Harutyunyan S.R.,University of Groningen
Chemical Communications | Year: 2012

The first catalytic enantioselective 1,2-addition of Grignard reagents to ketones is presented. This additive-free copper(i) catalyzed 1,2-addition provides chiral allylic tertiary alcohols with an er of up to 98:2 and excellent yields due to the complete shift of overwhelming 1,4-selectivity of copper(i)-catalysts towards 1,2-selectivity in the addition reaction to enones. © 2012 The Royal Society of Chemistry.


Van Der Heide F.,University of Groningen
Best Practice and Research: Clinical Gastroenterology | Year: 2016

This review focuses on the acquired causes, diagnosis, and treatment of intestinal malabsorption. Intestinal absorption is a complex process that depends on many variables, including the digestion of nutrients within the intestinal lumen, the absorptive surface of the small intestine, the membrane transport systems, and the epithelial absorptive enzymes. Acquired causes of malabsorption are classified by focussing on the three phases of digestion and absorption: 1) luminal/digestive phase, 2) mucosal/absorptive phase, and 3) transport phase. Most acquired diseases affect the luminal/digestive phase. These include short bowel syndrome, extensive small bowel inflammation, motility disorders, and deficiencies of digestive enzymes or bile salts. Diagnosis depends on symptoms, physical examination, and blood and stool tests. There is no gold standard for the diagnosis of malabsorption. Further testing should be based on the specific clinical context and the suspected underlying disease. Therapy is directed at nutritional support by enteral or parenteral feeding and screening for and supplementation of deficiencies in vitamins and minerals. Early enteral feeding is important for intestinal adaptation in short bowel syndrome. Medicinal treatment options for diarrhoea in malabsorption include loperamide, codeine, cholestyramine, or antibiotics. © 2016 Elsevier Ltd. All rights reserved.