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Mazer S.J.,University of California at Santa Barbara | Mazer S.J.,Stellenbosch Institute for Advanced Study STIAS | Travers S.E.,North Dakota State University | Cook B.I.,NASA | And 8 more authors.
American Journal of Botany | Year: 2013

Premise of the study: Numerous long-term studies in seasonal habitats have tracked interannual variation in first flowering date (FFD) in relation to climate, documenting the effect of warming on the FFD of many species. Despite these efforts, long-term phenological observations are still lacking for many species. If we could forecast responses based on taxonomic affinity, however, then we could leverage existing data to predict the climate-related phenological shifts of many taxa not yet studied. Methods: We examined phenological time series of 1226 species occurrences (1031 unique species in 119 families) across seven sites in North America and England to determine whether family membership (or family mean FFD) predicts the sensitivity of FFD to standardized interannual changes in temperature and precipitation during seasonal periods before flowering and whether families differ significantly in the direction of their phenological shifts. Key results: Patterns observed among species within and across sites are mirrored among family means across sites; earlyflowering families advance their FFD in response to warming more than late-flowering families. By contrast, we found no consistent relationships among taxa between mean FFD and sensitivity to precipitation as measured here. Conclusions: Family membership can be used to identify taxa of high and low sensitivity to temperature within the seasonal, temperate zone plant communities analyzed here. The high sensitivity of early-flowering families (and the absence of earlyflowering families not sensitive to temperature) may reflect plasticity in flowering time, which may be adaptive in environments where early-season conditions are highly variable among years. © 2013 Botanical Society of America.


Schmidt V.,Max Delbrück Center for Molecular Medicine | Baum K.,Max Delbrück Center for Molecular Medicine | Lao A.,University of Rostock | Rateitschak K.,University of Rostock | And 9 more authors.
EMBO Journal | Year: 2012

The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-β (Aβ) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Aβ production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles. © 2012 European Molecular Biology Organization | All Rights Reserved.


Kossow C.,University of Rostock | Jose D.,University of Rostock | Jose D.,Max Delbrück Center for Molecular Medicine | Jaster R.,University of Rostock | And 3 more authors.
IET Systems Biology | Year: 2012

Interferon-γ (IFNγ)-mediated signal transduction via upregulation of signal transducer and activator of transcription (STAT) 1 leads to the expression of the mucin (MUC) 4 gene in pancreatic cancer cells. Upregulation of STAT1 may also implicate STAT1 tyrosine- or serine-phosphorylation. Experimental data indicate that reaction steps involved in IFNγ-induced serine-phosphorylation of STAT1 vary between cell types in contrast to conserved IFNγ-induced tyrosine-phosphorylation of STAT1. The above observations raise the following two questions: (i) How does IFNγ stimulation regulates serine-phosphorylation of STAT1 in the pancreatic cancer cell line CD18/HPAF? (ii) Which type of STAT1 acts as a transcription factor of MUC4? Our objective is to address these two questions by data-driven mathematical modelling. Simulation results of the parameterised ordinary differential equation models show that serine-phosphorylation of unphosphorylated STAT1 occurs in the cytoplasm. In contrast, serine-phosphorylation of tyrosine-phosphorylated STAT1 can take place in the cytoplasm or in the nucleus. In addition, our results propose that unphosphorylated or serine-phosphorylated STAT1 can act as transcription factors of MUC4, either alone by progressive binding to different sites in the promoter or both together. © 2012 The Institution of Engineering and Technology.


Lao A.,University of Rostock | Schmidt V.,Max Delbrück Center for Molecular Medicine | Schmitz Y.,University of Rostock | Willnow T.E.,Max Delbrück Center for Molecular Medicine | And 2 more authors.
BMC Systems Biology | Year: 2012

Background: Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer's disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor.Results: In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose-response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade.Conclusions: Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer's disease. © 2012 Lao et al.; licensee BioMed Central Ltd.


Michielsen K.,Ghent University | Beauclair R.,Stellenbosch Institute for Advanced Study STIAS | Delva W.,Ghent University | Delva W.,Stellenbosch Institute for Advanced Study STIAS | And 3 more authors.
BMC Public Health | Year: 2012

Background: While the HIV epidemic is levelling off in sub-Saharan Africa, it remains at an unacceptably high level. Young people aged 15-24years remain particularly vulnerable, resulting in a regional HIV prevalence of 1.4% in young men and 3.3% in young women. This study assesses the effectiveness of a peer-led HIV prevention intervention in secondary schools in Rwanda on young peoples sexual behavior, HIV knowledge and attitudes. Methods. In a non-randomized longitudinal controlled trial, fourteen schools were selected in two neighboring districts in Rwanda Bugesera (intervention) and Rwamagana (control). Students (n=1950) in eight intervention and six control schools participated in three surveys (baseline, six and twelve months in the intervention). Analysis was done using linear and logistic regression using generalized estimation equations adjusted for propensity score. Results: The overall retention rate was 72%. Time trends in sexual risk behavior (being sexually active, sex in last six months, condom use at last sex) were not significantly different in students from intervention and control schools, nor was the intervention associated with increased knowledge, perceived severity or perceived susceptibility. It did significantly reduce reported stigma. Conclusions: Analyzing this and other interventions, we identified several reasons for the observed limited effectiveness of peer education: 1) intervention activities (spreading information) are not tuned to objectives (changing behavior); 2) young people prefer receiving HIV information from other sources than peers; 3) outcome indicators are not adequate and the context of the relationship in which sex occurs and the context in which sex occurs is ignored. Effectiveness of peer education may increase through integration in holistic interventions and redefining peer educators role as focal points for sensitization and referral to experts and services. Finally, we argue that a narrow focus on sexual risks will never significantly turn the tide. © 2012 Michielsen et al.; licensee BioMed Central Ltd.


Zonetti S.,Catholic University of Louvain | Govaerts J.,Catholic University of Louvain | Govaerts J.,University Abomey Calavi | Govaerts J.,Stellenbosch Institute for Advanced Study STIAS
Journal of Physics A: Mathematical and Theoretical | Year: 2012

We present an interesting reformulation of a collection of dilaton gravity models in two spacetime dimensions into a field theory of two decoupled Liouville fields in flat space, in the presence of a Maxwell gauge field. An effective action is also obtained, encoding the dynamics of the dilaton field and the single gravitational degree of freedom in a decoupled regime. This effective action represents an interesting starting point for future work, including the canonical quantization of these classes of nontrivial models of gravity-coupled matter systems. © 2012 IOP Publishing Ltd.


Govaerts J.,Catholic University of Louvain | Govaerts J.,University Abomey Calavi | Govaerts J.,Stellenbosch Institute for Advanced Study STIAS | Zonetti S.,Catholic University of Louvain
Classical and Quantum Gravity | Year: 2011

A two-dimensional matter-coupled model of quantum gravity is studied in the Dirac approach to constrained dynamics in the presence of a cosmological constant. It is shown that after partial fixing to the conformal gauge, the requirement of a quantum realization of the conformal algebra for physical quantum states of the fields naturally constrains the cosmological constant to take values in a well-determined and mostly discrete spectrum. Furthermore, the contribution of the quantum fluctuations of the single dynamical degree of freedom in the gravitational sector, namely the conformal mode, to the cosmological constant is negative, in contrast to the positive contributions of the quantum fluctuations of the matter fields, possibly opening an avenue towards addressing the cosmological constant problem in a more general context. © 2011 IOP Publishing Ltd.


Wolkenhauer O.,University of Rostock | Wolkenhauer O.,Stellenbosch Institute for Advanced Study STIAS | Shibata D.K.,University of Southern California | Mesarovic M.D.,Case Western Reserve University
BMC Systems Biology | Year: 2011

Background: Multilevelness is a defining characteristic of complex systems. For example, in the intestinal tissue the epithelial lining is organized into crypts that are maintained by a niche of stem cells. The behavior of the system 'as a whole' is considered to emerge from the functioning and interactions of its parts. What we are seeking here is a conceptual framework to demonstrate how the fate of intestinal crypts is an emergent property that inherently arises from the complex yet robust underlying biology of stem cells.Results: We establish a conceptual framework in which to formalize cross-level principles in the context of tissue organization. To this end we provide a definition for stemness, which is the propensity of a cell lineage to contribute to a tissue fate. We do not consider stemness a property of a cell but link it to the process in which a cell lineage contributes towards tissue (mal)function. We furthermore show that the only logically feasible relationship between the stemness of cell lineages and the emergent fate of their tissue, which satisfies the given criteria, is one of dominance from a particular lineage.Conclusions: The dominance theorem, conceived and proven in this paper, provides support for the concepts of niche succession and monoclonal conversion in intestinal crypts as bottom-up relations, while crypt fission is postulated to be a top-down principle. © 2011 Wolkenhauer et al; licensee BioMed Central Ltd.


Zonetti S.,Catholic University of Louvain | Govaerts J.,Catholic University of Louvain | Govaerts J.,University Abomey Calavi | Govaerts J.,Stellenbosch Institute for Advanced Study STIAS
Journal of Physics: Conference Series | Year: 2013

We address the cosmological constant problem in the context of two-dimensional dilaton-Maxwell gravity, coupled to an arbitrary number of scalar matter fields. We are able to quantize the model non-perturbatively; we determine that the realization of the classical symmetries at the quantum level provides a mechanism that fixes the value of the cosmological constant. © Published under licence by IOP Publishing Ltd.


Wolkenhauer O.,University of Rostock | Wolkenhauer O.,Stellenbosch Institute for Advanced Study STIAS | Auffray C.,University of Lyon | Jaster R.,University of Rostock | And 3 more authors.
Pediatric Research | Year: 2013

As research institutions prepare roadmaps for "systems medicine," we ask how this differs from applications of systems biology approaches in medicine and what we (should) have learned from about one decade of funding in systems biology. After surveying the area, we conclude that systems medicine is the logical next step and necessary extension of systems biology, and we focus on clinically relevant applications. We specifically discuss three related notions. First, more interdisciplinary collaborations are needed to face the challenges of integrating basic research and clinical practice: integration, analysis, and interpretation of clinical and nonclinical data for diagnosis, prognosis, and therapy require advanced statistical, computational, and mathematical tools. Second, strategies are required to (i) develop and maintain computational platforms for the integration of clinical and nonclinical data, (ii) further develop technologies for quantitative and time-resolved tracking of changes in gene expression, cell signaling, and metabolism in relation to environmental and lifestyle influences, and (iii) develop methodologies for mathematical and statistical analyses of integrated data sets and multilevel models. Third, interdisciplinary collaborations represent a major challenge and are difficult to implement. For an efficient and successful initiation of interdisciplinary systems medicine programs, we argue that epistemological, ontological, and sociological aspects require attention. Copyright © 2013 International Pediatric Research Foundation, Inc.

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