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Cambridge, United Kingdom

The University of Cambridge is a collegiate public research university in Cambridge, England. Founded in 1209, Cambridge is the second-oldest university in the English-speaking world and the world's third-oldest surviving university. It grew out of an association formed by scholars leaving the University of Oxford after a dispute with townsfolk; the two "ancient universities" have many common features and are often jointly referred to as "Oxbridge".Cambridge is formed from a variety of institutions which include 31 constituent colleges and over 100 academic departments organised into six Schools. The university occupies buildings throughout the town, many of which are of historical importance. The colleges are self-governing institutions founded as integral parts of the university. In the year ended 31 July 2014, the university had a total income of £1.51 billion, of which £371 million was from research grants and contracts. The central university and colleges have a combined endowment of around £4.9 billion, the largest of any university outside the United States. Cambridge is a member of many associations, and forms part of the "golden triangle" of English universities and Cambridge University Health Partners, an academic health science centre. The university is closely linked with the development of the high-tech business cluster known as "Silicon Fen".Students' learning involves lectures and laboratory sessions organised by departments, and supervisions provided by the colleges. The university operates eight arts, cultural, and scientific museums, including the Fitzwilliam Museum and a botanic garden. Cambridge's libraries hold a total of around 15 million books, 8 million of which are in Cambridge University Library which is a legal deposit library. Cambridge University Press, a department of the university, is the world's oldest publishing house and the second-largest university press in the world. Cambridge is regularly placed among the world's best universities in different university rankings. Beside academic studies, student life is centred on the colleges and numerous pan-university artistic activities, sports clubs and societies.Cambridge has many notable alumni, including several eminent mathematicians, scientists, politicians, and 90 Nobel laureates who have been affiliated with it. Throughout its history, the university has featured in literature and artistic works by numerous authors including Geoffrey Chaucer, E. M. Forster and C. P. Snow. Wikipedia.


Terentjev E.,University of Cambridge
Nature Materials | Year: 2013

The range of possible topological structures in liquid crystals can be widened through the use of confined volumes with prescribed boundary conditions. The first generation of such confined systems were simple spherical liquid-crystal droplets elastic to surface-anchoring constants. Very recently, more intricate topological structures have been achieved by threading nematic liquid-crystal droplets with one or more thin fibers. With one fiber, the resulting volume is topologically equivalent to a torus, but the topology becomes much more complicated when more fibres cross inside the droplet and impose a specific boundary condition on their surface. As with liquid crystals confined in droplets, much of the physics depends on particle size: topological charge only emerges for particles bigger than the critical diameter. Also, the bigger the particle, the less likely it is that a disclination ring will be stable because the core of the disclination increases in length with particle size whereas the point defect does not.


Snaith H.J.,University of Oxford | Ducati C.,University of Cambridge
Nano Letters | Year: 2010

Improving the solar light harvesting and photon-to-electron conversion efficiency for hybrid, organic?inorganic photovoltaics are critical challenges. Titania based solid-state hybrid solar cells are moderately efficient at converting visible photons to electrons, but major electrical losses still remain. A material based paradigm shift is required to dramatically enhance the performance of these devices. Here, we present an investigation into solid-state dye-sensitized solar cells (SDSCs) incorporating a molecular hole-transporter and mesoporous tin oxide electrodes, in place of titania usually employed. We investigate the influence of treating the surface of the SnO2 with different oxides and find that MgO "passivated" SnO2 electrodes demonstrate an unprecedented absorbed photon-to-electron conversion efficiency of near unity across a broad spectral range. A dual surface treatment of TiO2 followed by MgO enables tuning of the solar cell photovoltage, fill factor, and efficiency with visible light absorbing cells delivering 3% solar-to-electrical full sun power conversion efficiency. © 2010 American Chemical Society.


Choudhary R.,University of Cambridge
Building and Environment | Year: 2012

This paper presents a Bayesian approach for developing city-scale energy models of the built environment and demonstrates its application to non-domestic buildings in Greater London. The work draws upon available information of the building stock, such as: mapping databases, floorspace statistics, energy benchmarks, and measured energy consumption reported in display energy certificates of public buildings. The resulting model is able to describe the spread due to variation of energy consumption across buildings within a similar category. These spreads (or distributions) can be used for estimating the probability distribution of the gross energy consumption per local authority in Greater London. The work is driven by the need to quantify future energy demand of buildings in their urban context as a function of projected growth of buildings and populations, refurbishments, policies incentivizing energy efficiency measures, and changes in building operation. The focus on the non-domestic sector enables a framework that accommodates diverse set of activities and uses of buildings within an urban region. © 2011 Elsevier Ltd.


Khaled W.T.,University of Cambridge | Liu P.,Wellcome Trust Sanger Institute
Seminars in Cell and Developmental Biology | Year: 2014

The development and advances in gene targeting technology over the past three decades has facilitated the generation of cancer mouse models that recapitulate features of human malignancies. These models have been and still remain instrumental in revealing the complexities of human cancer biology. However, they will need to evolve in the post-genomic era of cancer research. In this review we will highlight some of the key developments over the past decades and will discuss the new possibilities of cancer mouse models in the light of emerging powerful gene manipulating tools. © 2014.


Frezza C.,University of Cambridge
International Journal of Biochemistry and Cell Biology | Year: 2014

Mitochondria are intracellular organelles thought to have evolved from an alphaproteobacterium engulfed by the ancestor of the eukaryotic cell, an archeon, two billion years ago. Although mitochondria are frequently recognised as the "power plant" of the cell, the function of these organelles go beyond the simple generation of ATP. In fact, mounting evidence suggests that mitochondria are involved in several cellular processes, from regulation of cell death to signal transduction. Given this important role in cell physiology, mitochondrial dysfunction has been frequently associated with human diseases including cancer. Importantly, recent evidence suggests that mitochondrial function is directly regulated by oncogenes and tumour suppressors. However, the consequences of deregulation of mitochondrial function in tumour formation are still unclear. In this review, I propose that mitochondria play a pivotal role in shaping the oncogenic signalling cascade and that mitochondrial dysfunction, in some circumstances, is a required step for cancer transformation. © 2014 Elsevier Ltd.


Scott J.F.,University of Cambridge
NPG Asia Materials | Year: 2013

A short review is given of the recent work on single-phase crystals that are ferroelectric and ferromagnetic at or near room temperature. BiFeO3 is mentioned only briefly, because it has been reviewed in detail elsewhere very recently; emphasis instead is on copper oxide, perovskite oxides with mixed B-site occupancy (such as Pb(Fe1/2Ta1/2) x(ZryTi1-y)1-xO3 and related Nb and W compounds), Fe-, Co-, and Mn-based Aurivilius-phase oxides and hexaferrites.


Herbert J.,University of Cambridge
Psychological Medicine | Year: 2013

Background Cortisol plays a multifaceted role in major depression disorder (MDD). Diurnal rhythms are disturbed, there is increased resistance to the feedback action of glucocorticoids, excess cortisol may induce MDD, basal levels may be higher and the post-awakening cortisol surge accentuated in those at risk for MDD. Does this suggest new avenues for studying MDD or its clinical management? Method The relevant literature was reviewed. Results Cortisol contributes to genetic variants for the risk for MDD and the way that environmental events amplify risk. The corticoids' influence begins prenatally, but continues into adulthood. The impact of cortisol at each phase depends not only on its interaction with other factors, such as psychological traits and genetic variants, but also on events that have, or have not, occurred previously. Conclusions This review suggests that the time is now right for serious consideration of the role of cortisol in a clinical context. Estimates of cortisol levels and the shape of the diurnal rhythm might well guide the understanding of subtypes of MDD and yield additional indicators for optimal treatment. Patients with disturbed cortisol rhythms might benefit from restitution of those rhythms; they may be distinct from those with more generally elevated levels, who might benefit from cortisol blockade. Higher levels of cortisol are a risk for subsequent depression. Should manipulation of cortisol or its receptors be considered as a preventive measure for some of those at very high risk of future MDD, or to reduce other cortisol-related consequences such as long-term cognitive decline? © 2012 Cambridge University Press.


Nagengast A.J.,University of Cambridge
PLoS computational biology | Year: 2010

Many aspects of human motor behavior can be understood using optimality principles such as optimal feedback control. However, these proposed optimal control models are risk-neutral; that is, they are indifferent to the variability of the movement cost. Here, we propose the use of a risk-sensitive optimal controller that incorporates movement cost variance either as an added cost (risk-averse controller) or as an added value (risk-seeking controller) to model human motor behavior in the face of uncertainty. We use a sensorimotor task to test the hypothesis that subjects are risk-sensitive. Subjects controlled a virtual ball undergoing Brownian motion towards a target. Subjects were required to minimize an explicit cost, in points, that was a combination of the final positional error of the ball and the integrated control cost. By testing subjects on different levels of Brownian motion noise and relative weighting of the position and control cost, we could distinguish between risk-sensitive and risk-neutral control. We show that subjects change their movement strategy pessimistically in the face of increased uncertainty in accord with the predictions of a risk-averse optimal controller. Our results suggest that risk-sensitivity is a fundamental attribute that needs to be incorporated into optimal feedback control models.


McGrew W.C.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Modelling the behaviour of extinct hominins is essential in order to devise useful hypotheses of our species' evolutionary origins for testing in the palaeontological and archaeological records. One approach is to model the last common ancestor (LCA) of living apes and humans, based on current ethological and ecological knowledge of our closest living relations. Such referential modelling is based on rigorous, ongoing field studies of the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). This paper reviews recent findings from nature, focusing on those with direct implications for hominin evolution, e.g. apes, using elementary technology to access basic resources such as food and water, or sheltering in caves or bathing as thermoregulatory adaptations. I give preference to studies that directly address key issues, such as whether stone artefacts are detectible before the Oldowan, based on the percussive technology of hammer and anvil use by living apes. Detailed comparative studies of chimpanzees living in varied habitats, from rainforest to savannah, reveal that some behavioural patterns are universal (e.g. shelter construction), while others show marked (e.g. extractive foraging) or nuanced (e.g. courtship) cross-populational variation. These findings allow us to distinguish between retained, primitive traits of the LCA versus derived ones in the human lineage.


Desselberger U.,University of Cambridge
Virus Research | Year: 2014

Recent advances of rotavirus (RV) basic and applied research are reviewed. They consist of determination of the RV particle structure and functions of structural proteins, classification into genotypes based on whole genome analyses, description of the RV genome and gene protein assignments, description of the viral replication cycle and of functions of RV-encoded non-structural proteins as well as cellular proteins and cellular organelles involved, the present status of RV genetics and reverse genetics, molecular determinants of pathogenesis and pathophysiology, the RV-specific humoral and cell-mediated immune responses, innate immune responses and correlates of protection, laboratory diagnosis, differential diagnosis and present status of treatment, the molecular epidemiology and mechanisms of evolution of RVs, the development and universal application of RV vaccines as well as issues arising from present universal RV vaccination programs and work on alternative vaccines. The review concludes by presenting problems requiring further exploration and perspectives of future basic and translational research. © 2014 The Authors.


The nicotinic acetylcholine (ACh) receptor, at the neuromuscular junction, is a neurotransmitter-gated ion channel that has been fine-tuned through evolution to transduce a chemical signal into an electrical signal with maximum efficiency and speed. It is composed from three similar and two identical polypeptide chains, arranged in a ring around a narrow membrane pore. Central to the design of this assembly is a hydrophobic gate in the pore, more than 50 Å away from sites in the extracellular domain where ACh binds. Although the molecular properties of the receptor have been explored intensively over the last few decades, only recently have structures emerged revealing its complex architecture and illuminating how ACh entering the binding sites opens the distant gate. Postsynaptic membranes isolated from the (muscle-derived) electric organ of the Torpedo ray have underpinned most of the structural studies: the membranes form tubular vesicles having receptors arranged on a regular surface lattice, which can be imaged directly in frozen physiological solutions. Advances in electron crystallographic techniques have also been important, enabling analysis of the closed- and open-channel forms of the receptor in unreacted tubes or tubes reacted briefly with ACh. The structural differences between these two forms show that all five subunits participate in a concerted conformational change communicating the effect of ACh binding to the gate, but that three of them (αγ, β and δ) play a dominant role. Flexing of oppositely facing pore-lining α-helices is the principal motion determining the closed/open state of the gate. These results together with the findings of biochemical, biophysical and other structural studies allow an integrated description of the receptor and of its mode of action at the synapse. Copyright © 2013 Cambridge University Press.


Miron V.E.,Queens Medical Research Institute | Franklin R.J.M.,University of Cambridge
Journal of Neurochemistry | Year: 2014

Microglia are the resident macrophages of the central nervous system that survey the microenvironment for signals of injury or infection. The response to such signals induces an inflammatory response involving macrophages derived from both resident microglia and recruited circulating monocytes. Although implicated as contributors to autoimmune-mediated injury, microglia/ macrophages have recently been shown to be critical for the important central nervous system regenerative process of remyelination. This functional dichotomy may reflect their ability to be polarized along a continuum of activation states including the well-characterized cytotoxic M1 and regenerative M2 phenotypes. Here, we review the roles of microglia, monocytes and the macrophages which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of M1 and M2 phenotypes and how the pro-regenerative role of the innate immune system is altered by ageing. © 2014 International Society for Neurochemistry.


Nally D.,University of Cambridge
Transactions of the Institute of British Geographers | Year: 2011

Beginning with Foucault's writing on food provisioning in the mercantile period, this paper explores how a moral economy of hunger is gradually replaced by a political economy of food security that promotes market mechanisms as a better protection against scarcity. In Western Europe the emergence of political liberalism and laissez-faire economics substantially shaped how hunger and scarcity were conceptualised and socially managed. Beyond Europe these social forces were manifest in the development of colonial plantations. Here the transformation of non-capitalist social formations into market economies - what Harvey (2003) terms 'accumulation by dispossession'- was a foundational moment in the development of a global provisioning system that undermined the anti-scarcity strategies of some populations, while ensuring food security for others. The subsequent discovery of the 'Global South' hunger, together with the desire to encourage better habits and purer morals among 'backward' peoples, created the context in which further curative interventions, designed to consolidate a capitalist food economy, were valorised and maintained. These reflections set up the final part of the paper, where I contextualise recent efforts to present agro-biotechnologies as a pro-welfare and anti-scarcity response. Moving beyond the causes of hunger to explore its strategic function, this analysis highlights how corporate agribusiness - in partnership with the life sciences - is attempting to recondition human, animal and bacterial life in order to quicken the reproduction of capital. I term this new moment in the commercialisation of food systems accumulation by molecularisation. The paper concludes by examining how the corporate management of food folds into biopolitical strategies for managing life, including the lives of the hungry poor who are 'let die' as commercial interests supplant human needs. © 2010 The Author. Transactions of the Institute of British Geographers © 2010 Royal Geographical Society (with the Institute of British Geographers).


Scott J.F.,University of Cambridge
Advanced Materials | Year: 2010

This essay discusses recent work on bismuth ferrite, which reveals theoretically and experimentally a phase transition under stress that does not change symmetry but changes the c/a lattice constant ratio. As shown by Ishibashi, such transitions must be discontinuous and are described by free energies eighth-order in polarization P. Such a predicted two-step change in P is also known in potassium nitrate films. © 2010 WILEY-VCH Verlag GmbH &. Co. KGaA.


Doorbar J.,University of Cambridge
Journal of Pathology | Year: 2016

Human papillomaviruses (HPVs) cause a range of serious diseases, including the vast majority of cervical cancers, most anal cancers and around half of head and neck cancers. They are also responsible for troublesome benign epithelial lesions, including genital warts and laryngeal papillomas, and in some individuals HPVs lead to recurrent respiratory papillomatosis and other difficult-to-manage diseases. As a result, there is a great need for model systems that accurately mimic papillomavirus infections in humans. This is complicated by the diverse variety of HPVs, which now number over 200 types, and the different strategies they have evolved to persist in the population. The most well-developed models involve the culture of HPV-containing keratinocytes in organotypic raft culture, an approach which appears to accurately mimic the life cycle of several of the high-risk cancer-associated HPV types. Included amongst these are HPV16 and 18, which cause the majority of cervical cancers. The low-risk HPV types persist less well in tissue-culture models, and our ability to study the productive life cycle of these viruses is more limited. Although ongoing research is likely to improve this situation, animal models of papillomavirus disease can provide considerable basic information as to how lesions form, regress and can be controlled by the immune system. The best studied are cottontail rabbit papillomavirus, rabbit oral papillomavirus and, more recently, mouse papillomavirus (MmuPV), the last of which is providing exciting new insights into viral tropisms and immune control. In addition, transgenic models of disease have helped us to understand the consequences of persistent viral gene expression and the importance of co-factors such as hormones and UV irradiation in the development of neoplasia and cancer. It is hoped that such disease models will eventually lead us to better understanding and better treatments for human disease. © 2015 Pathological Society of Great Britain and Ireland.


Huntington J.A.,University of Cambridge
Thrombosis and Haemostasis | Year: 2014

The serine protease thrombin is the effector enzyme of blood coagulation. It has many activities critical for the formation of stable clots, including cleavage of fibrinogen to fibrin, activation of platelets and conversion of procofactors to active cofactors. Thrombin carries-out its multiple functions by utilising three special features: a deep active site cleft and two anion binding exosites (exosite I and II). Similarly, thrombin inhibitors have evolved to exploit the unique features of thrombin to achieve rapid and specific inactivation of thrombin. Exogenous thrombin inhibitors come from several different protein families and are generally found in the saliva of haematophagous animals (blood suckers) as part of an anticoagulant cocktail that allows them to feed. Crystal structures of several of these inhibitors reveal how peptides and proteins can be targeted to thrombin in different and interesting ways. Thrombin activity must also be regulated by endogenous inhibitors so that thrombi do not occlude blood flow and cause thrombosis. A single protein family, the serpins, provides all four of the endogenous thrombin inhibitors found in man. The crystal structures of these serpins bound to thrombin have been solved, revealing a similar exosite-dependence on complex formation. In addition to forming the recognition complex, serpins destroy the structure of thrombin, allowing them to be released from cofactors and substrates for clearance. This review examines how the special features of thrombin have been exploited by evolution to achieve inhibition of the ultimate coagulation protease. © Schattauer 2014.


Huntington J.A.,University of Cambridge
Journal of Thrombosis and Haemostasis | Year: 2013

Thrombin is the central protease in the blood coagulation network. It has multiple substrates and cofactors, and it appears that four serpins are responsible for inhibiting the thrombin produced in haemostasis and thrombosis. Structural studies conducted over the last 10 years have resolved how thrombin recognises these serpins with the aid of cofactors. Although antithrombin (AT), protein C inhibitor (PCI), heparin cofactor II (HCII) and protease nexin-1 (PN1) all share a common fold and mechanism of protease inhibition, they have evolved radically different mechanisms for cofactor-assisted thrombin recognition. This is likely to be due to the varied environments in which thrombin is found. In this review, I discuss the unusual structural features of thrombin that are involved in substrate and cofactor recognition, the serpin mechanism of protease inhibition and the fate of thrombin in the complex, and how the four thrombin-specific serpins exploit the special features of thrombin to accelerate complex formation. © 2013 International Society on Thrombosis and Haemostasis.


Crilly N.,University of Cambridge
Design Studies | Year: 2013

Concepts of function are central to design but statements about a device's functions can be interpreted in different ways. This raises problems for researchers trying to clarify the foundations of design theory and for those developing design support-tools that can represent and reason about function. By showing how functions relate systems to their sub-systems and super-systems, this article illustrates some limitations of existing function terminology and some problems with existing function statements. To address these issues, a system-relative function terminology is introduced. This is used to demonstrate that systems function not only with respect to their most local super-system, but also with respect to their more global super-systems. © 2012 Elsevier Ltd. All rights reserved.


Yang X.-S.,University of Cambridge
Engineering with Computers | Year: 2013

Design problems in industrial engineering often involve a large number of design variables with multiple objectives, under complex nonlinear constraints. The algorithms for multiobjective problems can be significantly different from the methods for single objective optimization. To find the Pareto front and non-dominated set for a nonlinear multiobjective optimization problem may require significant computing effort, even for seemingly simple problems. Metaheuristic algorithms start to show their advantages in dealing with multiobjective optimization. In this paper, we extend the recently developed firefly algorithm to solve multiobjective optimization problems. We validate the proposed approach using a selected subset of test functions and then apply it to solve design optimization benchmarks. We will discuss our results and provide topics for further research. © 2012 Springer-Verlag London Limited.


Del Zanna G.,University of Cambridge
Astronomy and Astrophysics | Year: 2012

A collection of the best solar and laboratory spectra in the soft X-rays is used to perform a preliminary benchmark in this wavelength region, by comparing observed with predicted wavelengths and calibrated solar irradiances. The benchmark focuses on the Fe ix-Fe xiv ions, for which we have recently calculated the relevant atomic data; however, a few other ions have also been benchmarked. The iron ions dominate the soft X-rays, however a large fraction of the strongest soft X-ray lines due to n = 4 → n = 3 transitions were previously unidentified. The strongest transitions are all identified here, in particular the decays from the core-excited levels (3s 3p l 4s, l = 5,4,3,2,1 for Fe x, Fe xi, Fe xii, Fe xiii, and Fe xiv, respectively), which are the strongest soft X-ray transitions from these ions. Many new identifications are proposed, some only tentatively. Good agreement in terms of solar irradiances between the soft-Xray and EUV (n = 3 → n = 3) transitions is found, confirming the reliability of the new large-scale calculations. Some of the new atomic data and identifications are particularly important for the Solar Dynamic Observatory (SDO) Atmospheric Imaging Assembly (AIA) 94 Å © 2012 ESO.


Kumareswaran K.,University of Cambridge
Discovery medicine | Year: 2012

The prevalence of type 1 diabetes is escalating worldwide. Novel therapies and management strategies are needed to reduce associated morbidity. Aggressive blood glucose lowering using conventional insulin replacement regimens is limited by the risk of hypoglycemia. Even the most motivated patients may struggle to manage day-to-day variability in insulin requirements. The artificial pancreas or closed-loop insulin delivery may improve outcomes, building on recent technological progress and combining continuous glucose monitoring with insulin pump therapy. So far, closed-loop prototypes have been evaluated under controlled conditions suggesting improved glucose control and a reduced risk of hypoglycemia. Limitations include suboptimal accuracy and reliability of continuous glucose monitors and delays associated with subcutaneous insulin delivery. Outpatient evaluation is required as the next step, leading to deployment into clinical practice.


Li W.,University of Cambridge
Proceedings of the American Thoracic Society | Year: 2010

More than 70% of cases of heritable pulmonary arterial hypertension are due to heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor-β/BMP superfamily. Among the many mutations identified, some involve substitution of cysteine residues in the ligand-binding domain or the kinase domains of BMPR-II. These mutants are characterized by retention within the endoplasmic reticulum. This retention causes loss of function in terms of phosphorylation of downstream Smad1, Smad5, and Smad8 and the transcription of BMP target genes. The retention has a dominant negative effect on BMP signaling because it also impairs trafficking of the associated type I receptor. Studies suggest a more severe phenotype in patients with this class of mutation. We have shown that trafficking of cysteine-substituted mutants can be partially restored in the presence of chemical chaperones. Restoration of cell surface expression of ligand-binding domain mutants leads to partial rescue of BMP signaling and suggests that small-molecule pharmacological chaperones may be a therapeutic option in these patients.


Del Zanna G.,University of Cambridge
Astronomy and Astrophysics | Year: 2012

The coronal lines that are observable in the Hinode EUV Imaging Spectrometer (EIS) wavelengths are assessed with new atomic data that have recently become available for a range of important ions. EIS spectral lines are identified based on their spatial variation across different solar regions, their wavelengths, and their intensities. Two off-limb observations are presented, one above an active region, and one in the quiet Sun. The spectra are relatively free of low-temperature lines. Accurate wavelengths and intensities are provided. The observed and predicted line intensities generally agree excellently, once blending is taken into account. The main diagnostics available for measuring the electron density of the solar corona using EIS are highlighted with the use of the emissivity ratio technique. Densities obtained from different ions agree excellently. Most of the previous identifications are confirmed. A considerable number of weaker lines still await identification, however. The approximate formation temperature of the main unidentified lines is provided to aid the identification process. The EIS radiometric calibration appears to be in need of revision. A new quiet-Sun argon/iron relative abundance of 0.16, in line with Galactic measurements, is found. The abundances of sulphur and argon in the "background" unresolved active region emission are found to be lower by a factor of about two at 1.5 MK, and even lower at 3 MK. © 2012 ESO.


McMahon H.T.,University of Cambridge | Boucrot E.,Birkbeck, University of London
Journal of Cell Science | Year: 2015

Membrane curvature is an important parameter in defining the morphology of cells, organelles and local membrane subdomains. Transport intermediates have simpler shapes, being either spheres or tubules. The generation and maintenance of curvature is of central importance for maintaining trafficking and cellular functions. It is possible that local shapes in complex membranes could help to define local subregions. In this Cell Science at a Glance article and accompanying poster, we summarize how generating, sensing and maintaining high local membrane curvature is an active process that is mediated and controlled by specialized proteins using general mechanisms: (i) changes in lipid composition and asymmetry, (ii) partitioning of shaped transmembrane domains of integral membrane proteins or protein or domain crowding, (iii) reversible insertion of hydrophobic protein motifs, (iv) nanoscopic scaffolding by oligomerized hydrophilic protein domains and, finally, (v) macroscopic scaffolding by the cytoskeleton with forces generated by polymerization and by molecular motors.We also summarize some of the discoveries about the functions of membrane curvature, where in addition to providing cell or organelle shape, local curvature can affect processes like membrane scission and fusion as well as protein concentration and enzyme activation on membranes. © 2015. Published by The Company of Biologists Ltd.


Baglin T.,University of Cambridge
British Journal of Haematology | Year: 2013

Summary: Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. For some patients these oral direct inhibitors (ODIs) offer substantial benefits over oral vitamin K antagonists (VKA). However, for the majority of patients with good anticoagulant control with VKAs the advantages of the ODIs are primarily convenience and few drug interactions. The drugs are prescribed at fixed dose without the need for monitoring or dose adjustment in the majority of patients and the rapid onset of anticoagulation and short half-life make initiation and interruption of anticoagulation considerably easier than with VKAs. As yet, specific antidotes to ODIs are not available for clinical use but these are in development as rapid reversal agents. As with all anticoagulants produced so far, there is a correlation between intensity of anticoagulation and bleeding. Consequently, the need to consider the balance of benefit and risk in each individual patient is no less important than with VKA therapy. Dabigatran and rivaroxaban have been chosen for this review as examples of a thrombin inhibitor and an inhibitor of factor Xa respectively. The clinical application of these drugs is the focus of the review. © 2013 John Wiley & Sons Ltd.


Marcinak S.J.,University of Cambridge
Proceedings of the American Thoracic Society | Year: 2010

The early steps in the biogenesis of secreted and membrane proteins occur in the lumen of the endoplasmic reticulum (ER), where resident proteins that make up the ER machinery assist in their folding, maturation, and complex assembly. Variation in the load of ER client proteins and in the function of the organelle's aforementioned machinery for coping with that load can lead to an imbalance between the two that is referred to as ER stress. This triggers a cellular response, mediated by highly conserved signaling pathways that collectively restore equilibrium to the protein-folding environment in the organelle by increasing the expression of genes that enhance nearly all aspects of ER function, and by transiently repressing the biosynthesis of new client proteins. Evidence accrued over the past 10 years suggests that ER stress and response to it influence the fate of mutant proteins that fold inefficiently, impact on the functionality of cells and tissues that cope with unusual loads of ER client proteins, and intersect with signaling pathways that influence inflammation and cancer biology. Here, we review some of the basic workings of unfolded protein response and relate them to processes that are of potential relevance to pulmonary disease.


Bateson P.,University of Cambridge
Neuroscience and Biobehavioral Reviews | Year: 2015

Finding a link between learning and a change in the brain was only a first step in establishing a representation of the imprinting object. A series of overlapping experiments were necessary to eliminate alternative explanations. Once completed, a structure, the intermediate and medial mesopallium (IMM), was found to be strongly linked to the formation of a neural representation of the object used for imprinting the birds. With the site identified, lesion experiments showed that it was necessary for imprinting but not associative learning.Also the two sides of the brain responded differently with the left IMM acting as a permanent store and the right side acting as a way station to other parts of the brain. The collaborative work led to many studies by Gabriel Horn with others on the molecular and cellular bases of imprinting, and also to neural net modelling and behavioural studies with me on the nature of category formation in intact animals. © 2014 Elsevier Ltd.


Wadhams P.,University of Cambridge
Ambio | Year: 2012

We summarize the latest results on the rapid changes that are occurring to Arctic sea ice thickness and extent, the reasons for them, and the methods being used to monitor the changing ice thickness. Arctic sea ice extent had been shrinking at a relatively modest rate of 3-4%per decade (annually averaged) but after 1996 this speeded up to 10% per decade and in summer 2007 there was a massive collapse of ice extent to a new record minimum of only 4.1 million km 2. Thickness has been falling at a more rapid rate (43% in the 25 years from the early 1970s to late 1990s) with a specially rapid loss of mass from pressure ridges. The summer 2007 event may have arisen from an interaction between the long-term retreat and more rapid thinning rates. We review thickness monitoring techniques that show the greatest promise on different spatial and temporal scales, and for different purposes. We show results from some recent work from submarines, and speculate that the trends towards retreat and thinning will inevitably lead to an eventual loss of all ice in summer, which can be described as a 'tipping point' in that the former situation, of an Arctic covered with mainly multi-year ice, cannot be retrieved. © 2012 Royal Swedish Academy of Sciences.


Ogilvie G.I.,University of Cambridge
Monthly Notices of the Royal Astronomical Society | Year: 2012

The acceleration of an outflow along inclined magnetic field lines emanating from an accretion disc can be studied in the local approximation, as employed in the computational model known as the shearing box. By including the slow magnetosonic point within the computational domain, the rate of mass loss in the outflow can be calculated. The accretion rates of mass and magnetic flux can also be determined, although some effects of cylindrical geometry are omitted. We formulate a simple model for the study of this problem and present the results of one-dimensional numerical simulations and supporting calculations. Quasi-steady solutions are obtained for relatively strong poloidal magnetic fields for which the magnetorotational instability is suppressed. In this regime the rate of mass loss decreases extremely rapidly with increasing field strength, or with decreasing surface density or temperature. If the poloidal magnetic field in an accretion disc can locally achieve an appropriate strength and inclination, then a rapid burst of ejection may occur. For weaker fields it may be possible to study the launching process in parallel with the magnetorotational instability, but this will require three-dimensional simulations. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Hyatt A.J.,University of Cambridge
Investigative ophthalmology & visual science | Year: 2012

To develop a contact lens capable of releasing antibiotics for a minimum of 8 hours for the treatment of bacterial keratitis. Fibrin gel was loaded with vancomycin or gentamicin and then shaped into a curved disc. The disc was then used to coat the surface of a commercial contact lens or was sealed between two lenses. Separate contact lenses were soaked in solutions of vancomycin or gentamicin. The in vitro release kinetics for each system was determined using PBS at 37°C and a particle-enhanced turbidimetric inhibition immunoassay. The bioactivity of the antibiotics released from the fibrin was confirmed by using a microbiological assay. Vancomycin and gentamicin were released at similar rates from soaked contact lenses and a coating of fibrin gel; however, the amounts of antibiotic delivered by the two systems differed considerably. The fibrin coating released over three times more gentamicin but less than one-fifth that of the lenses soaked in vancomycin. When fibrin was encapsulated between two contact lenses, significantly more controlled release was observed. For all systems, bactericidal amounts of vancomycin and gentamicin were released throughout the three-day testing period. As a delivery system, fibrin gel loaded with gentamicin performs better than contact lenses soaked in gentamicin. The opposite is true for vancomycin, where soaked lenses outperform fibrin gel. These systems could potentially be used as a treatment for bacterial keratitis.


Baglin T.,University of Cambridge
Journal of Thrombosis and Haemostasis | Year: 2013

Orally active small molecules that selectively and specifically inhibit coagulation serine proteases have been developed for clinical use. Dabigatran etexilate, rivaroxaban and apixaban are given at fixed doses and do not require monitoring. In most circumstances, these drugs have predictable bioavailability, pharmacokinetic effects, and pharmacodynamic effects. However, there will be clinical circumstances when assessment of the anticoagulant effect of these drugs will be required. The effect of these drugs on laboratory tests has been determined in vitro by spiking normal samples with a known concentration of active compound, or ex vivo by using plasma samples from volunteers and patients. Data on the sensitivity of different reagents are now available, and so guidance as to the effect and interpretation of a test result is now possible. Laboratories should be aware of the sensitivity of their own assays to each drug. This may be achieved by using appropriate calibrated plasma samples. © 2013 International Society on Thrombosis and Haemostasis.


Risdall J.E.,Royal Netherlands Navy | Menon D.K.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2011

There is an increasing incidence of military traumatic brain injury (TBI), and similar injuries are seen in civilians in war zones or terrorist incidents. Indeed, blast-induced mild TBI has been referred to as the signature injury of the conflicts in Iraq and Afghanistan. Assessment involves schemes that are common in civilcian practice but, in common with civilian TBI, takes little account of information available from modern imaging (particularly diffusion tensor magnetic resonance imaging) and emerging biomarkers. The efficient logistics of clinical care delivery in the field may have a role in optimizing outcome. Clinical care has much in common with civilian TBI, but intracranial pressure monitoring is not always available, and protocols need to be modified to take account of this. In addition, severe early oedema has led to increasing use of decompressive craniectomy, and blast TBI may be associated with a higher incidence of vasospasm and pseudoaneurysm formation. Visual and/or auditory deficits are common, and there is a significant risk of post-traumatic epilepsy. TBI is rarely an isolated finding in this setting, and persistent post-concussive symptoms are commonly associated with post-traumatic stress disorder and chronic pain, a constellation of findings that has been called the polytrauma clinical triad. © 2011 The Royal Society.


Aarseth S.J.,University of Cambridge
Monthly Notices of the Royal Astronomical Society | Year: 2012

We report on results of fully consistent N-body simulations of globular cluster models with N= 100000 members containing neutron stars and black holes (BHs). Using the improved 'algorithmic regularization' method of Hellström & Mikkola for compact subsystems, the new code nbody7 enables for the first time general relativistic coalescence to be achieved for post-Newtonian terms and realistic parameters. Following an early stage of mass segregation, a few BHs form a small dense core which usually leads to the formation of one dominant binary. The subsequent evolution by dynamical shrinkage involves the competing processes of ejection and mergers by radiation energy loss. Unless the binary is ejected, long-lived triple systems often exhibit Kozai cycles with extremely high inner eccentricity (e > 0.999) which may terminate in coalescence at a few Schwarzschild radii. A characteristic feature is that ordinary stars as well as BHs and even BH binaries are ejected with high velocities. On the basis of the models studied so far, the results suggest a limited growth of a few remaining stellar mass BHs in globular clusters. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Scheres S.H.W.,University of Cambridge
Journal of Structural Biology | Year: 2012

RELION, for REgularized LIkelihood OptimizatioN, is an open-source computer program for the refinement of macromolecular structures by single-particle analysis of electron cryo-microscopy (cryo-EM) data. Whereas alternative approaches often rely on user expertise for the tuning of parameters, RELION uses a Bayesian approach to infer parameters of a statistical model from the data. This paper describes developments that reduce the computational costs of the underlying maximum a posteriori (MAP) algorithm, as well as statistical considerations that yield new insights into the accuracy with which the relative orientations of individual particles may be determined. A so-called gold-standard Fourier shell correlation (FSC) procedure to prevent overfitting is also described. The resulting implementation yields high-quality reconstructions and reliable resolution estimates with minimal user intervention and at acceptable computational costs. © 2012 Elsevier Inc.


Holman D.,University of Cambridge
Sociology of Health and Illness | Year: 2014

Talking treatments are underused in England by working-class people: their higher rates of common mental disorders compared with their middle-class counterparts are not matched by an increased use of these treatments. Given that, overall, talking treatments are effective in tackling depression and anxiety, understanding their underuse is important. Based upon semi-structured interview data I argue that a framework centred on individuals' cultural dispositions towards treatment can help with this task. Following Bourdieu, such dispositions can be traced to social structural conditioning factors, together comprising the habitus. Four key dispositions emerge from the data: verbalisation and introspection, impetus for emotional health, relation to medical authority and practical orientation to the future. In turn, these dispositions are rooted in the material, health, occupational and educational characteristics of working-class circumstances. Tracing these circumstances offers suggestions for increasing the use of this service. © 2013 Foundation for the Sociology of Health & Illness/John Wiley & Sons Ltd.


Amos W.,University of Cambridge
Proceedings of the Royal Society B: Biological Sciences | Year: 2010

Single nucleotide polymorphisms (SNPs) are distributed highly non-randomly in the human genome through a variety of processes from ascertainment biases (i.e. the preferential development of SNPs around interesting genes) to the action of mutation hotspots and natural selection. However, with more systematic SNP development, one might expect an increasing proportion of SNPs to be distributed more or less randomly. Here, I test this null hypothesis using stochastic simulations and compare this output with that of an alternative hypothesis that mutations are more likely to occur near existing SNPs, a possibility suggested both by molecular studies of meiotic mismatch repair in yeast and by data showing that SNPs cluster around heterozygous deletions. A purely Poisson process generates SNP clusters that differ from equivalent data from human chromosome 1 in both the frequency of different-sized clusters and the SNP density within each cluster, even for small clusters of just four or five SNPs, while clusters on the X chromosome differ from those on the autosomes. In contrast, modest levels of mutational non-independence generate a reasonable fit to the real data for both cluster frequency and density, and also exhibit the evolutionary transience noted for 'mutation hotspots'. Mutational nonindependence therefore provides an interesting new hypothesis that appears capable of explaining the distribution of SNPs in the human genome. © 2010 The Royal Society.


Clark L.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Gambling is a widespread form of entertainment that may afford unique insights into the interaction between cognition and emotion in human decision-making. It is also a behaviour that can become harmful, and potentially addictive, in a minority of individuals. This article considers the status of two dominant approaches to gambling behaviour. The cognitive approach has identified a number of erroneous beliefs held by gamblers, which cause them to over-estimate their chances of winning. The psychobiological approach has examined case-control differences between groups of pathological gamblers and healthy controls, and has identified dysregulation of brain areas linked to reward and emotion, including the ventromedial prefrontal cortex (vmPFC) and striatum, as well as alterations in dopamine neurotransmission. In integrating these two approaches, recent data are discussed that reveal anomalous recruitment of the brain reward system (including the vmPFC and ventral striatum) during two common cognitive distortions in gambling games: the near-miss effect and the effect of personal control. In games of chance, near-misses and the presence of control have no objective influence on the likelihood of winning. These manipulations appear to harness a reward system that evolved to learn skill-oriented behaviours, and by modulating activity in this system, these cognitive distortions may promote continued, and potentially excessive, gambling. © 2010 The Royal Society.


Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. The National Institute for Health Research Health Technology Assessment programme.


Schultz W.,University of Cambridge
Physiological Reviews | Year: 2015

Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act. © 2015 the American Physiological Society.


Parker D.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2010

Neuronal networks assemble the cellular components needed for sensory, motor and cognitive functions. Any rational intervention in the nervous system will thus require an understanding of network function. Obtaining this understanding is widely considered to be one of the major tasks facing neuroscience today. Network analyses have been performed for some years in relatively simple systems. In addition to the direct insights these systems have provided, they also illustrate some of the difficulties of understanding network function. Nevertheless, in more complex systems (including human), claims are made that the cellular bases of behaviour are, or will shortly be, understood. While the discussion is necessarily limited, this issue will examine these claims and highlight some traditional and novel aspects of network analyses and their difficulties. This introduction discusses the criteria that need to be satisfied for network understanding, and how they relate to traditional and novel approaches being applied to addressing network function. © 2010 The Royal Society.


This protocol has been designed to generate neural precursor cells (NPCs) from human embryonic stem cells (hESCs) using a physiological oxygen (O(2)) level of 3% (previously termed hypoxia) and chemically defined conditions. The first stage involves suspension culture of hESC colonies at 3% O(2), where they acquire a neuroepithelial identity over a period of 2 weeks. This timescale is comparable to that observed at 20% O(2), but survival is enhanced. Sequential application of retinoic acid and purmorphamine (PM), from day 14 to day 28, directs differentiation toward spinal motor neurons. Alternatively, addition of fibroblast growth factor-8 and PM generates midbrain dopaminergic neurons. OLIG2 (encoding oligodendrocyte lineage transcription factor 2) induction in motor neuron precursors is twofold greater than that at 20% O(2), whereas EN1 (encoding engrailed homeobox 1) expression is enhanced fivefold. NPCs (at 3% O(2)) can be differentiated into all three neural lineages, and such cultures can be maintained long term in the absence of neurotrophins. The ability to generate defined cell types at 3% O(2) should represent a significant advancement for in vitro disease modeling and potentially for cell-based therapies.


Burrows M.,University of Cambridge
Journal of Experimental Biology | Year: 2010

The hind legs of Issus (Hemiptera, lssidae) move in the same plane underneath the body, an arrangement that means they must also move synchronously to power jumping. Moreover, they move so quickly that energy must be stored before a jump and then released suddenly. High speed imaging and analysis of the mechanics of the proximal joints of the hind legs show that mechanical mechanisms ensure both synchrony of movements and energy storage. The hind trochantera move first in jumping and are synchronised to within 30s. Synchrony is achieved by mechanical interactions between small protrusions from each trochantera which fluoresce bright blue under specific wavelengths of ultra-violet light and which touch at the midline when the legs are cocked before a jump. In dead Issus, a depression force applied to a cocked hind leg, or to the tendon of its trochanteral depressor muscle causes a simultaneous depression of both hind legs. The protrusion of the hind leg that moves first nudges the other hind leg so that both move synchronously. Contractions of the trochanteral depressor muscles that precede a jump bend the metathoracic pleural arches of the internal skeleton. Large areas of these bow-shaped structures fluoresce bright blue in ultraviolet light, and the intensity of this fluorescence depends on the pH of the bathing saline. These are key signatures of the rubber-like protein resilin. The remainder of a pleural arch consists of stiff cuticle. Bending these composite structures stores energy and their recoil powers jumping. © 2010. Published by The Company of Biologists Ltd.


Vinothkumar K.R.,University of Cambridge | Zhu J.,MRC Mitochondrial Biology Unit | Hirst J.,MRC Mitochondrial Biology Unit
Nature | Year: 2014

Complex I (NADH:ubiquinone oxidoreductase) is essential for oxidative phosphorylation in mammalian mitochondria. It couples electron transfer from NADH to ubiquinone with proton translocation across the energy-transducing inner membrane, providing electrons for respiration and driving ATP synthesis. Mammalian complex I contains 44 different nuclear- and mitochondrial-encoded subunits, with a combined mass of 1 MDa. The 14 conserved 'core' subunits have been structurally defined in the minimal, bacterial complex, but the structures and arrangement of the 30 'supernumerary' subunits are unknown. Here we describe a 5 Å resolution structure of complex I from Bos taurus heart mitochondria, a close relative of the human enzyme, determined by single-particle electron cryo-microscopy. We present the structures of the mammalian core subunits that contain eight iron-sulphur clusters and 60 transmembrane helices, identify 18 supernumerary transmembrane helices, and assign and model 14 supernumerary subunits. Thus, we considerably advance knowledge of the structure of mammalian complex I and the architecture of its supernumerary ensemble around the core domains. Our structure provides insights into the roles of the supernumerary subunits in regulation, assembly and homeostasis, and a basis for understanding the effects of mutations that cause a diverse range of human diseases. ©2014 Macmillan Publishers Limited. All rights reserved.


Hernandez-Ainsa S.,University of Cambridge
The Analyst | Year: 2013

We report a simple and efficient way to accomplish the chemical modification of glass nanopores by means of lipid self-assembly. Lipid coating improves the success rate of these glass nanopores as biosensors to detect λ-DNA.


Scott J.F.,University of Cambridge
Annual Review of Materials Research | Year: 2011

Electrocaloric materials are reviewed through a discussion of ferroelectric crystals used to achieve refrigeration via adiabatic depolarization. Related thermodynamics is briefly summarized, but emphasis is on experiments and materials. © 2011 by Annual Reviews. All rights reserved.


Vendruscolo M.,University of Cambridge
Current Opinion in Structural Biology | Year: 2012

The description of protein folding at the proteome level requires further principles in addition to those that govern this phenomenon for individual molecules. An important aspect of the increased complexity of the folding process in the cellular environment is that proteins tend to be metastable against aggregation, as they are often expressed at levels at which they are poorly soluble. The maintenance of the solubility of the proteome requires the coordinated intervention of a range of quality control mechanisms, which include molecular chaperones, trafficking and degradation pathways, post-translational modifications and transcriptional and translational control. As these regulatory mechanisms should always be active to keep proteins in their soluble state, their impairment upon ageing or environmental stress can lead to the disruption of protein homeostasis resulting in uncontrolled widespread aggregation and disease. © 2012 Elsevier Ltd.


Donnachie A.,University of Manchester | Landshoff P.V.,University of Cambridge
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2013

It is shown that pp and pp- data, including those from the TOTEM experiment, agree well with Regge theory. © 2013 Elsevier B.V.


Lester C.G.,University of Cambridge
Journal of High Energy Physics | Year: 2011

This document describes some special cases in which the stransverse mass, MT2, may be calculated by non-iterative algorithms. The most notable special case is that in which the visible particles and the hypothesised invisible particles are massless - a situation relevant to its current usage in the Large Hadron Collider as a discovery variable, and a situation for which no analytic answer was previously known. We also derive an expression for M T2 in another set of new (though arguably less interesting) special cases in which the missing transverse momentum must point parallel or anti parallel to the visible momentum sum. In addition, we find new derivations for already known MT2 solutions in a manner that maintains manifest contralinear boost invariance throughout, providing new insights into old results. Along the way, we stumble across some unexpected results and make conjectures relating to geometric forms of Meff and HT and their relationship to MT2. © SISSA 2011.


Amaral A.I.,University of Cambridge
Journal of Inherited Metabolic Disease | Year: 2013

Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes. © 2012 SSIEM and Springer Science+Business Media Dordrecht.


Franze K.,University of Cambridge
Development (Cambridge) | Year: 2013

The development of the nervous system has so far, to a large extent, been considered in the context of biochemistry, molecular biology and genetics. However, there is growing evidence that many biological systems also integrate mechanical information when making decisions during differentiation, growth, proliferation, migration and general function. Based on recent findings, I hypothesize that several steps during nervous system development, including neural progenitor cell differentiation, neuronal migration, axon extension and the folding of the brain, rely on or are even driven by mechanical cues and forces. © 2013. Published by The Company of Biologists Ltd.


Bowsher C.G.,University of Cambridge
Journal of the Royal Society Interface | Year: 2011

Understanding how information is encoded and transferred by biochemical networks is of fundamental importance in cellular and systems biology. This requires analysis of the relationships between the stochastic trajectories of the constituent molecular (or submolecular) species that comprise the network. We describe how to identify conditional independences between the trajectories or time courses of groups of species. These are robust network properties that provide important insight into how information is processed. An entire network can then be decomposed exactly into modules on informational grounds. In the context of signalling networks with multiple inputs, the approach identifies the routes and species involved in sequential information processing between input and output modules. An algorithm is developed which allows automated identification of decompositions for large networks and visualization using a tree that encodes the conditional independences. Only stoichiometric information is used and neither simulations nor knowledge of rate parameters are required. A bespoke version of the algorithm for signalling networks identifies the routes of sequential encoding between inputs and outputs, visualized as paths in the tree. Application to the toll-like receptor signalling network reveals that inputs can be informative in ways unanticipated by steady-state analyses, that the information processing structure is not well described as a bow tie, and that encoding for the interferon response is unusually sparse compared with other outputs of this innate immune system. © 2010 The Royal Society.


Juhas M.,University of Cambridge
Critical Reviews in Microbiology | Year: 2015

Horizontal gene transfer has a tremendous impact on the genome plasticity, adaptation and evolution of bacteria. Horizontally transferred mobile genetic elements are involved in the dissemination of antibiotic resistance and virulence genes, thus contributing to the emergence of novel "superbugs". This review provides update on various mechanisms of horizontal gene transfer and examines how horizontal gene transfer contributes to the evolution of pathogenic bacteria. Special focus is paid to the role horizontal gene transfer plays in pathogenicity of the emerging human pathogens: hypervirulent Clostridium difficile and Escherichia coli (including the most recent haemolytic uraemic syndrome outbreak strain) and methicillin-resistant Staphylococcus aureus (MRSA), which have been associated with largest outbreaks of infection recently. © 2015 Informa Healthcare USA, Inc.


Whittle A.,University of Cambridge
Journal of Molecular Endocrinology | Year: 2012

Obesity rates are increasing alongside those of its co-morbidities, placing a huge strain on health systems across the globe. Evidence points to inappropriate levels of ectopic lipid accumulation outside of adipose tissue being a major factor in the progression of many of these diseases. Brown adipose tissue (BAT) has a huge capacity to remove lipids from the circulatory system to fuel thermogenesis. Multiple studies have now confirmed the existence of active BAT in adult humans, making strategies aimed at activating it a potential therapeutic option in obese subjects. In recent years, researchers working in murine models have found a wide range of endogenous molecules with specific roles regulating BAT. These findings place BAT firmly within the wider network of physiological regulation covering global metabolism. They also highlight the possibility of targeting thermogenesis in a safe and specific manner to remove potentially harmful lipids released from stressed or failing white adipose tissue in obese states. © 2012 Society for Endocrinology.


Regulatory elements in the 3′ untranslated regions (UTRs) of eukaryotic mRNAs influence mRNA localization, translation, and stability. 3′-UTR length is determined by the location at which mRNAs are cleaved and polyadenylated. The use of alternative polyadenylation sites is common, and can be regulated in different situations. I present a new method to identify cleavage and polyadenylation sites (CS s) at the genome-wide level. The approach is strand-specific, avoids RNA enzymatic modification steps that can introduce sequence-specific biases, and uses unique molecular identifiers to ensure that all identified CS originates from individual RNA molecules. I applied this method to create the first comprehensive genome-wide map of polyadenylation sites of the fission yeast Schizosaccharomyces pombe, comprising the analysis of 2,021,000 individual mRNAs that defined 8,883 CS s. CS s were identified for 90% of coding genes and 50% of ncRNAs. Alternative polyadenylation was prevalent in both groups, with 41% and 45% of all detected genes, respectively, displaying more than one CS . The specificity of the cleavage reaction was gene-specific, resulting in highly variable levels of heterogeneity in 3′-UTR lengths. Finally, I show that for both coding and non-coding genes, the most common regulatory motif associated with CS s in fission yeast is the canonical human AAUAAA sequence. © 2013 Landes Bioscience.


Willoughby D.,University of Cambridge
Biochemical Society Transactions | Year: 2012

Cross-talk between cAMP and Ca 2+ signalling pathways plays a critical role in cellular homoeostasis. Several AC (adenylate cyclase) isoforms, catalysing the production of cAMP from ATP, display sensitivity to submicromolar changes in intracellular Ca 2+ and, as a consequence, are key sites for Ca 2+ and cAMP interplay. Interestingly, these Ca 2+ -regulated ACs are not equally responsive to equivalent Ca 2+ rises within the cell, but display a remarkable selectivity for regulation by SOCE (store-operated Ca 2+ entry). Over the years, considerable efforts at investigating this phenomenon have provided indirect evidence of an intimate association between Ca 2+ -sensitive AC isoforms and sites of SOCE. Now, recent identification of the molecular components of SOCE [namely STIM1 (stromal interaction molecule 1) and Orai1], coupled with significant advances in the generation of high-resolution targeted biosensors for Ca 2+ and cAMP, have provided the first detailed insight into the organization of the cellular microdomains associated with Ca 2+ -regulated ACs. In the present review, I summarize the findings that have helped to provide our most definitive understanding of the selective regulation of cAMP signalling by SOCE. ©The Authors Journal compilation ©2012 Biochemical Society.


Bull A.D.,University of Cambridge
Journal of Machine Learning Research | Year: 2011

In the efficient global optimization problem, we minimize an unknown function f, using as few observations f(x) as possible. It can be considered a continuum-armed-bandit problem, with noiseless data, and simple regret. Expected-improvement algorithms are perhaps the most popular methods for solving the problem; in this paper, we provide theoretical results on their asymptotic behaviour. Implementing these algorithms requires a choice of Gaussian-process prior, which determines an associated space of functions, its reproducing-kernel Hilbert space (RKHS). When the prior is fixed, expected improvement is known to converge on the minimum of any function in its RKHS. We provide convergence rates for this procedure, optimal for functions of low smoothness, and describe a modified algorithm attaining optimal rates for smoother functions. In practice, however, priors are typically estimated sequentially from the data. For standard estimators, we show this procedure may never find the minimum of f. We then propose alternative estimators, chosen to minimize the constants in the rate of convergence, and show these estimators retain the convergence rates of a fixed prior. © 2011 Adam D. Bull.


Hunter R.H.F.,University of Cambridge
Reproductive BioMedicine Online | Year: 2012

Deep body temperature in mammals is generally but incorrectly regarded as uniform. Alterations of temperature in oviducts and preovulatory Graafian follicles may play a vital role in gamete maturation, fertilization and early embryonic development. At a molecular level, the conformation of regulatory proteins is susceptible to changes in temperature. Deviation from physiological temperature during IVF procedures could thereby exert a profound influence on patterns of gene expression as the embryonic genome unfolds during early cleavage stages and act to generate specific anomalies. Systematic studies are urgently required. The temperature of internal body organs in mammals such as rabbits and humans is widely regarded as uniform, but this is not correct. Temperatures in reproductive tissues such as ovaries and oviducts vary according to the stage of a menstrual or oestrous cycle. Such changes in temperature are thought to be critically involved in the maturation of eggs and spermatozoa and thus in events shortly before and after fertilization. Proteins in the cytoplasm and nuclei of eggs and very young embryos respond to small shifts in temperature by changing their three-dimensional shape. Conformational modifications in regulatory proteins in the nucleus would influence patterns of gene expression in developing embryos and may, when perturbed, alter the sexual phenotype of an individual. In the practical context of IVF, studies are needed of the influence of culturing gametes and embryos at different temperatures and ranges of temperature on the patterns of gene expression in preimplantation embryos. © 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Sale J.E.,University of Cambridge | Lehmann A.R.,University of Sussex | Woodgate R.,U.S. National Institutes of Health
Nature Reviews Molecular Cell Biology | Year: 2012

The past 15 years have seen an explosion in our understanding of how cells replicate damaged DNA and how this can lead to mutagenesis. The Y-family DNA polymerases lie at the heart of this process, which is commonly known as translesion synthesis. This family of polymerases has unique features that enable them to synthesize DNA past damaged bases. However, as they exhibit low fidelity when copying undamaged DNA, it is essential that they are only called into play when they are absolutely required. Several layers of regulation ensure that this is achieved. © 2012 Macmillan Publishers Limited. All rights reserved.


Bemporad F.,University of Cambridge | Chiti F.,University of Florence
Chemistry and Biology | Year: 2012

The conversion of proteins from their native state to misfolded oligomers is associated with, and thought to be the cause of, a number of human diseases, including Alzheimer's disease, Parkinson's disease, and systemic amyloidoses. The study of the structure, mechanism of formation, and biological activity of protein misfolded oligomers has been challenged by the metastability, transient formation, and structural heterogeneity of such species. In spite of these difficulties, in the past few years, many experimental approaches have emerged that enable the detection and the detailed molecular study of misfolded oligomers. In this review, we describe the basic and generic knowledge achieved on protein oligomers, describing the mechanisms of oligomer formation, the methodologies used thus far for their structural determination, and the structural elements responsible for their toxicity. © 2012 Elsevier Ltd.


Parish M.M.,University of Cambridge
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We address the problem of a single "spin-down" impurity atom interacting attractively with a spin-up Fermi gas in two dimensions (2D). We consider the case where the mass of the impurity is greater than or equal to the mass of a spin-up fermion. Using a variational approach, we resolve the questions raised by previous studies and show that there is, in fact, a transition between polaron and molecule (dimer) ground states in 2D. For the molecule state, we use a variational wave function with a single particle-hole excitation on the Fermi sea and we find that its energy matches that of the exact solution in the limit of infinite impurity mass. Thus, we expect the variational approach to provide a reliable tool for investigating 2D systems. © 2011 American Physical Society.


Green D.A.,University of Cambridge
Bulletin of the Astronomical Society of India | Year: 2011

I describe a colour scheme that is appropriate for the screen display of intensity images. This-unlike many currently available schemes-is designed to be monotonically increasing in terms of its perceived brightness. Also, when printed on a black and white postscript printer, the scheme results in a greyscale with monotonically increasing brightness. This scheme has recently been incorporated into the radio astronomical analysis packages CASA and AIPS.


Fearon D.T.,University of Cambridge
Cancer immunology research | Year: 2014

The fibroblastic element of the tumor microenvironment has been of great interest to cancer biologists but less so to cancer immunologists. Yet, the sharing of a common mesenchymal cell type in the stroma of tumors and at sites of chronic inflammatory lesions, some of which have an autoimmune basis, has been a strong hint that this cellular component of the tumor microenvironment may have an immunologic function. Recent studies have confirmed this possibility. These fibroblast-like cells, which are termed carcinoma-associated fibroblasts (CAF), can be identified by their expression of the membrane protein, fibroblast activation protein-α (FAP). The conditional depletion of the FAP(+) CAF permits immune control not only of an artificial, transplanted tumor, but also of an autochthonous model of pancreatic ductal adenocarcinoma (PDA) that replicates the molecular, histologic, clinical, and immunologic characteristics of the human disease. Immune suppression by the FAP(+) CAF is mediated by CXCL12, the chemokine that binds to cancer cells and excludes T cells by a mechanism that depends on signaling by the CXCL12 receptor CXCR4. Inhibition of CXCR4 leads to the elimination of cancer cells by enabling the rapid, intratumoral accumulation of preexisting, PDA-specific CD8(+) T cells, and reveals the antitumor efficacy of the T-cell checkpoint antagonist anti-PD-L1. Recent studies have also shown that the FAP(+) CAF is related to FAP-expressing stromal cells of normal tissues, demonstrating that cancers recruit a member of an essential stromal cell lineage that is involved not only in wound repair but also in normal tissue homeostasis. These findings extend the concept introduced by cancer biologists that the fibroblastic component of tumors has a critical role in the adaptation of the cancer to the host. ©2014 AACR.


Deigan K.E.,U.S. National Institutes of Health | Deigan K.E.,University of Cambridge | Ferre-D'Amare A.R.,U.S. National Institutes of Health
Accounts of Chemical Research | Year: 2011

Riboswitches are messenger RNA (mRNA) domains that regulate gene function in response to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, thus representing an inviting new class of biomolecular target for the development of antibiotics and chemical-biological tools. In this Account, we briefly review the discovery of riboswitches in the first years of the 21st century and their ensuing characterization over the past decade. We then discuss the progress achieved so far in using riboswitches as a focus for drug discovery, considering both the value of past serendipity and the particular challenges that confront current researchers.Five mechanisms of gene regulation have been determined for riboswitches. Most bacterial riboswitches modulate either transcription termination or translation initiation in response to ligand binding. All known examples of eukaryotic riboswitches, and some bacterial riboswitches, control gene expression by alternative splicing. The glmS riboswitch, which is widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding: its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of a trans-acting riboswitch is known.Three-dimensional structures have been determined for representatives of 13 structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs have attracted widespread interest as potential drug targets, riboswitches show special promise due to the diversity of small-molecule recognition strategies that are on display in their ligand-binding pockets. Moreover, riboswitches have evolved to recognize small-molecule ligands, which is unique among known structured RNA domains.Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment-based screening approach employing equilibrium dialysis that may be generically useful has demonstrated early success. Riboswitch-mediated gene regulation is widely employed by bacteria; however, only the thiamine pyrophosphate-responsive riboswitch has thus far been found in eukaryotes. Thus, riboswitches are particularly attractive as targets for antibacterials. Indeed, antimicrobials with previously unknown mechanisms have been found to function by binding riboswitches and causing aberrant gene expression. © Published 2011 by the American Chemical Society.


In Dirac-Bergmann constrained dynamics, a first-class constraint typically does not alone generate a gauge transformation. By direct calculation it is found that each first-class constraint in Maxwell's theory generates a change in the electric field E→ by an arbitrary gradient, spoiling Gauss's law. The secondary first-class constraint pi, i=0 still holds, but being a function of derivatives of momenta (mere auxiliary fields), it is not directly about the observable electric field (a function of derivatives of Aμ), which couples to charge. Only a special combination of the two first-class constraints, the Anderson-Bergmann-Castellani gauge generator G, leaves E→ unchanged. Likewise only that combination leaves the canonical action invariant-an argument independent of observables. If one uses a first-class constraint to generate instead a canonical transformation, one partly strips the canonical coordinates of physical meaning as electromagnetic potentials, vindicating the Anderson-Bergmann Lagrangian orientation of interesting canonical transformations. The need to keep gauge-invariant the relation q˙-δHδp=-Ei-pi=0 supports using the gauge generator and primary Hamiltonian rather than the separate first-class constraints and the extended Hamiltonian. Partly paralleling Pons's criticism, it is shown that Dirac's proof that a first-class primary constraint generates a gauge transformation, by comparing evolutions from identical initial data, cancels out and hence fails to detect the alterations made to the initial state. It also neglects the arbitrary coordinates multiplying the secondary constraints inside the canonical Hamiltonian. Thus the gauge-generating property has been ascribed to the primaries alone, not the primary-secondary team G. Hence the Dirac conjecture about secondary first-class constraints as generating gauge transformations rests upon a false presupposition about primary first-class constraints. Clarity about Hamiltonian electromagnetism will be useful for an analogous treatment of GR. © 2014 Elsevier Inc.


Keyser U.F.,University of Cambridge
Journal of the Royal Society Interface | Year: 2011

Nanopores are emerging as powerful tools for the detection and identification of macromolecules in aqueous solution. In this review, we discuss the recent development of active and passive controls over molecular transport through nanopores with emphasis on biosensing applications. We give an overview of the solutions developed to enhance the sensitivity and specificity of the resistive-pulse technique based on biological and solid-state nanopores. © 2011 The Royal Society.


Al-Lamki R.S.,University of Cambridge | Mayadas T.N.,Brigham and Womens Hospital
Kidney International | Year: 2015

Tumor necrosis factor (TNF), initially reported to induce tumor cell apoptosis and cachexia, is now considered a central mediator of a broad range of biological activities from cell proliferation, cell death and differentiation to induction of inflammation and immune modulation. TNF exerts its biological responses via interaction with two cell surface receptors: TNFR1 and TNFR2. (TNFRs). These receptors trigger shared and distinct signaling pathways upon TNF binding, which in turn result in cellular outputs that may promote tissue injury on one hand but may also induce protective, beneficial responses. Yet the role of TNF and its receptors specifically in renal disease is still not well understood. This review describes the expression of the TNFRs, the signaling pathways induced by them and the biological responses of TNF and its receptors in various animal models of renal diseases, and discusses the current outcomes from use of TNF biologics and TNF biomarkers in renal disorders. © 2014 International Society of Nephrology.


Ortega-Hernandez J.,University of Cambridge
Current Biology | Year: 2015

Summary The Cambrian fossil record of euarthropods (extant arachnids, myriapods, crustaceans, hexapods) has played a major role in understanding the origins of these successful animals and indicates that early ancestors underwent an evolutionary transition from soft-bodied taxa (lobopodians) to more familiar sclerotized forms with jointed appendages [1-3]. Recent advances in paleoneurology and developmental biology show that this major transformation is reflected by substantial changes in the head region of early euarthropods, as informed by the segmental affinity of the cephalic appendages [1, 4-6]. However, data on the implications of this reorganization for non-appendicular exoskeletal structures are lacking, given the difficulty of inferring the precise segmental affinities of these features. Here, I report neurological remains associated with the stalked eyes and "anterior sclerite" in the (middle Cambrian) Burgess Shale euarthropods Helmetia expansa and Odaraia alata and provide evidence that these features are associated with nerve traces originating from the anterior brain region, the protocerebrum. The position of the protocerebral ganglia in exceptionally preserved Cambrian euarthropods indicates the homology of the anterior sclerite in extinct groups (e.g., fuxianhuiids, bivalved forms, artiopodans [7, 8]) and allows new comparisons with the dorsal cephalic plate of radiodontans, large nektonic predators whose anterior segmental organization bears fundamental similarities to that of Paleozoic lobopodians [1, 6, 9, 10]. These observations allow reconstruction of the segmental architecture of the head region in the earliest sclerotized euarthropods and demonstrate the deep homology between exoskeletal features in an evolutionary continuum of taxa with distinct types of body organization. © 2015 Elsevier Ltd.


Murphy G.,University of Cambridge
Genome Biology | Year: 2011

Orchestration of the growth and remodeling of tissues and responses of cells to their extracellular environment is mediated by metalloproteinases of the Metzincin clan. This group of proteins comprises several families of endopeptidases in which a zinc atom is liganded at the catalytic site to three histidine residues and an invariant methionine residue. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous protein regulators of the matrix metalloproteinase (MMPs) family, and also of families such as the disintegrin metalloproteinases (ADAM and ADAMTS). TIMPs therefore have a pivotal role in determining the influence of the extracellular matrix, of cell adhesion molecules, and of many cytokines, chemokines and growth factors on cell phenotype. The TIMP family is an ancient one, with a single representative in lower eukaryotes and four members in mammals. Although much is known about their mechanism of action in proteinase regulation in mammalian cells, less is known about their functions in lower organisms. Recently, non-inhibitory functions of TIMPs have been identified in mammalian cells, including signaling roles downstream of specific receptors. There are clearly still questions to be answered with regard to their overall roles in biology. © 2011 BioMed Central Ltd.


Stanley M.,University of Cambridge
Current Opinion in Infectious Diseases | Year: 2010

PURPOSE OF REVIEW: Prophylactic human papillomavirus (HPV) L1 virus like particle (VLP) vaccines have been shown, in large randomized controlled clinical trials, to be very immunogenic, well tolerated and highly efficacious against ano-genital disease caused by the vaccine HPV types. However, these vaccines, at the present, protect against only two of the 15 oncogenic genital HPV types, they are expensive, delivered by intramuscular injection and require a cold chain. RECENT FINDINGS: The challenges are to develop cheap, thermostable vaccines that can be delivered by noninjectable methods that provide long-term (decades) protection at mucosal surfaces to most, if not all, oncogenic HPV types that is as good as the current VLP vaccines. Polyvalent VLP vaccines covering several oncogenic types are in clinical trials. The most promising of the non-VLP second generation vaccines include L1 capsomers and L2 protein and peptides, suitably adjuvanted. Recent data on the mechanism of viral entry and the dynamics of the interaction of the viral capsid proteins L1 and L2 with the cell surface provide a rationale for the protection offered by these new approaches. SUMMARY: These second generation vaccines are immunogenic and can provide broad protection but are either at early stage in clinical trial or not in trials. The current VLP prophylactic vaccines are likely to be the only option for the coming decade. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Lauga E.,University of Cambridge
Physics of Fluids | Year: 2014

The biological fluids encountered by self-propelled cells display complex microstructures and rheology. We consider here the general problem of low-Reynolds number locomotion in a complex fluid. Building on classical work on the transport of particles in viscoelastic fluids, we demonstrate how to mathematically derive three integral theorems relating the arbitrary motion of an isolated organism to its swimming kinematics in a non-Newtonian fluid. These theorems correspond to three situations of interest, namely, (1) squirming motion in a linear viscoelastic fluid, (2) arbitrary surface deformation in a weakly non-Newtonian fluid, and (3) small-amplitude deformation in an arbitrarily non-Newtonian fluid. Our final results, valid for a wide-class of swimmer geometry, surface kinematics, and constitutive models, at most require mathematical knowledge of a series of Newtonian flow problems, and will be useful to quantity the locomotion of biological and synthetic swimmers in complex environments. © 2014 AIP Publishing LLC.


Yang X.-S.,University of Cambridge
Studies in Computational Intelligence | Year: 2010

Metaheuristic algorithms such as particle swarm optimization, firefly algorithm and harmony search are now becoming powerful methods for solving many tough optimization problems. In this paper, we propose a new metaheuristic method, the Bat Algorithm, based on the echolocation behaviour of bats. We also intend to combine the advantages of existing algorithms into the new bat algorithm. After a detailed formulation and explanation of its implementation, we will then compare the proposed algorithm with other existing algorithms, including genetic algorithms and particle swarm optimization. Simulations show that the proposed algorithm seems much superior to other algorithms, and further studies are also discussed. © 2010 Springer-Verlag Berlin Heidelberg.


Sheridan G.K.,University of Cambridge | Murphy K.J.,University College Dublin
Open Biology | Year: 2013

An essential aspect of normal brain function is the bidirectional interaction and communication between neurons and neighbouring glial cells. To this end, the brain has evolved ligand-receptor partnerships that facilitate crosstalk between different cell types. The chemokine, fractalkine (FKN), is expressed on neuronal cells, and its receptor, CX3CR1, is predominantly expressed on microglia. This review focuses on several important functional roles for FKN/CX3CR1 in both health and disease of the central nervous system. It has been posited that FKN is involved in microglial infiltration of the brain during development. Microglia, in turn, are implicated in the developmental synaptic pruning that occurs during brain maturation. The abundance of FKN on mature hippocampal neurons suggests a homeostatic non-inflammatory role in mechanisms of learning and memory. There is substantial evidence describing a role for FKN in hippocampal synaptic plasticity. FKN, on the one hand, appears to prevent excess microgli l activation in the absence of injury while promoting activation of microglia and astrocytes during inflammatory episodes. Thus, FKN appears to be neuroprotective in some settings, whereas it contributes to neuronal damage in others. Many progressive neuroinflammatory disorders that are associated with increased microglial activation, such as Alzheimer's disease, show disruption of the FKN/CX3CR1 communication system. Thus, targeting CX3CR1 receptor hyperactivation with specific antagonists in such neuroinflammatory conditions may eventually lead to novel neurotherapeutics. © 2013 The Authors.


Mersini-Houghton L.,University of Cambridge | Mersini-Houghton L.,University of North Carolina at Chapel Hill
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2014

Particle creation leading to Hawking radiation is produced by the changing gravitational field of the collapsing star. The two main initial conditions in the far past placed on the quantum field from which particles arise, are the Hartle-Hawking vacuum and the Unruh vacuum. The former leads to a time-symmetric thermal bath of radiation, while the latter to a flux of radiation coming out of the collapsing star. The energy of Hawking radiation in the interior of the collapsing star is negative and equal in magnitude to its value at future infinity. This work investigates the backreaction of Hawking radiation on the interior of a gravitationally collapsing star, in a Hartle-Hawking initial vacuum. It shows that due to the negative energy Hawking radiation in the interior, the collapse of the star stops at a finite radius, before the singularity and the event horizon of a black hole have a chance to form. That is, the star bounces instead of collapsing to a black hole. A trapped surface near the last stage of the star's collapse to its minimum size may still exist temporarily. Its formation depends on the details of collapse. Results for the case of Hawking flux of radiation with the Unruh initial state, will be given in a companion paper II. © 2014 The Author.


Robertson J.,University of Cambridge
Journal of Materials Chemistry | Year: 2012

The catalytic chemical vapour deposition of carbon nanotubes on transition metal catalysts from hydrocarbons is analysed in terms of concepts of heterogeneous catalysis, which leads to a 'volcano plot' of the catalyst efficiency vs. the metal d orbital energy. In this plot, noble metals are inefficient because they dissociate the feedstock poorly, the early transition metals are inefficient because their surface sites become blocked by absorbed carbon and they do not release the nanotube, while the optimum catalyst dissociates the feedstock readily and releases the nanotube. The model is extended to explain why graphene CVD works best with non-optimum catalysts. For silicon nanowires, the rather high stability of metal silicides limits the nanowire growth rates and may explain why there are few alternatives to gold as a catalyst. © 2012 The Royal Society of Chemistry.


Nelson D.E.,University of Cambridge
Open biology | Year: 2013

F-box proteins (FBPs) are substrate-recruiting subunits of Skp1-cullin1-FBP (SCF)-type E3 ubiquitin ligases. To date, 69 FBPs have been identified in humans, but ubiquitinated substrates have only been identified for a few, with the majority of FBPs remaining 'orphans'. In recent years, a growing body of work has identified non-canonical, SCF-independent roles for about 12% of the human FBPs. These atypical FBPs affect processes as diverse as transcription, cell cycle regulation, mitochondrial dynamics and intracellular trafficking. Here, we provide a general review of FBPs, with a particular emphasis on these expanded functions. We review Fbxo7 as an exemplar of this special group as it has well-defined roles in both SCF and non-SCF complexes. We review its function as a cell cycle regulator, via its ability to stabilize p27 protein and Cdk6 complexes, and as a proteasome regulator, owing to its high affinity binding to PI31. We also highlight recent advances in our understanding of Fbxo7 function in Parkinson's disease, where it functions in the regulation of mitophagy with PINK1 and Parkin. We postulate that a few extraordinary FBPs act as platforms that seamlessly segue their canonical and non-canonical functions to integrate different cellular pathways and link their regulation.


Janowitz T.,University of Cambridge
Science Translational Medicine | Year: 2010

Worldwide, traumatic brain injury (TBI) is a major cause of mortality and morbidity with a substantial predicted increase in incidence. Despite an obvious need, there are no pharmacological treatment options for TBI because translation of neuroprotection from preclinical studies to clinical practice has so far failed. Here, we identify potential causes for this failure. We suggest that those monitoring and investigation tools that are commonly used in patients with TBI may provide an experimental medicine route to facilitate a more rational approach to translational research. This suggestion is underpinned by existing research data on disease biology, drug delivery, and treatment response obtained with these methods.


Lestas I.,University of Cambridge
IEEE Transactions on Automatic Control | Year: 2012

We show that for a general class of distributed power control algorithms in wireless networks, if a feasible steady state power allocation exists, this is asymptotically stable for arbitrary gains and time varying heterogeneous delays. The analysis exploits certain contraction properties of the interference in such algorithms, and makes use of Lyapunov Razumikhin functions to address the infinite dimensional character of the problem. © 2012 IEEE.


Zegerman P.,Cancer Research UK Research Institute | Zegerman P.,University of Cambridge | Diffley J.F.X.,Cancer Research UK Research Institute
Nature | Year: 2010

The initiation of eukaryotic DNA replication is regulated by three protein kinase classes: cyclin-dependent kinases (CDK), Dbf4-dependent kinase (DDK) and the DNA damage checkpoint kinases1. CDK phosphorylation of two key initiation factors, Sld2 and Sld3, promotes essential interactions with Dpb11 (refs 2-4), whereasDDKacts by phosphorylating subunits of the Mcm2-7 helicase5.CDKhas an additional role in replication by preventing the re-loading of Mcm2-7 during the S, G2 and M phases6, thus preventing origin re-firing and re-replication. During the G1 phase, bothCDKandDDKare downregulated, which allows origin licensing and prevents premature replication initiation 3. Origin firing is also inhibited during the S phase when DNA damage or replication fork stalling activates the checkpoint kinases7-10. Here we show that, analogous to the situation in the G1 phase, the Saccharomyces cerevisiae checkpoint kinase Rad53 inhibits both CDK-and DDK-dependent pathways, which acts redundantly to block further origin firing. Rad53 acts on DDK directly by phosphorylating Dbf4, whereas the CDK pathway is blocked by Rad53-mediated phosphorylation of the downstream CDK substrate, Sld3. This allows CDK to remain active during the S phase in the presence of DNA damage, which is crucial to prevent re-loading of Mcm2-7 onto origins that have already fired6. Our results explain how checkpoints regulate origin firing and demonstrate that the slowing of S phase by the 'intra-S checkpoint' is primarily due to the inhibition of origin firing. © 2010 Macmillan Publishers Limited. All rights reserved.


Keverne E.B.,University of Cambridge
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Mammalian brain development commences during foeto-placental development and is strongly influenced by the epigenetic regulation of imprinted genes. The foetal placenta exerts considerable influence over the functioning of the adult maternal hypothalamus, and this occurs at the same time as the foetus itself is developing a hypothalamus. Thus, the action and interaction of two genomes in one individual, the mother, has provided a template for co-adaptive functions across generations that are important for maternal care and resource transfer, while co-adaptively shaping the mothering capabilities of each subsequent generation. The neocortex is complex, enabling behavioural diversity and cultural learning such that human individuals are behaviourally unique. Retrotransposons may, in part, be epigenetic mediators of such brain diversity. Interestingly some imprinted genes are themselves retrotransposon-derived, and retrotransposon silencing by DNA methylation is thought to have contributed to the evolutionary origins of imprint control regions. The neocortex has evolved to be adaptable and sustain both short-term and long-term synaptic connections that underpin learning and memory. The adapted changes are not themselves inherited, but the predisposing mechanisms for such epigenetic changes are heritable. This provides each generation with the same ability to make new adaptations while constrained by a transgenerational knowledge-based predisposition to preserve others.


Avouac J.-P.,University of Cambridge
Annual Review of Earth and Planetary Sciences | Year: 2015

Understanding the partitioning of seismic and aseismic fault slip is central to seismotectonics as it ultimately determines the seismic potential of faults. Thanks to advances in tectonic geodesy, it is now possible to develop kinematic models of the spatiotemporal evolution of slip over the seismic cycle and to determine the budget of seismic and aseismic slip. Studies of subduction zones and continental faults have shown that aseismic creep is common and sometimes prevalent within the seismogenic depth range. Interseismic coupling is generally observed to be spatially heterogeneous, defining locked patches of stress accumulation, to be released in future earthquakes or aseismic transients, surrounded by creeping areas. Clay-rich tectonites, high temperature, and elevated pore-fluid pressure seem to be key factors promoting aseismic creep. The generally logarithmic time evolution of afterslip is a distinctive feature of creeping faults that suggests a logarithmic dependency of fault friction on slip rate, as observed in laboratory friction experiments. Most faults can be considered to be paved with interlaced patches where the friction law is either rate-strengthening, inhibiting seismic rupture propagation, or rate-weakening, allowing for earthquake nucleation. The rate-weakening patches act as asperities on which stress builds up in the interseismic period; they might rupture collectively in a variety of ways. The pattern of interseismic coupling can help constrain the return period of the maximum- magnitude earthquake based on the requirement that seismic and aseismic slip sum to match long-term slip. Dynamic models of the seismic cycle based on this conceptual model can be tuned to reproduce geodetic and seismological observations. The promise and pitfalls of using such models to assess seismic hazard are discussed. Copyright © 2015 by Annual Reviews. All rights reserved.


Nemec N.,University of Cambridge
Physical Review B - Condensed Matter and Materials Physics | Year: 2010

The computational cost of a Monte Carlo algorithm can only be meaningfully discussed when taking into account the magnitude of the resulting statistical error. Aiming for a fixed error per particle, we study the scaling behavior of the diffusion Monte Carlo method for large quantum systems. We identify the correlation within the population of walkers as the dominant scaling factor for large systems. While this factor is negligible for small and medium sized systems that are typically studied, it ultimately shows exponential scaling. The scaling factor can be estimated straightforwardly for each specific system and we find that is typically only becomes relevant for systems containing more than several hundred atoms. © 2010 The American Physical Society.


Weatheritt R.J.,University of Toronto | Gibson T.J.,Structural and Computational Biology Unit | Babu M.M.,University of Cambridge
Nature Structural and Molecular Biology | Year: 2014

Although many proteins are localized after translation, asymmetric protein distribution is also achieved by translation after mRNA localization. Why are certain mRNA transported to a distal location and translated on-site? Here we undertake a systematic, genome-scale study of asymmetrically distributed protein and mRNA in mammalian cells. Our findings suggest that asymmetric protein distribution by mRNA localization enhances interaction fidelity and signaling sensitivity. Proteins synthesized at distal locations frequently contain intrinsically disordered segments. These regions are generally rich in assembly-promoting modules and are often regulated by post-translational modifications. Such proteins are tightly regulated but display distinct temporal dynamics upon stimulation with growth factors. Thus, proteins synthesized on-site may rapidly alter proteome composition and act as dynamically regulated scaffolds to promote the formation of reversible cellular assemblies. Our observations are consistent across multiple mammalian species, cell types and developmental stages, suggesting that localized translation is a recurring feature of cell signaling and regulation.


Al Olama A.A.,University of Cambridge
Nature Genetics | Year: 2014

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of >10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10-8; 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease. © 2014 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Koser C.U.,University of Cambridge | Ellington M.J.,Public Health England | Peacock S.J.,Wellcome Trust Sanger Institute
Trends in Genetics | Year: 2014

Following recent improvements in sequencing technologies, whole-genome sequencing (WGS) is positioned to become an essential tool in the control of antibiotic resistance, a major threat in modern healthcare. WGS has already found numerous applications in this area, ranging from the development of novel antibiotics and diagnostic tests through to antibiotic stewardship of currently available drugs via surveillance and the elucidation of the factors that allow the emergence and persistence of resistance. Numerous proof-of-principle studies have also highlighted the value of WGS as a tool for day-to-day infection control and, for some pathogens, as a primary diagnostic tool to detect antibiotic resistance. However, appropriate data analysis platforms will need to be developed before routine WGS can be introduced on a large scale. © 2014.


Visvader J.E.,Walter and Eliza Hall Institute of Medical Research | Visvader J.E.,University of Melbourne | Stingl J.,University of Cambridge
Genes and Development | Year: 2014

The mammary epithelium is highly responsive to local and systemic signals, which orchestrate morphogenesis of the ductal tree during puberty and pregnancy. Based on transplantation and lineage tracing studies, a hierarchy of stem and progenitor cells has been shown to exist among the mammary epithelium. Lineage tracing has highlighted the existence of bipotent mammary stem cells (MaSCs) in situ as well as long-lived unipotent cells that drive morphogenesis and homeostasis of the ductal tree. Moreover, there is accumulating evidence for a heterogeneous MaSC compartment comprising fetal MaSCs, slow-cycling cells, and both long-term and short-term repopulating cells. In parallel, diverse luminal progenitor subtypes have been identified in mouse and human mammary tissue. Elucidation of the normal cellular hierarchy is an important step toward understanding the "cells of origin" and molecular perturbations that drive breast cancer. © 2014 Visvader and Stingl.


Thomas J.M.,University of Cambridge
Physical Chemistry Chemical Physics | Year: 2014

Very substantial advances have recently been made in the design and construction of solid catalysts and in elucidating both their mode of operation and the factors that determine their selectivity and longevity. This Perspective explains how and why such progress has been made. One important factor, the deployment of single-site heterogeneous and enzymatic catalysts, used either alone or in conjunction with other strategies, including metabolic engineering, enables a multitude of new products (for example, environmentally clean jet fuel) to be readily manufactured. In a practical sense SSHCs enable the advantages of homogeneous and to a lesser degree enzymatic catalysts to be united with those of heterogeneous ones. With the aid of the vastly increasing families of nanoporous solids, desired catalytically active sites may be engineered in atomic detail on their inner, accessible surfaces, thereby opening up new possibilities in synthetic organic chemistry-as in the smooth formation of C-C and CN bonds in a number of intermolecular reactions-as well as in photocatalysts and in fluidized catalytic cracking of hydrocarbons. © 2014 the Partner Organisations.


Jung H.,Yonsei University | Gkogkas C.G.,University of Edinburgh | Sonenberg N.,McGill University | Holt C.E.,University of Cambridge
Cell | Year: 2014

The subcellular position of a protein is a key determinant of its function. Mounting evidence indicates that RNA localization, where specific mRNAs are transported subcellularly and subsequently translated in response to localized signals, is an evolutionarily conserved mechanism to control protein localization. On-site synthesis confers novel signaling properties to a protein and helps to maintain local proteome homeostasis. Local translation plays particularly important roles in distal neuronal compartments, and dysregulated RNA localization and translation cause defects in neuronal wiring and survival. Here, we discuss key findings in this area and possible implications of this adaptable and swift mechanism for spatial control of gene function. © 2014 The Authors.


Worbe Y.,University of Cambridge
Molecular Psychiatry | Year: 2015

Human decision-making arises from both reflective and reflexive mechanisms, which underpin goal-directed and habitual behavioural control. Computationally, these two systems of behavioural control have been described by different learning algorithms, model-based and model-free learning, respectively. Here, we investigated the effect of diminished serotonin (5-hydroxytryptamine) neurotransmission using dietary tryptophan depletion (TD) in healthy volunteers on the performance of a two-stage decision-making task, which allows discrimination between model-free and model-based behavioural strategies. A novel version of the task was used, which not only examined choice balance for monetary reward but also for punishment (monetary loss). TD impaired goal-directed (model-based) behaviour in the reward condition, but promoted it under punishment. This effect on appetitive and aversive goal-directed behaviour is likely mediated by alteration of the average reward representation produced by TD, which is consistent with previous studies. Overall, the major implication of this study is that serotonin differentially affects goal-directed learning as a function of affective valence. These findings are relevant for a further understanding of psychiatric disorders associated with breakdown of goal-directed behavioural control such as obsessive-compulsive disorders or addictions.Molecular Psychiatry advance online publication, 14 April 2015; doi:10.1038/mp.2015.46. © 2015 Macmillan Publishers Limited


Thomas J.M.,University of Cambridge
Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences | Year: 2012

The concept of single-site heterogeneous catalysis, herein defined and extensively illustrated, offers a strategy for the design of new solid catalysts. By capitalizing on the opportunities presented by nanoporous materials to assemble a wide range of new, well-defined, catalytically active centres, it is possible to bring about numerous environmentally benign processes that can replace traditional methods of chemical production. The latter often employs aggressive, corrosive or hazardous reagents. By using both microporous (less than 20Å diameter) and mesoporous solids (20-500Å diameter), abundant scope exists for the construction and application of shape-selective, regio-selective and enantioselective catalysts. © 2012 The Royal Society.


Anderson E.,University of Cambridge
Classical and Quantum Gravity | Year: 2014

Classical and semiclassical schemes are presented that are timeless at the primary level and recover time from Mach's 'time is to be abstracted from change' principle at the emergent secondary level. The semiclassical scheme is a Machian variant of the semiclassical approach to the problem of time in quantum gravity. The classical scheme is Barbour's, cast here explicitly as the classical precursor of the semiclassical approach. Thus the two schemes have been married up, as equally-Machian and necessarily distinct, since the latter's timestandard is abstracted in part from quantum change. I provide perturbative schemes for these in which the timefunction is to be determined rather than assumed. This paper is useful modelling as regards the Halliwell-Hawking arena for the quantum origin of the inhomogeneous cosmological fluctuations. © 2014 IOP Publishing Ltd.


In this protocol, we describe how to isolate keratinocytes from adult mouse epidermis, fractionate them into different sub-populations on the basis of cell surface markers and examine their function in an in vivo skin reconstitution assay with disaggregated neonatal dermal cells. We also describe how the isolated keratinocytes can be subjected to clonal analysis in vitro and in vivo and how to enrich for hair follicle-inducing dermal papilla cells in the dermal preparation. Using these approaches, it is possible to compare the capacity of different populations of adult epidermal stem cells to proliferate and to generate progeny that differentiate along the different epidermal lineages. Isolating, fractionating and grafting cells for the skin reconstitution assay is normally spread over 2 d. Clonal growth in culture is assessed after 14 d, while evaluation of the grafts is carried out after 4-5 weeks.


Leyser O.,University of Cambridge
PLoS Biology | Year: 2014

Once again, there are calls to reopen the debate on genetically modified (GM) crops. I find these calls frustrating and unnecessarily decisive. In my opinion the GM debate, on both sides, continues to hamper the urgent need to address the diverse and pressing challenges of global food security and environmental sustainability. The destructive power of the debate comes from its conflation of unrelated issues, coupled with deeply rooted misconceptions of the nature of agriculture. © 2014 Ottoline Leyser.


Schmidt M.F.,University of Cambridge
Trends in Biotechnology | Year: 2014

miRNAs, short ribonucleic acid gene regulators, are increasingly popular drug targets. Traditionally 'undruggable' proteins can be targeted via their miRNA gene regulators, enabling the treatment of diseases that, at present, seem impossible to cure. However, addressing miRNAs requires innovation at the level of drug discovery. This review article outlines the potential of miRNAs as drug targets, focuses on the challenges of developing miRNA-targeting drugs, and surveys new advances. The aim is to provide an orientation guide for scientists, as well business analysts, to help them navigate the jungle of different approaches in miRNA drug discovery. © 2014 Elsevier Ltd.


Oyen M.L.,University of Cambridge
International Materials Reviews | Year: 2014

Interest in hydrogel materials is growing rapidly, due to the potential for hydrogel use in tissue engineering and drug delivery applications, and as coatings on medical devices. However, a key limitation with the use of hydrogel materials in many applications is their relatively poor mechanical properties compared with those of (less biocompatible) solid polymers. In this review, basic chemistry, microstructure and processing routes for common natural and synthetic hydrogel materials are explored first. Underlying structure-properties relationships for hydrogels are considered. A series of mechanical testing modalities suitable for hydrogel characterisation are next considered, including emerging test modalities, such as nanoindentation and atomic force microscopy (AFM) indentation. As the data analysis depends in part on the material's constitutive behaviour, a series of increasingly complex constitutive models will be examined, including elastic, viscoelastic and theories that explicitly treat the multiphasic poroelastic nature of hydrogel materials. Results from the existing literature on agar and polyacrylamide mechanical properties are compiled and compared, highlighting the challenges and uncertainties inherent in the process of gel mechanical characterisation. © 2014 Institute of Materials, Minerals and Mining and ASM International.


Jones K.S.,University of Cambridge
The British journal of nutrition | Year: 2012

25-Hydroxyvitamin D (25(OH)D) half-life is a potential biomarker for investigating vitamin D metabolism and requirements. We performed a pilot study to assess the approach and practical feasibility of measuring 25(OH)D half-life after an oral dose. A total of twelve healthy Gambian men aged 18-23 years were divided into two groups to investigate the rate and timing of (1) absorption and (2) plasma disappearance after an 80 nmol oral dose of 25(OH)D2. Fasting blood samples were collected at baseline and, in the first group, every 2 h post-dose for 12 h, at 24 h, 48 h and on day 15. In the second group, fasting blood samples were collected on days 3, 4, 5, 6, 9, 12, 15, 18 and 21. Urine was collected for 2 h after the first morning void at baseline and on day 15. 25(OH)D2 plasma concentration was measured by ultra-performance liquid chromatography-tandem MS/MS and corrected for baseline. Biomarkers of vitamin D, Ca and P metabolism were measured at baseline and on day 15. The peak plasma concentration of 25(OH)D2 was 9·6 (sd 0·9) nmol/l at 4·4 (sd 1·8) h. The terminal slope of 25(OH)D2 disappearance was identified to commence from day 6. The terminal half-life of plasma 25(OH)D2 was 13·4 (sd 2·7) d. There were no significant differences in plasma 25(OH)D3, total 1,25(OH)2D, parathyroid hormone, P, Ca and ionised Ca and urinary Ca and P between baseline and day 15 and between the two groups. The present study provides data on the plasma response to oral 25(OH)D2 that will underpin and contribute to the further development of studies to investigate 25(OH)D half-life.


Ciccarelli C.,University of Cambridge
Nature Physics | Year: 2016

Materials that crystallize in diamond-related lattices, with Si and GaAs as their prime examples, are at the foundation of modern electronics. Simultaneously, inversion asymmetries in their crystal structure and relativistic spin–orbit coupling led to discoveries of non-equilibrium spin-polarization phenomena that are now extensively explored as an electrical means for manipulating magnetic moments in a variety of spintronic structures. Current research of these relativistic spin–orbit torques focuses primarily on magnetic transition-metal multilayers. The low-temperature diluted magnetic semiconductor (Ga, Mn)As, in which spin–orbit torques were initially discovered, has so far remained the only example showing the phenomenon among bulk non-centrosymmetric ferromagnets. Here we present a general framework, based on the complete set of crystallographic point groups, for identifying the potential presence and symmetry of spin–orbit torques in non-centrosymmetric crystals. Among the candidate room-temperature ferromagnets we chose to use NiMnSb, which is a member of the broad family of magnetic Heusler compounds. By performing all-electrical ferromagnetic resonance measurements in single-crystal epilayers of NiMnSb we detect room-temperature spin–orbit torques generated by effective fields of the expected symmetry and of a magnitude consistent with our ab initio calculations. © 2016 Nature Publishing Group


Clatworthy M.R.,University of Cambridge
Transplant International | Year: 2014

There has been increasing interest in the role played by B cells and their associated antibody in the immune response to an allograft, driven by the need to undertake antibody-incompatible transplantation and evidence suggesting that B cells play a role in acute T-cell-mediated rejection and in acute and chronic antibody-mediated rejection. This review focuses on the molecular events, both activating and inhibitory, which control B-cell activation, and considers how this information might inform therapeutic strategies. Potential targets include the BAFF (B-cell-activating factor belonging to the tumour necrosis factor family) and CD40-CD40L pathways and inhibitory molecules, such as CD22 and FcγRIIB. B cells can also play an immunomodulatory role via interleukin (IL)10 production and may contribute to transplant tolerance. The expansion of allograft-specific IL10-producing B cells may be an additional therapeutic goal. Thus, the treatment paradigm required in transplantation has shifted from that of simple B-cell depletion, to that of a more subtle, differential manipulation of different B-cell subsets. © 2013 Steunstichting ESOT. Published by John Wiley & Sons Ltd.


Michaels T.C.T.,University of Cambridge
Nature Physics | Year: 2016

In nature, fast, high-power-density actuation can be achieved through the release of stored elastic energy by exploiting mechanical instabilities in systems including the closure of the Venus flytrap and the dispersal of plant or fungal spores. Here, we use droplet microfluidics to tailor the geometry of a nanoscale self-assembling supra-molecular polymer to create a mechanical instability. We show that this strategy allows the build-up of elastic energy as a result of peptide self-assembly, and its release within milliseconds when the buckled geometry of the nanotube confined within microdroplets becomes unstable with respect to the straight form. These results overcome the inherent limitations of self-assembly for generating large-scale actuation on the sub-second timescale and illuminate the possibilities and performance limits of irreversible actuation by supra-molecular polymers. © 2016 Nature Publishing Group


Smith M.R.,University of Cambridge | Caron J.-B.,Royal Ontario Museum | Caron J.-B.,University of Toronto
Nature | Year: 2015

The molecularly defined clade Ecdysozoa comprises the panarthropods (Euarthropoda, Onychophora and Tardigrada) and the cycloneuralian worms (Nematoda, Nematomorpha, Priapulida, Loricifera and Kinorhyncha). These disparate phyla are united by their means of moulting, but otherwise share few morphological characters-none of which has a meaningful fossilization potential. As such, the early evolutionary history of the group as a whole is largely uncharted. Here we redescribe the 508-million-year-old stem-group onychophoran Hallucigenia sparsa from the mid-Cambrian Burgess Shale. We document an elongate head with a pair of simple eyes, a terminal buccal chamber containing a radial array of sclerotized elements, and a differentiated foregut that is lined with acicular teeth. The radial elements and pharyngeal teeth resemble the sclerotized circumoral elements and pharyngeal teeth expressed in tardigrades, stem-group euarthropods and cycloneuralian worms. Phylogenetic results indicate that equivalent structures characterized the ancestral panarthropod and, seemingly, the ancestral ecdysozoan, demonstrating the deep homology of panarthropod and cycloneuralian mouthparts, and providing an anatomical synapomorphy for the ecdysozoan supergroup. © 2015 Macmillan Publishers Limited. All rights reserved.


Wales D.J.,University of Cambridge
Chemical Physics Letters | Year: 2013

A new basin-sampling scheme is introduced to obtain equilibrium thermodynamic properties by combining results from global optimisation and parallel tempering calculations. Regular minimisation is used to obtain a two-dimensional density of states. A model anharmonic form is optimised using a multihistogram approach for potential energy bins corresponding to local minima, connecting the results obtained for low and high temperatures. This procedure provides accurate densities of states and thermodynamic properties for benchmark atomic clusters exhibiting broken ergodicity. It can also be used to calculate the potential energy density of local minima for distinct permutation-inversion isomers and distinct structures. © 2013 Elsevier Ltd. All rights reserved.


Chen X.,University of Cambridge
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2011

Experimentally distinguishing different primordial universe paradigms that lead to the Big Bang model is an outstanding challenge in modern cosmology and astrophysics. We show that a generic type of signals that exist in primordial universe models can be used for such purpose. These signals are induced by tiny oscillations of massive fields and manifest as features in primordial density perturbations. They are capable of recording the time-dependence of the scale factor of the primordial universe, and therefore provide direct evidence for specific paradigm. These signals present special opportunities and challenges for experiments and data analyses. © 2011 Elsevier B.V.


Mirazon Lahr M.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

The evolution of modern humans was a complex process, involving major changes in levels of diversity through time. The fossils and stone tools that record the spatial distribution of our species in the past form the backbone of our evolutionary history, and one that allows us to explore the different processes-cultural and biological-that acted to shape the evolution of different populations in the face of major climate change. Those processes created a complex palimpsest of similarities and differences, with outcomes that were at times accelerated by sharp demographic and geographical fluctuations. The result is that the population ancestral to all modern humans did not look or behave like people alive today. This has generated questions regarding the evolution of human universal characters, as well as the nature and timing of major evolutionary events in the history of Homo sapiens. The paucity of African fossils remains a serious stumbling block for exploring some of these issues. However, fossil and archaeological discoveries increasingly clarify important aspects of our past, while breakthroughs from genomics and palaeogenomics have revealed aspects of the demography of Late Quaternary Eurasian hominin groups and their interactions, as well as those between for- agers and farmers. This paper explores the nature and timing of key moments in the evolution of human diversity, moments in which population collapse followed by differential expansion of groups set the conditions for transitional periods. Five transitions are identified (i) at the origins of the species, 240-200 ka; (ii) at the time of the first major expansions, 130-100 ka; (iii) during a period of dispersals, 70-50 ka; (iv) across a phase of local/regional structuring of diversity, 45-25 ka; and (v) during a phase of significant extinction of hunter-gatherer diversity and expansion of particular groups, such as farmers and later societies (the Holocene Filter), 15-0 ka. © 2016 The Authors.


Foley R.A.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2016

Humans are uniquely unique, in terms of the extreme differences between them and other living organisms, and the impact they are having on the bio-sphere. The evolution of humans can be seen, as has been proposed, as one of the major transitions in evolution, on a par with the origins of multicellular organisms or the eukaryotic cell (Maynard Smith & Szathmáry 1997 Major transitions in evolution). Major transitions require the evolution of greater complexity and the emergence of new evolutionary levels or processes. Does human evolution meet these conditions? I explore the diversity of evidence on the nature of transitions in human evolution. Four levels of transition are proposed-baseline, novel taxa, novel adaptive zones and major transitions-and the pattern of human evolution considered in the light of these. The primary conclusions are that changes in human evolution occur continuously and cumulatively; that novel taxa and the appearance of new adaptations are not clustered very tightly in particular periods, although there are three broad transitional phases (Pliocene, Plio-Pleistocene and later Quaternary). Each phase is distinctive, with the first based on ranging and energetics, the second on technology and niche expansion, and the third on cognition and cultural processes. I discuss whether this constitutes a ‘major transition’ in the context of the evolutionary processes more broadly; the role of behaviour in evolution; and the opportunity provided by the rich genetic, phenotypic (fossil morphology) and behavioural (archaeological) record to examine in detail major transitions and the microevolutionary patterns underlying macroevolutionary change. It is suggested that the evolution of the hominin lineage is consistent with a mosaic pattern of change. © 2016 The Author(s) Published by the Royal Society. All rights reserved.


Hofmann J.,University of Cambridge
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2011

We apply the operator-product expansion to determine the asymptotic form of the current response of a Fermi gas in two and three dimensions. The leading-order term away from the one-particle peak is proportional to a quantity known as the contact, the coefficient of which is determined exactly. We also calculate the dynamic structure factor and the high-frequency tails of the spectral viscosities as a function of the scattering length. Our results are used to derive certain sum rules for the viscosities. © 2011 American Physical Society.


Nitadori K.,University of Tsukuba | Aarseth S.J.,University of Cambridge
Monthly Notices of the Royal Astronomical Society | Year: 2012

We describe the use of graphics processing units (GPUs) for speeding up the code nbody6 which is widely used for direct N-body simulations. Over the years, the N 2 nature of the direct force calculation has proved a barrier for extending the particle number. Following an early introduction of force polynomials and individual time steps, the calculation cost was first reduced by the introduction of a neighbour scheme. After a decade of GRAPE computers which speeded up the force calculation further, we are now in the era of GPUs where relatively small hardware systems are highly cost effective. A significant gain in efficiency is achieved by employing the GPU to obtain the so-called regular force which typically involves some 99 per cent of the particles, while the remaining local forces are evaluated on the host. However, the latter operation is performed up to 20 times more frequently and may still account for a significant cost. This effort is reduced by parallel SSE/AVX procedures where each interaction term is calculated using mainly single precision. We also discuss further strategies connected with coordinate and velocity prediction required by the integration scheme. This leaves hard binaries and multiple close encounters which are treated by several regularization methods. The present nbody6-gpu code is well balanced for simulations in the particle range 10 4-2 × 10 5 for a dual-GPU system attached to a standard PC. © 2012 The Authors Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Brown G.C.,University of Cambridge | Borutaite V.,Lithuanian University of Health Sciences
Mitochondrion | Year: 2012

It is often assumed that mitochondria are the main source of reactive oxygen species (ROS) in mammalian cells, but there is no convincing experimental evidence for this in the literature. What evidence there is suggests mitochondria are a significant source for ROS, which may have physiological and pathological effects. But quantitatively, endoplasmic reticulum and peroxisomes have a greater capacity to produce ROS than mitochondria, at least in liver. In most cells and physiological or pathological conditions there is a lack of evidence for or against mitochondria being the main source of cellular ROS. Mitochondria can rapidly degrade ROS and thus are potential sinks for ROS, but whether mitochondria act as net sources or sinks within cells in particular conditions is unknown. © 2011 Elsevier B.V. and Mitochondria Research Society.


Guazzelli E.,CNRS IUSTI - University Institute of Thermodynamic Industrial Systems) | Hinch J.,University of Cambridge
Annual Review of Fluid Mechanics | Year: 2011

This review concentrates on the fluctuations of the velocities of sedimenting spheres, and on the structural instability of a suspension of settling fibers. For many years, theoretical estimates and numerical simulations predicted the fluctuations of the velocities of spheres to increase with the size of the container, whereas experiments found no such variation. Two ideas have increased our understanding. First, the correlation length of the velocity fluctuations was found experimentally to be 20 interparticle separations. Second, in dilute suspensions, a vertical variation in the concentration due to the spreading of the front with the clear fluid can inhibit the velocity fluctuations. In a very dilute regime, a homogeneous suspension of fibers suffers a spontaneous instability in which fast descending fiber-rich columns are separated by rising fiber-sparse columns. In a semidilute regime, the settling is hindered, more so than for spheres. © 2011 by Annual Reviews. All rights reserved.


Compston J.,University of Cambridge
Endocrine | Year: 2012

In recent years, there has been growing interest in the potential use of combination therapy in the management of osteoporosis in postmenopausal women. Possible regimens include sequential or combined use of anti-resorptive drugs or combinations of anabolic and anti-resorptive agents, given concurrently or in sequence. Combined therapy with antiresorptive drugs usually produces greater increases in bone mineral density (BMD) than monotherapy but there is no evidence that this results in greater anti-fracture efficacy. The use of bisphosphonates before strontium ranelate or PTH peptides blunts the BMD response. Combined PTH and antiresorptive therapy results in more rapid gains in spine BMD and a greater increase in hip BMD than PTH monotherapy in the first year of treatment but greater gains in both spine and hip BMD are seen with PTH monotherapy than combined therapy after 2 years of treatment. Anti-resorptive therapy after PTH therapy maintains or increases the gains in BMD. Further research is required to establish the cost-effectiveness and safety of combined and sequential regimens. © Springer Science+Business Media, LLC 2011.


McQuilton P.,University of Cambridge | St Pierre S.E.,Harvard University | Thurmond J.,Indiana University
Nucleic Acids Research | Year: 2012

FlyBase (http://flybase.org) is the leading database and web portal for genetic and genomic information on the fruit fly Drosophila melanogaster and related fly species. Whether you use the fruit fly as an experimental system or want to apply Drosophila biological knowledge to another field of study, FlyBase can help you successfully navigate the wealth of available Drosophila data. Here, we review the FlyBase web site with novice and less-experienced users of FlyBase in mind and point out recent developments stemming from the availability of genome-wide data from the modENCODE project. The first section of this paper explains the organization of the web site and describes the report pages available on FlyBase, focusing on the most popular, the Gene Report. The next section introduces some of the search tools available on FlyBase, in particular, our heavily used and recently redesigned search tool QuickSearch, found on the FlyBase homepage. The final section concerns genomic data, including recent modENCODE (http://www.modencode.org) data, available through our Genome Browser, GBrowse. © The Author(s) 2011.


Castelnovo C.,University of Cambridge
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

In this paper we study the behavior of the entanglement measure dubbed negativity in the context of the toric code model. Using a replica method introduced recently by Calabrese, Cardy, and Tonni, we obtain an exact expression which illustrates how the nonlocal correlations present in a topologically ordered state reflect in the behavior of the negativity of the system. We find that the negativity has a leading area-law contribution if the subsystems are in direct contact with one another (as expected in a zero-range correlated model). We also find a topological contribution directly related to the topological entropy, provided that the partitions are topologically nontrivial in both directions on a torus. We further confirm by explicit calculation that the negativity captures only quantum contributions to the entanglement. Indeed, we show that the negativity vanishes identically for the classical topologically ordered eight-vertex model, which on the contrary exhibits a finite von Neumann entropy, inclusive of topological correction. © 2013 American Physical Society.


Bhadeshia H.K.D.H.,University of Cambridge
Philosophical Magazine | Year: 2013

It is generally assumed that the phase diagrams and equilibrium thermodynamic data that apply to the conventional Fe-C system, also are relevant to the case where supersaturated ferrite is in contact with austenite. It seems that this may not be correct, since a change in the symmetry of the ferrite unit cell in the presence of excess carbon has the potential to alter the nature of the phase equilibrium. The implications of these discoveries are presented in the context of the early recognition by Cottrell and co-workers, of the importance that should be attached to the tetragonal symmetry of the octahedral interstices in the ferritic allotrope of iron. © 2013 Taylor & Francis.


Beri B.,University of Cambridge
Physical Review Letters | Year: 2013

We present a powerful and general approach to describe the coupling of Majorana fermions to external leads, of interacting or noninteracting electrons. Our picture has the Klein factors of bosonization appearing as extra Majorana fermions hybridizing with the physical ones. We demonstrate the power of this approach, analyzing a highly nontrivial SO(M) Kondo problem arising in topological superconductors with M Majorana-lead couplings, allowing for arbitrary M and for conduction electron interactions. Mapping the problem on a quantum Brownian motion model we find robust non-Fermi liquid behavior, even for Fermi liquid leads, and a quantum phase transition between insulating and Kondo regimes when the leads form Luttinger liquids. In particular, for M=4 we find a stable realization of the two-channel Kondo fixed point. Obtaining the linear conductance at low temperatures, we predict transport signatures of this Majorana-Kondo-Luttinger physics. © 2013 American Physical Society.


Pitalua-Garcia D.,University of Cambridge
Physical Review Letters | Year: 2013

How much information can a transmitted physical system fundamentally communicate? We introduce the principle of quantum information causality, which states the maximum amount of quantum information that a quantum system can communicate as a function of its dimension, independently of any previously shared quantum physical resources. We present a new quantum information task, whose success probability is upper bounded by the new principle, and show that an optimal strategy to perform it combines the quantum teleportation and superdense coding protocols with a task that has classical inputs. © 2013 American Physical Society.


The hypothalamus regulates the key hormonal signalling events essential for reproduction and fertility in mammals. The gonadotrophin-releasing hormone (GnRH) neurons are the principal neurons of the complex neuronal network that co-ordinates multiple internal homeostatic and external factors necessary for fertility. Kisspeptin neurons are one of the major regulators of GnRH neuronal activity, but the ways in which kisspeptin neurons, located in the arcuate nucleus (ARN) and rostral periventricular area of the third ventricle (RP3V), control GnRH neurons are poorly understood. This study focused on the use of anterograde and retrograde tracing techniques to establish the neuronal projection patterns of kisspeptin cells in the female mouse brain. Both anterograde and retrograde tracing studies highlight the complexity of the kisspeptin neuronal system and indicate that both ARN and RP3V kisspeptin neurons may participate in a variety of limbic functions. In relationship to the GnRH neuronal network, these investigations demonstrate that rostral ARN kisspeptin neurons may also project to GnRH neuronal cell bodies. However, we found no anatomical evidence to suggest that kisspeptin neurons innervate GnRH nerve terminals in the external layer of the median eminence. These studies provide a neuroanatomical framework for the further elucidation of the functions of the ARN and RP3V kisspeptin neuron populations. © 2013 The Physiological Society.


Routh A.F.,University of Cambridge
Reports on Progress in Physics | Year: 2013

When thin films of colloidal fluids are dried, a range of transitions are observed and the final film profile is found to depend on the processes that occur during the drying step. This article describes the drying process, initially concentrating on the various transitions. Particles are seen to initially consolidate at the edge of a drying droplet, the so-called coffee-ring effect. Flow is seen to be from the centre of the drop towards the edge and a front of close-packed particles passes horizontally across the film. Just behind the particle front the now solid film often displays cracks and finally the film is observed to de-wet. These various transitions are explained, with particular reference to the capillary pressure which forms in the solidified region of the film. The reasons for cracking in thin films is explored as well as various methods to minimize its effect. Methods to obtain stratified coatings through a single application are considered for a one-dimensional drying problem and this is then extended to two-dimensional films. Different evaporative models are described, including the physical reason for enhanced evaporation at the edge of droplets. The various scenarios when evaporation is found to be uniform across a drying film are then explained. Finally different experimental techniques for examining the drying step are mentioned and the article ends with suggested areas that warrant further study. © 2013 IOP Publishing Ltd.


Bowman R.W.,University of Glasgow | Bowman R.W.,University of Cambridge | Padgett M.J.,University of Glasgow
Reports on Progress in Physics | Year: 2013

The phenomenon of light's momentum was first observed in the laboratory at the beginning of the twentieth century, and its potential for manipulating microscopic particles was demonstrated by Ashkin some 70 years later. Since that initial demonstration, and the seminal 1986 paper where a single-beam gradient-force trap was realized, optical trapping has been exploited as both a rich example of physical phenomena and a powerful tool for sensitive measurement. This review outlines the underlying theory of optical traps, and explores many of the physical observations that have been made in such systems. These phenomena include 'optical binding', where trapped objects interact with one another through the trapping light field. We also discuss a number of the applications of 'optical tweezers' across the physical and life sciences, as well as covering some of the issues involved in constructing and using such a tool. © 2013 IOP Publishing Ltd.


Figueras P.,University of Cambridge | Wiseman T.,Imperial College London
Physical Review Letters | Year: 2013

We explore use of the harmonic Einstein equations to numerically find stationary black holes where the problem is posed on an ingoing slice that extends into the interior of the black hole. Requiring no boundary conditions at the horizon beyond smoothness of the metric, this method may be applied for horizons that are not Killing. As a nontrivial illustration we find black holes which, via AdS-CFT, describe a time-independent CFT plasma flowing through a static spacetime which asymptotes to Minkowski in the flow's past and future, with a varying spatial geometry in between. These are the first nonperturbative examples of stationary black holes which do not have Killing horizons. When the CFT spacetime slowly varies, the CFT stress tensor derived from gravity is well described by viscous hydrodynamics. For fast variation it is not, and the solutions are stationary analogs of dynamical quenches, with the plasma being suddenly driven out of equilibrium. We find evidence these flows become unstable for sufficiently strong quenches, and speculate the instability may be turbulent. © 2013 American Physical Society.


Lamacraft A.,University of Cambridge
Physical Review A - Atomic, Molecular, and Optical Physics | Year: 2013

We study scattering of three equal-mass particles in one dimension. Integrable interactions are synonymous with nondiffractive scattering, meaning that the set of incoming momenta for any scattering event coincides with the set of outgoing momenta. A system is integrable if the two-particle scattering matrix obeys the Yang-Baxter equation. Nonintegrable interactions correspond to diffractive scattering, where the set of outgoing momenta may take on all values consistent with energy and momentum conservation. Such processes play a vital role in the kinetics of one-dimensional gases, where binary collisions are unable to alter the distribution function. When integrability is broken weakly, the result is a small diffractive scattering amplitude. Our main result is a simple formula for the diffractive part of the scattering amplitude, when the violation of the Yang-Baxter equation is small. Although the derivation is given for δ-function interactions, the result depends only on the two-particle scattering matrix, and should therefore also apply to finite-range interactions close to integrable. © 2013 American Physical Society.


Ensor R.,University of Cambridge
Journal of child psychology and psychiatry, and allied disciplines | Year: 2010

Young siblings' antisocial behaviour is common yet its impact has received relatively little research attention. We examined trajectories of antisocial behaviour for a socially diverse sample (n = 99, 58 boys and 41 girls) who were filmed with their older siblings (52 boys and 47 girls) at ages 3 and 6 and with unfamiliar peers at age 6. Latent growth models were used to analyse three indicators of antisocial behaviour (refusal to share/interact, bullying and harming). The average trajectory of antisocial behaviour towards siblings was stable and particularly high for boys with brothers and for children of mothers with no educational qualifications. Sustained and escalating antisocial behaviours towards siblings predicted bullying and refusals to share/interact with unfamiliar peers, independent of associations with concurrent antisocial behaviour towards sibling. These findings highlight the importance of a developmental perspective when examining antisocial behaviour between young siblings. © 2010 The Authors. Journal of Child Psychology and Psychiatry © 2010 Association for Child and Adolescent Mental Health.


Best R.B.,University of Cambridge
Current Opinion in Structural Biology | Year: 2012

Theory and experiment have provided answers to many of the fundamental questions of protein folding; a remaining challenge is an accurate, high-resolution picture of folding mechanism. Atomistic molecular simulations with explicit solvent are the most promising method for providing this information, by accounting more directly for the physical interactions that stabilize proteins. Although simulations of folding with such force fields are extremely challenging, they have become feasible as a result of recent advances in computational power, accuracy of the energy functions or 'force fields', and methods for improving sampling of folding events. I review the recent progress in these areas, and highlight future challenges and questions that we may hope to address with these methods. I also attempt to place atomistic models into the context of the energy landscape view of protein folding, and coarse-grained simulations. © 2012 Elsevier Ltd.


Palacios I.M.,University of Cambridge
Briefings in Functional Genomics | Year: 2013

Cells are able to recognize and degrade aberrant transcripts in order to self-protect from potentially toxic proteins. Various pathways detect aberrant RNAs in the cytoplasm and are dependent on translation. One of these pathways is the nonsense-mediated RNA decay (NMD). NMD is a surveillance mechanism that degrades transcripts containing nonsense mutations, preventing the translation of possibly harmful truncated proteins. For example, the degradation of a nonsense harming β-globin allele renders normal phenotypes. On the other hand, regulating NMD is also important in those cases when the produced aberrant protein is better than having no protein, as it has been shown for cystic fibrosis. These findings reflect the important role for NMD in human health. In addition, NMD controls the levels of physiologic transcripts, which defines this pathway as a novel gene expression regulator, with huge impact on homeostasis, cell growth and development. While the mechanistic details of NMD are being gradually understood, the physiological role of this RNA surveillance pathway still remains largely unknown. This is a brief and simplified review on various aspects of NMD, such as the nature of the NMD targets, the mechanism of target degradation and the links between NMD and cell growth, animal development and diseases. © The Author 2012. Published by Oxford University Press. All rights reserved.


Peake N.,University of Cambridge | Parry A.B.,Rolls-Royce
Annual Review of Fluid Mechanics | Year: 2011

In this review we describe current scientific and technological issues in the quest to reduce aeroengine noise, in the face of predicted rapid increases in the volume of air traffic, on the one hand, and increasingly strict environmental regulation, on the other. Alongside conventional ducted turbofan designs, new open-rotor contra-rotating power plants are currently under development, which present their own noise challenges. The key sources of tonal and broadband noise, and the way in which noise propagates away from the source, are surveyed in both cases. We also consider in detail two key aspects underpinning the flow physics that continue to receive considerable attention, namely the acoustics of swirling flow and unsteady flow-blade interactions. Finally, we describe possible innovations in open-rotor engine design for low noise.


Paardekooper S.-J.,University of Cambridge
Monthly Notices of the Royal Astronomical Society | Year: 2012

We study numerical convergence in local two-dimensional hydrodynamical simulations of self-gravitating accretion discs with a simple cooling law. It is well known that there exists a steady gravitoturbulent state, in which cooling is balanced by dissipation of weak shocks, with a net outward transport of angular momentum. Previous results indicated that if cooling is too fast (typical time-scale 3Ω -1, where Ω is the local angular velocity), this steady state cannot be maintained and the disc will fragment into gravitationally bound clumps. We show that, in the two-dimensional local approximation, this result is in fact not converged with respect to numerical resolution and longer time integration. Irrespective of the cooling time-scale, gravitoturbulence consists of density waves as well as transient clumps. These clumps will contract because of the imposed cooling, and collapse into bound objects if they can survive for long enough. Since heating by shocks is very local, the destruction of clumps is a stochastic process. High numerical resolution and long integration times are needed to capture this behaviour. We have observed fragmentation for cooling times up to 20Ω -1, almost a factor of 7 higher than in previous simulations. Fully three-dimensional simulations with a more realistic cooling prescription are necessary to determine the effects of the use of the two-dimensional approximation and a simple cooling law. © 2012 The Author Monthly Notices of the Royal Astronomical Society © 2012 RAS.


Robertson J.,University of Cambridge | Clark S.J.,Durham University
Physical Review B - Condensed Matter and Materials Physics | Year: 2011

The chemical trends of limits to doping of many semiconducting metal oxides is analyzed in terms of the formation energies needed to form the compensating defects. The n-type oxides are found to have high electron affinities and charge neutrality levels that lie in midgap or the upper part of their gap, whereas p-type oxides have small photoionization potentials and charge neutrality levels lying in the lower gap. The doping-limit energy range is found to vary with the bulk free energy of the compound. © 2011 American Physical Society.


Davidson P.A.,University of Cambridge
Physics of Fluids | Year: 2011

We consider high Reynolds number, freely-decaying, isotropic turbulence in which the large scales evolve in a self-similar manner when normalized by the integral scales, u and ℓ As it is well known, a range of possible behaviors may be observed depending on the form of the longitudinal velocity correlation at large separation, u2f∞ u2f∞ (r →∞) We consider the cases u2f1 = cmr-m, 2 ≤ m ≤ 6, whose spectral counterpart is E(k→0) ~ cmkm-1 for m > 6, with or without a ln k correction, and E(k→0) ~ Ik4 for m = 6. (I is Loitsyansky's integral.) It has long been known that the cm are invariants for m < 6, which demands u2'm = constant during the decay. This, in turn, sets the energy decay rate as u2 ~ t-(1-p)2m=(m+2), where p is the power-law exponent for the normalized dissipation rate, εℓ/-u3 ~ t-p, observed empirically to be a small positive number in grid turbulence. We systematically explore the properties of these different classes of turbulence and arrive at the following conclusions. (i) The invariance of cm is a direct consequence of linear momentum conservation for m ≤ 4, and angular momentum conservation for m = 5. (ii) The classical spectra of Saffman, E(k→0) ~ c3k2, and Batchelor, E(k→0) ~ Ik4, are robust in the sense that they emerge from a broad class of initial conditions. In particular, it is necessary only that {ωiω'j}∞≤ O(r-8) at t = 0. The non-classical spectra (m = 2; 4; 5), on the other hand, require very specific initial conditions in order to be realized, of the form {ωiω'j}∞ = O(r-(m)2)). (Note the equality rather than the inequality here.) This makes the nonclassical spectra less likely to be observed in practice. (iii) The case of m = 2, which is usually associated with the u2 ~ t-1 decay law, is pathological in a number of respects. For example, its spectral tensor diverges as k→0, and the long-range correlations {uiu'j} ∞ = O(r-2) are too strong to be a consequence of the Biot-Savart law. (It is the Biot-Savart law that lies behind the longrange correlations in the classical spectra.) This suggests that m = 2 spectra are unlikely to manifest themselves in grid turbulence. A detailed review of the available experimental data is consistent with this assertion. We conclude, therefore, that the minimum energy decay rate in homogeneous grid turbulence is most probably that of Saffman turbulence. © 2011 American Institute of Physics.


Barrie P.J.,University of Cambridge
Physical Chemistry Chemical Physics | Year: 2012

The kinetic compensation effect states that there is a linear relationship between Arrhenius parameters ln A and E for a family of related processes. It is a widely observed phenomenon in many areas of science, notably heterogeneous catalysis. This paper explores mathematical, rather than physicochemical, explanations for the compensation effect in certain situations. Three different topics are covered theoretically and illustrated by examples. Firstly, the effect of systematic errors in experimental kinetic data is explored, and it is shown that these create apparent compensation effects. Secondly, analysis of kinetic data when the Arrhenius parameters depend on another parameter is examined. In the case of temperature programmed desorption (TPD) experiments when the activation energy depends on surface coverage, it is shown that a common analysis method induces a systematic error, causing an apparent compensation effect. Thirdly, the effect of analysing the temperature dependence of an overall rate of reaction, rather than a rate constant, is investigated. It is shown that this can create an apparent compensation effect, but only under some conditions. This result is illustrated by a case study for a unimolecular reaction on a catalyst surface. Overall, the work highlights the fact that, whenever a kinetic compensation effect is observed experimentally, the possibility of it having a mathematical origin should be carefully considered before any physicochemical conclusions are drawn.


Jain A.,University of Cambridge
Reproductive BioMedicine Online | Year: 2012

Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia; each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia. Endothelin (ET)-1 has been implicated in a diverse range of signalling events in a wide variety of target tissues. Given its potent vasoactive function and the prevalence of hypertension in pre-eclampsia, there has been extensive research on the role of ET-1 in this disorder. Indeed, ET-1 has been suggested to contribute to hypertension in pre-eclampsia. Recently, ET-1 has also been implicated in the induction of both oxidative stress and endoplasmic reticulum stress in pre-eclampsia, each of which has been proposed to contribute to many of the clinical manifestations of this disorder. ET-1 has been shown to activate key signalling molecules that lead to induction of these stress pathways. The use of ET-receptor antagonists could block oxidative and endoplasmic reticulum stress. Hence, further research into the role of ET-1 in pre-eclampsia may lead to the development of possible strategies to circumvent these stress pathways and the associated pathology that occurs in pre-eclampsia. © 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Yates L.R.,Wellcome Trust Sanger Institute | Campbell P.J.,Wellcome Trust Sanger Institute | Campbell P.J.,University of Cambridge
Nature Reviews Genetics | Year: 2012

The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces that act on nascent cancer clones as they evolve and have shown insight into the mutational processes that generate genetic variation. Here we review our emerging understanding of the dynamic evolution of the cancer genome and of the implications for basic cancer biology and the development of antitumour therapy. © 2012 Macmillan Publishers Limited. All rights reserved.


Tate C.G.,University of Cambridge
Trends in Biochemical Sciences | Year: 2012

G-protein-coupled receptors (GPCRs) are medically important membrane proteins that are targeted by over 30% of small molecule drugs. At the time of writing, 15 unique GPCR structures have been determined, with 77 structures deposited in the PDB database, which offers new opportunities for drug development and for understanding the molecular mechanisms of GPCR activation. Many different factors have contributed to this success, but if there is one single factor that can be singled out as the foundation for producing well-diffracting GPCR crystals, it is the stabilisation of the detergent-solubilised receptor-ligand complex. This review will focus predominantly on one of the successful strategies for the stabilisation of GPCRs, namely the thermostabilisation of GPCRs using systematic mutagenesis coupled with thermostability assays. Structures of thermostabilised GPCRs bound to a wide variety of ligands have been determined, which has led to an understanding of ligand specificity; why some ligands act as agonists as opposed to partial or inverse agonists; and the structural basis for receptor activation. © 2012.


St Johnston D.,University of Cambridge
PLoS Biology | Year: 2015

Since its heyday in the 1980s and 90s, the field of developmental biology has gone into decline; in part because it has been eclipsed by the rise of genomics and stem cell biology, and in part because it has seemed less pertinent in an era with so much focus on translational impact. In this essay, I argue that recent progress in genome-wide analyses and stem cell research, coupled with technological advances in imaging and genome editing, have created the conditions for the renaissance of a new wave of developmental biology with greater translational relevance. © 2015 Daniel St Johnston.


Therborn G.,University of Cambridge
Environment and Planning A | Year: 2011

Urban studies in the social sciences have for two decades been driven by a hegemonic conception, under slightly different, competing labels: world city, global city, and world city networks. While making important cognitive contributions, it has, I argue, been fundamentally flawed in assuming nation-states and state-processed national economies to be unimportant to the world economy and to world/global cities. While in several ways enriching urban knowledge, its dominance has also impoverished urban research by reducing cities to zip codes of firms and labour markets, leaving out that cities are also places of meaningful built environments, in which people live and interact. Basic assumptions and arguments of the world/global city idea by the three most distin-guished representatives of the approach - John Friedmann, Saskia Sassen, and Peter J Taylor - are critically scrutinized. The current economic crisis has demonstrated these assumptions and arguments about cities in the world economy as untenable. The economic crisis is spawning a paradigmatic crisis, which should be seen as an opportunity for wider views of cities to be opened up. © 2011 Pion Ltd and its Licensors.


de Vries P.J.,University of Cambridge
Neurotherapeutics | Year: 2010

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation. © 2010 The American Society for Experimental NeuroTherapeutics, Inc.


Blake M.,University of Cambridge
Journal of High Energy Physics | Year: 2015

We provide a hydrodynamical description of a holographic theory with broken translation invariance. We use the fluid/gravity correspondence to systematically obtain both the constitutive relations for the currents and the Ward identity for momentum relaxation in a derivative expansion. Beyond leading order in the strength of momentum relaxation, our results differ from a model previously proposed by Hartnoll et al. As an application of these techniques we consider charge and heat transport in the boundary theory. We derive the low frequency thermoelectric transport coefficients of the holographic theory from the linearised hydrodynamics. © 2015, The Author(s).


Arvanitakis A.S.,University of Cambridge
Classical and Quantum Gravity | Year: 2015

We look at solutions of minimal massive gravity (MMG), a generalization of topologically massive gravity that improves upon its holographic properties. It is shown that generically (in MMG parameter space) all conformally flat solutions of vacuum MMG are locally isometric to one of the two (A)dS vacua of the theory. We then couple a scalar field, and find that domain wall solutions can only interpolate between these two vacua precisely when the bulk graviton is tachyonic. Finally, we find a non-BTZ AdS black hole solution satisfying Brown-Henneaux boundary conditions, which lies within the 'bulk/ boundary unitarity region'. © 2015 IOP Publishing Ltd.


Beri B.,University of Cambridge
Physical Review B - Condensed Matter and Materials Physics | Year: 2012

Recent theoretical progress has identified a class of time-reversal invariant topological superconductors, called helical superconductors. While candidate materials exist, to the best of our knowledge, no such system has been observed yet in experiments. Existing proposals for the detection of this phase provide only indirect and partial information, and often are quite difficult to implement experimentally. Here we show that the presence of this phase can be directly probed through the easily measurable nonlocal charge conductance. Focusing on a ring geometry, we suggest two experiments that provide robust qualitative signatures that unambiguously reveal the helical superconductor phase. © 2012 American Physical Society.


The purpose of this study was to prospectively evaluate the value of diffusion-weighted MRI (DWI) for the assessment of extracapsular extension (ECE) in patients with prostate cancer. Between November 2010 and April 2012, 40 patients with intermediate- to high-risk prostate cancer were prospectively recruited. MR images were obtained at 3 T with a phased-array coil. Two independent readers scored the T2-weighted images alone and then in combination with DW images. ROIs were drawn on the apparent diffusion coefficient (ADC) maps, and histogram-derived values were calculated. Whole-mount histopathologic examination was the standard of reference. Reader performance was analyzed, and differences in patient characteristics and histogram-based ADC values, according to ECE status, were evaluated. ECE was present in 23 of 40 (58%) patients and 23 of 43 (53%) tumors. The sensitivity for side-specific ECE detection significantly increased, from 0.22 to 0.44 for reader 1 and 0.33 to 0.82 for reader 2 (both p < 0.05) without a significant change in specificity for either reader with the addition of DWI and ADC mapping. The positive and negative predictive values for both readers also increased. The ADC parameters of median and 10th and 25th centiles showed a statistically significant difference between tumors with and those without ECE (p < 0.05). The addition of DWI and ADC mapping to T2-weighted MRI improved the accuracy of preoperative detection of ECE. Median and 10th and 25th centile ADC values were significantly associated with the presence of ECE and may be useful in the pretreatment assessment of patients with prostate cancer.


Expression of transgenes is central to forward and reverse genetic analysis in Trypanosoma brucei. The inducible expression of transgenes in trypanosomes is based on the tetracycline repressor binding to a tetracycline operator to prevent transcription in the absence of tetracycline. The same inducible system is used to produce double-stranded RNA for RNAi knockdown of target genes. This study describes a new plasmid pSPR2.1 that drives consistent high-level expression of tetracycline repressor in procyclic form trypanosomes. A complementary expression plasmid, p3227, was constructed. The major difference between this and current plasmids is the separation of the inducible transgene and selectable marker promoters by the plasmid backbone. The plasmid p3227 was able to support inducible expression in cell lines containing pSPR2.1 as well as the established Lister 427 29-13 cell line. p3666, a derivative of p3227, was made for inducible expression of stem loop RNAi constructs and was effective for knockdown of DRBD3, which had proved problematic using existing RNAi plasmids with head-to-head promoters. The plasmid system was also able to support inducible transgene expression and DRBD3 RNAi knockdown in bloodstream form cells expressing tetracycline repressor from an integrated copy of the plasmid pHD1313.


Tan L.T.,University of Cambridge
Clinical Oncology | Year: 2011

Aims: Image-guided brachytherapy (IGBT) is the new gold standard for cervix cancer brachytherapy. In 2009, the Royal College of Radiologists (RCR) published a guidance document to facilitate the implementation of IGBT for cervix cancer in the UK. This paper reports the progress since the publication of the RCR document. Materials and methods: Questionnaires were sent to 45 UK centres known to offer brachytherapy for cervix cancer in 2011. Replies were received from 43 (96%) centres. Details collected included brachytherapy machine, imaging technique for brachytherapy planning, applicator design and total dose to point A from external beam radiotherapy and brachytherapy. The results were compared with the 2008 survey reported in the RCR document. Results: The number of centres offering computed tomography (CT) or magnetic resonance imaging (MRI)-based IGBT for cervix cancer has increased to 32 (71%) in 2011 compared with 12 (26%) in 2008. Although the most common applicator design in 2011 remains the tandem-ovoid applicator (71%), more respondents are using the tandem-ring applicator (29% versus 9% in 2008). Only seven (16%) centres are routinely prescribing <70Gy 10 to point A in 2011 compared with10 (22%) in 2008. Conclusion: Considerable progress with implementing IGBT for cervix cancer has been made in the UK since the publication of the RCR guidance document. © 2011 The Royal College of Radiologists.


Baulcombe D.C.,University of Cambridge
Current Opinion in Plant Biology | Year: 2015

Recent evidence indicates two-way traffic of silencing RNA between filamentous organisms and their plant hosts. There are also indications that suppressors of RNA silencing are transferred from filamentous organisms into host plant cells where they influence the innate immune system. Here I use virus disease as a template for interpretation of RNA silencing in connection with filamentous organisms and infected plant cells. I propose that host plant interactions of these organisms are influenced by RNA silencing networks in which there are: small interfering RNAs from the host that are transported into the filamentous organism and vice versa; silencing suppressors from the organism that are transported into the host; endogenous small interfering RNAs and micro RNAs that target components of the innate immune system or endogenous suppressors of the innate immune system. © 2015 Elsevier Ltd.


Much scholarship in chemical education draws upon the model of there being three 'levels' at which the teaching and learning of chemistry operates, a notion which is often represented graphically in terms of a triangle with the apices labelled as macroscopic, submicroscopic and symbolic. This model was proposed by Johnstone who argued that chemistry education needs to take into account ideas deriving from psychological research on cognition about how information is processed in learning. Johnstone's model, or the 'chemistry triplet', has been widely taken-up in chemistry education, but has also been developed and reconceptualised in diverse ways such that there is no canonical form generally adopted in the community. Three decades on from the introduction of Johnstone's model of the three levels, the present perspective article revisits both the analysis of chemical knowledge itself, and key ideas from the learning sciences that can offer insights into how to best teach the macroscopic, submicroscopic and symbolic aspects of chemical knowledge. © 2013 The Royal Society of Chemistry.


Johnson C.M.,University of Cambridge
Archives of Biochemistry and Biophysics | Year: 2013

Differential scanning calorimetry measures the heat capacity of states and the excess heat associated with transitions that can be induced by temperature change. The integral of the excess heat capacity is the enthalpy for this process. Despite this potentially intimidating sounding physical chemistry background, DSC has found almost universal application in studying biological macromolecules. In the case of proteins, DSC can be used to determine equilibrium thermodynamic stability and folding mechanism but can also be used in a more qualitative manner screening for thermal stability as an indicator for, ligand binding, pharmaceutical formulation or conditions conducive to crystal growth. DSC usually forms part of a wider biophysical characterisation of the biological system of interest and so the literature is diverse and difficult to categorise for the technique in isolation. This review therefore describes the potential uses of DSC in studying protein folding and stability, giving brief examples of applications from the recent literature. There have also been some interesting developments in the use of DSC to determine barrier heights for fast folding proteins and in studying complex protein mixtures such as human plasma that are considered in more detail. © 2012 Elsevier Inc. All rights reserved.


Perlmutter E.,University of Cambridge
Journal of High Energy Physics | Year: 2014

We show that for a d-dimensional CFT in flat space, the Rényi entropy Sq across a spherical entangling surface has the following property: in an expansion around q = 1, the first correction to the entanglement entropy is proportional to CT, the coefficient of the stress tensor vacuum two-point function, with a fixed d-dependent coefficient. This is equivalent to a similar statement about the free energy of CFTs living on S 1 x Hd-1 with inverse temperature β = 2πq. In addition to furnishing a direct argument applicable to all CFTs, we exhibit this result using a handful of gravity and field theory computations. Knowledge of CT thus doubles as knowledge of Rényi entropies in the neighborhood of q = 1, which we use to establish new results in 3d vector models at large N. © The Authors.


Agathocleous M.,University of Texas Southwestern Medical Center | Harris W.A.,University of Cambridge
Trends in Cell Biology | Year: 2013

Stem and progenitor cells proliferate and give rise to other types of cells through differentiation. Deregulation of this process can lead to many diseases including cancer. Recent evidence suggests that an extensive metabolic reconfiguration of cancer cells allows them to sustain pathological growth by providing anabolic intermediates for biosynthesis. This raises the question of the physiological role of metabolic pathways during normal cell growth and differentiation. Metabolism changes with differentiation, and metabolic pathways may be controlled by the same signals that control cell proliferation and differentiation. However, metabolism could also reciprocally influence these signals. The role of metabolic regulation may extend beyond the provision of intermediates for the biosynthetic needs of proliferation, to affect cell differentiation. Here we bring together a large number of recent studies that support this suggestion and illustrate some of the mechanisms by which metabolism is linked to cell proliferation and differentiation. © 2013 Elsevier Ltd.


Merkenschlager M.,Imperial College London | Odom D.T.,University of Cambridge
Cell | Year: 2013

Current epigenomics approaches have facilitated the genome-wide identification of regulatory elements based on chromatin features and transcriptional regulator binding and have begun to map long-range interactions between regulatory elements and their targets. Here, we focus on the emerging roles of CTCF and the cohesin in coordinating long-range interactions between regulatory elements. We discuss how species-specific transposable elements may influence such interactions by remodeling the CTCF binding repertoire and suggest that cohesin's association with enhancers, promoters, and sites defined by CTCF binding has the potential to form developmentally regulated networks of long-range interactions that reflect and promote cell-type-specific transcriptional programs. © 2013 Elsevier Inc.


Carvalho B.S.,University of Cambridge | Irizarry R.A.,Johns Hopkins University
Bioinformatics | Year: 2010

Motivation: The availability of flexible open source software for the analysis of gene expression raw level data has greatly facilitated the development of widely used preprocessing methods for these technologies. However, the expansion of microarray applications has exposed the limitation of existing tools. Results: We developed the oligo package to provide a more general solution that supports a wide range of applications. The package is based on the BioConductor principles of transparency, reproducibility and efficiency of development. It extends the existing tools and leverages existing code for visualization, accessing data and widely used preprocessing routines. The oligo package implements a unified paradigm for preprocessing data and interfaces with other BioConductor tools for downstream analysis. Our infrastructure is general and can be used by other BioConductor packages. © The Author 2010. Published by Oxford University Press. All rights reserved.


Wolpert D.M.,University of Cambridge | Diedrichsen J.,University College London | Flanagan J.R.,Queens University
Nature Reviews Neuroscience | Year: 2011

The exploits of Martina Navratilova and Roger Federer represent the pinnacle of motor learning. However, when considering the range and complexity of the processes that are involved in motor learning, even the mere mortals among us exhibit abilities that are impressive. We exercise these abilities when taking up new activities-whether it is snowboarding or ballroom dancing-but also engage in substantial motor learning on a daily basis as we adapt to changes in our environment, manipulate new objects and refine existing skills. Here we review recent research in human motor learning with an emphasis on the computational mechanisms that are involved. © 2011 Macmillan Publishers Limited. All rights reserved.


Huntington J.A.,University of Cambridge
Journal of Thrombosis and Haemostasis | Year: 2011

Serpins have been studied as a distinct protein superfamily since the early 80s. In spite of the poor sequence homology between family members, serpins share a highly conserved core structure that is critical for their functioning as serine protease inhibitors. Therefore, discoveries made about one serpin can be related to the others. In this short review, I introduce the serpin structure and general mechanism of protease inhibition, and illustrate, using recent crystallographic and biochemical data on antithrombin (AT), how serpin activity can be modulated by cofactors. The ability of the serpins to undergo conformational change is critical for their function, but it also renders them uniquely susceptible to mutations that perturb their folding, leading to deficiency and disease. A recent crystal structure of an AT dimer revealed that serpins can participate in large-scale domain-swaps to form stable polymers, and that such a mechanism may explain the accumulation of misfolded serpins within secretory cells. Serpins play important roles in haemostasis and fibrinolysis, and although each will have some elements specifically tailored for its individual function, the mechanisms described here provide a general conceptual framework. © 2011 International Society on Thrombosis and Haemostasis.


Trowsdale J.,University of Cambridge | Knight J.C.,University of Oxford
Annual Review of Genomics and Human Genetics | Year: 2013

Over several decades, various forms of genomic analysis of the human major histocompatibility complex (MHC) have been extremely successful in picking up many disease associations. This is to be expected, as the MHC region is one of the most gene-dense and polymorphic stretches of human DNA. It also encodes proteins critical to immunity, including several controlling antigen processing and presentation. Single-nucleotide polymorphism genotyping and human leukocyte antigen (HLA) imputation now permit the screening of large sample sets, a technique further facilitated by high-throughput sequencing. These methods promise to yield more precise contributions of MHC variants to disease. However, interpretation of MHC-disease associations in terms of the functions of variants has been problematic. Most studies confirm the paramount importance of class I and class II molecules, which are key to resistance to infection. Infection is likely driving the extreme variation of these genes across the human population, but this has been difficult to demonstrate. In contrast, many associations with autoimmune conditions have been shown to be specific to certain class I and class II alleles. Interestingly, conditions other than infections and autoimmunity are also associated with the MHC, including some cancers and neuropathies. These associations could be indirect, owing, for example, to the infectious history of a particular individual and selective pressures operating at the population level. Copyright © 2013 by Annual Reviews. All rights reserved.


Camps J.,University of Cambridge
Journal of High Energy Physics | Year: 2014

We derive an extension of the Ryu-Takayanagi prescription for curvature squared theories of gravity in the bulk, and comment on a prescription for more general theories. This results in a new entangling functional, that contains a correction to Wald's entropy. The new term is quadratic in the extrinsic curvature. The coefficient of this correction is a second derivative of the lagrangian with respect to the Riemann tensor. For Gauss-Bonnet gravity, the new functional reduces to Jacobson-Myers'. © 2014 The Author(s).


Tytherleigh-Strong G.,University of Cambridge
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association | Year: 2013

To report the results of a series of 10 patients who underwent an arthroscopic excision of the sternoclavicular joint (SCJ) for osteoarthritis refractory to conservative treatment. We undertook an arthroscopic excision of the SCJ in 10 patients with osteoarthritis. There were 7 female and 3 male patients with a mean age at surgery of 53 years (range, 42 to 62 years). Patients were assessed preoperatively and at follow-up with the Constant score and the Rockwood SCJ scoring system. The mean follow-up was 28 months (range, 17 to 41 months; SD, 8.1 months). Surgery was undertaken as a day case with no shoulder immobilization. All of the patients had regained their preoperative or full range of movement within 2 weeks of surgery. At most recent follow-up, 7 patients had no pain and 3 had slight pain with activity. The median Constant score had increased from 64.5 (range, 41 to 77) to 83 (range, 61 to 95), and the median Rockwood score had increased from 6 (range, 4 to 7) to 13.5 (range, 9 to 15) (maximum, 15). On the basis of these findings, the clinical results were rated as excellent (13 to 15) in 7 patients, good (10 to 12) in 2, and fair (7 to 9) in 1. There were no complications and, specifically, no problems with joint stability. The results of this study show that arthroscopic SCJ excision is a satisfactory treatment for SCJ osteoarthritis refractory to conservative measures. Level IV, therapeutic case series. Copyright © 2013 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.


Donos A.,University of Cambridge | Gauntlett J.P.,Imperial College London
Journal of High Energy Physics | Year: 2014

Using simple holographic models in D = 4 spacetime dimensions we construct black hole solutions dual to d = 3 CFTs at finite charge density with a Q-lattice deformation. At zero temperature we find new ground state solutions, associated with broken translation invariance in either one or both spatial directions, which exhibit insulating or metallic behaviour depending on the parameters of the holographic theory. For low temperatures and small frequencies, the real part of the optical conductivity exhibits a power-law behaviour. We also obtain an expression for the the DC conductivity at finite temperature in terms of horizon data of the black hole solutions. © 2014 The Author(s).


Monie T.P.,University of Cambridge
Trends in Biochemical Sciences | Year: 2013

For the first time there is now clear biochemical and biophysical evidence indicating that members of the nucleotide-binding domain and leucine-rich repeat containing (NLR) family can be activated as a result of direct interaction between the receptor and ligand. NLRX1 leucine-rich repeats bind to RNA; murine NAIP (NLR family, apoptosis inhibitory protein) 5 binds flagellin directly; and NOD (nucleotide-binding oligomerization domain containing) 1 and NOD2 may interact directly with fragments of peptidoglycan. It remains to be seen if NLRP3 has a specific ligand, but progress has been made in addressing its mechanism of activation, with cellular imbalances and mitochondrial dysfunction being important. This review updates our understanding of NLR activation in light of these recent advances and their impact on the NLR research. © 2013 Elsevier Ltd.


Carr J.P.,University of Cambridge
Advances in virus research | Year: 2010

Induced mechanisms are by definition imperceptible or less active in uninfected, unstressed, or untreated plants, but can be activated by pathogen infection, stress, or chemical treatment to inhibit the replication and movement of virus in the host. In contrast, defenses that are pre-existing or serve to limit virus propagation and spread in otherwise susceptible hosts are considered to be "basal" in nature. Both forms of resistance can be genetically determined. Most recessive resistance genes that control resistance to viruses appear not to depend upon inducible mechanisms but rather maintain basal resistance by producing nonfunctional variants of factors, specifically translation initiation factors, required by the virus for successful exploitation of the host cell protein synthetic machinery. In contrast, most dominant resistance genes condition the induction of broad-scale changes in plant biochemistry and physiology that are activated and regulated by various signal transduction pathways, particularly those regulated by salicylic acid, jasmonic acid, and ethylene. These induced changes include localized plant cell death (associated with the hypersensitive response, HR) and the upregulation of resistance against many types of pathogen throughout the plant (systemic acquired resistance, SAR). Unfortunately, it is still poorly understood how virus infection is inhibited and restricted during the HR and in plants exhibiting SAR. Resistance to viruses is not always genetically predetermined and can be highly adaptive in nature. This is exemplified by resistance based on RNA silencing, which appears to play roles in both induced and basal resistance to viruses. To counter inducible resistance mechanisms, viruses have acquired counter-defense factors to subvert RNA silencing. Some of these factors may affect signal transduction pathways controlled by salicylic acid and jasmonic acid. In this chapter, we review current knowledge of defensive signaling in resistance to viruses including the nature and roles of low molecular weight, proteinaceous, and small RNA components of defensive signaling. We discuss the differences and similarities of defenses and defensive signaling directed against viral versus nonviral pathogens, the potential role of RNA silencing as an effector in resistance and possible regulator of defensive signaling, crosstalk and overlap between antiviral systems, and interference with and manipulation of host defensive systems by the viruses themselves. Copyright © 2010 Elsevier Inc. All rights reserved.


Tong D.,University of Cambridge
Journal of High Energy Physics | Year: 2014

We construct the two dimensional N = (0, 4) gauge theory that lives on the world volume of D1-branes and intersecting D5-branes. We conjecture that this theory flows in the infra-red to a fixed point with large N = (4, 4) superconformal symmetry. The central charge of the conformal field theory is shown to coincide with the holographic dual of string theory compactified on AdS3 × S3 × S3 × S 1. © The Authors.


Murphy A.C.,University of Cambridge
Natural Product Reports | Year: 2011

The depletion of fossil fuel stocks will prohibit their use as the main feedstock of future industrial processes. Biocatalysis is being increasingly used to reduce fossil fuel reliance and to improve the sustainability, efficiency and cost of chemical production. Even with their current small market share, biocatalyzed processes already generate ∼US$50 billion and it has been estimated that they could be used to produce up to 20% of fine chemicals by 2020. Until the advent of molecular biological technologies, the compounds that were readily accessible from renewable biomass were restricted to naturally-occurring metabolites. However, metabolic engineering has considerably broadened the range of compounds now accessible, providing access to compounds that cannot be otherwise reliably sourced, as well as replacing established chemical processes. This review presents the case for continued efforts to promote the adoption of biocatalyzed processes, highlighting successful examples of industrial chemical production from biomass and/or via biocatalyzed processes. A selection of emerging technologies that may further extend the potential and sustainability of biocatalysis are also presented. As the field matures, metabolic engineering will be increasingly crucial in maintaining our quality of life into a future where our current resources and feedstocks cannot be relied upon. © 2011 The Royal Society of Chemistry.


Balk J.,University of Cambridge | Pilon M.,Colorado State University
Trends in Plant Science | Year: 2011

In plants iron-sulfur (Fe-S) proteins are found in the plastids, mitochondria, cytosol and nucleus, where they are essential for numerous physiological and developmental processes. Recent mutant studies, mostly in Arabidopsis thaliana, have identified three pathways for the assembly of Fe-S clusters. The plastids harbor the SUF (sulfur mobilization) pathway and operate independently, whereas cluster assembly in the cytosol depends on the emerging CIA (cytosolic iron-sulfur cluster assembly) pathway and mitochondria. The latter organelles use the ISC (iron-sulfur cluster) assembly pathway. In all three pathways the assembly process can be divided into a first stage where S and Fe are combined on a scaffold protein, and a second stage in which the Fe-S cluster is transferred to a target protein. The second stage might involve different carrier proteins with specialized functions. © 2010 Elsevier Ltd.


Leyser O.,University of Cambridge
Current Biology | Year: 2011

Evolution has provided at least two particularly successful independent solutions to the problems of multicellularity - animals and higher plants. An obvious requirement for successful multicellularity is communication between different parts of the organism, both locally, for example between neighbouring cells, and over very long distances. Recent advances in understanding hormone signalling networks in plants are beginning to reveal how co-ordination of activity across the whole plant body can be achieved despite the lack of a control centre, typical of animal systems. Of particular importance in this distributed regulatory approach are the self-organising properties of the transport system for the plant hormone auxin. This review examines the integrative role of the auxin transport network in co-ordinating plant growth and development. © 2011 Elsevier Ltd.


Furner I.J.,University of Cambridge | Matzke M.,Gregor Mendel Institute of Molecular Plant Biology
Current Opinion in Plant Biology | Year: 2011

The primary sequence of the genome is broadly constant and superimposed upon that constancy is the postreplicative modification of a small number of cytosine residues to 5-methylcytosine. The pattern of methylation is non-random; some sequence contexts are frequently methylated and some rarely methylated and some regions of the genome are highly methylated and some rarely methylated. Once established, methylation is not static: it can potentially change in response to developmental or environmental cues and this may result in correlated changes in gene expression. Changes can occur passively owing to a failure to maintain DNA methylation through rounds of DNA replication, or actively, through the action of enzymes with DNA glycosylase activity. Recent advances in genetic analyses and the generation of high resolution, genome-wide methylation maps are revealing in unprecedented detail the patterns and dynamic changes of DNA methylation in plants. © 2010 Elsevier Ltd.


Berkowitz M.L.,University of North Carolina at Chapel Hill | Vacha R.,University of Cambridge
Accounts of Chemical Research | Year: 2012

In a sense, life is defined by membranes, because they delineate the barrier between the living cell and its surroundings. Membranes are also essential for regulating the machinery of life throughout many interfaces within the cell's interior. A large number of experimental, computational, and theoretical studies have demonstrated how the properties of water and ionic aqueous solutions change due to the vicinity of membranes and, in turn, how the properties of membranes depend on the presence of aqueous solutions. Consequently, understanding the character of aqueous solutions at their interface with biological membranes is critical to research progress on many fronts.The importance of incorporating a molecular-level description of water into the study of biomembrane surfaces was demonstrated by an examination of the interaction between phospholipid bilayers that can serve as model biological membranes. The results showed that, in addition to well-known forces, such as van der Waals and screened Coulomb, one has to consider a repulsion force due to the removal of water between surfaces. It was also known that physicochemical properties of biological membranes are strongly influenced by the specific character of the ions in the surrounding aqueous solutions because of the observation that different anions produce different effects on muscle twitch tension.In this Account, we describe the interaction of pure water, and also of aqueous ionic solutions, with model membranes. We show that a symbiosis of experimental and computational work over the past few years has resulted in substantial progress in the field. We now better understand the origin of the hydration force, the structural properties of water at the interface with phospholipid bilayers, and the influence of phospholipid headgroups on the dynamics of water. We also improved our knowledge of the ion-specific effect, which is observed at the interface of the phospholipid bilayer and aqueous solution, and its connection with the Hofmeister series.Nevertheless, despite substantial progress, many issues remain unresolved. Thus, for example, we still cannot satisfactorily explain the force of interaction between phospholipid bilayers immersed in aqueous solutions of NaI. Although we try to address many issues here, the scope of the discussion is limited and does not cover such important topics as the influence of ionic solutions on phases of bilayers, the influence of salts on the properties of Langmuir monolayers containing lipid molecules, or the influence of aqueous solutions on bilayers containing mixtures of lipids. We anticipate that the future application of more powerful experimental techniques, in combination with more advanced computational hardware, software, and theory, will produce molecular-level information about these important topics and, more broadly, will further illuminate our understanding of interfaces between aqueous solutions and biological membranes. © 2011 American Chemical Society.


Pellegrini L.,University of Cambridge
Sub-cellular biochemistry | Year: 2012

Initiation of DNA synthesis in eukaryotic replication depends on the Pol α-primase complex, a multi-protein complex endowed with polymerase and primase activity. The Pol α-primase complex assembles the RNA-DNA primers required by the processive Pol δ and Pol ε for bulk DNA synthesis on the lagging and leading strand, respectively. During primer synthesis, the primase subunits synthesise de novo an oligomer of 7-12 ribonucleotides in length, which undergoes limited extension with deoxyribonucleotides by Pol α. Despite its central importance to DNA replication, little is known about the mechanism of primer synthesis by the Pol α-primase complex, which comprises the steps of initiation, 'counting' and hand-off of the RNA primer by the primase to Pol α, followed by primer extension with dNTPs and completion of the RNA-DNA hybrid primer. Recent biochemical and structural work has started to provide some insight into the molecular basis of initiation of DNA synthesis. Important advances include the structural characterisation of the evolutionarily related archaeal primase, the elucidation of the mechanism of interaction between Pol α and its B subunit and the observation that the regulatory subunit of the primase contains an iron-sulfur cluster domain that is essential for primer synthesis.


Wallace C.,University of Cambridge
Genetic Epidemiology | Year: 2013

Integration of data from genome-wide single nucleotide polymorphism (SNP) association studies of different traits should allow researchers to disentangle the genetics of potentially related traits within individually associated regions. Formal statistical colocalisation testing of individual regions requires selection of a set of SNPs summarising the association in a region. We show that the SNP selection method greatly affects type 1 error rates, with published studies having used methods expected to result in substantially inflated type 1 error rates. We show that either avoiding variable selection and instead testing the most informative principal components or integrating over variable selection using Bayesian model averaging can help control type 1 error rates. Application to data from Graves' disease and Hashimoto's thyroiditis reveals a common genetic signature across seven regions shared between the diseases, and indicates that in five of six regions associated with Graves' disease and not Hashimoto's thyroiditis, this more likely reflects genuine absence of association with the latter rather than lack of power. Our examination, by simulation, of the performance of colocalisation tests and associated software will foster more widespread adoption of formal colocalisation testing. Given the increasing availability of large expression and genetic association datasets from disease-relevant tissue and purified cell populations, coupled with identification of regulatory sequences by projects such as ENCODE, colocalisation analysis has the potential to reveal both shared genetic signatures of related traits and causal disease genes and tissues. © 2013 WILEY PERIODICALS, INC.


Hardie R.C.,University of Cambridge
Current Biology | Year: 2012

Two new studies introduce the power of Drosophila genetics to polarization vision, revealing distinct photoreceptor inputs to polarotactic behaviour mediated by dorsal and ventral eye regions. © 2012 Elsevier Ltd.


Villarroya F.,University of Barcelona | Vidal-Puig A.,University of Cambridge | Vidal-Puig A.,Wellcome Trust Sanger Institute
Cell Metabolism | Year: 2013

If we could avoid the side effects associated with global sympathetic activation, activating brown adipose tissue to increase thermogenesis would be a safe way to lose weight. The discovery of adrenergic-independent brown fat activators opens the prospect of developing this alternative way to efficiently and safely induce negative energy balance. © 2013 Elsevier Inc.


Parkes M.,University of Cambridge | Cortes A.,University of Queensland | Van Heel D.A.,Queen Mary, University of London | Brown M.A.,University of Queensland
Nature Reviews Genetics | Year: 2013

Shared aetiopathogenic factors among immune-mediated diseases have long been suggested by their co-familiality and co-occurrence, and molecular support has been provided by analysis of human leukocyte antigen (HLA) haplotypes and genome-wide association studies. The interrelationships can now be better appreciated following the genotyping of large immune disease sample sets on a shared SNP array: the 'Immunochip'. Here, we systematically analyse loci shared among major immune-mediated diseases. This reveals that several diseases share multiple susceptibility loci, but there are many nuances. The most associated variant at a given locus frequently differs and, even when shared, the same allele often has opposite associations. Interestingly, risk alleles conferring the largest effect sizes are usually disease-specific. These factors help to explain why early evidence of extensive 'sharing' is not always reflected in epidemiological overlap. © 2013 Macmillan Publishers Limited. All rights reserved.


Thompson B.J.,Cancer Research UK Research Institute | Pichaud F.,University College London | Roper K.,University of Cambridge
Nature Reviews Molecular Cell Biology | Year: 2013

Cell polarity and cell-cell junctions have pivotal roles in organizing cells into tissues and in mediating cell-cell communication. The transmembrane protein Crumbs has a well-established role in the maintenance of epithelial polarity, and it can also regulate signalling via the Notch and Hippo pathways to influence tissue growth. The functions of Crumbs in epithelial polarity and Hippo-mediated growth depend on its short intracellular domain. Recent evidence now points to a conserved and fundamental role for the extracellular domain of Crumbs in mediating homophilic Crumbs-Crumbs interactions at cell-cell junctions. © 2013 Macmillan Publishers Limited. All rights reserved.


Pinsker F.,University of Cambridge | Flayac H.,Ecole Polytechnique Federale de Lausanne
Physical Review Letters | Year: 2014

We theoretically demonstrate the generation of dark soliton trains in a one-dimensional exciton-polariton condensate within experimentally accessible schemes. In particular, we show that the frequency of the train can be finely tuned fully optically or electrically to provide a stable and efficient output signal modulation. Taking the polarization of the condensate into account, we elucidate the possibility of forming on-demand half-soliton trains. © 2014 American Physical Society.


Donos A.,University of Cambridge | Gauntlett J.P.,Imperial College London
Journal of High Energy Physics | Year: 2014

We introduce a new framework for constructing black hole solutions that are holographically dual to strongly coupled field theories with explicitly broken translation invariance. Using a classical gravitational theory with a continuous global symmetry leads to constructions that involve solving ODEs instead of PDEs. We study in detail D = 4 Einstein-Maxwell theory coupled to a complex scalar field with a simple mass term. We construct black holes dual to metallic phases which exhibit a Drude-type peak in the optical conductivity, but there is no evidence of an intermediate scaling that has been reported in other holographic lattice constructions. We also construct black holes dual to insulating phases which exhibit a suppression of spectral weight at low frequencies. We show that the model also admits a novel AdS 3 × ℝ solution. © 2014 The Author(s).


Stanley M.,University of Cambridge
Gynecologic Oncology | Year: 2010

Human papillomaviruses (HPVs) are a large family of small double-stranded DNA viruses that infect squamous epithelia. It has been established that infection with specific HPV types is a contributing factor to different types of anogenital cancer, including vulval, vaginal, anal, penile, and head and neck cancers. Approximately 4% of all cancers are associated with HPV. HPV infection is the major cause of cervical cancer and genital warts. Genital HPV infections are very common, are sexually transmitted, and have a peak prevalence between ages 18 and 30. Most of these infections clear spontaneously, but in 10-20% of women, these infections remain persistent and are at risk of progression to grade 2/3 cervical intraepithelial neoplasm (CIN) and eventually to invasive cancer of the cervix (ICC). CINs are genetically unstable lesions with a 30-40% risk of progression to ICC. If left untreated, they form a spectrum of increasing cytological atypia, ranging from low-grade CIN1 to high-grade CIN3; the latter are caused almost exclusively by high-risk HPVs, HPV 16 and 18. Infection with HPV requires a microabrasion in the genital epithelium. The oncogenic properties of high-risk HPV reside in the E6 and E7 genes, which if inappropriately expressed in dividing cells deregulate cell division and differentiation. HPV DNA testing has been shown consistently to be superior to cytology in terms of sensitivity and positive predictive value and will become a major tool in cervical cancer screening, at least in the developed countries. © 2010.


Kirchhausen T.,Harvard University | Owen D.,University of Cambridge | Harrison S.C.,Howard Hughes Medical Institute
Cold Spring Harbor Perspectives in Biology | Year: 2014

Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation. © 2014 Cold Spring Harbor Laboratory Press; all rights reserved.


Kemp G.J.,University of Liverpool | Brindle K.M.,University of Cambridge
Diabetes | Year: 2012

Magnetic resonance spectroscopy (MRS) methods offer a potentially valuable window into cellular metabolism. Measurement of flux between inorganic phosphate (Pi) and ATP using 31P MRS magnetization transfer has been used in resting muscle to assess what is claimed to be mitochondrial ATP synthesis and has been particularly popular in the study of insulin effects and insulin resistance. However, the measured Pi→ATP flux in resting skeletal muscle is far higher than the true rate of oxidative ATP synthesis, being dominated by a glycolytically mediated Pi↔ATP exchange reaction that is unrelated to mitochondrial function. Furthermore, even if measured accurately, the ATP production rate in resting muscle has no simple relationship to mitochondrial capacity as measured either ex vivo or in vivo. We summarize the published measurements of Pi→ATP flux, concentrating on work relevant to diabetes and insulin, relate it to current understanding of the physiology of mitochondrial ATP synthesis and glycolytic Pi↔ATP exchange, and discuss some possible implications of recently reported correlations between Pi→ATP flux and other physiological measures. © 2012 by the American Diabetes Association.


Robertson J.,University of Cambridge | Wallace R.M.,University of Texas at Dallas
Materials Science and Engineering R: Reports | Year: 2015

The scaling of complementary metal oxide semiconductor (CMOS) transistors has led to the silicon dioxide layer used as a gate dielectric becoming so thin that the gate leakage current becomes too large. This led to the replacement of SiO2 by a physically thicker layer of a higher dielectric constant or 'high-K' oxide such as hafnium oxide. Intensive research was carried out to develop these oxides into high quality electronic materials. In addition, the incorporation of Ge in the CMOS transistor structure has been employed to enable higher carrier mobility and performance. This review covers both scientific and technological issues related to the high-K gate stack - the choice of oxides, their deposition, their structural and metallurgical behaviour, atomic diffusion, interface structure, their electronic structure, band offsets, electronic defects, charge trapping and conduction mechanisms, reliability, mobility degradation and oxygen scavenging to achieve the thinnest oxide thicknesses. The high K oxides were implemented in conjunction with a replacement of polycrystalline Si gate electrodes with metal gates. The strong metallurgical interactions between the gate electrodes and the HfO2 which resulted an unstable gate threshold voltage resulted in the use of the lower temperature 'gate last' process flow, in addition to the standard 'gate first' approach. Work function control by metal gate electrodes and by oxide dipole layers is discussed. The problems associated with high K oxides on Ge channels are also discussed. © 2014 Elsevier B.V. All rights reserved.


Bartolomei M.S.,University of Pennsylvania | Ferguson-Smith A.C.,University of Cambridge
Cold Spring Harbor Perspectives in Biology | Year: 2011

Normal mammalian development requires a maternal and paternal contribution, which is attributed to imprinted genes, or genes that are expressed from a single parental allele. Approximately 100 imprinted genes have been reported in mammals thus far. Imprinted genes are controlled by cis-acting regulatory elements, termed imprinting control regions (ICRs), which have parental-specific epigenetic modifications, including DNA methylation. ICRs are methylated by de novo DNA methyltransferases during germline development; these parental-specific modifications must be maintained following fertilization when the genome is extensively reprogrammed. Many imprinted genes reside in ~1-megabase clusters, with two major mechanisms of imprinting regulation currently recognized, CTCF-dependent insulators and long noncoding RNAs. Unclustered imprinted genes are generally regulated by germline-derived differential promoter methylation. Here, we describe the identification and functions of imprinted genes, cis-acting control sequences, trans-acting factors, and imprinting mechanisms in clusters. Finally, we define questions that require more extensive research. © 2011 Cold Spring Harbor Laboratory Press.


The common severe Z mutation (E342K) of α1-antitrypsin forms intracellular polymers that are associated with liver cirrhosis. The native fold of this protein is well-established and models have been proposed from crystallographic and biophysical data for the stable inter-molecular configuration that terminates the polymerization pathway. Despite these molecular 'snapshots', the details of the transition between monomer and polymer remain only partially understood. We surveyed the RCL (reactive centre loop) of α1-antitrypsin to identify sites important for progression, through intermediate states, to polymer. Mutations at P14P12 and P4, but not P10P8 or P2P1', resulted in a decrease in detectable polymer in a cell model that recapitulates the intracellular polymerization of the Z variant, consistent with polymerization from a near-native conformation. We have developed a FRET (Förster resonance energy transfer)-based assay to monitor polymerization in small sample volumes. An in vitro assessment revealed the position-specific effects on the unimolecular and multimolecular phases of polymerization: the P14P12 region self-inserts early during activation, while the interaction between P6P4 and β-sheet A presents a kinetic barrier late in the polymerization pathway. Correspondingly, mutations at P6P4, but not P14P12, yield an increase in the overall apparent activation energy of association from ~360 to 550 kJ mol(-1).


The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.285. © 2015 Macmillan Publishers Limited


Frost S.D.,University of Cambridge
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2013

Epidemiological models have highlighted the importance of population structure in the transmission dynamics of infectious diseases. Using HIV-1 as an example of a model evolutionary system, we consider how population structure affects the shape and the structure of a viral phylogeny in the absence of strong selection at the population level. For structured populations, the number of lineages as a function of time is insufficient to describe the shape of the phylogeny. We develop deterministic approximations for the dynamics of tips of the phylogeny over evolutionary time, the number of 'cherries', tips that share a direct common ancestor, and Sackin's index, a commonly used measure of phylogenetic imbalance or asymmetry. We employ cherries both as a measure of asymmetry of the tree as well as a measure of the association between sequences from different groups. We consider heterogeneity in infectiousness associated with different stages of HIV infection, and in contact rates between groups of individuals. In the absence of selection, we find that population structure may have relatively little impact on the overall asymmetry of a tree, especially when only a small fraction of infected individuals is sampled, but may have marked effects on how sequences from different subpopulations cluster and co-cluster.


Doping is one of the most important methods to control charge carrier concentration in semiconductors. Ideally, the introduction of dopants should not perturb the ordered microstructure of the semiconducting host. In some systems, such as modulation-doped inorganic semiconductors or molecular charge transfer crystals, this can be achieved by spatially separating the dopants from the charge transport pathways. However, in conducting polymers, dopants tend to be randomly distributed within the conjugated polymer, and as a result the transport properties are strongly affected by the resulting structural and electronic disorder. Here, we show that in the highly ordered lamellar microstructure of a regioregular thiophene-based conjugated polymer, a small-molecule p-type dopant can be incorporated by solid state diffusion into the layers of solubilizing side chains without disrupting the conjugated layers. In contrast to more disordered systems, this allows us to observe coherent, free-electron-like charge transport properties, including a nearly ideal Hall effect in a wide temperature range, a positive magnetoconductance due to weak localization and the Pauli paramagnetic spin susceptibility. © 2016 Nature Publishing Group


Jackson R.J.,University of Cambridge
Cold Spring Harbor Perspectives in Biology | Year: 2013

Internal ribosome entry sites/segments (IRESs) were first discovered over 20 years ago in picornaviruses, followed by the discovery of two other types of IRES in hepatitis C virus (HCV), and the dicistroviruses, which infect invertebrates. In the meantime, reports of IRESs in eukaryotic cellular mRNAs started to appear, and the list of such putative IRESs continues to grow to the point in which it now stands at ~100, 80% of them in vertebrate mRNAs. Despite initial skepticism from some quarters, there now seems universal agreement that there is genuine internal ribosome entry on the viral IRESs. However, the same cannot be said for cellular mRNA IRESs, which continue to be shrouded in controversy. The aim of this article is to explain why vertebrate mRNA IRESs remain controversial, and to discuss ways in which these controversies might be resolved. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Thomas S.J.M.,University of Cambridge
Angewandte Chemie - International Edition | Year: 2011

Rising to the challenge: A reliable, stable, safe, and low-cost method of producing H 2 from H 2O is needed so that this high-energy-density gas can serve as a cleaner source of energy, particularly for low-temperature fuel-cell-powered devices. An atomically dispersed Pt catalyst (see picture) recently developed on an inexpensive and inert support could well hold the key. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Clayton D.,University of Cambridge
Biostatistics | Year: 2010

Homer and others (2008. Resolving individuals contributing trace amounts of DNA to highly complex mixtures using high-density SNP genotyping microarrays. PLoS Genetics 4, e1000167) recently showed that, given allele frequency data for a large number of single nucleotide polymorphisms in a sample together with corresponding population "reference" frequencies, by typing an individual's DNA sample at the same set of loci it can be inferred whether or not the individual was a member of the sample. This observation has been responsible for precautionary removal of large amounts of summary data from public access. This and further work on the problem has followed a frequentist approach. This paper sets out a Bayesian analysis of this problem which clarifies the role of the reference frequencies and allows incorporation of prior probabilities of the individual's membership in the sample. © 2010 The Author.


Hardie R.C.,University of Cambridge
Wiley Interdisciplinary Reviews: Membrane Transport and Signaling | Year: 2012

Phototransduction in Drosophila is mediated by a G-protein coupled phospholipase C (PLC) cascade leading to graded membrane depolarization. It is the preferred model for phototransduction in microvillar photoreceptors and an important model for the ubiquitous phosphoinositide signaling cascade. The photoreceptors respond sensitively to single photons 10-100× more rapidly than vertebrate rods, yet still light adapt to signal under full sunlight. Incident light is absorbed and transduced in the rhabdomere, a 1-2 μm diameter, 100 μm long waveguide composed of ~30,000 tightly packed microvilli, which contain the visual pigment rhodopsin and all the major components of the cascade. PLC hydrolyzes phosphatidyl-inositol (4,5) bisphosphate (PIP2) to generate diacylglycerol (DAG), inositol (1,4,5) trisphosphate (InsP3), and also a proton. This results in activation of two classes of Ca2+ permeable cation channels, TRP and TRPL-the prototypical members of the transient receptor potential (TRP) superfamily of cation channels. Recent evidence suggests that the channels may be activated in a combinatorial manner by two neglected consequences of PLC activity, namely simultaneous depletion of PIP2 and acidification. Several components of the cascade, including TRP, PLC, and protein kinase C are assembled into multimolecular signaling complexes by the PDZ-domain scaffolding protein INAD. Ca2+ influx via TRP channels is essential for rapid kinetics, amplification, and light adaptation and mediates both positive and negative feedback via multiple downstream targets, including the channels, rhodopsin, and PLC. This Ca2+-dependent feedback along with the ultracompartmentalization provided by the microvillar design and molecular scaffolding is critical for the combination of sensitivity, rapid kinetics, and broad dynamic range. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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.


Adamo T.,University of Cambridge
Journal of High Energy Physics | Year: 2014

We study the multiparticle factorization properties of two worldsheet theories which - at tree-level - describe the scattering of massless particles in four dimensions: the Berkovits-Witten twistor-string for N= 4 super-Yang-Mills coupled to N= 4 conformal supergravity, and the Skinner twistor-string for N= 8 supergravity. By considering these string-like theories, we can study factorization at the level of the worldsheet before any Wick contractions or integrals have been performed; this is much simpler than considering the factorization properties of the amplitudes themselves. In Skinner's twistor-string this entails the addition of worldsheet gravity as well as a formalism that represents all external states in a manifestly symmetric way, which we develop explicitly at genus zero. We confirm that the scattering amplitudes of Skinner's theory, as well as the gauge theory amplitudes for the planar sector of the Berkovits-Witten theory, factorize appropriately at genus zero. In the non-planar sector, we find behavior indicative of conformal gravity in the Berkovits-Witten twistor-string. We contrast factorization in twistor-strings with the story in ordinary string theory, and also make some remarks on higher genus factorization and disconnected prescriptions. © 2014 The Author(s).


Taviani V.,University of Cambridge
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine | Year: 2011

Aortic pulse wave velocity (PWV) is an independent determinant of cardiovascular risk. Although aortic stiffening with age is well documented, the interaction between aging and regional aortic PWV is still a debated question. We measured global and regional PWV in the descending aorta of 56 healthy subjects aged 25-76 years using a one-dimensional, interleaved, Fourier velocity encoded pulse sequence with cylindrical excitation. Repeatability across two magnetic resonance examinations (n = 19) and accuracy against intravascular pressure measurements (n = 4) were assessed. The global PWV was found to increase nonlinearly with age. The thoracic aorta was found to stiffen the most with age (PWV [thoracic, 20-40 years] = 4.7 ± 1.1 m/s; PWV [thoracic, 60-80 years] = 7.9 ± 1.5 m/s), followed by the mid- (PWV [mid-abdominal, 20-40 years] = 4.9 ± 1.3 m/s; PWV [mid-abdominal, 60-80 years] = 7.4 ± 1.9 m/s) and distal abdominal aorta (PWV [distal abdominal, 20-40 years] = 4.8 ± 1.4 m/s; PWV [distal abdominal, 60-80 years] = 5.7 ± 1.4 m/s). Good agreement was found between repeated magnetic resonance measurements and between magnetic resonance PWVs and the gold-standard. Fourier velocity encoded M-mode allowed to measure global and regional PWV in the descending aorta. There was a preferential stiffening of the thoracic aorta with age, which may be due to progressive fragmentation of elastin fibers in this region. © 2010 Wiley-Liss, Inc.


Pierce B.L.,University of Chicago | Burgess S.,University of Cambridge
American Journal of Epidemiology | Year: 2013

Mendelian randomization (MR) is a method for estimating the causal relationship between an exposure and an outcome using a genetic factor as an instrumental variable (IV) for the exposure. In the traditional MR setting, data on the IV, exposure, and outcome are available for all participants. However, obtaining complete exposure data may be difficult in some settings, due to high measurement costs or lack of appropriate biospecimens. We used simulated data sets to assess statistical power and bias for MR when exposure data are available for a subset (or an independent set) of participants. We show that obtaining exposure data for a subset of participants is a cost-efficient strategy, often having negligible effects on power in comparison with a traditional complete-data analysis. The size of the subset needed to achieve maximum power depends on IV strength, and maximum power is approximately equal to the power of traditional IV estimators. Weak IVs are shown to lead to bias towards the null when the subsample is small and towards the confounded association when the subset is relatively large. Various approaches for confidence interval calculation are considered. These results have important implications for reducing the costs and increasing the feasibility of MR studies. © 2013 © The Author 2013. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.


A long-standing goal of molecular biologists has been to construct DNA-binding proteins for the control of gene expression. The classical Cys2His2 (C2H2) zinc finger design is ideally suited for such purposes. Discriminating between closely related DNA sequences both in vitro and in vivo, this naturally occurring design was adopted for engineering zinc finger proteins (ZFPs) to target genes specifically. Zinc fingers were discovered in 1985, arising from the interpretation of our biochemical studies on the interaction of the Xenopus protein transcription factor IIIA (TFIIIA) with 5S RNA. Subsequent structural studies revealed its three-dimensional structure and its interaction with DNA. Each finger constitutes a self-contained domain stabilized by a zinc (Zn) ion ligated to a pair of cysteines and a pair of histidines and also by an inner structural hydrophobic core. This discovery showed not only a new protein fold but also a novel principle of DNA recognition. Whereas other DNA-binding proteins generally make use of the 2-fold symmetry of the double helix, functioning as homo- or heterodimers, zinc fingers can be linked linearly in tandem to recognize nucleic acid sequences of varying lengths. This modular design offers a large number of combinatorial possibilities for the specific recognition of DNA (or RNA). It is therefore not surprising that the zinc finger is found widespread in nature, including 3% of the genes of the human genome. The zinc finger design can be used to construct DNA-binding proteins for specific intervention in gene expression. By fusing selected zinc finger peptides to repression or activation domains, genes can be selectively switched off or on by targeting the peptide to the desired gene target. It was also suggested that by combining an appropriate zinc finger peptide with other effector or functional domains, e.g. from nucleases or integrases to form chimaeric proteins, genomes could be modified or manipulated. The first example of the power of the method was published in 1994 when a three-finger protein was constructed to block the expression of a human oncogene transformed into a mouse cell line. The same paper also described how a reporter gene was activated by targeting an inserted 9-base pair (bp) sequence, which acts as the promoter. Thus, by fusing zinc finger peptides to repression or activation domains, genes can be selectively switched off or on. It was also suggested that, by combining zinc fingers with other effector or functional domains, e.g. from nucleases or integrases, to form chimaeric proteins, genomes could be manipulated or modified. Several applications of such engineered ZFPs are described here, including some of therapeutic importance, and also their adaptation for breeding improved crop plants. © 2010 Cambridge University Press.


Winzer C.,University of Cambridge
Energy Policy | Year: 2012

Energy security. 11Energy security, the security of energy supplies or more shortly security of supply are used as synonyms both in this article and in other parts of literature. is one of the main targets of energy policy. However, the term has not been clearly defined, which makes it hard to measure and difficult to balance against other policy objectives. We review the multitude of definitions of energy security. They can be characterized according to the sources of risk, the scope of the impacts, and the severity filters in the form of the speed, size, sustention, spread, singularity and sureness of impacts. Using a stylized case study for three European countries, we illustrate how the selection of conceptual boundaries along these dimensions determines the outcome. This can be avoided by more clearly separating between security of supply and other policy objectives. This leads us to the definition of energy security as the continuity of energy supplies relative to demand. © 2012 Elsevier Ltd.


Zernicka-Goetz M.,University of Cambridge
Current Biology | Year: 2013

Cells of early mouse embryo were considered for a long time to acquire cell fate at random. Recent analyses argue against this simple model. © 2013 Elsevier Ltd.


Velu C.,University of Cambridge
Technovation | Year: 2015

In this study, we address the question of how the degree of business model innovation affects the survival of new firms. We present a newly constructed data set of 129 new firms that launched electronic trading platforms in the US bond market between 1995 and 2004 following the advent of Internet technology. We analyze the founding and survival of these new firms during the period of our study. We find that new firms with a high or low degree of business model innovation are more likely to survive for longer than new firms with a moderate degree of business model innovation. We show that partnering with third-party firms with complementary assets reduces the survival of new firms as the degree of business model innovation increases. We discuss the implications of our findings for managers, policy-makers and researchers. © 2014 Elsevier Ltd. All rights reserved.


Overholm H.,University of Cambridge
Technovation | Year: 2015

This study suggests that in the entrepreneurial communities of emerging industries, individual entrepreneurs may simultaneously create opportunities that spill over to others and discover opportunities already created by others. Extant opportunity literature, focused on single actors and their personal networks or on the information function of market prices, is largely mute on the role of opportunities in value networks with distributed entrepreneurial efforts. Ecosystem theory, a literature stream that seldom intersects opportunity literature, contributes with a conceptual framework to study the question. The paper seeks to shed light on how opportunities are created or discovered by new ventures as they are involved in the interlinked endeavor of forming a new ecosystem. The study examines five case studies of US ventures in the early phase of the solar service industry, an industry in which entrepreneurs offer customers access to solar panels as a service rather than as a product. These ventures inadvertently created an industry ecosystem together, as they could not protect the value created by their business partners' new knowledge, or by the emerging social webs between partners. They shaped opportunities together, passing value back and forth amongst themselves. This paper offers fundamental observations on how opportunity creation and discovery is distributed among a community of entrepreneurs as a business ecosystem grows. © 2014 Elsevier Ltd. All rights reserved.


Tankebe J.,University of Cambridge
British Journal of Criminology | Year: 2010

Nearly every study of police corruption hypothesizes that public experience of police corruption undermines the moral standing of the police. However, scarcely any studies actually test the hypothesis. My aim in this empirical study is to compare the effects of three dimensions of police corruption on perceptions of police trustworthiness, procedural justice and effectiveness. These three dimensions of corruption are personal experience, vicarious experience and subjective evaluations of police anti-corruption measures. The data come from a survey of people living in Accra, Ghana. The findings show that both vicarious experiences of corruption and satisfaction with reform measures explain assessments of police trustworthiness, procedural justice and effectiveness, but that personal experiences of police corruption do not do so.


Lew V.L.,University of Cambridge
Current Biology | Year: 2011

A recent study reveals that the intraerythrocytic asexual reproduction cycle of Plasmodium falciparum ends with the ruptured erythrocyte membrane curling outwards, buckling, everting and vesiculating. Analogy with the sequence seen during spontaneous inside-out vesiculation of erythrocyte membranes suggests that the parasite co-opts pre-existing cytoskeletal conformations to facilitate terminal merozoite dispersal. © 2011 Elsevier Ltd.


A key target in the study of layered intrusions is to constrain the liquid line of descent of the magma. However, the evolution of the interstitial liquid is rarely considered, and its liquid line of descent is often assumed to be equivalent to that of the bulk magma. Because of extensive sub-solidus and diffusional changes that occur in slowly cooled rocks, clues to the composition of the interstitial liquid can only be obtained using very slowly diffusing trace elements and components. This study uses the Ti concentrations and anorthite contents of interstitial plagioclase to consider the compositional evolution of the interstitial liquid in the Skaergaard Intrusion. Ti-XAn zoning of interstitial plagioclase does not follow the same cryptic variations that develop in plagioclase primocrysts as a function of stratigraphic height, demonstrating that the bulk and interstitial liquid lines of descent are not equivalent. After Fe-Ti oxides start to crystallize, Ti concentrations decrease in both primocryst and interstitial plagioclase as a result of decreasing melt Ti. However, in the interstitial plagioclase within a single thin section, divergent trends develop adjacent to fine-grained interstitial pockets containing diverse mineral assemblages, which are interpreted to represent the crystallized products of late-stage immiscible liquids. These trends vary systematically as a function of stratigraphic height and spatial location within the intrusion. The distribution and compositions of these plagioclase zoning trends are used to comment on the spatial distribution and differential movement of interstitial immiscible liquids within the intrusion. © The Author 2010. Published by Oxford University Press. All rights reserved.


Bermudez M.A.,University of Cambridge
Philosophical transactions of the Royal Society of London. Series B, Biological sciences | Year: 2014

Sensitivity to time, including the time of reward, guides the behaviour of all organisms. Recent research suggests that all major reward structures of the brain process the time of reward occurrence, including midbrain dopamine neurons, striatum, frontal cortex and amygdala. Neuronal reward responses in dopamine neurons, striatum and frontal cortex show temporal discounting of reward value. The prediction error signal of dopamine neurons includes the predicted time of rewards. Neurons in the striatum, frontal cortex and amygdala show responses to reward delivery and activities anticipating rewards that are sensitive to the predicted time of reward and the instantaneous reward probability. Together these data suggest that internal timing processes have several well characterized effects on neuronal reward processing.


Brennan P.,University of Bristol | Keverne E.B.,University of Cambridge
Neuroscience and Biobehavioral Reviews | Year: 2015

Chemosensory systems play vital roles in the lives of most mammals, including the detection and identification of predators, as well as sex and reproductive status and the identification of individual conspecifics. All of these capabilities require a process of recognition involving a combination of innate (kairomonal/pheromonal) and learned responses. Across very different phylogenies, the mechanisms for pheromonal and odour learning have much in common. They are frequently associated with plasticity of GABA-ergic feedback at the initial level of processing the chemosensory information, which enhances its pattern separation capability. Association of odourant features into an odour object primarily involves anterior piriform cortex for non-social odours. However, the medial amygdala appears to be involved in both the recognition of social odours and their association with chemosensory information sensed by the vomeronasal system. Unusually not only the sensory neurons themselves, but also the GABA-ergic interneurons in the olfactory bulb are continually being replaced, with implications for the induction and maintenance of learned chemosensory responses. © 2014.


Cohen S.,Technion - Israel Institute of Technology | Nathan J.A.,University of Cambridge | Goldberg A.L.,Harvard University
Nature Reviews Drug Discovery | Year: 2014

Atrophy occurs in specific muscles with inactivity (for example, during plaster cast immobilization) or denervation (for example, in patients with spinal cord injuries). Muscle wasting occurs systemically in older people (a condition known as sarcopenia); as a physiological response to fasting or malnutrition; and in many diseases, including chronic obstructive pulmonary disorder, cancer-associated cachexia, diabetes, renal failure, cardiac failure, Cushing syndrome, sepsis, burns and trauma. The rapid loss of muscle mass and strength primarily results from excessive protein breakdown, which is often accompanied by reduced protein synthesis. This loss of muscle function can lead to reduced quality of life, increased morbidity and mortality. Exercise is the only accepted approach to prevent or slow atrophy. However, several promising therapeutic agents are in development, and major advances in our understanding of the cellular mechanisms that regulate the protein balance in muscle include the identification of several cytokines, particularly myostatin, and a common transcriptional programme that promotes muscle wasting. Here, we discuss these new insights and the rationally designed therapies that are emerging to combat muscle wasting. © 2014 Macmillan Publishers Limited. All rights reserved.


Eisner M.,University of Cambridge
British Journal of Criminology | Year: 2011

This paper examines the frequency of violent death and regicide amongst 1,513 monarchs in 45 monarchies across Europe between AD 600 and 1800. The analyses reveal that all types of violence combined account for about 22 per cent of all deaths. Murder is by far the most important violent cause of death, accounting for about 15 per cent of all deaths and corresponding to a homicide rate of about 1,000 per 100,000 ruler-years. Analyses of trends over time reveal a significant decline in the frequency of both battle deaths and homicide between the Early Middle Ages and the end of the eighteenth century. A significant part of the drop occurred during the first half of the period, suggesting that the civilizing processes assumed by Norbert Elias started between the seventh and the twelfth centuries. Finally, preliminary analyses suggest that regicide has a significant 'autoregressive' component in that the murder of the predecessor and the pre-predecessor increases the risk of homicide for the current monarch. It is suggested that such bundles of regicide may be interpreted as part of extended periods of civil wars and feuding that accompanied the state-building process. The paper concludes by suggesting several individual and contextual risk factors that may be involved in the risk of regicide. © 2011 The Author.


Kilmartin J.V.,University of Cambridge
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2014

The yeast spindle pole body (SPB) is the functional equivalent of the centrosome. Most SPB components have been identified and their functions partly established. This involved a large variety of techniques which are described here, and the potential use of some of these in the centrosome field is highlighted. In particular, very useful structural information on the SPB was obtained from a reconstituted complex, γ-tubulin complex, and also from a sub-particle, SPB cores, prepared by extraction of an enriched SPB preparation. The labelling of SPB proteins with GFP at the N or C termini, using GFP tags inserted into the genome, gave informative electron microscopy localization and fluorescence resonance energy transfer data. Examples are given of more precise functional data obtained by removing domains from one SPB protein, Spc110p, without affecting its essential function. Finally, a structural model for SPB duplication is described and the differences between SPB and centrosome duplication discussed. © 2014 The Author(s) Published by the Royal Society.


Thomas J.M.,University of Cambridge
Energy and Environmental Science | Year: 2014

The amount of energy and chemicals extracted to date from sunlight by the solar fuels community is minute in comparison with the corresponding amounts being regularly extracted from non-renewable sources. This brief appraisal discusses why. © 2014 The Royal Society of Chemistry.


Martincorena I.,Wellcome Trust Sanger Institute | Campbell P.J.,Wellcome Trust Sanger Institute | Campbell P.J.,University of Cambridge
Science | Year: 2015

Spontaneously occurring mutations accumulate in somatic cells throughout a person's lifetime. The majority of these mutations do not have a noticeable effect, but some can alter key cellular functions. Early somatic mutations can cause developmental disorders, whereas the progressive accumulation of mutations throughout life can lead to cancer and contribute to aging. Genome sequencing has revolutionized our understanding of somatic mutation in cancer, providing a detailed view of the mutational processes and genes that drive cancer. Yet, fundamental gaps remain in our knowledge of how normal cells evolve into cancer cells. We briefly summarize a number of the lessons learned over 5 years of cancer genome sequencing and discuss their implications for our understanding of cancer progression and aging. © 2015, American Association for the Advancement of Science. All rights reserved.


This article reviews, first, the prospects, practices and principles of generating solar fuels. It does so with an analysis of recent progress in the light-driven emission of H2 (and other fuels) as well as O2 from water. To place this challenge in perspective, some current practices entailing the use of well-proven solid catalysts developed for fossil-based feedstocks, are described. The massive differences between proven methods of generating fuel and chemicals from non-renewable and from solar radiation are emphasized with the aid of numerous quantitative examples. Whilst it is acknowledged that a key action in reducing the liberation of greenhouse gases (GHG) is to tackle the challenge of decreasing their evolution in power generation and in the production of steel, aluminium and other bulk commodities (metals, alloys, concrete and ceramics), nevertheless much can be done to diminish the emission of CO2 (and to use it as feedstock) through the agency of new, designed solid catalysts and microalgae. Solar-thermal converters are also attractive alternatives, even though they are more likely to be used centrally rather than in small modular units like 'artificial leaves,' some of which are promising for the purposes of generating energy (and perhaps fuel) in a delocalized, modular manner. A tall order: This Review focuses partly on current challenges in photocatalysis and the comparative promise of solar-thermal converters. Existing industrial catalysts that process non-renewable feedstocks and the need for their replacement are also discussed, including those for ammoxidation, the benign synthesis of nylon, PET, and catalytic cracking. The combined use of metabolic engineering and designed single-site nanoporous catalysts for processing renewable feedstocks is outlined. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Camilloni C.,University of Cambridge
Nature Structural and Molecular Biology | Year: 2016

Although detailed pictures of ribosome structures are emerging, little is known about the structural and cotranslational folding properties of nascent polypeptide chains at the atomic level. Here we used solution-state NMR spectroscopy to define a structural ensemble of a ribosome–nascent chain complex (RNC) formed during protein biosynthesis in Escherichia coli, in which a pair of immunoglobulin-like domains adopts a folded N-terminal domain (FLN5) and a disordered but compact C-terminal domain (FLN6). To study how FLN5 acquires its native structure cotranslationally, we progressively shortened the RNC constructs. We found that the ribosome modulates the folding process, because the complete sequence of FLN5 emerged well beyond the tunnel before acquiring native structure, whereas FLN5 in isolation folded spontaneously, even when truncated. This finding suggests that regulating structure acquisition during biosynthesis can reduce the probability of misfolding, particularly of homologous domains. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.


Kramer S.,University of Cambridge
Molecular and Biochemical Parasitology | Year: 2012

Kinetoplastids, including the human pathogens Trypanosoma brucei, Trypanosoma cruzi and Leishmania, are the only known organisms that do not regulate the transcription of protein coding genes transcribed by RNA polymerase II. Yet, profound changes in gene expression are induced by many different external stimuli and stresses, the extreme example are cascades of changes in gene expression initiated by differentiation triggers that ultimately and irreversibly result in the massive morphological and metabolic changes observed during life-cycle progression. This review explores how kinetoplastids change gene expression by looking at life-cycle stage specific changes in chromatin, mRNA processing, mRNA stability, mRNA translation, protein stability and protein modifications. © 2011 Elsevier B.V. All rights reserved.


The "heterozygote instability" (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost "out of Africa" and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology. © 2013 William Amos.


Nivette A.E.,University of Cambridge
Homicide Studies | Year: 2011

Cross-national research has increased in the past few decades, resulting in a large body of empirical research. In particular, cross-national studies are often limited in data sources, which restrict variable selection to debatable proxy indicators. This study therefore uses meta-analytic techniques to examine major cross-national predictors of homicide to determine strengths and weaknesses in theory and design. The findings indicate several critical limitations to cross-national research, including biased sample composition, a lack of theoretical clarity in predictor operationalizations, and an overwhelming reliance on cross-sectional design. The predictors that showed the strongest mean effects were Latin American regional dummy variables, income inequality indicators and the Decommodification Index. Conversely, static population indicators, democracy indices, and measures of economic development had the weakest effects on homicide. © 2011 SAGE Publications.


Woodhouse J.,University of Cambridge
Reports on Progress in Physics | Year: 2014

To understand the design and function of the violin requires investigation of a range of scientific questions. This paper presents a review: the relevant physics covers the nonlinear vibration of a bowed string, the vibration of the instrument body, and the consequent sound radiation. Questions of discrimination and preference by listeners and players require additional studies using the techniques of experimental psychology, and these are also touched on in the paper. To address the concerns of players and makers of instruments requires study of the interaction of all these factors, coming together in the concept of 'playability' of an instrument. © 2014 IOP Publishing Ltd.


Perlmutter E.,University of Cambridge
Journal of High Energy Physics | Year: 2014

We extend and refine recent results on Rényi entropy in two-dimensional con-formal field theories at large central charge. To do so, we examine the effects of higher spin symmetry and of allowing unequal left and right central charges, at leading and sub-leading order in large total central charge. The result is a straightforward generalization of previously derived formulae, supported by both gravity and CFT arguments. The preceding statements pertain to CFTs in the ground state, or on a circle at unequal left- and right-moving temperatures. For the case of two short intervals in a CFT ground state, we derive certain universal contributions to Rényi and entanglement entropy from Virasoro primaries of arbitrary scaling weights, to leading and next-to-leading order in the interval size; this result applies to any CFT. When these primaries are higher spin currents, such terms are placed in one-to-one correspondence with terms in the bulk 1-loop determinants for higher spin gauge fields propagating on handlebody geometries. © 2014 The Author(s).


Theobald D.,University of Cambridge
British Journal of Criminology | Year: 2011

The Cambridge Study in Delinquent Development is a prospective longitudinal survey of 411 South London males from age 8 to age 48. In this survey, it was previously found that men who marry relatively early reduce their offending behaviour after marriage, unlike those who marry relatively late. Further analyses confirmed that the original findings were not caused by regression to the mean. Comparisons between those who married at age 25 or older and those who married at age 18-24 on risk factors at age 8-32 suggest that the later-married men tended to be more nervous, more likely to have experienced a broken home, to be drug users and binge-drinkers, to maintain aggressive attitudes from age 18 to 32, and to continue to go out with their male friends after marriage. The later-married men tended to marry older women who had less influence than younger women on their offending behaviour. They were more likely to be long-term low-rate offenders than those who married early. © The Author 2010. Published by Oxford University Press on behalf of the Centre for Crime and Justice Studies (ISTD).


Mason M.J.,University of Cambridge
Hearing Research | Year: 2013

The middle ear apparatus varies considerably among living mammals. Body size, phylogeny and acoustic environment all play roles in shaping ear structure and function, but experimental studies aimed ultimately at improving our understanding of human hearing can sometimes overlook these important species differences. This review focuses on three groups of mammals, bringing together anatomical, zoological and physiological information in order to highlight unusual features of their middle ears and attempt to interpret their function." Microtype" ears, found in species such as mice and bats, are associated with high-frequency hearing. The orbicular apophysis, the focus of some recent developmental studies on mouse ears, is characteristic of microtype mallei but is not found in humans or other " freely mobile" species. The apophysis increases ossicular inertia about the anatomical axis of rotation: its adaptive purpose in a high-frequency ear is still not clear.Subterranean mammals have convergently evolved a " freely mobile" ossicular morphology which appears to favour lower-frequency sound transmission. More unusual features found in some of these animals include acoustically coupled middle ear cavities, the loss of middle ear muscles and hypertrophied ossicles which are believed to subserve a form of inertial bone conduction.Middle ears of the rodent group Ctenohystrica (which includes guinea pigs and chinchillas, important models in hearing research) show some striking characteristics which together comprise a unique type of auditory apparatus requiring a classification of its own, referred to here as the " Ctenohystrica type" These characteristics include a distinctive malleus morphology, fusion of the malleus and incus, reduction or loss of the stapedius muscle, a synovial stapedio-vestibular articulation and, in chinchillas, enormously expanded middle ear cavities. These characteristics may be functionally linked and associated with the excellent low-frequency hearing found in these animals.The application of new experimental and imaging data into increasingly sophisticated models continues to improve our understanding of middle ear function. However, a more rigorous comparative approach and a better appreciation of the complex patterns of convergent and divergent evolution reflected in the middle ear structures of living mammals are also needed, in order to put findings from different species into the appropriate context.This article is part of a Special Issue entitled " MEMRO 2012" © 2012 Elsevier B.V.


Gurtin Z.B.,University of Cambridge
Reproductive BioMedicine Online | Year: 2011

In March 2010, Turkey became the first country to legislate against the cross-border travel of its citizens seeking third-party reproductive assistance. Although the use of donor eggs, donor spermatozoa and surrogacy had been illegal in Turkey since the introduction of a regulatory framework for assisted reproductive treatment in 1987, men and women were free to access these treatments in other jurisdictions. In some cases, such travel for cross-border reproductive care (CBRC) was even facilitated by sophisticated arrangements between IVF clinics in Turkey and in other countries, particularly in Cyprus. However, new amendments to Turkey's assisted reproduction legislation specifically forbid travel for the purposes of third-party assisted reproduction. This article outlines the cultural context of assisted reproductive treatment in Turkey; details the Turkish assisted reproduction legislation, particularly as it pertains to third-party reproductive assistance; explores Turkish attitudes towards donor gametes and surrogacy; assesses the existence and extent of CBRC prior to March 2010; and discusses some of the legal, ethical and practical implications of the new legislation. As CBRC becomes an increasingly pertinent issue, eliciting debate and discussion at both national and international levels, it is important to carefully consider the particular circumstances and potential consequences of this unique example. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Kelly A.,University of Cambridge
Acta Crystallographica Section A: Foundations of Crystallography | Year: 2013

This paper recounts the atmosphere in the Cavendish Laboratory during Lawrence Braggs triumphant final years there through the eyes and the work of a young research student, and hence reflects some measure of Braggs personality. The opportunity is taken to deal in detail with Braggs contribution to our understanding of crystal plasticity, which is seldom described, being overshadowed by his many superb contributions to the determination of crystal structure. Bragg produced in 1940-1942, through his development of the bubble model of a crystal structure, the first demonstration of how crystal dislocations move. His suggestion of the use of microbeams led rather directly to the development of modern thin-film transmission electron microscopy.


Boyd I.L.,University of St. Andrews | Freer-Smith P.H.,Japan Forestry and Forest Products Research Institute | Gilligan C.A.,University of Cambridge | Godfray H.C.J.,University of Oxford
Science | Year: 2013

Trees and forests provide a wide variety of ecosystem services in addition to timber, food, and other provisioning services. New approaches to pest and disease management are needed that take into account these multiple services and the different stakeholders they benefit, as well as the likelihood of greater threats in the future resulting from globalization and climate change. These considerations will affect priorities for both basic and applied research and how trade and phytosanitary regulations are formulated.


Ghahramani Z.,University of Cambridge
Nature | Year: 2015

How can a machine learn from experience? Probabilistic modelling provides a framework for understanding what learning is, and has therefore emerged as one of the principal theoretical and practical approaches for designing machines that learn from data acquired through experience. The probabilistic framework, which describes how to represent and manipulate uncertainty about models and predictions, has a central role in scientific data analysis, machine learning, robotics, cognitive science and artificial intelligence. This Review provides an introduction to this framework, and discusses some of the state-of-the-art advances in the field, namely, probabilistic programming, Bayesian optimization, data compression and automatic model discovery. © 2015 Macmillan Publishers Limited. All rights reserved.


Ogilvie G.I.,University of Cambridge
Annual Review of Astronomy and Astrophysics | Year: 2014

Astrophysical fluid bodies that orbit close to one another induce tidal distortions and flows that are subject to dissipative processes. The spin and orbital motions undergo a coupled evolution over astronomical timescales, which is relevant for many types of binary star, short-period extrasolar planetary systems, and the satellites of the giant planets in the Solar System. I review the principal mechanisms that have been discussed for tidal dissipation in stars and giant planets in both linear and nonlinear regimes. I also compare the expectations based on theoretical models with recent observational findings. Copyright © 2014 by Annual Reviews.


Sirringhaus H.,University of Cambridge | Sirringhaus H.,Plastic Logic Ltd
Advanced Materials | Year: 2014

Over the past 25 years, organic field-effect transistors (OFETs) have witnessed impressive improvements in materials performance by 3-4 orders of magnitude, and many of the key materials discoveries have been published in Advanced Materials. This includes some of the most recent demonstrations of organic field-effect transistors with performance that clearly exceeds that of benchmark amorphous silicon-based devices. In this article, state-of-the-art in OFETs are reviewed in light of requirements for demanding future applications, in particular active-matrix addressing for flexible organic light-emitting diode (OLED) displays. An overview is provided over both small molecule and conjugated polymer materials for which field-effect mobilities exceeding > 1 cm2 V-1 s-1 have been reported. Current understanding is also reviewed of their charge transport physics that allows reaching such unexpectedly high mobilities in these weakly van der Waals bonded and structurally comparatively disordered materials with a view towards understanding the potential for further improvement in performance in the future. The mobility of organic field-effect transistors (OFETs) has improved dramatically over the past 25 years, and now exceeds that of amorphous silicon. OFETs are being used in products such as flexible electronic paper displays. Current understanding of the charge transport physics that allows such unexpectedly high mobilities to be reached in van der Waals-bonded molecular and polymeric semiconductors is reviewed. © 2014 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Wales D.J.,University of Cambridge
ACS Nano | Year: 2014

Particles restricted to spherical or curved surfaces can produce materials that behave very differently from analogues that are essentially flat. In particular, the appearance of defects can change the mechanical and optoelectrical properties. The length scales involved range from atomistic to mesoscopic and present an exciting frontier of research for both experiment and theory in molecular, materials, and soft matter science. © 2014 American Chemical Society.


Thakor A.S.,Stanford University | Thakor A.S.,University of British Columbia | Thakor A.S.,University of Cambridge | Gambhir S.S.,Stanford University
CA Cancer Journal for Clinicians | Year: 2013

In recent years, there has been an unprecedented expansion in the field of nanomedicine with the development of new nanoparticles for the diagnosis and treatment of cancer. Nanoparticles have unique biological properties given their small size and large surface area-to-volume ratio, which allows them to bind, absorb, and carry compounds such as small molecule drugs, DNA, RNA, proteins, and probes with high efficiency. Their tunable size, shape, and surface characteristics also enable them to have high stability, high carrier capacity, the ability to incorporate both hydrophilic and hydrophobic substances and compatibility with different administration routes, thereby making them highly attractive in many aspects of oncology. This review article will discuss how nanoparticles are able to function as carriers for chemotherapeutic drugs to increase their therapeutic index; how they can function as therapeutic agents in photodynamic, gene, and thermal therapy; and how nanoparticles can be used as molecular imaging agents to detect and monitor cancer progression. CA Cancer J Clin 2013;63:395-418. © 2013 American Cancer Society, Inc.


Bennett D.L.H.,University of Oxford | Woods C.G.,University of Cambridge
The Lancet Neurology | Year: 2014

The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of molecular events underlying the detection and transmission of noxious stimuli by the peripheral nervous system. For example, the voltage-gated sodium ion channel Nav1.7 is expressed selectively in sensory and autonomic neurons; inactivating mutations in SCN9A, which encodes Nav1.7, result in congenital insensitivity to pain, whereas gain-of-function mutations in this gene produce distinct pain syndromes such as inherited erythromelalgia, paroxysmal extreme pain disorder, and small-fibre neuropathy. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav1.8 (SCN10A) and Nav1.9 (SCN11A) lead to small-fibre neuropathy and congenital insensitivity to pain, respectively. Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development-eg, using human sensory neurons differentiated from human induced pluripotent stem cells. Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development. © 2014 Elsevier Ltd.


Venkitaraman A.R.,University of Cambridge
Science | Year: 2014

Germline mutations in BRCA1 and BRCA2 predispose to common human malignancies, most notably tumors of the breast and ovaries. The proteins encoded by these genes have been implicated in a plethora of biochemical interactions and biological functions, confounding attempts to coherently explain how their inactivation promotes carcinogenesis. Here, I argue that tumor suppression by BRCA1 and BRCA2 originates from their fundamental role in controlling the assembly and activity of macromolecular complexes that monitor chromosome duplication, maintenance, and segregation across the cell cycle. A tumor-suppressive role for the BRCA proteins as "chromosome custodians" helps to explain the clinical features of cancer susceptibility after their inactivation, provides foundations for the rational therapy of BRCA-deficient cancers, and offers general insights into the mechanisms opposing early steps in human carcinogenesis.


Lomas D.A.,University of Cambridge
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2013

The past 50 years have seen huge advances in our understanding of the pathogenesis of alpha-1 antitrypsin deficiency. It is widely accepted that the common severe Z deficiency allele causes mutant alpha-1 antitrypsin to be retained as inclusions of ordered polymers within hepatocytes. This causes circulating deficiency of an important proteinase inhibitor, an excess of neutrophil elastase and therefore tissue destruction and emphysema. However, the past two decades have led to a shift in the paradigm from a disease that results from simply an imbalance of enzymes and inhibitors to one in which there is growing recognition that the polymers themselves play a role, not only in the liver disease, but also in the associated emphysema, vasculitis and panniculitis. Much of this has been dealt with in previous, more detailed reviews (1-5). I have therefore taken this opportunity of the 50th anniversary of the discovery of alpha-1 antitrypsin deficiency to present a personal overview of the past 22 years. This review considers the description of alpha-1 antitrypsin polymers, an assessment of their role in the different components of alpha-1 antitrypsin deficiency, the role of polymers in other diseases and how our understanding of polymerisation can be exploited to develop novel therapeutic strategies. The ultimate aim of our work is to develop a cure for alpha-1 antitrypsin deficiency. © 2013 Informa Healthcare USA, Inc.


Bateson P.,University of Cambridge
Biological Journal of the Linnean Society | Year: 2014

The article focuses on the active role of the organism in the subsequent evolution of its descendants. Choice, control of the environment, adaptability, and mobility all play their part. This growth area in biology and other active centres of research on epigenetics and different forms of inheritance are re-invigorating evolutionary biology. Many evolutionary biologists have taken the view that an understanding of development is irrelevant to theories of evolution. However, the integration of several disciplines now suggests that the orthodoxy is misplaced. © 2013 The Linnean Society of London.


Brown N.H.,University of Cambridge
Cold Spring Harbor perspectives in biology | Year: 2011

The extracellular matrix (ECM) and its receptors make diverse contributions to development. The ECM comes in a variety of forms, including the more "standard" ECM that is internal to the animal and on the basal side of epithelial sheets, as well as the apical ECM, which is especially elaborated in the invertebrates to form the exoskeleton. ECM proteins accumulate adjacent to particular target tissues in the developing animal by a variety of mechanisms: local synthesis in the target tissue; local synthesis by migrating cells; and secretion from a distant source and capture by the target tissue. The diverse developmental functions of the ECM are discussed, including the generation of a road for cell migration, creation of morphogenetic checkpoints for differentiation, modulation of morphogen gradients, insulation of organs, gluing together cell layers, and providing structure for the organism.


Baker C.M.,University of Cambridge | Best R.B.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases
Wiley Interdisciplinary Reviews: Computational Molecular Science | Year: 2014

Intrinsically disordered proteins (IDPs) are a class of protein that, in the native state, possess no well-defined secondary or tertiary structure, existing instead as dynamic ensembles of conformations. They are biologically important, with approximately 20% of all eukaryotic proteins disordered, and found at the heart of many biochemical networks. To fulfil their biological roles, many IDPs need to bind to proteins and/or nucleic acids. And although unstructured in solution, IDPs typically fold into a well-defined three-dimensional structure upon interaction with a binding partner. The flexibility and structural diversity inherent to IDPs makes this coupled folding and binding difficult to study at atomic resolution by experiment alone, and computer simulation currently offers perhaps the best opportunity to understand this process. But simulation of coupled folding and binding is itself extremely challenging; these molecules are large and highly flexible, and their binding partners, such as DNA or cyclins, are also often large. Therefore, their study requires either simplified representations, advanced enhanced sampling schemes, or both. It is not always clear that existing simulation techniques, optimized for studying folded proteins, are well suited to IDPs. In this article, we examine the progress that has been made in the study of coupled folding and binding using molecular dynamics simulation. We summarize what has been learnt, and examine the state of the art in terms of both methodologies and models. We also consider the lessons to be learnt from advances in other areas of simulation and highlight the issues that remain of be addressed. © 2013 John Wiley & Sons, Ltd.


Halls M.L.,University of Cambridge
Cold Spring Harbor perspectives in biology | Year: 2011

Interplay between the signaling pathways of the intracellular second messengers, cAMP and Ca(2+), has vital consequences for numerous essential physiological processes. Although cAMP can impact on Ca(2+)-homeostasis at many levels, Ca(2+) either directly, or indirectly (via calmodulin [CaM], CaM-binding proteins, protein kinase C [PKC] or Gβγ subunits) may also regulate cAMP synthesis. Here, we have evaluated the evidence for regulation of adenylyl cyclases (ACs) by Ca(2+)-signaling pathways, with an emphasis on verification of this regulation in a physiological context. The effects of compartmentalization and protein signaling complexes on the regulation of AC activity by Ca(2+)-signaling pathways are also addressed. Major gaps are apparent in the interactions that have been assumed, revealing a need to comprehensively clarify the effects of Ca(2+) signaling on individual ACs, so that the important ramifications of this critical interplay between Ca(2+) and cAMP are fully appreciated.


Bullmore E.T.,University of Cambridge | Bassett D.S.,University of California at Santa Barbara
Annual Review of Clinical Psychology | Year: 2011

Brain graphs provide a relatively simple and increasingly popular way of modeling the human brain connectome, using graph theory to abstractly define a nervous system as a set of nodes (denoting anatomical regions or recording electrodes) and interconnecting edges (denoting structural or functional connections). Topological and geometrical properties of these graphs can be measured and compared to random graphs and to graphs derived from other neuroscience data or other (nonneural) complex systems. Both structural and functional human brain graphs have consistently demonstrated key topological properties such as small-worldness, modularity, and heterogeneous degree distributions. Brain graphs are also physically embedded so as to nearly minimize wiring cost, a key geometric property. Here we offer a conceptual review and methodological guide to graphical analysis of human neuroimaging data, with an emphasis on some of the key assumptions, issues, and trade-offs facing the investigator. Copyright © 2011 by Annual Reviews. All rights reserved.


Clutton-Brock T.,University of Cambridge | Sheldon B.C.,University of Oxford
Science | Year: 2010

Decades-long field studies require unusual dedication but provide unique insight into animal behavior and ecology.


Tucker P.G.,University of Cambridge
Progress in Aerospace Sciences | Year: 2011

The choice of turbulence model can have a strong impact on results for many turbomachinery zones. Palliative corrections to them and also transition modeling can have a further profound solution impact. The spectral gaps necessary for theoretically valid URANS solutions are also lacking in certain turbomachinery zones. Large Eddy Simulation (LES) alleviates the serious area of turbulence modeling uncertainty but with an extreme increase in computational cost. However, there seems a lack of validation data to explore in depth the performance of LES and thus strategies to refine it. LES best practices are needed. Although LES is, obviously, much less model dependent than RANS, grids currently used for more practical simulations are clearly insufficiently fine for the LES model and numerical schemes not to be playing an excessively strong role. Very few turbomachinery simulations make use of properly constructed, correlated turbulence inflow. Even if this is attempted, most measurement sets are incomplete and lack an adequate basis for modeling this inflow. Gas turbines are highly complex coupled systems and hence inflow and outflow boundary condition specification needs to go beyond just synthesizing turbulent structures and preventing their reflection. Despite the strong limitations of the dissipative Smagorinsky model, it still sees the most wide spread use, generally, in excessively dissipative flow solvers. Monotone Integrated LES (MILES) related approaches, hybrid LESRANS and more advanced LES models seem to have an equal but subservient frequency of use in turbomachinery applications. Clearly the introduction of a RANS layer can have a substantial accuracy penalty. However, it does allow LES to be rationally used, albeit in a diluted sense for industrial applications. The Reynolds numbers found in turbomachinery are substantial. However, in certain areas evidence suggests they will not be enough to ensure a long inertial subrange and hence the use of standard LES modeling practices. Despite the excessively coarse grids used in much of the LES work reviewed, with essentially RANS based codes, meaningful results are often gained. This can perhaps be attributed to the choice of cases, these being ones for which RANS modeling gives extremely poor performance. It is a concern that for practical turbomachinery LES studies grid densities used tend to have an Reynolds number scaling to a strong negative power. © 2011 Elsevier Ltd. All rights reserved.


Dimitrakopoulos E.G.,University of Cambridge
Engineering Structures | Year: 2011

In this paper the seismic response of short skew bridges with deck-abutment pounding joints is revisited. The permanent deck rotations and transverse displacements of such bridges after the recent earthquake in Chile created an incentive to revisit their non-conventional behaviour. A novel non-smooth rigid body approach is proposed to analyze the seismic response of pounding skew bridges which involves oblique frictional multi-contact phenomena. The coupling of the response, due to contact, is analysed in depth. It is shown that the tendency of skew bridges to exhibit transverse displacements and/or rotate (and hence unseat) after deck-abutment collisions is not a factor of the skew angle alone, but rather of the plan geometry plus friction. This is expressed with proposed dimensionless criteria. The study also unveils that the coupling is more pronounced in the low range of the frequency spectrum (short-period excitations/flexible structures) and presents novel dimensionless response spectra for the transverse displacements and rotations, triggered by oblique contact in a skew bridge subsystem. Despite the complexity of the response, the proposed spectra highlight a clear pattern. The dimensionless rotations, arising from contact, decline as the ratio of the structural versus excitation frequency increases and become practically negligible in the upper range of the frequency spectrum. Finally, a pilot application to a typical skew bridge is presented. © 2010 Elsevier Ltd.


Loh X.J.,University of Cambridge
Journal of Applied Polymer Science | Year: 2013

A series of copolymers with poly(dimethylaminoethyl methacrylate) (P(DMAEMA)), and poly(propylene glycol methacrylate) (PPGMA) segments were synthesized by atom transfer radical polymerization (ATRP) technique. The composition and structural information of the copolymers were studied by gel permeation chromatography (GPC), 1H-NMR, and TGA. The critical micellization concentrations (CMCs), as well as thermodynamic parameters for micelle formation, of these water-soluble copolymers were determined at different temperatures. The micelles formed were temperature and pH responsive as determined by lower critical solution temperature (LCST) measurements at different pH environments. At elevated temperatures and low pH, micelles will form with the hydrophobic P(PPGMA) core and the hydrophilic P(DMAEMA) corona. When the temperature is lowered and the pH raised, the morphology of the micelles are "reversed." In this situation, micelles will form with the hydrophobic P(DMAEMA) core and the hydrophilic P(PPGMA) corona. Preliminary cytotoxicity studies were carried out and showed that these copolymers were nontoxic to cells. These copolymers thus show significant promise for use as a multiresponsive carrier vehicle for the delivery of drugs and other therapeutics to the body. Copyright © 2012 Wiley Periodicals, Inc.


Brambley E.J.,University of Cambridge
Journal of Sound and Vibration | Year: 2013

Surface modes, being duct modes localized close to the duct wall, are analysed within a lined cylindrical duct with uniform flow apart from a thin boundary layer. As well as full numerical solutions of the Pridmore-Brown equation, simplified mathematical models are given where the duct lining and boundary layer are lumped together and modelled using a single boundary condition (a modification of the Myers boundary condition previously proposed by the author), from which a surface mode dispersion relation is derived. For a given frequency, up to six surface modes are shown to exist, rather than the maximum of four for uniform slipping flow. Not only is the different number and behaviour of surface modes important for frequency-domain mode-matching techniques, which depend on having found all relevant modes during matching, but the thin boundary layer is also shown to lead to different convective and absolute stability than for uniform slipping flow. Numerical examples are given comparing the predictions of the surface mode dispersion relation to full solutions of the Pridmore-Brown equation, and the accuracy with which surface modes are predicted is shown to be significantly increased compared with the uniform slipping flow assumption. The importance of not only the boundary layer thickness but also its profile (tanh or linear) is demonstrated. A Briggs-Bers stability analysis is also performed under the assumption of a mass-spring-damper or Helmholtz resonator impedance model. © 2013 Elsevier Ltd.


Zhang Z.-R.,U.S. National Institutes of Health | Zhang Z.-R.,Yale University | Bonifacino J.S.,U.S. National Institutes of Health | Hegde R.S.,University of Cambridge
Cell | Year: 2013

Newly synthesized membrane proteins are queried by ubiquitin ligase complexes and triaged between degradative and nondegradative fates. The mechanisms that convert modest differences in substrate-ligase interactions into decisive outcomes of ubiquitination are not well understood. Here, we reconstitute membrane protein recognition and ubiquitination in liposomes using purified components from a viral-mediated degradation pathway. We find that substrate-ligase interactions in the membrane directly influence processivity of ubiquitin attachment to modulate polyubiquitination. Unexpectedly, differential processivity alone could not explain the differential fates in cultured cells of degraded and nondegraded clients. Both computational and experimental analyses identified continuous deubiquitination as a prerequisite for maximal substrate discrimination. Deubiquitinases reduce polyubiquitin dwell times preferentially on clients that dissociate more rapidly from the ligase. This explains how small differences in substrate-ligase interaction can be amplified into larger differences in net degradation. These results provide a conceptual framework for substrate discrimination during membrane protein quality control. © 2013 The Authors.


Draper S.J.,University of Oxford | Heeney J.L.,University of Cambridge
Nature Reviews Microbiology | Year: 2010

Recent developments in the use of viruses as vaccine vectors have been facilitated by a better understanding of viral biology. Advances occur as we gain greater insight into the interrelationship of viruses and the immune system. Viral-vector vaccines remain the best means to induce cellular immunity and are now showing promise for the induction of strong humoral responses. The potential benefits for global health that are offered by this field reflect the scope and utility of viruses as vaccine vectors for human and veterinary applications, with targets ranging from certain types of cancer to a vast array of infectious diseases. © 2010 Macmillan Publishers Limited. All rights reserved.


Todd J.A.,University of Cambridge
Immunity | Year: 2010

Recent genetic mapping and gene-phenotype studies have revealed the genetic architecture of type 1 diabetes. At least ten genes so far can be singled out as strong causal candidates. The known functions of these genes indicate the primary etiological pathways of this disease, including HLA class II and I molecules binding to preproinsulin peptides and T cell receptors, T and B cell activation, innate pathogen-viral responses, chemokine and cytokine signaling, and T regulatory and antigen-presenting cell functions. This review considers research in the field of type 1 diabetes toward identifying disease mechanisms using genetic approaches. The expression and functions of these pathways, and, therefore, disease susceptibility, will be influenced by epigenetic and environmental factors. Certain inherited immune phenotypes will be early precursors of type 1 diabetes and could be useful in future clinical trials. © 2010 Elsevier Inc.


Woods A.W.,University of Cambridge
Annual Review of Fluid Mechanics | Year: 2010

This review describes a range of natural processes leading to the formation of turbulent buoyant plumes, largely relating to volcanic processes, in which there are localized, intense releases of energy. Phenomena include volcanic eruption columns, bubble plumes in lakes, hydrothermal plumes, and plumes beneath the ice in polar oceans. We assess how the dynamics is affected by heat transfer, particle fallout and recycling, and Earth's rotation, as well as explore some of the mixing of the ambient fluid produced by plumes in a confined geometry. Copyright © 2010 by Annual Reviews. All rights reserved.


Salje E.K.H.,University of Cambridge
American Mineralogist | Year: 2015

Tweed, twin, and porous microstructures are traditionally studied in mineralogy to understand the thermal history of minerals, and to identify their properties such as chemical transport and elastic behavior. Recently, the same research area has blossomed in material sciences and physics with the aim to design and build devices that are based on the properties of nano-structures. Only the very existence and the properties of tweed, twins, and holes matters in this quest while the crystalline matrix plays only a minor role in the current search for novel device materials. This development has largely bypassed mineralogists while physicists did not profit from the age-long experience of mineralogists in dealing with such materials. In this Invited Centennial article, I will first discuss some key findings and approaches to foster the transfer of ideas in both directions: mineralogists can potentially inspire material scientists while the physics of the fine structure of twin walls and tweed can help mineralogists understand mineral properties in much more detail than hereto possible. Besides the observation that novel physical properties can spring from microstructures, most recent work also includes the dynamics of microstructures under external stress or electric fields. The dynamics is virtually always non-smooth or "jerky." One of the best studied jerk distribution is that of collapsing porous minerals under stress, where the main focus of research is the identification of precursor effects as warning signs for larger events such as the collapse of mines, boreholes, or even regional earthquakes. The underlying physics is the same as in large earthquakes (which can be modeled but not observed in laboratory experiments). The agreement between laboratory experiments of porous collapse and large-scale earthquakes goes well beyond each quake's statistics and includes waiting-time distributions and the Omori law of after-shocks. The same approach is used to characterize high-tech materials in aircraft industry and functional materials such as used in electronic memory devices, ferroelectric sensors and non-volatile memories and ferromagnets. © 2015 by Walter de Gruyter Berlin/Boston 2015.


Edmonds M.,University of Cambridge
Earth and Planetary Science Letters | Year: 2015

An enigmatic record of light lithophile element (LLE) zoning in pyroxenes in basaltic shergottite meteorites, whereby LLE concentrations decrease dramatically from the cores to the rims, has been interpreted as being due to partitioning of LLE into a hydrous vapor during magma ascent to the surface on Mars. These trends are used as evidence that Martian basaltic melts are water-rich (McSween et al., 2001). Lithium and boron are light lithophile elements (LLE) that partition into volcanic minerals and into vapor from silicate melts, making them potential tracers of degassing processes during magma ascent to the surface of Earth and of other planets. While LLE degassing behavior is relatively well understood for silica-rich melts, where water and LLE concentrations are relatively high, very little data exists for LLE abundance, heterogeneity and degassing in basaltic melts. The lack of data hampers interpretation of the trends in the shergottite meteorites. Through a geochemical study of LLE, volatile and trace elements in olivine-hosted melt inclusions from Kilauea Volcano, Hawaii, it can be demonstrated that lithium behaves similarly to the light to middle rare Earth elements during melting, magma mixing and fractionation. Considerable heterogeneity in lithium and boron is inherited from mantle-derived primary melts, which is dominant over the fractionation and degassing signal. Lithium and boron are only very weakly volatile in basaltic melt erupted from Kilauea Volcano, with vapor-melt partition coefficients <0.1. Degassing of LLE is further inhibited at high temperatures. Pyroxene and associated melt inclusion LLE concentrations from a range of volcanoes are used to quantify lithium pyroxene-melt partition coefficients, which correlate negatively with melt H2O content, ranging from 0.13 at low water contents to <0.08 at H2O contents >4 wt%. The observed terrestrial LLE partitioning behavior is extrapolated to Martian primitive melts through modeling. The zoning observed in the shergottite pyroxenes is only consistent with degassing of LLE from a Martian melt near its liquidus temperature if the vapor-melt partition coefficient was an order of magnitude larger than observed on Earth. The range in LLE and trace elements observed in shergottite pyroxenes are instead consistent with concurrent mixing and fractionation of heterogeneous melts from the mantle. © 2014 Elsevier B.V..


Kaufman J.,University of Cambridge
Current Opinion in Immunology | Year: 2015

Outside of mammals, antigen processing and presentation have only been investigated in chickens. The chicken MHC is organized differently than mammals, allowing the co-evolution of polymorphic genes, with each MHC haplotype having a set of TAP1, TAP2 and tapasin alleles directed to high expression of a single classical class I molecule. However, the class I alleles vary in the size of peptide-binding repertoire, along with a suite of other properties. The salient features of the chicken MHC are found in many non-mammalian vertebrates, and are likely to have been set at the origin of the adaptive immune system of jawed vertebrates, with unrelated genes co-evolving to set up the original pathways. Half a billion years later, various features of presentation and resistance to disease still reflect this ancestral arrangement. © 2015 Elsevier Ltd.


Hayhurst A.N.,University of Cambridge
Combustion and Flame | Year: 2013

It has been previously shown that the pyrolysis of one, dried sewage sludge can be modelled using 25 first-order, parallel reactions. Here a " computer experiment" has been performed on the pyrolysis of particles of that sewage sludge, whose thermal decomposition has been simplified to involve nine parallel, first-order reactions, which " cover" the 25 steps measured previously. The activation energies of these nine reactions range from 110 to 310kJ/mol in equal steps of 25kJ/mol. The pre-exponential factors of these, equally weighted, reactions increase from 1.0×109 to 1.5×1018s-1, in accord with the previous measurements. It is found that the Arrhenius plot for the effective, overall rate constant governing the fall in mass during the kinetically controlled pyrolysis of this surrogate sewage sludge is curved, but approximated well by the expression: 8.5×1010 exp {- (140±30kJ/mol)/RT} s-1. This simple result enables a time-scale to be evaluated for the kinetics of this fuel's pyrolysis and suggests that the thermal decomposition of this solid fuel might sometimes be described by just one chemical reaction. It turns out that such a " one-step model" often fails as a description of pyrolysis, because there is a wide, intermediate range of temperature, where some steps are reaction-controlled, whilst others are governed by heat transfer. Thus devolatilisation of a solid fuel has to be considered in terms of many reactions being involved. The situation is rationalised by assigning to each single reaction involved in devolatilisation its own " decomposition temperature" , at which, depending on particle size, that reaction changes from kinetic to heat transfer control at higher temperatures. Otherwise, if the Biot number is larger than unity, reaction fronts pass through a pyrolysing particle, creating a shrinking core, where that reaction has not yet occurred. However, if the Biot number is much less than unity, each step in the chemical mechanism proceeds uniformly throughout a heated particle, but attains an almost constant rate, as soon as its decomposition temperature is reached. Decomposition temperatures depend on particle size and are evaluated for the sewage sludge under consideration. The importance of particle size and also the Nusselt and pyrolysis numbers is also investigated, as well as how best to measure the kinetics of pyrolysis. Such kinetic measurements are more difficult to make for biomasses and waste fuels than for coals. © 2012 The Combustion Institute.


Cai Y.-F.,McGill University | Wang Y.,University of Cambridge
Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics | Year: 2014

Inspired by quantum gravitational physics, the approach of non-commutative (NC) phase space leads to a modified dispersion relation of gravitational waves. This feature, if applied to the very early universe, gives rise to a modified power spectrum of primordial tensor perturbations with a suppression of power on large scales. We confront this phenomenon with the BICEP2 and Planck experiments, and show that inflation with the modified dispersion relation can simultaneously fit the observations better than the standard inflationary paradigm. In particular, the numerical result implies that with the latest cosmological microwave background (CMB) observations, a quantum gravity modified power spectrum of primordial tensor modes is preferred at a statistical significance of more than 3. σ compared with the minimal model. Our study indicates that the potential tension between the BICEP2 and Planck data may be resolved by quantum gravity effects. © 2014 Elsevier B.V.


Galvin R.,University of Cambridge
Sustainable Cities and Society | Year: 2012

German Federal policy on thermal renovation of existing homes was evaluated in terms of how well it is achieving its stated goal of reducing GHG emissions from home heating by 80% within 40 years. The study examined both the technical efficacy of the policy in relation to the actual built environment in which it is set, and the prevailing policy discourse that drives and promotes the policy. It was found that the policy is falling far short of achieving its aims, mostly because the regulations are too strict to be workable in most cases. The thermal parameters demanded by the regulations are technically feasible and economically viable only for certain types of ideal house design and for homeowners willing to accept high economic risk with distant payback times. Hence the policy is out of touch with both the physical realities of the majority of German homes, and the economic outlook of homeowners. © 2012 Elsevier B.V.


Yang X.-S.,University of Cambridge
International Journal of Bio-Inspired Computation | Year: 2010

Modern optimisation algorithms are often metaheuristic, and they are very promising in solving NP-hard optimisation problems. In this paper, we show how to use the recently developed firefly algorithm to solve non-linear design problems. For the standard pressure vessel design optimisation, the optimal solution found by FA is far better than the best solution obtained previously in the literature. In addition, we also propose a few new test functions with either singularity or stochastic components but with known global optimality and thus they can be used to validate new optimisation algorithms. Possible topics for further research are also discussed. Copyright © 2010 Inderscience Enterprises Ltd.


Gurdon J.B.,University of Cambridge
Nature Reviews Molecular Cell Biology | Year: 2016

This issue of Nature Reviews Molecular Cell Biology celebrates the 10th anniversary of the pioneering 2006 publication reporting the derivation of induced pluripotent stem cells. Earlier work that led in this direction included nuclear transfer experiments in Amphibia and then in mammals (including humans), followed by the derivation of embryonic stem cells and the identification of cell type-determining transcription factors. Cell replacement therapy for certain human disorders may soon be available. However, a major threat to progress is from regulatory bodies intimidated by compensatory legal judgments. © 2016 Macmillan Publishers Limited. All rights reserved.


Davidson P.A.,University of Cambridge
Journal of Fluid Mechanics | Year: 2010

We consider freely decaying, statistically axisymmetric turbulence evolving in the presence of a background rotation, an imposed stratification or a uniform magnetic field. We focus on the case of Saffman turbulence in which E(k→0) ∼ k2 and show that, if the large scales evolve in a self-similar manner, then u2⊥2ℓ2∥= constant in rotating, stratified and magnetohydrodynamic turbulence. This may be contrasted with E(k→0) ∼ k4 turbulence, in which u 2⊥2ℓ4∥ ≈ constant. (Here the subscripts ⊥ and ∥indicate directions perpendicular and parallel to the axis of symmetry, andℓ⊥ℓ∥, and u⊥ are suitably defined integral scales.) This constraint on the integral scales allows us to make simple, testable predictions for the temporal evolution of ∥⊥ℓ∥, and u⊥ in all three systems. There are only limited data sets against which to compare these predictions, but they are consistent with those data which are currently available. © 2010 Cambridge University Press.


Pollitt M.G.,University of Cambridge
Energy Policy | Year: 2012

The aim of this paper is to discuss the period of energy privatisation and liberalisation which began in the 1980s within its wider historical context. The key issues are what has been learned from this recent period, and how significant is it in the light of an energy transition to low carbon energy system by 2050? Energy liberalisation has led to positive and globally widespread but modest efficiency gains but a lack of clearly visible direct benefits to households in many countries. It has significantly improved the governance of monopoly utilities (via independent regulators), the prospects for competition and innovation, and the quality of policy instruments for environmental emissions control (through the emergence of trading mechanisms). We conclude that it is not liberalisation per se that will determine the movement towards a low carbon energy transition, but the willingness of societies to bear the cost, which will be significant no matter what the extent of liberalisation. © 2012 Elsevier Ltd.


Beardsall K.,University of Cambridge
Archives of disease in childhood. Fetal and neonatal edition | Year: 2013

Recent studies have highlighted the need for improved methods of monitoring glucose control in intensive care to reduce hyperglycaemia, without increasing the risk of hypoglycaemia. Continuous glucose monitoring is increasingly used in children with diabetes, but there are little data regarding its use in the preterm infant, particularly at extremes of glucose levels and over prolonged periods. This study aimed to assess the accuracy of the continuous glucose monitoring sensor (CGMS) across the glucose profile, and to determine whether there was any deterioration over a 7 day period. Prospectively collected CGMS data from the NIRTURE Trial was compared with the data obtained simultaneously using point of care glucose monitors. An international multicentre randomised controlled trial. One hundred and eighty-eight very low birth weight control infants. Optimal accuracy, performance goals (American Diabetes Association consensus), Bland Altman, Error Grid analyses and accuracy. The mean (SD) duration of CGMS recordings was 156.18 (29) h (6.5 days), with a total of 5207 paired glucose levels. CGMS data correlated well with point of care devices (r=0.94), with minimal bias. It met the Clarke Error Grid and Consensus Grid criteria for clinical significance. Accuracy of single readings to detect set thresholds of hypoglycaemia, or hyperglycaemia was poor. There was no deterioration over time from insertion. CGMS can provide information on trends in glucose control, and guidance on the need for blood glucose assessment. This highlights the potential use of CGMS in optimising glucose control in preterm infants.


Chen X.,University of Cambridge
Journal of Cosmology and Astroparticle Physics | Year: 2010

We compute a novel type of large non-Gaussianity due to small periodic features in general single field inflationary models. We show that the non-Bunch-Davies vacuum component generated by features, although has a very small amplitude, can have significant impact on the non-Gaussianity. Three mechanisms are turned on simultaneously in such models, namely the resonant effect, non-Bunch-Davies vacuum and higher derivative kinetic terms, resulting in a bispectrum with distinctive shapes and running. The size can be equal to or larger than that previously found in each single mechanism. Our full results, including the resonant and folded resonant non-Gaussianities, give the leading order bispectra due to general periodic features in general single field inflation. © 2010 IOP Publishing Ltd and SISSA.


Chow D.D.K.,University of Cambridge
Classical and Quantum Gravity | Year: 2010

We investigate Killing tensors for various black hole solutions of supergravity theories. Rotating black holes of an ungauged theory, toroidally compactified heterotic supergravity, with NUT parameters and two U(1) gauge fields are constructed. If both charges are set equal, then the solutions simplify, and then there are concise expressions for rank-2 conformal Killing-Stäckel tensors. These are induced by rank-2 Killing-Stäckel tensors of a conformally related metric that possesses a separability structure. We directly verify the separation of the Hamilton-Jacobi equation on this conformally related metric and of the null Hamilton-Jacobi and massless Klein-Gordon equations on the 'physical' metric. Similar results are found for more general solutions; we mainly focus on those with certain charge combinations equal in gauged supergravity but also consider some other solutions. © 2010 IOP Publishing Ltd.


Figueras P.,University of Cambridge | Wiseman T.,Imperial College London
Physical Review Letters | Year: 2011

We show how to construct low energy solutions to the Randall-Sundrum II (RSII) model by using an associated five-dimensional anti-de Sitter space (AdS 5) and/or four-dimensional conformal field theory (CFT 4) problem. The RSII solution is given as a perturbation of the AdS 5-CFT 4 solution, with the perturbation parameter being the radius of curvature of the brane metric compared to the AdS length ℓ. The brane metric is then a specific perturbation of the AdS 5-CFT 4 boundary metric. For low curvatures the RSII solution reproduces 4D general relativity on the brane. Recently, AdS 5-CFT 4 solutions with a 4D Schwarzschild boundary metric were numerically constructed. We modify the boundary conditions to numerically construct large RSII static black holes with radius up to ∼20ℓ. For a large radius, the RSII solutions are indeed close to the associated AdS 5-CFT 4 solution. © 2011 American Physical Society.


Levasseur L.P.,University of Cambridge
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

We present a new, recursive approach to stochastic inflation which is self-consistent and solves multiple problems that plagued a certain number of previous studies, in particular, in realistic contexts where the background spacetime is taken to be dynamical, where there is more than one field present (especially with a mass hierarchy), or where the role played by backreaction is suspected to be important. We first review the formalism of stochastic inflation as it is usually heuristically presented, that is, deriving the Langevin equations from the field equations of motion, and summarize previous results on the subject. We demonstrate where inconsistent approximations to the Langevin equations are commonly made and show how these can be avoided. This setup shares many similarities with quantum Brownian motion and out-of-equilibrium statistical quantum dynamics. We hence review how path integral techniques can be applied to the stochastic inflationary context. We show that this formalism is consistent with the standard approach. We then develop a natural perturbative expansion and use it to calculate the one-loop corrected Langevin equations. © 2013 American Physical Society.


Drummond I.T.,University of Cambridge
Physical Review D - Particles, Fields, Gravitation and Cosmology | Year: 2013

By means of simple models in a flat spacetime manifold we examine some of the issues that arise when quantizing interacting quantum fields in multimetric backgrounds. In particular we investigate the maintenance of a causal structure in the models. In this context we introduce and explain the relevance of an interpolating metric that is a superposition of the individual metrics in the models. We study the renormalization of a model with quartic interactions and elucidate the structure of the renormalization group and its implications for Lorentz symmetry breakdown. © 2013 American Physical Society.


Taylor C.W.,University of Cambridge
Cold Spring Harbor perspectives in biology | Year: 2010

Inositol 1,4,5-trisphosphate receptors (IP(3)R) and their relatives, ryanodine receptors, are the channels that most often mediate Ca(2+) release from intracellular stores. Their regulation by Ca(2+) allows them also to propagate cytosolic Ca(2+) signals regeneratively. This brief review addresses the structural basis of IP(3)R activation by IP(3) and Ca(2+). IP(3) initiates IP(3)R activation by promoting Ca(2+) binding to a stimulatory Ca(2+)-binding site, the identity of which is unresolved. We suggest that interactions of critical phosphate groups in IP(3) with opposite sides of the clam-like IP(3)-binding core cause it to close and propagate a conformational change toward the pore via the adjacent N-terminal suppressor domain. The pore, assembled from the last pair of transmembrane domains and the intervening pore loop from each of the four IP(3)R subunits, forms a structure in which a luminal selectivity filter and a gate at the cytosolic end of the pore control cation fluxes through the IP(3)R.


Harrison N.,Los Alamos National Laboratory | Sebastian S.E.,University of Cambridge