Showing papers by "Newcastle University published in 2012"
Daniel J. Klionsky1, Fábio Camargo Abdalla2, Hagai Abeliovich3, Robert T. Abraham4 +1284 more•Institutions (463)
TL;DR: These guidelines are presented for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
4,316 citations
Wellcome Trust Sanger Institute1, Broad Institute2, University of Groningen3, University of Pittsburgh4, Cedars-Sinai Medical Center5, Yale University6, University of Cambridge7, University of Chicago8, Harvard University9, Katholieke Universiteit Leuven10, University of Liège11, King's College London12, Université de Montréal13, New Jersey Institute of Technology14, Cleveland Clinic15, Peninsula College of Medicine and Dentistry16, Université libre de Bruxelles17, Aarhus University18, University of Adelaide19, University of Kiel20, Flinders University21, McGill University22, Ludwig Maximilian University of Munich23, Charité24, Icahn School of Medicine at Mount Sinai25, University of Bonn26, Karolinska Institutet27, Torbay Hospital28, University of Auckland29, Christchurch Hospital30, Imperial College London31, Queen's University32, University of Oslo33, Lithuanian University of Health Sciences34, Emory University35, Casa Sollievo della Sofferenza36, Ghent University37, University of Western Australia38, University of Edinburgh39, Queensland Health40, Newcastle University41, University of Dundee42, University of Manchester43, University of Amsterdam44, University of Maribor45, Royal Hospital for Sick Children46, Guy's and St Thomas' NHS Foundation Trust47, QIMR Berghofer Medical Research Institute48, Norfolk and Norwich University Hospital49, Leiden University50, Technische Universität München51, University of Toronto52, University of Pennsylvania53, Johns Hopkins University54, University of Queensland55
TL;DR: A meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans is undertaken, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls.
Abstract: Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.
4,094 citations
TL;DR: A model of how to do shared decision making that is based on choice, option and decision talk is proposed that is practical, easy to remember, and can act as a guide to skill development.
Abstract: The principles of shared decision making are well documented but there is a lack of guidance about how to accomplish the approach in routine clinical practice. Our aim here is to translate existing conceptual descriptions into a three-step model that is practical, easy to remember, and can act as a guide to skill development. Achieving shared decision making depends on building a good relationship in the clinical encounter so that information is shared and patients are supported to deliberate and express their preferences and views during the decision making process. To accomplish these tasks, we propose a model of how to do shared decision making that is based on choice, option and decision talk. The model has three steps: a) introducing choice, b) describing options, often by integrating the use of patient decision support, and c) helping patients explore preferences and make decisions. This model rests on supporting a process of deliberation, and on understanding that decisions should be influenced by exploring and respecting “what matters most” to patients as individuals, and that this exploration in turn depends on them developing informed preferences.
2,596 citations
University of Louisville1, Rush University Medical Center2, University of North Carolina at Chapel Hill3, University of Amsterdam4, University of Pennsylvania5, Mayo Clinic6, University of Göttingen7, Columbia University Medical Center8, University of Cambridge9, Stavanger University Hospital10, Autonomous University of Barcelona11, Ikerbasque12, Newcastle University13, Istanbul University14
TL;DR: These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
Abstract: Mild cognitive impairment is common in nondemented Parkinson's disease (PD) patients and may be a harbinger of dementia. In view of its importance, the Movement Disorder Society commissioned a task force to delineate diagnostic criteria for mild cognitive impairment in PD. The proposed diagnostic criteria are based on a literature review and expert consensus. This article provides guidelines to characterize the clinical syndrome and methods for its diagnosis. The criteria will require validation, and possibly refinement, as additional research improves our understanding of the epidemiology, presentation, neurobiology, assessment, and long-term course of this clinical syndrome. These diagnostic criteria will support future research efforts to identify at the earliest stage those PD patients at increased risk of progressive cognitive decline and dementia who may benefit from clinical interventions at a predementia stage.
1,867 citations
TL;DR: There is a substantial (if incomplete) evidence base to guide choice of knowledge translation activities targeting healthcare professionals and consumers and there are a profusion of innovative approaches that warrant further evaluation.
Abstract: One of the most consistent findings from clinical and health services research is the failure to translate research into practice and policy. As a result of these evidence-practice and policy gaps, patients fail to benefit optimally from advances in healthcare and are exposed to unnecessary risks of iatrogenic harms, and healthcare systems are exposed to unnecessary expenditure resulting in significant opportunity costs. Over the last decade, there has been increasing international policy and research attention on how to reduce the evidence-practice and policy gap. In this paper, we summarise the current concepts and evidence to guide knowledge translation activities, defined as T2 research (the translation of new clinical knowledge into improved health). We structure the article around five key questions: what should be transferred; to whom should research knowledge be transferred; by whom should research knowledge be transferred; how should research knowledge be transferred; and, with what effect should research knowledge be transferred? We suggest that the basic unit of knowledge translation should usually be up-to-date systematic reviews or other syntheses of research findings. Knowledge translators need to identify the key messages for different target audiences and to fashion these in language and knowledge translation products that are easily assimilated by different audiences. The relative importance of knowledge translation to different target audiences will vary by the type of research and appropriate endpoints of knowledge translation may vary across different stakeholder groups. There are a large number of planned knowledge translation models, derived from different disciplinary, contextual (i.e., setting), and target audience viewpoints. Most of these suggest that planned knowledge translation for healthcare professionals and consumers is more likely to be successful if the choice of knowledge translation strategy is informed by an assessment of the likely barriers and facilitators. Although our evidence on the likely effectiveness of different strategies to overcome specific barriers remains incomplete, there is a range of informative systematic reviews of interventions aimed at healthcare professionals and consumers (i.e., patients, family members, and informal carers) and of factors important to research use by policy makers. There is a substantial (if incomplete) evidence base to guide choice of knowledge translation activities targeting healthcare professionals and consumers. The evidence base on the effects of different knowledge translation approaches targeting healthcare policy makers and senior managers is much weaker but there are a profusion of innovative approaches that warrant further evaluation.
1,796 citations
TL;DR: It is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, and herein is outlined the current consensus nomenclature, and the differences between the medullOBlastoma subgroups.
Abstract: Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.
1,501 citations
University of Leeds1, Jet Propulsion Laboratory2, University of Colorado Boulder3, Technical University of Denmark4, Durham University5, University of Texas at Austin6, Ohio State University7, University College London8, Technische Universität München9, Lamont–Doherty Earth Observatory10, Johns Hopkins University Applied Physics Laboratory11, Newcastle University12, University of Tasmania13, Utrecht University14, University of Kansas15, Swansea University16, Goddard Space Flight Center17, University of Ottawa18, University of California, Irvine19, University of Bristol20, British Antarctic Survey21, University of Innsbruck22, Delft University of Technology23
TL;DR: There is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty, and the mass balance of Earth’s polar ice sheets is estimated by combining the results of existing independent techniques.
Abstract: We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic adjustment to estimate the mass balance of Earth’s polar ice sheets. We find that there is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by –142 ± 49, +14 ± 43, –65 ± 26, and –20 ± 14 gigatonnes year−1, respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year−1 to the rate of global sea-level rise.
1,215 citations
TL;DR: The world breaks everyone and afterward many are strong at the broken places as mentioned in this paper, which is a common refrain in the book "A Farewell to Arms" by Ernest Hemingway.
Abstract: Introduction The world breaks everyone and afterward many are strong at the broken places. (Ernest Hemingway, A Farewell to Arms, 1929) We live in challenging times with a heightened sense of uncer...
1,152 citations
TL;DR: By in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics, which indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts.
Abstract: Oligodendrocytes, the myelin-forming glial cells of the central nervous system, maintain long-term axonal integrity. However, the underlying support mechanisms are not understood. Here we identify a metabolic component of axon-glia interactions by generating conditional Cox10 (protoheme IX farnesyltransferase) mutant mice, in which oligodendrocytes and Schwann cells fail to assemble stable mitochondrial cytochrome c oxidase (COX, also known as mitochondrial complex IV). In the peripheral nervous system, Cox10 conditional mutants exhibit severe neuropathy with dysmyelination, abnormal Remak bundles, muscle atrophy and paralysis. Notably, perturbing mitochondrial respiration did not cause glial cell death. In the adult central nervous system, we found no signs of demyelination, axonal degeneration or secondary inflammation. Unlike cultured oligodendrocytes, which are sensitive to COX inhibitors, post-myelination oligodendrocytes survive well in the absence of COX activity. More importantly, by in vivo magnetic resonance spectroscopy, brain lactate concentrations in mutants were increased compared with controls, but were detectable only in mice exposed to volatile anaesthetics. This indicates that aerobic glycolysis products derived from oligodendrocytes are rapidly metabolized within white matter tracts. Because myelinated axons can use lactate when energy-deprived, our findings suggest a model in which axon-glia metabolic coupling serves a physiological function.
1,141 citations
TL;DR: Emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontococcal inflammation, andperiodontal inflammation negatively affecting glycaemic control is supported.
Abstract: Periodontitis is a common chronic inflammatory disease characterised by destruction of the supporting structures of the teeth (the periodontal ligament and alveolar bone). It is highly prevalent (severe periodontitis affects 10–15% of adults) and has multiple negative impacts on quality of life. Epidemiological data confirm that diabetes is a major risk factor for periodontitis; susceptibility to periodontitis is increased by approximately threefold in people with diabetes. There is a clear relationship between degree of hyperglycaemia and severity of periodontitis. The mechanisms that underpin the links between these two conditions are not completely understood, but involve aspects of immune functioning, neutrophil activity, and cytokine biology. There is emerging evidence to support the existence of a two-way relationship between diabetes and periodontitis, with diabetes increasing the risk for periodontitis, and periodontal inflammation negatively affecting glycaemic control. Incidences of macroalbuminuria and end-stage renal disease are increased twofold and threefold, respectively, in diabetic individuals who also have severe periodontitis compared to diabetic individuals without severe periodontitis. Furthermore, the risk of cardiorenal mortality (ischaemic heart disease and diabetic nephropathy combined) is three times higher in diabetic people with severe periodontitis than in diabetic people without severe periodontitis. Treatment of periodontitis is associated with HbA1c reductions of approximately 0.4%. Oral and periodontal health should be promoted as integral components of diabetes management.
1,110 citations
TL;DR: This Review discusses how growth of the sacculus is sensitive to mechanical force and nutritional status, and describes the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling.
Abstract: How bacteria grow and divide while retaining a defined shape is a fundamental question in microbiology, but technological advances are now driving a new understanding of how the shape-maintaining bacterial peptidoglycan sacculus grows. In this Review, we highlight the relationship between peptidoglycan synthesis complexes and cytoskeletal elements, as well as recent evidence that peptidoglycan growth is regulated from outside the sacculus in Gram-negative bacteria. We also discuss how growth of the sacculus is sensitive to mechanical force and nutritional status, and describe the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling.
University of Paris1, Ruhr University Bochum2, University of Cambridge3, University of California, Davis4, University of Massachusetts Dartmouth5, University of Paris-Sud6, University of Manchester7, University of Pennsylvania8, University of California, San Diego9, University of Oxford10, Utrecht University11, University of Zurich12, Heidelberg University13, King's College London14, University of Warwick15, Medical University of Vienna16, Newcastle University17, Emory University18
TL;DR: This article critically discusses the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders, highlighting the needs to characterize the cellular and cerebral circuits underpinning cognitive function and identify more effective treatments.
Abstract: Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.
TL;DR: This paper systematically outline the optimization challenges that arise when developing technology to support ride-sharing and survey the related operations research models in the academic literature.
TL;DR: First, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress are tested.
Abstract: Dysregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. Dysfunction of one DNA repair pathway may be compensated for by the function of another compensatory DDR pathway, which may be increased and contribute to resistance to DNA-damaging chemotherapy and radiotherapy. Therefore, DDR pathways make an ideal target for therapeutic intervention; first, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress. These hypotheses are currently being tested in the laboratory and are being translated into clinical studies.
German Cancer Research Center1, University Hospital Heidelberg2, University of Toronto3, Stanford University4, University of Amsterdam5, VU University Amsterdam6, Newcastle University7, University of Bonn8, University of Hamburg9, Manchester Academic Health Science Centre10, University of Cambridge11, Karolinska Institutet12, Medical University of Vienna13, Curie Institute14, Paris Descartes University15, Harvard University16
TL;DR: A meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies shows how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.
Abstract: Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future.
TL;DR: Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.
Abstract: Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing-remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.
Institut national de la recherche agronomique1, University of Greifswald2, Trinity College, Dublin3, University of Newcastle4, University Medical Center Groningen5, University of York6, Braunschweig University of Technology7, Newcastle University8, Technical University of Denmark9, Humboldt University of Berlin10, ETH Zurich11, Pasteur Institute12, University of Göttingen13
TL;DR: The transcriptomes of Bacillus subtilis exposed to a wide range of environmental and nutritional conditions that the organism might encounter in nature are reported, offering an initial understanding of why certain regulatory strategies may be favored during evolution of dynamic control systems.
Abstract: Bacteria adapt to environmental stimuli by adjusting their transcriptomes in a complex manner, the full potential of which has yet to be established for any individual bacterial species. Here, we report the transcriptomes of Bacillus subtilis exposed to a wide range of environmental and nutritional conditions that the organism might encounter in nature. We comprehensively mapped transcription units (TUs) and grouped 2935 promoters into regulons controlled by various RNA polymerase sigma factors, accounting for ~66% of the observed variance in transcriptional activity. This global classification of promoters and detailed description of TUs revealed that a large proportion of the detected antisense RNAs arose from potentially spurious transcription initiation by alternative sigma factors and from imperfect control of transcription termination.
TL;DR: The analysis suggests that the dual (or triple) three-phase PMAC motor drive may be a favored choice for general aerospace applications, striking a balance between necessary redundancy and undue complexity, while maintaining a balanced operation following a failure.
Abstract: This paper presents an overview of motor drive technologies used for safety-critical aerospace applications, with a particular focus placed on the choice of candidate machines and their drive topologies. Aircraft applications demand high reliability, high availability, and high power density while aiming to reduce weight, complexity, fuel consumption, operational costs, and environmental impact. New electric driven systems can meet these requirements and also provide significant technical and economic improvements over conventional mechanical, hydraulic, or pneumatic systems. Fault-tolerant motor drives can be achieved by partitioning and redundancy through the use of multichannel three-phase systems or multiple single-phase modules. Analytical methods are adopted to compare caged induction, reluctance, and PM motor technologies and their relative merits. The analysis suggests that the dual (or triple) three-phase PMAC motor drive may be a favored choice for general aerospace applications, striking a balance between necessary redundancy and undue complexity, while maintaining a balanced operation following a failure. The modular single-phase approach offers a good compromise between size and complexity but suffers from high total harmonic distortion of the supply and high torque ripple when faulted. For each specific aircraft application, a parametrical optimization of the suitable motor configuration is needed through a coupled electromagnetic and thermal analysis, and should be verified by finite-element analysis.
German Cancer Research Center1, University of Toronto2, Harvard University3, Broad Institute4, University of British Columbia5, Heidelberg University6, Memorial Sloan Kettering Cancer Center7, Vanderbilt University8, Sanford-Burnham Institute for Medical Research9, Medical University of Vienna10, Curie Institute11, University of Lausanne12, Seoul National University13, Johns Hopkins University14, University of Lyon15, University of Pittsburgh16, University of Michigan17, University of Alabama at Birmingham18, Catholic University of the Sacred Heart19, Erasmus University Rotterdam20, Boston Children's Hospital21, University of Washington22, Masaryk University23, McMaster University24, Hamilton Health Sciences25, Duke University26, McGill University27, McGill University Health Centre28, Newcastle University29, University of California, San Francisco30, University of Debrecen31, Tohoku University32, Saint Louis University33, Washington University in St. Louis34, University of California, Los Angeles35, Emory University36, University of Cincinnati37, Kumamoto University38, Semmelweis University39, University of Arkansas for Medical Sciences40, University of Naples Federico II41, Chonnam National University42, University of São Paulo43, University of Colorado Denver44, University of Ulsan45, University of Calgary46, Stanford University47
TL;DR: Somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas are reported, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Groups 4, which suggest future avenues for rational, targeted therapy.
Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
TL;DR: If the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-σκB subunits.
Abstract: It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.
TL;DR: It is shown, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomere irrespective of telomerase activity, and that all persistent foci are associated with telomeres.
Abstract: Telomeres are specialized nucleoprotein structures, which protect chromosome ends and have been implicated in the ageing process. Telomere shortening has been shown to contribute to a persistent DNA damage response (DDR) during replicative senescence, the irreversible loss of division potential of somatic cells. Similarly, persistent DDR foci can be found in stress-induced senescence, although their nature is not understood. Here we show, using immuno-fluorescent in situ hybridization and ChIP, that up to half of the DNA damage foci in stress-induced senescence are located at telomeres irrespective of telomerase activity. Moreover, live-cell imaging experiments reveal that all persistent foci are associated with telomeres. Finally, we report an age-dependent increase in frequencies of telomere-associated foci in gut and liver of mice, occurring irrespectively of telomere length. We conclude that telomeres are important targets for stress in vitro and in vivo and this has important consequences for the ageing process.
TL;DR: A CD141hi DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c+ and CD14+ tissue DCs and superior at cross-presenting soluble antigens was identified.
TL;DR: In this article, a detailed theoretical and experimental comparison of the two perturb and observe (P&O) implementation techniques on the basis of system stability, performance characteristics, and energy utilization for standalone PV pumping systems is presented.
Abstract: The energy utilization efficiency of commercial photovoltaic (PV) pumping systems can be significantly improved by employing simple perturb and observe (P&O) maximum power point tracking algorithms. Two such P&O implementation techniques, reference voltage perturbation and direct duty ratio perturbation, are commonly utilized in the literature but no clear criteria for the suitable choice of method or algorithm parameters have been presented. This paper presents a detailed theoretical and experimental comparison of the two P&O implementation techniques on the basis of system stability, performance characteristics, and energy utilization for standalone PV pumping systems. The influence of algorithm parameters on system behavior is investigated and the various advantages and drawbacks of each technique are identified for different weather conditions. Practical results obtained using a 1080-Wp PV array connected to a 1-kW permanent magnet dc motor-centrifugal pump set show very good agreement with the theoretical analysis and numerical simulations.
University of Oxford1, University of Leicester2, Imperial College London3, Newcastle University4, University of Dundee5, University of Southampton6, University of Nottingham7, Queen's University Belfast8, University of Warwick9, University College London10, Cardiff University11, Avon and Wiltshire Mental Health Partnership NHS Trust12, University of Cambridge13
TL;DR: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months.
Abstract: A b s t r ac t Background Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer’s disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer’s disease (a score of 5 to 13 on the Standardized Mini–Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS. Results Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone. Conclusions In patients with moderate or severe Alzheimer’s disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer’s Society; Current Controlled Trials number, ISRCTN49545035.)
TL;DR: It is shown here that senescent cells induce a DNA damage response, characteristic for senescence, in neighbouring cells via gap junction‐mediated cell–cell contact and processes involving ROS, which can induce a bystander effect, spreading senescences towards their neighbours in vitro and, possibly, in vivo.
Abstract: Senescent cells produce and secrete various bioactive molecules including interleukins, growth factors, matrix-degrading enzymes and reactive oxygen species (ROS). Thus, it has been proposed that senescent cells can damage their local environment, and a stimulatory effect on tumour cell growth and invasiveness has been documented. However, it was unknown what effect, if any, senescent cells have on their normal, proliferation-competent counterparts. We show here that senescent cells induce a DNA damage response, characteristic for senescence, in neighbouring cells via gap junction-mediated cell-cell contact and processes involving ROS. Continuous exposure to senescent cells induced cell senescence in intact bystander fibroblasts. Hepatocytes bearing senescence markers clustered together in mice livers. Thus, senescent cells can induce a bystander effect, spreading senescence towards their neighbours in vitro and, possibly, in vivo.
07 Oct 2012
TL;DR: Digits is a wrist-worn sensor that recovers the full 3D pose of the user's hand, which enables a variety of freehand interactions on the move and is specifically designed to be low-power and easily reproducible using only off-the-shelf hardware.
Abstract: Digits is a wrist-worn sensor that recovers the full 3D pose of the user's hand. This enables a variety of freehand interactions on the move. The system targets mobile settings, and is specifically designed to be low-power and easily reproducible using only off-the-shelf hardware. The electronics are self-contained on the user's wrist, but optically image the entirety of the user's hand. This data is processed using a new pipeline that robustly samples key parts of the hand, such as the tips and lower regions of each finger. These sparse samples are fed into new kinematic models that leverage the biomechanical constraints of the hand to recover the 3D pose of the user's hand. The proposed system works without the need for full instrumentation of the hand (for example using data gloves), additional sensors in the environment, or depth cameras which are currently prohibitive for mobile scenarios due to power and form-factor considerations. We demonstrate the utility of Digits for a variety of application scenarios, including 3D spatial interaction with mobile devices, eyes-free interaction on-the-move, and gaming. We conclude with a quantitative and qualitative evaluation of our system, and discussion of strengths, limitations and future work.
TL;DR: The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.
Abstract: Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.
TL;DR: The published literature on the implementation of e-health focused on organizational issues, neglecting the wider social framework that must be considered when introducing new technologies.
Abstract: Resumen Factores que promueven o dificultan la implementacion de los sistemas de telemedicina: revision sistematica explicativa Objetivo Realizar una revision sistematica de la literatura existente sobre la implementacion de la telemedicina para identificar: (1) los obstaculos y estimulos para la implementacion de la telemedicina, y (2) las lagunas pendientes en la investigacion sobre el tema. Metodos Se realizo una busqueda en MEDLINE, EMBASE, CINAHL, PSYCINFO y la Cochrane Library de revisiones publicadas entre el 1 de enero de 1995 y el 17 de marzo de 2009. Los estudios debian ser revisiones sistematicas, revisiones narrativas, metasintesis cualitativas o metaetnografias sobre la implementacion de la telemedicina. Los resumenes y documentos se investigaron doblemente y se extrajeron los datos del pais de origen, el area de la telemedicina, la fecha de publicacion, los objetivos y metodos, las bases de datos buscadas, los criterios de inclusion y exclusion y el numero de documentos. Se analizaron los datos de forma cualitativa mediante un proceso de normalizacion como marco de codificacion explicativo.
TL;DR: A meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease identifies novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
TL;DR: Meta-regression suggested that increasing numbers of identified BCTs are not necessarily associated with better outcomes, and post-hoc ratings of intervention components in published trials can lead to the identification of components and theories for behaviour change practice and research.
Abstract: Reducing obesity is an important preventive strategy for people who are at increased risk of major disabling or life-threatening conditions. Behavioural treatments for obesity are complex and involve several components aiming to facilitate behaviour change. Systematic reviews need to assess the components that moderate intervention effects. Electronic databases and journals were searched for randomised controlled trials of behavioural interventions targeting dietary and/or physical activity change for obese adults (mean BMI≥30, mean age≥40 years) with risk factors and follow-up data≥12 weeks. A reliable taxonomy of theory-congruent behaviour change techniques (BCTs; Abraham & Michie, 2008) was used to identify programme components. Meta-regression suggested that increasing numbers of identified BCTs are not necessarily associated with better outcomes. The BCTs provision of instructions (β =− 2.69, p=0.02), self-monitoring (β = − 3.37, p<0.001), relapse prevention (β = − 2.63, p=0.02) and promptin...