Showing papers by "Newcastle University published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy 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.
For example, 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 versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase 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. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
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. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. 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 assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.
5,050 citations
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.
4,804 citations
TL;DR: Liraglutide was safe, well tolerated, and led to histological resolution of non-alcoholic steatohepatitis, warranting extensive, longer-term studies.
1,285 citations
TL;DR: Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems.
Abstract: Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum.
1,199 citations
TL;DR: The findings suggest that deficiencies in social relationships are associated with an increased risk of developing CHD and stroke in high-income countries.
Abstract: Background The influence of social relationships on morbidity is widely accepted, but the size of the risk to cardiovascular health is unclear.
Objective We undertook a systematic review and meta-analysis to investigate the association between loneliness or social isolation and incident coronary heart disease (CHD) and stroke.
Methods Sixteen electronic databases were systematically searched for longitudinal studies set in high-income countries and published up until May 2015. Two independent reviewers screened studies for inclusion and extracted data. We assessed quality using a component approach and pooled data for analysis using random effects models.
Results Of the 35 925 records retrieved, 23 papers met inclusion criteria for the narrative review. They reported data from 16 longitudinal datasets, for a total of 4628 CHD and 3002 stroke events recorded over follow-up periods ranging from 3 to 21 years. Reports of 11 CHD studies and 8 stroke studies provided data suitable for meta-analysis. Poor social relationships were associated with a 29% increase in risk of incident CHD (pooled relative risk: 1.29, 95% CI 1.04 to 1.59) and a 32% increase in risk of stroke (pooled relative risk: 1.32, 95% CI 1.04 to 1.68). Subgroup analyses did not identify any differences by gender.
Conclusions Our findings suggest that deficiencies in social relationships are associated with an increased risk of developing CHD and stroke. Future studies are needed to investigate whether interventions targeting loneliness and social isolation can help to prevent two of the leading causes of death and disability in high-income countries.
Study registration number CRD42014010225.
1,015 citations
National Institute for Health Research1, Wellcome Trust Sanger Institute2, University of Cambridge3, NHS Blood and Transplant4, European Bioinformatics Institute5, Barts Health NHS Trust6, Radboud University Nijmegen7, University of Geneva8, Katholieke Universiteit Leuven9, University of Oxford10, Wellcome Trust Centre for Human Genetics11, British Heart Foundation12, University of Amsterdam13, Newcastle University14, McGill University15, Pompeu Fabra University16, University College London17, Churchill Hospital18, John Radcliffe Hospital19
TL;DR: A genome-wide association analysis in the UK Biobank and INTERVAL studies is performed, providing evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations betweenBlood cell indices and cardiovascular disease may be non-causal.
982 citations
Christian Fuchsberger1, Christian Fuchsberger2, Jason Flannick3, Jason Flannick4 +346 more•Institutions (77)
TL;DR: In this paper, the authors performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing for 12,940 individuals from five ancestry groups.
Abstract: The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
866 citations
Pierre-and-Marie-Curie University1, French Institute of Health and Medical Research2, San Antonio Military Medical Center3, University of Antwerp4, Paris Diderot University5, University of Melbourne6, Catholic University of Leuven7, University of Angers8, Duke University9, University of Virginia10, Radboud University Nijmegen11, Newcastle University12, university of lille13, Virginia Commonwealth University14, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico15, Semmelweis University16
TL;DR: A post-hoc analysis of data from trial of patients with NASH showed that elafibranor (120 mg/d for 1 year) resolved NASH without fibrosis worsening, based on a modified definition, in the intention-to-treat analysis and in patients with moderate or severe NASH.
813 citations
TL;DR: The findings from this review can guide the development and evaluation of interventions promoting maintenance of health behaviours and help in the development of an integrated theory of behaviour change maintenance.
Abstract: Background: Behaviour change interventions are effective in supporting individuals in achieving temporary behaviour change. Behaviour change maintenance, however, is rarely attained. The aim of this review was to identify and synthesise current theoretical explanations for behaviour change maintenance to inform future research and practice.Methods: Potentially relevant theories were identified through systematic searches of electronic databases (Ovid MEDLINE, Embase, PsycINFO). In addition, an existing database of 80 theories was searched, and 25 theory experts were consulted. Theories were included if they formulated hypotheses about behaviour change maintenance. Included theories were synthesised thematically to ascertain overarching explanations for behaviour change maintenance. Initial theoretical themes were cross-validated.Findings: One hundred and seventeen behaviour theories were identified, of which 100 met the inclusion criteria. Five overarching, interconnected themes representing theor...
748 citations
Katholieke Universiteit Leuven1, University of Bologna2, Royal Prince Alfred Hospital3, University of California, Davis4, University of Milan5, Radboud University Nijmegen6, Scripps Health7, Curie Institute8, University of Amsterdam9, Medical University of Vienna10, Newcastle University11, University of Padua12, Ludwig Maximilian University of Munich13, Virginia Commonwealth University14, Utrecht University15, Autonomous University of Barcelona16, Université de Montréal17, University of Birmingham18, University Health Network19, Erasmus University Rotterdam20, University of Gothenburg21, Intercept Pharmaceuticals22
TL;DR: Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo.
Abstract: Background Primary biliary cholangitis (formerly called primary biliary cirrhosis) can progress to cirrhosis and death despite ursodiol therapy. Alkaline phosphatase and bilirubin levels correlate with the risk of liver transplantation or death. Obeticholic acid, a farnesoid X receptor agonist, has shown potential benefit in patients with this disease. Methods In this 12-month, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 217 patients who had an inadequate response to ursodiol or who found the side effects of ursodiol unacceptable to receive obeticholic acid at a dose of 10 mg (the 10-mg group), obeticholic acid at a dose of 5 mg with adjustment to 10 mg if applicable (the 5-10-mg group), or placebo. The primary end point was an alkaline phosphatase level of less than 1.67 times the upper limit of the normal range, with a reduction of at least 15% from baseline, and a normal total bilirubin level. Results Of 216 patients who underwent randomization and received at least one dose of obeticholic acid or placebo, 93% received ursodiol as background therapy. The primary end point occurred in more patients in the 5-10-mg group (46%) and the 10-mg group (47%) than in the placebo group (10%; P Conclusions Obeticholic acid administered with ursodiol or as monotherapy for 12 months in patients with primary biliary cholangitis resulted in decreases from baseline in alkaline phosphatase and total bilirubin levels that differed significantly from the changes observed with placebo. There were more serious adverse events with obeticholic acid. (Funded by Intercept Pharmaceuticals; POISE ClinicalTrials.gov number, NCT01473524; Current Controlled Trials number, ISRCTN89514817.).
TL;DR: How the counter-regulatory and tolerogenic functions of IDO can be targeted for cancer immunotherapy are discussed and an overview of the current clinical progress in this area is presented.
TL;DR: The vibronic coupling rISC model is used to predict this behaviour and describes how rISC and TADF are affected by external perturbation, substantiating the model of rISC.
Abstract: Knowing the underlying photophysics of thermally activated delayed fluorescence (TADF) allows proper design of high efficiency organic light-emitting diodes. We have proposed a model to describe reverse intersystem crossing (rISC) in donor–acceptor charge transfer molecules, where spin–orbit coupling between singlet and triplet states is mediated by one of the local triplet states of the donor (or acceptor). This second order, vibronically coupled mechanism describes the basic photophysics of TADF. Through a series of measurements, whereby the energy ordering of the charge transfer (CT) excited states and the local triplet are tuned in and out of resonance, we show that TADF reaches a maximum at the resonance point, substantiating our model of rISC. Moreover, using photoinduced absorption, we show how the populations of both singlet and triplet CT states and the local triplet state change in and out of resonance. Our vibronic coupling rISC model is used to predict this behaviour and describes how rISC and TADF are affected by external perturbation.
Katholieke Universiteit Leuven1, Wellcome Trust Sanger Institute2, Montreal Heart Institute3, Canterbury Christ Church University4, Wellcome Trust Centre for Human Genetics5, University of Chicago6, University of Kiel7, Peninsula College of Medicine and Dentistry8, University of Adelaide9, Royal Adelaide Hospital10, Casa Sollievo della Sofferenza11, Ludwig Maximilian University of Munich12, Johns Hopkins University13, Yale University14, Broad Institute15, Cedars-Sinai Medical Center16, University of Pittsburgh17, University of Auckland18, University of Otago19, Christchurch Hospital20, Children's Hospital of Philadelphia21, Örebro University22, Oslo University Hospital23, University of Edinburgh24, Lithuanian University of Health Sciences25, University of Western Australia26, University of Cambridge27, University of Liège28, Leiden University Medical Center29, University Medical Center Groningen30, Royal Hospital for Sick Children31, Newcastle University32, University of Toronto33, Royal Brisbane and Women's Hospital34, QIMR Berghofer Medical Research Institute35
TL;DR: The largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
University of Vienna1, University of Edinburgh2, Massey University3, Newcastle University4, University of Copenhagen5, University of Glasgow6, Massachusetts Institute of Technology7, Boston College8, Fred Hutchinson Cancer Research Center9, University of Aberdeen10, San Diego State University11, Institut national de la recherche agronomique12, University of Birmingham13, Agricultural Research Organization, Volcani Center14, University of Jena15, University of Lausanne16, University of Warwick17, University of Amsterdam18, Delft University of Technology19, Temple University20, Technical University of Denmark21, Columbia University22
TL;DR: In this paper, the authors argue that the ability to predict and manage the function of these highly complex, dynamically changing communities is limited, and that close coordination of experimental data collection and method development with mathematical model building is needed to achieve significant progress in understanding of microbial dynamics and function.
Abstract: The importance of microbial communities (MCs) cannot be overstated. MCs underpin the biogeochemical cycles of the earth’s soil, oceans and the atmosphere, and perform ecosystem functions that impact plants, animals and humans. Yet our ability to predict and manage the function of these highly complex, dynamically changing communities is limited. Building predictive models that link MC composition to function is a key emerging challenge in microbial ecology. Here, we argue that addressing this challenge requires close coordination of experimental data collection and method development with mathematical model building. We discuss specific examples where model–experiment integration has already resulted in important insights into MC function and structure. We also highlight key research questions that still demand better integration of experiments and models. We argue that such integration is needed to achieve significant progress in our understanding of MC dynamics and function, and we make specific practical suggestions as to how this could be achieved.
TL;DR: An ecological model of the ways that participants in implementation and health improvement processes interact with contexts is presented and it is shown how these processes involve interactions between mechanisms of resource mobilisation, collective action and negotiations with context that contribute to self-organisation in complex adaptive systems.
Abstract: Context is a problem in research on health behaviour change, knowledge translation, practice implementation and health improvement. This is because many intervention and evaluation designs seek to eliminate contextual confounders, when these represent the normal conditions into which interventions must be integrated if they are to be workable in practice. We present an ecological model of the ways that participants in implementation and health improvement processes interact with contexts. The paper addresses the problem of context as it affects processes of implementation, scaling up and diffusion of interventions. We extend our earlier work to develop Normalisation Process Theory and show how these processes involve interactions between mechanisms of resource mobilisation, collective action and negotiations with context. These mechanisms are adaptive. They contribute to self-organisation in complex adaptive systems. Implementation includes the translational efforts that take healthcare interventions beyond the closed systems of evaluation studies into the open systems of ‘real world’ contexts. The outcome of these processes depends on interactions and negotiations between their participants and contexts. In these negotiations, the plasticity of intervention components, the degree of participants’ discretion over resource mobilisation and actors’ contributions, and the elasticity of contexts, all play important parts. Understanding these processes in terms of feedback loops, adaptive mechanisms and the practical compromises that stem from them enables us to see the mechanisms specified by NPT as core elements of self-organisation in complex systems.
TL;DR: Significantly more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were reported while patients were receiving WBRT, although there was no evidence of a difference in the rate of serious adverse events between the two groups.
TL;DR: Higher education in the United Kingdom has rather lagged behind other countries in developing an interest in, scholarly research on, and realisation about the importance of student engagement as mentioned in this paper. This...
Abstract: Higher Education in the United Kingdom has rather lagged behind other countries in developing an interest in, scholarly research on, and realisation about the importance of student engagement. This...
TL;DR: This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.
Abstract: While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.
Wellcome Trust Sanger Institute1, University of Cambridge2, McGill University3, European Bioinformatics Institute4, Pompeu Fabra University5, University College London6, NHS Blood and Transplant7, Radboud University Nijmegen8, Max Planck Society9, University of Geneva10, New York University11, British Heart Foundation12, Newcastle University13, University of Amsterdam14
TL;DR: High-resolution genetic, epigenetic, and transcriptomic profiling in three major human immune cell types from up to 197 individuals yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
TL;DR: A model spin‐vibronic Hamiltonian is used to reveal the crucial role of non‐Born‐Oppenheimer effects in determining k rISC and demonstrates that vibronic (nonadiabatic) coupling between the lowest local excitation triplet and lowest charge transfer triplet opens the possibility for significant second‐order coupling effects and increasesk rISC by about four orders of magnitude.
Abstract: Factors influencing the rate of reverse intersystem crossing (krISC ) in thermally activated delayed fluorescence (TADF) emitters are critical for improving the efficiency and performance of third-generation heavy-metal-free organic light-emitting diodes (OLEDs). However, present understanding of the TADF mechanism does not extend far beyond a thermal equilibrium between the lowest singlet and triplet states and consequently research has focused almost exclusively on the energy gap between these two states. Herein, we use a model spin-vibronic Hamiltonian to reveal the crucial role of non-Born-Oppenheimer effects in determining krISC . We demonstrate that vibronic (nonadiabatic) coupling between the lowest local excitation triplet (3 LE) and lowest charge transfer triplet (3 CT) opens the possibility for significant second-order coupling effects and increases krISC by about four orders of magnitude. Crucially, these simulations reveal the dynamical mechanism for highly efficient TADF and opens design routes that go beyond the Born-Oppenheimer approximation for the future development of high-performing systems.
TL;DR: Whereas the strictest regimes of PA management attempted to exclude anthropogenic influences to achieve biological conservation objectives, PAs that explicitly integrated local people as stakeholders tended to be more effective at achieving joint biological conservation and socioeconomic development outcomes.
Abstract: Protected areas (PAs) are a key strategy for protecting biological resources, but they vary considerably in their effectiveness and are frequently reported as having negative impacts on local people. This has contributed to a divisive and unresolved debate concerning the compatibility of environmental and socioeconomic development goals. Elucidating the relationship between positive and negative social impacts and conservation outcomes of PAs is key for the development of more effective and socially just conservation. We conducted a global meta-analysis on 165 PAs using data from 171 published studies. We assessed how PAs affect the well-being of local people, the factors associated with these impacts, and crucially the relationship between PAs' conservation and socioeconomic outcomes. Protected areas associated with positive socioeconomic outcomes were more likely to report positive conservation outcomes. Positive conservation and socioeconomic outcomes were more likely to occur when PAs adopted comanagement regimes, empowered local people, reduced economic inequalities, and maintained cultural and livelihood benefits. Whereas the strictest regimes of PA management attempted to exclude anthropogenic influences to achieve biological conservation objectives, PAs that explicitly integrated local people as stakeholders tended to be more effective at achieving joint biological conservation and socioeconomic development outcomes. Strict protection may be needed in some circumstances, yet our results demonstrate that conservation and development objectives can be synergistic and highlight management strategies that increase the probability of maximizing both conservation performance and development outcomes of PAs.
TL;DR: The results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
Abstract: Cell senescence is an important tumour suppressor mechanism and driver of ageing. Both functions are dependent on the development of the senescent phenotype, which involves an overproduction of pro-inflammatory and pro-oxidant signals. However, the exact mechanisms regulating these phenotypes remain poorly understood. Here, we show the critical role of mitochondria in cellular senescence. In multiple models of senescence, absence of mitochondria reduced a spectrum of senescence effectors and phenotypes while preserving ATP production via enhanced glycolysis. Global transcriptomic analysis by RNA sequencing revealed that a vast number of senescent-associated changes are dependent on mitochondria, particularly the pro-inflammatory phenotype. Mechanistically, we show that the ATM, Akt and mTORC1 phosphorylation cascade integrates signals from the DNA damage response (DDR) towards PGC-1β-dependent mitochondrial biogenesis, contributing to aROS-mediated activation of the DDR and cell cycle arrest. Finally, we demonstrate that the reduction in mitochondrial content in vivo, by either mTORC1 inhibition or PGC-1β deletion, prevents senescence in the ageing mouse liver. Our results suggest that mitochondria are a candidate target for interventions to reduce the deleterious impact of senescence in ageing tissues.
TL;DR: It is suggested that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution.
Abstract: The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age. We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution. DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.
Proceedings Article•
09 Jul 2016TL;DR: This paper rigorously explore deep, convolutional, and recurrent approaches across three representative datasets that contain movement data captured with wearable sensors, and describes how to train recurrent approaches in this setting, introduces a novel regularisation approach, and illustrates how they outperform the state-of-the-art on a large benchmark dataset.
Abstract: Human activity recognition (HAR) in ubiquitous computing is beginning to adopt deep learning to substitute for well-established analysis techniques that rely on hand-crafted feature extraction and classification methods. However, from these isolated applications of custom deep architectures it is difficult to gain an overview of their suitability for problems ranging from the recognition of manipulative gestures to the segmentation and identification of physical activities like running or ascending stairs. In this paper we rigorously explore deep, convolutional, and recurrent approaches across three representative datasets that contain movement data captured with wearable sensors. We describe how to train recurrent approaches in this setting, introduce a novel regularisation approach, and illustrate how they outperform the state-of-the-art on a large benchmark dataset. We investigate the suitability of each model for HAR, across thousands of recognition experiments with randomly sampled model configurations, explore the impact of hyperparameters using the fANOVA framework, and provide guidelines for the practitioner who wants to apply deep learning in their problem setting.
TL;DR: A review of faculty development initiatives designed to improve teaching effectiveness synthesized findings related to intervention types, study characteristics, individual and organizational outcomes, key features, and community building to hold implications for practice and research.
Abstract: Background: This review, which focused on faculty development initiatives designed to improve teaching effectiveness, synthesized findings related to intervention types, study characteristics, individual and organizational outcomes, key features, and community building.Methods: This review included 111 studies (between 2002 and 2012) that met the review criteria.Findings: Overall satisfaction with faculty development programs was high. Participants reported increased confidence, enthusiasm, and awareness of effective educational practices. Gains in knowledge and skills, and self-reported changes in teaching behaviors, were frequently noted. Observed behavior changes included enhanced teaching practices, new educational initiatives, new leadership positions, and increased academic output. Organizational changes were infrequently explored. Key features included evidence-informed educational design, relevant content, experiential learning, feedback and reflection, educational projects, intentional co...
Icahn School of Medicine at Mount Sinai1, University Hospital of Lausanne2, Royal Surrey County Hospital3, Freeman Hospital4, Newcastle University5, Maastricht University6, University of Edinburgh7, Beaujon Hospital8, University of Tokyo9, University of Texas MD Anderson Cancer Center10, University of Zurich11
TL;DR: The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the Delphi method and prospective studies need to confirm the clinical use of the suggested protocol.
Abstract: Enhanced Recovery After Surgery (ERAS) is a multimodal pathway developed to overcome the deleterious effect of perioperative stress after major surgery. In colorectal surgery, ERAS pathways reduced perioperative morbidity, hospital stay and costs. Similar concept should be applied for liver surgery. This study presents the specific ERAS Society recommendations for liver surgery based on the best available evidence and on expert consensus. A systematic review was performed on ERAS for liver surgery by searching EMBASE and Medline. Five independent reviewers selected relevant articles. Quality of randomized trials was assessed according to the Jadad score and CONSORT statement. The level of evidence for each item was determined using the GRADE system. The Delphi method was used to validate the final recommendations. A total of 157 full texts were screened. Thirty-seven articles were included in the systematic review, and 16 of the 23 standard ERAS items were studied specifically for liver surgery. Consensus was reached among experts after 3 rounds. Prophylactic nasogastric intubation and prophylactic abdominal drainage should be omitted. The use of postoperative oral laxatives and minimally invasive surgery results in a quicker bowel recovery and shorter hospital stay. Goal-directed fluid therapy with maintenance of a low intraoperative central venous pressure induces faster recovery. Early oral intake and mobilization are recommended. There is no evidence to prefer epidural to other types of analgesia. The current ERAS recommendations were elaborated based on the best available evidence and endorsed by the Delphi method. Nevertheless, prospective studies need to confirm the clinical use of the suggested protocol.
TL;DR: It is found that aa acutely activate AMPK concurrently with mTOR, and it is shown that AMPK under aa sufficiency acts to sustain autophagy, which may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes.
Abstract: Amino acids (aa) are not only building blocks for proteins, but also signalling molecules, with the mammalian target of rapamycin complex 1 (mTORC1) acting as a key mediator. However, little is known about whether aa, independently of mTORC1, activate other kinases of the mTOR signalling network. To delineate aa-stimulated mTOR network dynamics, we here combine a computational–experimental approach with text mining-enhanced quantitative proteomics. We report that AMP-activated protein kinase (AMPK), phosphatidylinositide 3-kinase (PI3K) and mTOR complex 2 (mTORC2) are acutely activated by aa-readdition in an mTORC1-independent manner. AMPK activation by aa is mediated by Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ). In response, AMPK impinges on the autophagy regulators Unc-51-like kinase-1 (ULK1) and c-Jun. AMPK is widely recognized as an mTORC1 antagonist that is activated by starvation. We find that aa acutely activate AMPK concurrently with mTOR. We show that AMPK under aa sufficiency acts to sustain autophagy. This may be required to maintain protein homoeostasis and deliver metabolite intermediates for biosynthetic processes. mTORC1 is known to mediate the signalling activity of amino acids. Here, the authors combine modelling with experiments and find that amino acids acutely stimulate mTORC2, IRS/PI3K and AMPK, independently of mTORC1. AMPK activation through CaMKKβ sustains autophagy under non-starvation conditions.
TL;DR: The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction in the Western world and is increasing owing to its close association with obesity and insulin resistance. NAFLD represents a spectrum of liver disease that, in a minority of patients, can lead to progressive nonalcoholic steatohepatitis (NASH), fibrosis, and ultimately hepatocellular carcinoma and liver failure. NAFLD is a complex trait resulting from the interaction between environmental exposure and a susceptible polygenic background and comprising multiple independent modifiers of risk, such as the microbiome. The molecular mechanisms that combine to define the transition to NASH and progressive disease are complex, and consequently, no pharmacological therapy currently exists to treat NASH. A better understanding of the pathogenesis of NAFLD is critical if new treatments are to be discovered.
TL;DR: A consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.
Abstract: Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.