Showing papers by "University of Melbourne published in 2012"
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2010 aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex, using the Cause of Death Ensemble model.
11,809 citations
TL;DR: In this paper, the authors estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010.
9,324 citations
TL;DR: In this article, a search for the Standard Model Higgs boson in proton-proton collisions with the ATLAS detector at the LHC is presented, which has a significance of 5.9 standard deviations, corresponding to a background fluctuation probability of 1.7×10−9.
9,282 citations
TL;DR: Prevalence and severity of health loss were weakly correlated and age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010, but population growth and ageing have increased YLD numbers and crude rates over the past two decades.
7,021 citations
TL;DR: The results for 1990 and 2010 supersede all previously published Global Burden of Disease results and highlight the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account.
6,861 citations
TL;DR: The results indicated that feedback may be more effective when baseline performance is low, the source is a supervisor or colleague, it is provided more than once, and the role of context and the targeted clinical behaviour was assessed.
Abstract: Background Audit and feedback continues to be widely used as a strategy to improve professional practice. It appears logical that healthcare professionals would be prompted to modify their practice if given feedback that their clinical practice was inconsistent with that of their peers or accepted guidelines. Yet, audit and feedback has not been found to be consistently effective. Objectives To assess the effects of audit and feedback on the practice of healthcare professionals and patient outcomes. Search strategy We searched the Cochrane Effective Practice and Organisation of Care Group's register up to January 2001. This was supplemented with searches of MEDLINE and reference lists, which did not yield additional relevant studies. Selection criteria Randomised trials of audit and feedback (defined as any summary of clinical performance over a specified period of time) that reported objectively measured professional practice in a healthcare setting or healthcare outcomes. Data collection and analysis Two reviewers independently extracted data and assessed study quality. Quantitative (meta-regression), visual and qualitative analyses were undertaken. Main results We included 85 studies, 48 of which have been added to the previous version of this review. There were 52 comparisons of dichotomous outcomes from 47 trials with over 3500 health professionals that compared audit and feedback to no intervention. The adjusted RDs of non-compliance with desired practice varied from 0.09 (a 9% absolute increase in non-compliance) to 0.71 (a 71% decrease in non-compliance) (median = 0.07, inter-quartile range = 0.02 to 0.11). The one factor that appeared to predict the effectiveness of audit and feedback across studies was baseline non-compliance with recommended practice. Reviewer's conclusions Audit and feedback can be effective in improving professional practice. When it is effective, the effects are generally small to moderate. The absolute effects of audit and feedback are more likely to be larger when baseline adherence to recommended practice is low.
4,946 citations
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
University of Melbourne1, Singapore National Eye Center2, Allergan3, Aarhus University4, National Yang-Ming University5, University of London6, University of Southern Denmark7, Colorado School of Public Health8, Erasmus University Rotterdam9, Yamagata University10, University of Wisconsin-Madison11, L V Prasad Eye Institute12, University of Warwick13, University of Pittsburgh14, University of Turin15, Madras Medical College16, Rutgers University17, The Heart Research Institute18, Johns Hopkins University19, University of Southern California20, University of Sydney21, Capital Medical University22, Kyushu University23, Centers for Disease Control and Prevention24, National University of Singapore25
TL;DR: Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR, and these data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence.
Abstract: OBJECTIVE To examine the global prevalence and major risk factors for diabetic retinopathy (DR) and vision-threatening diabetic retinopathy (VTDR) among people with diabetes. RESEARCH DESIGN AND METHODS A pooled analysis using individual participant data from population-based studies around the world was performed. A systematic literature review was conducted to identify all population-based studies in general populations or individuals with diabetes who had ascertained DR from retinal photographs. Studies provided data for DR end points, including any DR, proliferative DR, diabetic macular edema, and VTDR, and also major systemic risk factors. Pooled prevalence estimates were directly age-standardized to the 2010 World Diabetes Population aged 20–79 years. RESULTS A total of 35 studies (1980–2008) provided data from 22,896 individuals with diabetes. The overall prevalence was 34.6% (95% CI 34.5–34.8) for any DR, 6.96% (6.87–7.04) for proliferative DR, 6.81% (6.74–6.89) for diabetic macular edema, and 10.2% (10.1–10.3) for VTDR. All DR prevalence end points increased with diabetes duration, hemoglobin A 1c , and blood pressure levels and were higher in people with type 1 compared with type 2 diabetes. CONCLUSIONS There are approximately 93 million people with DR, 17 million with proliferative DR, 21 million with diabetic macular edema, and 28 million with VTDR worldwide. Longer diabetes duration and poorer glycemic and blood pressure control are strongly associated with DR. These data highlight the substantial worldwide public health burden of DR and the importance of modifiable risk factors in its occurrence. This study is limited by data pooled from studies at different time points, with different methodologies and population characteristics.
3,282 citations
TL;DR: In this paper, a longitudinal study of 128 patients with Alzheimer's disease was conducted, where the authors used the participant's age at baseline assessment and the parent's age to calculate the estimated years from expected symptom onset (age of the participant minus parent's ages at symptom onset).
Abstract: A B S T R AC T BACKGROUND The order and magnitude of pathologic processes in Alzheimer’s disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer’s disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant’s age at baseline assessment and the parent’s age at the onset of symptoms of Alzheimer’s disease to calculate the estimated years from expected symptom onset (age of the participant minus parent’s age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)42 in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimer’s disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer’s disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer’s disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)
2,907 citations
TL;DR: An architectural framework and principles for energy-efficient Cloud computing are defined and the proposed energy-aware allocation heuristics provision data center resources to client applications in a way that improves energy efficiency of the data center, while delivering the negotiated Quality of Service (QoS).
2,511 citations
Harvard University1, Sarah Cannon Research Institute2, University of California, San Francisco3, University of Colorado Denver4, University of Sydney5, Vanderbilt University6, University of Pennsylvania7, University of Melbourne8, University of South Florida9, University of Texas MD Anderson Cancer Center10, GlaxoSmithKline11
TL;DR: Dabrafenib and trametinib were safely combined at full monotherapy doses, and the rate of pyrexia was increased with combination therapy, whereas the rates of proliferative skin lesions was nonsignificantly reduced.
Abstract: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of da braf e nib and 2 mg of tra me ti nib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03). Conclusions Da braf e nib and tra me ti nib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.)
TL;DR: The concept of the stabilizer, using two qubits, is introduced, and the single-qubit Hadamard, S and T operators are described, completing the set of required gates for a universal quantum computer.
Abstract: This article provides an introduction to surface code quantum computing. We first estimate the size and speed of a surface code quantum computer. We then introduce the concept of the stabilizer, using two qubits, and extend this concept to stabilizers acting on a two-dimensional array of physical qubits, on which we implement the surface code. We next describe how logical qubits are formed in the surface code array and give numerical estimates of their fault tolerance. We outline how logical qubits are physically moved on the array, how qubit braid transformations are constructed, and how a braid between two logical qubits is equivalent to a controlled-not. We then describe the single-qubit Hadamard, Ŝ and T operators, completing the set of required gates for a universal quantum computer. We conclude by briefly discussing physical implementations of the surface code. We include a number of Appendices in which we provide supplementary information to the main text. © 2012 American Physical Society.
TL;DR: As the population ages, the global number of individuals with low back pain is likely to increase substantially over the coming decades, with the highest prevalence among female individuals and those aged 40-80 years.
Abstract: Objective
To perform a systematic review of the global prevalence of low back pain, and to examine the influence that case definition, prevalence period, and other variables have on prevalence.
Methods
We conduced a new systematic review of the global prevalence of low back pain that included general population studies published between 1980 and 2009. A total of 165 studies from 54 countries were identified. Of these, 64% had been published since the last comparable review.
Results
Low back pain was shown to be a major problem throughout the world, with the highest prevalence among female individuals and those aged 40–80 years. After adjusting for methodologic variation, the mean ± SEM point prevalence was estimated to be 11.9 ± 2.0%, and the 1-month prevalence was estimated to be 23.2 ± 2.9%.
Conclusion
As the population ages, the global number of individuals with low back pain is likely to increase substantially over the coming decades. Investigators are encouraged to adopt recent recommendations for a standard definition of low back pain and to consult a recently developed tool for assessing the risk of bias of prevalence studies.
TL;DR: This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.
Abstract: The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody-drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.
TL;DR: New understandings of the diverse and dynamic effects on adolescent health include insights into the effects of puberty and brain development, together with social media, which provide important opportunities to improve health, both in adolescence and later in life.
Johns Hopkins University1, Scripps Mercy Hospital2, Kingsbrook Jewish Medical Center3, Brigham Young University4, University of Minnesota5, Columbia University6, Boston Children's Hospital7, American Physical Therapy Association8, Marianjoy Rehabilitation Hospital and Clinics9, University of Melbourne10, University of Technology, Sydney11, National Institutes of Health12, Houston Methodist Hospital13, University of Chicago14, Northwestern University15, American Academy of Hospice and Palliative Medicine16, University of Cincinnati17, Society of Critical Care Medicine18
TL;DR: Improving care for intensive care survivors and their families requires collaboration between practitioners and researchers in both the inpatient and outpatient settings, and three major themes emerged from the conference.
Abstract: Background:Millions of patients are discharged from intensive care units annually. These intensive care survivors and their families frequently report a wide range of impairments in their health status which may last for months and years after hospital discharge.Objectives:To report on a 2-day Socie
TL;DR: A competitive analysis is conducted and competitive ratios of optimal online deterministic algorithms for the single VM migration and dynamic VM consolidation problems are proved, and novel adaptive heuristics for dynamic consolidation of VMs are proposed based on an analysis of historical data from the resource usage by VMs.
Abstract: The rapid growth in demand for computational power driven by modern service applications combined with the shift to the Cloud computing model have led to the establishment of large-scale virtualized data centers. Such data centers consume enormous amounts of electrical energy resulting in high operating costs and carbon dioxide emissions. Dynamic consolidation of virtual machines (VMs) using live migration and switching idle nodes to the sleep mode allows Cloud providers to optimize resource usage and reduce energy consumption. However, the obligation of providing high quality of service to customers leads to the necessity in dealing with the energy-performance trade-off, as aggressive consolidation may lead to performance degradation. Because of the variability of workloads experienced by modern applications, the VM placement should be optimized continuously in an online manner. To understand the implications of the online nature of the problem, we conduct a competitive analysis and prove competitive ratios of optimal online deterministic algorithms for the single VM migration and dynamic VM consolidation problems. Furthermore, we propose novel adaptive heuristics for dynamic consolidation of VMs based on an analysis of historical data from the resource usage by VMs. The proposed algorithms significantly reduce energy consumption, while ensuring a high level of adherence to the service level agreement. We validate the high efficiency of the proposed algorithms by extensive simulations using real-world workload traces from more than a thousand PlanetLab VMs. Copyright © 2011 John Wiley & Sons, Ltd.
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TL;DR: This paper presents a Cloud centric vision for worldwide implementation of Internet of Things, and expands on the need for convergence of WSN, the Internet and distributed computing directed at technological research community.
Abstract: Ubiquitous sensing enabled by Wireless Sensor Network (WSN) technologies cuts across many areas of modern day living. This offers the ability to measure, infer and understand environmental indicators, from delicate ecologies and natural resources to urban environments. The proliferation of these devices in a communicating-actuating network creates the Internet of Things (IoT), wherein, sensors and actuators blend seamlessly with the environment around us, and the information is shared across platforms in order to develop a common operating picture (COP). Fuelled by the recent adaptation of a variety of enabling device technologies such as RFID tags and readers, near field communication (NFC) devices and embedded sensor and actuator nodes, the IoT has stepped out of its infancy and is the the next revolutionary technology in transforming the Internet into a fully integrated Future Internet. As we move from www (static pages web) to web2 (social networking web) to web3 (ubiquitous computing web), the need for data-on-demand using sophisticated intuitive queries increases significantly. This paper presents a cloud centric vision for worldwide implementation of Internet of Things. The key enabling technologies and application domains that are likely to drive IoT research in the near future are discussed. A cloud implementation using Aneka, which is based on interaction of private and public clouds is presented. We conclude our IoT vision by expanding on the need for convergence of WSN, the Internet and distributed computing directed at technological research community.
TL;DR: An approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data is presented.
Abstract: We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.
TL;DR: A review of historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery, and a discussion of how natural product chemistry has resulted in the identification of many drug candidates are highlighted.
Abstract: Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed.
TL;DR: This methodology is shown to provide superior delineations of a number of known white matter tracts, in a manner robust to crossing fiber effects, and has been compiled into a software package, called MRtrix, which has been made freely available for use by the scientific community.
Abstract: In recent years, diffusion-weighted magnetic resonance imaging has attracted considerable attention due to its unique potential to delineate the white matter pathways of the brain. However, methodologies currently available and in common use among neuroscientists and clinicians are typically based on the diffusion tensor model, which has comprehensively been shown to be inadequate to characterize diffusion in brain white matter. This is due to the fact that it is only capable of resolving a single fiber orientation per voxel, causing incorrect fiber orientations, and hence pathways, to be estimated through these voxels. Given that the proportion of affected voxels has been recently estimated at 90%, this is a serious limitation. Furthermore, most implementations use simple “deterministic” streamlines tracking algorithms, which have now been superseded by “probabilistic” approaches. In this study, we present a robust set of tools to perform tractography, using fiber orientations estimated using the validated constrained spherical deconvolution method, coupled with a probabilistic streamlines tracking algorithm. This methodology is shown to provide superior delineations of a number of known white matter tracts, in a manner robust to crossing fiber effects. These tools have been compiled into a software package, called MRtrix, which has been made freely available for use by the scientific community. © 2012 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 22, 53–66, 2012 © 2012 Wiley Periodicals, Inc.
University of Cologne1, Max Planck Society2, University of Bonn3, Ghent University4, Broad Institute5, Stanford University6, Technical University of Dortmund7, Columbia University8, University of Melbourne9, St. Vincent's Health System10, University of Jena11, Casa Sollievo della Sofferenza12, University of Groningen13, VU University Amsterdam14, University of Bologna15, University of Liverpool16, University of Oslo17, University of Zurich18, Peter MacCallum Cancer Centre19, Institut Gustave Roussy20, University of Grenoble21, Vanderbilt University22, Harvard University23, University of Washington24, University of Strasbourg25
TL;DR: This study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
Abstract: Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis(1-3). We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 +/- 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice(4). Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
TL;DR: The evidence supporting most recommendations for antithrombotic therapy in neonates and children remains weak and Studies addressing appropriate drug target ranges and monitoring requirements are urgently required in addition to site- and clinical situation-specific thrombosis management strategies.
TL;DR: Accumulating evidence suggests that it will be imperative to target all CSC subsets within the tumor to prevent relapse and that the CSC concept will have clinical relevance in specific cases.
La Trobe University1, Harvard University2, German Cancer Research Center3, Yale University4, Morehouse School of Medicine5, Autonomous University of Barcelona6, University of Massachusetts Medical School7, Semmelweis University8, Cardiff University9, Ikerbasque10, Karolinska Institutet11, Pohang University of Science and Technology12, Allahabad University13, Ghent University14, University of Melbourne15, London Metropolitan University16, Erasmus University Rotterdam17, University of Mainz18, National University of Singapore19, University of Oslo20, University of Gothenburg21, University of Valencia22, Umeå University23, University of Freiburg24, University of Amsterdam25, Utrecht University26, Johns Hopkins University27, Mayo Clinic28, Ohio State University29, University of Cambridge30, University of Zurich31, Curie Institute32, Michigan State University33, Autonomous University of Madrid34, University of Helsinki35, Aalborg University36, University of Louisville37, Carlos III Health Institute38, Centre national de la recherche scientifique39, Heidelberg University40
TL;DR: Vesiclepedia is a community-annotated compendium of molecular data on extracellular vesicles that aims to provide a single authoritative source for information on vesicle structure and function.
Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.
Harvard University1, University of Queensland2, Johns Hopkins University3, ICF International4, Centre for Mental Health5, Boston University6, University of Sydney7, University of Melbourne8, Imperial College London9, University of New South Wales10, University of California, San Diego11, Emory University12, University of Pennsylvania13, Autonomous University of Barcelona14, University of London15, National Institutes of Health16, French Institute of Health and Medical Research17, Medical Research Council18, Auckland University of Technology19, Federal University of São Paulo20, National Institute of Population and Social Security Research21, Howard University22, Flinders University23, Erasmus University Rotterdam24, King's College London25, Karolinska Institutet26, University of California, San Francisco27, All India Institute of Medical Sciences28, Nova Southeastern University29, University of Miami30, Swansea University31, Tehran University of Medical Sciences32, Queen Mary University of London33, Allen Institute for Brain Science34, University of Cape Town35, Columbia University36, Watford General Hospital37, Centro Studi GISED38, University of Oxford39, Deakin University40, University of British Columbia41, University of Toronto42, Box Hill Hospital43, Vanderbilt University44, University of Washington45, Brandeis University46, University of Tokyo47, The Queen's Medical Center48, Norwegian University of Science and Technology49, China Medical Board50, University of Cambridge51, Royal Cornwall Hospital52, Cedars-Sinai Medical Center53, Shanghai Jiao Tong University54
TL;DR: In this paper, a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach.
TL;DR: There is evidence that a range of interventions can improve mental health literacy, including whole-of-community campaigns, interventions in educational settings, Mental Health First Aid training, and information websites.
Abstract: For major physical diseases, it is widely accepted that members of the public will benefit by knowing what actions they can take for prevention, early intervention, and treatment. However, this type of public knowledge about mental disorders (mental health literacy) has received much less attention. There is evidence from surveys in several countries for deficiencies in (a) the public's knowledge of how to prevent mental disorders, (b) recognition of when a disorder is developing, (c) knowledge of help-seeking options and treatments available, (d) knowledge of effective self-help strategies for milder problems, and (e) first aid skills to support others affected by mental health problems. Nevertheless, there is evidence that a range of interventions can improve mental health literacy, including whole-of-community campaigns, interventions in educational settings, Mental Health First Aid training, and information websites. There is also evidence for historical improvements in mental health literacy in some countries. Increasing the community's mental health literacy needs to be a focus for national policy and population monitoring so that the whole community is empowered to take action for better mental health.
TL;DR: It is shown that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance, and data suggest that MAIT cells use these metabolites to detect microbial infection.
Abstract: Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection.
TL;DR: It is demonstrated that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and shown that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
Abstract: Cancer immunoediting, the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T-cell recognition of tumour antigens drives the immunological destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective antitumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2(-/-) mice that phenotypically resemble nascent primary tumour cells. Using class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T-cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
TL;DR: This Review provides a broad overview of the field of neurogastroenterology, with a focus on the roles of the ENS in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement.
Abstract: Neurogastroenterology is defined as neurology of the gastrointestinal tract, liver, gallbladder and pancreas and encompasses control of digestion through the enteric nervous system (ENS), the central nervous system (CNS) and integrative centers in sympathetic ganglia. This Review provides a broad overview of the field of neurogastroenterology, with a focus on the roles of the ENS in the control of the musculature of the gastrointestinal tract and transmucosal fluid movement. Digestion is controlled through the integration of multiple signals from the ENS and CNS; neural signals also pass between distinct gut regions to coordinate digestive activity. Moreover, neural and endocrine control of digestion is closely coordinated. Interestingly, the extent to which the ENS or CNS controls digestion differs considerably along the digestive tract. The importance of the ENS is emphasized by the life-threatening effects of certain ENS neuropathies, including Hirschsprung disease and Chagas disease. Other ENS disorders, such as esophageal achalasia and gastroparesis, cause varying degrees of dysfunction. The neurons in enteric reflex pathways use a wide range of chemical messengers that signal through an even wider range of receptors. These receptors provide many actual and potential targets for modifying digestive function.