Showing papers by "La Trobe 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
Nicholas J Kassebaum1, Megha Arora1, Ryan M Barber1, Zulfiqar A Bhutta2 +679 more•Institutions (268)
TL;DR: In this paper, the authors used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.
1,533 citations
Karolinska Institutet1, Karolinska University Hospital2, Pasteur Institute3, University of Toulouse4, Wolfson Centre for Age-Related Diseases5, University of Cambridge6, University of New South Wales7, Pierre-and-Marie-Curie University8, La Trobe University9, Umeå University10, University of British Columbia11, University of Geneva12, Douglas Mental Health University Institute13, Alzheimer Europe14, University of Cologne15, German Center for Neurodegenerative Diseases16, London School of Economics and Political Science17, Radboud University Nijmegen18, Rockefeller University19, VU University Medical Center20, University of Southern California21, Brigham and Women's Hospital22, University of Copenhagen23, UCL Institute of Neurology24, University of Gothenburg25
TL;DR: This poster aims to demonstrate the efforts towards in-situ applicability of EMMARM, which aims to provide real-time information about the physical and cognitive properties of Alzheimer's disease and other dementias.
Abstract: Defeating Alzheimer's disease and other dementias : a priority for European science and society
1,215 citations
TL;DR: ExoCarta is described, a manually curated Web-based compendium of exosomal proteins, RNAs and lipids, which features dynamic protein-protein interaction networks and biological pathways of exOSomal proteins.
942 citations
Istituto Giannina Gaslini1, Utrecht University2, McGill University3, University of Glasgow4, La Trobe University5, University of Melbourne6, Harvard University7, Boston Children's Hospital8, Royal Children's Hospital9, University of Oxford10, University of Western Australia11, Princess Margaret Hospital for Children12, University of Washington13, University of Minnesota14, University of Colorado Denver15, Children's of Alabama16, University of Groningen17
TL;DR: This trial found no evidence that just under an hour of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at two years of age compared to RA.
839 citations
TL;DR: The combined data indicate that activity modification, improved rehabilitation and return-to-play guidelines, and the use of integrative neuromuscular training may help athletes more safely reintegrate into sport and reduce second injury in this at-risk population.
Abstract: Background:Injury to the ipsilateral graft used for reconstruction of the anterior cruciate ligament (ACL) or a new injury to the contralateral ACL are disastrous outcomes after successful ACL reconstruction (ACLR), rehabilitation, and return to activity. Studies reporting ACL reinjury rates in younger active populations are emerging in the literature, but these data have not yet been comprehensively synthesized.Purpose:To provide a current review of the literature to evaluate age and activity level as the primary risk factors in reinjury after ACLR.Study Design:Systematic review and meta-analysis.Methods:A systematic review of the literature was conducted via searches in PubMed (1966 to July 2015) and EBSCO host (CINAHL, Medline, SPORTDiscus [1987 to July 2015]). After the search and consultation with experts and rating of study quality, 19 articles met inclusion for review and aggregation. Population demographic data and total reinjury (ipsilateral and contralateral) rate data were recorded from each in...
725 citations
TL;DR: The first large, detailed survey of current worldwide practices for the isolation and characterization of EVs is reported, with Ultracentrifugation remains the most commonly used isolation method and only 9% of respondents used only 1 characterization method, with others using 2 or more methods.
Abstract: Extracellular vesicles (EVs) represent an important mode of intercellular communication. Research in this field has grown rapidly in the last few years, and there is a plethora of techniques for the isolation and characterization of EVs, many of which are poorly standardized. EVs are heterogeneous in size, origin and molecular constituents, with considerable overlap in size and phenotype between different populations of EVs. Little is known about current practices for the isolation, purification and characterization of EVs. We report here the first large, detailed survey of current worldwide practices for the isolation and characterization of EVs. Conditioned cell culture media was the most widely used material (83%). Ultracentrifugation remains the most commonly used isolation method (81%) with 59% of respondents use a combination of methods. Only 9% of respondents used only 1 characterization method, with others using 2 or more methods. Sample volume, sample type and downstream application all influenced the isolation and characterization techniques employed.
654 citations
TL;DR: Understanding this reciprocal interaction of IFNs will enable the development of improved single-agent or combination therapies that exploit IFN pathways and new 'omics'-based biomarkers to indicate responsive patients.
Abstract: The interferons (IFNs) are a family of cytokines that protect against disease by direct effects on target cells and by activating immune responses. The production and actions of IFNs are finely tuned to achieve maximal protection and avoid the potential toxicity associated with excessive responses. IFNs are back in the spotlight owing to mounting evidence that is reshaping how we can exploit this pathway therapeutically. As IFNs can be produced by, and act on, both tumour cells and immune cells, understanding this reciprocal interaction will enable the development of improved single-agent or combination therapies that exploit IFN pathways and new 'omics'-based biomarkers to indicate responsive patients.
628 citations
TL;DR: The nature of EV subtypes, strategies for isolating EVs from both cell-culture media and body fluids, and procedures for quantifying EVs are discussed, as well as various applications of EVs in clinical diagnosis.
Abstract: Two broad categories of extracellular vesicles (EVs), exosomes and shed microvesicles (sMVs), which differ in size distribution as well as protein and RNA profiles, have been described. EVs are known to play key roles in cell-cell communication, acting proximally as well as systemically. This Review discusses the nature of EV subtypes, strategies for isolating EVs from both cell-culture media and body fluids, and procedures for quantifying EVs. We also discuss proteins selectively enriched in exosomes and sMVs that have the potential for use as markers to discriminate between EV subtypes, as well as various applications of EVs in clinical diagnosis.
589 citations
TL;DR: This review serves as an introductory overview of EVs, their biogenesis and molecular composition, and their physiological roles are still ill-defined.
Abstract: Intercellular communication was long thought to be regulated exclusively through direct contact between cells or via release of soluble molecules that transmit the signal by binding to a suitable receptor on the target cell, and/or via uptake into that cell. With the discovery of small secreted vesicular structures that contain complex cargo, both in their lumen and the lipid membrane that surrounds them, a new frontier of signal transduction was discovered. These “extracellular vesicles” (EV) were initially thought to be garbage bags through which the cell ejected its waste. Whilst this is a major function of one type of EV, i.e., apoptotic bodies, many EVs have intricate functions in intercellular communication and compound exchange; although their physiological roles are still ill-defined. Additionally, it is now becoming increasingly clear that EVs mediate disease progression and therefore studying EVs has ignited significant interests among researchers from various fields of life sciences. Consequently, the research effort into the pathogenic roles of EVs is significantly higher even though their protective roles are not well established. The “Focus on extracellular vesicles” series of reviews highlights the current state of the art regarding various topics in EV research, whilst this review serves as an introductory overview of EVs, their biogenesis and molecular composition.
TL;DR: This report provides national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.
United States Geological Survey1, Wake Forest University2, University of Minnesota3, Utah State University4, Martin Luther University of Halle-Wittenberg5, Utrecht University6, University of Oldenburg7, University of Tartu8, University of Washington9, Trinity College, Dublin10, Imperial College London11, University of Wisconsin-Madison12, University of Colorado Boulder13, United States Department of Agriculture14, Queensland University of Technology15, University of Maryland, College Park16, University of Oxford17, University of Nebraska–Lincoln18, University of Guelph19, La Trobe University20, Commonwealth Scientific and Industrial Research Organisation21, Colorado State University22
TL;DR: It is found that an integrative model has substantially higher explanatory power than traditional bivariate analyses and several surprising findings that conflict with classical models are revealed.
Abstract: How ecosystem productivity and species richness are interrelated is one of the most debated subjects in the history of ecology. Decades of intensive study have yet to discern the actual mechanisms behind observed global patterns. Here, by integrating the predictions from multiple theories into a single model and using data from 1,126 grassland plots spanning five continents, we detect the clear signals of numerous underlying mechanisms linking productivity and richness. We find that an integrative model has substantially higher explanatory power than traditional bivariate analyses. In addition, the specific results unveil several surprising findings that conflict with classical models. These include the isolation of a strong and consistent enhancement of productivity by richness, an effect in striking contrast with superficial data patterns. Also revealed is a consistent importance of competition across the full range of productivity values, in direct conflict with some (but not all) proposed models. The promotion of local richness by macroecological gradients in climatic favourability, generally seen as a competing hypothesis, is also found to be important in our analysis. The results demonstrate that an integrative modelling approach leads to a major advance in our ability to discern the underlying processes operating in ecological systems.
TL;DR: This consensus statement was to present and synthesise current evidence to make recommendations for return to sport decision-making, clinical practice and future research directions related to returning athletes to sport.
Abstract: Deciding when to return to sport after injury is complex and multifactorial-an exercise in risk management. Return to sport decisions are made every day by clinicians, athletes and coaches, ideally in a collaborative way. The purpose of this consensus statement was to present and synthesise current evidence to make recommendations for return to sport decision-making, clinical practice and future research directions related to returning athletes to sport. A half day meeting was held in Bern, Switzerland, after the First World Congress in Sports Physical Therapy. 17 expert clinicians participated. 4 main sections were initially agreed upon, then participants elected to join 1 of the 4 groups-each group focused on 1 section of the consensus statement. Participants in each group discussed and summarised the key issues for their section before the 17-member group met again for discussion to reach consensus on the content of the 4 sections. Return to sport is not a decision taken in isolation at the end of the recovery and rehabilitation process. Instead, return to sport should be viewed as a continuum, paralleled with recovery and rehabilitation. Biopsychosocial models may help the clinician make sense of individual factors that may influence the athlete's return to sport, and the Strategic Assessment of Risk and Risk Tolerance framework may help decision-makers synthesise information to make an optimal return to sport decision. Research evidence to support return to sport decisions in clinical practice is scarce. Future research should focus on a standardised approach to defining, measuring and reporting return to sport outcomes, and identifying valuable prognostic factors for returning to sport.
TL;DR: A comprehensive survey of smart electricity meters and their utilization is presented focusing on key aspects of the metering process, different stakeholder interests, and the technologies used to satisfy stakeholder interest.
Abstract: Smart meters have been deployed in many countries across the world since early 2000s. The smart meter as a key element for the smart grid is expected to provide economic, social, and environmental benefits for multiple stakeholders. There has been much debate over the real values of smart meters. One of the key factors that will determine the success of smart meters is smart meter data analytics, which deals with data acquisition, transmission, processing, and interpretation that bring benefits to all stakeholders. This paper presents a comprehensive survey of smart electricity meters and their utilization focusing on key aspects of the metering process, different stakeholder interests, and the technologies used to satisfy stakeholder interests. Furthermore, the paper highlights challenges as well as opportunities arising due to the advent of big data and the increasing popularity of cloud environments.
University of Queensland1, University of Adelaide2, Griffith University3, University Medical Center Groningen4, University of Utah5, National Institute for Health Research6, University of London7, Zürcher Fachhochschule8, Hannover Medical School9, La Trobe University10, University of British Columbia11, University of Melbourne12, French Institute of Health and Medical Research13, University of Florence14, University of Auckland15, Monash University16, Southmead Hospital17, University of Bristol18, University of Manchester19, Central Manchester University Hospitals NHS Foundation Trust20, Mater Health Services21, Columbia University22
TL;DR: In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts and programs at community and country level need to improve health in disadvantaged families.
TL;DR: It is shown that 25 subunits are strictly required for assembly of a functional complex and 1 subunit is essential for cell viability, and coupling gene-editing technology with proteomics represents a powerful tool for dissecting large multi-subunit complexes and enables the study of complex dysfunction at a cellular level.
Abstract: Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the mitochondrial respiratory chain and is composed of 45 subunits in humans, making it one of the largest known multi-subunit membrane protein complexes. Complex I exists in supercomplex forms with respiratory chain complexes III and IV, which are together required for the generation of a transmembrane proton gradient used for the synthesis of ATP. Complex I is also a major source of damaging reactive oxygen species and its dysfunction is associated with mitochondrial disease, Parkinson's disease and ageing. Bacterial and human complex I share 14 core subunits that are essential for enzymatic function; however, the role and necessity of the remaining 31 human accessory subunits is unclear. The incorporation of accessory subunits into the complex increases the cellular energetic cost and has necessitated the involvement of numerous assembly factors for complex I biogenesis. Here we use gene editing to generate human knockout cell lines for each accessory subunit. We show that 25 subunits are strictly required for assembly of a functional complex and 1 subunit is essential for cell viability. Quantitative proteomic analysis of cell lines revealed that loss of each subunit affects the stability of other subunits residing in the same structural module. Analysis of proteomic changes after the loss of specific modules revealed that ATP5SL and DMAC1 are required for assembly of the distal portion of the complex I membrane arm. Our results demonstrate the broad importance of accessory subunits in the structure and function of human complex I. Coupling gene-editing technology with proteomics represents a powerful tool for dissecting large multi-subunit complexes and enables the study of complex dysfunction at a cellular level.
TL;DR: Early graft ruptures were more prevalent in patients who underwent surgery when they were younger than 18 years versus those in the 18- to 19-year age group, and males had higher rates of graft rupture than did females.
Abstract: Background:Younger age is being increasingly recognized as a risk factor for anterior cruciate ligament (ACL) graft rupture and contralateral ACL injury after ACL reconstruction. Recent reports estimate second ACL injury rates to be in the range of 20% to 40%, which is a significant concern and requires further exploration.Purpose:The primary purpose was to determine the rates of graft rupture and injury to the contralateral native ACL in younger athletes. We also sought to explore the influence of sex and age groupings (<18 years vs 18-19 years at the time of surgery) on the risk of subsequent ACL injury.Study Design:Cohort study; Level of evidence, 3.Methods:The study cohort consisted of 354 consecutive patients who were younger than 20 years when they underwent their first primary hamstring tendon autograft ACL reconstruction. The number of subsequent ACL injuries (graft rupture or a contralateral injury to the native ACL) was determined at a mean follow-up of 5 years (range, 3-10 years). Subgroup anal...
Martin Luther University of Halle-Wittenberg1, Helmholtz Centre for Environmental Research - UFZ2, University of Minnesota3, Queensland University of Technology4, Utah State University5, Utrecht University6, University of Oldenburg7, University of Guelph8, Iowa State University9, University of Washington10, University of Toronto11, University of Buenos Aires12, Sun Yat-sen University13, University of California, San Diego14, University of California, Santa Barbara15, University of Colorado Boulder16, University of KwaZulu-Natal17, University of California, Berkeley18, University of Kentucky19, Monash University20, La Trobe University21, Commonwealth Scientific and Industrial Research Organisation22, Lancaster University23, Yale University24
TL;DR: In this paper, the authors show that plant species diversity decreased when a greater number of limiting nutrients were added across 45 grassland sites from a multi-continent experimental network, even after controlling for effects of plant biomass, and even where biomass production was not nutrient-limited.
Abstract: Niche dimensionality provides a general theoretical explanation for biodiversity-more niches, defined by more limiting factors, allow for more ways that species can coexist. Because plant species compete for the same set of limiting resources, theory predicts that addition of a limiting resource eliminates potential trade-offs, reducing the number of species that can coexist. Multiple nutrient limitation of plant production is common and therefore fertilization may reduce diversity by reducing the number or dimensionality of belowground limiting factors. At the same time, nutrient addition, by increasing biomass, should ultimately shift competition from belowground nutrients towards a one-dimensional competitive trade-off for light. Here we show that plant species diversity decreased when a greater number of limiting nutrients were added across 45 grassland sites from a multi-continent experimental network. The number of added nutrients predicted diversity loss, even after controlling for effects of plant biomass, and even where biomass production was not nutrient-limited. We found that elevated resource supply reduced niche dimensionality and diversity and increased both productivity and compositional turnover. Our results point to the importance of understanding dimensionality in ecological systems that are undergoing diversity loss in response to multiple global change factors.
TL;DR: The 4th International Patellofemoral Research Retreat was held in Manchester, UK, over 3 days (September 2–4th, 2015) and developed a consensus statement addressing different presentation categories, including PFP and factors that influence PFP.
Abstract: Patellofemoral pain (PFP) typically presents as diffuse anterior knee pain, usually with activities such as squatting, running, stair ascent and descent. It is common in active individuals across the lifespan,1–4 and is a frequent cause for presentation at physiotherapy, general practice, orthopaedic and sports medicine clinics in particular.5 ,6 Its impact is profound, often reducing the ability of those with PFP to perform sporting, physical activity and work-related activities pain-free. Increasing evidence suggests that it is a recalcitrant condition, persisting for many years.7–9 In an attempt to share recent innovations, build on the first three successful biennial retreats and define the ‘state of the art’ for this common, impactful condition; the 4th International Patellofemoral Pain Research Retreat was convened.
The 4th International Patellofemoral Research Retreat was held in Manchester, UK, over 3 days (September 2–4th, 2015). After undergoing peer-review for scientific merit and relevance to the retreat, 67 abstracts were accepted for the retreat (50 podium presentations, and 17 short presentations). The podium and short presentations were grouped into five categories; (1) PFP, (2) factors that influence PFP (3) the trunk and lower extremity (4) interventions and (5) systematic analyses. Three keynote speakers were chosen for their scientific contribution in the area of PFP. Professor Andrew Amis spoke on the biomechanics of the patellofemoral joint. Professor David Felson spoke on patellofemoral arthritis,10 and Dr Michael Ratleff's keynote theme was PFP in the adolescent patient.11 As part of the retreat, we held structured, whole-group discussions in order to develop consensus relating to the work presented at the meeting as well as evidence gathered from the literature.
### Consensus development process
In our past three International Patellofemoral Research Retreats, we developed a consensus statement addressing different presentation categories.12–14 In Manchester in 2015, we revised the format. For the exercise and …
TL;DR: Higher-intensity aerobic training programmes, supplemented by resistance training, have been recommended and deemed safe for cardiac rehabilitation patients by many authorities and should therefore be considered when developing an international consensus for exercise prescription in cardiac rehabilitation.
Abstract: BackgroundCardiac rehabilitation is an important component in the continuum of care for individuals with cardiovascular disease, providing a multidisciplinary education and exercise programme to im...
University of Adelaide1, University of California, Santa Cruz2, Broad Institute3, Harvard University4, Howard Hughes Medical Institute5, La Trobe University6, Pontifical Catholic University of Peru7, University of Magallanes8, National University of Central Buenos Aires9, University of Tarapacá10, University of Sydney11
TL;DR: The exact timing, route, and process of the initial peopling of the Americas remains uncertain despite much research as discussed by the authors, which is constrained by the lack of suitable calibration points and low genetic diversity of Native Americans.
Abstract: The exact timing, route, and process of the initial peopling of the Americas remains uncertain despite much research. Archaeological evidence indicates the presence of humans as far as southern Chile by 14.6 thousand years ago (ka), shortly after the Pleistocene ice sheets blocking access from eastern Beringia began to retreat. Genetic estimates of the timing and route of entry have been constrained by the lack of suitable calibration points and low genetic diversity of Native Americans. We sequenced 92 whole mitochondrial genomes from pre-Columbian South American skeletons dating from 8.6 to 0.5 ka, allowing a detailed, temporally calibrated reconstruction of the peopling of the Americas in a Bayesian coalescent analysis. The data suggest that a small population entered the Americas via a coastal route around 16.0 ka, following previous isolation in eastern Beringia for ~2.4 to 9 thousand years after separation from eastern Siberian populations. Following a rapid movement throughout the Americas, limited gene flow in South America resulted in a marked phylogeographic structure of populations, which persisted through time. All of the ancient mitochondrial lineages detected in this study were absent from modern data sets, suggesting a high extinction rate. To investigate this further, we applied a novel principal components multiple logistic regression test to Bayesian serial coalescent simulations. The analysis supported a scenario in which European colonization caused a substantial loss of pre-Columbian lineages.
TL;DR: The continuum model of tendon pathology, proposed in 2009, synthesised clinical and laboratory-based research to guide treatment choices for the clinical presentations of tendinopathy and may help guide targeted treatments and improved patient outcomes.
Abstract: The pathogenesis of tendinopathy and the primary biological change in the tendon that precipitates pathology have generated several pathoaetiological models in the literature. The continuum model of tendon pathology, proposed in 2009, synthesised clinical and laboratory-based research to guide treatment choices for the clinical presentations of tendinopathy. While the continuum has been cited extensively in the literature, its clinical utility has yet to be fully elucidated. The continuum model proposed a model for staging tendinopathy based on the changes and distribution of disorganisation within the tendon. However, classifying tendinopathy based on structure in what is primarily a pain condition has been challenged. The interplay between structure, pain and function is not yet fully understood, which has partly contributed to the complex clinical picture of tendinopathy. Here we revisit and assess the merit of the continuum model in the context of new evidence. We (1) summarise new evidence in tendinopathy research in the context of the continuum, (2) discuss tendon pain and the relevance of a model based on structure and (3) describe relevant clinical elements (pain, function and structure) to begin to build a better understanding of the condition. Our goal is that the continuum model may help guide targeted treatments and improved patient outcomes.
TL;DR: The results suggest that the new BayesRC method was equal to or more powerful than BayesR for detecting candidate causal variants and for genomic prediction of milk traits.
Abstract: Dense SNP genotypes are often combined with complex trait phenotypes to map causal variants, study genetic architecture and provide genomic predictions for individuals with genotypes but no phenotype. A single method of analysis that jointly fits all genotypes in a Bayesian mixture model (BayesR) has been shown to competitively address all 3 purposes simultaneously. However, BayesR and other similar methods ignore prior biological knowledge and assume all genotypes are equally likely to affect the trait. While this assumption is reasonable for SNP array genotypes, it is less sensible if genotypes are whole-genome sequence variants which should include causal variants. We introduce a new method (BayesRC) based on BayesR that incorporates prior biological information in the analysis by defining classes of variants likely to be enriched for causal mutations. The information can be derived from a range of sources, including variant annotation, candidate gene lists and known causal variants. This information is then incorporated objectively in the analysis based on evidence of enrichment in the data. We demonstrate the increased power of BayesRC compared to BayesR using real dairy cattle genotypes with simulated phenotypes. The genotypes were imputed whole-genome sequence variants in coding regions combined with dense SNP markers. BayesRC increased the power to detect causal variants and increased the accuracy of genomic prediction. The relative improvement for genomic prediction was most apparent in validation populations that were not closely related to the reference population. We also applied BayesRC to real milk production phenotypes in dairy cattle using independent biological priors from gene expression analyses. Although current biological knowledge of which genes and variants affect milk production is still very incomplete, our results suggest that the new BayesRC method was equal to or more powerful than BayesR for detecting candidate causal variants and for genomic prediction of milk traits. BayesRC provides a novel and flexible approach to simultaneously improving the accuracy of QTL discovery and genomic prediction by taking advantage of prior biological knowledge. Approaches such as BayesRC will become increasing useful as biological knowledge accumulates regarding functional regions of the genome for a range of traits and species.
Monash University1, Laval University2, University of Warwick3, Griffith University4, University of Ottawa5, American Physical Therapy Association6, University of the West of England7, Radboud University Nijmegen8, University of British Columbia9, University of Sydney10, Okanagan College11, Bond University12, University of Otago13, University of South Australia14, La Trobe University15, University of Southern Denmark16, West Virginia University17, The George Institute for Global Health18, EHESP19, VU University Medical Center20, University of Edinburgh21, Utrecht University22, VU University Amsterdam23, University of Oxford24, King's College London25
TL;DR: The CERT, a 16-item checklist developed by an international panel of exercise experts, is designed to improve the reporting of exercise programs in all evaluative study designs and contains 7 categories: materials, provider, delivery, location, dosage, tailoring, and compliance.
Abstract: BACKGROUND: Exercise interventions are often incompletely described in reports of clinical trials, hampering evaluation of results and replication and implementation into practice. OBJECTIVE: The aim of this study was to develop a standardized method for reporting exercise programs in clinical trials: the Consensus on Exercise Reporting Template (CERT). DESIGN AND METHODS: Using the EQUATOR Network's methodological framework, 137 exercise experts were invited to participate in a Delphi consensus study. A list of 41 items was identified from a meta-epidemiologic study of 73 systematic reviews of exercise. For each item, participants indicated agreement on an 11-point rating scale. Consensus for item inclusion was defined a priori as greater than 70% agreement of respondents rating an item 7 or above. Three sequential rounds of anonymous online questionnaires and a Delphi workshop were used. RESULTS: There were 57 (response rate=42%), 54 (response rate=95%), and 49 (response rate=91%) respondents to rounds 1 through 3, respectively, from 11 countries and a range of disciplines. In round 1, 2 items were excluded; 24 items reached consensus for inclusion (8 items accepted in original format), and 16 items were revised in response to participant suggestions. Of 14 items in round 2, 3 were excluded, 11 reached consensus for inclusion (4 items accepted in original format), and 7 were reworded. Sixteen items were included in round 3, and all items reached greater than 70% consensus for inclusion. LIMITATIONS: The views of included Delphi panelists may differ from those of experts who declined participation and may not fully represent the views of all exercise experts. CONCLUSIONS: The CERT, a 16-item checklist developed by an international panel of exercise experts, is designed to improve the reporting of exercise programs in all evaluative study designs and contains 7 categories: materials, provider, delivery, location, dosage, tailoring, and compliance. The CERT will encourage transparency, improve trial interpretation and replication, and facilitate implementation of effective exercise interventions into practice.
TL;DR: MiD51 and Mff coordinate and regulate the action of Drp1 at the mitochondrial outer membrane during homeostatic mitochondrial fission, as assessed with gene-editing technology.
Abstract: Cytosolic dynamin-related protein 1 (Drp1, also known as DNM1L) is required for both mitochondrial and peroxisomal fission. Drp1-dependent division of these organelles is facilitated by a number of adaptor proteins at mitochondrial and peroxisomal surfaces. To investigate the interplay of these adaptor proteins, we used gene-editing technology to create a suite of cell lines lacking the adaptors MiD49 (also known as MIEF2), MiD51 (also known as MIEF1), Mff and Fis1. Increased mitochondrial connectivity was observed following loss of individual adaptors, and this was further enhanced following the combined loss of MiD51 and Mff. Moreover, loss of adaptors also conferred increased resistance of cells to intrinsic apoptotic stimuli, with MiD49 and MiD51 showing the more prominent role. Using a proximity-based biotin labeling approach, we found close associations between MiD51, Mff and Drp1, but not Fis1. Furthermore, we found that MiD51 can suppress Mff-dependent enhancement of Drp1 GTPase activity. Our data indicates that Mff and MiD51 regulate Drp1 in specific ways to promote mitochondrial fission.
TL;DR: In this article, a systematic review was conducted to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration.
Abstract: Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden on both patient and health resources. A comprehensive analysis of reported interventions is not currently available, but is needed to better inform caregivers about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at-risk for ulceration. The available medical scientific literature in PubMed, EMBASE, CINAHL, and the Cochrane database was searched for original research studies on preventative interventions. Both controlled and non-controlled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers, and extracted and presented in evidence and risk of bias tables. From the identified records, a total of 30 controlled studies (of which 19 RCTs) and another 44 non-controlled studies were assessed and described. Few controlled studies, of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions, as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient. To prevent recurrence, some evidence exists for integrated foot care when it includes a combination of professional foot treatment, therapeutic footwear and patient education; for just a single session of patient education, no evidence exists. Surgical interventions can be effective in selected patients, but the evidence base is small. The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong, but is small for the use of other, sometimes widely applied, interventions, and is practically non-existent for the prevention of a first foot ulcer and non-plantar foot ulcer. More controlled studies of high quality are needed in these areas.
TL;DR: It is determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs.
Abstract: Small membranous secretions from tumor cells, termed exosomes, contribute significantly to intercellular communication and subsequent reprogramming of the tumor microenvironment. Here, we use optical imaging to determine that exogenously administered fluorescently labeled exosomes derived from highly metastatic murine breast cancer cells distributed predominantly to the lung of syngeneic mice, a frequent site of breast cancer metastasis. At the sites of accumulation, exosomes were taken up by CD45+ bone marrow-derived cells. Subsequent long-term conditioning of naive mice with exosomes from highly metastatic breast cancer cells revealed the accumulation of myeloid-derived suppressor cells in the lung and liver. This favorable immune suppressive microenvironment was capable of promoting metastatic colonization in the lung and liver, an effect not observed from exosomes derived from nonmetastatic cells and liposome control vesicles. Furthermore, we determined that breast cancer exosomes directly suppressed T-cell proliferation and inhibited NK cell cytotoxicity, and hence likely suppressed the anticancer immune response in premetastatic organs. Together, our findings provide novel insight into the tissue-specific outcomes of breast cancer-derived exosome accumulation and their contribution to immune suppression and promotion of metastases. Cancer Res; 76(23); 6816-27. ©2016 AACR.
TL;DR: In this paper, a range of criminal behaviours that are perpetrated with the aid of digital technologies have been investigated and much of this focus has been on high-tech computations, however, most of which has been focused on high technology computations.
Abstract: Considerable scholarly attention has been paid to a range of criminal behaviours that are perpetrated with the aid of digital technologies. Much of this focus, however, has been on high-tech comput...