Messina (\u3cem\u3eMelilotus siculus\u3c/em\u3e)–A New Pasture Legume for Saltland

Messina (Melilotus siculus ((Turra) Vitman ex B.D. Jacks)) is a new annual pasture legume for saltland in temperate Australia and regions of the world that experience Mediterranean climates. Messina has greater tolerance to the combined stresses of salinity and water-logging than existing commercial pasture legumes. Coupled with desirable agronomic traits these characteristics give messina the capacity to rehabilitate saltland and increase productivity on land where existing legumes fail. This paper reviews the agronomic perform-ance of messina in relation to top soil salinity levels

Skeletal dysplasia-causing TRPV4 mutations suppress the hypertrophic differentiation of human iPSC-derived chondrocytes

Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human-induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype (WT). There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations up-regulated several anterio

A systematic review of strategies to recruit and retain primary care doctors

Background There is a workforce crisis in primary care. Previous research has looked at the reasons underlying recruitment and retention problems, but little research has looked at what works to improve recruitment and retention. The aim of this systematic review is to evaluate interventions and strategies used to recruit and retain primary care doctors internationally. Methods A systematic review was undertaken. MEDLINE, EMBASE, CENTRAL and grey literature were searched from inception to January 2015.Articles assessing interventions aimed at recruiting or retaining doctors in high income countries, applicable to primary care doctors were included. No restrictions on language or year of publication. The first author screened all titles and abstracts and a second author screened 20%. Data extraction was carried out by one author and checked by a second. Meta-analysis was not possible due to heterogeneity. Results 51 studies assessing 42 interventions were retrieved. Interventions were categorised into thirteen groups: financial incentives (n=11), recruiting rural students (n=6), international recruitment (n=4), rural or primary care focused undergraduate placements (n=3), rural or underserved postgraduate training (n=3), well-being or peer support initiatives (n=3), marketing (n=2), mixed interventions (n=5), support for professional development or research (n=5), retainer schemes (n=4), re-entry schemes (n=1), specialised recruiters or case managers (n=2) and delayed partnerships (n=2). Studies were of low methodological quality with no RCTs and only 15 studies with a comparison group. Weak evidence supported the use of postgraduate placements in underserved areas, undergraduate rural placements and recruiting students to medical school from rural areas. There was mixed evidence about financial incentives. A marketing campaign was associated with lower recruitment. Conclusions This is the first systematic review of interventions to improve recruitment and retention of primary care doctors. Although the evidence base for recruiting and care doctors is weak and more high quality research is needed, this review found evidence to support undergraduate and postgraduate placements in underserved areas, and selective recruitment of medical students. Other initiatives covered may have potential to improve recruitment and retention of primary care practitioners, but their effectiveness has not been established

AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL

CHD7 Targets Active Gene Enhancer Elements to Modulate ES Cell-Specific Gene Expression

CHD7 is one of nine members of the chromodomain helicase DNA–binding domain family of ATP–dependent chromatin remodeling enzymes found in mammalian cells. De novo mutation of CHD7 is a major cause of CHARGE syndrome, a genetic condition characterized by multiple congenital anomalies. To gain insights to the function of CHD7, we used the technique of chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP–Seq) to map CHD7 sites in mouse ES cells. We identified 10,483 sites on chromatin bound by CHD7 at high confidence. Most of the CHD7 sites show features of gene enhancer elements. Specifically, CHD7 sites are predominantly located distal to transcription start sites, contain high levels of H3K4 mono-methylation, found within open chromatin that is hypersensitive to DNase I digestion, and correlate with ES cell-specific gene expression. Moreover, CHD7 co-localizes with P300, a known enhancer-binding protein and strong predictor of enhancer activity. Correlations with 18 other factors mapped by ChIP–seq in mouse ES cells indicate that CHD7 also co-localizes with ES cell master regulators OCT4, SOX2, and NANOG. Correlations between CHD7 sites and global gene expression profiles obtained from Chd7+/+, Chd7+/−, and Chd7−/− ES cells indicate that CHD7 functions at enhancers as a transcriptional rheostat to modulate, or fine-tune the expression levels of ES–specific genes. CHD7 can modulate genes in either the positive or negative direction, although negative regulation appears to be the more direct effect of CHD7 binding. These data indicate that enhancer-binding proteins can limit gene expression and are not necessarily co-activators. Although ES cells are not likely to be affected in CHARGE syndrome, we propose that enhancer-mediated gene dysregulation contributes to disease pathogenesis and that the critical CHD7 target genes may be subject to positive or negative regulation

Agribusiness Sheep Updates - 2004 part 2

Precision Pastures Using Species Diversity to Improve Pasture Performance Anyou Liu and Clinton Revell, Department of Agriculture, Western Australia New Annual Pasture Legumes for Sheep Graziers Phil Nichols, Angelo Loi, Brad Nutt and Darryl McClements Department of Agriculture Western Australia Pastures from Space – Can Satellite Estimates of Pasture Growth Rate be used to Increase Farm Profit? Lucy Anderton, Stephen Gherardi and Chris Oldham Department of Agriculture Western Australia Summer-active Perennial Grasses for Profitable Sheep Production Paul Sanford and John Gladman, Department of Agriculture, Western Australia Pastures From Space – Validation Of Predictions Of Pasture Growth Rates DONALD, G.E.A, EDIRISINGHE, A.A, HENRY, D.A.A, MATA, G.A, GHERARDI, S.G.B, OLDHAM, C.M.B, GITTINS, S.P.B AND SMITH, R. C. G.C ACSIRO, Livestock Industries, PMB 5, Wembley, WA, 6913. BDepartment of Agriculture Western Australia, Bentley, WA, 6983. C Department of Land Information Western Australia, Floreat, WA, 6214. Production and Management of Biserrula Pasture - Managing the Risk of Photosensitivity Dr Clinton Revell and Roy Butler, Department of Agriculture Western Australia Meat Quality of Sheep Grazed on a Saltbush-based Pasture Kelly Pearce1,2, David Masters1, David Pethick2, 1 CSIRO LIVESTOCK INDUSTRIES, WEMBLEY, WA 2 SCHOOL OF VETERINARY AND BIOMEDICAL SCIENCE, MURDOCH UNIVERSITY, MURDOCH, WA Precision Sheep Lifetime Wool – Carryover Effects on Subsequent Reproduction of the Ewe Flock Chris Oldham, Department of Agriculture Western Australia Andrew Thompson, Primary Industries Research Victoria (PIRVic), Dept of Primary Industries, Hamilton, Vic Ewe Productivity Trials - a Linked Analysis Ken Hart, Johan Greeff, Department of Agriculture Western Australia, Beth Paganoni, School of Animal Biology, Faculty of Natural and Agricultural Sciences, University of Western Australia. Grain Finishing Systems For Prime Lambs Rachel Kirby, Matt Ryan, Kira Buttler, Department of Agriculture, Western Australia The Effects of Nutrition and Genotype on the Growth and Development, Muscle Biochemistry and Consumer Response to Lamb Meat David Pethick, Department of Veterinary Science, Murdoch University, WA, Roger Heggarty and David Hopkins, New South Wales Agriculture ‘Lifetime Wool’ - Effects of Nutrition During Pregnancy and Lactation on Mortality of Progeny to Hogget Shearing Samantha Giles, Beth Paganoni and Tom Plaisted, Department of Agriculture Western Australia, Mark Ferguson and Darren Gordon, Primary Industries Research Victoria (PIRVic), Dept of Primary Industries, Hamilton, Vic Lifetime Wool - Target Liveweights for the Ewe Flock J. Young, Farming Systems Analysis Service, Kojonup, C. Oldham, Department of Agriculture Western Australia, A. Thompson, Primary Industries Research Victoria (PIRVic), Hamilton, VIC Lifetime Wool - Effects of Nutrition During Pregnancy and Lactation on the Growth and Wool Production of their Progeny at Hogget Shearing B. Paganoni, University of Western Australia, Nedlands WA, C. Oldham, Department of Agriculture Western Australia, M. Ferguson, A. Thompson, Primary Industries Research Victoria (PIRVic), Hamilton, VIC RFID Technology – Esperance Experiences Sandra Brown, Department of Agriculture Western Australia The Role of Radio Frequency Identification (RFID) Technology in Prime Lamb Production - a Case Study. Ian McFarland, Department of Agriculture, Western Australia. John Archer, Producer, Narrogin, Western Australia Win with Twins from Merinos John Milton, Rob Davidson, Graeme Martin and David Lindsay The University of Western Australia Precision Sheep Need Precision Wool Harvesters Jonathan England, Castle Carrock Merinos, Kingston SE, South Australia Business EBVs and Indexes – Genetic Tools for your Toolbox Sandra Brown, Department of Agriculture Western Australia Green Feed Budget Paddock Calculator Mandy Curnow, Department of Agriculture Western Australia Minimising the Impact of Drought - Evaluating Flock Recovery Options using the ImPack Model Karina P. Wood, Ashley K. White, B. Lloyd Davies, Paul M. Carberry, NSW Department of Primary Industries (NSW DPI), Lifetime Wool - Modifying GrazFeed® for WA Mike Hyder, Department of Agriculture Western Australia , Mike Freer, CSIRO Plant Industry, Canberra, A.C.T. , Andrew van Burgel, and Kazue Tanaka, Department of Agriculture Western Australia Profile Calculator – A Way to Manage Fibre Diameter Throughout the Year to Maximise Returns Andrew Peterson, Department of Agriculture, Western Australia Pasture Watch - a Farmer Friendly Tool for Downloading and Analysing Pastures from Space Data Roger Wiese,Fairport Technologies International, South Perth, WA, Stephen Gherardi, BDepartment of Agriculture Western Australia, Gonzalo Mata, CCSIRO, Livestock Industries, Wembley, Western Australia, and Chris Oldham, Department of Agriculture Western Australia Sy Sheep Cropping Systems An Analysis of a Cropping System Containing Sheep in a Low Rainfall Livestock System. Evan Burt, Amanda Miller, Anne Bennett, Department of Agriculture, Western Australia Lucerne-based Pasture for the Central Wheatbelt – is it Good Economics? Felicity FluggeA, Amir AbadiA,B and Perry DollingA,B,A CRC for Plant-based Management of Dryland Salinity: BDept. of Agriculture, WA Sheep and Biserrula can Control Annual Ryegrass Dean Thomas, John Milton, Mike Ewing and David Lindsay, The University of WA, Clinton Revell, Department of Agriculture, Western Australia Sustainable Management Pasture Utilisation, Fleece Weight and Weaning Rate are Integral to the Profitability of Dohnes and SAMMs. Emma Kopke,Department of Agriculture Western Australia, John Young, Farming Systems Analysis Service Environmental Impact of Sheep Confinement Feeding Systems E A Dowling and E K Crossley, Department of Agriculture, Western Australia Smart Grazing Management for Production and Environmental Outcomes Dr Brien E (Ben) Norton, Centre for the Management of Arid Environments, Curtin University of Technology, WA Common Causes of Plant Poisoning in the Eastern Wheatbelt of Western Australia. Roy Butler, Department of Agriculture, Western Australia Selecting Sheep for Resistance to Worms and Production Trait Responses John Karlsson, Johan Greeff, Department of Agriculture, Western Australia, Geoff Pollott, Imperial College, London UK Production and Water Use of Lucerne and French Serradella in Four Soil Types, Diana Fedorenko1,4, Darryl McClements2,4 and Robert Beard3,4, 12Department of Agriculture, Western Australia; 3Farmer, Meckering; 4CRC for Plant-based Management of Dryland Salinity. Worm Burdens in Sheep at Slaughter Brown Besier, Department of Agriculture Western Australia, Una Ryan, Caroline Bath, Murdoch Universit

Global, regional, and national burden of neurological disorders during 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250.7 [95% uncertainty interval (UI) 229.1 to 274.7] million, comprising 10.2% of global DALYs) and the second-leading cause group of deaths (9.4 [9.1 to 9.7] million], comprising 16.8% of global deaths). The most prevalent neurological disorders were tensiontype headache (1505 9 [UI 1337.3 to 1681.6 million cases]), migraine (958.8 [872.1 to 1055.6] million), medication overuse headache (58.5 [50.8 to 67.4 million]), and Alzheimer's disease and other dementias (46.0 [40.2 to 52.7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36.7%, and the number of DALYs by 7.4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26.1% and 29.7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.Peer reviewe

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Many Labs 5:Testing pre-data collection peer review as an intervention to increase replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3?9; median total sample = 1,279.5, range = 276?3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (?r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00?.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19?.50)