A mutation in γ-tubulin alters microtubule dynamics and organization and is synthetically lethal with the kinesin-like protein Pkl1p

This is the publisher's version, also available electronically from "http://www.molbiolcell.org".Mitotic segregation of chromosomes requires spindle pole functions for microtubule nucleation, minus end organization, and regulation of dynamics. γ-Tubulin is essential for nucleation, and we now extend its role to these latter processes. We have characterized a mutation in γ-tubulin that results in cold-sensitive mitotic arrest with an elongated bipolar spindle but impaired anaphase A. At 30°C cytoplasmic microtubule arrays are abnormal and bundle into single larger arrays. Three-dimensional time-lapse video microscopy reveals that microtubule dynamics are altered. Localization of the mutant γ-tubulin is like the wild-type protein. Prediction of γ-tubulin structure indicates that non-α/β-tubulin protein–protein interactions could be affected. The kinesin-like protein (klp)Pkl1p localizes to the spindle poles and spindle and is essential for viability of the γ-tubulin mutant and in multicopy for normal cell morphology at 30°C. Localization and function of Pkl1p in the mutant appear unaltered, consistent with a redundant function for this protein in wild type. Our data indicate a broader role for γ-tubulin at spindle poles in regulating aspects of microtubule dynamics and organization. We propose that Pkl1p rescues an impaired function of γ-tubulin that involves non-tubulin protein–protein interactions, presumably with a second motor, MAP, or MTOC component

Development of the Human Fetal Kidney from Mid to Late Gestation in Male and Female Infants

BACKGROUND During normal human kidney development, nephrogenesis (the formation of nephrons) is complete by term birth, with the majority of nephrons formed late in gestation. The aim of this study was to morphologically examine nephrogenesis in fetal human kidneys from 20 to 41weeks of gestation. METHODS Kidney samples were obtained at autopsy from 71 infants that died acutely in utero or within 24h after birth. Using image analysis, nephrogenic zone width, the number of glomerular generations, renal corpuscle cross-sectional area and the cellular composition of glomeruli were examined. Kidneys from female and male infants were analysed separately. FINDINGS The number of glomerular generations formed within the fetal kidneys was directly proportional to gestational age, body weight and kidney weight, with variability between individuals in the ultimate number of generations (8 to 12) and in the timing of the cessation of nephrogenesis (still ongoing at 37weeks gestation in one infant). There was a slight but significant (r2=0.30, P=0.001) increase in renal corpuscle cross-sectional area from mid gestation to term in females, but this was not evident in males. The proportions of podocytes, endothelial and non-epithelial cells within mature glomeruli were stable throughout gestation. INTERPRETATION These findings highlight spatial and temporal variability in nephrogenesis in the developing human kidney, whereas the relative cellular composition of glomeruli does not appear to be influenced by gestational age.This study was supported by funding from the National Health and Medical Research Council (NHMRC) (1011136) of Australia and National Institutes of Health (NIH) USA grant 3U01DK094526-04S1 (PI A P McMahon). Author Danica Ryan was the recipient of the Biomedicine Discovery Scholarship from Monash University and author Megan R. Sutherland was supported by a NHMRC CJ Martin Fellowship

'Turning the tide' on hyperglycemia in pregnancy : insights from multiscale dynamic simulation modeling

INTRODUCTION: Hyperglycemia in pregnancy (HIP, including gestational diabetes and pre-existing type 1 and type 2 diabetes) is increasing, with associated risks to the health of women and their babies. Strategies to manage and prevent this condition are contested. Dynamic simulation models (DSM) can test policy and program scenarios before implementation in the real world. This paper reports the development and use of an advanced DSM exploring the impact of maternal weight status interventions on incidence of HIP. METHODS: A consortium of experts collaboratively developed a hybrid DSM of HIP, comprising system dynamics, agent-based and discrete event model components. The structure and parameterization drew on a range of evidence and data sources. Scenarios comparing population-level and targeted prevention interventions were simulated from 2018 to identify the intervention combination that would deliver the greatest impact. RESULTS: Population interventions promoting weight loss in early adulthood were found to be effective, reducing the population incidence of HIP by 17.3% by 2030 (baseline ('business as usual' scenario)=16.1%, 95% CI 15.8 to 16.4; population intervention=13.3%, 95% CI 13.0 to 13.6), more than targeted prepregnancy (5.2% reduction; incidence=15.3%, 95% CI 15.0 to 15.6) and interpregnancy (4.2% reduction; incidence=15.5%, 95% CI 15.2 to 15.8) interventions. Combining targeted interventions for high-risk groups with population interventions promoting healthy weight was most effective in reducing HIP incidence (28.8% reduction by 2030; incidence=11.5, 95% CI 11.2 to 11.8). Scenarios exploring the effect of childhood weight status on entry to adulthood demonstrated significant impact in the selected outcome measure for glycemic regulation, insulin sensitivity in the short term and HIP in the long term. DISCUSSION: Population-level weight reduction interventions will be necessary to 'turn the tide' on HIP. Weight reduction interventions targeting high-risk individuals, while beneficial for those individuals, did not significantly impact forecasted HIP incidence rates. The importance of maintaining interventions promoting healthy weight in childhood was demonstrated

‘I just think it’s dirty and lazy’: Fat surveillance and erotic capital

Contextualised within the UK mediascape, this article discusses how fat signifies the classed failures of neoliberalism. Because class aspiration, entrepreneurialism and the myth of the competitive individual are pivotal to the political economy of neoliberalism, fat is increasingly and vehemently vilified as abject across media platforms. Fat-surveillance media, which are marketed specifically to women by their visuals, gendered community, language, and structures of feeling, participate in a ‘gynaeopticon’ where the controlling gaze is female, and the many women regulate the many women. Rather than being a top-down form of governance and discipline such as in the panopticon, control is affectively devolved among systems or networks of the policing gaze. As well as monitoring women along the lines of class, I argue that these media circumscribe the de-individualising possibilities and passions of the libido

Beyond the black box: promoting mathematical collaborations for elucidating interactions in soil ecology

This work is licensed under a Creative Commons Attribution 4.0 International License.Understanding soil systems is critical because they form the structural and nutritional foundation for plants and thus every terrestrial habitat and agricultural system. In this paper, we encourage increased use of mathematical models to drive forward understanding of interactions in soil ecological systems. We discuss several distinctive features of soil ecosystems and empirical studies of them. We explore some perceptions that have previously deterred more extensive use of models in soil ecology and some advances that have already been made using models to elucidate soil ecological interactions. We provide examples where mathematical models have been used to test the plausibility of hypothesized mechanisms, to explore systems where experimental manipulations are currently impossible, or to determine the most important variables to measure in experimental and natural systems. To aid in the development of theory in this field, we present a table describing major soil ecology topics, the theory previously used, and providing key terms for theoretical approaches that could potentially address them. We then provide examples from the table that may either contribute to important incremental developments in soil science or potentially revolutionize our understanding of plant–soil systems. We challenge scientists and mathematicians to push theoretical explorations in soil systems further and highlight three major areas for the development of mathematical models in soil ecology: theory spanning scales and ecological hierarchies, processes, and evolution

Beyond the black box: Promoting mathematical collaborations for elucidating interactions in soil ecology

© 2019 The Authors. Understanding soil systems is critical because they form the structural and nutritional foundation for plants and thus every terrestrial habitat and agricultural system. In this paper, we encourage increased use of mathematical models to drive forward understanding of interactions in soil ecological systems. We discuss several distinctive features of soil ecosystems and empirical studies of them. We explore some perceptions that have previously deterred more extensive use of models in soil ecology and some advances that have already been made using models to elucidate soil ecological interactions. We provide examples where mathematical models have been used to test the plausibility of hypothesized mechanisms, to explore systems where experimental manipulations are currently impossible, or to determine the most important variables to measure in experimental and natural systems. To aid in the development of theory in this field, we present a table describing major soil ecology topics, the theory previously used, and providing key terms for theoretical approaches that could potentially address them. We then provide examples from the table that may either contribute to important incremental developments in soil science or potentially revolutionize our understanding of plant-soil systems. We challenge scientists and mathematicians to push theoretical explorations in soil systems further and highlight three major areas for the development of mathematical models in soil ecology: Theory spanning scales and ecological hierarchies, processes, and evolution

Realist synthesis : illustrating the method for implementation research

BackgroundRealist synthesis is an increasingly popular approach to the review and synthesis of evidence, which focuses on understanding the mechanisms by which an intervention works (or not). There are few published examples of realist synthesis. This paper therefore fills a gap by describing, in detail, the process used for a realist review and synthesis to answer the question \u27what interventions and strategies are effective in enabling evidence-informed healthcare?\u27 The strengths and challenges of conducting realist review are also considered. MethodsThe realist approach involves identifying underlying causal mechanisms and exploring how they work under what conditions. The stages of this review included: defining the scope of the review (concept mining and framework formulation); searching for and scrutinising the evidence; extracting and synthesising the evidence; and developing the narrative, including hypotheses. ResultsBased on key terms and concepts related to various interventions to promote evidenceinformed healthcare, we developed an outcome-focused theoretical framework. Questions were tailored for each of four theory/intervention areas within the theoretical framework and were used to guide development of a review and data extraction process. The search for literature within our first theory area, change agency, was executed and the screening procedure resulted in inclusion of 52 papers. Using the questions relevant to this theory area, data were extracted by one reviewer and validated by a second reviewer. Synthesis involved organisation of extracted data into evidence tables, theming and formulation of chains of inference, linking between the chains of inference, and hypothesis formulation. The narrative was developed around the hypotheses generated within the change agency theory area. ConclusionsRealist synthesis lends itself to the review of complex interventions because it accounts for context as well as outcomes in the process of systematically and transparently synthesising relevant literature. While realist synthesis demands flexible thinking and the ability to deal with complexity, the rewards include the potential for more pragmatic conclusions than alternative approaches to systematic reviewing. A separate publication will report the findings of the review. <br /

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

INTRODUCTION: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. METHODS: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles. RESULTS: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. DISCUSSION: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD

Reassessing the Evidence Hierarchy in Asthma: Evaluating Comparative Effectiveness

Classical randomized controlled trials are the gold standard in medical evidence because of their high internal validity. However, their necessarily strict design can limit their external validity and the ability to extrapolate these data to real world patients. Therefore, alternatively designed studies may play a complementary role in evaluating the comparative effectiveness of therapies in nonidealized patients in more naturalistic, real world settings. Observational studies have high external validity and can evaluate real world outcomes. Their strength lies in hypothesis generation and testing and in identifying areas in which further clinical trials may be required. Pragmatic trials are designed to maximize applicability of trial results to usual care settings by relying on clinically important outcomes and enrolling a wide range of participants. A combination of these approaches is preferable and necessary