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Identification of Arabidopsis \u3ci\u3eGPAT9\u3c/i\u3e (At5g60620) as an Essential Gene Involved In Triacylglycerol Biosynthesis

The first step in the biosynthesis of nearly all plant membrane phospholipids and storage triacylglycerols is catalyzed by a glycerol-3-phosphate acyltransferase (GPAT). The requirement for an endoplasmic reticulum (ER)-localized GPAT for both of these critical metabolic pathways was recognized more than 60 years ago. However, identification of the gene(s) encoding this GPAT activity has remained elusive. Here, we present the results of a series of in vivo, in vitro, and in silico experiments in Arabidopsis (Arabidopsis thaliana) designed to assign this essential function to AtGPAT9. This gene has been highly conserved throughout evolution and is largely present as a single copy in most plants, features consistent with essential housekeeping functions. A knockout mutant of AtGPAT9 demonstrates both male and female gametophytic lethality phenotypes, consistent with the role in essential membrane lipid synthesis. Significant expression of developing seed AtGPAT9 is required for wild-type levels of triacylglycerol accumulation, and the transcript level is directly correlated to the level of microsomal GPAT enzymatic activity in seeds. Finally, the AtGPAT9 protein interacts with other enzymes involved in ER glycerolipid biosynthesis, suggesting the possibility of ER-localized lipid biosynthetic complexes. Together, these results suggest that GPAT9 is the ER-localized GPAT enzyme responsible for plant membrane lipid and oil biosynthesis

The Evolving Role of Physicians - Don’t Forget the Generalist Primary Care Providers; Comment on “Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians”

The editorial “Non-physician Clinicians in Sub-Saharan Africa and the Evolving Role of Physicians” by Eyal et al describes non-physician clinicians’ (NPC) need for mentorship and support from physicians. We emphasise the same need of support for front line generalist primary healthcare providers who carry out complex tasks yet may have an inadequate skill mix

A school-based intervention to promote physical activity among adolescent girls: Rationale, design, and baseline data from the Girls in Sport group randomised controlled trial

Background: Physical activity levels decline markedly among girls during adolescence. School-based interventions that are multi-component in nature, simultaneously targeting curricular, school environment and policy, and community links, are a promising approach for promoting physical activity. This report describes the rationale, design and baseline data from the Girls in Sport group randomised trial, which aims to prevent the decline in moderate-to-vigorous intensity physical activity (MVPA) among adolescent girls. Methods/design: A community-based participatory research approach and action learning framework are used with measurements at baseline and 18-month follow-up. Within each intervention school, a committee develops an action plan aimed at meeting the primary objective (preventing the decline in accelerometer-derived MVPA). Academic partners and the State Department of Education and Training act as critical friends. Control schools continue with their usual school programming. 24 schools were matched then randomized into intervention (n = 12) and control (n = 12) groups. A total of 1518 girls (771 intervention and 747 control) completed baseline assessments (86% response rate). Useable accelerometer data (≥ 10 hrs/day on at least 3 days) were obtained from 79% of this sample (n = 1199). Randomisation resulted in no differences between intervention and control groups on any of the outcomes. The mean age (SE) of the sample was 13.6 (± 0.02) years and they spent less than 5% of their waking hours in MVPA (4.85 ± 0.06). Discussion: Girls in Sport will test the effectiveness of schools working towards the same goal, but developing individual, targeted interventions that bring about changes in curriculum, school environment and policy, and community links. By using community-based participatory research and an action learning framework in a secondary school setting, it aims to add to the body of literature on effective school-based interventions through promoting and sustaining increased physical activity participation among adolescent girls

Lower Rotational Inertia and Larger Leg Muscles Indicate More Rapid Turns in Tyrannosaurids Than in Other Large Theropods

Synopsis: Tyrannosaurid dinosaurs had large preserved leg muscle attachments and low rotational inertia relative to their body mass, indicating that they could turn more quickly than other large theropods. Methods: To compare turning capability in theropods, we regressed agility estimates against body mass, incorporating superellipse-based modeled mass, centers of mass, and rotational inertia (mass moment of inertia). Muscle force relative to body mass is a direct correlate of agility in humans, and torque gives potential angular acceleration. Agility scores therefore include rotational inertia values divided by proxies for (1) muscle force (ilium area and estimates of m. caudofemoralis longus cross-section), and (2) musculoskeletal torque. Phylogenetic ANCOVA (phylANCOVA) allow assessment of differences in agility between tyrannosaurids and non-tyrannosaurid theropods (accounting for both ontogeny and phylogeny). We applied conditional error probabilities a(p) to stringently test the null hypothesis of equal agility. Results: Tyrannosaurids consistently have agility index magnitudes twice those of allosauroids and some other theropods of equivalent mass, turning the body with both legs planted or pivoting over a stance leg. PhylANCOVA demonstrates definitively greater agilities in tyrannosaurids, and phylogeny explains nearly all covariance. Mass property results are consistent with those of other studies based on skeletal mounts, and between different figure-based methods (our main mathematical slicing procedures, lofted 3D computer models, and simplified graphical double integration). Implications: The capacity for relatively rapid turns in tyrannosaurids is ecologically intriguing in light of their monopolization of large (\u3e400 kg), toothed dinosaurian predator niches in their habitats

Translating dosage compensation to trisomy 21

Down syndrome is the leading genetic cause of intellectual disabilities, occurring in 1 out of 700 live births. Given that Down syndrome is caused by an extra copy of chromosome 21 that involves over-expression of 400 genes across a whole chromosome, it precludes any possibility of a genetic therapy. Our lab has long studied the natural dosage compensation mechanism for X chromosome inactivation. To “dosage compensate” X-linked genes between females and males, the X-linked XIST gene produces a large non-coding RNA that silences one of the two X chromosomes in female cells. The initial motivation of this study was to translate the natural mechanisms of X chromosome inactivation into chromosome therapy for Down syndrome. Using genome editing with zinc finger nucleases, we have successfully inserted a large XIST transgene into Chromosome 21 in Down syndrome iPS cells, which results in chromosome-wide transcriptional silencing of the extra Chromosome 21. Remarkably, deficits in proliferation and neural growth are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro surmounts the major first step towards potential development of “chromosome therapy” for Down syndrome. The human iPSC-based trisomy correction system we established opens a unique opportunity to identify therapeutic targets and study transplantation therapies for Down syndrome