TCF/Lef regulates the Gsx ParaHox gene in central nervous system development in chordates

This research was supported by a BBSRC-DTG studentship to M.G.G, and Clarendon, ORS and EPA Cephalosporin scholarships to P.W.O.Background The ParaHox genes play an integral role in the anterior-posterior (A-P) patterning of the nervous system and gut of most animals. The ParaHox cluster is an ideal system in which to study the evolution and regulation of developmental genes and gene clusters, as it displays similar regulatory phenomena to its sister cluster, the Hox cluster, but offers a much simpler system with only three genes. Results Using Ciona intestinalis transgenics, we isolated a regulatory element upstream of Branchiostoma floridae Gsx that drives expression within the central nervous system of Ciona embryos. The minimal amphioxus enhancer region required to drive CNS expression has been identified, along with surrounding sequence that increases the efficiency of reporter expression throughout the Ciona CNS. TCF/Lef binding sites were identified and mutagenized and found to be required to drive the CNS expression. Also, individual contributions of TCF/Lef sites varied across the regulatory region, revealing a partial division of function across the Bf-Gsx-Up regulatory element. Finally, when all TCF/Lef binding sites are mutated CNS expression is not only abolished, but a latent repressive function is also unmasked. Conclusions We have identified a B. floridae Gsx upstream regulatory element that drives CNS expression within transgenic Ciona intestinalis, and have shown that this CNS expression is dependent upon TCF/Lef binding sites. We examine the evolutionary and developmental implications of these results, and discuss the possibility of TCF/Lef not only as a regulator of chordate Gsx, but as a deeply conserved regulatory factor controlling all three ParaHox genes across the Metazoa.Publisher PDFPeer reviewe

Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Musters, C. J. M., Ieromina, O., Barmentlo, S. H., Hunting, E. R., Schrama, M., Cieraad, E., Vijver, M. G., & van Bodegom, P. M. Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities. Ecosphere, 10(11), (2019): e02910, doi:10.1002/ecs2.2910.Temperate aquatic communities are highly diverse and seasonally variable, due to internal biotic processes and environmental drivers, including human‐induced stressors. The impact of drivers on species abundance is supposed to differ fundamentally depending on whether populations are experiencing limitations, which may shift over the season. However, an integrated understanding of how drivers structure communities seasonally is currently lacking. In order to partition the effect of drivers, we used random forests to quantify interactions between all taxa and environmental factors using macrofaunal data from 18 agricultural ditches sampled over two years. We found that, over the agricultural season, taxon abundance became increasingly better predicted by the abundances of co‐occurring taxa and nutrients compared to other abiotic factors, including pesticides. Our approach provides fundamental insights in community dynamics and highlights the need to consider changes in species interactions to understand the effects of anthropogenic stressors.The authors are grateful to B. Schaub of Water Board Rijnland for his help, E. Gertenaar for assistance in the fieldwork, M. Wouterse for DOC measurements, and B. Koese for help with taxonomic identification of macrofaunal samples. CM designed the study, did the statistical modeling and analyses, and wrote the draft paper; OI did field sampling and taxonomic identification and constructed the datasets; OI and HB structured the data; EH, MS, ES, MV, and PvB contributed to the study design and the conceptual improvement of the manuscript; all authors substantially revised the subsequent drafts

Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism

K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell K(ATP) currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po((0)) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po((0)) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2.We thank the Wellcome Trust (076436/Z/05/Z and 081188/A/06/Z), the Royal Society and the European Union (EuroDia, SHM‐CT‐2006‐518513 and EDICT, 201924) for support. FMA is a Royal Society Research Professor. Brittany Zadek was supported by an OXION studentship and Sarah Flanagan by a Sir Graham Wilkins Research Fellowship

Human practices promote presence and abundance of disease-transmitting mosquito species

Humans alter the environment at unprecedented rates through habitat destruction, nutrient pollution and the application of agrochemicals. This has recently been proposed to act as a potentially significant driver of pathogen-carrying mosquito species (disease vectors) that pose a health risk to humans and livestock. Here, we use a unique set of locations along a large geographical gradient to show that landscapes disturbed by a variety of anthropogenic stressors are consistently associated with vector-dominated mosquito communities for a wide range of human and livestock infections. This strongly suggests that human alterations to the environment promote the presence and abundance of disease vectors across large spatial extents. As such, it warrants further studies aimed at unravelling mechanisms underlying vector prevalence in mosquito communities, and opens up new opportunities for preventative action and predictive modelling of vector borne disease risks in relation to degradation of natural ecosystems

Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol

Introduction: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. Methods and analysis: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT). Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. Ethics and dissemination: The trial was approved by the London—Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890). Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate. This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. Trial registration number: ISRCTN87336549

Next generation sequencing of chromosomal rearrangements in patients with split-hand/split-foot malformation provides evidence for DYNC1I1 exonic enhancers of DLX5/6 expression in humans

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this recordSplit-hand/foot malformation type 1 is an autosomal dominant condition with reduced penetrance and variable expression. We report three individuals from two families with split-hand/split-foot malformation (SHFM) in whom next generation sequencing was performed to investigate the cause of their phenotype.Wellcome Trus

Rare single gene disorders:estimating baseline prevalence and outcomes worldwide

As child mortality rates overall are decreasing, non-communicable conditions, such as genetic disorders, constitute an increasing proportion of child mortality, morbidity and disability. To date, policy and public health programmes have focused on common genetic disorders. Rare single gene disorders are an important source of morbidity and premature mortality for affected families. When considered collectively, they account for an important public health burden, which is frequently under-recognised. To document the collective frequency and health burden of rare single gene disorders, it is necessary to aggregate them into large manageable groupings and take account of their family implications, effective interventions and service needs. Here, we present an approach to estimate the burden of these conditions up to 5 years of age in settings without empirical data. This approaches uses population-level demographic data, combined with assumptions based on empirical data from settings with data available, to provide population-level estimates which programmes and policy-makers when planning services can use

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Increase in Depression and Anxiety Among Australian Gay and Bisexual Men During COVID-19 Restrictions: Findings from a Prospective Online Cohort Study

We examined depression and anxiety prior to and during COVID-19 restrictions in Australian gay and bisexual men (GBM). In an online cohort, a COVID-19-focused survey was conducted in April 2020. During 2019 and in April 2020, 664 GBM completed the Patient Health Questionnaire (PHQ-9, measuring depression) and Generalized Anxiety Disorder Assessment (GAD-7, measuring anxiety). Increased depression and anxiety were defined as a ≥ 5 point increase on the respective scales. Mean PHQ-9 and GAD-7 scores increased between 2019 and 2020 (PHQ-9: from 5.11 in 2019 to 6.55 in 2020; GAD-7: from 3.80 in 2019 to 4.95 in 2020). The proportion of participants with moderate-severe depression (PHQ-9 ≥ 10) increased from 18.8% (n = 125) to 25.5% (n = 169), while the proportion of participants with moderate-severe anxiety (GAD-7 ≥ 10) increased from 12.7% (n = 84) to 17.3% (n = 115). Almost one-quarter of participants (n = 158, 23.8%) had increased depression; in these men, mean PHQ-9 increased from 2.49 in 2019 to 11.65 in 2020 (p < 0.001). One-in-five (20.6%) participants (n = 137) had increased anxiety; among these men, mean GAD-7 increased from 2.05 in 2019 to 10.22 in 2020 (p < 0.001). Increases were associated with concerns about job security, reduction in social and sexual connections and opportunities, and being personally concerned about COVID-19 itself. COVID-19 appeared to have a sudden and pronounced impact on depression and anxiety in Australian GBM, with a significant minority showing sharp increases. Ongoing monitoring is required to determine longer-term impacts and GBM need access to appropriate and sensitive supports both during and after the COVID-19 pandemic