Prediction of local wind climatology from Met Office models: Virtual Met Mast techniques

The Met Office has developed the Virtual Met Mast™ (VMM) tool for assessing the feasibility of potential wind farm sites. It provides site-specific climatological wind information for both onshore and offshore locations. The VMM relies on existing data from past forecasts from regional-scale numerical weather prediction (NWP) models, to which corrections are applied to account for local site complexity. The techniques include corrections to account for the enhanced roughness lengths used in NWP models to represent drag due to sub-grid orography, and downscaling methods which predict local wind acceleration over small-scale terrain. The corrected NWP data are extended to cover long periods (decades) using a technique in which the data are related to alternative long-term datasets. For locations in the UK the VMM currently relies on operational mesoscale model forecast data at 4km horizontal resolution. Predictions have been verified against observations made at typical wind turbine hub heights at over 80 sites across the UK. In general the predictions compare well with the observations. The techniques provide an efficient method for screening potential wind resource sites. Examples of how the VMM techniques can be used to produce local wind maps are also presented

Sdmg1 is a conserved transmembrane protein associated with germ cell sex determination and germline-soma interactions in mice

In mammals, the supporting cell lineage in an embryonic gonad communicates the sex-determining decision to various sexually dimorphic cell types in the developing embryo, including the germ cells. However the molecular nature of the sex-determining signals that pass from the supporting cells to the germ cells is not well understood. We have identified a conserved transmembrane protein, Sdmg1, due to its male-specific expression in mouse embryonic gonads. Sdmg1 is expressed in the Sertoli cells of embryonic testes from 12.5 dpc, and in granulosa cells of growing follicles in adult ovaries. In Sertoli cells, Sdmg1 is localised to endosomes, and knock-down of Sdmg1 in Sertoli cell lines causes mis-localisation of the secretory SNARE Stx2 and defects in membrane trafficking. Upregulation of Sdmg1 appears to be part of a larger programme of changes to membrane trafficking pathways in embryonic Sertoli cells, and perturbing secretion in male embryonic gonads in organ culture causes male-to-female germ cell sex reversal. These data suggest that changes that occur in the cell biology of embryonic Sertoli cells may facilitate the communication of male sex-determining decisions to the germ cells during embryonic development

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis

Background & Aims: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. Methods: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. Results: Based on IHC, PSC patients could be subdivided into two groups showing either low (80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. Conclusion: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2

Multilevel analyses of related public health indicators: The European Surveillance of Congenital Anomalies (EUROCAT) Public Health Indicators

BACKGROUND:Public health organisations use public health indicators to guide health policy. Joint analysis of multiple public health indicators can provide a more comprehensive understanding of what they are intended to evaluate. OBJECTIVE:To analyse variaitons in the prevalence of congenital anomaly-related perinatal mortality attributable to termination of pregnancy for foetal anomaly (TOPFA) and prenatal diagnosis of congenital anomaly prevalence. METHODS:We included 55 363 cases of congenital anomalies notified to 18 EUROCAT registers in 10 countries during 2008-12. Incidence rate ratios (IRR) representing the risk of congenital anomaly-related perinatal mortality according to TOPFA and prenatal diagnosis prevalence were estimated using multilevel Poisson regression with country as a random effect. Between-country variation in congenital anomaly-related perinatal mortality was measured using random effects and compared between the null and adjusted models to estimate the percentage of variation in congenital anomaly-related perinatal mortality accounted for by TOPFA and prenatal diagnosis. RESULTS:The risk of congenital anomaly-related perinatal mortality decreased as TOPFA and prenatal diagnosis prevalence increased (IRR 0.79, 95% confidence interval [CI] 0.72, 0.86; and IRR 0.88, 95% CI 0.79, 0.97). Modelling TOPFA and prenatal diagnosis together, the association between congenital anomaly-related perinatal mortality and TOPFA prevalence became stronger (RR 0.70, 95% CI 0.61, 0.81). The prevalence of TOPFA and prenatal diagnosis accounted for 75.5% and 37.7% of the between-country variation in perinatal mortality, respectively. CONCLUSION:We demonstrated an approach for analysing inter-linked public health indicators. In this example, as TOPFA and prenatal diagnosis of congenital anomaly prevalence decreased, the risk of congenital anomaly-related perinatal mortality increased. Much of the between-country variation in congenital anomaly-related perinatal mortality was accounted for by TOPFA, with a smaller proportion accounted for by prenatal diagnosis

Effects of Treatment Setting on Outcomes of Flexibly-Dosed Intensive Cognitive Behavioral Therapy for Pediatric OCD : A Randomized Controlled Pilot Trial

Funding Information: The study authors would like to acknowledge the planning support of Drs. Eric Storch and Katherine Martinez, the recruitment and administrative support of the Provincial OCD Program Team at BC Children's Hospital, and the participation of all families. Funding. This study was supported by postdoctoral awards to RS from the Michael Smith Foundation for Health Research (#17821) and the BC Children's Hospital Research Institute. Both awards provided salary support for RS as well as research funds to support study implementation (e.g., staff salaries, participant reimbursement, etc.). A private donation to the Provincial OCD Program via the BC Children's Hospital Foundation also supported some research costs. Funding Information: This study was supported by postdoctoral awards to RS from the Michael Smith Foundation for Health Research (#17821) and the BC Children’s Hospital Research Institute. Both awards provided salary support for RS as well as research funds to support study implementation (e.g., staff salaries, participant reimbursement, etc.). A private donation to the Provincial OCD Program via the BC Children’s Hospital Foundation also supported some research costs. Publisher Copyright: © Copyright © 2021 Selles, Naqqash, Best, Franco-Yamin, Qiu, Ferreira, Deng, Hannesdottir, Oberth, Belschner, Negreiros, Farrell and Stewart.Introduction: Optimizing individual outcomes of cognitive-behavioral therapy (CBT) remains a priority. Methods: Youth were randomized to receive intensive CBT at a hospital clinic (n = 14) or within their home (n = 12). Youth completed 3 × 3 h sessions (Phase I) and up to four additional 3-h sessions as desired/needed (Phase II). An independent evaluator assessed youth after Phase I, Phase II (when applicable), and at 1- and 6-months post-treatment. A range of OCD-related (e.g., severity, impairment) and secondary (e.g., quality of life, comorbid symptoms) outcomes were assessed. Results: Families' satisfaction with the treatment program was high. Of study completers (n = 22), five youth (23%) utilized no Phase II sessions and 9 (41%) utilized all four (Median Phase II sessions: 2.5). Large improvements in OCD-related outcomes and small-to-moderate benefits across secondary domains were observed. Statistically-significant differences in primary outcomes were not observed between settings; however, minor benefits for home-based treatment were observed (e.g., maintenance of gains, youth comfort with treatment). Discussion: Intensive CBT is an efficacious treatment for pediatric OCD. Families opted for differing doses based on their needs. Home-based treatment, while not substantially superior to hospital care, may offer some value, particularly when desired/relevant. Clinical Trial Registration: www.ClinicalTrials.gov; https://clinicaltrials.gov/ct2/show/NCT03672565, identifier: NCT03672565.Peer reviewe

Using RGB-D sensors and evolutionary algorithms for the optimization of workstation layouts

[EN] RGB-D sensors can collect postural data in an automatized way. However, the application of these devices in real work environments requires overcoming problems such as lack of accuracy or body parts' occlusion. This work presents the use of RGB-D sensors and genetic algorithms for the optimization of workstation layouts. RGB-D sensors are used to capture workers' movements when they reach objects on workbenches. Collected data are then used to optimize workstation layout by means of genetic algorithms considering multiple ergonomic criteria. Results show that typical drawbacks of using RGB-D sensors for body tracking are not a problem for this application, and that the combination with intelligent algorithms can automatize the layout design process. The procedure described can be used to automatically suggest new layouts when workers or processes of production change, to adapt layouts to specific workers based on their ways to do the tasks, or to obtain layouts simultaneously optimized for several production processes.This work was supported by the Programa estatal de investigacion, desarrollo e innovacion orientada a los retos de la sociedad of the Government of Spain under Grant TIN2013-42504-R.Diego-Mas, JA.; Poveda Bautista, R.; Garzon-Leal, D. (2017). Using RGB-D sensors and evolutionary algorithms for the optimization of workstation layouts. Applied Ergonomics. 65:530-540. doi:10.1016/j.apergo.2017.01.012S5305406

The genome-defence gene Tex19.1 suppresses LINE-1 retrotransposons in the placenta and prevents intra-uterine growth retardation in mice

DNA methylation plays an important role in suppressing retrotransposon activity in mammalian genomes, yet there are stages of mammalian development where global hypomethylation puts the genome at risk of retrotransposition-mediated genetic instability. Hypomethylated primordial germ cells appear to limit this risk by expressing a cohort of retrotransposon-suppressing genome-defence genes whose silencing depends on promoter DNA methylation. Here, we investigate whether similar mechanisms operate in hypomethylated trophectoderm-derived components of the mammalian placenta to couple expression of genome-defence genes to the potential for retrotransposon activity. We show that the hypomethylated state of the mouse placenta results in activation of only one of the hypomethylation-sensitive germline genome-defence genes: Tex19.1. Tex19.1 appears to play an important role in placenta function as Tex19.1(−/−) mouse embryos exhibit intra-uterine growth retardation and have small placentas due to a reduction in the number of spongiotrophoblast, glycogen trophoblast and sinusoidal trophoblast giant cells. Furthermore, we show that retrotransposon mRNAs are derepressed in Tex19.1(−/−) placentas and that protein encoded by the LINE-1 retrotransposon is upregulated in hypomethylated trophectoderm-derived cells that normally express Tex19.1. This study suggests that post-transcriptional genome-defence mechanisms are operating in the placenta to protect the hypomethylated cells in this tissue from retrotransposons and suggests that imbalances between retrotransposon activity and genome-defence mechanisms could contribute to placenta dysfunction and disease

The Tissue-Specific Rep8/UBXD6 Tethers p97 to the Endoplasmic Reticulum Membrane for Degradation of Misfolded Proteins

The protein known as p97 or VCP in mammals and Cdc48 in yeast is a versatile ATPase complex involved in several biological functions including membrane fusion, protein folding, and activation of membrane-bound transcription factors. In addition, p97 plays a central role in degradation of misfolded secretory proteins via the ER-associated degradation pathway. This functional diversity of p97 depends on its association with various cofactors, and to further our understanding of p97 function it is important that these cofactors are identified and analyzed. Here, we isolate and characterize the human protein named Rep8 or Ubxd6 as a new cofactor of p97. Mouse Rep8 is highly tissue-specific and abundant in gonads. In testes, Rep8 is expressed in post-meiotic round spermatids, whereas in ovaries Rep8 is expressed in granulosa cells. Rep8 associates directly with p97 via its UBX domain. We show that Rep8 is a transmembrane protein that localizes to the ER membrane with its UBX domain facing the cytoplasm. Knock-down of Rep8 expression in human cells leads to a decreased association of p97 with the ER membrane and concomitantly a retarded degradation of misfolded ER-derived proteasome substrates. Thus, Rep8 tethers p97 to the ER membrane for efficient ER-associated degradation

A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition

Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synap–tic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI), a prominent form of shortterm synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of endocannabinoids in synaptic transmission as a feedback mechanism both at synaptic and network level