B006 Effects of losartan in an experimental model of metabolic syndrome

IntroductionA large body of experimental and clinical evidence indicates that some AT1 receptor antagonists may have beneficial metabolic effects in addition to their well-known cardiovascular actions. Whether or not these metabolic effects are related to additional PPARγ agonist activity of some AT1 antagonists is still under debate. Therefore, the aim of the present study was to check the cardiovascular and metabolic effects of losartan lacking any PPAR agonist activity in a suitable experimental model of metabolic syndrome, namely SHHF rats (Spontaneously Hypertensive, Heart Failure). These rats exhibit obesity, hypertension, dyslipidemia and glucose intolerance. They lack leptin receptors. WKY and SH rats were considered as control of SHHF rats.MethodsLosartan was delivered in the drinking water (10mg/kg/day during 3 months) to 12-week-old male rats. Cardiovascular and metabolic parameters were measured at the end of the treatment and compared to those of untreated SHHF rats at the same age. Intravenous glucose tolerance tests (IVGTT) were also performed. Total cholesterol, LDL, HDL, triglycerides and glucose were measured on plasma samples (0,5ml) taken from caudal veins. Blood pressure was measured (right femoral artery) under pentobarbital anaesthesia (60mg/kg, ip).Mean values±SEM are presented. P values < 0.05 were considered significant. Unpaired Student¡¦s t-tests were used for intergroup comparisons.ResultsEffects of a 3-month treatment are shown in the previous table (SHHF rats).* : p<0.05Losartan impaired significantly glucose tolerance in SHHF rats.The treatment had no significant metabolic effect in WKY and SH rats.ConclusionOur study showed that, at an antihypertensive dose, losartan impaired glucose tolerance, fasted glycaemia, plasma triglycerides and free fatty acids in SHHF rats whereas it had no significant metabolic effect in WKY and SH rats

Prevalence and risk factors of low back pain among undergraduate students of a sports and physical education institute in Tunisia

Introduction: For obvious reasons, athletes are at greater risk of sustaining a lumber (lower) spine injury due to physical activity. To our knowledge, no previous studies have examined the prevalence of low back pain (LBP) in a Tunisian sports and physical education institute.Aim: To assess the prevalence of LBP in different sports among students studying in a sports and physical education institute in Tunisia, to determine the causes of the injuries, and to propose solutions.Methods: A total of 3,379 boys and 2,579 girls were studied. A retrospective cross-sectional survey was conducted on a group of students aged 18.524.5 years at the Higher Institute of Sport and Physical Education of Sfax to estimate the prevalence of LBP and its relation to the type of sports. Data on age, weight, height, smoking, and the sport in which the student was injured in the low back were collected from the institute health service records from 2005 until 2013.Results: LBP was reported by 879 of the 5,958 study participants (14.8%). The prevalence of LBP was significantly higher (pB0.001) in females (17.6%) than in males (12.5%). LBP prevalence did not differ by body mass index or smoking habit (p0.05). The sports associated with the higher rates of LBP were gymnastics, judo, handball, and volleyball, followed by basketball and athletics.Conclusion: LBP is frequent among undergraduate students of a sports and physical education institute in Tunisia. It is strongly associated with fatigue after the long periods of training in different sports. Gymnastics, judo, handball, and volleyball were identified as high-risk sports for causing LBP.Keywords: low back pain; sports students; sports training; risk factor

Tiling genomes of pathogenic viruses identifies potent antiviral shRNAs and reveals a role for secondary structure in shRNA efficacy

shRNAs can trigger effective silencing of gene expression in mammalian cells, thereby providing powerful tools for genetic studies, as well as potential therapeutic strategies. Specific shRNAs can interfere with the replication of pathogenic viruses and are currently being tested as antiviral therapies in clinical trials. However, this effort is hindered by our inability to systematically and accurately identify potent shRNAs for viral genomes. Here we apply a recently developed highly parallel sensor assay to identify potent shRNAs for HIV, hepatitis C virus (HCV), and influenza. We observe known and previously unknown sequence features that dictate shRNAs efficiency. Validation using HIV and HCV cell culture models demonstrates very high potency of the top-scoring shRNAs. Comparing our data with the secondary structure of HIV shows that shRNA efficacy is strongly affected by the secondary structure at the target RNA site. Artificially introducing secondary structure to the target site markedly reduces shRNA silencing. In addition, we observe that HCV has distinct sequence features that bias HCV-targeting shRNAs toward lower efficacy. Our results facilitate further development of shRNA based antiviral therapies and improve our understanding and ability to predict efficient shRNAs

Challenges of Global Agriculture in a Climate Change Context by 2050 (AgCLIM50)

This report presents a global integrated assessment of the range of potential economic impacts of climate change and stringent mitigation measures in the agricultural sector. The analysis employs five global multi-region multi-commodity models and covers selected combinations of socioeconomic storylines and climate signals by mid-century. Model inputs are harmonised by using the same projections for population and GDP growth, as well as relative biophysical crop yield changes due to climate change. Model results can differ depending on model characteristics and the specific quantitative implementations of the socioeconomic storylines.JRC.D.4-Economics of Agricultur

Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

© The Author(s) 2021.LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.This work was supported in part by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades (M.A.R) (BFU2017-88265-P); the National Organization for Rare Disorders (K.C.O.), and the Loma Linda University Pathology Research Endowment Fund (K.C.O.)

Synaptic proximity enables NMDAR signalling to promote brain metastasis.

Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.This work was principally supported by grants from the Swiss National Science Foundation and the European Research Council, and by a gift from the Biltema Foundation that was administered by the ISREC Foundation, Lausanne, Switzerland

Large scale statistical inference of signaling pathways from RNAi and microarray data

<p>Abstract</p> <p>Background</p> <p>The advent of RNA interference techniques enables the selective silencing of biologically interesting genes in an efficient way. In combination with DNA microarray technology this enables researchers to gain insights into signaling pathways by observing downstream effects of individual knock-downs on gene expression. These secondary effects can be used to computationally reverse engineer features of the upstream signaling pathway.</p> <p>Results</p> <p>In this paper we address this challenging problem by extending previous work by Markowetz <it>et al</it>., who proposed a statistical framework to score networks hypotheses in a Bayesian manner. Our extensions go in three directions: First, we introduce a way to omit the data discretization step needed in the original framework via a calculation based on <it>p</it>-values instead. Second, we show how prior assumptions on the network structure can be incorporated into the scoring scheme using regularization techniques. Third and most important, we propose methods to scale up the original approach, which is limited to around 5 genes, to large scale networks.</p> <p>Conclusion</p> <p>Comparisons of these methods on artificial data are conducted. Our proposed module network is employed to infer the signaling network between 13 genes in the ER-<it>α </it>pathway in human MCF-7 breast cancer cells. Using a bootstrapping approach this reconstruction can be found with good statistical stability.</p> <p>The code for the module network inference method is available in the latest version of the <it>R</it>-package <it>nem</it>, which can be obtained from the Bioconductor homepage.</p

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

A Comparative Analysis Shows Morphofunctional Differences between the Rat and Mouse Melanin-Concentrating Hormone Systems

Sub-populations of neurons producing melanin-concentrating hormone (MCH) are characterized by distinct projection patterns, birthdates and CART/NK3 expression in rat. Evidence for such sub-populations has not been reported in other species. However, given that genetically engineered mouse lines are now commonly used as experimental models, a better characterization of the anatomy and morphofunctionnal organization of MCH system in this species is then necessary. Combining multiple immunohistochemistry experiments with in situ hybridization, tract tracing or BrdU injections, evidence supporting the hypothesis that rat and mouse MCH systems are not identical was obtained: sub-populations of MCH neurons also exist in mouse, but their relative abundance is different. Furthermore, divergences in the distribution of MCH axons were observed, in particular in the ventromedial hypothalamus. These differences suggest that rat and mouse MCH neurons are differentially involved in anatomical networks that control feeding and the sleep/wake cycle