Expression of Colonization Factor CS5 of Enterotoxigenic Escherichia coli (ETEC) Is Enhanced In Vivo and by the Bile Component Na Glycocholate Hydrate

Enterotoxigenic Escherichia coli (ETEC) is an important cause of acute watery diarrhoea in developing countries. Colonization factors (CFs) on the bacterial surface mediate adhesion to the small intestinal epithelium. Two of the most common CFs worldwide are coli surface antigens 5 and 6 (CS5, CS6). In this study we investigated the expression of CS5 and CS6 in vivo, and the effects of bile and sodium bicarbonate, present in the human gut, on the expression of CS5. Five CS5+CS6 ETEC isolates from adult Bangladeshi patients with acute diarrhoea were studied. The level of transcription from the CS5 operon was approximately 100-fold higher than from the CS6 operon in ETEC bacteria recovered directly from diarrhoeal stool without sub-culturing (in vivo). The glyco-conjugated primary bile salt sodium glycocholate hydrate (NaGCH) induced phenotypic expression of CS5 in a dose-dependent manner and caused a 100-fold up-regulation of CS5 mRNA levels; this is the first description of NaGCH as an enteropathogenic virulence inducer. The relative transcription levels from the CS5 and CS6 operons in the presence of bile or NaGCH in vitro were similar to those in vivo. Another bile salt, sodium deoxycholate (NaDC), previously reported to induce enteropathogenic virulence, also induced expression of CS5, whereas sodium bicarbonate did not

Mixtures of long-term exposure to ambient air pollution, built environment and temperature and stroke incidence across Europe

Introduction: The complex interplay of multiple environmental factors and cardiovascular has scarcely been studied. Within the EXPANSE project, we evaluated the association between long-term exposure to multiple environmental indices and stroke incidence across Europe. Methods: Participants from three traditional adult cohorts (Germany, Netherlands and Sweden) and four administrative cohorts (Catalonia [region Spain], Rome [city-wide], Greece and Sweden [nationwide]) were followed until incident stroke, death, migration, loss of follow-up or study end. We estimated exposures at residential addresses from different exposure domains: air pollution (nitrogen dioxide (NO2), particulate matter < 2.5 μm (PM2.5), black carbon (BC), ozone), built environment (green/blue spaces, impervious surfaces) and meteorology (seasonal mean and standard deviation of temperatures). Associations between environmental exposures and stroke were estimated in single and multiple-exposure Cox proportional hazard models, and Principal Component (PC) Analyses derived prototypes for specific exposures domains. We carried out random effects meta-analyses by cohort type. Results: In over 15 million participants, increased levels of NO2 and BC were associated with increased higher stroke incidence in both cohort types. Increased Normalized Difference Vegetation Index (NDVI) was associated with a lower stroke incidence in both cohort types, whereas an increase in impervious surface was associated with an increase in stroke incidence. The first PC of the air pollution domain (PM2.5, NO2 and BC) was associated with an increase in stroke incidence. For the built environment, higher levels of NDVI and lower levels of impervious surfaces were associated with a protective effect [%change in HR per 1 unit = −2.0 (95 %CI, −5.9;2.0) and −1.1(95 %CI, −2.0; −0.3) for traditional adult and administrative cohorts, respectively]. No clear patterns were observed for distance to blue spaces or temperature parameters. Conclusions: We observed increased HRs for stroke with exposure to PM2.5, NO2 and BC, lower levels of greenness and higher impervious surface in single and combined exposure models

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract: Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Matematik på en förskola ­ Vad står i läroplanen och behövs ämnesdidaktiska kunskaper?

SyfteSyftet med vår fallstudie är att undersöka om några lärare följer förskolans läroplan när det gäller matematik. Vi vill också ta reda på matematikinnehållet på en förskola samt om lärarna där vet vad barnen lär sig för matematik. HuvudfrågorFöljer några lärare förskolans läroplan när det gäller matematik? Vad för matematikinnehåll arbetar man med? Hur vet dessa lärare vad barnen lär sig för matematik? Metod och material För att söka svar på våra frågor så har vi valt tre undersökningsmetoder, vilket brukar kallas för trianguleringsmetoden. Först valde vi intervjuer vilka vi sedan kompletterade med observationer för att se om lärarna gjorde det de berättade vid intervjuerna. Dessutom har vi samtalat med några barn och ställt frågor för att få en inblick i deras grundläggande taluppfattning. Resultat Fallstudien tycks visa att om lärare saknar ämnesdidaktiska kunskaper så verkar man få problem med att följa läroplanens intentioner, vilket också kan försvåra möjligheten till att arbetet med förskolans hela matematikinnehåll på ett grundläggande sätt. Dessutom tycks det uppstå brister i att följa och dokumentera barnens lärande och man verkar fokusera mer på "görande". Betydelse för läraryrket Eget intresse för matematik hos lärare är bra men ämnesdidaktiska kunskaper tycks ha en avgörande betydelse för förskolans matematik och det finns behov av kompetensutveckling för att barn ska ges möjligheter att sträva mot målen

The use of biomarkers for the etiologic diagnosis of MCI in Europe: an EADC survey

We investigated the use of Alzheimer's disease (AD) biomarkers in European Alzheimer's Disease Consortium centers and assessed their perceived usefulness for the etiologic diagnosis of mild cognitive impairment (MCI). We surveyed availability, frequency of use, and confidence in diagnostic usefulness of markers of brain amyloidosis (amyloid positron emission tomography [PET], cerebrospinal fluid [CSF] Aβ42) and neurodegeneration (medial temporal atrophy [MTA] on MR, fluorodeoxyglucose positron emission tomography [FDG-PET], CSF tau). The most frequently used biomarker is visually rated MTA (75% of the 37 responders reported using it "always/frequently") followed by CSF markers (22%), FDG-PET (16%), and amyloid-PET (3%). Only 45% of responders perceive MTA as contributing to diagnostic confidence, where the contribution was rated as "moderate". Seventy-nine percent of responders felt "very/extremely" comfortable delivering a diagnosis of MCI due to AD when both amyloid and neuronal injury biomarkers were abnormal (P &lt; .02 versus any individual biomarker). Responders largely agreed that a combination of amyloidosis and neuronal injury biomarkers was a strongly indicative AD signature

Neuropeptide Y (NPY) in cerebrospinal fluid from patients with Huntington's Disease : increased NPY levels and differential degradation of the NPY1-30 fragment

Huntington's disease (HD) is an inherited and fatal polyglutamine neurodegenerative disorder caused by an expansion of the CAG triplet repeat coding region within the HD gene. Progressive dysfunction and loss of striatal GABAergic medium spiny neurons (MSNs) may account for some of the characteristic symptoms in HD patients. Interestingly, in HD, MSNs expressing neuropeptide Y (NPY) are spared and their numbers is even up-regulated in HD patients. In line with this, we report here on increased immuno-linked NPY (IL-NPY) levels in human cerebrospinal fluid (hCSF) from HD patients. As this antibody-based detection of NPY may provide false positive differences due to the antibody-based detections of only fragments of NPY, the initial finding was validated by investigating the proteolytic stability of NPY in hCSF using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and selective inhibitors. A comparison between resulting NPY-fragments and detailed epitope analysis verified significant differences of IL-NPY1-36/3-36 and NPY1-30 levels between HD patients and control subjects. Ex vivo degradomics analysis demonstrated that NPY is initially degraded to NPY1-30 by cathepsin D (CTSD) in both HD patients and control subjects. Yet, NPY1-30 is then further differentially hydrolyzed by thimet oligopeptidase (TOP) in HD patients and by neprilysin (NEP) in control subjects. Furthermore, altered hCSF TOP-inhibitor Dynorphin A1-13 (Dyn-A1-13 ) and TOP-substrate Dyn-A1-8 levels indicate an impaired Dyn-A-TOP network in HD patients. Thus, we conclude that elevated IL-NPY-levels in conjunction with TOP- / NEP-activity/protein as well as Dyn-A1-13 -protein levels may serve as a potential biomarker in human CSF of HD. This article is protected by copyright. All rights reserved

Single-cell multi-omics of human preimplantation embryos shows susceptibility to glucocorticoids

The preconceptual, intrauterine, and early life environments can have a profound and long-lasting impact on the developmental trajectories and health outcomes of the offspring. Given the relatively low success rates of assisted reproductive technologies (ART; similar to 25%), additives and adjuvants, such as glucocorticoids, are used to improve the success rate. Considering the dynamic developmental events that occur during this window, these exposures may alter blastocyst formation at a molecular level, and as such, affect not only the viability of the embryo and the ability of the blastocyst to implant, but also the developmental trajectory of the first three cell lineages, ultimately influencing the physiology of the embryo. In this study, we present a comprehensive single-cell transcriptome, methylome, and small RNA atlas in the day 7 human embryo. We show that, despite no change in morphology and developmental features, preimplantation glucocorticoid exposure reprograms the molecular profile of the trophectoderm (TE) lineage, and these changes are associated with an altered metabolic and inflammatory response. Our data also suggest that glucocorticoids can precociously mature the TE sublineages, supported by the presence of extravillous trophoblast markers in the polar sublineage and presence of X Chromosome dosage compensation. Further, we have elucidated that epigenetic regulation-DNA methylation and microRNAs (miRNAs)-likely underlies the transcriptional changes observed. This study suggests that exposures to exogenous compounds during preimplantation may unintentionally reprogram the human embryo, possibly leading to suboptimal development and longer-term health outcomes