Rosacrosby0376

This association was reduced after adjusting for factors in the extended family (β = 1.93; 95% CI 1.16 to 2.71) and the nuclear family (β = 1.20; 95% CI 0.39 to 2.01). Maternal at-risk drinking had a smaller association with child emotional problems (β = 1.80; 95% CI 1.26 to 2.34). This association was reduced after adjusting for factors in the extended family (β = 0.67; 95% CI -0.12 to 1.46) and the nuclear family (β = 0.58; 95% CI -0.31 to 1.48). CONCLUSIONS The results suggest an association between maternal at-risk drinking and child behavior problems. A reduction in maternal drinking may improve outcomes for children with such symptoms. Copyright © 2020 by the American Academy of Pediatrics.Toxicology - the study of how chemicals interact with biological systems - has clear relevance to human health and disease. Persistent exposure to natural and synthetic chemicals is an unavoidable part of living on our planet; yet, we understand very little about the effects of exposure to the vast majority of chemicals. While epidemiological studies can provide strong statistical inference linking chemical exposure to disease, research in model systems is essential to elucidate the mechanisms of action and to predict outcomes. Most research in toxicology utilizes a handful of mammalian models that represent a few distinct branches of the evolutionary tree. This narrow focus constrains the understanding of chemical-induced disease processes and systems that have evolved in response to exposures. We advocate for casting a wider net in environmental toxicology research to utilize diverse model systems, including zebrafish, and perform more mechanistic studies of cellular responses to chemical exposures to shift the perception of toxicology as an applied science to that of a basic science. This more-inclusive perspective will enrich the field and should remain central to research on chemical-induced disease. © 2020. Published by The Company of Biologists Ltd.For the first time, a meeting dedicated to the tyrosine kinase receptors DDR1 and DDR2 took place in Bordeaux, a famous and historical city in the south of France. Over the course of 3 days, the meeting allowed 60 participants from 11 different countries to exchange ideas and their new findings about these unique collagen receptors, focusing on their role in various physiological and pathological conditions and addressing their mechanisms of regulation and signalling. The involvement of these receptors in different pathologies was also considered, with emphasis on cancer development and potential therapeutic applications. Here, we summarize the key elements of this meeting. © 2020. Published by The Company of Biologists Ltd.AIMS An association between antibody deficiency and clozapine use in individuals with schizophrenia has recently been reported. We hypothesised that if clozapine-associated hypogammaglobulinaemia was clinically relevant this would manifest in referral patterns. METHODS Retrospective case note review of patients referred and assessed by Immunology Centre for Wales (ICW) between January 2005 and July 2018 with extraction of clinical and immunological features for individuals with diagnosis of schizophrenia-like illness. RESULTS 1791 adult patients were assessed at ICW during this period; 23 patients had a psychiatric diagnosis of schizophrenia or schizoaffective disorder. Principal indications for referral were findings of low calculated globulin and immunoglobulins. Clozapine was the single most commonly prescribed antipsychotic (17/23), disproportionately increased relative to reported use in the general schizophrenia population (OR 6.48, 95% CI 1.79 to 23.5). Clozapine therapy was noted in 6/7 (86%) of patients subsequently requiring immunoglobulin replacement therapy (IgRT). Marked reduction of class-switched memory B cells (CSMB) and plasmablasts were observed in clozapine-treated individuals relative to healthy age-matched controls. Clozapine duration is associated with CSMB decline. One patient discontinued clozapine, with gradual recovery of IgG levels without use of IgRT. CONCLUSIONS Our findings are consistent with enrichment of clozapine-treatment within schizophrenic individuals referred for ICW assessment over the last 13 years. These individuals displayed clinical patterns closely resembling the primary immunodeficiency common variable immunodeficiency, however appears reversible on drug cessation. This has diagnostic, monitoring and treatment implications for psychiatry and immunology teams and directs prospective studies to address causality and the wider implications for this patient group. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.Cystic neutrophilic granulomatous mastitis (CNGM) is a rare subtype of granulomatous mastitis with a highly distinct histological pattern often associated with Corynebacterium species. CNGM is characterised by suppurative lipogranulomas that are composed of central lipid vacuoles rimmed by neutrophils and an outer cuff of epithelioid histiocytes. Some of the lipid vacuoles may contain sparse, rod-shaped, gram-positive bacilli that can be easily missed or dismissed. The surrounding mixed inflammatory infiltrate contains Langhans-type giant cells, lymphocytes and neutrophils. Eprosartan CNGM occurs in reproductive age women with a history of pregnancy and typically presents as a palpable mass that can be painful. CNGM has many mimickers, most significantly breast carcinoma. In many cases, CNGM has significant pathological and clinical overlap with other forms of granulomatous mastitis. Given the association with Corynebacterium species, early diagnosis of CNGM is essential in offering patients the most appropriate treatment. Prolonged antibiotic therapy specifically directed to corynebacteria is required, sometimes even beyond resolution of clinical symptoms. This comprehensive review of the existing literature on CNGM describes clinical-pathological features, microbiological findings, challenges associated with the microscopic differential diagnosis, clinical implications of this diagnosis and emerging treatment options. Morphological criteria and suggested comments to convey the degree of diagnostic certainty are also proposed for standard pathology reporting. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Measuring the physical size of the cell is valuable in understanding cell growth control. Current single-cell volume measurement methods for mammalian cells are labor-intensive, inflexible, and can cause cell damage. We introduce CTRL Cell Topography Reconstruction Learner, a label-free technique incorporating the Deep Learning algorithm and the Fluorescence Exclusion method for reconstructing cell topography and estimating mammalian cell volume from DIC microscopy images alone. The method achieves quantitative accuracy, requires minimal sample preparation, and applies to a wide range of biological and experimental conditions. The method can be used to track single-cell volume dynamics over arbitrarily long time periods. Using this method, we observe that bigger newborn cells grow larger (sizer) for HT1080 fibrosarcoma cells and there is a noticeable reduction in cell size fluctuations at 25% completion of the cell cycle in HT1080 fibrosarcoma cells. © 2020. Published by The Company of Biologists Ltd.Efficient migration on adhesive surfaces involves the protrusion of lamellipodial actin networks and their subsequent stabilization by nascent adhesions. The actin binding protein lamellipodin (Lpd) is thought to play a critical role in lamellipodium protrusion, by delivering Ena/VASP proteins onto the growing plus ends of actin filaments and by interacting with the WAVE regulatory complex (WRC), an activator of the Arp2/3 complex, at the leading edge. Using B16-F1 melanoma cell lines, we demonstrate that genetic ablation of Lpd compromises protrusion efficiency and coincident cell migration without altering essential parameters of lamellipodia, including their maximal rate of forward advancement and actin polymerization. We also confirmed lamellipodia and migration phenotypes with CRISPR/Cas9-mediated Lpd knockout Rat2 fibroblasts, excluding cell type-specific effects. Moreover, computer-aided analysis of cell edge morphodynamics on B16-F1 cell lamellipodia revealed that loss of Lpd correlates with reduced temporal protrusion maintenance as a prerequisite of nascent adhesion formation. We conclude that Lpd optimizes protrusion and nascent adhesion formation by counteracting frequent, chaotic retraction and membrane ruffling. © 2020. Published by The Company of Biologists Ltd.Oncogenes can create metabolic vulnerabilities in cancer cells. We tested how AKT and MYC affect the ability of cells to shift between respiration and glycolysis. Using immortalized mammary epithelial cells, we discovered that constitutively active AKT but not MYC induced cell death in galactose culture, where cells rely on oxidative phosphorylation for energy generation. However, the negative effects of AKT were temporary, and AKT-expressing cells recommenced growth after ∼15 days in galactose. To identify the mechanisms regulating AKT-mediated cell death, we used metabolomics and found that AKT cells dying in galactose upregulated glutathione metabolism. Proteomic profiling revealed that AKT cells dying in galactose also upregulated nonsense-mediated mRNA decay, a marker of sensitivity to oxidative stress. We therefore measured levels of reactive oxygen species (ROS) and discovered that galactose induced ROS exclusively in cells expressing AKT. Furthermore, ROS were required for galactose-induced death of AKT-expressing cells. We then confirmed that galactose induced ROS-mediated cell death in breast cancer cells with upregulated AKT signaling. These results demonstrate that AKT but not MYC restricts the flexibility of cancer cells to use oxidative phosphorylation. © 2020. Published by The Company of Biologists Ltd.A novel 2,3-benzodiazepine-4 derivative, named 1g, has recently been shown to function as an anti-proliferative compound. We now show that it perturbs the formation of a functional mitotic spindle, inducing a spindle assembly checkpoint (SAC)-dependent arrest in human cells. Live analysis of individual microtubules indicates that 1g promotes a rapid and reversible reduction in microtubule growth. Unlike most anti-mitotic compounds, 1g does not interfere directly with tubulin, nor perturbs microtubules assembly in vitro The observation that 1g also triggers a SAC-dependent mitotic delay associated with chromosome segregation in Drosophila neural stem cells, suggests it targets a conserved microtubules regulation module in human and flies. Altogether, our results indicate that 1g is a novel promising antimitotic drug with the unique properties altering microtubules growth and mitotic spindle organization. © 2020. Published by The Company of Biologists Ltd.Regulation of proliferation, apoptosis and cell cycle is crucial for the physiology of germ cells. Their malfunction contributes to infertility and germ cell tumours. Kinesin KIF18A is an important regulator of those processes in animal germ cells. Posttranscriptional regulation of KIF18A has not been extensively explored. Due to the presence of PUM Binding Elements (PBEs), KIF18A mRNA is a potential target of PUMs, RNA-binding proteins of posttranscriptional gene regulation (PTGR). We conducted RNA co-immunoprecipitation combined with RT-qPCR, as well as luciferase reporter assay by applying appropriate luciferase construct encoding the wild type KIF18A 3'UTR, upon PUMs overexpression or knockdown in TCam-2 cells representing human male germ cells. We found that KIF18A is repressed by PUM1 and PUM2. To study how this regulation influences KIF18A function, MTS proliferation assay, apoptosis and cell cycle analysis using flow cytometry was performed upon KIF18A mRNA siRNA knockdown. KIF18A significantly influences proliferation, apoptosis and cell cycle, these effects being opposite to PUM effects.