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Additionally, PHLPP1 inhibition significantly reduced HG-induced apoptosis and restored PI3K/AKT/mTOR pathway activity in H9c2 cells. selleckchem Furthermore, pretreatment with LY294002, an inhibitor of PI3K/Akt/mTOR pathway, abolished the anti-apoptotic effect of PHLPP1 inhibition. CONCLUSION Our study indicated that PHLPP1 inhibition alleviated cardiac dysfunction via activating the PI3K/Akt/mTOR signalling pathway in DCM. Therefore, PHLPP1 may be a novel therapeutic target for human DCM. © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.The aim of this study was to gain a better understanding of the venous leg ulcer (VLU) management in primary health care settings located in Melbourne metropolitan and rural Victoria, Australia. We explored health professionals' perspective on the use of the Australian and New Zealand Venous Leg Ulcer Clinical Practice Guideline (VLU CPG) to identify the main challenges of VLU CPG uptake in clinical practice. We conducted semi-structured interviews with 15 general practitioners (GPs) and 20 practice nurses (PNs), including two Aboriginal health nurses. The Theoretical Domains Framework guided data collection and analysis. Data were analysed using a theory-driven analysis. We found a lack of awareness of the VLU CPGs, which resulted in suboptimal knowledge and limited adherence to evidence-based recommendations. Environmental factors, such as busy nature of clinical environment and absence of handheld Doppler ultrasound, as well as social and professional identity factors, such as reliance on previous experience and colleague's advice, influenced the uptake of the VLU CPGs in primary care. Findings of this study will inform development of interventions to increase the uptake of the VLU CPG in primary care settings and to reduce the evidence-practice gap in VLU management by health professionals. © 2020 Medicalhelplines.com Inc and John Wiley & Sons Ltd.Vitamin D is involved in brain health and function. Our objective was to determine whether lower 25-hydroxyvitamin D (25OHD) concentration was associated with focal brain volume reduction in older adults. Serum 25OHD concentration was measured among 53 older adults (72 ± 5 years; 38% female; mean 25OHD = 67.3 ± 20.8 nmol/L). Gray matter volume (GMV) was automatically segmented using voxel-based morphometry with CAT12 software. Covariables were age, gender, education, total intracranial volume, and season. Serum 25OHD was positively associated with GMV in left calcarine sulcus (P  less then  0.05, TFCE, FWE-corrected). We found atrophy of the calcarine sulcus with lower 25OHD concentrations in older adults. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.Germline mutation in the PTEN gene is the genetic basis of PTEN hamartoma tumor syndrome with the affected individuals harboring features of autism spectrum disorders. Characterizing a panel of 14 autism-associated PTEN missense mutations revealed reduced protein stability, catalytic activity, and subcellular distribution. Nine out of 14 (64%) PTEN missense mutants had reduced protein expression with most mutations confined to the C2 domain. Selected mutants displayed enhanced polyubiquitination and shortened protein half-life, but that did not appear to involve the polyubiquitination sites at lysine residues at codon 13 or 289. Analyzing their intrinsic lipid phosphatase activities revealed that 78% (11 out of 14) of these mutants had twofold to 10-fold reduction in catalytic activity toward phosphatidylinositol phosphate substrates. Analyzing the subcellular localization of the PTEN missense mutants showed that 64% (nine out of 14) had altered nuclear-to-cytosol ratios with four mutants (G44D, H123Q, E157G, and D326N) showing greater nuclear localization. The E157G mutant was knocked-in to an induced pluripotent stem cell line and recapitulated a similar nuclear targeting preference. Furthermore, iPSCs expressing the E157G mutant were more proliferative at the neural progenitor cell stage but exhibited more extensive dendritic outgrowth. In summary, the combination of biological changes in PTEN is expected to contribute to the behavioral and cellular features of this neurodevelopmental disorder. © 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.The cell wall integrity (CWI) pathway mediates the response of Saccharomyces cerevisiae to cell wall alterations. Stress at the cell surface is detected by mechanosensors, which transduce the signal to a protein kinase cascade that involves Pkc1, Bck1, Mkk1/Mkk2, the mitogen-activated protein kinase (MAPK) Slt2 and the transcription factor Rlm1. We incorporated a positive feedback loop into this pathway by placing a hyperactive MKK1 allele under the control of the Rlm1-regulated MLP1 promoter. This circuit operates as a signal amplifier and leads to a highly increased Slt2 activation under stimulating conditions. Triggering the CWI pathway in cells engineered with this circuit, which we have named the Integrity Pathway Activation Circuit (IPAC), results in strong growth inhibition. Exploitation of this hypersensitive phenotype allowed the identification of novel proteins that contribute in signalling to Rlm1 in response to cell surface stressing agents such as Congo red, zymolyase and SDS. Among these proteins, the MAPK kinase kinase Ssk2 of the osmoregulatory high-osmolarity glycerol (HOG) pathway, but not its paralogue Ssk22, proved to be necessary for the SDS-induced IPAC-mediated growth inhibition. We found the existence of an Ssk1-independent Ssk2-Pbs2-Hog1-CWI pathway signalling axis that contributes to Slt2 activation in response to cell surface stress. We also demonstrated that the MAP kinase kinases Mkk1 and Pbs2 and the MAPKs Slt2 and Hog1 of the HOG and CWI pathways interact physically, forming a complex. Our results show how a simple synthetic circuit can be used as a powerful tool for a better understanding of signalling pathways. © 2020 Universidad Complutense de Madrid. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.