22, 95% CI, 1.00-1.51; RR 1.21, 95% CI, 1.09-1.35), and moderate-to-severe NAFLD (RR 1.66, 95% CI, 1.07-2.57; RR 1.68, 95% CI, 1.41-1.99) in adulthood. No association was observed for the risks of stroke or mild NAFLD. Adjustments for age, alcohol, smoking, body mass index, and physical activity nullified some associations. The associations were generally stronger in women than in men. In summary, foetal and childhood exposure to famine may confer greater risks of developing certain cardiometabolic conditions in adulthood, particularly in women. The extent to which risks for cardiometabolic conditions are associated with early-life famine appears to be determined by certain factors in adulthood. © 2020 World Obesity Federation.The purpose of this bi-institutional retrospective study was to determine whether survival for dogs with extremity osteosarcoma (OS) is improved through the use of stereotactic radiotherapy (SRT; a single fraction of 25 Gy, or 36 Gy total given in three consecutive daily fractions) plus chemotherapy, vs lower dose conventionally planned and delivered hypofractionated radiotherapy (CHRT; 14-20 Gy total in 1-2 consecutive daily fractions) plus chemotherapy. We also sought to determine whether baseline pain severity influences oncologic outcomes following radiotherapy for canine extremity OS. The medical records of 82 dogs undergoing radiotherapy for confirmed or presumed OS were reviewed. In dogs receiving combinations of both chemotherapy and radiotherapy, survival was significantly longer with SRT vs CHRT (median overall survival time 350 vs 147 days; P = .031). In a univariate analysis, dogs with pulmonary metastases and high pain at the time of irradiation had short overall survival times; use of high radiation doses and chemotherapy were associated with improved survival. Separate multivariable models were built to assess the predictive nature of various factors that might influence event-free or overall survival in dogs treated with radiotherapy, with or without chemotherapy; for dogs treated with both chemotherapy and radiotherapy, overall survival times were significantly longer when baseline pain scores were ‘low’ (vs ‘high’; hazard ratio 0.258; P = .030), radiation doses were high (hazard ratio 0.943; P = .034). Neither pain nor radiation dose were associated with survival in dogs treated with radiotherapy, without chemotherapy. © 2020 John Wiley & Sons Ltd.Members of the GxGD-type intramembrane aspartyl proteases have emerged as key players not only in fundamental cellular processes such as B-cell development or protein glycosylation, but also in development of pathologies, such as Alzheimer’s disease or hepatitis virus infections. However, one member of this protease family, signal peptide peptidase-like 2c (SPPL2c), remains orphan and its capability of proteolysis as well as its physiological function is still enigmatic. Here, we demonstrate that SPPL2c is catalytically active and identify a variety of SPPL2c candidate substrates using proteomics. The majority of the SPPL2c candidate substrates cluster to the biological process of vesicular trafficking. Analysis of selected SNARE proteins reveals proteolytic processing by SPPL2c that impairs vesicular transport and causes retention of cargo proteins in the endoplasmic reticulum. As a consequence, the integrity of subcellular compartments, in particular the Golgi, is disturbed. Together with a strikingly high physiological SPPL2c expression in testis, our data suggest involvement of SPPL2c in acrosome formation during spermatogenesis. © 2019 The Authors.Alzheimer’s dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer’s disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 μM. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. read more In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.Duloxetine is a selective serotonine-noradrenaline re-uptake inhibitor, used in the treatment of depression, anxiety, neuropathic pain, and urinary incontinence [1]. Muscular side effects reported in the leaflet of the drug include muscle pain, muscle cramps, muscle stiffness, myocloni, and trismus [2]. Aripiprazole is an atypical neuroleptic drug used for the treatment of schizophrenia [3]. Muscular side effects of aripiprazole include rhabdomyolysis, myalgia, and muscle stiffness [4]. Only few reports from the medical literature report these side effects in patients taking these drugs [5]. Here we report a female who developed severe incapacitating muscular side effects when taking these compounds in combination for years. © 2020 John Wiley & Sons Ltd.As comprehensive sequencing technologies gain widespread use, questions about so-called secondary findings (SF) require urgent consideration. The American College of Medical Genetics and Genomics has recommended to report SF in 59 genes (ACMG SF v2.0) including four actionable genes associated with inherited primary arrhythmia syndromes (IPAS) such as catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, and Brugada syndrome. Databases provide conflicting results for the purpose of identifying pathogenic variants in SF associated with IPAS at a level of sufficient evidence for clinical return. As IPAS account for a significant proportion of sudden cardiac deaths (SCD) in young and apparently healthy individuals, variant interpretation has a great impact on diagnosis and prevention of disease. Of 6381 individuals, 0.4% carry pathogenic variants in one of the four actionable genes related to IPAS RYR2, KCNQ1, KCNH2, and SCN5A. Comparison of the databases ClinVar, Leiden Open-source Variant Database, and Human Gene Mutation Database showed impactful differences (0.