Primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by small brain size with mental retardation. CPAP/CENPJ, a known microcephaly gene, plays a key role in centriole biogenesis. Here, we generated a previously unreported conditional knockout allele in the mouse Cpap gene. Our results showed that conditional Cpap deletion preferentially induces formation of monopolar spindles in radial glia progenitors (RGPs) and causes robust apoptosis that severely disrupts embryonic brains. Interestingly, microcephalic brains with reduced apoptosis are detected in the conditional Cpap gene-deleted mice, which lose only one allele of p53, while simultaneous removal of p53 and Cpap rescues RGPs death. Furthermore, Cpap deletion leads to cilia loss, RGPs mislocalization, junctional integrity disruption, massive heterotopia, and severe cerebellar hypoplasia. Together, these findings indicate that complete CPAP loss leads to severe and complex phenotypes in developing mouse brain, and provide new insights into the causes of MCPH.RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS is the most frequently mutated oncogene. Here we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations.  https://www.selleckchem.com/products/ots964.html  Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidyl serine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by a structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied rocaglamide-mediated effects on RAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and treatment with rocaglamide reduces NSCLC tumours in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications.Intracellular pools of the heterotrimeric G-protein alpha-subunit, Gαi3, has been shown to promote growth factor signaling, while at the same time inhibiting the activation of JNK and autophagic signaling following nutrient starvation. The precise molecular mechanisms linking Gαi3 to both stress and growth factor signaling remain poorly understood. Importantly, JNK-mediated phosphorylation of Bcl-2 was shown to activate autophagic signaling following nutrient deprivation. Our data shows that activated Gαi3 decreases Bcl-2 phosphorylation, whereas biochemical inhibitors of Gαi3, such as RGS4 and AGS3, markedly increase the levels of phosphorylated Bcl-2. Manipulation of the palmitoylation status and intracellular localization of RGS4 suggests that Gαi3 modulates phosphorylated Bcl-2 levels and autophagic signaling from discreet TGN38-labelled vesicle pools. Consistent with an important role for these molecules in normal tissue responses to nutrient-deprivation, increased Gαi signaling within nutrient-starved adrenal glands from RGS4-KO mice resulted in a dramatic abrogation of autophagic flux, compared to wild type tissues. Together, these data suggest that the activity of Gαi3 and RGS4 from discreet TGN38-labelled vesicle pools are critical regulators of autophagic signaling via their ability to modulate phosphorylation of Bcl-2.Leishmania spp are obligate intracellular parasites that infect phagocytes, notably macrophages. No information is available on how Leishmania parasites respond to pyroptosis of their host cell, known to limit microbial infection. Here, we analyzed the pyroptotic process and the fate of intracellular amastigotes at the single cell level using high-content, real-time imaging. Bone marrow-derived macrophages were infected with virulent L. amazonensis amastigotes and sequentially treated with lipopolysaccharide and adenosine triphosphate for pyroptosis induction. Real-time monitoring identified distinct pyroptotic phases, including rapid decay of the parasitophorous vacuole (PV), progressive cell death, and translocation of the luminal PV membrane to the cell surface in 40% of macrophages, resulting in the extracellular exposure of amastigotes that remained anchored to PV membranes. Electron microscopy analyses revealed an exclusive polarized orientation of parasites, with the anterior pole exposed toward the extracellular milieu, and the parasite posterior pole attached to the PV membrane. Exposed parasites retain their full infectivity towards naïve macrophages suggesting that host cell pyroptosis may contribute to parasite dissemination.Background The exploitation of synthetic data in healthcare is at an early stage. Synthetic data generation could unlock the vast potential within healthcare datasets that are too sensitive for release due to privacy concerns. Several synthetic data generators have been developed to date, however studies evaluating their efficacy and generalisability are scarce. Objective This work sets out to understand the difference in performance of supervised machine learning models trained on synthetic data compared with those trained on real data. Methods A total of 19 open healthcare datasets containing both categorical and numerical data have been selected for experimental work. Synthetic data is generated using three popular synthetic data generators that apply Classification and Regression Trees, parametric and Bayesian network approaches. Real and synthetic data are used (separately) to train five supervised machine learning models stochastic gradient descent, decision tree, k-nearest neighbors, random forest and m policy decision-making.Background Musculoskeletal conditions are the second greatest contributor to disability worldwide and have significant individual, societal, and economic implications. Due to the growing burden of musculoskeletal disability, an integrated and strategic response is urgently required. Digital health interventions provide high-reach, low-cost, readily accessible, and scalable interventions for large patient populations that address time and resource constraints. Objective This review aimed to investigate if digital health interventions are effective in reducing pain and functional disability in patients with musculoskeletal conditions. Methods A systematic review was undertaken to address the research objective. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review protocol was registered with the International Prospective Register of Systematic Reviews before commencement of the study. The following databases were searched Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Cumulative Index to Nursing and Allied Health Literature, and Scopus from January 1, 2000, to November 15, 2019, using search terms and database specific-medical subject headings terms in various combinations appropriate to the research objective.