Activating mutations in LRRK2 kinase causes Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va’s role in ciliogenesis.The novel coronavirus (SARS-CoV-2) from Wuhan China discovered in December 2019 has since developed into a global epidemic. Presently, we constructed and analyzed the phylo-geo-network of SARS-CoV-2 genomes from across India to understand the viral evolution in the country. A total of 611 full-length genomes from different states of India were extracted from the EpiCov repository of GISAID initiative on 6 June, 2020. Their alignment with the reference sequence (Wuhan, NCBI accession number NC_045512.2) uncovered 270 parsimony informative sites. Furthermore, 339 genomes were divided into 51 haplogroups. The network revealed the core haplogroup as that of reference sequence NC_045512.2 (Haplogroup A1) with 157 identical sequences present across 16 states. Remaining haplogroups had less then 10 identical sequences across a maximum of three states. Selleck Tariquidar Some states with fewer samples had more haplogroups. Forty-one haplogroups were localized exclusively to any one state. The two most common lineages are B6 and B1 (Pangolin) whereas clade A2a (Covidex) appears to be the most predominant in India. Because the pandemic is still emerging, the observations need to be monitored.

Severe intraventricular hemorrhage (IVH) is a leading mortality risk factor among extremely premature neonates. Because other life-threatening conditions also occur in this population, it is unclear whether severe IVH is independently associated with death. The existence and potential implications of regional variation in severe IVH-associated mortality are unknown.

We performed a retrospective cohort study of mechanically ventilated neonates born at 22 to 29 weeks’ gestation who received care in 242 American NICUs between 2000 and 2014. After building groups composed of propensity score-matched and center-matched pairs, we used the Cox proportional hazards analysis to test our hypothesis that severe IVH would be associated with greater all-cause in-hospital mortality, defined as death before transfer or discharge. We also performed propensity score-matched subgroup analyses, comparing severe IVH-associated mortality among 4 geographic regions of the United States.

In our analysis cohort, we identified s and neonatologists is strongly influenced by ultrasound-based IVH assessment and classification.Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8+ tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. In vitro, small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow-derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti-PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing SMPD3 expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8+ T-cell-dependent immune responses and overcome resistance to anti-PD-1.

The COVID-19 pandemic has asked unprecedented questions of governments around the world. Policy responses have disrupted usual patterns of movement in society, locally and globally, with resultant impacts on national economies and human well-being. These interventions have primarily centred on enforcing lockdowns and introducing social distancing recommendations, leading to questions of trust and competency around the role of institutions and the administrative apparatus of state. This study demonstrates the unequal societal impacts in population movement during a national ‘lockdown’.

We use nationwide mobile phone movement data to quantify the effect of an enforced lockdown on population mobility by neighbourhood deprivation using an ecological study design. We then derive a mobility index using anonymised aggregated population counts for each neighbourhood (2253 Census Statistical Areas; mean population n=2086) of national hourly mobile phone location data (7.45 million records, 1 March 2020-20 July 2020) for New Zealand (NZ).