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Detection of asymptomatic or subclinical novel human coronavirus SARS-CoV-2 infection is critical for understanding the overall prevalence and infection potential of COVID-19. To estimate the cumulative prevalence of SARS-CoV-2 infection in China, we evaluated the host serologic response, measured by the levels of immunoglobulins M and G in 17,368 individuals, in the city of Wuhan, the epicenter of the COVID-19 pandemic in China, and geographic regions in the country, during the period from 9 March 2020 to 10 April 2020. In our cohorts, the seropositivity in Wuhan varied between 3.2% and 3.8% in different subcohorts. Seroposivity progressively decreased in other cities as the distance to the epicenter increased. Patients who visited a hospital for maintenance hemodialysis and healthcare workers also had a higher seroprevalence of 3.3% (51 of 1,542, 2.5-4.3%, 95% confidence interval (CI)) and 1.8% (81 of 4,384, 1.5-2.3%, 95% CI), respectively. More studies are needed to determine whether these results are generalizable to other populations and geographic locations, as well as to determine at what rate seroprevalence is increasing with the progress of the COVID-19 pandemic. Serologic surveillance has the potential to provide a more faithful cumulative viral attack rate for the first season of this novel SARS-CoV-2 infection.Metastatic melanoma is challenging to manage. Although targeted- and immune therapies have extended survival, most patients experience therapy resistance. The adaptability of melanoma cells in nutrient- and therapeutically-challenged environments distinguishes melanoma as an ideal model for investigating therapy resistance. In this review, we discuss the current available repertoire of melanoma models including two- and three-dimensional tissue cultures, organoids, genetically engineered mice and patient-derived xenograft. In particular, we highlight how each system recapitulates different features of melanoma adaptability and can be used to better understand melanoma development, progression and therapy resistance.Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/- and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/- and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/- pups born to Dhcr7+/- dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/- offspring to levels approaching those seen in a mouse model of Smith-Lemli-Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1-3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.Evidence from epidemiological and laboratory studies, as well as randomized placebo-controlled trials, suggests supplementation with n-3 polyunsaturated fatty acids (PUFAs) may be efficacious for treatment of major depressive disorder (MDD). The mechanisms underlying n-3 PUFAs potential therapeutic properties remain unknown. There are suggestions in the literature that glial hypofunction is associated with depressive symptoms and that antidepressants may normalize glial function. In this study, induced pluripotent stem cells (iPSC)-derived neuronal stem cell lines were generated from individuals with MDD. Astrocytes differentiated from patient-derived neuronal stem cells (iNSCs) were verified by GFAP. Cells were treated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or stearic acid (SA). buy GSK864 During astrocyte differentiation, we found that n-3 PUFAs increased GFAP expression and GFAP positive cell formation. BDNF and GDNF production were increased in the astrocytes derived from patients subsequent to n-3 PUFA treatment. Stearic Acid (SA) treatment did not have this effect. CREB activity (phosphorylated CREB) was also increased by DHA and EPA but not by SA. Furthermore, when these astrocytes were treated with n-3 PUFAs, the cAMP antagonist, RP-cAMPs did not block n-3 PUFA CREB activation. However, the CREB specific inhibitor (666-15) diminished BDNF and GDNF production induced by n-3 PUFA, suggesting CREB dependence. Together, these results suggested that n-3 PUFAs facilitate astrocyte differentiation, and may mimic effects of some antidepressants by increasing production of neurotrophic factors. The CREB-dependence and cAMP independence of this process suggests a manner in which n-3 PUFA could augment antidepressant effects. These data also suggest a role for astrocytes in both MDD and antidepressant action.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Numerous cell surface receptors and receptor-like proteins (RLPs) undergo activation or deactivation via a transmembrane domain (TMD). A subset of plant RLPs distinctively localizes to the plasma membrane-lined pores called plasmodesmata. Those RLPs include the Arabidopsis thaliana Plasmodesmata-located protein (PDLP) 5, which is well known for its vital function regulating plasmodesmal gating and molecular movement between cells. In this study, we report that the TMD, although not a determining factor for the plasmodesmal targeting, serves essential roles for the PDLP5 function. In addition to its role for membrane anchoring, the TMD mediates PDLP5 self-interaction and carries an evolutionarily conserved motif that is essential for PDLP5 to regulate cell-to-cell movement. Computational modeling-based analyses suggest that PDLP TMDs have high propensities to dimerize. We discuss how a specific mode(s) of TMD dimerization might serve as a common mechanism for PDLP5 and other PDLP members to regulate cell-to-cell movement.
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