Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor–related orphan nuclear receptor γt (RORγt)–dependent effector T lymphocytes [e.g., T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes

Survivin, an apoptosis inhibitor/cell-cycle regulator, is critically required for suppression of apoptosis and ensuring normal cell division in the G2/M phase of the cell cycle. It is highly expressed in a cell cycle-regulated manner and localizes together with caspase-3 on microtubules within centrosomes. Whether survivin is a physiologically relevant caspase inhibitor has been unclear due to the difficulties with obtaining correctly folded survivin and finding the right conditions for inhibition assay. In this study, recombinant, active human survivin was expressed in Escherichia coli and purified to homogeneity. The protein, existing as a homodimer in solution, binds caspase-3 and -7 tightly with dissociation constants of 20.9 and 11.5 nM, respectively, when evaluated by surface plasmon resonance spectroscopy. Consistently, survivin potently inhibits the cleavage of a physiological substrate poly(ADP-ribose) polymerase and an artificial tetrapeptide by caspase-3 and -7 in vitro with apparent inhibition constants of 36.0 and 16.5 nM, respectively. The data suggest that sequestering caspase-3 and -7 in inhibited states on microtubules is at least one mechanism of survivin in the suppression of default apoptosis in the G2/M phase. The localization of survivin on microtubules, which is essential for its function, should increase the protective activity at the action site.

Maternal immune activation (MIA) contributes to behavioral abnormalities associated with neurodevelopmental disorders in both primate and rodent offspring1-4. In humans, epidemiological studies suggest that exposure of fetuses to maternal inflammation increases the likelihood of developing Autism Spectrum Disorder (ASD)5-7. We recently demonstrated that interleukin-17a (IL-17a) produced by Th17 cells, CD4+ T helper effector cells involved in multiple inflammatory conditions, is required in pregnant mice to induce behavioral as well as cortical abnormalities in the offspring exposed to MIA8. However, it is unclear if other maternal factors are required to promote MIA-associated phenotypes. Moreover, underlying mechanisms by which MIA leads to T cell activation with increased IL-17a in the maternal circulation are not well understood. Here, we show that MIA phenotypes in offspring require maternal intestinal bacteria that promote Th17 cell differentiation. Pregnant mice that had been colonized with the mouse commensal segmented filamentous bacteria (SFB) or human commensal bacteria that induce intestinal Th17 cells were more likely to produce offspring with MIA-associated abnormalities. We also show that small intestine dendritic cells (DCs) from pregnant, but not from non-pregnant, females upon exposure to MIA secrete IL-1β/IL-23/IL-6 and stimulate T cells to produce IL-17a. Overall, our data suggest that defined gut commensal bacteria with a propensity to induce Th17 cells may increase the risk for neurodevelopmental disorders in offspring of pregnant mothers undergoing immune system activation due to infections or autoinflammatory syndromes.

SummaryEmbryonic stem cells hold great promise for various diseases because of their unlimited capacity for self-renewal and ability to differentiate into any cell type in the body. However, despite over 3 decades of research, there have been no reports on the safety and potential efficacy of pluripotent stem cell progeny in Asian patients with any disease. Here, we report the safety and tolerability of subretinal transplantation of human embryonic-stem-cell (hESC)-derived retinal pigment epithelium in four Asian patients: two with dry age-related macular degeneration and two with Stargardt macular dystrophy. They were followed for 1 year. There was no evidence of adverse proliferation, tumorigenicity, ectopic tissue formation, or other serious safety issues related to the transplanted cells. Visual acuity improved 9–19 letters in three patients and remained stable (+1 letter) in one patient. The results confirmed that hESC-derived cells could serve as a potentially safe new source for regenerative medicine.

Introduction Progression of COVID-19 to severe disease and death is insufficiently understood. Objective Summarize the prevalence of risk factors and adverse outcomes and determine their associations in COVID-19 patients who were hospitalized. Methods We searched Medline, Embase and Web of Science for case-series and observational studies of hospitalized COVID-19 patients through August 31, 2020. Data were analyzed by fixed-effects meta-analysis using Shore’s adjusted confidence intervals to address heterogeneity. Results Seventy-seven studies comprising 38906 hospitalized patients met inclusion criteria; 21468 from the US-Europe and 9740 from China. Overall prevalence of death [% (95% CI)] from COVID-19 was 20% (18–23%); 23% (19–27%) in the US and Europe and 11% (7–16%) for China. Of those that died, 85% were aged≥60 years, 66% were males, and 66%, 44%, 39%, 37%, and 27% had hypertension, smoking history, diabetes, heart disease, and chronic kidney disease (CKD), respectively. The case fatality risk [%(95% CI)] were 52% (46–60) for heart disease, 51% (43–59) for COPD, 48% (37–63) for chronic kidney disease (CKD), 39% for chronic liver disease (CLD), 28% (23–36%) for hypertension, and 24% (17–33%) for diabetes. Summary relative risk (sRR) of death were higher for age≥60 years [sRR = 3.6; 95% CI: 3.0–4.4], males [1.3; 1.2–1.4], smoking history [1.3; 1.1–1.6], COPD [1.7; 1.4–2.0], hypertension [1.8; 1.6–2.0], diabetes [1.5; 1.4–1.7], heart disease [2.1; 1.8–2.4], CKD [2.5; 2.1–3.0]. The prevalence of hypertension (55%), diabetes (33%), smoking history (23%) and heart disease (17%) among the COVID-19 hospitalized patients in the US were substantially higher than that of the general US population, suggesting increased susceptibility to infection or disease progression for the individuals with comorbidities. Conclusions Public health screening for COVID-19 can be prioritized based on risk-groups. Appropriately addressing the modifiable risk factors such as smoking, hypertension, and diabetes could reduce morbidity and mortality due to COVID-19; public messaging can be accordingly adapted.

Uniform sampling from graphical realizations of a given degree sequence is a fundamental component in simulation-based measurements of network observables, with applications ranging from epidemics, through social networks to Internet modeling. Existing graph sampling methods are either link-swap based (Markov-Chain Monte Carlo algorithms) or stub-matching based (the Configuration Model). Both types are ill-controlled, with typically unknown mixing times for link-swap methods and uncontrolled rejections for the Configuration Model. Here we propose an efficient, polynomial time algorithm that generates statistically independent graph samples with a given, arbitrary, degree sequence. The algorithm provides a weight associated with each sample, allowing the observable to be measured either uniformly over the graph ensemble, or, alternatively, with a desired distribution. Unlike other algorithms, this method always produces a sample, without back-tracking or rejections. Using a central limit theorem-based reasoning, we argue, that for large , and for degree sequences admitting many realizations, the sample weights are expected to have a lognormal distribution. As examples, we apply our algorithm to generate networks with degree sequences drawn from power-law distributions and from binomial distributions.

BackgroundPrevious studies have documented the cardiometabolic health benefits of plant‐based diets; however, these studies were conducted in selected study populations that had narrow generalizability.Methods and ResultsWe used data from a community‐based cohort of middle‐aged adults (n=12 168) in the ARIC (Atherosclerosis Risk in Communities) study who were followed up from 1987 through 2016. Participants’ diet was classified using 4 diet indexes. In the overall plant‐based diet index and provegetarian diet index, higher intakes of all or selected plant foods received higher scores; in the healthy plant‐based diet index, higher intakes of only the healthy plant foods received higher scores; in the less healthy plant‐based diet index, higher intakes of only the less healthy plant foods received higher scores. In all indexes, higher intakes of animal foods received lower scores. Results from Cox proportional hazards models showed that participants in the highest versus lowest quintile for adherence to overall plant‐based diet index or provegetarian diet had a 16%, 31% to 32%, and 18% to 25% lower risk of cardiovascular disease, cardiovascular disease mortality, and all‐cause mortality, respectively, after adjusting for important confounders (all P<0.05 for trend). Higher adherence to a healthy plant‐based diet index was associated with a 19% and 11% lower risk of cardiovascular disease mortality and all‐cause mortality, respectively, but not incident cardiovascular disease (P<0.05 for trend). No associations were observed between the less healthy plant‐based diet index and the outcomes.ConclusionsDiets higher in plant foods and lower in animal foods were associated with a lower risk of cardiovascular morbidity and mortality in a general population.

Objective To evaluate the association between ultra-processed food intake and all-cause mortality and cardiovascular disease mortality in a nationally representative sample of U.S. adults. Design Prospective analyses of reported frequency of ultra-processed food intake in 1988-1994 and all-cause mortality and cardiovascular disease mortality through 2011 Setting The Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) Participants Adult participants (≥20y, n=11,898) Results Over a median follow-up of 19 years, individuals in the highest quartile of frequency of ultra-processed food intake (e.g. sugar-sweetened or artificially-sweetened beverages, sweetened milk, sausage or other reconstructed meats, sweetened cereals, confectionery desserts) had a 31% higher risk of all-cause mortality, after adjusting for demographic and socioeconomic confounders, and health behaviors (adjusted HR: 1.31; 95% CI: 1.09, 1.58; P-trend=0.001). No association with cardiovascular disease mortality was observed (P-trend=0.86). Conclusions Higher frequency of ultra-processed food intake was associated with higher risk of all-cause mortality in a representative sample of U.S. adults. More longitudinal studies with dietary data reflecting the modern food supply are needed to confirm our results.