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

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.

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Semiconductor process development for state-of-the-art devices is a complex task that requires up to years of development. The complexity comes from the need to tune a significant number of process knobs in latest process tools, to meet multiple on-wafer performance targets, across an entire wafer. AppliedPRO® is a software and library of algorithms developed by Applied Materials for process recipe optimization to meet simultaneous process requirements across the entire wafer. The software is tailored to semiconductor use-cases and designed to be primarily used by process engineers to make critical decisions with confidence during process development. Over 100 use-cases have been generated for various semiconductor chips manufacturers, showing faster development time, less development resources, and higher process engineer productivity. This paper shows the use-case of Samsung N+1 Logic BEOL Spacer-Etch process recipe optimization using AppliedPRO®. We utilized AppliedPRO® structured design of experiment methodology and machine-learning algorithms to simultaneously model 10 process-recipe knobs of Applied Materials’ Centris® Sym3® X Etch system and their effect on 8 on-wafer metrics, and determine optimal process knob conditions for minimizing Spacer-tail, which is a key performance metric, while keeping other metrics close to spec. These optimized conditions reduced Spacer-tail by 73% on coupons, which was also validated on full-wafer. These optimal results were previously unachievable in all the previous experimental trials before introducing AppliedPRO®.