Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.

BackgroundIntracellular calcium is an important ion involved in the regulation and modulation of many neuronal functions. From regulating cell cycle and proliferation to initiating signaling cascades and regulating presynaptic neurotransmitter release, the concentration and timing of calcium activity governs the function and fate of neurons. Changes in calcium transients can be used in high-throughput screening applications as a basic measure of neuronal maturity, especially in developing or immature neuronal cultures derived from stem cells.ResultsUsing human induced pluripotent stem cell derived neurons and dissociated mouse cortical neurons combined with the calcium indicator Fluo-4, we demonstrate that PeakCaller reduces type I and type II error in automated peak calling when compared to the oft-used PeakFinder algorithm under both basal and pharmacologically induced conditions.ConclusionHere we describe PeakCaller, a novel MATLAB script and graphical user interface for the quantification of intracellular calcium transients in neuronal cultures. PeakCaller allows the user to set peak parameters and smoothing algorithms to best fit their data set. This new analysis script will allow for automation of calcium measurements and is a powerful software tool for researchers interested in high-throughput measurements of intracellular calcium.

IntroductionWe aimed to integrate all available epidemiological evidence to characterise an exposure–response model of ambient fine particulate matter (PM2.5) and the risk of chronic kidney disease (CKD) across the spectrum of PM2.5 concentrations experienced by humans. We then estimated the global and national burden of CKD attributable to PM2.5.MethodsWe collected data from prior studies on the association of PM2.5 with CKD and used an integrative meta-regression approach to build non-linear exposure–response models of the risk of CKD associated with PM2.5 exposure. We then estimated the 2017 global and national incidence, prevalence, disability-adjusted life-years (DALYs) and deaths due to CKD attributable to PM2.5 in 194 countries and territories. Burden estimates were generated by linkage of risk estimates to Global Burden of Disease study datasets.ResultsThe exposure–response function exhibited evidence of an increase in risk with increasing PM2.5 concentrations, where the rate of risk increase gradually attenuated at higher PM2.5 concentrations. Globally, in 2017, there were 3 284 358.2 (95% UI 2 800 710.5 to 3 747 046.1) incident and 122 409 460.2 (108 142 312.2 to 136 424 137.9) prevalent cases of CKD attributable to PM2.5, and 6 593 134.6 (5 705 180.4 to 7 479 818.4) DALYs and 211 019.2 (184 292.5 to 236 520.4) deaths due to CKD attributable to PM2.5. The burden was disproportionately borne by low income and lower middle income countries and exhibited substantial geographic variability, even among countries with similar levels of sociodemographic development. Globally, 72.8% of prevalent cases of CKD attributable to PM2.5 and 74.2% of DALYs due to CKD attributable to PM2.5 were due to concentrations above 10 µg/m3, the WHO air quality guidelines.ConclusionThe global burden of CKD attributable to PM2.5 is substantial, varies by geography and is disproportionally borne by disadvantaged countries. Most of the burden is associated with PM2.5 levels above the WHO guidelines, suggesting that achieving those targets may yield reduction in CKD burden.

In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future.