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Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change - increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7-21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7-21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type-specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.

BACKGROUND: Autism spectrum disorder involves neurodevelopmental dysregulations that lead to visible symptoms at early stages of life. Many autism spectrum disorder-related mechanisms suggested by animal studies are supported by demonstrated improvement in autistic-like phenotypes in adult animals following experimental reversal of dysregulated mechanisms. However, whether such mechanisms also act at earlier stages to cause autistic-like phenotypes is unclear. METHODS: We used Shank2-/- mice carrying a mutation identified in human autism spectrum disorder (exons 6 and 7 deletion) and combined electrophysiological and behavioral analyses to see whether early pathophysiology at pup stages is different from late pathophysiology at juvenile and adult stages and whether correcting early pathophysiology can normalize late pathophysiology and abnormal behaviors in juvenile and adult mice. RESULTS: Early correction of a dysregulated mechanism in young mice prevents manifestation of autistic-like social behaviors in adult mice. Shank2-/- mice, known to display N-methyl-D-aspartate receptor (NMDAR) hypofunction and autistic-like behaviors at postweaning stages after postnatal day 21 (P21), show the opposite synaptic phenotype-NMDAR hyperfunction-at an earlier preweaning stage (∼P14). Moreover, this NMDAR hyperfunction at P14 rapidly shifts to NMDAR hypofunction after weaning (∼P24). Chronic suppression of the early NMDAR hyperfunction by the NMDAR antagonist memantine (P7-P21) prevents NMDAR hypofunction and autistic-like social behaviors from manifesting at later stages (∼P28 and P56). CONCLUSIONS: Early NMDAR hyperfunction leads to late NMDAR hypofunction and autistic-like social behaviors in Shank2-/- mice, and early correction of NMDAR dysfunction has the long-lasting effect of preventing autistic-like social behaviors from developing at later stages.

In this research, we analyze the real data in the NAND Flash memory industry using a control chart. There are thousands of electrical measures for each NAND Flash memory chip. We monitor these data through a control chart to ensure that the manufacturing process is in control. For better interpretability, we apply a univariate control chart technique to each variable. However, most existing control charts, such as the EWMA chart, do not include between-subgroup variations but only within-subgroup variations. They often obtain too narrow control limits for some variables, which leads too many subgroups to fall outside the control limits. To overcome this issue, we apply a control chart under a mixed-effects modeling framework to include both within-subgroup and between-subgroup variations. Additionally, the EWMA chart assumes that all the items are normally distributed; however, we frequently encounter that a normal assumption is violated. To overcome this limitation, we apply a robust approach based on a nonparametric sign chart. Furthermore, we introduce a p-value combination method to increase the statistical power for the gradual change detection of a statistical process. Our study show that the proposed control chart can efficiently monitor the real data in the NAND Flash memory industry. [ABSTRACT FROM AUTHOR]

Introduction Asian dust is a seasonal meteorological phenomenon caused by dust storms that originate in the deserts of Mongolia and northern China and are carried eastward along mid-latitude westerlies to [...], BACKGROUND: Potential adverse health effects of Asian dust exposure have been reported, but systematic reviews and quantitative syntheses are lacking. OBJECTIVE: We reviewed epidemiologic studies that assessed the risk of mortality, hospital admissions, and symptoms/dysfunction associated with exposure to Asian dust. METHODS: We performed a systematic search of PubMed and Web of Science to identify studies that reported the association between Asian dust exposure and human health outcomes. We conducted separate meta-analyses using a random-effects model for mortality and hospital admissions for a specific health outcome and assessed pooled estimates for each lag when at least three studies were available for a specific lag. RESULTS: We identified 89 studies that met our inclusion criteria for the systematic review, and 21 studies were included in the meta-analysis. The pooled estimates (percentage changes) of mortality from circulatory and respiratory causes for Asian dust days vs. non- Asian dust days were 2.33% [95% confidence interval (CI): 0.76, 3.93] increase at lag 0 and 3.99% (95% CI: 0.08, 8.06) increase at lag 3, respectively. The increased risk for hospital admissions for respiratory disease, asthma, and pneumonia peaked at lag 3 by 8.85% (95% CI: 0.80, 17.55), 14.55% (95% CI: 6.74, 22.94), and 8.51% (95% CI: 2.89, 14.44), respectively. Seven of 12 studies reported reduced peak expiratory flow, and 16 of 21 studies reported increased respiratory symptoms associated with Asian dust exposure. There were substantial variations between the studies in definitions of Asian dust, study designs, model specifications, and confounder controls. DISCUSSION: We found evidence of increased mortality and hospital admissions for circulatory and respiratory events. However, the number of studies included in the meta-analysis was not large and further evidences are merited to strengthen our conclusions. Standardized protocols for epidemiological studies would facilitate interstudy comparisons. https://doi.org/10.1289/EHP5312

Introduction Suicide is a significant public health concern. It is the second leading cause of death among young people 15-29 years of age, and there were an estimated 803,900 deaths [...], Background: Previous literature suggests that higher ambient temperature may play a role in increasing the risk of suicide. However, no multicountry study has explored the shape of the association and the role of moderate and extreme heat across different locations. Objectives: We examined the short-term temperature-suicide relationship using daily time-series data collected for 341 locations in 12 countries for periods ranging from 4 to 40 y. Methods: We conducted a two-stage meta-analysis. First, we performed location-specific time-stratified case-crossover analyses to examine the temperature-suicide association for each location. Then, we used a multivariate meta-regression to combine the location-specific lag-cumulative nonlinear associations across all locations and by country. Results: A total of 1,320,148 suicides were included in this study. Higher ambient temperature was associated with an increased risk of suicide in general, and we observed a nonlinear association (inverted J-shaped curve) with the highest risk at 27[degrees]C. The relative risk (RR) for the highest risk was 1.33 (95% CI: 1.30, 1.36) compared with the risk at the first percentile. Country-specific results showed that the nonlinear associations were more obvious in northeast Asia (Japan, South Korea, and Taiwan). The temperature with the highest risk of suicide ranged from the 87th to 88th percentiles in the northeast Asian countries, whereas this value was the 99th percentile in Western countries (Canada, Spain, Switzerland, the UK, and the United States) and South Africa, where nearly linear associations were estimated. The country-specific RRs ranged from 1.31 (95% CI: 1.19, 1.44) in the United States to 1.65 (95% CI: 1.40, 1.93) in Taiwan, excluding countries where the results were substantially uncertain. Discussion: Our findings showed that the risk of suicide increased with increasing ambient temperature in many countries, but to varying extents and not necessarily linearly. This temperature-suicide association should be interpreted cautiously, and further evidence of the relationship and modifying factors is needed. https://doi.org/10.1289/EHP4898