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Background: Per-and polyfluoroalkyl substances (PFAS) contamination may disrupt sleep through disrupted metabolic and immune functions. The study aims to investigate the association and potential mechanism between PFAS and sleep. Methods: We included 136 young adults recruited between 2014-2018 and 76 were re-assessed between 2020-2022. Additional 8 participants only had complete data between 2020-2022. Plasma PFAS (PFOS, PFOA, PFHxS, PFHpS, PFPeS, PFNA, PFDA) were measured at both visits using liquid-chromatography high-resolution mass spectrometry. Plasma proteins were measured by Olink® Explore 384 Cardiometabolic and Inflammation Panel I. Sleep duration was self-reported at both visits along with follow-up sleep disturbance and sleep-related impairment using validated instruments. We utilized multiple linear regression to explore the association between individual PFAS (in tertile) and these sleep outcomes. PFAS associated with sleep outcomes were subjected to computational toxicology analysis using the Comparative Toxicogenomics Database and Toxicology in the 21st Century database to identify potential genetic links between them. Mediation analysis using proteomic data was then performed to confirm the findings from computational toxicology analysis. Results: At baseline, one tertile increase in PFDA was associated with 0.39 (95 % CI: 0.05, 0.73) hours of shorter nightly sleep duration, and, at follow-up, PFHxS and PFOA were associated with 0.39 (95 % CI: 0.05, 0.72) and 0.32 (95 % CI: 0.01, 0.63) hours shorter sleep duration, respectively. One tertile increase in PFOS exposure was associated with a 2.99-point increase in sleep disturbance scores (95 % CI: 0.67, 5.31) and a 3.35-point increase in sleep-related impairment scores (95 % CI: 0.51, 6.20). Computational toxicology and mediation analyses identified potential mediating roles for several proteins in the PFAS-sleep associations, including 11-beta-dehydrogenase isozyme 1 (HSD11B1), cathepsin B (CTSB) and several immune system-related proteins. Conclusion: Future large scale epidemiological and mechanistic studies should confirm our findings and test effect measure modification of the associations by age.

Abstract Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Abstract To assess cardiometabolic profiles and proteomics to identify biomarkers associated with the metabolically healthy and unhealthy obesity. Young adults (N = 156) enrolled were classified as not having obesity, metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO) based on NCEP ATP-III criteria. Plasma proteomics at study entry were measured using Olink Cardiometabolic Explore panel. Linear regression was used to assess associations between proteomics and obesity groups as well as cardiometabolic traits of glucose, insulin, and lipid profiles at baseline and follow-up visits. Enriched biological pathways were further identified based on the significant proteomic features. Among the baseline 95 (61%) and 61 (39%) participants classified as not having obesity and having obesity (8 MHO and 53 MUHO), respectively. Eighty of the participants were followed-up with an average 4.6 years. Forty-one proteins were associated with obesity (FDR

ABSTRACTIn this work, wire arc additive manufactured IN718 materials with different textures and defect characteristics were obtained via two deposition strategies: parallel mode (P_mode) and oscillation mode (O_mode). The influences of these microstructure variables on the low-cycle fatigue (LCF) properties were systematically investigated by experimental and crystal plasticity finite element (CPFE) frameworks. Results revealed that the weak texture of the O_mode sample may be detrimental to LCF due to strain incompatibility between adjacent grains. However, large-sized pore defects in the P_mode samples significantly increased the dispersity of LCF life. The sensitivity of fatigue crack initiation to critical defect size and location was further accurately captured based on the stored energy density criterion, and the fatigue crack nucleation life was also quantified. Finally, the LCF limit was calculated based on the Coffin–Manson equation, and the life prediction intervals of WAAMed-IN718 alloys with different deposition strategies were unified.

ABSTRACTMicrostructural defects in laser powder bed fusion (LPBF) metallic materials are correlated with processing parameters. A multi-physics model and a crystal plasticity framework are employed to predict microstructure growth in molten pools and assess the impact of manufacturing defects on plastic damage parameters. Criteria for optimising the LPBF process are identified, addressing microstructural defects and tensile properties of LPBF Hastelloy X at various volumetric energy densities (VED). The results show that higher VED levels foster a specific Goss texture {110} , with irregular lack of fusion defects significantly affecting plastic damage, especially near the material surface. A critical threshold emerges between manufacturing defects and grain sizes in plastic strain accumulation. The optimal processing window for superior Hastelloy X mechanical properties ranges from 43 to 53 J/mm3. This work accelerates the development of superior strength-ductility alloys via LPBF, streamlining the trial-and-error process and reducing associated costs.

Abstract Aneuploidy, a deviation of the chromosome number from euploidy, is one of the hallmarks of cancer. High levels of aneuploidy are generally correlated with metastasis and poor prognosis in cancer patients. However, the causality of aneuploidy in cancer metastasis remains to be explored. Here we demonstrate that teratomas derived from aneuploid murine embryonic stem cells (ESCs), but not from isogenic diploid ESCs, disseminated to multiple organs, for which no additional copy number variations were required. Notably, no cancer driver gene mutations were identified in any metastases. Aneuploid circulating teratoma cells were successfully isolated from peripheral blood and showed high capacities for migration and organ colonization. Single-cell RNA sequencing of aneuploid primary teratomas and metastases identified a unique cell population with high stemness that was absent in diploid ESCs-derived teratomas. Further investigation revealed that aneuploid cells displayed decreased proteasome activity and overactivated endoplasmic reticulum (ER) stress during differentiation, thereby restricting the degradation of proteins produced from extra chromosomes in the ESC state and causing differentiation deficiencies. Noticeably, both proteasome activator Oleuropein and ER stress inhibitor 4-PBA can effectively inhibit aneuploid teratoma metastasis.

Abstract Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Background: Strong epidemiological evidence shows positive associations between exposure to per- and polyfluoroalkyl substances (PFAS) and adverse cardiometabolic outcomes (e.g., diabetes, hypertension, and dyslipidemia). However, the underlying cardiometabolic-relevant biological activities of PFAS in humans remain largely unclear. Aim: We evaluated the associations of PFAS exposure with high-throughput proteomics in Hispanic youth. Material and Methods: We included 312 overweight/obese adolescents from the Study of Latino Adolescents at Risk (SOLAR) between 2001 and 2012, along with 137 young adults from the Metabolic and Asthma Incidence Research (Meta-AIR) between 2014 and 2018. Plasma PFAS (i.e., PFOS, PFOA, PFHxS, PFHpS, PFNA) were quantified using liquid-chromatography high-resolution mass spectrometry. Plasma proteins (n = 334) were measured utilizing the proximity extension assay using an Olink Explore Cardiometabolic Panel I. We conducted linear regression with covariate adjustment to identify PFAS-associated proteins. Ingenuity Pathway Analysis, protein-protein interaction network analysis, and protein annotation were used to investigate alterations in biological functions and protein clusters. Results: Results after adjusting for multiple comparisons showed 13 significant PFAS-associated proteins in SOLAR and six in Meta-AIR, sharing similar functions in inflammation, immunity, and oxidative stress. In SOLAR, PFNA demonstrated significant positive associations with the largest number of proteins, including ACP5, CLEC1A, HMOX1, LRP11, MCAM, SPARCL1, and SSC5D. After considering the mixture effect of PFAS, only SSC5D remained significant. In Meta-AIR, PFAS mixtures showed positive associations with GDF15 and IL6. Exploratory analysis showed similar findings. Specifically, pathway analysis in SOLAR showed PFOA- and PFNA-associated activation of immune-related pathways, and PFNA-associated activation of inflammatory response. In Meta-AIR, PFHxS-associated activation of dendric cell maturation was found. Moreover, PFAS was associated with common protein clusters of immunoregulatory interactions and JAK-STAT signaling in both cohorts. Conclusion: PFAS was associated with broad alterations of the proteomic profiles linked to pro-inflammation and immunoregulation. The biological functions of these proteins provide insight into potential molecular mechanisms of PFAS toxicity.

Background: Per- and polyfluoroalkyl substances (PFAS) are pollutants linked to adverse health effects. Diet is an important source of PFAS exposure, yet it is unknown how diet impacts longitudinal PFAS levels. Objective: To determine if dietary intake and food sources were associated with changes in blood PFAS concentrations among Hispanic young adults at risk of metabolic diseases. Methods: Predominantly Hispanic young adults from the Children’s Health Study who underwent two visits (CHS; n = 123) and young adults from NHANES 2013–2018 who underwent one visit (n = 604) were included. Dietary data at baseline was collected using two 24-hour dietary recalls to measure individual foods and where foods were prepared/consumed (home/restaurant/fast-food). PFAS were measured in blood at both visits in CHS and cross-sectionally in NHANES. In CHS, multiple linear regression assessed associations of baseline diet with longitudinal PFAS; in NHANES, linear regression was used. Results: In CHS, all PFAS except PFDA decreased across visits (all p

Abstract Background Few studies have assessed air pollution exposure association with birthweight during both preconception and gestational periods. Methods Leveraging a preconception cohort consisting of 14220 pregnant women and newborn children in Shanghai, China during 2016–2018, we aim to assess associations of NO2 and PM2.5 exposure, derived from high-resolution spatial-temporal models, during preconception and gestational periods with outcomes including term birthweight, birthweight Z-score, small-for-gestational age (SGA) and large-for-gestational age (LGA). Linear and logistic regressions were used to estimate 3-month preconception and trimester-averaged air pollution exposure associations; and distributed lag models (DLM) were used to identify critical exposure windows at the weekly resolution from preconception to delivery. Two-pollutant models and children’s sex-specific associations were explored. Results After controlling for covariates, one standard deviation (SD) (11.5 μg/m3, equivalent to 6.1 ppb) increase in NO2 exposure during the second and the third trimester was associated with 13% (95% confidence interval: 2 – 26%) and 14% (95% CI: 1 – 29%) increase in SGA, respectively; and one SD (9.6 μg/m3) increase in PM2.5 exposure during the third trimester was associated with 15% (95% CI: 1 – 31%) increase in SGA. No association have been found for outcomes of birthweight, birthweight Z-score and LGA. DLM found that gestational weeks 22–32 were a critical window, when NO2 exposure had strongest associations with SGA. The associations of air pollution exposure tended to be stronger in female newborns than in male newborns. However, no significant associations of air pollution exposure during preconception period on birthweight outcomes were found. Conclusion Consistent with previous studies, we found that air pollution exposure during mid-to-late pregnancy was associated with adverse birthweight outcomes.

Background and Aim: Ambient air pollution (AAP) exposure has been associated with altered blood lipids and liver fat in young adults. MicroRNAs regulate gene expression and may mediate these relationships. This work investigated associations between AAP exposure, serum microRNA networks, lipid profiles, and non-alcoholic fatty liver disease (NAFLD) risk in young adults. Methods: Participants were 170 young adults (17–22 years) from the Meta-AIR cohort of the Children’s Health Study (CHS). Residential AAP exposure (PM2.5, PM10, NO2, 8-hour maximum O3, redox-weighted oxidative capacity [Oxwt]) was spatially interpolated from monitoring stations via inverse-distance-squared weighting. Fasting serum lipids were assayed. Liver fat was imaged by MRI and NAFLD was defined by ≥ 5.5% hepatic fat fraction. Serum microRNAs were measured via NanoString and microRNA networks were constructed by weighted gene correlation network analysis. The first principal component of each network represented its expression profile. Multivariable mixed effects regression models adjusted for sociodemographic, behavioral, and clinical covariates; baseline CHS town code was a random effect. Effects estimates are scaled to one standard deviation of exposure. Mediation analysis explored microRNA profiles as potential mediators of exposure-outcome associations. DIANA-mirPATH identified overrepresented gene pathways targeted by miRNA networks. Results: Prior-month Oxwt was associated with NAFLD (OR=3.45; p = 0.003) and inversely associated with microRNA Network A (β = −0.016; p = 0.026). Prior-year NO2 was associated with non-HDL-cholesterol (β = 7.13; p = 0.01) and inversely associated with miRNA Network A (β = −0.019; p = 0.022). Network A expression was inversely associated with NAFLD (OR=0.35; p = 0.010) and non-HDL-C (β = −6.94 mg/dL; p = 0.035). Network A members miR-199a/b-3p and miR-130a, which both target fatty acid synthase, mediated 21% of the association between prior-month Oxwt exposure with NAFLD (p = 0.048) and 23.3% of the association between prior-year NO2 exposure and non-HDL-cholesterol (p = 0.026), respectively. Conclusions: Exposure to AAP may contribute to adverse lipid profiles and NAFLD risk among young adults via altered expression of microRNA profiles.

Background: Autism Spectrum Disorder (ASD) risk is highly heritable, with potential additional non-genetic factors, such as prenatal exposure to ambient particulate matter with aerodynamic diameter

Background: There is increasing evidence for adverse health effects associated with aircraft-emitted particulate matter (PM) exposures, which are largely in the ultrafine (PM0.1) size fraction, but no previous study has examined neurodevelopmental outcomes. Objective: To assess associations between maternal exposure to aircraft ultrafine particles (UFP) during pregnancy and offspring autism spectrum disorder (ASD) diagnosis. Methods: This large, representative cohort study included 370,723 singletons born in a single healthcare system. Demographic data, maternal health information, and child’s ASD diagnosis by age 5 were extracted from electronic medical records. Aircraft exposure estimates for PM0.1 were generated by the University of California Davis/California Institute of Technology Source Oriented Chemical Transport model. Cox proportional hazard models were used to assess associations between maternal exposure to aircraft PM0·1 in pregnancy and ASD diagnosis, controlling for covariates. Results: Over the course of follow-up, 4,554 children (1.4 %) were diagnosed with ASD. Increased risk of ASD was associated with maternal exposure to aircraft PM0.1 [hazard ratio, HR: 1.02, (95 % confidence interval (CI): 1.01–1.03) per IQR = 0.02 µg/m3 increase during pregnancy. Associations were robust to adjustment for total PM0.1 and fine particulate matter (PM2.5), near-roadway air pollution, and other covariates. Noise adjustment modestly attenuated estimates of UFP effects, which remained statistically significant. Discussion: The results strengthen the emerging evidence that maternal particulate matter exposure during pregnancy is associated with offspring ASD diagnosis and identify aircraft-derived PM0.1 as novel targets for further study and potential regulation.

The assessment of “omics” signatures may contribute to personalized medicine and precision nutrition. However, the existing literature is still limited in the homogeneity of participants’ characteristics and in limited assessments of integrated omics layers. Our objective was to use post-prandial metabolomics and fasting proteomics to identify biological pathways and functions associated with diet quality in a population of primarily Hispanic young adults. We conducted protein and metabolite-wide association studies and functional pathway analyses to assess the relationships between a priori diet indices, Healthy Eating Index-2015 (HEI) and Dietary Approaches to Stop Hypertension (DASH) diets, and proteins (n = 346) and untargeted metabolites (n = 23,173), using data from the MetaAIR study (n = 154, 61% Hispanic). Analyses were performed for each diet quality index separately, adjusting for demographics and BMI. Five proteins (ACY1, ADH4, AGXT, GSTA1, F7) and six metabolites (undecylenic acid, betaine, hyodeoxycholic acid, stearidonic acid, iprovalicarb, pyracarbolid) were associated with both diets (p < 0.05), though none were significant after adjustment for multiple comparisons. Overlapping proteins are involved in lipid and amino acid metabolism and in hemostasis, while overlapping metabolites include amino acid derivatives, bile acids, fatty acids, and pesticides. Enriched biological pathways were involved in macronutrient metabolism, immune function, and oxidative stress. These findings in young Hispanic adults contribute to efforts to develop precision nutrition and medicine for diverse populations.

Background: Traffic-related air pollution exposure is associated with increased risk of autism spectrum disorder (ASD). It is unknown whether carbonaceous material from vehicular tailpipe emissions or redox-active non-tailpipe metals, eg. from tire and brake wear, are responsible. We assessed ASD associations with fine particulate matter (PM2.5) tracers of tailpipe (elemental carbon [EC] and organic carbon [OC]) and non-tailpipe (copper [Cu]; iron [Fe] and manganese [Mn]) sources during pregnancy in a large cohort. Methods: This retrospective cohort study included 318,750 children born in Kaiser Permanente Southern California (KPSC) hospitals during 2001–2014, followed until age 5. ASD cases were identified by ICD codes. Monthly estimates of PM2.5 and PM2.5 constituents EC, OC, Cu, Fe, and Mn with 4 km spatial resolution were obtained from a source-oriented chemical transport model. These exposures and NO2 were assigned to each maternal address during pregnancy, and associations with ASD were assessed using Cox regression models adjusted for covariates. PM constituent effect estimates were adjusted for PM2.5 and NO2 to assess independent effects. To distinguish ASD risk associated with non-tailpipe from tailpipe sources, the associations with Cu, Fe, and Mn were adjusted for EC and OC, and vice versa. Results: There were 4559 children diagnosed with ASD. In single-pollutant models, increased ASD risk was associated with gestational exposures to tracers of both tailpipe and non-tailpipe emissions. The ASD hazard ratios (HRs) per inter-quartile increment of exposure) for EC, OC, Cu, Fe, and Mn were 1.11 (95% CI: 1.06–1.16), 1.09 (95% CI: 1.04–1.15), 1.09 (95% CI: 1.04–1.13), 1.14 (95% CI: 1.09–1.20), and 1.17 (95% CI: 1.12–1.22), respectively. Estimated effects of Cu, Fe, and Mn (reflecting non-tailpipe sources) were largely unchanged in two-pollutant models adjusting for PM2.5, NO2, EC or OC. In contrast, ASD associations with EC and OC were markedly attenuated by adjustment for non-tailpipe sources. Conclusion: Results suggest that non-tailpipe emissions may contribute to ASD. Implications are that reducing tailpipe emissions, especially from vehicles with internal combustion engines, may not eliminate ASD associations with traffic-related air pollution.

The growing literature demonstrating air pollution associations on COVID-19 mortality contains studies predominantly examining long-term exposure, with few on short-term exposure, and rarely both together to estimate independent associations. Because mechanisms by which air pollution may impact COVID-19 mortality risk function over timescales ranging from years to days, and given correlation among exposure time windows, consideration of both short- and long-term exposure is of importance. We assessed the independent associations between COVID-19 mortality rates with short- and long-term air pollution exposure by modeling both concurrently. Using California death certificate data COVID-19-related deaths were identified, and decedent residential information used to assess short- (4-week mean) and long-term (6-year mean) exposure to particulate matter

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) in silico, which suppressed SARS-CoV-2 replication in vitro. In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers (P

Importance: Previous studies have reported associations between in utero exposure to regional air pollution and autism spectrum disorders (ASD). In utero exposure to components of near-roadway air pollution (NRAP) has been linked to adverse neurodevelopment in animal models, but few studies have investigated NRAP association with ASD risk. Objective: To identify ASD risk associated with in utero exposure to NRAP in a large, representative birth cohort. Design, Setting, and Participants: This retrospective pregnancy cohort study included 314,391 mother–child pairs of singletons born between 2001 and 2014 at Kaiser Permanente Southern California (KPSC) hospitals. Maternal and child data were extracted from KPSC electronic medical records. Children were followed until: clinical diagnosis of ASD, non-KPSC membership, death, or December 31, 2019, whichever came first. Exposure to the complex NRAP mixture during pregnancy was assessed using line-source dispersion models to estimate fresh vehicle emissions from freeway and non-freeway sources at maternal addresses during pregnancy. Vehicular traffic load exposure was characterized using advanced telematic models combining traditional traffic counts and travel-demand models with cell phone and vehicle GPS data. Cox proportional-hazard models estimated hazard ratios (HR) of ASD associated with near-roadway traffic load and dispersion-modeled NRAP during pregnancy, adjusted for covariates. Non-freeway NRAP was analyzed using quintile distribution due to nonlinear associations with ASD. Exposures: Average NRAP and traffic load exposure during pregnancy at maternal residential addresses. Main Outcomes: Clinical diagnosis of ASD. Results: A total of 6,291 children (5,114 boys, 1,177 girls) were diagnosed with ASD. The risk of ASD was associated with pregnancy-average exposure to total NRAP [HR(95% CI): 1.03(1.00,1.05) per 5 ppb increase in dispersion-modeled NOx] and to non-freeway NRAP [HR(95% CI) comparing the highest to the lowest quintile: 1.19(1.11, 1.27)]. Total NRAP had a stronger association in boys than in girls, but the association with non-freeway NRAP did not differ by sex. The association of freeway NRAP with ASD risk was not statistically significant. Non-freeway traffic load exposure demonstrated associations with ASD consistent with those of NRAP and ASD. Conclusions: In utero exposure to near-roadway air pollution, particularly from non-freeway sources, may increase ASD risk in children.

Summary: Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 × 10−9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

Hot stamping is an important manufacturing process for sheet metal parts. However, it is easy to produce defects such as thinning and cracking in the drawing area during the stamping process. In this paper, the finite element solver ABAQUS/Explicit was used to establish the numerical model of the magnesium alloy hot-stamping process. The stamping speed (2~10 mm/s), the blank-holder force (3~7 kN), and the friction coefficient (0.12~0.18) were selected as the influencing factors. Taking the maximum thinning rate obtained through simulation as the optimization objective, the response surface methodology (RSM) was applied to optimize the influencing factors in sheet hot stamping at a forming temperature of 200 °C. The results showed that the maximum thinning rate of sheet metal was most influenced by the blank-holder force, and the interaction between the stamping speed and the blank-holder force/friction coefficient had a great influence on the maximum thinning rate. The optimal value of the maximum thinning rate of the hot-stamped sheet was 7.37%. Through the experimental verification for the hot-stamping process scheme, the maximum relative error between the simulation and the experimental results was 8.72%. This proves the accuracy of the established finite element model and the response surface model. This research provides a feasible optimization scheme for the analysis of the hot-stamping process of magnesium alloys.

Human mobility influenced the spread of the COVID-19 virus, as revealed by the high spatiotemporal granularity location service data gathered from smart devices. We conducted time series clustering analysis to delineate the relationships between human mobility patterns (HMPs) and their social determinants in California (CA) using aggregated smart device tracking data from SafeGraph. We first identified four types of temporal patterns for five human mobility indicator changes by applying dynamic-time-warping self-organizing map clustering methods. We then performed an analysis of variance and linear discriminant analysis on the HMPs with 17 social, economic, and demographic variables. Asians, children under five, adults over 65, and individuals living below the poverty line were found to be among the top contributors to the HMPs, including the HMP with a significant increase in the median home dwelling time and the HMP with emerging weekly patterns in full-time and part-time work devices. Our findings show that the CA shelter-in-place policy had varying impacts on HMPs, with socially disadvantaged places showing less compliance. The HMPs may help practitioners to anticipate the efficacy of non-pharmaceutical interventions on cases and deaths in pandemics.

Few studies have examined the association between greenness exposure and birth outcomes. This study aims to identify critical exposure time windows during preconception and pregnancy for the association between greenness exposure and birth weight. A cohort of 13 890 pregnant women and newborns in Shanghai, China from 2016–2019 were included in the study. We assessed greenness exposure using Normalized Difference Vegetation Index (NDVI) during the preconception and gestational periods, and evaluated the association with term birthweight, birthweight z -score, small-for-gestational age, and large-for-gestational age using linear and logistic regressions adjusting for key maternal and newborn covariates. Ambient temperature, relative humidity, ambient levels of fine particles (PM _2.5 ) and nitrogen dioxide (NO _2 ) assessed during the same period were adjusted for as sensitivity analyses. Furthermore, we explored the potential different effects by urbanicity and park accessibility through stratified analysis. We found that higher greenness exposure at the second trimester of pregnancy and averaged exposure during the entire pregnancy were associated with higher birthweight and birthweight Z -score. Specifically, a 0.1 unit increase in second trimester averaged NDVI value was associated with an increase in birthweight of 10.2 g (95% CI: 1.8–18.5 g) and in birthweight Z -score of 0.024 (0.003–0.045). A 0.1 unit increase in an averaged NDVI during the entire pregnancy was associated with 10.1 g (95% CI: 1.0–19.2 g) increase in birthweight and 0.025 (0.001–0.048) increase in birthweight Z -score. Moreover, the associations were larger in effect size among urban residents than suburban residents and among residents without park accessibility within 500 m compared to those with park accessibility within 500 m. Our findings suggest that increased greenness exposure, particularly during the second trimester, may be beneficial to birth weight in a metropolitan area.

Background: Air pollution exposure has been associated with increased risk of COVID-19 incidence and mortality by ecological analyses. Few studies have investigated the specific effect of traffic-related air pollution on COVID-19 severity. Objective: To investigate the associations of near-roadway air pollution (NRAP) exposure with COVID-19 severity and mortality using individual-level exposure and outcome data. Methods: The retrospective cohort includes 75,010 individuals (mean age 42.5 years, 54% female, 66% Hispanic) diagnosed with COVID-19 at Kaiser Permanente Southern California between 3/1/2020–8/31/2020. NRAP exposures from both freeways and non-freeways during 1-year prior to the COVID-19 diagnosis date were estimated based on residential address history using the CALINE4 line source dispersion model. Primary outcomes include COVID-19 severity defined as COVID-19-related hospitalizations, intensive respiratory support (IRS), intensive care unit (ICU) admissions within 30 days, and mortality within 60 days after COVID-19 diagnosis. Covariates including socio-characteristics and comorbidities were adjusted for in the analysis. Result: One standard deviation (SD) increase in 1-year-averaged non-freeway NRAP (0.5 ppb NOx) was associated with increased odds of COVID-19-related IRS and ICU admission [OR (95% CI): 1.07 (1.01, 1.13) and 1.11 (1.04, 1.19) respectively] and increased risk of mortality (HR = 1.10, 95% CI = 1.03, 1.18). The associations of non-freeway NRAP with COVID-19 outcomes were largely independent of the effect of regional fine particulate matter and nitrogen dioxide exposures. These associations were generally consistent across age, sex, and race/ethnicity subgroups. The associations of freeway and total NRAP with COVID-19 severity and mortality were not statistically significant. Conclusions: Data from this multiethnic cohort suggested that NRAP, particularly non-freeway exposure in Southern California, may be associated with increased risk of COVID-19 severity and mortality among COVID-19 infected patients. Future studies are needed to assess the impact of emerging COVID-19 variants and chemical components from freeway and non-freeway NRAP.

Young-onset type 2 diabetes and prediabetes is a growing epidemic. Poor diet is a known risk factor for T2D in older adults, but the contribution of diet to risk factors for T2D is not well-described in youth. Our objective was to examine the relationship of diet quality with prediabetes, glucose regulation, and adiposity in young adults. A cohort of young adults (n = 155, age 17–22) was examined between 2014–2018, and 89 underwent a follow-up visit from 2020–2022. At each visit, participants completed diet and body composition assessments and an oral glucose tolerance test. Adherence to four dietary patterns was assessed: Dietary Approaches to Stop Hypertension (DASH), Healthy Eating Index (HEI), Mediterranean diet, and Diet Inflammatory Index (DII). Regression analyses were used to determine adjusted associations of diet with risk for prediabetes and adiposity. Each one-point increase in DASH or HEI scores between visits reduced the risk for prediabetes at follow-up by 64% (OR, 95% CI: 0.36, 0.17–0.68) and 9% (OR, 95% CI: 0.91, 0.85–0.96), respectively. The DASH diet was inversely associated with adiposity, while DII was positively associated with adiposity. In summary, positive changes in HEI and DASH scores were associated with reduced risk for prediabetes in young adults.

Objective: To examine the prospective associations between exposure to perfluoroalkyl substances (PFASs) and longitudinal measurements of glucose metabolism in high-risk overweight and obese Hispanic children. Methods: Forty overweight and obese Hispanic children (8–14 years) from urban Los Angeles underwent clinical measures and 2-hour oral glucose tolerance tests (OGTT) at baseline and a follow-up visit (range: 1–3 years after enrollment). Baseline plasma perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), and the plasma metabolome were measured by liquid-chromatography with high-resolution mass spectrometry. Multiple linear regression models were used to assess the association between baseline PFASs and changes in glucose homeostasis over follow-up. A metabolome-wide association study coupled with pathway enrichment analysis was performed to evaluate metabolic dysregulation associated with plasma PFASs concentrations. We performed a structural integrated analysis aiming to characterize the joint impact of all factors and to identify latent clusters of children with alterations in glucose homeostasis, based on their exposure and metabolomics profile. Results: Each ln (ng/ml) increase in PFOA and PFHxS concentrations was associated with a 30.6 mg/dL (95% CI: 8.8–52.4) and 10.2 mg/dL (95% CI: 2.7–17.7) increase in 2-hour glucose levels, respectively. A ln (ng/ml) increase in PFHxS concentrations was also associated with 17.8 mg/dL increase in the glucose area under the curve (95% CI: 1.5–34.1). Pathway enrichment analysis showed significant alterations of lipids (e.g., glycosphingolipids, linoleic acid, and de novo lipogenesis), and amino acids (e.g., aspartate and asparagine, tyrosine, arginine and proline) in association to PFASs exposure. The integrated analysis identified a cluster of children with increased 2-h glucose levels over follow up, characterized by increased PFAS levels and altered metabolite patterns. Conclusions: This proof-of-concept analysis shows that higher PFAS exposure was associated with dysregulation of several lipid and amino acid pathways and longitudinal alterations in glucose homeostasis in Hispanic youth. Larger studies are needed to confirm these findings and fully elucidate the underlying biological mechanisms. Keywords: Perfluoroalkyl substances, Type 2 diabetes, Glucose metabolism, Metabolomics, Children

(1) Background: The developmental origins of health and disease (DOHaD) hypothesis links adverse fetal exposures with developmental mal-adaptations and morbidity later in life. Short- and long-term exposures to air pollutants are known contributors to health outcomes; however, the potential for developmental health effects of air pollution exposures during gestation or early-childhood have yet to be reviewed and synthesized from a DOHaD lens. The objective of this study is to summarize the literature on cardiovascular and metabolic, respiratory, allergic, and neuropsychological health outcomes, from prenatal development through early childhood, associated with early-life exposures to outdoor air pollutants, including traffic-related and wildfire-generated air pollutants. (2) Methods: We conducted a search using PubMed and the references of articles previously known to the authors. We selected papers that investigated health outcomes during fetal or childhood development in association with early-life ambient or source-specific air pollution exposure. (3) Results: The current literature reports that prenatal and early-childhood exposures to ambient and traffic-related air pollutants are associated with a range of adverse outcomes in early life, including cardiovascular and metabolic, respiratory and allergic, and neurodevelopmental outcomes. Very few studies have investigated associations between wildfire-related air pollution exposure and health outcomes during prenatal, postnatal, or childhood development. (4) Conclusion: Evidence from January 2000 to January 2022 supports a role for prenatal and early-childhood air pollution exposures adversely affecting health outcomes during development. Future studies are needed to identify both detrimental air pollutants from the exposure mixture and critical exposure time periods, investigate emerging exposure sources such as wildfire, and develop feasible interventional tools.

Background: Per- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown. Objective: The aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults. Methods: A total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated. Results: Higher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p

Animal work indicates exposure to air pollutants may alter the composition of the gut microbiota. This study examined relationships between air pollutants and the gut microbiome in young adults residing in Southern California. Our results demonstrate significant associations between exposure to air pollutants and the composition of the gut microbiome using whole-genome sequencing. Higher exposure to 24-hour O3 was associated with lower Shannon diversity index, higher Bacteroides caecimuris, and multiple gene pathways, including L-ornithine de novo biosynthesis as well as pantothenate and coenzyme A biosynthesis I. Among other pollutants, higher NO2 exposure was associated with fewer taxa, including higher Firmicutes. The percent variation in gut bacterial composition that was explained by air pollution exposure was up to 11.2% for O3 concentrations, which is large compared to the effect size for many other covariates reported in healthy populations. This study provides the first evidence of significant associations between exposure to air pollutants and the compositional and functional profile of the human gut microbiome. These results identify O3 as an important pollutant that may alter the human gut microbiome. Keywords: Air pollution, Gut microbiome, Whole genome sequencing

Great advances have been made in functional Magnetic Resonance Imaging (fMRI) studies, including the use of longitudinal design to more accurately identify changes in brain development across childhood and adolescence. While longitudinal fMRI studies are necessary for our understanding of typical and atypical patterns of brain development, the variability observed in fMRI blood-oxygen-level dependent (BOLD) signal and its test-retest reliability in developing populations remain a concern. Here we review the current state of test-retest reliability for child and adolescent fMRI studies (ages 5–18 years) as indexed by intraclass correlation coefficients (ICC). In addition to highlighting ways to improve fMRI test-retest reliability in developmental cognitive neuroscience research, we hope to open a platform for dialogue regarding longitudinal fMRI study designs, analyses, and reporting of results. Keywords: fMRI, Test-retest reliability, Intraclass correlation, Development

Abstract Background Evidence suggests that childhood near-roadway air pollution (NRAP) exposures contribute to increased body mass index (BMI); however, effects of NRAP exposure during the vulnerable periods including in utero and first year of life have yet to be established. In this study, we examined whether exposure to elevated concentrations of NRAP during in utero and/or first year of life increase childhood BMI growth. Methods Participants in the Children’s Health Study enrolled from 2002 to 2003 with annual visits over a four-year period and who changed residences before study entry were included (n = 2318). Annual height and weight were measured and lifetime residential NRAP exposures including in utero and first year of life periods were estimated by nitrogen oxides (NOx) using the California line-source dispersion model. Linear mixed effects models assessed in utero or first year near-road freeway and non-freeway NOx exposures and BMI growth after adjusting for age, sex, race/ethnicity, parental education, Spanish questionnaire, and later childhood near-road NOx exposure. Results A two-standard deviation difference in first year of life near-road freeway NOx exposure was associated with a 0.1 kg/m2 (95% confidence interval (CI): 0.03, 0.2) faster increase in BMI growth per year and a 0.5 kg/m2 (95% CI: 0.02, 0.9) higher attained BMI at age 10 years. Conclusions Higher exposure to early life NRAP increased the rate of change of childhood BMI and resulted in a higher attained BMI at age 10 years that were independent of later childhood exposures. These findings suggest that elevated early life NRAP exposures contribute to increased obesity risk in children.

Objective: Growing evidence indicates exposure to air pollution contributes to obesity and cardiometabolic disease risk in children and adults, however studies are lacking in young adulthood, an important transitional period in the life course. The aim of this study was to examine the associations of short- and long-term regional ambient and near-roadway air pollution (NRAP) exposures on adiposity and cardiometabolic health in young adults aged 17–22 years. Methods: From 2014 to 2018, a subset of participants (n = 158) were recruited from the Children's Health Study to participate in the Meta-AIR (Metabolic and Asthma Incidence Research) study to assess obesity (body composition and abdominal adiposity) and cardiometabolic health (fasting glucose, fasting insulin and lipid profiles) measures. Prior 1-month and 1-year average air pollution exposures were calculated from residential addresses. This included nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameter

Background: Air pollution exposure has been shown to increase the risk of obesity and metabolic dysfunction in animal models and human studies. However, the metabolic pathways altered by air pollution exposure are unclear, especially in adolescents and young adults who are at a critical period in the development of cardio-metabolic diseases. Objectives: The aim of this study was to examine the associations between air pollution exposure and indices of fatty acid and amino acid metabolism. Methods: A total of 173 young adults (18–23 years) from eight Children's Health Study (CHS) Southern California communities were examined from 2014 to 2018. Near-roadway air pollution (NRAP) exposure (freeway and non-freeway) and regional air pollution exposure (nitrogen dioxide, ozone and particulate matter) during one year before the study visit were estimated based on participants' residential addresses. Serum concentrations of 64 targeted metabolites including amino acids, acylcarnitines, non-esterified fatty acid (NEFA) and glycerol were measured in fasting serum samples. Principal component analysis of metabolites was performed to identify metabolite clusters that represent key metabolic pathways. Mixed effects models were used to analyze the associations of air pollution exposure with metabolomic principal component (PC) scores and individual metabolite concentrations adjusting for potential confounders. Results: Higher lagged one-year averaged non-freeway NRAP exposure was associated with higher concentrations of NEFA oxidation byproducts and higher NEFA-related PC score (all p's ≤ 0.038). The effect sizes were larger among obese individuals (interaction p = 0.047). Among females, higher freeway NRAP exposure was also associated with a higher NEFA-related PC score (p = 0.042). Among all participants, higher freeway NRAP exposure was associated with a lower PC score for lower concentrations of short- and median-chain acylcarnitines (p = 0.044). Conclusions: Results of this study indicate that NRAP exposure is associated with altered fatty acid metabolism, which could contribute to the metabolic perturbation in obese youth. Keywords: Traffic, Air pollution, Obesity, Metabolic diseases, Metabolomics

Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study.2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r(2)>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ± 100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis.Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p

The implementation of renewable portfolio standards inevitably affects the strategic behavior and performance of tradable green certificate (TGC) market participants and brings policy risks and market risks. Contract is considered an effective governance tool to avoid the risks of TGC trading and helps TGC market participants to make scientific decisions. The article built a TGC contract model while considering the uncertainty of TGC supply and demand and provided a scientific analysis for designing TGC contracts. Finally, a numerical example was given to verify the optimal solution of the TGC contract model. The main results of this study are as follows: (1) higher electricity retail price could contribute to increasing the optimal trading volume and price of the TGC contract; (2) an increase in the wholesale price of electricity could decrease the optimal trading price of the TGC contract, but its impact on the optimal trading volume depends on the quota ratio designed by the government; (3) the impact of unit fines on the TGC contract is completely different from that of a lower price limit, where a low unit penalty and a high lower price limit for the TGC trading system could improve the trading volume of the TGC contract while reducing its price; and (4) transaction costs inhibit the trading volume of TGC contracts, but the impact on the optimal price depends on the size of transaction costs shared by different market participants; the transaction costs should be equally borne between the different market participants in order to eliminate the impact of transaction costs on the trading price of the TGC contract. [ABSTRACT FROM AUTHOR]