Short tandem repeat expansions in cortical layer-specific genes implicate in phenotypic severity and adaptability of autism spectrum disorder.

AIM: Short tandem repeats (STRs) are repetitive DNA sequences and highly mutable in various human disorders. While the involvement of STRs in various genetic disorders has been extensively studied, their role in autism spectrum disorder (ASD) remains largely unexplored. In this study, we aimed to investigate genetic association of STR expansions with ASD using whole genome sequencing (WGS) and identify risk loci associated with ASD phenotypes. METHODS: We analyzed WGS data of 634 ASD families and performed genome-wide evaluation for 12,929 STR loci. We found rare STR expansions that exceeded normal repeat lengths in autism cases compared to unaffected controls. By integrating single cell RNA and ATAC sequencing datasets of human postmortem brains, we prioritized STR loci in genes specifically expressed in cortical development stages. A deep learning method was used to predict functionality of ASD-associated STR loci. RESULTS: In ASD cases, rare STR expansions predominantly occurred in early cortical layer-specific genes involved in neurodevelopment, highlighting the cellular specificity of STR-associated genes in ASD risk. Leveraging deep learning prediction models, we demonstrated that these STR expansions disrupted the regulatory activity of enhancers and promoters, suggesting a potential mechanism through which they contribute to ASD pathogenesis. We found that individuals with ASD-associated STR expansions exhibited more severe ASD phenotypes and diminished adaptability compared to non-carriers. CONCLUSION: Short tandem repeat expansions in cortical layer-specific genes are associated with ASD and could potentially be a risk genetic factor for ASD. Our study is the first to show evidence of STR expansion associated with ASD in an under-investigated population.

Association between metabolic syndrome and mortality in patients with COVID-19: A nationwide cohort study.

OBJECTIVES: We investigated the association between metabolic syndrome (MetS) and mortality among coronavirus disease 2019 (COVID-19) patients in Korea. METHODS: We analyzed 3876 individuals aged ≥ 20 years who were confirmed with COVID-19 from January 1 to June 4, 2020 based on the Korea National Health Insurance Service (NHIS)-COVID-19 database and had undergone health examination by NHIS between 2015 and 2017. Multivariable Cox proportional hazard regression analyses were performed. RESULTS: Of total participants, the prevalence of MetS was 21.0% (n = 815). During 58.6 days of mean follow-up, 3.1 % (n = 120) of the participants died. Compared to individuals without MetS, COVID-19 patients with MetS had a significantly increased mortality risk after adjusting for confounders in total participants (hazard ratio [HR]: 1.68, 95 % confidence interval [CI]: 1.14-2.47) and women (HR: 2.41, 95 % CI: 1.17-4.96). A low high-density lipoprotein cholesterol level in total participants (HR: 1.63, 95 % CI: 1.12-2.37) and hyperglycemia in women (HR: 1.97, 95 % CI: 1.01-3.84) was associated with higher mortality risk. The mortality risk increased as the number of MetS components increased among total participants and women (P for trend = 0.009 and 0.016, respectively). In addition, MetS groups had higher mortality risk in aged ≥ 60 years (HR: 1.60, 95 % CI: 1.07-2.39), and never-smokers (2.08, 1.21-3.59). CONCLUSIONS: The presence of MetS and greater number of its components were associated with increased mortality risks particularly in female patients with COVID-19. Managing MetS may contribute to better outcomes of COVID-19.

Associations between local acidosis induced by renal LDHA and renal fibrosis and mitochondrial abnormalities in patients with diabetic kidney disease.

During the progression of diabetic kidney disease (DKD), renal lactate metabolism is rewired. The relationship between alterations in renal lactate metabolism and renal fibrosis in patients with diabetes has only been partially established due to a lack of biopsy tissues from patients with DKD and the intricate mechanism of lactate homeostasis. The role of lactate dehydrogenase A (LDHA)-mediated lactate generation in renal fibrosis and dysfunction in human and animal models of DKD was explored in this study. Measures of lactate metabolism (urinary lactate levels and LDHA expression) and measures of DKD progression (estimated glomerular filtration rate and Wilms' tumor-1 expression) were strongly negatively correlated in patients with DKD. Experiments with streptozotocin-induced DKD rat models and the rat renal mesangial cell model confirmed our findings. We found that the pathogenesis of DKD is linked to hypoxia-mediated lactic acidosis, which leads to fibrosis and mitochondrial abnormalities. The pathogenic characteristics of DKD were significantly reduced when aerobic glycolysis or LDHA expression was inhibited. Further studies will aim to investigate whether local acidosis caused by renal LDHA might be exploited as a therapeutic target in patients with DKD.

A 24-Month Effects of Methylphenidate Use on Growth in Children and Adolescents With Attention Deficit Hyperactivity Disorder.

OBJECTIVE: The primary objective of this study was to investigate the effect of methylphenidate (MPH) on height, weight, and body mass index (BMI) in drug-naive children and adolescents with attention deficit hyperactivity disorder (ADHD) over 24 months. The secondary objective was to investigate whether the age of MPH initiation and sex act as risk factors for growth retardation. METHODS: A total of 82 patients with ADHD were included. Weight, height, and BMI were measured at baseline and every 6 months up to 24 months. Weight, height, and BMI data were converted to z-scores and analyzed using two-way repeated-measures ANOVA and multiple linear regression. RESULTS: The z-score of height, weight and BMI decreased from the baseline values. The z-scores of height were at baseline 0.002; 6 months -0.100; 12 months -0.159; 18 months -0.159; 24 months -0.186. The z-scores of weight were at baseline 0.104; 6 months -0.155; 12 months -0.256; 18 months -0.278; 24 months -0.301. Here were no age and sex differences of height, weight, and BMI. CONCLUSION: The use of MPH was associated with attenuation of weight and height gain rates in children and adolescents with ADHD.

Defect Analysis of Solution-Based Process CIGS Thin-Film Solar Cells Using Technology Computer-Aided Design.

Copper indium gallium sulfur selenide (Cu(In1-xGax)SeS, CIGS) thin film solar cells are fabricated using a solution-based process, and their defect models are studied through a computer-aided design method. Cu(In1-xGax)SeS is structured with a graded bandgap by controlling the ambient gas and precursor composition, during the fabrication process. The defects in the CIGS are modeled as two donor-like defects, which are differently distributed as per the CIGS grain size (large and small grains at upper and bottom layers, respectively), whereas those in the cadmium sulfide (CdS)/CIGS interface are modeled as a complex model of both donor- and acceptor-like defects in the CdS, near the interface. By measuring the external quantum efficiency and current density-voltage characteristics, the best-fitting match of the simulated values with the measured values are obtained. The simulation results demonstrate that the defects (defect density of ~7 × 1018) in the CdS interface are more serious, compared to the CIGS defects (defect density of ~2 × 1015 in the bottom), which were initially expected to be more severe because of grain nonuniformity. For increasing the cell efficiency, we establish that the process and material quality need to be further improved not only during CIGS formation using a multistep spin-coated precursor but also during the initial deposition of the CdS buffer. This numerical approach can enable better understanding of the defect behavior in solar cells, and indicate directions for improvement in the fabrication process and device structure, for developing high-efficiency solution-based CIGS solar cells.

Interaction of serotonergic and noradrenergic gene variants in panic disorder.

OBJECTIVE: Panic disorder is an anxiety disorder with an estimated heritability of 48%. Associations findings have been obtained with candidate genes from both serotonergic and noradrenergic pathways including regulatory and coding variants of the serotonin receptor 1A gene, the monoamine oxidase A gene, the catechol-O-methyltransferase gene and the norepinephrine transporter gene. METHODS: In the present study, an analysis of interactions between the functional serotonin receptor 1A polymorphism, the norepinephrine transporter variants and the other respective polymorphisms of the above-mentioned genes is reported. The analysis is based on genotype results from 115 cases and 115 age and sex-matched controls. RESULTS: A nominally significant (P=0.04) interaction between the serotonin receptor 1A and the catechol-O-methyltransferase polymorphisms was observed. Stratified analysis revealed that the odds ratio of each polymorphism was highest in the presence of the low-risk genotype(s) of the other polymorphism and low in the presence of the high-risk genotype(s) of the other polymorphism. CONCLUSIONS: This is the first possible interaction of genetic variations in panic disorder that has been observed. As the sample size was small and no adjustment for multiple testing was made, the assessment of the interacting risk alleles needs replication in a larger sample with higher power.