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Associations between genetic liability to attention deficit hyperactivity disorder and methamphetamine abuse
No full text[[abstract]]Background: Attention deficit hyperactivity disorder (ADHD) and substance use disorder co-occurs frequently. Both methamphetamine abuse and ADHD is heritable and probably highly polygenic. Shared genetic factors may explain the high comorbidity between methamphetamine abuse and ADHD. In this study, we hypothesize methamphetamine abuse may be genetically correlated with ADHD. Aims & Objectives: The aim of the study was to examine the association of common genetic variants (i.e., single nucleotide polymorphisms [SNPs]) across the whole genome with methamphetamine abuse and to examine the genetic overlap between ADHD and methamphetamine abuse as well as other methamphetamine use variables. Method: 143 treatment-seeking patients with methamphetamine abuse were recruited in Taipei City Hospital and 77,520 healthy individuals were Taiwan Biobank’ s participants with no prior history of psychiatric or substance use disorders. Genome-wide single nucleotide polymorphism genotyping, demographics, and clinical information were obtained. We conducted an exploratory genome-wide association analysis (GWAS) for methamphetamine abuse vs. healthy individuals. ADHD GWAS summary statistics from Psychiatric Genomics Consortium were utilized as the discovery datasets to compute a polygenic risk score (PRS) of ADHD for each subject in our study sample. We also examined the relationship between ADHD-PRS and methamphetamine use characteristics among the patients with methamphetamine abuse. Results: Preliminary genome wide analysis revealed a significant SNP rs66510859 on chromosome 7 (P-value= 2.04E-09) associated with methamphetamine abuse. Methamphetamine abuse was significantly associated with ADHD-PRS with a P-value threshold of 0.05. ADHD-PRS with P-value threshold of 0.5 was associated with log-transformed earlier age of first use (beta=-6.1, p=0.02) and log-transformed regular use (beta=-6.0, p=0.01) after adjustment for covariates. Discussion & Conclusion: Methamphetamine abuse may be genetically correlated with ADHD. Further study will examine the causal relationships between the genetic liability to ADHD, the Adult ADHD Self-Report Scale score, and clinical characteristics of methamphetamine abuse by using causal mediation analysis and Mendelian randomization
Neuropsychological features as mediators between psychopathologies and heart rate variability: The sex defferences
No full text[[abstract]]Background: Heart rate variability (HRV), as an index of para- sympathetic activity, has been reported to be lower in individuals with common mental disorders (depression, anxiety, and som- atic symptoms) than in healthy individuals in previous studies. Several meta-analyses have supported this result, but the effect sizes of the differences between patients and healthy individuals are mostly low to moderate, making it difficult for small sample studies to demonstrate between-group differences. Therefore, the mechanisms underlying the link between the psychopathologies of common mental disorders and HRV require further investiga- tion. In recent years, the theory of the frontal-vagal network has gained increasing attention. Furthermore, the relationship between psychopathologies and HRV has been reported to differ between sexes. Aims & Objectives: Under the hypothesis that disorder status af- fects cognitive function, we examined whether neuropsychological features can be mediators between psychopathologies and HRV and possible sex differences. Method: We recruited 359 individuals with and without common mental disorders. Questionnaires were used to measure their psychopathologies. Eight tests from the Cambridge Neuropsychological Test Automated Battery were selected to measure neuropsychological functions. Resting-state HRV meas- urements were obtained for 5 min. The associations among these constructs were analyzed using multiple linear regression analysis and structural equation modelling. Results: When psychopathologies and neuropsychological fea- tures were simultaneously included as independent variables, most psychopathologies did not exhibit significant associations with HRV. Among women, Reaction Time (RTI, a task of psychomotor speed) indicator mediated the relationship between depression and low-frequency power (LF); Emotion Recognition Task (ERT, a task of emotional regulation) indicator mediated the relationship be- tween health anxiety and high-frequency power (HF). Among men, Intra-Extra Dimensional Set Shift (IED, a task of shifting) indi- cator mediated the relationship between depression and LF; Match to Sample Visual Search (MTS, a task of selective attention) indi- cator mediated the relationship between health cognition and HF. The depression-RTI-LF pathway in women tended to lower HRV; whereas health anxiety-ERT-HF in women, depression-IED-LF and health cognition-MTS-HF in men tended to increase HRV. Discussion & Conclusion: Our findings support the notion that neuropsychological features mediate the relationship between psychopathologies and HRV, and that sex differences exist. Keywords: heart rate variability, common mental disorders, neuro- psychological tests, mediation, sex differenc
Differential risks of exposure to acrylamide in adult asthma clusters
No full text[[abstract]]To the editor, The increase in asthma prevalence can be attributed more to environmental factors than genetic factors [1], and a significant degree of phenotypic heterogeneity in asthma is well recog-nized, but the underlying causes remain unclear. Exposure to acrylamide is primarily from occupational exposure, smoking, or dietary intake [2], posing a risk to the nervous and repro-ductive systems [3], but its potential adverse effect on asthma and the immune system remains to be defined. To evaluate the exposure to acrylamide and its varying effects on asthma and its phenotypes, we conducted a case–control study consisting of 365 participants with current asthma and 235 healthy controls (Tables S1 and S2). The study was approved by the ethics com-mittees of the National Health Research Institutes in Miaoli, Taiwan, the ethics committees of the participating hospitals, and informed consent from all participants.The case group had significantly higher levels of acrylamide metabolite in urine compared to controls (Table 1; median, 15.99 vs. 12.82 μg/g creatinine, p < 0.001). Logistic regression and multinomial logistic regression analyses revealed that higher urinary acrylamide metabolites levels were significantly associated with increased odds ratios for current asthma (ORs: 1.52, 95% CI: 1.04–2.24; Figure 1 and Table S3). Stratified by asthma phenotypes [4], significant acrylamide exposure risk was observed in Clusters E (young male current smokers with early- onset; OR: 1.84, 95% CI:1.16–2.92), A (older non- atopic females with late- onset; OR: 1.80, 95% CI: 1.28–2.51), C (older males with second- hand smoke exposure; OR: 1.70, 95% CI: 1.23–2.36), F (never smoking atopic males with early- onset; OR: 1.48, 95% CI: 1.02–2.13), and D (atopic females with high BMI and poor lung function; OR: 1.53, 95% CI: 1.05–2.21). To identify factors contributing to differences in acrylamide ex-posure, we performed a stratified analysis considering both occupational and non- occupational factors (Table S4). Among non- occupational factors, smoking, second- hand smoke ex-posure, and daily transportation by car and motorcycle were identified as potential contributors to the association with cur-rent asthma. Notably, we observed that commerce was associ-ated with the highest levels of acrylamide xposure. Analysis revealed that the primary contribution to this exposure came from Cluster A. Additionally, the level of an oxidative stress marker, HEL [5], was significantly correlated with urinary acrylamide metabolite in both cases and controls (Table 1; ρ = 0.48 and ρ = 0.25, respectively), as well as in Clusters A and B (ρ = 0.69 and ρ = 0.60, respectively).Clusters C and E, which had a history of smoking, highlight the increased risk of acrylamide exposure and the importance of identifying its sources [6]. For Cluster F, acrylamide exposure may have been associated with both workplace and household second- hand smoke exposure. Moreover, Cluster A mainly comprised non- atopic asthma females, whereas Cluster D was dominated by atopic females with a higher BMI. Cluster B mainly consisted of atopic females with a lower BMI, but urinary acrylamide metabolites were not considered crucial factors in environmental exposure. These three clusters highlighted potential variations in the sources of acrylamide exposure.In summary, this study provides novel evidence linking acryl-amide exposure to current asthma, using urinary metabolites as a reliable marker of exposure from various sources [7]. We observed significant differences in acrylamide exposure risk between asthma cases and controls, with varying levels across phenotypic clusters, highlighting the diverse environmental risk factors and their impact on asthma phenotypes. However, our study had some limitations, including the cross- sectional study design and the lack of dietary and detailed occupational exposure data, which limited our ability to establish causality and fully characterize acrylamide exposure sources. While identifying exposure sources is critical for public health, the primary aim of this study is to raise awareness of acrylamide exposure among asthma researchers and emphasize the need for future studies that integrate comprehensive exposure data and employ longitudinal designs to better understand the heterogeneity and its effects on asthma control
Trace proteinuria is a high-risk marker for developing ESRD and for shortening the lifespan: Findings from an 18-year follow-up cohort with half a million Asian participants
No full text[[abstract]]Background: Trace proteinuria, obtained by urine dipstick, has not received its due attention in clinic visits. It was particularly overlooked in the younger people, even though it had three times more trace proteinuria than the elderly. This study aims to investigate its role in kidney diseases such as End Stage Renal Disease and its association with mortality outcomes and life-shortening effects in a large Asian cohort. Methods: A cohort of 646,987 adults, who have undergone health screening programs successively since 1994, were followed for a median of 18 years. Through encrypted identification numbers, 49,216 deaths and 4,101 ESRD cases were identified. Dipstick, in contrast to the old color-comparison method, is a semi-automated computer- assisted urinalysis system. Results reported as trace, 1+, 2+, and more. The association between proteinuria, ESRD, and mortality risks was evaluated using Cox proportional hazards models. Results: Trace proteinuria existed around 5% among healthy adults, contributed to nearly half of all CKD (9.5%), with younger adults (age <60 years) having a threefold higher prevalence than the elderly (age 60 years). Trace proteinuria significantly increased the risk of ESRD independent of eGFR, with up to 4-5 folds in normal eGFR subjects. The HR was 3.54, 95% CI: 2.67, 4.69 when eGFR 90 ; HR: 3.86, 95% CI: 3.08, 4.84 when eGFR 60-89; HR: 12.26, 95% CI: 9.24, 16.28 when eGFR 45-59; HR: 44.60, 95% CI: 31.39, 60.55 when eGFR 30-44 ml/min/1.73m^2) when compared with negative proteinuria. Participants with trace proteinuria also had a significantly higher risk of all-cause mortality (HR: 1.48, 95% CI: 1.42, 1.54), and associated with a reduction in life expectancy of up to 4-5 years. Dipstick tests demonstrated relatively high sensitivity (84%) and specificity (96%) in detecting microalbuminuria. Conclusions: Trace proteinuria, overlooked in the clinics, was associated with a 4-5 fold increase in developing ESRD later in life and a shortened lifespan of five years, with nearly 50% increase in all-cause mortality. Trace proteinuria can be screened easily in the clinic or among the public with a dipstick, an inexpensive test with instant results. More than 80% with microalbuminuria in an apparently healthy population could be identified
Machine-learning assisted discovery unveils novel interplay between gut microbiota and host metabolic disturbance in diabetic kidney disease
No full text[[abstract]]Diabetic kidney disease (DKD) is a serious healthcare dilemma. Nonetheless, the interplay between the functional capacity of gut microbiota and their host remains elusive for DKD. This study aims to elucidate the functional capability of gut microbiota to affect kidney function of DKD patients. A total of 990 subjects were enrolled consisting of a control group (n = 455), a type 2 diabetes mellitus group (DM, n = 204), a DKD group (n = 182) and a chronic kidney disease group (CKD, n = 149). Full-length sequencing of 16S rRNA genes from stool DNA was conducted. Three findings are pinpointed. Firstly, new types of microbiota biomarkers have been created using a machine-learning (ML) method, namely relative abundance of a microbe, presence or absence of a microbe, and the hierarchy ratio between two different taxonomies. Four different panels of features were selected to be analyzed: (i) DM vs. Control, (ii) DKD vs. DM, (iii) DKD vs. CKD, and (iv) CKD vs. Control. These had accuracy rates between 0.72 and 0.78 and areas under curve between 0.79 and 0.86. Secondly, 13 gut microbiota biomarkers, which are strongly correlated with anthropometric, metabolic and/or renal indexes, concomitantly identified by the ML algorithm and the differential abundance method were highly discriminatory. Finally, the predicted functional capability of a DKD-specific biomarker, Gemmiger spp. is enriched in carbohydrate metabolism and branched-chain amino acid (BCAA) biosynthesis. Coincidentally, the circulating levels of various BCAAs (L-valine, L-leucine and L-isoleucine) and their precursor, L-glutamate, are significantly increased in DM and DKD patients, which suggests that, when hyperglycemia is present, there has been alterations in various interconnected pathways associated with glycolysis, pyruvate fermentation and BCAA biosynthesis. Our findings demonstrate that there is a link involving the gut-kidney axis in DKD patients. Furthermore, our findings highlight specific gut bacteria that can acts as useful biomarkers; these could have mechanistic and diagnostic implications
Highly efficient CRISPR-Cas9 base editing in Bifidobacterium with bypass of restriction modification systems
No full text[[abstract]]Intestinal microbiota members of the Bifidobacterium genus are increasingly explored as probiotics and therapeutics. However, the paucity of genetic tools and the widespread restriction modification (RM) systems in Bifidobacterium limit our ability to genetically manipulate these bacteria. Here we established a CRISPR-Cas9 cytosine base editor system (cBEST) for portable genome editing in bifidobacteria. Harboring different promoters characterized in this study, these cBEST plasmids showed a range of editing efficiencies in different strains and genomic contexts, highlighting the importance of fine-tuning base editor and sgRNA expression. Additionally, we showed that disruption or bypass of RM systems dramatically improved editing efficiencies in otherwise hard-to-edit genomic loci and Bifidobacterium strains. Notably, we demonstrated the use of RM-disrupted Bifidobacterium longum strains for simultaneous assembly, amplification, and methylation of the all-in-one editing plasmids, greatly streamlining the workflow for high-efficiency base editing. Last but not least, we showed the portability of cBESTs using the same editing construct to disrupt a conserved metabolic gene in multiple Bifidobacterium species. Looking ahead, the ability to efficiently edit and engineer bifidobacterial genomes will give rise to new opportunities for research and applications toward improving human health.IMPORTANCEThe ability to genetically manipulate specific genes and biological pathways in Bifidobacterium is essential to unlocking their probiotic and therapeutic potential in human health applications. The DNA double-strand break-free CRISPR-Cas9 cytosine base editor system established in this work allows portable and efficient base editing in Bifidobacterium spp. We further showed that bypass of restriction modification systems significantly improved base editing efficiency, especially for hard-to-edit genomic loci and strains. This expanded Bifidobacterium genome editing toolbox should facilitate mechanistic investigations into the roles of Bifidobacterium in host physiology and disease
Modelling COVID-19 epidemic curve in Taipei City, Taiwan by a citywide wastewater SARS-CoV-2 surveillance
No full text[[abstract]]Over 70 countries have adopted wastewater surveillance during the COVID-19 pandemic as a novel tool to detect unidentified cases and monitor epidemic curves. However, epidemic prediction models are highly site-specific, necessitating tailored approaches. This study aimed to establish a citywide wastewater surveillance system and develop an epidemic prediction model for Taipei City, Taiwan. From May to August 2022, wastewater samples were collected daily from the Xinyi and Neihu districts and twice weekly from the remaining 10 districts. SARS-CoV-2 genetic material was quantified using RT-qPCR, and a “relative signal” was calculated as the ratio of SARS-CoV-2 viral concentration to the concentration of the human RNase P gene to normalize variability in sample collection. Regression analysis based on data from the two districts was conducted to forecast new COVID-19 cases. On average, wastewater samples contained 1,829.0 ± 2,237.7 viral copies per liter, with relative signals averaging 17.1 ± 16.7. The best-fitting model, adjusted for temperature, indicated that a 1 % increase in viral signals corresponded to an approximately 0.27 % rise in the future 5-day moving average of new cases. With an R-squared value of 0.78, the model demonstrated robust explanatory power. The model, validated via a paired sample t-test, reliably estimated epidemic trends with no significant difference between predicted and reported cases in the other 10 districts. These findings suggest that wastewater viral surveillance can be an effective supplementary tool for epidemic forecasting in urban settings like Taipei, where high sewer connectivity is in place
Mechanism of malignant transformation in arecoline-exposed human oral keratinocytes
No full text[[abstract]]Areca nut chewing is associated with oral potentially malignant disorders (OPMDs), a spectrum of precancerous lesions with variable rates of malignant transformation (1.7–16.9%). This study investigates the molecular alterations underlying this process. Three immortalized oral keratinocyte lines were repeatedly exposed to arecoline, the primary alkaloid in areca nuts, for 5–8months. RNA-seq analysis and functional assays were conducted on vehicle control and arecoline-treated cell pairs. Two of the three cell lines transformed after arecoline exposure, exhibiting anchorage-independent growth in vitro and tumorigenicity in vivo. The upregulated pathways included reactive oxygen species metabolism, cell cycle progression, and regulation of stem cell. Increased expression of stemness-related genes was observed in clinical datasets including oral cancer and OPMDs. This change of gene expression suggests a potential association with epigenetic reprogramming, a recently identified hallmark of cancer. In summary, this study identifies potential molecular targets for intervention and highlights the role of epigenetic alterations in arecoline-induced malignant transformation
ISG15-mediated modulation of CD8 T cell dysfunction for immunotherapy sensitivity in OSCC
No full text[[abstract]]Patients with oral squamous cell carcinoma (OSCC) often have poor responses to immunotherapy, necessitating predictive biomarkers. We identified interferon-stimulated gene 15 (ISG15) as a prognostic biomarker in OSCC. Our study elucidates ISG15'srole in T cell dysfunction within the tumor microenvironment, inhibiting CD8 T cell activation and promoting inhibitory receptor expression via receptor-independent signaling. In an OSCC model, ISG15-overexpressing tumors display heightened tumorigenesis but exhibit sensitivity to anti-PD-1 antibody treatment, partially restoring T cell function. Anti-PD-1 therapy reverses key markers of T cell dysfunction, particularly in ISG15-overexpressing tumors. ISG15 emerges as a potential biomarker for identifying immunotherapy-sensitive OSCC patients, underscoring the tumor microenvironment's complexity and the potential of immune checkpoint blockade to counteract ISG15-induced T cell dysfunction