Explore the vast range of titles available.

The structure of lincomycin A consists of the unusual eight-carbon thiosugar core methyllincosamide (MTL) decorated with a pendent N-methylprolinyl moiety. Previous studies on MTL biosynthesis have suggested GDP-D-erythro-α-D-gluco-octose and GDP-D-α-D-lincosamide as key intermediates in the pathway. However, the enzyme-catalyzed reactions resulting in the conversion of GDP-D-erythro-α-D-gluco-octose to GDP-D-α-D-lincosamide have not yet been elucidated. Herein, a biosynthetic subpathway involving the activities of four enzymes—LmbM, LmbL, CcbZ, and CcbS (the LmbZ and LmbS equivalents in the closely related celesticetin pathway)—is reported. These enzymes catalyze the previously unknown biosynthetic steps including 6-epimerization, 6,8-dehydration, 4-epimerization, and 6-transamination that convert GDP-D-erythro-α-D-gluco-octose to GDP-D-α-D-lincosamide. Identification of these reactions completes the description of the entire lincomycin biosynthetic pathway. This work is significant since it not only resolves the missing link in octose core assembly of a thiosugar-containing natural product but also showcases the sophistication in catalytic logic of enzymes involved in carbohydrate transformations.

Background The roles of p53 and HER2 in gastric adenocarcinoma (GAC) have been extensively studied; nevertheless, the contribution of mitochondrial transcription factor A (TFAM) remains unclear. Concerning TFAM’s pivotal role in mitochondrial biogenesis, this study aimed to evaluate the TFAM expression in GAC and to assess its associations with p53 and HER2 expressions and clinicopathological outcomes. Methods We retrospectively analyzed 77 GAC patients who underwent upfront gastrectomy at Taipei Hospital between 2012 and 2021. Their clinicopathological profiles were recorded in detail. Immunohistochemical (IHC) staining for TFAM, p53, and HER2 protein expressions was semiquantified using IHC pixelwise H-score analyzed by ImageJ plugins IHC profiler. Associations between two continuous variables were assessed by Spearman’s correlation coefficient (CC), and trendlines were fitted using SPSS’s curve estimation function. The optimal cutoff for survival discrimination was derived from receiver operating characteristic (ROC) curve analysis by selecting the threshold with the highest Youden index and area under the curve (AUC). Prognostic variables with a Log-rank test p -value ≤ 0.1 were entered into a multi-variate Cox proportional hazards regression (Cox regression) model to identify independent ones and their relative hazards ratio (HR). Results TFAM IHC pixelwise H-score was significantly associated with advanced T and N status, lymphovascular invasion, perineural invasion and poor differentiation (all’s p  < 0.05), and was inversely correlated with tumor size (Spearman’s rho CC = -0.402, p  < 0.001) in a logarithmic distribution ( p  < 0.001). A positive correlation (Spearman’s rho CC = 0.312, p  = 0.006) in cubic distribution ( p  < 0.001) was observed between p53and TFAM IHC pixelwise H-scores. ROC analysis yielded a TFAM IHC pixelwise H-score cutoff of 43.0 (AUC = 0.650, 95%CI = 0.515–0.785, p  = 0.047; sensitivity = 0.490, specificity = 0.810) to dichotomize high and low groups. In multi-variate Cox regression, low TFAM IHC pixelwise H-score (HR = 2.332, 95%CI = 1.136–4.787, p  = 0.021), M1 status (HR = 3.582, 95%CI = 1.608–7.979, p  = 0.002), and perineural invasion (HR = 4.506, 95%CI = 1.541–13.177, p  = 0.006) were identified as independent variables to poor prognosis with elevated HRs. Among patients with high TFAM expression, higher HER2 IHC pixelwise H-score was associated with elevated hazard (HR = 1.010, 95%CI = 1.002–1.019, p  = 0.020, Cox regression, uni-variate). Among M1 patients, higher p53 IHC pixelwise H-score was related to elevated hazard (HR = 1.029, 95%CI = 1.004–1.056, p  = 0.025, Cox regression, uni-variate). Conclusions ROC and multi-variate Cox regression identified low TFAM expression as an independent poor prognostic variable for operable GAC patients, implying its potential as a quantitative prognostic biomarker. The observed associations with p53 and HER2 are hypothesis-generating and they require further validation to clarify TFAM’s role in Warburg effect and GAC progression.

We used gastric cancer cell line AGS and clinical samples to investigate the roles of mitochondrial DNA (mtDNA) alterations and mitochondrial respiratory dysfunction in gastric adenocarcinoma (GAC). A total of 131 clinical samples, including 17 normal gastric mucosa (N-GM) from overweight patients who had received sleeve gastrectomy and 57 paired non-cancerous gastric mucosae (NC-GM) and GAC from GAC patients who had undergone partial/subtotal/total gastrectomy, were recruited to examine the copy number and D310 sequences of mtDNA. The gastric cancer cell line AGS was used with knockdown (KD) mitochondrial transcription factor A (TFAM) to achieve mitochondrial dysfunction through a decrease of mtDNA copy number. Parental (PT), null-target (NT), and TFAM-KD-(A/B/C) represented the parental, control, and TFAM knocked-down AGS cells, respectively. These cells were used to compare the parameters reflecting mitochondrial biogenesis, glycolysis, and cell migration activity. The median mtDNA copy numbers of 17 N-GM, 57 NC-GM, and 57 GAC were 0.058, 0.055, and 0.045, respectively. The trend of decrease was significant (p = 0.030). In addition, GAC had a lower mean mtDNA copy number of 0.055 as compared with the paired NC-GM of 0.078 (p < 0.001). The mean mtDNA copy number ratio (mtDNA copy number of GAC/mtDNA copy number of paired NC-GM) was 0.891. A total of 35 (61.4%) GAC samples had an mtDNA copy number ratio ≤0.804 (p = 0.017) and 27 (47.4%) harbored a D310 mutation (p = 0.047), and these patients had shorter survival time and poorer prognosis. After effective knockdown of TFAM, TFAM-KD-B/C cells expressed higher levels of hexokinase II (HK-II) and v-akt murine thymoma viral oncogene homolog 1 gene (AKT)-encoded AKT, but lower levels of phosphorylated pyruvate dehydrogenase (p-PDH) than did the NT/PT AGS cells. Except for a higher level of p-PDH, the expression levels of these proteins remained unchanged in TFAM-KD-A, which had a mild knockdown of TFAM. Compared to those of NT, TFAM-KD-C had not only a lower mtDNA copy number (p = 0.050), but also lower oxygen consumption rates (OCR), including basal respiration (OCRBR), ATP-coupled respiration (OCRATP), reserve capacity (OCRRC), and proton leak (OCRPL)(all with p = 0.050). In contrast, TFAM-KD-C expressed a higher extracellular acidification rate (ECAR)/OCRBR ratio (p = 0.050) and a faster wound healing migration at 6, 12, and 18 h, respectively (all with p = 0.050). Beyond a threshold, the decrease in mtDNA copy number, the mtDNA D310 mutation, and mitochondrial dysfunction were involved in the carcinogenesis and progression of GACs. Activation of PDH might be considered as compensation for the mitochondrial dysfunction in response to glucose metabolic reprogramming or to adjust mitochondrial plasticity in GAC.

Objectives Work is often a barrier for women to continue breastfeeding after they have given birth. Breastfeeding support is an important part of workplace health promotion. We investigated the implementation of breastfeeding promotion and gender equality polices in workplaces with the Taiwan Badge of Accredited Healthy Workplace. Methods Our samples consisted of 1648 corporations with the badge of Accredited Healthy Workplace issued by the Bureau of Health Promotion from 2007 to 2008. Concomitantly, 2000 corporations without accreditation were randomly selected from the National Business Directory as the control group. Data were collected from self‐administered questionnaires. Logistic regression was used to examine the association with breast‐feeding promotion and other variables in Taiwanese workplaces. Results Members of accredited group of 1089/1648 (66.1%) and the control group of 526/2000 (26.3%) responded to the questionnaire. The accredited companies had more mother‐friendly settings, including breastfeeding policies and documents, appropriate breastmilk preserving equipment and settings in the workplace. In the accredited group, breastfeeding rate of mothers returning to work after giving birth was 64.3% in 2008 (1 year after giving birth) and 60.4% in 2009 (1 year after giving birth), while the rate of the control group was 59.1% in 2008 and 51% in 2009. Conclusion Accredited corporations are better at breastfeeding support than those of the control group. This might be related to the company size, location, and the implementation of tobacco control and/or occupational health promotion policies, which may increase awareness of healthy workplaces and influence maternal protection positively.

Purposes Our aim is to build and evaluate models to screen for clinically significant nephrolithiasis in overweight and obesity populations using machine learning (ML) methodologies and simple health checkup clinical and urine parameters easily obtained in clinics. Methods We developed ML models to screen for clinically significant nephrolithiasis (kidney stone > 2 mm) in overweight and obese populations (body mass index, BMI ≥ 25 kg/m 2 ) using gender, age, BMI, gout, diabetes mellitus, estimated glomerular filtration rate, bacteriuria, urine pH, urine red blood cell counts, and urine specific gravity. The data were collected from hospitals in Kaohsiung, Taiwan between 2012 and 2021. Results Of the 2928 subjects we enrolled, 1148 (39.21%) had clinically significant nephrolithiasis and 1780 (60.79%) did not. The testing dataset consisted of data collected from 574 subjects, 235 (40.94%) with clinically significant nephrolithiasis and 339 (59.06%) without. One model had a testing area under curve of 0.965 (95% CI, 0.9506–0.9794), a sensitivity of 0.860 (95% CI, 0.8152–0.9040), a specificity of 0.947 (95% CI, 0.9230–0.9708), a positive predictive value of 0.918 (95% CI, 0.8820–0.9544), and negative predictive value of 0.907 (95% CI, 0.8756–0.9371). Conclusion This ML-based model was found able to effectively distinguish the overweight and obese subjects with clinically significant nephrolithiasis from those without. We believe that such a model can serve as an easily accessible and reliable screening tool for nephrolithiasis in overweight and obesity populations and make possible early intervention such as lifestyle modifications and medication for prevention stone complications.

The Kaposi’s sarcoma-associated herpesvirus (KSHV)-encoded ORF50 protein is a potent transcriptional activator essential for triggering KSHV lytic reactivation. Despite extensive studies, little is known about whether ORF50 possesses the ability to repress gene expression or has an antagonistic action to cellular transcription factors. Previously, we demonstrated that human oncoprotein MDM2 can promote the degradation of ORF50 protein. Herein, we show that abundant ORF50 expression in cells can conversely downregulate MDM2 expression via repressing both the upstream (P1) and internal (P2) promoters of the MDM2 gene. Deletion analysis of the MDM2 P1 promoter revealed that there were two ORF50-dependent negative response elements located from −102 to −63 and from −39 to +1, which contain Sp1-binding sites. For the MDM2 P2 promoter, the ORF50-dependent negative response element was identified in the region from −110 to −25, which is coincident with the location of two known p53-binding sites. Importantly, we further demonstrated that overexpression of Sp1 or p53 in cells indeed upregulated MDM2 expression; however, coexpression with ORF50 protein remarkably reduced the Sp1- or p53-mediated MDM2 upregulation. Collectively, our findings propose a reciprocal negative regulation between ORF50 and MDM2 and uncover that ORF50 decreases MDM2 expression through repressing Sp1- and p53-mediated transactivation.

The present study aimed to use event-related potentials with the stop-signal task to investigate the effects of trait anxiety on inhibitory control, error monitoring, and post-error adjustments. The stop-signal reaction time (SSRT) was used to evaluate the behavioral competence of inhibitory control. Electrophysiological signals of error-related negativity (ERN) and error positivity (Pe) were used to study error perception and error awareness, respectively. Post-error slowing (PES) was applied to examine the behavioral adjustments after making errors. The results showed that SSRT and PES did not differ significantly between individuals with high trait anxiety (HTA) and those with low trait anxiety (LTA). However, individuals with HTA demonstrated reduced ERN amplitudes and prolonged Pe latencies than those with LTA. Prolonged Pe latencies were also significantly associated with poorer post-error adjustments. In conclusion, HTA led to reduced cortical responses to error monitoring. Furthermore, inefficient conscious awareness of errors might lead to maladaptive post-error adjustments.

Background Association between smoking and sleep apnea is well-known from previous studies. However, the influence of secondhand smoke (SHS), which is a potential risk factor of obstructive sleep apnea (OSA), remains unclear. Our aim was to investigate the relationship between SHS and OSA using a meta-analysis. Materials and methods For the meta-analysis, searches were performed in MEDLINE, EMBASE, and Web of Science databases on January 10, 2022, by combining various keywords including “SHS exposure” and “OSA”. Data were extracted using defined inclusion and exclusion criteria. Fixed-effects model meta-analyses were used to pool risk ratio (RR) estimates with their 95% confidence intervals (CI). I 2 was used to assess heterogeneity. Moreover, we performed subgroup meta-analyses of children-adults, and smoker fathers and mothers. Results In total, 267 articles were obtained through an electronic search. Twenty-six articles were included in our analysis according to the inclusion and exclusion criteria. We found evidence of an association between SHS exposure and possible OSA (RR 1.64, 95% CI 1.44–1.88). The results of the subgroup analyses showed that children passive smokers (RR 1.84, 95% CI 1.60–2.13) were at greater risks of possible OSA than adult passive smokers (RR 1.35, 95% CI 1.21–1.50). Also, significant differences were observed in mothers with smoking exposure (RR 2.61, 95% CI 1.62–4.21, p  < 0.0001), as well as in fathers with smoking exposure (RR 2.15, 95% CI 0.98–4.72, p  = 0.06). Short conclusion. Our meta-analysis confirmed that SHS exposure is significantly associated with OSA. In the subgroup analyses, the association of SHS and possible OSA was significant in both children and adults, as well as in smoker mothers and fathers. Highlights 1. This is a meta-analysis to evaluate the relationship between secondhand smoke (SHS) exposure and obstructive sleep apnea (OSA) in both adults and children. 2. Our meta-analysis revealed a significantly positive association between SHS exposure and possible OSA in children and adults. 3. Both smoking in mothers and fathers are associated with significantly higher risk of OSA in children.

This study aimed to investigate the performance of innovative and traditional cardiometabolic indices, including body mass index (BMI), waist circumference (WC), Chinese visceral adiposity index (CVAI), visceral adiposity index, lipid accumulation product, a body shape index (ABSI), body roundness index, conicity index (CI), triglyceride-glucose (TyG) index, TyG-BMI, and TyG-WC, in estimating atherosclerotic cardiovascular disease (ASCVD) risk in 3143 Taiwanese adults aged 20–79 years. Elevated 10-year ASCVD risk was defined as ≥7.5% using the Pooled Cohort Equations. The performance of different indices in estimating elevated ASCVD risk was assessed by receiver operating characteristic (ROC) curves. In multivariate-adjusted logistic regression analyses, all cardiometabolic indices (p-value < 0.001) were significantly associated with elevated ASCVD risk in both genders, except for ABSI and CI in women. In particular, CVAI had the largest area under the curve (AUC) in men (0.721) and women (0.883) in the ROC analyses. BMI had the lowest AUC in men (0.617), while ABSI had the lowest AUC in women (0.613). The optimal cut-off value for CVAI was 83.7 in men and 70.8 in women. CVAI performed best among various cardiometabolic indices in estimating elevated ASCVD risk. CVAI may be a reliable index for identifying people at increased risk of ASCVD.

Primary biliary cholangitis (PBC) is a chronic liver autoimmune disease with augmented T helper (Th) 1 and corresponding cytokine IFN-γ immune responses. Using 2-octynoic acid (2-OA) coupled to OVA (2-OA-OVA)-induced mouse models of autoimmune cholangitis (inducible chemical xenobiotic models of PBC), our previous study demonstrated that overexpression of IFN-γ in the model mice enhanced liver inflammation upon disease initiation, but subsequently led to the suppression of chronic inflammation with an increase in interleukin-30 (IL-30) levels. In this study, we investigated whether IL-30 had an immunosuppressive function and whether it could be part of an immune therapeutic regimen for PBC, by treating model mice with murine IL-30-expressing recombinant adeno-associated virus (AAV-mIL-30). We first defined the effects of AAV-mIL-30 in vivo by administering it to a well-known concanavalin A (ConA)-induced hepatitis model of mice and found that AAV-mIL-30 reduced the numbers of activated CD25+CD4+ T cells and the levels of serum IFN-γ and IL-12. In autoimmune cholangitis, decreased numbers of activated CD4+ T cells and Foxp3+ regulatory T cells were noted in the mice treated with AAV-mIL-30 at 3 weeks after the 2-OA-OVA immunization. Treatment with IL-30 did not change the features of autoimmune cholangitis including autoantibodies, cell infiltration, and collagen deposition in the liver at 11 weeks of examination. However, increased levels of cytokines and chemokines were observed. These results suggest that IL-30 suppresses not only CD4+ T cells but also regulatory T cells. Additionally, the administration of IL-30 did not suppress liver inflammation in the murine model of PBC.