The potential association between metabolic disorders and pulmonary tuberculosis: a Mendelian randomization study.

BACKGROUND: Metabolic disorders (MetDs) have been demonstrated to be closely linked to numerous diseases. However, the precise association between MetDs and pulmonary tuberculosis (PTB) remains poorly understood. METHOD: Summary statistics for exposure and outcomes from genome-wide association studies (GWASs) for exposures and outcomes were obtained from the BioBank Japan Project (BBJ) Gene-exposure dataset. The 14 clinical factors were categorized into three groups: metabolic laboratory markers, blood pressure, and the MetS diagnostic factors. The causal relationship between metabolic factors and PTB were analyzed using two-sample Mendelian Randomization (MR). Additionally, the direct effects on the risk of PTB were investigated through multivariable MR. The primary method employed was the inverse variance-weighted (IVW) model. The sensitivity of this MR analysis was evaluated using MR-Egger regression and the MR-PRESSO global test. RESULTS: According to the two-sample MR, HDL-C, HbA1c, TP, and DM were positively correlated with the incidence of active TB. According to the multivariable MR, HDL-C (IVW: OR 2.798, 95% CI 1.484-5.274, P = 0.001), LDL (IVW: OR 4.027, 95% CI 1.140-14.219, P = 0.03) and TG (IVW: OR 2.548, 95% CI 1.269-5.115, P = 0.009) were positively correlated with the occurrence of PTB. TC (OR 0.131, 95% CI 0.028-0.607, P = 0.009) was negatively correlated with the occurrence of PTB. We selected BMI, DM, HDL-C, SBP, and TG as the diagnostic factors for metabolic syndrome. DM (IVW, OR 1.219, 95% CI 1.040-1.429 P = 0.014) and HDL-C (IVW, OR 1.380, 95% CI 1.035-1.841, P = 0.028) were directly correlated with the occurrence of PTB. CONCLUSIONS: This MR study demonstrated that metabolic disorders, mainly hyperglycemia, and dyslipidemia, are associated with the incidence of active pulmonary tuberculosis.

Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y (2006-2010) at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained ∼ 54 % of the total effect.

Corrigendum: Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.

[This corrects the article DOI: 10.3389/fimmu.2023.1181697.].

m6A-methylated Lonp1 drives mitochondrial proteostasis stress to induce testicular pyroptosis upon environmental cadmium exposure.

Cadmium (Cd) is a widely distributed typical environmental pollutant and one of the most toxic heavy metals. It is well-known that environmental Cd causes testicular damage by inducing classic types of cell death such as cell apoptosis and necrosis. However, as a new type of cell death, the role and mechanism of pyroptosis in Cd-induced testicular injury remain unclear. In the current study, we used environmental Cd to generate a murine model with testicular injury and AIM2-dependent pyroptosis. Based on the model, we found that increased cytoplasmic mitochondrial DNA (mtDNA), activated mitochondrial proteostasis stress occurred in Cd-exposed testes. We used ethidium bromide to generate mtDNA-deficient testicular germ cells and further confirmed that increased cytoplasmic mtDNA promoted AIM2-dependent pyroptosis in Cd-exposed cells. Uracil-DNA glycosylase UNG1 overexpression indicated that environmental Cd blocked UNG-dependent repairment of damaged mtDNA to drive the process in which mtDNA releases to cytoplasm in the cells. Interestingly, we found that environmental Cd activated mitochondrial proteostasis stress by up-regulating protein expression of LONP1 in testes. Testicular specific LONP1-knockdown significantly reversed Cd-induced UNG1 protein degradation and AIM2-dependent pyroptosis in mouse testes. In addition, environmental Cd significantly enhanced the m6A modification of Lonp1 mRNA and its stability in testicular germ cells. Knockdown of IGF2BP1, a reader of m6A modification, reversed Cd-induced upregulation of LONP1 protein expression and pyroptosis activation in testicular germ cells. Collectively, environmental Cd induces m6A modification of Lonp1 mRNA to activate mitochondrial proteostasis stress, increase cytoplasmic mtDNA content, and trigger AIM2-dependent pyroptosis in mouse testes. These findings suggest that mitochondrial proteostasis stress is a potential target for the prevention of testicular injury.

Impacts of ultrasound-assisted Fenton degradation and alkaline de-esterification on structural properties and biological effects of pectic polysaccharides from Tartary buckwheat leaves.

Tartary buckwheat (Fagopyrum tataricum (L.) Gaertn) leaf has abundant rhamnogalacturonan-I enriched pectic polysaccharides, which exert various health-promoting effects. Nevertheless, the potential relationship between the chemical structure and the biological function of pectic polysaccharides from Tartary buckwheat leaves (TBP) remains unclear. Therefore, to bridge the gap between the chemical structure and the biological function of TBP, the impacts of ultrasound-assisted Fenton degradation (UFD) and mild alkaline de-esterification (MAD) on structural properties and biological effects of TBP were systematically studied. Compared with the native TBP (molecular mass, 9.537 × 104 Da), the molecular masses of degraded TBPs (TBP-MMW, 4.811 × 104 Da; TBP-LMW, 2.101 × 104 Da) were significantly reduced by the UFD modification, while their primary chemical structures were overall stable. Besides, compared with the native TBP (esterification degree, 22.73 %), the esterification degrees of de-esterified TBPs (TBP-MDE, 14.27 %; TBP-LDE, 6.59 %) were notably reduced by the MAD modification, while their primary chemical structures were also overall stable. Furthermore, the results revealed that both UFD and MAD modifications could significantly improve the antioxidant, antiglycation, and immunostimulatory effects of TBP. Indeed, TBP's biological effects were negatively correlated to its molecular mass and esterification degree, while positively linked to its free uronic acids. The findings demonstrate that both UFD and MAD modifications are promising techniques for the structural modification of TBP, which can remarkedly promote its biological effects. Besides, the present results are conducive to better understanding TBP's structure-bioactivity relationship.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.

Effects of replacing fishmeal with soybean meal on the immune and antioxidant capacity, and intestinal metabolic functions of red swamp crayfish Procambarus clarkii.

Excess utilization of plant protein sources in animal feed has been found to adversely affect the antioxidant properties and immunity of animals. While the role of gut microbes in plant protein-induced inflammation has been identified in various models, the specific mechanisms regulating gut microbes in crustaceans remain unclear. Accordingly, this study was designed to investigate the effects of replacing fishmeal with soybean meal (SM) on the hepatopancreas antioxidant and immune capacities, and gut microbial functions of crayfish, as well as the potential microbial regulatory mechanisms. 750 crayfish (4.00 g) were randomly divided into five groups: SS0, SS25, SS50, SS75, and SS100, and fed diets with different levels of soybean meal substituted for fishmeal for six weeks. High SM supplementation proved detrimental to maintaining hepatopancreas health, as indicated by an increase in hemolymph MDA content, GPT, and GOT activities, the observed rupture of hepatopancreas cell basement membranes, along with the decreased number of hepatopancreatic F cells. Moreover, crayfish subjected to high SM diets experienced obvious inflammation in hepatopancreas, together with up-regulated mRNA expression levels of nfkb, alf, and tlr (p<0.05), whereas the lzm mRNA expression level exhibited the highest value in the SS25 group. Furthermore, hepatopancreas antioxidant properties highly attenuated by the level of dietary SM substitution levels, as evidenced by the observed increase in MDA content (p<0.05), decrease in GSH content (p<0.05), and inhabitation of SOD, CAT, GPx, and GST activities (p<0.05), along with down-regulated hepatopancreas cat, gpx, gst, and mmnsod mRNA expression levels via inhibiting nrf2/keap1 pathway. Functional genes contributing to metabolism identified that high SM diets feeding significantly activated lipopolysaccharide biosynthesis, revealing gut dysfunction acted as the cause of inflammation. The global microbial co-occurrence network further indicated that the microbes contributing more to serum indicators and immunity were in module eigengene 17 (ME17). A structural equation model revealed that the genes related to alf directly drove the serum enzyme activities through microbes in ME17, with OTU399 and OTU533 identified as major biomarkers and classified into Proteobacteria that secrete endotoxins. To conclude, SM could replace 25 % of fishmeal in crayfish diets without negatively affecting immunity, and antioxidant capacity. Excessive SM levels contributed to gut dysfunction and weakened the innate immune system of crayfish.

Salmonella Grumpensis Causing Diarrhea in Children - Shanghai Municipality, China, 2023.

What is already known about this topic?: Foodborne diseases are a growing public health concern with a notable disease burden in China. What is added by this report?: Two children with diarrhea visited a healthcare facility within 24 hours on August 1 and 2, 2023. Salmonella Grumpensis was detected in their stool samples by the public health laboratory. Whole genome sequencing (WGS) analysis revealed characteristics typical of outbreak strains. Although the origin of the outbreak was unknown, the possibility of a hidden shared infection was deemed feasible. What are the implications for public health practice?: It underscores the importance of thorough genomic surveillance to promptly detect emerging pathogens. Public health laboratories play a crucial role by utilizing advanced genomic technologies for accurate pathogen identification and timely warning systems.

Bioinformatic validation and machine learning-based exploration of purine metabolism-related gene signatures in the context of immunotherapeutic strategies for nonspecific orbital inflammation.

Background: Nonspecific orbital inflammation (NSOI) represents a perplexing and persistent proliferative inflammatory disorder of idiopathic nature, characterized by a heterogeneous lymphoid infiltration within the orbital region. This condition, marked by the aberrant metabolic activities of its cellular constituents, starkly contrasts with the metabolic equilibrium found in healthy cells. Among the myriad pathways integral to cellular metabolism, purine metabolism emerges as a critical player, providing the building blocks for nucleic acid synthesis, such as DNA and RNA. Despite its significance, the contribution of Purine Metabolism Genes (PMGs) to the pathophysiological landscape of NSOI remains a mystery, highlighting a critical gap in our understanding of the disease's molecular underpinnings. Methods: To bridge this knowledge gap, our study embarked on an exploratory journey to identify and validate PMGs implicated in NSOI, employing a comprehensive bioinformatics strategy. By intersecting differential gene expression analyses with a curated list of 92 known PMGs, we aimed to pinpoint those with potential roles in NSOI. Advanced methodologies, including Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), facilitated a deep dive into the biological functions and pathways associated with these PMGs. Further refinement through Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) enabled the identification of key hub genes and the evaluation of their diagnostic prowess for NSOI. Additionally, the relationship between these hub PMGs and relevant clinical parameters was thoroughly investigated. To corroborate our findings, we analyzed expression data from datasets GSE58331 and GSE105149, focusing on the seven PMGs identified as potentially crucial to NSOI pathology. Results: Our investigation unveiled seven PMGs (ENTPD1, POLR2K, NPR2, PDE6D, PDE6H, PDE4B, and ALLC) as intimately connected to NSOI. Functional analyses shed light on their involvement in processes such as peroxisome targeting sequence binding, seminiferous tubule development, and ciliary transition zone organization. Importantly, the diagnostic capabilities of these PMGs demonstrated promising efficacy in distinguishing NSOI from non-affected states. Conclusions: Through rigorous bioinformatics analyses, this study unveils seven PMGs as novel biomarker candidates for NSOI, elucidating their potential roles in the disease's pathogenesis. These discoveries not only enhance our understanding of NSOI at the molecular level but also pave the way for innovative approaches to monitor and study its progression, offering a beacon of hope for individuals afflicted by this enigmatic condition.

Stabilization of Pd0 by Cu Alloying: Theory-Guided Design of Pd3Cu Electrocatalyst for Anodic Methanol Carbonylation.

Electrocatalytic carbonylation of CO and CH3OH to dimethyl carbonate (DMC) on metallic palladium (Pd) electrode offers a promising strategy for C1 valorization at the anode. However, its broader application is limited by the high working potential and the low DMC selectivity accompanied with severe methanol self-oxidation. Herein, our theoretical analysis of the intermediate adsorption interactions on both Pd0 and Pd4+ surfaces revealed that inevitable reconstruction of Pd surface under strongly oxidative potential diminishes its CO adsorption capacity, thus damaging the DMC formation. Further theoretical modeling indicates that doping Pd with Cu not only stabilizes low-valence Pd in oxidative environments but also lowers the overall energy barrier for DMC formation. Guided by this insight, we developed a facile two-step thermal shock method to prepare PdCu alloy electrocatalysts for DMC. Remarkably, the predicted Pd3Cu demonstrated the highest DMC selectivity among existing Pd-based electrocatalysts, reaching a peaked DMC selectivity of 93 % at 1.0 V versus Ag/AgCl electrode. (Quasi) in situ spectra investigations further confirmed the predicted dual role of Cu dopant in promoting Pd-catalyzed DMC formation.

A pulmonary artery was embolized in a patient with an occluded pulmonary vein to manage massive hemoptysis.

BACKGROUND: Stenosis and obliteration of the pulmonary vein can be developed by multiple diseases and might cause hemoptysis. Traditional therapy including surgical procedure and conservative treatments might be inappropriate choices to manage massive hemoptysis. CASE PRESENTATION: A 64-year-old man, diagnosed with advanced stage IVA lung squamous cell carcinoma, presented with dyspnea and recurrent, massive hemoptysis. An initial contrast-enhanced computed tomography revealed a giant tumor in the left lung hilus and occlusion of the left superior pulmonary vein. Despite immediate selective bronchial artery embolization and simultaneous embolization of an anomalous branch of the internal thoracic artery, the massive hemoptysis continued. Subsequently, embolization of the left superior pulmonary artery was performed, achieving functional pulmonary lobectomy, which successfully treated the hemoptysis without relapse during a six-month follow-up. The patient continues to undergo cancer therapy and remains stable. CONCLUSIONS: This case successfully managed massive hemoptysis associated with lung cancer invasion into the pulmonary vein through functional pulmonary lobectomy via embolization of the corresponding pulmonary artery.

The diagnostic performance of GeneXpert MTB/RIF in tuberculosis meningitis: A multicentre accuracy study.

OBJECTIVES: To evaluate the performance of GeneXpert MTB/RIF (Xpert) for tuberculous meningitis (TBM) and to identify additional indicators to improve diagnostic accuracy. METHODS: An accuracy study was conducted. During 2011-2019, 243 TBM with 140 non-TBM in three TB-designated facilities in China were enrolled. Microbiological evidence of M tuberculosis (Mtb) in CSF was used as the reference. Additional indicators were identified by Boosted-Classification and Regression Tree (CART), the improvement of diagnostic performance was evaluated by ROC. RESULTS: The diagnostic sensitivity of Xpert was 71.1 % for definite TBM, and 5.5 % for probable/possible TBM. The positive rate of Xpert was improved with cerebrospinal fluid (CSF) increasing volume and was associated with CSF color (yellow). The additional indicators obtained by CART were CSF lactate and glucose and increased the sensitivity to 96.1 % (definite TBM) and 84.6 % (probable/possible TBM). CONCLUSIONS: The diagnostic performance of Xpert was satisfactory in definite TBM and would significantly be improved by the additional use of CSF lactate and glucose.

Progress of Angiogenesis Signal Pathway and Antiangiogenic Drugs in Nasopharyngeal Carcinoma.

Nasopharyngeal cancer is a rare cancer with unique ethnic and geographic distribution. Since nasopharyngeal cancer often originates from the pharyngeal crypt, early symptoms are not obvious. They are difficult to detect in time, and the disease is usually diagnosed and treated only when it has progressed to an advanced-stage. Since angiogenesis is essential for the growth and invasion of solid tumors, antiangiogenic therapy has become a common treatment strategy for many solid tumors, and it has also achieved remarkable results in the treatment of nasopharyngeal carcinoma, which is prone to recurrence and distant metastasis. In this paper, we review the latest research progress of antiangiogenic drugs for nasopharyngeal carcinoma and their antiangiogenic mechanism of action and further propose some promising antiangiogenic therapeutic targets.

Constructing artificial gap junctions to mediate intercellular signal and mass transport.

Natural gap junctions are a type of channel protein responsible for intercellular signalling and mass communication. However, the scope of applications for these proteins is limited as they cannot be prepared at a large scale and are unable to spontaneously insert into cell membranes in vitro. The construction of artificial gap junctions may provide an alternative strategy for preparing analogues of the natural proteins and bottom-up building blocks necessary for the synthesis of artificial cells. Here we show the construction of artificial gap junction channels from unimolecular tubular molecules consisting of alternately arranged positively and negatively charged pillar[5]arene motifs. These molecules feature a hydrophobic-hydrophilic-hydrophobic triblock structure that allows them to efficiently insert into two adjacent plasma membranes and stretch across the gap between the two membranes to form gap junctions. Similar to natural gap junction channels, the synthetic channels could mediate intercellular signal coupling and reactive oxygen species transmission, leading to cellular activity.

Prognosis of immune checkpoint inhibitor-induced myasthenia gravis: a single center experience and systematic review.

Background: Immune checkpoint inhibitors (ICI)-induced myasthenia gravis (MG) is an uncommon but potentially fatal neurotoxicity. We aim to help physicians familiarize themselves with the clinical characteristics of ICI-induced MG, facilitating early diagnosis and prompt intervention. Methods: We searched the Chinese People's Liberation Army General Hospital medical record system from January 2017 to August 2023 for patients diagnosed with ICI-induced MG. We systematically reviewed the literature until August 2023 to identify all similar patients. We collected clinical information on these patients. Results: 110 patients were identified, 9 from our institution and 101 from case reports. In our institution, Median age was 66 years (range: 49-79 years). 6 were males. The most common was lung cancer (n = 4). All patients had no previous history of MG and received PD-1 or PD-L1 inhibitors. The median time from ICI initiation to first MG symptoms was 4 weeks (range: 2-15 weeks). ICIs were discontinued in all patients. Most patients initially received high-dose corticosteroids, and their symptoms improved. Some patients are discharged with corticosteroids maintenance therapy. In addition, 55 patients (50%) with concomitant myositis and/or myocarditis and MG-induced mortality were more common in the myositis and/or myocarditis group (10.9% vs. 34.5%, p = 0.016). Overlap of myositis with MG (OR = 3.148, p = 0.009) and anti-AChR antibody positivity (OR = 3.364, p = 0.005) were both significantly associated with poor outcomes. Conclusion: Our study reveals the prognosis of ICI-induced MG and suggests that myositis and/or myocarditis are severe comorbidities of ICI-induced MG, emphasizing the importance of early diagnosis and clinical intervention.

Causal relationship between feelings and cognitive decline: An univariable and multivariable Mendelian randomization study.

BACKGROUND: While the impact of depression on cognition is well-documented, the relationship between feelings and cognition has received limited attention. AIM: To explore the potential association between feelings and cognition with a two-sample Mendelian randomization (MR) analysis. METHODS: Our analysis utilized genome-wide association data on various feelings (fed-up feelings, n = 453071; worrier/anxious feelings, n = 450765; guilty feelings, n = 450704; nervous feelings, n = 450700; sensitivity/hurt feelings, n = 449419; miserableness, n = 454982; loneliness/isolation, n = 455364; happiness, n = 152348) in the European population and their impact on cognitive functions (intelligence, n = 269867). Conducting a univariable MR (UVMR) analysis to assess the relationship between feelings and cognition. In this analysis, we applied the inverse variance weighting (IVW), weighted median, and MR Egger methods. Additionally, we performed sensitivity analysis (leave-one-out analysis), assessed heterogeneity (using MR-PRESSO and Cochran's Q test), and conducted multiple validity test (employing MR-Egger regression). Subsequently, a multivariable MR (MVMR) analysis was employed to examine the impact of feelings on cognition. IVW served as the primary method in the multivariable analysis, complemented by median-based and MR-Egger methods. RESULTS: In this study, UVMR indicated that sensitivity/hurt feelings may have a negative causal effect on cognition (OR = 0.63, 95%CI: 0.43-0.92, P = 0.017). After adjustment of other feelings using MVMR, a direct adverse causal effect on cognition was observed (ORMVMR = 0.39, 95%CI: 0.17-0.90, PMVMR = 0.027). While a potential increased risk of cognitive decline was observed for fed-up feelings in the UVMR analysis (ORUVMR = 0.64, 95%CI: 0.42-0.97, PUVMR = 0.037), this effect disappeared after adjusting for other feelings (ORMVMR = 1.42, 95%CI: 0.43-4.74, PMVMR = 0.569). These findings were generally consistent across MV-IVW, median-based, and MR-Egger analyses. MR-Egger regression revealed pleiotropy in the impact of worrier/anxious feelings on cognition, presenting a challenge in identifying the effect. Notably, this study did not demonstrate any significant impact of guilty feelings, nervous feelings, miserableness, or loneliness/isolation on cognition. Due to a limited number of instrumental variables for happiness, this study was unable to analyze the relationship between happiness and cognition. CONCLUSION: This MR study finds that sensitivity/hurt feelings are associated with cognitive decline, while the link between worrier/anxious feelings and cognition remains inconclusive. Insufficient evidence supports direct associations between happiness, guilty feelings, nervous feelings, miserableness, loneliness/isolation, and cognition.

Precirrhotic Primary Biliary Cholangitis with Portal Hypertension: Bile Duct Injury Correlate.

Background/Aims: : The histological characteristics and natural history of precirrhotic primary biliary cholangitis (PBC) with portal hypertension (PH) are unclear. Our aim was to clarify the prevalence, risk factors, and histological characteristics of precirrhotic PBC patients with PH. Methods: : This retrospective study compared the clinical features, histological characteristics, and response to ursodeoxycholic acid (UDCA) between the PH and non-PH groups of precirrhotic PBC patients. Results: : Out of 165 precirrhotic PBC patients, 40 (24.2%) also had PH. According to histological stage 1, 2 and 3 disease, 5.3% (1/19), 17.3% (17/98), and 45.8% (22/48) of patients also had PH, respectively. Precirrhotic PBC with PH was significantly positively correlated with bile duct loss, degree of cytokeratin 7 positivity, and degree of fibrosis in the portal area, but significantly negatively correlated with lymphoid follicular aggregation. Compared to the non-PH group, patients in the PH group showed a higher prevalence of obliterative portal venopathy, incomplete septal fibrosis, portal tract abnormalities and non-zonal sinusoidal dilatation (p<0.05). In addition, patients with PH were more likely to present with symptoms of jaundice, ascites, epigastric discomfort, a poorer response to UDCA, and more decompensation events (p<0.05). High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values were risk factors for precirrhotic PBC with PH. Conclusions: : Approximately 24.2% of precirrhotic PBC patients have PH, which is histologically related to the injury of bile ducts. High alkaline phosphatase levels, low white blood cell counts, high Mayo scores, and high FIB-4 index values are associated with increased risk of precirrhotic PBC with PH.

Pathways explaining racial/ethnic and socio-economic disparities in brain white matter integrity outcomes in the UK Biobank study.

Pathways explaining racial/ethnic and socio-economic status (SES) disparities in white matter integrity (WMI) reflecting brain health, remain underexplored, particularly in the UK population. We examined racial/ethnic and SES disparities in diffusion tensor brain magnetic resonance imaging (dMRI) markers, namely global and tract-specific mean fractional anisotropy (FA), and tested total, direct and indirect effects through lifestyle, health-related and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40-70 y at baseline assessment (47% men). Multiple linear regression models were conducted, testing independent associations of race/ethnicity, socio-economic and other downstream factors in relation to global mean FA, while stratifying by Alzheimer's Disease polygenic Risk Score (AD PRS) tertiles. Race (Non-White vs. White) and lower SES predicted poorer WMI (i.e. lower global mean FA) at follow-up, with racial/ethnic disparities in FAmean involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across tract-specific FA outcomes, with SES-FAmean total effect being partially mediated (41% of total effect = indirect effect). Furthermore, the association of poor cognition with FAmean was markedly stronger in the two uppermost AD PRS tertiles compared to the lower tertile (T2 and T3: ß±SE: -0.0009 ± 0.0001 vs. T1: ß±SE: -0.0005 ± 0.0001, P < 0.001), independently of potentially confounding factors. Race and lower SES were generally important determinants of adverse WMI outcomes, with partial mediation of socio-economic disparities in global mean FA through lifestyle, health-related and cognition factors. The association of poor cognition with lower global mean FA was stronger at higher AD polygenic risk.

Chromosomal localization of mutated genes in non-syndromic familial thyroid cancer.

Familial non-medullary thyroid carcinoma (FNMTC) is a type of thyroid cancer characterized by genetic susceptibility, representing approximately 5% of all non-medullary thyroid carcinomas. While some cases of FNMTC are associated with familial multi-organ tumor predisposition syndromes, the majority occur independently. The genetic mechanisms underlying non-syndromic FNMTC remain unclear. Initial studies utilized SNP linkage analysis to identify susceptibility loci, including the 1q21 locus, 2q21 locus, and 4q32 locus, among others. Subsequent research employed more advanced techniques such as Genome-wide Association Study and Whole Exome Sequencing, leading to the discovery of genes such as IMMP2L, GALNTL4, WDR11-AS1, DUOX2, NOP53, MAP2K5, and others. But FNMTC exhibits strong genetic heterogeneity, with each family having its own pathogenic genes. This is the first article to provide a chromosomal landscape map of susceptibility genes associated with non-syndromic FNMTC and analyze their potential associations. It also presents a detailed summary of variant loci, characteristics, research methodologies, and validation results from different countries.

Molecular crosstalk and putative mechanisms underlying mitochondrial quality control: The hidden link with methylmercury-induced cognitive impairment.

Methylmercury (MeHg) is a neurotoxin associated with foetal neurodevelopmental and adult cognitive deficits. Neurons are highly dependent on the tricarboxylic acid cycle and oxidative phosphorylation to produce ATP and meet their high energy demands. Therefore, mitochondrial quality control (MQC) is critical for neuronal homeostasis. While existing studies have generated a wealth of data on the toxicity of MeHg, the complex cascades and molecular pathways governing the mitochondrial network remain to be elucidated. Here, 0.6, 1.2 and 2.4 mg/kg body weight of MeHg were administered intragastrically to pregnant Sprague Dawley rats to model maternal MeHg exposure. The results of the in vivo study revealed that MeHg-treated rats tended to perform more directionless repetitive strategies in the Morris Water Maze and fewer target-orientation strategies than control offspring. Moreover, pathological injury and synaptic toxicity were observed in the hippocampus. Transmission electron microscopy (TEM) demonstrated that the autophagosomes encapsulated damaged mitochondria, while showing a typical mitochondrial fission phenotype, which was supported by the activation of PINK1-dependent key regulators of mitophagy. Moreover, there was upregulation of DRP1 and FIS1. Additionally, MeHg compensation promoted mitochondrial biogenesis, as evidenced by the activation of the mitochondrial PGC1-α-NRF1-TFAM signalling pathway. Notably, SIRT3/AMPK was activated by MeHg, and the expression and activity of p-AMPK, p-LKB1 and SIRT3 were consistently coordinated. Collectively, these findings provide new insights into the potential molecular mechanisms regulating MeHg-induced cognitive deficits through SIRT3/AMPK MQC network coordination.