Background and Aims Anti-gp210 and antimitochondrial antibody (AMA) are important serological markers in primary biliary cholangitis (PBC). This study aimed to characterize the clinical features of anti-gp210-positive, AMA-negative patients with abnormal liver function and to explore factors associated with a final diagnosis of PBC in this retrospective cohort. Methods We retrospectively identified 93 anti-gp210-positive, AMA-negative patients. Clinical, biochemical, serological, pathological, and follow-up data were reviewed. Because the non-PBC group comprised multiple etiologies with different clinical and pathophysiological characteristics, comparisons between the PBC and non-PBC groups were considered exploratory and were interpreted with caution. Results Forty-eight patients were classified as PBC and 45 as non-PBC after clinical evaluation. Compared with the non-PBC group, patients with PBC had higher alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) levels, a higher anticentromere antibody (ACA) positivity rate, and higher anti-gp210 titers, whereas total bilirubin (TBIL) and aspartate aminotransferase (AST) levels were lower. During follow-up, anti-gp210 became negative in 1 of 23 followed PBC patients and in 6 of 20 followed non-PBC patients. Given the small follow-up subgroup, this observation is descriptive and should be interpreted cautiously. Conclusion Anti-gp210 positivity in AMA-negative patients supports consideration of PBC, but anti-gp210 positivity may also be detected in a subset of non-PBC liver diseases. In this retrospective cohort, higher anti-gp210 titers and a more cholestatic biochemical profile were more frequently observed in patients ultimately classified as PBC. These findings should be interpreted in light of the heterogeneity of the non-PBC group and the exploratory nature of the analyses.

Despite achieving functional cure with pegylated interferon-based therapy, a significant proportion of chronic hepatitis B (CHB) patients experience recurrence, even in the presence of high anti-HBs titers. Robust predictors to identify these at-risk individuals are lacking. We aimed to develop and validate a novel model integrating viral (HBcrAg) and host immune (anti-HBc, anti-HBs) biomarkers for personalized recurrence prediction. In this ambispective cohort, 84 CHB patients with functional cure (28 recurrence [R], 56 non-recurrence [NR]) were rigorously selected via 1:2 propensity score matching and followed for ≥ 96 weeks. Serum levels of HBcrAg, anti-HBc, and anti-HBs at end-of-treatment (EOT) were quantified. Independent predictors were identified by logistic regression, and diagnostic performance was evaluated by ROC analysis. At EOT, the R group had significantly higher HBcrAg levels than the NR group (3.30 ± 1.13 vs. 2.26 ± 1.04 log10 U/mL; p < 0.001), along with lower anti-HBc levels (2.53 ± 0.77 vs. 3.22 ± 0.53 log10 IU/mL; p < 0.001) and lower anti-HBs levels (1.89 ± 0.82 vs. 2.26 ± 0.56 log10 IU/mL; p = 0.014). Multivariate analysis confirmed HBcrAg (OR = 3.48, p = 0.001) and anti-HBc (OR = 0.10, p = 0.001) as independent predictors, while anti-HBs lost significance. The combined three-marker model outperformed any single biomarker, achieving an AUC of 0.88 (95

AIM: To evaluate ocular surface characteristics and dry eye symptoms in primary biliary cholangitis (PBC) patients with seasonal allergic conjunctivitis (SAC). METHODS: This retrospective case-control study included 73 PBC patients: 38 with SAC (PBC+SAC group, 38 eyes) and 35 controls (35 eyes). All the participants underwent comprehensive ocular surface assessment and ocular surface disease index (OSDI) scoring. The severity of ocular allergy in PBC+SAC group was indicated by total ocular symptom score (TOSS), and correlation analysis was carried out between TOSS and ocular parameters. RESULTS: Age (59.60±10.69y vs 58.72±11.13y, P=0.629) and gender distribution (34 vs 32 females, P=0.713) did not differ significantly between groups. Compared to controls, the PBC+SAC group had higher dry eye prevalence (65.79% vs 28.57%, P=0.002), higher OSDI score [median: 34.3 (interquartile range, IQR: 26.05, 43.6) vs 21.2 (IQR: 15.15, 31.2), P<0.001], shorter non-invasive tear film breakup time [NIBUT, median: 4.16s (IQR: 2.52, 6.48) vs 6.88s (IQR: 4.81, 9.28), P<0.001], more severe upper meibomian gland loss (P<0.001), higher corneal fluorescein staining score [median: 1 (IQR: 0, 1) vs 0 (IQR: 0, 0.25), P<0.001], and higher rates of meibomian gland duct thinning (60.53% vs 31.43%, P=0.004) and distortion (73.68% vs 25.71%, P=0.001). TOSS was positively correlated with OSDI score (r=0.484, P<0.001) in PBC+SAC group but not with other ocular parameters (all P>0.05). CONCLUSION: PBC patients with SAC have higher dry eye prevalence and more severe dry eye symptoms, mainly evaporative dry eye with obvious upper meibomian gland morphological abnormalities. Allergic symptom severity is positively correlated with dry eye discomfort, suggesting allergic inflammation may exacerbate ocular surface burden in PBC patients.

BACKGROUND:Autoimmune liver diseases, including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and their overlap syndrome (OS), involve immune-mediated liver injury, with OS occurring in 1.2%-25% of PBC patients. OS carries a higher risk of cirrhosis, hepatocellular carcinoma, and reduced survival. While its pathogenesis remains unclear, gut microbiota dysbiosis and serum metabolite alterations may play key roles. This study uses 16S rRNA sequencing and liquid chromatography-mass spectrometry (LC-MS) metabolomics to compare gut microbiota and serum metabolites among PBC, AIH, and OS patients, and explores their associations with liver function. AIM:To differentiate OS from PBC and AIH based on gut microbiota, serum metabolites, and liver function. METHODS:Gut microbiota profiles were analyzed using 16S rRNA sequencing, while untargeted serum metabolomics was conducted via LC-MS. Comparative analyses were performed to identify differences in microbial composition and serum metabolite levels among PBC, AIH, and OS groups. Correlation analyses and network visualization techniques were applied to elucidate the interactions among liver function parameters, gut microbiota, and serum metabolites in OS patients. RESULTS:Compared to patients with PBC or AIH, OS patients demonstrated significantly reduced microbial diversity and richness. Notable taxonomic shifts included decreased abundances of Firmicutes, Bacteroidetes, and Actinobacteria, alongside increased levels of Proteobacteria and Verrucomicrobia. Distinct serum metabolites, such as pentadecanoic acid and aminoimidazole carboxamide ribonucleotide, were identified in OS patients. Correlation analysis revealed that aspartate aminotransferase (AST) levels were negatively associated with the bacterial genus Fusicatenibacter and the metabolite L-Tyrosine. A microbial-metabolite network diagram further confirmed a strong association between Fusicatenibacter and L-Tyrosine in OS patients. CONCLUSION:OS patients show decreased gut microbiota diversity and unique serum metabolites. Multi-omics linked AST, Fusicatenibacter, and L-Tyrosine, revealing OS mechanisms and diagnostic potential.

BACKGROUND:About 1/3 of primary biliary cholangitis (PBC) patients suffered from poor response worldwide. And these patients present intestinal disturbances. We aimed to identify signatures of microbiota and metabolites in PBC patients with poor response, comparing to patients with response.METHODS:This study enrolled 25 subjects (14 PBC patients with response and 11 PBC patients with poor response). Metatranscriptomics and metabolomics analysis were carried out on their fecal.RESULTS:PBC patients with poor response had significant differences in the composition of bacteria, characterized by decreased Gemmiger etc. and increased Ruminococcus etc. The differential microbiota functions characterized by decreased abundance of elongation factor Tu and elongation factor G base on the KO database, as well as decreased abundance of Replicase large subunit etc. based on the SWISS-PROT database. PBC with poor response also had significant differences in 17 kinds of bacterial metabolites, characterized by decreased level of metabolites vital in bile acids metabolism pathway (L-Cysteine etc.) and the all-trans-Retinoic acid, a kind of immune related metabolite. The altered microbiota was associated with the differential expressed metabolites and clinical liver function indicators. 1 bacterial genera, 2 bacterial species and 9 metabolites simultaneously discriminated PBC with poor response from PBC with response with high accuracy.CONCLUSION:PBC patients with poor response exhibit unique changes in microbiota and metabolite. Gut microbiota and metabolite-based algorithms could be used as additional tools for differential prediction of PBC with poor prognosis.

BACKGROUND:Primary biliary cholangitis (PBC) is associated closely with the gut microbiota. This study aimed to explore the characteristics of the gut microbiota after the progress of PBC to cirrhosis. METHOD:This study focuses on utilizing the 16S rRNA gene sequencing method to screen for differences in gut microbiota in PBC patients who progress to cirrhosis. Then, we divided the data into training and verification sets and used seven different machine learning (ML) models to validate them respectively, calculating and comparing the accuracy, F1 score, precision, and recall, and screening the dominant intestinal flora affecting PBC cirrhosis. RESULT:PBC cirrhosis patients showed decreased diversity and richness of gut microbiota. Additionally, there are alterations in the composition of gut microbiota in PBC cirrhosis patients. The abundance of Faecalibacterium and Gemmiger bacteria significantly decreases, while the abundance of Veillonella and Streptococcus significantly increases. Furthermore, machine learning methods identify Streptococcus and Gemmiger as the predominant gut microbiota in PBC patients with cirrhosis, serving as non-invasive biomarkers (AUC = 0.902). CONCLUSION:Our study revealed that PBC cirrhosis patients gut microbiota composition and function have significantly changed. Streptococcus and Gemmiger may become a non-invasive biomarker for predicting the progression of PBC progress to cirrhosis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease. During the diagnostic process, the patient's autoimmune antibodies are routinely examined. Approximately 20% of PBC patients have positive anti-centromere antibody (ACA). We evaluated the clinical characteristics of ACA-positive and ACA-negative PBC patients to explain the differences in disease progression between these two groups. Retrospective data from 961 PBC patients at Beijing Youan Hospital from 2010 to 2019 were gathered and separated into two groups based on ACA positivity. We collected and evaluated clinical laboratory indices, gastroscopy findings, and liver function assessments. In addition, 60 liver biopsies were available for comparison between the 2 groups. Pathologists staged the histological findings using the Ludwig staging criteria and Nakanuma staging and grading. Immunohistochemical staining was also performed on liver biopsies to examine the expression of cytokeratin 7 (CK7) in the tissue. A synthesis of clinical indicators in the large cohort showed that alanine transaminase, aspartate aminotransferase, total bilirubin, IgG, white blood cell, and platelet were significantly lower in the ACA-positive group, indicating that the overall status of liver injury was more moderate in the ACA-positive group. Additionally, ACA-positive patients in the non-cirrhotic group were more likely to present with gastroesophageal varices related to portal hypertension. Finally, analysis of pathologic findings showed that parameters were mostly comparable in the two groups, but CK7 differed and was more significantly lower in the ACA-positive group in albumin-bilirubin grade 2 and 3 patients. In summary, we characterized and compared the clinical features of ACA-positive and ACA-negative PBC patients, corroborating previous studies on the relationship between ACA positivity and portal hypertension cross-sectionally. It suggested that gastroesophageal varices might happen in the earlier course of PBC natural progression in the ACA-positive group.

Background The Albumin-Bilirubin (ALBI) score and grade are widely used to stratify patients with primary biliary cholangitis (PBC) into different disease statuses and risk levels. Recent studies have increasingly highlighted the role of gut microbiota in autoimmune liver diseases. This study aimed to investigate the differences in gut microbiota among PBC patients with varying ALBI grades.Methods Clinical data and stool samples were collected from outpatient and inpatient PBC patients between 2019 and 2022. Gut microbiota profiles were obtained using 16S rDNA sequencing of stool samples. We analyzed alpha diversity, beta diversity, LEfSe analysis and pathway function prediction. Additionally, various machine learning methods-including random forest (RF), lasso, gradient boosting machine (GBM) and support vector machine (SVM)-were employed to identify key features and to build and validate predictive models using bootstrap techniques.Results Clinical characteristics of ALBI grade 1 patients were comparatively better than those of ALBI grade 2 and 3 patients, including multiple laboratory indices. Gut microbiota analysis revealed that species richness and balance were higher in ALBI grade 1 patients. Both the comparison of the most abundant genera and the linear discriminant analysis (LDA) in LEfSe demonstrated that Lachnospira had a higher abundance and better discriminative ability in ALBI grade 1. Pathway function prediction indicated that sulfur metabolism was upregulated in higher ALBI grades. Furthermore, RF identified 10 specific genera, which were then used to build and validate models for discriminating PBC patients according to their ALBI grades. All three models, developed using different machine learning methods, demonstrated good discrimination ability (mean AUC 0.75-0.80).Conclusion This study highlights significant differences in gut microbiota profiles among PBC patients with different ALBI grades. The increased abundance of Lachnospira and upregulation of sulfur metabolism pathways are notable in patients with lower ALBI grades. The machine learning models developed based on gut microbiota features offer promising tools for discriminating between PBC patients with varying disease severities, which could enhance the precision of treatment strategies.

ObjectiveTo evaluate the dynamic disinfection effect of the upper-room 222 nm ultraviolet radiation on the air in different areas of the emergency department, and to provide references for a new solution of air disinfection that man-machine coexisted in the medical and healthcare institutions.MethodsThe upper-room 222 nm ultraviolet radiation air sterilizers were installed at a height of 2.3‒2.6 m from the ground in the observation room, computed tomography (CT) scanning room, rescue room and consulting room of the emergency department in Beijing Tiantan Hospital, Capital Medical University . The test area was divided into a 222 nm ultraviolet group and a control group according to whether the 222 nm ultraviolet germicidal air disinfection was conducted or not. The experimental group started air disinfection at 8:00 a.m., and the air sampling was conducted from 9:00 a.m. to 16:00 p.m., with a 10 min sampling interval of every 1 hour. While the control group only collected air sample with the same air sampling method used in the experimental group, without air disinfection. The air microbial sampler with six-level sieve impingement was used for the air sampling, and the differences in the total number of airborne bacterial colonies were compared between the two groups.ResultsA total of 128 air samples were collected in the trial, of which 64 were from the experimental group and 64 from the control group. The total number of airborne bacterial colonies in the experimental group was lower than that in the control group (all P<0.001), and was maintained at a lower level throughout the entire period. The killing rate of 222 nm ultraviolet radiation to airborne microorganisms was approximately 55.76% to 76.33% in different sampling areas. The qualified rates of the total number of dynamic airborne bacterial colonies in the observation room, rescue room and consulting room were improved from 12.50%, 37.50% and 25.00% to 81.25%, 100.00% and 100.00%, respectively (all P<0.001). Over 62.50% of the time, the air quality in the consulting room and CT room in the 222 nm ultraviolet group met the environment standards for airborne bacterial colony criteria of class Ⅰ or class Ⅱ.ConclusionThe upper-room 222 nm ultraviolet radiation germicidal disinfection can effectively reduce the total number of airborne bacterial colonies and improve the environment for emergency department, and the continuous using of it is helpful for keeping the air safe and clean.

The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPRer) and the mitochondrial unfolded protein response (UPRmt) in the development of several neurodegenerative diseases.

Overexposure to manganese (Mn) is conducive to neurodegenerative diseases and neuronal injury. Persistent activation of the integrated stress response (ISR) has a substantial impact on the etiology of neurodegenerative disorders by interfering with intracellular homeostasis. Nevertheless, the precise mechanism through which ISR engages in Mn-related neurotoxicity remains unclear. Sirtuin 1 (SIRT1), a typical NAD+-dependent protein deacetylase, which is known to participate in Mn-induced neuronal damage. Therefore, the aim of our study was to clarify how SIRT1 regulates persistent ISR activation in mouse hippocampal neuronal cells (HT-22 cells) exposed to various concentrations of Mn. We discovered that persistent ISR activation was engaged in Mn-triggered mitochondrial and exogenous apoptotic signaling pathways, which was attributed to the excessive phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Growth arrest and DNA damage-inducible protein 34 (GADD34) is known to be responsible for down-regulating the phosphorylation of eIF2α. However, Mn promoted GADD34 protein expression and its acetylation level. We further investigated the effect of SIRT1 on the acetylation of GADD34 by overexpressing and silencing SIRT1. We discovered that SIRT1 activation significantly declined the acetylation level of GADD34, thus alleviating persistent ISR activation-mediated neuronal apoptosis in HT-22 cells-treated with Mn. In summary, these results suggested that Mn induced persistent activation of the ISR by inhibition of SIRT1 on deacetylation of GADD34.

目的:系统评价索磷维伏在真实世界中作为丙型肝炎病毒(HCV)挽救治疗的有效性和安全性.方法:计算机检索PubMed、Embase、Cochrane Library、Web of Science、ClinicalTrials.gov、中国知网、万方、维普和中国生物医学文献等数据库,纳入以索磷维伏为挽救治疗方案的真实世界研究.根据ROBINS-I工具对纳入研究的质量进行评价.采用Stata 15.0和RevMan 5.4软件进行Meta分析.结果:共纳入11项研究,包括1460例HCV感染者,持续治疗12周的人群总体持续病毒应答(SVR12)率为93％(95％CI:0.91～0.95),基因3型人群的SVR12率明显低于非基因3型(OR=0.35,95％CI:0.15～0.81,P=0.01),肝硬化人群的SVR12率低于非肝硬化人群(OR=0.46,95％CI:0.22～0.92,P=0.03).不良事件(AE)发生率为39.47％.最常见的AE为头痛(11.05％)、乏力(7.37％)、恶心(6.14％)、疲劳(5.96％)和腹泻(5.26％).因AE而终止治疗的仅有5人.结论:与临床试验结果一致,索磷维伏适用于既往治疗失败的HCV患者,是一种高效且耐受性良好的挽救性治疗方案.

Background/Aims: To investigate the autoantibody against fumarate hydratase (FH), which is a specific liver failure-associated antigen (LFAA) and determine whether it can be used as a biomarker to evaluate the prognosis of acute-on-chronic liver failure (ACLF). Methods: An immunoproteomic approach was applied to screen specific LFAAs related to differential prognosis of ACLF (n=60). Enzyme-linked immunosorbent assay (ELISA) technology was employed for the validation of the frequency and titer of autoantibodies against FH in ACLF patients with different prognoses (n=82). Moreover, we clarified the expression of autoantibodies against FH in patients with chronic hepatitis B (n=60) and hepatitis B virus-related liver cirrhosis (n=60). The dynamic changes in the titers of autoantibodies against FH were analyzed by sample collection at multiple time points during the clinical course of eight ACLF patients with different prognoses. Results: Ultimately, 15 LFAAs were screened and identified by the immunoproteomic approach. Based on ELISA-based verification, anti-FH/Fumarate hydratase protein autoantibody was chosen to verify its expression in ACLF patients. ACLF patients had a much higher anti-FH autoantibody frequency (76.8%) than patients with liver cirrhosis (10%, p=0.000), patients with chronic hepatitis B (6.7%, p=0.022), and normal humans (0%, p=0.000). More importantly, the frequency and titer of anti-FH protein autoantibodies in the serum of ACLF patients with a good prognosis were much higher than that of patients with a poor prognosis (83.9% vs 61.5%, p=0.019; 1.41±0.85 vs 0.94±0.56, p=0.017, respectively). The titer of anti-FH autoantibodies showed dynamic changes in the clinical course of ACLF. Conclusions: The anti-FH autoantibody in serum may be a potential biomarker for predicting the prognosis of ACLF.

Clinical novitiate provided a learning platform for medical students to apply theoretical knowledge to clinical practice,which was an important step for medical students to complete the role transformation to clinicians.At present,the difficulty of clinical teaching of infectious diseases was gradually increasing,which showed that the theoretical learning of online teaching was not stable,the lack of special probation materials,the gradual reduction of typical cases,the teaching method was single,the age gradient of teachers was single,the fear of infectious diseases of students and the poor compliance of patients.In order to improve the quality of clinical practice teaching,a series of reform measures should be taken including building stable online learning platform,establishing the trainee teaching materials and typical cases,improving teaching methods,strengthening the training of the teacher,strengthening medical humanities education,paying attention to training students clinical thinking ability and improving patients’ compliance and so on.Finally,through the clinical novitiate,students could be trained to have certain clinical thinking ability of infectious diseases and build a bridge for medical students to transition into a qualified clinician.

Programed cell death plays a key role in promoting human development and maintaining homeostasis. Ferroptosis is a recently identified pattern of programmed cell death that is closely associated with the onset and progression of neurodegenerative diseases. Ferroptosis is mainly caused by the intracellular accumulation of iron-dependent lipid peroxides. The cysteine/glutamate antibody Solute carrier family 7 member 11 (SLC7A11, also known as xCT) functions to import cysteine for glutathione biosynthesis and antioxidant defense. SLC7A11 has a significant impact on ferroptosis, and inhibition of SLC7A11 expression promotes ferroptosis. Moreover, SLC7A11 is also closely associated with neurodegenerative diseases. In this paper, we summarize the relationship between ferroptosis and neurodegenerative diseases and the role of SLC7A11 during this process. The various regulatory mechanisms of SLC7A11 are also discussed. In conclusion, we are looking forward to a theoretical basis for further understanding the occurrence and development of ferroptosis in SLC7A11 and neurodegenerative diseases, and to seek new clues for the treatment of neurodegenerative diseases.

自身免疫性肝炎是临床上引起肝功能异常的常见疾病之一,常见于中年女性,发病率逐渐上升,若不及时治疗,容易出现肝硬化及肝衰竭可能,逐渐引起临床重视.进修学习是医师提高专科诊疗知识的一个重要途径.文章总结分析科室近年来针对自身免疫性肝炎进修医师带教工作的体会,提倡规范带教及考核制度、实行专人带教模式、注重理论与实践相结合、加强师资队伍建设、分层带教及提高医患沟通能力,提高临床带教的质量.

Manganese (Mn) overexposure induces learning and memory impairments in mice by disrupting the functions of synapses and synaptic vesicles (SVs) in the hippocampus, which is associated with α-synuclein (α-Syn) overexpression. Rab26-dependent autophagy is a key signaling step required for impaired SV clearance; however, it is unclear whether Mn-induced α-Syn overexpression is linked to dysregulated Rab26-dependent autophagy in presynaptic neurons. In this study, we developed manganism models in male C57BL/6 mice and hippocampal primary neurons to observe the associations between Mn-induced α-Syn overexpression and impaired SV accumulation. The results of the in vivo experiments showed that 100 and 200 μmol/kg Mn exposure significantly impaired memory and synaptic plasticity in the mice, which was related to the accumulation of impaired SVs in the hippocampus. Consistent with the in vivo outcomes, the level of in vitro injured SVs in the 50 and 100 μmol/L Mn-exposed neuron group were higher than that in the control group. Moreover, 100 μmol/L Mn suppressed the initiation of Rab26-dependent autophagy at the synapse. Then, we transfected neurons with LV-α-Syn short hairpin RNA (shRNA) and exposed the neurons to Mn for an additional 24 h. Surprisingly, the area of colocalization between Rab26 and Atg16L1 and the expression level of LC3II-positive SVs were both higher in Mn-exposed LV-α-Syn shRNA-transfected neurons than those in Mn-treated normal or Mn-treated LV-scrambled shRNA-transfected neurons. Thus, Mn-induced α-Syn overexpression was responsible for the dysregulation of Rab26-dependent autophagy, thereby promoting the accumulation of injured SVs, and causing synaptotoxicity and cognitive and memory deficits in mice.

BACKGROUND:Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis. METHODS:Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs. FINDINGS:We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44-82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem. INTERPRETATION:This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss. FUNDING:National Science Foundation, and National Institutes of Health.

Occupational exposure and non-occupational exposure to excessive levels of manganese (Mn) result in neuronal cell damage through mitochondrial dysfunction. The functional integrity of mitochondria is maintained by mitophagy and mitochondrial biogenesis. Although Mn-induced S-nitrosylation of PTEN-induced putative kinase 1 (PINK1) can interfere with mitophagy, its effect on mitochondrial biogenesis remains unclear. In this study, we established a rat model of Mn poisoning or "manganism" to examine the relationship between PINK1 S-nitrosylation and impairment of mitochondrial biogenesis, and found that treatment with 60 mg/kg Mn induced marked neurobehavioral abnormalities in rats and significantly increased the S-nitrosylation level of PINK1. We also found that the nuclear-encoded peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A)-mediated mitochondrial biogenesis was significantly upregulated in rats treated with 15 and 30 mg/kg Mn, and downregulated in rats treated with 60 mg/kg Mn. We further investigated the role of S-nitrosylated PINK1 and its molecular mechanism in the high-dose Mn-mediated impairment of mitochondrial biogenesis in primary cultured neurons treated with the nitric oxide synthase 2 (NOS2) inhibitor 1400 W. Our results revealed that the PPARGC1A-mediated mitochondrial biogenesis was upregulated in neurons treated with 100 μM, but downregulated in neurons treated with 200 μM Mn, which was similar to the in vivo results. However, treatment with 1400W could effectively prevent the 200 μM Mn-mediated impairment of mitochondrial biogenesis by suppressing nitric oxide (NO)-mediated PINK1 S-nitrosylation and rescuing Parkin-interacting substrate (PARIS, ZNF746) degradation, thereby upregulating mitochondrial biogenesis via PPARGC1A. These findings demonstrated that S-nitrosylation of PINK1 and subsequent prevention of ZNF746 degradation were crucial signaling processes involved in the Mn-mediated impairment of mitochondrial biogenesis, which might serve as an underlying mechanism of Mn-induced neurotoxicity. Furthermore, this study provided a reliable target for the prevention and treatment of manganism.