Plasma thrombomodulin as a candidate biomarker for the diagnosis and prognosis of HBV-related acute-on-chronic liver failure.

Background and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF. Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA). Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥8.4 ng/mL. Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.

Mitochondria: one of the vital hubs for molecular hydrogen's biological functions.

As a novel antioxidant, a growing body of studies has documented the diverse biological effects of molecular hydrogen (H2) in a wide range of organisms, spanning animals, plants, and microorganisms. Although several possible mechanisms have been proposed, they cannot fully explain the extensive biological effects of H2. Mitochondria, known for ATP production, also play crucial roles in diverse cellular functions, including Ca2+ signaling, regulation of reactive oxygen species (ROS) generation, apoptosis, proliferation, and lipid transport, while their dysfunction is implicated in a broad spectrum of diseases, including cardiovascular disorders, neurodegenerative conditions, metabolic disorders, and cancer. This review aims to 1) summarize the experimental evidence on the impact of H2 on mitochondrial function; 2) provide an overview of the mitochondrial pathways underlying the biological effects of H2, and 3) discuss H2 metabolism in eukaryotic organisms and its relationship with mitochondria. Moreover, based on previous findings, this review proposes that H2 may regulate mitochondrial quality control through diverse pathways in response to varying degrees of mitochondrial damage. By combining the existing research evidence with an evolutionary perspective, this review emphasizes the potential hydrogenase activity in mitochondria of higher plants and animals. Finally, this review also addresses potential issues in the current mechanistic study and offers insights into future research directions, aiming to provide a reference for future studies on the mechanisms underlying the action of H2.

Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure.

Background & Aims: HBV-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome associated with high short-term mortality. This study aims to reveal the molecular basis and identify novel HBV-ACLF biomarkers. Methods: Seventy patients with HBV-ACLF and different short-term (28 days) outcomes underwent transcriptome sequencing using peripheral blood mononuclear cells. Candidate biomarkers were confirmed in two external cohorts using ELISA. Results: Cellular composition analysis with peripheral blood mononuclear cell transcriptomics showed that the proportions of monocytes, T cells and natural killer cells were significantly correlated with 28-day mortality. Significant metabolic dysregulation of carbohydrate, energy and amino acid metabolism was observed in ACLF non-survivors. V-set and immunoglobulin domain-containing 4 (VSIG4) was the most robust predictor of patient survival (adjusted p = 1.74 × 10-16; variable importance in the projection = 1.21; AUROC = 0.89) and was significantly correlated with pathways involved in the progression of ACLF, including inflammation, oxidative phosphorylation, tricarboxylic acid cycle and T-cell activation/differentiation. Plasma VSIG4 analysis externally validated its diagnostic value in ACLF (compared with chronic liver disease and healthy groups, AUROC = 0.983). The prognostic performance for 28-/90-day mortality (AUROCs = 0.769/0.767) was comparable to that of three commonly used scores (COSSH-ACLFs, 0.867/0.884; CLIF-C ACLFs, 0.840/0.835; MELD-Na, 0.710/0.737). Plasma VSIG4 level, as an independent predictor, could be used to improve the prognostic performance of clinical scores. Risk stratification based on VSIG4 expression levels (>122 µg/ml) identified patients with ACLF at a high risk of death. The generality of VSIG4 in other etiologies was validated. Conclusions: This study reveals that immune-metabolism disorder underlies poor ACLF outcomes. VSIG4 may be helpful as a diagnostic and prognostic biomarker in clinical practice. Impact and implications: Acute-on-chronic liver failure (ACLF) is a lethal clinical syndrome associated with high mortality. We found significant immune cell alterations and metabolic dysregulation that were linked to high mortality in patients with HBV-ACLF based on transcriptomics using peripheral blood mononuclear cells. We identified VSIG4 (V-set and immunoglobulin domain-containing 4) as a diagnostic and prognostic biomarker in ACLF, which could specifically identify patients with ACLF at a high risk of death.

Generation and metabolomic characterization of functional ductal organoids with biliary tree networks in decellularized liver scaffolds.

Developing functional ductal organoids (FDOs) is essential for liver regenerative medicine. We aimed to construct FDOs with biliary tree networks in rat decellularized liver scaffolds (DLSs) with primary cholangiocytes isolated from mouse bile ducts. The developed FDOs were dynamically characterized by functional assays and metabolomics for bioprocess clarification. FDOs were reconstructed in DLSs retaining native structure and bioactive factors with mouse primary cholangiocytes expressing enriched biomarkers. Morphological assessment showed that biliary tree-like structures gradually formed from day 3 to day 14. The cholangiocytes in FDOs maintained high viability and expressed 11 specific biomarkers. Basal-apical polarity was observed at day 14 with immunostaining for E-cadherin and acetylated α-tubulin. The rhodamine 123 transport assay and active collection of cholyl-lysyl-fluorescein exhibited the specific functions of bile secretion and transportation at day 14 compared to those in monolayer and hydrogel culture systems. The metabolomics analysis with 1075 peak pairs showed that serotonin, as a key molecule of the tryptophan metabolism pathway linked to biliary tree reconstruction, was specifically expressed in FDOs during the whole period of culture. Such FDOs with biliary tree networks and serotonin expression may be applied for disease modeling and drug screening, which paves the way for future clinical therapeutic applications.

Therapeutic Potential of Molecular Hydrogen in Metabolic Diseases from Bench to Bedside.

Oxidative stress and chronic inflammation have been implicated in the pathophysiology of metabolic diseases, including diabetes mellitus (DM), metabolic syndrome (MS), fatty liver (FL), atherosclerosis (AS), and obesity. Molecular hydrogen (H2) has long been considered a physiologically inert gas. In the last two decades, accumulating evidence from pre-clinical and clinical studies has indicated that H2 may act as an antioxidant to exert therapeutic and preventive effects on various disorders, including metabolic diseases. However, the mechanisms underlying the action of H2 remain unclear. The purpose of this review was to (1) provide an overview of the current research on the potential effects of H2 on metabolic diseases; (2) discuss the possible mechanisms underlying these effects, including the canonical anti-oxidative, anti-inflammatory, and anti-apoptotic effects, as well as suppression of ER stress, activation of autophagy, improvement of mitochondrial function, regulation of gut microbiota, and other possible mechanisms. The potential target molecules of H2 will also be discussed. With more high-quality clinical trials and in-depth mechanism research, it is believed that H2 will eventually be applied to clinical practice in the future, to benefit more patients with metabolic disease.

ETS2 alleviates acute-on-chronic liver failure by suppressing excessive inflammation.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a syndrome with high short-term mortality. The mechanism of the transcription factor ETS2 in ACLF remains unclear. This study aimed to clarify the molecular basis of ETS2 in ACLF pathogenesis. Peripheral blood mononuclear cells from patients with HBV-ACLF (n = 50) were subjected to RNA sequencing. Transcriptome analysis showed that ETS2 expression was significantly higher in ACLF patients than in patients with chronic liver diseases and healthy subjects (all p < 0.001). Area-under-ROC analysis of ETS2 demonstrated high values for the prediction of 28-/90-day mortality in ACLF patients (0.908/0.773). Significantly upregulated signatures of the innate immune response (monocytes/neutrophils/inflammation-related pathways) were observed in ACLF patients with high ETS2 expression. Myeloid-specific ETS2 deficiency in liver failure mice resulted in deterioration of biofunctions and increased expression of pro-inflammatory cytokines (IL-6/IL-1ß/TNF-α). Knockout of ETS2 in macrophages confirmed the downregulation of IL-6 and IL-1ß caused by both HMGB1 and lipopolysaccharide, and an NF-κB inhibitor reversed the suppressive effect of ETS2. ETS2 is a potential prognostic biomarker of ACLF patients that alleviates liver failure by downregulating the HMGB1-/lipopolysaccharide-triggered inflammatory response and may serve as a therapeutic target for ACLF.

Orthotopic Transplantation of Functional Bioengineered Livers in Rats.

Functional bioengineered livers (FBLs) are promising alternatives to orthotopic liver transplantation. However, orthotopic transplantation of FBLs has not yet been reported. This study aimed to perform the orthotopic transplantation of FBLs in rats subjected to complete hepatectomy. FBLs were developed using rat whole decellularized liver scaffolds (DLSs) with human umbilical vein endothelial cells implanted via the portal vein, and human bone marrow mesenchymal stem cells (hBMSCs) and mouse hepatocyte cell line implanted via the bile duct. FBLs were evaluated in terms of endothelial barrier function, biosynthesis, and metabolism and orthotopically transplanted into rats to determine the survival benefit. The FBLs with well-organized vascular structures exhibited endothelial barrier function, with reduced blood cell leakage. The implanted hBMSCs and hepatocyte cell line were well aligned in the parenchyma of the FBLs. The high levels of urea, albumin, and glycogen in the FBLs indicated biosynthesis and metabolism. Orthotopic transplantation of FBLs achieved a survival time of 81.38 ± 4.263 min in rats (n = 8) subjected to complete hepatectomy, whereas control animals (n = 4) died within 30 min (p < 0.001). After transplantation, CD90-positive hBMSCs and the albumin-positive hepatocyte cell line were scattered throughout the parenchyma, and blood cells were limited within the vascular lumen of the FBLs. In contrast, the parenchyma and vessels were filled with blood cells in the control grafts. Thus, orthotopic transplantation of whole DLS-based FBLs can effectively prolong the survival of rats subjected to complete hepatectomy. In summary, this work was the first to perform the orthotopic transplantation of FBLs, with limited survival benefits, which still has important value for the advancement of bioengineered livers.

Predicting the survival benefit of liver transplantation in HBV-related acute-on-chronic liver failure: an observational cohort study.

Background: Liver transplantation (LT) is an effective therapy for acute-on-chronic liver failure (ACLF) but is limited by organ shortages. We aimed to identify an appropriate score for predicting the survival benefit of LT in HBV-related ACLF patients. Methods: Hospitalized patients with acute deterioration of HBV-related chronic liver disease (n = 4577) from the Chinese Group on the Study of Severe Hepatitis B (COSSH) open cohort were enrolled to evaluate the performance of five commonly used scores for predicting the prognosis and transplant survival benefit. The survival benefit rate was calculated to reflect the extended rate of the expected lifetime with vs. without LT. Findings: In total, 368 HBV-ACLF patients received LT. They showed significantly higher 1-year survival than those on the waitlist in both the entire HBV-ACLF cohort (77.2%/52.3%, p < 0.001) and the propensity score matching cohort (77.2%/27.6%, p < 0.001). The area under the receiver operating characteristic curve (AUROC) showed that the COSSH-ACLF II score performed best (AUROC 0.849) at identifying the 1-year risk of death on the waitlist and best (AUROC 0.864) at predicting 1-year outcome post-LT (COSSH-ACLFs/CLIF-C ACLFs/MELDs/MELD-Nas: AUROC 0.835/0.825/0.796/0.781; all p < 0.05). The C-indexes confirmed the high predictive value of COSSH-ACLF IIs. Survival benefit rate analyses showed that patients with COSSH-ACLF IIs 7-10 had a higher 1-year survival benefit rate from LT (39.2%-64.3%) than those with score <7 or >10. These results were prospectively validated. Interpretation: COSSH-ACLF IIs identified the risk of death on the waitlist and accurately predicted post-LT mortality and survival benefit for HBV-ACLF. Patients with COSSH-ACLF IIs 7-10 derived a higher net survival benefit from LT. Funding: This study was supported by the National Natural Science Foundation of China (No. 81830073, No. 81771196) and the National Special Support Program for High-Level Personnel Recruitment (Ten-thousand Talents Program).

Novel Insights in the Regulatory Mechanisms of Ferroptosis in Hepatocellular Carcinoma.

Ferroptosis is a newly defined programmed cell death, which by its mechanism differs from other programmed cell death processes such as apoptosis, necrosis, and autophagy. It has a unique morphology and biological properties that antioxidants and iron-chelating agents can regulate. Ferroptosis has the characteristics of iron ion deposition and dependence on lipid peroxidation. It can affect the progression of many cancers, including liver cancer, by inducing an intracellular iron-dependent accumulation of reactive oxygen species, providing new possibilities for cancer treatment. At present, great progress has been made in exploring the molecular mechanism of ferroptosis. In this review, we summarize the characteristics, mechanisms, and regulatory factors of ferroptosis in detail, discuss the progress of ferroptosis research in liver cancer, and provide directions and new ideas for the treatment of hepatocellular carcinoma.

Microhaplotype and Y-SNP/STR (MY): A novel MPS-based system for genotype pattern recognition in two-person DNA mixtures.

BACKGROUNDS: Y-chromosomal haplotypes based on Y-short tandem repeats (STRs) and Y-single nucleotide polymorphisms/insertion and deletion polymorphisms (SNPs/InDels) are used to characterize paternal lineages of unknown male trace donors. However, Y-chromosomal genetic markers are not currently sufficient for precise individual identification. Microhaplotype (MH), generally < 200 bp on autosomes and consisting of two or more SNPs, was recently introduced in forensic genetics with the development of massive parallel sequencing technology and may facilitate identification and DNA mixture deconvolution. Therefore, combining the two kinds of genetic markers may be beneficial in many forensic scenarios, especially crime scenes with male suspects, such as sexual assault cases. METHODS: In the present study, we developed a novel MPS-based panel, Microhaplotype and Y-SNP/STR (MY), by multiplex PCR and 150-bp paired-end sequencing, including 114 Y-SNPs (twelve dominant Y-DNA haplogroups), 45 Y-STRs (N-1 stutter < 0.09; estimated mutation rate < 5 × 10-3), and 22 MHs (allele coverage ratio > 0.91; pairwise distance > 10 Mb). Additionally, MY system-based genotype pattern recognition (GPR), a regression-based method to identify the genotype pattern for each MH locus, is proposed for two-person DNA mixture deconvolution. We integrated 26 two-person genotype combinations into nine genotype patterns and validated the application range of GPR based on DNA profiles of ten sets of simulated male-male DNA mixtures (1:10-1:2). RESULTS: The effective number of alleles (Ae) ranged from 3.62 to 14.72, with an average of 7.17, in 100 Chinese Guangdong Han individuals. The cumulative discrimination power was 1-5.00 × 10-31, and the cumulative power of exclusion was 1-5.00 × 10-8 and 1-4.85 × 10-12 for duo and trio paternity testing, respectively. Furthermore, the actual mixing ratio-depth of coverage (DoC) ratio (RDoC) regression relationships were established for different genetic markers and genotype patterns. In five overlapping areas, genotype differentiation of the major and minor contributors required likelihood ratio methods. In nonoverlapping areas, the genotype pattern could be recognized by comparing the observed RDoC and RDoC ranges. CONCLUSION: The GPR can be used to deconvolute two-person DNA mixtures (application range: 1:10-1:2) for individual identification.

Long-term and daily use of molecular hydrogen induces reprogramming of liver metabolism in rats by modulating NADP/NADPH redox pathways.

Molecular hydrogen (H2) has emerged as a new therapeutic option in several diseases and is widely adopted by healthy people. However, molecular data to support therapeutic functions attributed to the biological activities of H2 remain elusive. Here, using transcriptomic and metabolomic approaches coupled with biochemistry and micro-CT technics, we evaluated the effect of long-term (6 months) and daily use of H2 on liver function. Rats exposed 2 h daily to H2 either by drinking HRW (H2 dissolved in H2O) or by breathing 4% H2 gas showed reduced lipogenesis and enhanced lipolysis in the liver, which was associated with apparent loss of visceral fat and brown adipose tissue together with a reduced level of serum lipids. Both transcripts and metabolites enriched in H2-treated rats revealed alteration of amino acid metabolism pathways and activation of purine nucleotides and carbohydrate biosynthesis pathways. Analysis of the interaction network of genes and metabolites and correlation tests revealed that NADP is the central regulator of H2 induced metabolic alterations in the liver, which was further confirmed by an increase in the level of components of metabolic pathways that require NADP as substrate. Evidence of immune response regulation activity was also observed in response to exposure to H2. This work is the first to provide metabolomic and transcriptomic data to uncover molecular targets for the effect of prolonged molecular hydrogen treatment on liver metabolism.

Technology challenges among deaf and hard of hearing elders in China during COVID-19 pandemic emergency isolation: A qualitative study.

Digital technology can be an effective tool to facilitate emergency assistance in a pandemic, but many deaf and hard-of-hearing elders may experience challenges in using and adopting these technologies. In the context of the second wave of the COVID-19 outbreak, this study employs a qualitative research method based on in-depth interviews to explore technology challenges among deaf and hard-of-hearing elders in China. The results showed that this group's technology challenges arose mainly from barriers to the mastery of digital technology tools, among which barriers to the use of smartphones, to the accessibility of online medical consultations, and to the presentation of health codes, were most noteworthy. For the informants, these barriers led to social isolation and technology avoidance. What's more, the expectation of individuals to adopt certain types of digital intelligence technologies can inadvertently create inequities for disadvantaged groups and exacerbate the "digital divide." This study highlights the need for emergency management systems to be inclusive of elders with hearing loss in times of public health crises, by providing effective technology support and training to facilitate individuals' access to services and to safeguard their health, interests, and livelihood.

External Communication Barriers among Elderly Deaf and Hard of Hearing People in China during the COVID-19 Pandemic Emergency Isolation: A Qualitative Study.

The COVID-19 pandemic poses a great risk to older people with hearing impairment, who face a higher threshold of external communication after the implementation of the emergency isolation policy. As part of a study on the optimization of external communication among the deaf and hard of hearing (DHH) population in central China, this study employed a qualitative research method based on in-depth interviews to explore the needs and difficulties faced by the older DHH group in external communication during public health emergencies in Wuhan, China, in the context of the COVID-19 pandemic. The results showed that older DHH people had weak reception of critical information about the epidemic, and had suboptimal access to medical care during emergency quarantine, which increased interpersonal communication barriers to this group. The current findings highlight the urgent need for targeted strengthening of the original emergency communication and coordination mechanisms in public health emergencies, and for improving policy inclusiveness for older DHH individuals during the COVID-19 pandemic and emergencies alike.

Prudently conduct the engineering and synthesis of the SARS-CoV-2 virus.

In response to the outbreak of COVID-19 that has been sweeping the world, scientists reconstructed the SARS-CoV-2 rapidly using a synthetic genomics platform, in order to accelerate therapeutics and vaccine development. However, given the dual-use nature of this technology, there exists a high biosecurity risk. This paper points out the potential risks of the engineering SARS-CoV-2 virus and puts forward 6 questions to this work. The authors emphasize that the two basic values of safety/security and intellectual freedom of research must be considered evenly. From the perspective of responsible development of biotechnology, this paper calls for a careful assessment to the risks of the technology, replacing risky technologies with safe ones. The risks of publication also need to be strictly assessed. The authors believe, in addition to enhancing the "self-government" and self-discipline of scientists and scientific communities, government supervision must be reinforced, laws and regulations should be improved, and global regulation framework ought to be constructed.

Disease phenotype synonymous prediction through network representation learning from PubMed database.

Synonym mapping between phenotype concepts from different terminologies is difficult because terminology databases have been developed largely independently. Existing maps of synonymous phenotype concepts from different terminology databases are highly incomplete, and manually mapping is time consuming and laborious. Therefore, building an automatic method for predictive mapping of synonymous phenotypes is of special importance. We propose a classifier-based phenotype mapping prediction model (CPM) to predict synonymous relationships between phenotype concepts from different terminology databases. The model takes network semantic representations of phenotypes as input and predicts synonymous relationships by training binary classifiers with a voting strategy. We compared the performance of the CPM with a similarity-based phenotype mapping prediction model (SPM), which predicts mapping based on the ranked cosine similarity of candidate mapping concepts. Based on a network representation N2V-TFIDF, with a majority voting strategy method MV, the CPM achieved accuracy of 0.943, which was 15.4% higher than that of the SPM using the cosine similarity method (0.789) and 23.8% higher than that of the SSDTM method (0.724) proposed in our previous work.

[A survey on the infection rate of tuberculosis among employees of the antituberculosis institutions in Henan province, China].

OBJECTIVE: To study the situation of tuberculosis (TB) infection among the employees of the anti-TB institutions in Henan. METHODS: Cross-sectional study was adopted the employees working in all municipal-level- anti-TB institutions and 40 anti-TB institutions at county-level selected randomly from 109 counties of the province were regarded as surveyed objects. Tuberculin skin test (TST) was used to test the infection with PPD. RESULTS: 2153 employees accepting the TST and the positive rate was 60.6%, of which the positive rate was 66.1% among healthcare workers. Among the employees and healthcare workers, the positive rates of TST adjusted by the stratum weights between municipal-level and county-level institutions were 57.3% and 62.8% respectively with Chi-square test the analysis of multivariate logistic vegression, both positive rate and strong positive rate among healthcare workers, the employees older than 30 years of age and working in municipal-level institutions were significantly higher than those among non-healthcare workers, the employees younger than 30 years old and working in county-level institutions, respectively. There were not significant differences of positive and strong positive rates between employees with and without BCG-history, or between male employees and female employees. CONCLUSION: Program on TB infection control in anti-TB institutions of Henan were weak and the employees especiolly healthcare workers had a high vocational exposure.

[Treatment of AIDS patients with Chinese medicinal herbs qudu zengning capsule].

OBJECTIVE: To evaluate the therapeutic effect of QuDu ZengNing Capsule on AIDS. METHODS: QuDu ZengNing Capsule is a capsule containing extract from 4 Chinese medicinal herbs. Totally 1,000 AIDS patients were treated, among them 60 patients were clinically observed weekly. Blood routine tests, liver, heart and kidney function, X-ray, CD4, CD8 cells were examined before and after treatment at 1, 3, 6 month. The patients were treated with 4 capsules t.i.d for 6 months. RESULTS: The symptoms were improved in most of the patients, the CD4 cells increased from 115.0 to 295.2/ul and the viral load (RNA copies/ml) in most patients reduced markedly or maintained at the same level. CONCLUSION: These data indicated that QuDu ZengNing Capsule was effective for treatment of AIDS patients.