Liver in infections: a single-cell and spatial transcriptomics perspective.

The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases.

A novel prognostic nomogram for older patients with acute-on-chronic liver diseases (AoCLD): a nationwide, multicentre, prospective cohort study.

BACKGROUND: the incidence of acute-on-chronic liver disease (AoCLD) is increasing. OBJECTIVE: to investigate the clinical features and risk factors of AoCLD and construct an effective prognostic nomogram model for older patients with AoCLD. METHODS: data from 3,970 patients included in the CATCH-LIFE study were used, including 2,600 and 1,370 patients in the training and validation sets, respectively. Multivariate Cox regression analyses were performed to identify predictive risk factors in older individuals, and an easy-to-use nomogram was established. Performance was assessed using area under the curve, calibration plots and decision curve analysis (DCA). RESULTS: of the 3,949 patients with AoCLD, 809 were older with a higher proportion of autoimmune-related abnormalities, hepatitis C viral infection and schistosomiasis. In the older patient group, the incidence of cirrhosis, hepatic encephalopathy (HE), infection, ascites and gastrointestinal bleeding; neutrophil-to-lymphocyte ratio (NLR), aspartate-to-alanine transaminase ratio (AST/ALT), creatinine and blood urea nitrogen levels were higher, whereas incidence of acute-on-chronic liver failure, white blood cell, platelet and haemoglobin levels; albumin, total bilirubin (TB), AST and ALT levels; international normalised ratio (INR), estimated glomerular filtration rate and blood potassium levels were lower than in the younger group. The final nomogram was developed based on the multivariate Cox analysis in training cohort using six risk factors: ascites, HE grades, NLR, TB, INR and AST/ALT. Liver transplantation-free mortality predictions were comparable between the training and validation sets. DCA showed higher net benefit for the nomograph than the treat-all or treat-none strategies, with wider threshold probabilities ranges. CONCLUSIONS: our analysis will assist clinical predictions and prognoses in older patients with AoCLD.

An M0 macrophage-related prognostic model for hepatocellular carcinoma.

BACKGROUND: The role of M0 macrophages and their related genes in the prognosis of hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: Multidimensional bioinformatic methods were used to construct a risk score model using M0 macrophage-related genes (M0RGs). RESULTS: Infiltration of M0 macrophages was significantly higher in HCC tissues than in normal liver tissues (P = 2.299e-07). Further analysis revealed 35 M0RGs that were associated with HCC prognosis; two M0RGs (OLA1 and ATIC) were constructed and validated as a prognostic signature for overall survival of patients with HCC. Survival analysis revealed the positive relationship between the M0RG signature and unfavorable prognosis. Correlation analysis showed that this risk model had positive associations with clinicopathological characteristics, somatic gene mutations, immune cell infiltration, immune checkpoint inhibitor targets, and efficacy of common drugs. CONCLUSIONS: The constructed M0RG-based risk model may be promising for the clinical prediction of prognoses and therapeutic responses in patients with HCC.

[Research Progress on Enzyme-free Blood Glucose Sensor].

Blood glucose monitoring is of great significance to diabetic patients, and the development of rapid, accurate and real-time glucose detection technology has become a research hotspot nowadays. This study introduces the concept and classification of the enzyme-free glucose sensor, expounds enzymefree glucose sensor electrode characterization methods and the application progress of different materials in enzyme-free blood glucose sensors. Meanwhile, some problems of enzyme-free glucose sensor existing in the current research and its future application prospects also will be discussed.

Causal effects of gallstone disease on risk of gastrointestinal cancer in Chinese.

BACKGROUND: Gallstone disease (GSD) is associated with a higher risk of gastrointestinal (GI) cancer. However, it is unclear whether the associations are causal. METHODS: The prospective China Kadoorie Biobank (CKB) recorded 17,598 cases of GI cancer among 510,137 participants without cancer at baseline during 10 years of follow-up. Cox regression was used to estimate hazard ratios (HRs) for specific cancer by GSD status and duration. Mendelian randomisation was conducted to assess the genetic associations of GSD with specific cancer. RESULTS: Overall 6% of participants had symptomatic GSD at baseline. Compared with those without GSD, individuals with symptomatic GSD had adjusted HRs of 1.13 (1.01-1.29) for colorectal, 2.01 (1.78-2.26) for liver, 3.70 (2.88-4.87) for gallbladder, 2.31 (1.78-3.07) for biliary tract, and 1.38 (1.18-1.74) for pancreatic cancer. Compared with participants without GSD, the risks of colorectal, liver, gallbladder, biliary tract, and pancreatic cancer were highest during 0 to <5 years following disease diagnosis. There was evidence of genetic associations of GSD with these cancers, with odds ratios per 1-SD genetic score of 1.08 (1.05-1.11) for colorectal, 1.22 (1.19-1.25) for liver, 1.56 (1.49-1.64) for gallbladder, 1.39 (1.31-1.46) for biliary tract, and 1.16 (1.10-1.22) for pancreatic cancer. When meta-analysing the genetic estimates in CKB and UK Biobank, there was evidence of causal associations of GSD with colon cancer, gallbladder and biliary tract cancer (GBTC), and total GI cancer (RR per 1-SD: 1.05 [0.99-1.11], 2.00 [1.91-2.09], and 1.09 [1.05-1.13]). CONCLUSIONS: GSD was associated with higher risks of several GI cancers, warranting future studies on the underlying mechanisms.

Association of luteinizing hormone/choriogonadotropin receptor gene polymorphisms with polycystic ovary syndrome risk: a meta-analysis.

To investigate the association between Luteinizing hormone/choriogonadotropin receptor (LHCGR) gene polymorphisms and polycystic ovary syndrome (PCOS). A systematic literature search and meta-analysis using STATA software for included studies. Fourteen case-control studies containing rs13405728, rs4539842, and rs2293275 of LHCGR gene were included, which was comprised of 11,738 PCOS cases and 35,329 controls. Results of the meta-analysis showed a significant association between PCOS and rs13405728 (for G vs. A: OR = 0.735, 95% CI = 0.699-0.773, p<.001; For GG vs. AG + AA: OR = 0.578, 95% CI = 0.436-0.767, p<.001; For GG + AG vs. AA: OR = 0.817, 95% CI = 0.741-0.901, p<.001) in Asian populations, and rs4539842 (for ins/ins vs. ins/non + non/non: OR = 0.686, 95% CI = 0.483-0.974, p=.035) and rs2293275 (for AA vs. AG + GG: OR = 4.115, 95% CI = 1.033-16.38, p=.045) in Caucasian populations, respectively. LHCGR gene variations are population specifically associated with PCOS, which indicated these SNPs in LHCGR may contribute to the pathogenesis of PCOS and could be used as potential biomarkers to predict the risk of PCOS.

Ketamine Alleviates Depressive-Like Behaviors via Down-Regulating Inflammatory Cytokines Induced by Chronic Restraint Stress in Mice.

The purpose of the present study was to investigate whether ketamine's rapid antidepressant effects were associated with its anti-inflammatory actions and to explore the underlying molecular mechanism. Depressive-like behaviors was induced in mice using chronic restraint stress (CRS) method. Anti-depressive effects of ketamine were evaluated by forced swimming tests (FST) and sucrose preference test (SPT). Subsequently, brain tissue was harvested to investigate inflammatory response in the hippocampus via investigating reactive microglia numbers, serum cytokines levels and the toll-like receptor type 4 (TLR4)/p38 mitogen-activated protein kinase (MAPK) pathway. CRS exposure caused depressive-like behaviors in mice, which was associated with increased pre-inflammatory cytokines (interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and IL-6) levels, reactive microglia numbers and up-regulated regulatory molecules such as TLR4/p38 and P2X7 receptor in hippocampus. Such neurobehavioral and biochemical abnormalities were normalized by ketamine treatment. CRS-induced depression-like behaviours are associated with activation of hippocampal inflammatory response, whereas down-regulation of pro-inflammatory cytokines may contribute to ketamine's antidepressant effects in mice.

The draft genome, transcriptome, and microbiome of Dermatophagoides farinae reveal a broad spectrum of dust mite allergens.

BACKGROUND: A sequenced house dust mite (HDM) genome would advance our understanding of HDM allergens, a common cause of human allergies. OBJECTIVE: We sought to produce an annotated Dermatophagoides farinae draft genome and develop a combined genomic-transcriptomic-proteomic approach for elucidation of HDM allergens. METHODS: A D farinae draft genome and transcriptome were assembled with high-throughput sequencing, accommodating microbiome sequences. The allergen gene structures were validated by means of Sanger sequencing. The mite's microbiome composition was determined, and the predominant genus was validated immunohistochemically. The allergenicity of a ubiquinol-cytochrome c reductase binding protein homologue was evaluated with immunoblotting, immunosorbent assays, and skin prick tests. RESULTS: The full gene structures of 20 canonical allergens and 7 noncanonical allergen homologues were produced. A novel major allergen, ubiquinol-cytochrome c reductase binding protein-like protein, was found and designated Der f 24. All 40 sera samples from patients with mite allergy had IgE antibodies against rDer f 24. Of 10 patients tested, 5 had positive skin reactions. The predominant bacterial genus among 100 identified species was Enterobacter (63.4%). An intron was found in the 13.8-kDa D farinae bacteriolytic enzyme gene, indicating that it is of HDM origin. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed a phototransduction pathway in D farinae, as well as thiamine and amino acid synthesis pathways, which is suggestive of an endosymbiotic relationship between D farinae and its microbiome. CONCLUSION: An HDM genome draft produced from genomic, transcriptomic, and proteomic experiments revealed allergen genes and a diverse endosymbiotic microbiome, providing a tool for further identification and characterization of HDM allergens and development of diagnostics and immunotherapeutic vaccines.

HMGB1 in the interplay between autophagy and apoptosis in cancer.

Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.

Vagus nerve modulates acute-on-chronic liver failure progression via CXCL9.

BACKGROUND: Hepatic inflammatory cell accumulation and the subsequent systematic inflammation drive acute-on-chronic liver failure (ACLF) development. Previous studies showed that the vagus nerve exerts anti-inflammatory activity in many inflammatory diseases. Here, we aimed to identify the key molecule mediating the inflammatory process in ACLF and reveal the neuroimmune communication arising from the vagus nerve and immunological disorders of ACLF. METHODS: Proteomic analysis was performed and validated in ACLF model mice or patients, and intervention animal experiments were conducted using neutralizing antibodies. PNU-282987 (acetylcholine receptor agonist) and vagotomy were applied for perturbing vagus nerve activity. Single-cell RNA sequencing (scRNA-seq), flow cytometry, immunohistochemical and immunofluorescence staining, and CRISPR/Cas9 technology were used for in vivo or in vitro mechanistic studies. RESULTS: The unbiased proteomics identified C-X-C motif chemokine ligand 9 (CXCL9) as the greatest differential protein in the livers of mice with ACLF and its relation to the systematic inflammation and mortality were confirmed in patients with ACLF. Interventions on CXCL9 and its receptor C-X-C chemokine receptor 3 (CXCR3) improved liver injury and decreased mortality of ACLF mice, which were related to the suppressing of hepatic immune cells' accumulation and activation. Vagus nerve stimulation attenuated while vagotomy aggravated the expression of CXCL9 and the severity of ACLF. Blocking CXCL9 and CXCR3 ameliorated liver inflammation and increased ACLF-associated mortality in ACLF mice with vagotomy. scRNA-seq revealed that hepatic macrophages served as the major source of CXCL9 in ACLF and were validated by immunofluorescence staining and flow cytometry analysis. Notably, the expression of CXCL9 in macrophages was modulated by vagus nerve-mediated cholinergic signaling. CONCLUSIONS: Our novel findings highlighted that the neuroimmune communication of the vagus nerve-macrophage-CXCL9 axis contributed to ACLF development. These results provided evidence for neuromodulation as a promising approach for preventing and treating ACLF.

A dual watermarking scheme for identity protection.

A novel dual watermarking scheme with potential applications in identity protection, media integrity maintenance and copyright protection in both electronic and printed media is presented. The proposed watermarking scheme uses the owner's signature and fingerprint as watermarks through which the ownership and validity of the media can be proven and kept intact. To begin with, the proposed watermarking scheme is implemented on continuous-tone/greyscale images, and later extended to images achieved via multitoning, an advanced version of halftoning-based printing. The proposed watermark embedding is robust and imperceptible. Experimental simulations and evaluations of the proposed method show excellent results from both objective and subjective view-points.

The redox protein HMGB1 in cell death and cancer.

SIGNIFICANCE: As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. RECENT ADVANCES: HMGB1 is a non-histone nuclear protein that acts as a DNA chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depends on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy (e.g., chemotherapy, radiation therapy, and immunotherapy) depending on tumor types and stages. CRITICAL ISSUES: A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. FUTURE DIRECTIONS: Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease.

The Redox Protein High-Mobility Group Box 1 in Cell Death and Cancer.

Significance: As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. Recent Advances: HMGB1 is a nonhistone nuclear protein that acts as a deoxyribonucleic acid chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depend on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy (e.g., chemotherapy, radiation therapy, and immunotherapy) depending on the tumor types and stages. Critical Issues: A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. Future Directions: Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease. Antioxid. Redox Signal. 39, 569-590.

The role and mechanism of tryptophan - kynurenine metabolic pathway in depression.

Major depressive disorder (MDD) is a common mental illness characterized by persistent low mood and anhedonia, normally accompanied with cognitive impairment. Due to its rising incidence and high rate of recurrence and disability, MDD poses a substantial threat to patients' physical and mental health, as well as a significant economic cost to society. However, the etiology and pathogenesis of MDD are still unclear. Chronic inflammation may cause indoleamine-2,3-dioxygenase (IDO) to become overactive throughout the body and brain, resulting in excess quinolinic acid (QUIN) and less kynuric acid (KYNA) in the brain. QUIN's neurotoxicity damages glial cells and neurons, accelerates neuronal apoptosis, hinders neuroplasticity, and causes depression due to inflammation. Therefore, abnormal TRP-KYN metabolic pathway and its metabolites have been closely related to MDD, suggesting changes in the TRP-KYN metabolic pathway might contribute to MDD. In addition, targeting TRP-KYN with traditional Chinese medicine showed promising treatment effects for MDD. This review summarizes the recent studies on the TRP-KYN metabolic pathway and its metabolites in depression, which would provide a theoretical basis for exploring the etiology and pathogenesis of depression.

The hippocampal FTO-BDNF-TrkB pathway is required for novel object recognition memory reconsolidation in mice.

Memory reconsolidation refers to the process by which the consolidated memory was restored after reactivation (RA). Memory trace becomes labile after reactivation and inhibition of memory reconsolidation may disrupt or update the original memory trace, which provided a new strategy for the treatment of several psychiatric diseases, such as drug addiction and post-traumatic stress disorder. Fat mass and obesity-associated gene (FTO) is a novel demethylase of N6-methyladenosine (m6A) and it has been intensively involved in learning and memory. However, the role of FTO in memory reconsolidation has not been determined. In the present study, the function of FTO in memory reconsolidation was investigated in the novel object recognition (NOR) model in mice. The results showed that RA of NOR memory increased hippocampal FTO expression in a time-dependent manner, while FTO inhibitor meclofenamic acid (MA) injected immediately, but not 6 h after RA disrupted NOR memory reconsolidation. MA downregulated BDNF expression during NOR memory reconsolidation in the hippocampus, while the TrkB agonist 7,8-Dihydroxyflavone (7,8-DHF) reversed the disruptive effects of MA on NOR memory reconsolidation. Furthermore, overexpression of FTO increased BDNF expression via decreasing mRNA m6A in HT22 cells. Taken together, these results indicate that FTO may up-regulate the BDNF-TrkB pathway to promote NOR memory reconsolidation through m6A modification.

[Chemical constituents of Pileostegia viburnoides var. glabrescens].

OBJECTIVE: To study the chemical constituents of Pileostegia viburnoides var. glabrescens. METHODS: The compounds were isolated and purified by various techniques. Their structures were determined by physicochemical properties and spectral analysis. RESULTS: Five compounds were isolated and identified as friedelin (1), beta-sitosterol (2), umbelliferone (3), daucosterol (4) and skimmin (5). CONCLUSION: All the compounds were isolated from this genus for the first time.

[Study on chemical constituents of volatile oil from rhizomes and leaves of Pileostegia viburnoides var. glabrescens by GC-MS].

OBJECTIVE: To analyze the chemical constituents of volatile oil from the rhizomes and leaves of Pileostegia viburnoides var. glabrescens by GC-MS. METHODS: The volatile oil was extracted from the rhizomes and leaves of Pileostegia viburnoides var. glabrescens by steam distillation. The constituents of volatile oil were identified by GC-MS technology. RESULTS: 37 compounds were identified from the oil of rhizomes. 36 compounds were identified from the oil of leaves. The rhizomes and leaves volatile oil had 18 compounds in common. CONCLUSION: This study is the first one to report the volatile components of Pileostegia viburnoides var. glabrescens. It can provide a scientific basis for rational use of the rhizomes and leaves of Pileostegia viburnoides var. glabrescens.

[Progress in data mining techniques of diagnosis of breast cancer].

Data mining is to extract the interested information or knowledge from large databases using a series of techniques. The information and knowledge are generally hidden, unknown, but potentially useful, which can be expressed as concepts, rules, laws, modes or other forms. This article introduces the background and concepts of data mining, and reviews its application in medicine and the diagnosis of breast cancer for the most recent years. We also discuss the significance and current problems of this application in the diagnosis of breast cancer.

Deep Brain Stimulation in Drug Addiction Treatment: Research Progress and Perspective.

Drug addiction is a chronic psychiatric disorder characterized by compulsive drug-seeking and drug-using behavior, and a tremendous socioeconomic burden to society. Current pharmacological and psychosocial methods have shown limited treatment effects for substance abuse. Deep Brain Stimulation (DBS) is a novel treatment for psychiatric disease and has gradually gained popularity in the treatment of addiction. Addiction is characterized by neuroplastic changes in the nucleus accumbens (NAc), a key structure in the brain reward system, and DBS in this region has shown promising treatment effects. In this paper, the research progress on DBS for drug addiction has been reviewed. Specifically, we discuss the mechanism of NAc DBS for addiction treatment and summarize the results of clinical trials on DBS treatment for addiction to psychoactive substances such as nicotine, alcohol, cocaine, opioids and methamphetamine/amphetamine. In addition, the treatment effects of DBS in other brain regions, such as the substantia nigra pars reticulata (SNr) and insula are discussed.

Emerging Roles of FTO in Neuropsychiatric Disorders.

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.