Hepatoprotective effects of Xiaoyao San formula on hepatic steatosis and inflammation via regulating the sex hormones metabolism.

BACKGROUND: The modified Xiaoyao San (MXS) formula is an adjuvant drug recommended by the National Health Commission of China for the treatment of liver cancer, which has the effect of preventing postoperative recurrence and metastasis of hepatocellular carcinoma and prolonging patient survival. However, the molecular mechanisms underlying that remain unclear. AIM: To investigate the role and mechanisms of MXS in ameliorating hepatic injury, steatosis and inflammation. METHODS: A choline-deficient/high-fat diet-induced rat nonalcoholic steatohepatitis (NASH) model was used to examine the effects of MXS on lipid accumulation in primary hepatocytes. Liver tissues were collected for western blotting and immunohistochemistry (IHC) assays. Lipid accumulation and hepatic fibrosis were detected using oil red staining and Sirius red staining. The serum samples were collected for biochemical assays and NMR-based metabonomics analysis. The inflammation/lipid metabolism-related signaling and regulators in liver tissues were also detected to reveal the molecular mechanisms of MXS against NASH. RESULTS: MXS showed a significant decrease in lipid accumulation and inflammatory response in hepatocytes under metabolic stress. The western blotting and IHC results indicated that MXS activated AMPK pathway but inhibited the expression of key regulators related to lipid accumulation, inflammation and hepatic fibrosis in the pathogenesis of NASH. The metabonomics analysis systemically indicated that the arachidonic acid metabolism and steroid hormone synthesis are the two main target metabolic pathways for MXS to ameliorate liver inflammation and hepatic steatosis. Mechanistically, we found that MXS protected against NASH by attenuating the sex hormone-related metabolism, especially the metabolism of male hormones. CONCLUSION: MXS ameliorates inflammation and hepatic steatosis of NASH by inhibiting the metabolism of male hormones. Targeting male hormone related metabolic pathways may be the potential therapeutic approach for NASH.

Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration.

BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignant tumor that has a high incidence and mortality worldwide. Despite extensive studies, the detailed molecular mechanism of HCC development remains unclear. Studies have shown that the occurrence and development of HCC are closely related to abnormal gene expression. BCAR3 has been shown to be overexpressed in a variety of malignant tumors. However, the role of BCAR3 in HCC remains unclear. AIM: To investigate the expression of BCAR3 and BCAR3-related competing endogenous RNAs (ceRNAs) in HCC and their clinical significance, in order to provide new ideas for the diagnosis and treatment of HCC. METHODS: The data of HCC were obtained from the Cancer Genome Atlas database and The Genotype Tissue Expression, including transcriptome data and clinical information. Multiple common databases, including UALCAN, Timer 2.0, cBioPortal, LinkedOmics, starBase, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were used to analyse the expression of BCAR3, prognostic value, genetic alteration, co-expressed genes, differentially expressed genes, BCAR3 gene-related ceRNAs and functional enrichment analysis in HCC patients. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were used to analyze survival prognosis and the Spearman test was used to measure correlations between BCAR3 and immune functions. And R language package was used to analyze the correlation between BCAR3 and immune invasion of HCC. RESULTS: Our study indicated that BCAR3 was differentially expressed in various tumor tissues. The over-expression of BCAR3 gene was an unfavorable prognostic indicator for HCC patients, and associated with unfavorable cytogenetic risk and gene mutations. Moreover, most immune cells were positively correlated with BCAR3 (P < 0.05). According to the results of functional enrichment analysis, BCAR3 was involved in the positive regulation of epidermal growth factor receptor signaling pathway and ERBB signaling pathway, and was related to DNA replication and GTPase regulator activity. Finally, our study found that based on RAB30-DT and miR-19b-3p pathways, targeting BCAR3 might promote the occurrence and development of HCC. CONCLUSION: Collectively, this study indicated that the BCAR3 gene was involved in the occurrence and development of HCC, and it might be a new biomarker and therapeutic target for HCC, but the specific mechanism remains to be further verified.

Neutrophil extracellular traps - an a-list-actor in a variety of diseases.

Neutrophil extracellular traps (NETs) represent a response mechanism in which activated neutrophils release DNA-based webs, adorned with histones and neutrophil proteases, to capture and eliminate invasive microorganisms. However, when these neutrophils become excessively activated, much more proteases associated with NETs are liberated into surrounding tissues or bloodstreams, thereby altering the cellular milieu and causing tissue damage. Recent research has revealed that NETs may play significant roles in the emergence and progression of various diseases, spanning from infections, inflammation to autoimmune disorders and cancers. In this review, we delve deeply into the intricate and complex mechanisms that underlie the formation of NETs and their profound interplay with various clinical pathologies. We aim to describe the application perspectives of NETs related proteins in specific disease diagnosis and treatment.

Preparation, characterization, and application of gallic acid-mediated photodynamic chitosan-nanocellulose-based films.

In this study, an active film composed of gallic acid (GA), chitosan (CS), and cellulose nanocrystals (CNC) was prepared using a solution casting method and synergistic photodynamic inactivation (PDI) technology. Characterization of the film showed that the CS-CNC-GA composite film had high transparency and UV-blocking ability. The addition of GA (0.2 %-1.0 %) significantly enhanced the mechanical properties, water resistance, and thermal stability of the film. The tensile strength increased up to 46.30 MPa, and the lowest water vapor permeability was 1.16 × e-12 g/(cm·s·Pa). The PDI-treated CS-CNC-GA1.0 composite film exhibited significantly enhanced antibacterial activity, with inhibition zone diameters of 31.83 mm against Staphylococcus aureus and 21.82 mm against Escherichia coli. The CS-CNC-GA composite film also showed good antioxidant activity. Additionally, the CS-CNC-GA1.0 composite film generated a large amount of singlet oxygen under UV-C light irradiation. It was found that using the CS-CNC-GA1.0 composite film for packaging and storage of oysters at 4 °C effectively delayed the increase in pH, total colony count, and lipid oxidation in oysters. In conclusion, the CS-CNC-GA composite film based on PDI technology has great potential for applications in the preservation of aquatic products.

Helicobacter pylori infection delays neutrophil apoptosis and exacerbates inflammatory response.

Aim: Understanding molecular mechanisms of Helicobacter pylori (H. pylori)-induced inflammation is important for developing new therapeutic strategies for gastrointestinal diseases. Materials & methods: We designed an H. pylori-neutrophil infection model and explored the effects of H. pylori infection on neutrophils. Results: H. pylori infected neutrophils showed a low level of apoptosis. H. pylori stimulation activated the NACHT/LRR/PYD domain-containing protein 3 (NLRP3)-gasdermin-D (GSDMD) pathway for interleukin (IL)-1ß secretion. However, IL-1ß secretion was not completely dependent on GSDMD, as inhibition of autophagy significantly reduced IL-1ß release, and autophagy-related molecules were significantly upregulated in H. pylori-infected neutrophils. Conclusion: Therefore, H. pylori infection inhibits neutrophils apoptosis and induces IL-1ß secretion through autophagy. These findings may be utilized to formulate therapeutic strategies against H. pylori mediated chronic gastritis.

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Long-term trends in cancer incidence and mortality among U.S. children and adolescents: a SEER database analysis from 1975 to 2018.

Background: Childhood and adolescent cancer represent a significant health burden in the United States. Current and precise epidemiological data are crucial to develop effective cancer control plans and ultimately reduce the burden of childhood and adolescent cancer. Methods: We analyzed data obtained from cancer registries in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Age-standardized incidence and death rates, assessed using joinpoint analysis, were quantified as annual percentage changes (APC) and average percentage changes (AAPC). Results: The overall cancer incidence rate in 2008-2018 was 187.9 per 1,000,000 persons. Cancer incidence rates demonstrated a sustained upward trend, with an APC of 0.8 from 1975 to 2018. Incidence rates during 2008-2018 remained stable among non-Hispanic Black children but increased among other racial and ethnic groups. Leukemias, central nervous system tumors, and lymphomas were the most common cancer groups for patients aged 0-19 years. Cancer death rates decreased among children [AAPC, -1.3 (95% CI, -1.5 to -1.1)] during 2009-2019, while were stable among adolescents during that period. Conclusions: In this study, we analyzed cancer incidence and mortality rates and trends in children aged 0-19 years in the United States. Our findings revealed an overall increase in cancer incidence rates among children and adolescents, accompanied by a decline in cancer mortality rates over time. These rates and trends varied by age, sex, and particularly race and ethnicity, highlighting the significance of comprehending and addressing disparities and ultimately reducing the disease burden of childhood and adolescent cancer.

Helicobacter pylori-Induced Angiopoietin-Like 4 Promotes Gastric Bacterial Colonization and Gastritis.

Helicobacter pylori infection is characterized as progressive processes of bacterial persistence and chronic gastritis with features of infiltration of mononuclear cells more than granulocytes in gastric mucosa. Angiopoietin-like 4 (ANGPTL4) is considered a double-edged sword in inflammation-associated diseases, but its function and clinical relevance in H. pylori-associated pathology are unknown. Here, we demonstrate both pro-colonization and pro-inflammation roles of ANGPTL4 in H. pylori infection. Increased ANGPTL4 in the infected gastric mucosa was produced from gastric epithelial cells (GECs) synergistically induced by H. pylori and IL-17A in a cagA-dependent manner. Human gastric ANGPTL4 correlated with H. pylori colonization and the severity of gastritis, and mouse ANGPTL4 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il17a -/-, Angptl4 -/-, and Il17a -/- Angptl4 -/- mice. Mechanistically, ANGPTL4 bound to integrin αV (ITGAV) on GECs to suppress CXCL1 production by inhibiting ERK, leading to decreased gastric influx of neutrophils, thereby promoting H. pylori colonization; ANGPTL4 also bound to ITGAV on monocytes to promote CCL5 production by activating PI3K-AKT-NF-κB, resulting in increased gastric influx of regulatory CD4+ T cells (Tregs) via CCL5-CCR4-dependent migration. In turn, ANGPTL4 induced Treg proliferation by binding to ITGAV to activate PI3K-AKT-NF-κB, promoting H. pylori-associated gastritis. Overall, we propose a model in which ANGPTL4 collectively ensures H. pylori persistence and promotes gastritis. Efforts to inhibit ANGPTL4-associated pathway may prove valuable strategies in treating H. pylori infection.

Integrating mRNA transcripts and genomic information into genomic prediction.

Genomic prediction has emerged as a pivotal technology for the genetic evaluation of livestock, crops, and for predicting human disease risks. However, classical genomic prediction methods face challenges in incorporating biological prior information such as the genetic regulation mechanisms of traits. This study introduces a novel approach that integrates mRNA transcript information to predict complex trait phenotypes. To evaluate the accuracy of the new method, we utilized a Drosophila population that is widely employed in quantitative genetics researches globally. Results indicate that integrating mRNA transcript data can significantly enhance the genomic prediction accuracy for certain traits, though it does not improve phenotype prediction accuracy for all traits. Compared with GBLUP, the prediction accuracy for olfactory response to dCarvone in male Drosophila increased from 0.256 to 0.274. Similarly, the accuracy for cafe in male Drosophila rose from 0.355 to 0.401. The prediction accuracy for survival_paraquat in male Drosophila is improved from 0.101 to 0.138. In female Drosophila, the accuracy of olfactory response to 1hexanol increased from 0.147 to 0.210. In conclusion, integrating mRNA transcripts can substantially improve genomic prediction accuracy of certain traits by up to 43%, with range of 7% to 43%. Furthermore, for some traits, considering interaction effects along with mRNA transcript integration can lead to even higher prediction accuracy.

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity.

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

Screening of monoamine oxidase B inhibitors in Tibetan strawberry by ligand fishing based on enzyme functionalized cellulose filter paper.

Tibetan strawberry (Fragaria nubicola) is a wild medicinal and edible plant in Tibet possessing various health benefits such as neuroprotection and anti-oxidation. However, there has been little study reported on its chemical constituents. To investigate the inhibitors of monoamine oxidase B (MAO-B) in Tibetan strawberry, we immobilized the enzyme onto cellulose filter paper for the first time to develop a new screening method. Two known glycosides (compounds 1 and 2) and one new iridoid glucoside (Compound 3) were fished out by this method, which was found to effectively inhibit MAO-B with IC50 values of 16.95 ± 0.93, 24.69 ± 0.20, and 46.77 ± 0.78 µM, respectively. Molecular docking and kinetic analysis were performed to reveal the inhibition mechanism of these compounds. Furthermore, compound 1 exhibited neuroprotective effects against 6-OHDA-induced injury on PC12 cells. The developed method exhibits the advantages of rapidness and effectiveness in screening of MAO-B inhibitors from complex herbal extracts.

A case study of Duchenne muscular dystrophy caused by Alu element insertion in DMD gene and analysis of its gray-hair symptoms.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive genetic disorder caused by mutations in the DMD gene, which leads to a deficiency of the dystrophin protein. The main mutation types of this gene include exon deletions and duplications, point mutations, and insertions. These mutations disrupt the normal expression of dystrophin, ultimately leading to the disease. In this study, we reported a case of DMD caused by an insertion mutation in exon 59 (E59) of the DMD gene. The affected child exhibited significant abnormalities in related biochemical markers, early symptoms of DMD, and multiple gray hair. His mother and sister were carriers with slightly abnormal biochemical markers. The mother had mild clinical symptoms, while the sister had no clinical symptoms. Other family members were genetically and physically normal. Sequencing and sequence alignment revealed that the inserted fragment was an Alu element from the AluYa5 subfamily. This insertion produced two stop codons and a polyadenylate (polyA) tail. To understand the impact of this insertion on the DMD gene and its association with clinical symptoms, exonic splicing enhancer (ESE) prediction indicated that the insertion did not affect the splicing of E59. Therefore, we speculated that the insertion sequence would be present in the mRNA sequence of the DMD gene. The two stop codons and polyA tail likely terminate translation, preventing the production of functional dystrophin protein, which may be the mechanism leading to DMD. In addition to typical DMD symptoms, the child also exhibited premature graying of hair. This study reports, for the first time, a case of DMD caused by the insertion of an Alu element into the coding region of the DMD gene. This finding provides clues for studying gene mutations induced by Alu sequence insertion and expands the understanding of DMD gene mutations.

Exogenous autoinducer-2 alleviates intestinal damage in necrotizing enterocolitis via PAR2/MMP3 signaling pathway.

BACKGROUND: Imbalanced intestinal microbiota and damage to the intestinal barrier contribute to the development of necrotizing enterocolitis (NEC). Autoinducer-2 (AI-2) plays a crucial role in repairing intestinal damage and reducing inflammation. OBJECTIVE: This study aimed to investigate the impact of AI-2 on the expression of intestinal zonula occludens-1 (ZO-1) and occludin proteins in NEC. We evaluated its effects in vivo using NEC mice and in vitro using lipopolysaccharide (LPS)-stimulated intestinal cells. METHODS: Pathological changes in the intestines of neonatal mice were assessed using histological staining and scoring. Cell proliferation was measured using the cell counting kit-8 (CCK-8) assay to determine the optimal conditions for LPS and AI-2 interventions. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to analyze the mRNA levels of matrix metalloproteinase-3 (MMP3), protease activated receptor-2 (PAR2), interleukin-1ß (IL-1ß), and IL-6. Protein levels of MMP3, PAR2, ZO-1, and occludin were evaluated using western blot, immunohistochemistry, or immunofluorescence. RESULTS: AI-2 alleviated NEC-induced intestinal damage (P < 0.05) and enhanced the proliferation of damaged IEC-6 cells (P < 0.05). AI-2 intervention reduced the mRNA and protein expressions of MMP3 and PAR2 in intestinal tissue and cells (P < 0.05). Additionally, it increased the protein levels of ZO-1 and occludin (P < 0.05), while reducing IL-1ß and IL-6 mRNA expression (P < 0.05). CONCLUSION: AI-2 intervention enhances the expression of tight junction proteins (ZO-1 and occludin), mitigates intestinal damage in NEC neonatal mice and IEC-6 cells, potentially by modulating PAR2 and MMP3 signaling. AI-2 holds promise as a protective intervention for NEC. AI-2 plays a crucial role in repairing intestinal damage and reducing inflammation.

Characterization of a novel antioxidant byssal protein from Mytilus coruscus foot.

Mussel byssal proteins are of biomimetic importance for the development of novel underwater bio-adhesive agents. It is important to maintain a reduced state during the process of byssus adhesion. There are 19 mussel foot proteins (MFPs) have been reported in previous studies, among which only MFP-6 had been confirmed as an antioxidant protein in mussel byssus due to the function of cysteines, and playing an essential role in the redox balance of mussel byssus during adhesion process. Although the other four MFPs (MFP-16 ~ MFP-19) also have abundant cysteines, their function is still unknown. In this study, a novel mussel foot protein, named MFP-20, was identified from Mytilus coruscus foot. The sequential features, expression profile, and function of recombinant MFP-20 were verified. The results showed that MFP-20 has more abundant cysteines than other MFPs, the relative expression of mfp-20 was upregulated in Fe3+ stress and low pH seawater. In addition, different adhesive substrates induced significant changes of expression level of mfp-20. Furthermore, rMFP-20 showed strong antioxidant capacity in the DPPH assay, and the abundant cysteines in its sequence may play vital roles in the antioxidation activity. Our findings revealed the possible function of MFP-20 with a totally different sequence from the reported MFP-6 and provided new clues for exploring the redox balance of mussel byssus during the adhesion process.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation.

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.

LC/MS-guided isolation and GNPS procedures to identify flavonoid of HCoV-OC43 inhibitors.

The screening of based target compounds supported by LC/MS, MS/MS and Global Natural Products Social (GNPS) used to identify the compounds 1-10 of Butea monsperma. They were evaluated in human malignant embryonic rhabdomyoma cells (RD cells) infected with Human coronavirus OC43 (HCoV-OC43) and showed significant inhibitory activity. Target inhibition tests showed that compounds 6 and 8 inhibited the proteolytic enzyme 3CLpro, which is widely present in coronavirus and plays an important role in the replication process, with an effective IC50 value. The study confirmed that dioxymethylene of compound 8 may be a key active fragment in inhibiting coronavirus (EC50 7.2 µM, SI > 139.1). The results have led to identifying natural bioactive compounds for possible inhibiting HCoV-OC43 and developing drug for Traditional Chinese Medicine (TCM).

Geometric Understanding of Discriminability and Transferability for Visual Domain Adaptation.

To overcome the restriction of identical distribution assumption, invariant representation learning for unsupervised domain adaptation (UDA) has made significant advances in computer vision and pattern recognition communities. In UDA scenario, the training and test data belong to different domains while the task model is learned to be invariant. Recently, empirical connections between transferability and discriminability have received increasing attention, which is the key to understand the invariant representations. However, theoretical study of these abilities and in-depth analysis of the learned feature structures are unexplored yet. In this work, we systematically analyze the essentials of transferability and discriminability from the geometric perspective. Our theoretical results provide insights into understanding the co-regularization relation and prove the possibility of learning these abilities. From methodology aspect, the abilities are formulated as geometric properties between domain/cluster subspaces (i.e., orthogonality and equivalence) and characterized as the relation between the norms/ranks of multiple matrices. Two optimization-friendly learning principles are derived, which also ensure some intuitive explanations. Moreover, a feasible range for the co-regularization parameters is deduced to balance the learning of geometric structures. Based on the theoretical results, a geometry-oriented model is proposed for enhancing the transferability and discriminability via nuclear norm optimization. Extensive experiment results validate the effectiveness of the proposed model in empirical applications, and verify that the geometric abilities can be sufficiently learned in the derived feasible range.

Variant-specific antibody response following repeated SARS-CoV-2 vaccination and infection.

The ongoing emergence of SARS-CoV-2 variants poses challenges to the immunity induced by infections and vaccination. We conduct a 6-month longitudinal evaluation of antibody binding and neutralization of sera from individuals with six different combinations of vaccination and infection against BA.5, XBB.1.5, EG.5.1, and BA.2.86. We find that most individuals produce spike-binding IgG or neutralizing antibodies against BA.5, XBB.1.5, EG.5.1, and BA.2.86 2 months after infection or vaccination. However, compared to ancestral strain and BA.5 variant, XBB.1.5, EG.5.1, and BA.2.86 exhibit comparable but significant immune evasion. The spike-binding IgG and neutralizing antibody titers decrease in individuals without additional antigen exposure, and <50% of individuals neutralize XBB.1.5, EG.5.1, and BA.2.86 during the 6-month follow-up. Approximately 57% of the 107 followed up individuals experienced an additional infection, leading to improved binding IgG and neutralizing antibody levels against these variants. These findings provide insights into the impact of SARS-CoV-2 variants on immunity following repeated exposure.

Chlorogenic acid can improve spermatogenic dysfunction in rats with varicocele by regulating mitochondrial homeostasis and inhibiting the activation of NLRP3 inflammasomes by oxidative mitochondrial DNA and cGAS/STING pathway.

In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1ß, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.

Deep transcranial magnetic stimulation for schizophrenia: a systematic review.

Background: The efficacy and safety of deep transcranial magnetic stimulation (dTMS) as an intervention for schizophrenia remain unclear. This systematic review examined the efficacy and safety of dTMS for schizophrenia. Methods: A systematic search of Chinese (WanFang and Chinese Journal Net) and English databases (PubMed, EMBASE, PsycINFO, and Cochrane Library) were conducted. Results: Three randomized clinical trials (RCTs) comprising 80 patients were included in the analyses. Active dTMS was comparable to the sham treatment in improving total psychopathology, positive symptoms, negative symptoms, and auditory hallucinations measured by the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Auditory Hallucinations Rating Scale (AHRS), respectively. Only one RCT reported the effects on neurocognitive function measured by the Cambridge Neuropsychological Test Automated Battery (CANTAB), suggesting that dTMS may only improve one Stockings of Cambridge measure (i.e., subsequent times for five move problems). All three studies reported overall discontinuation rates, which ranged from 16.7% to 44.4%. Adverse events were reported in only one RCT, the most common being tingling/twitching (30.0%, 3/10), head/facial discomfort (30.0%, 3/10), and back pain (20.0%, 2/10). Conclusion: This systematic review suggests that dTMS does not reduce psychotic symptoms in schizophrenia, but it shows potential for improving executive functions. Future RCTs with larger sample sizes focusing on the effects of dTMS on psychotic symptoms and neurocognitive function in schizophrenia are warranted to further explore these findings.