Overexpression of DTX1 inhibits D-GalN/TNF-α-induced pyroptosis and inflammation in hepatocytes by regulating NLRP3 ubiquitination.

Background: Acute liver injury (ALI) is characterized by massive hepatocyte death and has high mortality and poor prognosis. Hepatocyte pyroptosis plays a key role in the pathophysiology of ALI and is involved in the inflammatory response mediated by NOD-like receptor protein 3 (NLRP3) inflammasome activation. Deltex 1 (DTX1) is a single transmembrane protein with ubiquitin E3 ligase activity and is closely involved in cell growth, differentiation, and apoptosis, as well as intracellular signal transduction. However, little is known about the influence of DTX1 on ALI. This study aimed to investigate the role of DTX1 in pyroptosis and inflammation induced by D-galactosamine (D-GalN) and tumor necrosis factoralpha (TNF-α) in human hepatocytes (LO2 cells) in vitro. Methods: Cell pyroptosis was measured by flow cytometry. The levels of DTX1, pyroptosis-associated proteins, and inflammatory cytokines were detected by quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. Immunofluorescence staining, co-immunoprecipitation, ubiquitination, and luciferase reporter and chromatin immunoprecipitation assays were performed to detect the regulation between DTX1 and NLRP3 or hepatocyte nuclear factor 4 alpha (HNF4α). Analysis of variance was performed to compare groups. Results: We found that DTX1 was decreased in D-GalN/TNF-α-induced LO2 cells. DTX1 overexpression significantly inhibited D-GalN/TNF-α-induced cell pyroptosis and inflammation. DTX1 interacted with NLRP3 and induced NLRP3 ubiquitination and degradation. Furthermore, by targeting NLRP3, DTX1 knockdown significantly induced cell pyroptosis and inflammation. In addition, HNF4α promoted DTX1 transcription by binding with its promoter. Conclusion: Our study revealed that DTX1 suppressed D-GalN/TNF-α-induced hepatocyte pyroptosis and inflammation by regulating NLRP3 ubiquitination.

Gating-Enhanced Hierarchical Structure Learning in Hyperbolic Space and Multi-scale Neighbor Topology Learning in Euclidean Space for Prediction of Microbe-Drug Associations.

Identifying drug-related microbes may help us explore how the microbes affect the functions of drugs by promoting or inhibiting their effects. Most previous methods for the prediction of microbe-drug associations focused on integrating the attributes and topologies of microbe and drug nodes in Euclidean space. The heterogeneous network composed of microbes and drugs has a hierarchical structure, and the hyperbolic space is helpful for reflecting the structure. However, the previous methods did not fully exploit the structure. We propose a multi-space feature learning enhanced microbe-drug association prediction method, MFLP, to fuse the hierarchical structure of microbe and drug nodes in hyperbolic space and the multiscale neighbor topologies in Euclidean space. First, we project the nodes of the microbe-drug heterogeneous network on the sphere in hyperbolic space and then construct a topology which implies hierarchical structure and forms a hierarchical attribute embedding. The node information from multiple types of neighbor nodes with the new topological structure in the tangent plane space of a sphere is aggregated by the designed gating-enhanced hyperbolic graph neural network. Second, the gate at the node feature level is constructed to adaptively fuse the hierarchical features of microbe and drug nodes from two adjacent graph neural encoding layers. Third, multiple neighbor topological embeddings for each microbe and drug node are formed by neighborhood random walks on the microbe-drug heterogeneous network, and they cover neighborhood topologies with multiple scales, respectively. Finally, as each scale of topological embedding contains its specific neighborhood topology, we establish an independent graph convolutional neural network for the topology and form the topological representations of microbe and drug nodes in Euclidean space. The comparison experiments based on cross validation showed that MFLP outperformed several advanced prediction methods, and the ablation experiments verified the effectiveness of MFLP's major innovations. The case studies on three drugs further demonstrated MFLP's ability in being applied to discover potential candidate microbes for the given drugs.

Low prevalence of testing for apolipoprotein B and lipoprotein (a) in the real world.

Objective: Apolipoprotein B (ApoB) and lipoprotein (a) (Lp[a]) are predictors of cardiovascular disease (CVD) risk; therefore, current recommendations for CVD risk assessment and management advocate that patients receive testing for ApoB and Lp(a) in addition to the standard lipid panel. However, US guidelines around ApoB and Lp(a) testing have evolved over time and vary slightly by expert committee. The objective of this analysis was to estimate the number of insured individuals in the USA who received any component of a lipid test, or ApoB and/or Lp(a) testing, during 2019. Methods: We conducted a cross-sectional analysis to estimate the prevalence of any component of a lipid test, ApoB, and/or Lp(a) in the USA using four different claim data sources (including Medicaid, Medicare, and commercially insured enrollees). Prevalence estimates were age-, sex-, payor-, and region-standardized to the 2019 US Annual Social and Economic Supplement of the Current Population Survey. We also described the clinical profile of patients who received lipid testing between 2019 and 2021 (cohort analysis) in Optum claims database. Enrollees were grouped into four non-mutually exclusive cohorts based on their completion of any component of the lipid panel, ApoB, Lp(a), or ApoB and Lp(a). Results: In the prevalence cohort, over a third (38 %) of insured adults in the USA underwent testing for any component of a lipid panel in 2019. This proportion was higher for individuals aged ≥65 years compared to younger adults (62% vs 31 %). The proportion of ApoB and Lp(a) testing represented only <1 % of testing for any component of a lipid panel. In the cohort analysis, we found that lipid testing increased with age and comorbidities. Conclusion: These data should be considered by guideline-issuing agencies and organizations to develop education campaigns encouraging more frequent use of tests beyond the standard lipid panel.

Biochar confers significant microbial resistance to ammonia toxicity in n-caproic acid production.

Microbial chain elongation integrating innovative bioconversion technologies with organic waste utilization can transition current energy-intensive n-caproic acid production to sustainable circular bioeconomy systems. However, ammonia-rich waste streams, despite their suitability, pose inhibitory challenges to these bioconversion processes. Herein, biochar was employed as an additive to enhance the activity of chain elongating microbes under ammonia inhibition conditions, with an objective to detail underlying mechanisms of improvements. Biochar addition significantly improved chain elongation performance even under severe ammonia stress (exceeding 8 g N/L), increasing n-caproic acid yields by 40 % to 158 % and reducing lag times by 51 % to 90 %, compared with the best-performing group without biochar addition. The material contribution to n-caproic production reached up to 94.3 % (at 4 g N/L). These enhancements were mainly attributed to the new electron syntrophy induced by biochar, which improved electron transfer system activity and electrical conductivity of the fermentation system. This is further substantiated by increased relative abundances of the genus Sporanaerobacter, electroactive bacteria, and up-regulated direct electron transfer-related genes including conductive pili and c-type cytochrome. This study demonstrates that biochar can confer robust resilience to ammonia toxicity in functional microbes, paving a way for efficient and sustainable n-caproic acid production.

Dynamic category-sensitive hypergraph inferring and homo-heterogeneous neighbor feature learning for drug-related microbe prediction.

MOTIVATION: The microbes in human body play a crucial role in influencing the functions of drugs, as they can regulate the activities and toxicities of drugs. Most recent methods for predicting drug-microbe associations are based on graph learning. However, the relationships among multiple drugs and microbes are complex, diverse and heterogeneous. Existing methods often fail to fully model the relationships. In addition, the attributes of drug-microbe pairs exhibit long-distance spatial correlations, which previous methods have not integrated effectively. RESULTS: We propose a new prediction method named DHDMP which is designed to encode the relationships among multiple drugs and microbes and integrate the attributes of various neighbor nodes along with the pairwise long-distance correlations. First, we construct a hypergraph with dynamic topology, where each hyperedge represents a specific relationship among multiple drug nodes and microbe nodes. Considering the heterogeneity of node attributes across different categories, we developed a node category-sensitive hypergraph convolution network to encode these diverse relationships. Second, we construct homogeneous graphs for drugs and microbes respectively, as well as drug-microbe heterogeneous graph, facilitating the integration of features from both homogeneous and heterogeneous neighbors of each target node. Third, we introduce a graph convolutional network with cross-graph feature propagation ability to transfer node features from homogeneous to heterogeneous graphs for enhanced neighbor feature representation learning. The propagation strategy aids in the deep fusion of features from both types of neighbors. Finally, we design spatial cross-attention to encode the attributes of drug-microbe pairs, revealing long-distance correlations among multiple pairwise attribute patches. The comprehensive comparison experiments showed our method outperformed state-of-the-art methods for drug-microbe association prediction. The ablation studies demonstrated the effectiveness of node category-sensitive hypergraph convolution network, graph convolutional network with cross-graph feature propagation, and spatial cross-attention. Case studies on 3 drugs further showed DHDMP's potential application in discovering the reliable candidate microbes for the interested drugs. AVAILABILITY: Source codes and supplementary materials are available at https://github.com/pingxuan-hlju/DHDM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Characterization of flare-ups and impact of garetosmab in adults with fibrodysplasia ossificans progressiva: a post hoc analysis of the randomized, double-blind, placebo-controlled LUMINA-1 trial.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare disorder, characterized by progressive heterotopic ossification (HO) and painful soft-tissue inflammatory flare-ups. This was a post hoc analysis from a phase 2 (NCT03188666) trial in which adults with FOP received intravenous anti-activin A antibody garetosmab 10 mg/kg or placebo every 4 wk over 28 wk (Period 1), followed by a 28-wk open-label treatment and extension (Periods 2 and 3). Here we describe flare-ups, their relationship to new HO lesions, and the impact of garetosmab on flare-ups. Volume of new HO lesions was measured by CT. Patient-reported flare-ups were defined by any 2 of the following: new onset of pain, swelling, joint stiffness, decrease in movement, or perceived presence of HO. Flare-ups were experienced by 71% (17/24) of placebo-treated patients, 59% (10/17) of whom developed a new HO lesion irrespective of flare-up location; 24% of flare-ups location-matched new HO lesions. Twenty-nine new HO lesions occurred in the placebo cohort by week 28, of which 12 (41%) occurred in the same location as new or ongoing flare-ups. A higher volume of newly formed heterotopic bone (week 28) occurred in placebo-treated patients who had experienced a prior flare-up vs those without (median [Q1:Q3] of 16.6 [12.0:31.1] vs 3.2 cm3). Garetosmab was previously shown to decrease patient-reported flare-up frequency in Period 1; here, garetosmab reduced the median (Q1:Q3) duration of patient-reported flares (15.0 [6.0:82.0] vs 48.0 [15.0:1.00] d) and the severity of flare-ups vs placebo. Frequency of corticosteroid use was numerically reduced in those treated with garetosmab (40.0%) vs placebo (58.3%). In this analysis, 71% of placebo-treated adults with FOP experienced flare-ups over 28 wk, which were associated with an increased volume of newly formed heterotopic bone. Garetosmab reduced the severity and duration of flare-ups, with effects sustained during the entire trial.

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder caused by mutations in the ACVR1 gene. People with FOP experience growth of new bone in places where bone does not usually develop. Soft tissues (like skeletal muscles) and connective tissues (like tendons and ligaments) are gradually replaced by bone beyond the normal skeleton­a process called heterotopic ossification (HO). People with FOP experience flare-ups, which are painful swellings of the soft tissues. In this clinical study in people with FOP, we looked at the number of flareups, whether flareups were linked to new HO lesions, and the impact of garetosmab (a monoclonal antibody) on flareups. At random, about half the patients received placebo, or inactive drug, with the other half receiving garetosmab, the study drug. Of the patients who received placebo, 71% had flare-ups and 59% percent of those who had flare-ups also had a new HO lesion, which was not always related to the location of the flare-up. We have previously shown that garetosmab reduces the number of flareups patients report. In this study, we show that garetosmab reduces the length and pain severity of flare-ups too. The treatment effects were maintained for the whole study.

Puerarin attenuates myocardial ischemic injury and endoplasmic reticulum stress by upregulating the Mzb1 signal pathway.

Objective: This study investigated the role of Mzb1 in puerarin protection against heart injury and dysfunction in acute myocardial infarction (AMI) mice. Methods: C57BL/6 mice were pretreated with and without puerarin at doses of 50 mg/kg and 100 mg/kg for 14 days before establishing the AMI model. An AMI model was induced by ligating the left descending anterior coronary artery, and AC16 cardiomyocytes were treated with H2O2 in vitro. Echocardiography was performed to measure cardiac function. DHE staining, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase assay, and DCFH-DA oxidative fluorescence staining were used to determine reactive oxygen species (ROS) production in vivo and in vitro. Bioinformatics analysis was used to predict potential upstream transcription factors of Mzb1. Results: Puerarin dose-dependently reduced myocardial infarction area and injury, accompanied by the improvement of cardiac function in AMI mice. AMI mice manifested an increase in myocardial oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and mitochondrial biogenesis dysfunction, which were inhibited by pretreatment with puerarin. Puerarin also prevented Mzb1 downregulation in the hearts of AMI mice or H2O2-treated AC16 cells. Consistent with the in vivo findings, puerarin inhibited H2O2-induced cardiomyocyte apoptosis, ER stress, and mitochondrial dysfunction, which were attenuated by siRNA Mzb1. Furthermore, the JASPAR website predicted that KLF4 may be a transcription factor for Mzb1. The expression of KLF4 was partially reversed by puerarin in the cardiomyocyte injury model, and KLF4 inhibitor (kenpaullone) inhibited Mzb1 expression and affected its function. Conclusion: These results suggest that puerarin can protect against cardiac injury by attenuating oxidative stress and endoplasmic reticulum stress through upregulating the KLF4/Mzb1 pathway and that puerarin may expand our armamentarium for the prevention and treatment of ischemic heart diseases.

Evolving molecular HIV clusters revealed genotype-specific dynamics in Guangzhou, China (2008-2020).

OBJECTIVES: This study investigated the genotype-specific dynamics of molecular HIV clusters (MHCs) in Guangzhou, China, aiming to enhance HIV control. METHODS: HIV pol sequences from people with HIV (PWH) in Guangzhou (2008-2020) were obtained for genotyping and molecular network creation. MHCs were identified and categorized into three types: emerging, growing, or stable. Clustering rates, proportions of cluster types, and members within each type were calculated and their trends were assessed using joinpoint regression. RESULTS: Among 8395 PWH, the most prevalent HIV-1 genotypes were CRF07_BC (39.7%) and CRF01_AE (32.6%). The genotype composition has been stable since 2012 (Ps > 0.05). The overall clustering rate was 43.3%, with significant variations across genotypes (P < 0.001), indicating genotype-specific transmission fitness. Significant declines in overall and genotype-specific clustering rates toward the end of 2020 (Ps < 0.05), potentially offer support for HIV control efforts in reducing local infections. The continuously increasing proportions of stable clusters and the gradually decreasing proportions of emerging and growing clusters (either Ps < 0.05 or Ps > 0.05) suggest a trend toward stable molecular network structure. However, growing clusters exhibited CRF55_01B, CRF07_BC, and CRF59_01B dominance that indicate their priority for interventions. CONCLUSION: The evolving MHCs highlight the genotype-specific cluster dynamics, providing fresh insights for enhanced prevention and control strategies.

Infertility-related stress is associated with quality of life through negative emotions among infertile outpatients.

Infertility is not a fatal disease but it really produces infertility-related stress and affects individuals' quality of life to a great extent. This study aims to investigate the relations among infertility-related stress, negative emotions and quality of life in infertile outpatients, and suppose gender difference as well as Dark Triad, which contained three dark personality traits: Machiavellianism, narcissism, and psychopathy, would moderate the relations. 105 infertile outpatients age range 20-49 completed a cross-sectional questionnaire on the Fertility Quality of Life scale, the Fertility Problem Inventory, the Hospital Anxiety and Depression Scale a the Chinese version of Dirty Dozen. Results showed that negative emotions mediated the relations between infertility-related stress and quality of life. Dark Triad could not moderate the relations between infertility-related stress, negative emotions, and quality of life, but gender can moderate the associations between infertility-related stress and negative emotions. Specifically, the association between infertility-related stress and negative emotions was stronger in men than in women. Infertility-related stress has direct and indirect effects on infertile outpatients' quality of life. It is important to consider the important roles of emotions and gender difference between patients, and delivering targeted intervention programs.

The Discovery of GIT1/ß-Pix Inhibitors: Virtual Screening and Biological Evaluation of New Small-molecule Compounds with Anti-invasion Effect in Gastrointestinal Neoplasms.

Background and Objective: GIT1 (G-protein-coupled receptor kinase interacting protein-1) has been found to be highly related with cancer cell invasion and metastasis in many cancer types. ß-Pix (p21-activated kinase-interacting exchange factor) is one of the proteins that interact with GIT1. Targeting GIT1/ß-Pix complex might be a potential therapeutic strategy for interfering cancer metastasis. However, at present, no well-recognized small-molecule inhibitor targeting GIT1/ß-Pix is available. Thus, we aim to discover novel GIT1/ß-Pix inhibitors with simple scaffold, high activity and low toxicity to develop new therapeutic strategies to restrain cancer metastasis. Methods: GIT1/ß-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/ß-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization. Results: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 µM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer. Conclusion: We discovered a new GIT1/ß-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/ß-Pix inhibitors for tumor treatment.

Association of long-term exposure to PM2.5 and its chemical components with the reduced quality of sleep.

Poor sleep quality is a widespread concern. While the influence of particle exposure on sleep disturbances has received considerable attention, research exploring other dimensions of sleep quality and the chemical components of the particles remains limited. We employed a marginal structural model to explore the association of long-term exposure to PM2.5 and its chemical components with poor sleep quality. The odds ratio (95 % CI) for poor sleep quality was 1.335 (1.292-1.378), 1.097 (1.080-1.113), 1.137 (1.100-1.174), 1.197 (1.156-1.240), and 1.124 (1.107-1.140) per IQR increase in the concentration of PM2.5, SO42-, NO3-, NH4+, and BC, respectively. The score (and 95 % CI) of sleep latency, use of sleep medication, habitual sleep efficiency, subjective sleep quality, and daytime dysfunction were affected by PM2.5, with an increase of 0.059 (0.050-0.069), 0.054 (0.049-0.059), 0.011 (0.008-0.014), 0.011 (0.005-0.018), and 0.026 (0.018-0.034) per IQR increase in PM2.5 concentrations, respectively. This study supports the association of long-term exposure to PM2.5 and its chemical components with poor sleep quality.

Assessing the modification impact of vaccination on the relationship of the Discomfort Index with hand, foot, and mouth disease in Guizhou: A multicounty study.

BACKGROUND: Hand, foot, and mouth disease (HFMD) is a major public health issue in China while temperature and humidity are well-documented predictors. However, evidence on the combined effect of temperature and humidity is still limited. It also remains unclear whether such an effect could be modified by the enterovirus 71 (EV71) vaccination. METHODS: Based on 320,042 reported HFMD cases during the summer months between 2012 and 2019, we conducted a study utilizing Distributed Lag Non-Linear Models (DLNM) and time-varying DLNM to examine how China's HFMD EV71 vaccine strategy would affect the correlation between meteorological conditions and HFMD risk. RESULTS: The incidence of HFMD changed with the Discomfort Index in an arm-shaped form. The 14-day cumulative risk of HFMD exhibited a statistically significant increase during the period of 2017-2019 (following the implementation of the EV71 vaccine policy) compared to 2012-2016 (prior to the vaccine implementation). For the total population, the range of relative risk (RR) values for HFMD at the 75th, 90th, and 99th percentiles increased from 1.082-1.303 in 2012-2016 to 1.836-2.022 in 2017-2019. In the stratified analyses, Han Chinese areas show stronger relative growth, with RR values at the 75th, 90th, and 99th percentiles increased by 14.3%, 39.1%, and 134.4% post-vaccination, compared to increases of 22.7%, 41.6%, and 38.8% in minority areas. Similarly, boys showed greater increases (24.4%, 47.7%, 121.5%) compared to girls (8.1%, 28.1%, 58.3%). Additionally, the central Guizhou urban agglomeration displayed a tendency for stronger relative growth compared to other counties. CONCLUSIONS: Although the EV71 vaccine policy has been implemented, it hasn't effectively controlled the overall risk of HFMD. There's been a shift in the main viral subtypes, potentially altering population susceptibility and influencing HFMD occurrences. The modulating effects of vaccine intervention may also be influenced by factors such as race, sex, and economic level.

Identification of NR3C2 as a functional diagnostic and prognostic biomarker and potential therapeutic target in non-small cell lung cancer.

Background: Non-small cell lung cancer (NSCLC), including the lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) subtypes, is a malignant tumor type with a poor 5-year survival rate. The identification of new powerful diagnostic biomarkers, prognostic biomarkers, and potential therapeutic targets in NSCLC is urgently required. Methods: The UCSC Xena, UALCAN, and GEO databases were used to screen and analyze differentially expressed genes, regulatory modes, and genetic/epigenetic alterations in NSCLC. The UCSC Xena database, GEO database, tissue microarray, and immunohistochemistry staining analyses were used to evaluate the diagnostic and prognostic values. Gain-of-function assays were performed to examine the roles. The ESTIMATE, TIMER, Linked Omics, STRING, and DAVID algorithms were used to analyze potential molecular mechanisms. Results: NR3C2 was identified as a potentially important molecule in NSCLC. NR3C2 is expressed at low levels in NSCLC, LUAD, and LUSC tissues, which is significantly related to the clinical indexes of these patients. Receiver operating characteristic curve analysis suggests that the altered NR3C2 expression patterns have diagnostic value in NSCLC, LUAD, and especially LUSC patients. Decreased NR3C2 expression levels can help predict poor prognosis in NSCLC and LUAD patients but not in LUSC patients. These results have been confirmed both with database analysis and real-world clinical samples on a tissue microarray. Copy number variation contributes to low NR3C2 expression levels in NSCLC and LUAD, while promoter DNA methylation is involved in its downregulation in LUSC. Two NR3C2 promoter methylation sites have high sensitivity and specificity for LUSC diagnosis with clinical application potential. NR3C2 may be a key participant in NSCLC development and progression and is closely associated with the tumor microenvironment and immune cell infiltration. NR3C2 co-expressed genes are involved in many cancer-related signaling pathways, further supporting a potentially significant role of NR3C2 in NSCLC. Conclusions: NR3C2 is a novel potential diagnostic and prognostic biomarker and therapeutic target in NSCLC.

The origin and spread of HIV-1 CRF59_01B epidemic in China: A molecular network and phylogeographic analysis.

Human immunodeficiency virus type 1 CRF59_01B, identified in China in 2013, has been detected nationwide, exhibiting notably high prevalence in Guangzhou and its vicinity. This study aimed to unravel its origin and migration. A data set was established, incorporating all available CRF59_01B pol gene sequences and their metadata from Guangzhou and the public database. Bayesian phylogeographic analysis demonstrated that CRF59_01B originated in Shenzhen, the neighboring city of Guangzhou, around 1998 with posterior probability of 0.937. Molecular network analysis detected 1131 transmission links and showed a remarkably high clustering rate (78.9%). Substantial inter-city transmissions (26.5%, 300/1131) were observed between Shenzhen and Guangzhou while inter-region transmissions linked Guangzhou with South (46) and Southwest (64) China. The centre of Guangzhou was the hub of CRF59_01B transmission, including the inflow from Shenzhen (3.57 events/year) and outflow to the outskirts of Guangzhou (>2 events/year). The large-scale analysis revealed significant migration from Shenzhen to Guangzhou (5.08 events/year) and North China (0.59 events/year), and spread from Guangzhou to Central (0.47 events/year), East (0.42 events/year), South (0.76 events/year), Southwest China (0.76 events/year) and Shenzhen (1.89 events/year). Shenzhen and Guangzhou served as the origin and the hub of CRF59_01B circulation, emphasizing inter-city cooperation and data sharing to confine its nationwide diffusion.

Case report: Complete response after transcatheter arterial chemoembolization combined with donafenib plus tislelizumab therapy for hepatocellular carcinoma with main trunk portal vein tumor thrombus in a patient coinfected with HIV and HBV.

Background: Coinfection with the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) occurs in 5-67% of patients with HIV. HIV weakens the human immune system and leads to various tumors. Patients with unresectable hepatocellular carcinoma (HCC) and HIV experience poor treatment efficacy and have a short survival period. Approximately 70% of cases of HCC are diagnosed at advanced stages due to the subtle onset of the disease. As a result, most cases are not suits for curative therapy. Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate-stage HCC and is commonly used to treat unresectable HCC in China. Recent advancements in systemic treatments have significantly enhanced the effectiveness of unresectable HCC treatment. Several previous study showed that combination treatment combination therapy can enhance the efficacy. Notably, studies proposed that TACE combined targeted drugs with immune checkpoint inhibitors results in a high objective response rate and overall survival. However, the novelty of this study lies in its report of a complete response using a triple combination in patients with HIV and HCC with main trunk portal vein tumor thrombus. Case presentation: A 57-year-old woman was diagnosed with HCC with a main trunk portal vein tumor thrombus combined with HIV infection, cirrhosis, and chronic viral hepatitis. She underwent TACE and was administered donafenib and tislelizumab. This triple therapy treatment regimen resulted in a clinical complete response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) based on contrast-enhanced computed tomography. Conclusion: We first used TACE combined with donafenib and tislelizumab for HCC patients with main trunk portal vein tumor thrombus and HIV-HBV coinfection and achieved complete response.

The T120P or M172V mutation on rv2172c confers high level para-aminosalicylic acid resistance in Mycobacterium tuberculosis.

Although para-aminosalicylic acid (PAS) has been used to treat tuberculosis for decades, mechanisms of resistance to this drug in Mycobacterium tuberculosis (M. tuberculosis) clinical isolates have not been thoroughly investigated. Previously, we found that decreased methylenetetrahydrofolate reductase (MTHFR) activity of Rv2172c led to increased sensitivity to antifolates in M. tuberculosis. In this study, we collected the genome-sequencing data of 173 PAS-resistant and 803 PAS-sensitive clinical isolates and analyzed rv2172c mutations in those 976 isolates. The results showed that two mutations (T120P and M172V) on rv2172c could be identified in a certain proportion (6.36%) of PAS-resistant isolates. The results of AlphaFold2 prediction indicated that the T120P or M172V mutation might affect the enzymatic activity of Rv2172c by influencing nicotinamide adenine dinucleotide (NADH) binding, and this was verified by subsequent biochemical analysis, demonstrating the role of residues Thr120 and Met172 on NADH binding and enzymatic activity of Rv2172c. In addition, the effect of rv2172c T120P or M172V mutation on methionine production and PAS resistance was determined in M. tuberculosis. The results showed that both T120P and M172V mutations caused increased intracellular methionine concentrations and high level PAS resistance. In summary, we discovered new molecular markers and also a novel mechanism of PAS resistance in M. tuberculosis clinical isolates and broadened the understanding of the NADH-dependent MTHFR catalytic mechanism of Rv2172c in M. tuberculosis, which will facilitate the molecular diagnosis of PAS resistance and also the development of new drugs targeting Rv2172c.

Exploration for the Priority of HIV Intervention: Modelling Health Impact and Cost-Effectiveness - Six Cities, Eastern China, 2019-2028.

Introduction: In order to enhance the effectiveness of resource allocation, regions must tailor their responses to their specific epidemiological and economic situations. Methods: Utilizing Spectrum software, we projected the cost-effectiveness of 10 chosen HIV interventions in six cities in eastern China from 2019 to 2028. We assessed three scenarios - Base, Achievable, and Idealized - for each city. The analysis included the projected number of HIV infections and deaths averted, as well as the incremental cost-effectiveness ratios for each intervention in the six cities. Results: In Shijiazhuang, Wuxi, Yantai, and Zhenjiang, cities with initially low antiretroviral therapy (ART) coverage, ART showed significant effectiveness, especially for males. Conversely, in Foshan and Ningbo, where ART coverage was notably high, oral pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) proved effective in the Idealized scenario. MSM outreach, ART for males, and ART for females demonstrated cost-effectiveness across all six cities in both Achievable and Idealized scenarios at the predefined thresholds for each city. Discussion: Maintaining an appropriate coverage rate for outreach to MSM can lead to cost-effectiveness. In cities with low ART coverage, scaling up ART remains a crucial intervention. In regions with high ART coverage, consideration may be given to the utilization of oral PrEP for MSM individuals, requiring budget allocation.

Advances in Small-Molecule Dual Inhibitors Targeting EGFR and HER2 Receptors as Anti-Cancer Agents.

As members of the protein tyrosine kinase family, the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor Receptor 2 (HER2) play essential roles in cellular signal transduction pathways. Overexpression or abnormal activation of EGFR and HER2 can lead to the development of various solid tumors. Therefore, they have been confirmed as biological targets for the development of anticancer drugs. Due to the fact that many cancers are highly susceptible to developing resistance to single-target EGFR inhibitors in clinical practice, dual inhibitors that target both EGFR and HER2 have been developed to increase efficacy, reduce drug resistance and interactions, and improve patient compliance. Currently, a variety of EGFR/HER2 dual inhibitors have been developed, with several drugs already approved for marketing or in clinical trials. In this review, we summarize recent advancements in small-molecule EGFR/HER2 dual inhibitors by focusing on structure-activity relationships and share novel insights into developing anticancer agents.

Rsad2 mediates Bisphenol A-induced actin cytoskeletal disruption in mouse spermatocytes.

Bisphenol A (BPA) is widely exposed in populations worldwide and has negative effects on spermatogenesis both in animals and humans. The homeostasis of the actin cytoskeleton in the spermatogenic epithelium is crucial for spermatogenesis. Actin cytoskeleton destruction in the seminiferous epithelium is one of the important reasons for BPA-induced spermatogenesis disorder. However, the underlying molecular mechanisms remain largely unexplored. Herein, we explored the role and mechanism of Rsad2, an interferon-stimulated gene in BPA-induced actin cytoskeleton disorder in mouse GC-2 spermatocyte cell lines. After BPA exposure, the actin cytoskeleton was dramatically disrupted and the cell morphology was markedly altered accompanied by a significant increase in Rsad2 expression both in mRNA and protein levels in GC-2 cells. Furthermore, the phalloidin intensities and cell morphology were restored obviously when interfering with the expression of Rsad2 in BPA-treated GC-2 cells. In addition, we observed a significant decrease in intracellular ATP levels after BPA treatment, while the ATP level was obviously upregulated when knocking down the expression of Rsad2 in BPA-treated cells compared to cells treated with BPA alone. Moreover, Rsad2 relocated to mitochondria after BPA exposure in GC-2 cells. BPA promoted Rsad2 expression by activating type I IFN-signaling in GC-2 cells. In summary, Rsad2 mediated BPA-induced actin cytoskeletal disruption in GC-2 cells, which provided data to reveal the mechanism of BPA-induced male reproductive toxicity.