Exploring the Mechanisms of Traditional Chinese Herbal Therapy in Gastric Cancer: A Comprehensive Network Pharmacology Study of the Tiao-Yuan-Tong-Wei decoction.

The use of herbal medicine as an adjuvant therapy in the management of gastric cancer has yielded encouraging outcomes, notably in enhancing overall survival rates and extending periods of disease remission. Additionally, herbal medicines have demonstrated potential anti-metastatic effects in gastric cancer. Despite these promising findings, there remains a significant gap in our understanding regarding the precise pharmacological mechanisms, the identification of specific herbal compounds, and their safety and efficacy profiles in the context of gastric cancer therapy. In addressing this knowledge deficit, the present study proposes a comprehensive exploratory analysis of the Tiao-Yuan-Tong-Wei decoction (TYTW), utilizing an integrative approach combining system pharmacology and molecular docking techniques. This investigation aims to elucidate the pharmacological actions of TYTW in gastric pathologies. It is hypothesized that the therapeutic efficacy of TYTW in counteracting gastric diseases stems from its ability to modulate key signaling pathways, thereby influencing PIK3CA activity and exerting anti-inflammatory effects. This modulation is observed predominantly in pathways such as PI3K/AKT, MAPK, and those directly associated with gastric cancer. Furthermore, the study explores how TYTW's metabolites (agrimoniin, baicalin, corosolic acid, and luteolin) interact with molecular targets like AKT1, CASP3, ESR1, IL6, PIK3CA, and PTGS2, and their subsequent impact on these critical pathways and biological processes. Therefore, this study represents preliminary research on the anticancer molecular mechanism of TYTW by performing network pharmacology and providing theoretical evidence for further experimental investigations.

Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection.

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-α and IL1-ß. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.

Pharmacogenomic Analysis of Combined Therapies against Glioblastoma Based on Cell Markers from Single-Cell Sequencing.

Glioblastoma is the most common and aggressive form of primary brain cancer and the lack of viable treatment options has created an urgency to develop novel treatments. Personalized or predictive medicine is still in its infancy stage at present. This research aimed to discover biomarkers to inform disease progression and to develop personalized prophylactic and therapeutic strategies by combining state-of-the-art technologies such as single-cell RNA sequencing, systems pharmacology, and a polypharmacological approach. As predicted in the pyroptosis-related gene (PRG) transcription factor (TF) microRNA (miRNA) regulatory network, TP53 was the hub gene in the pyroptosis process in glioblastoma (GBM). A LASSO Cox regression model of pyroptosis-related genes was built to accurately and conveniently predict the one-, two-, and three-year overall survival rates of GBM patients. The top-scoring five natural compounds were parthenolide, rutin, baeomycesic acid, luteolin, and kaempferol, which have NFKB inhibition, antioxidant, lipoxygenase inhibition, glucosidase inhibition, and estrogen receptor agonism properties, respectively. In contrast, the analysis of the cell-type-specific differential expression-related targets of natural compounds showed that the top five subtype cells targeted by natural compounds were endothelial cells, microglia/macrophages, oligodendrocytes, dendritic cells, and neutrophil cells. The current approach-using the pharmacogenomic analysis of combined therapies-serves as a model for novel personalized therapeutic strategies for GBM treatment.

Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing.

Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy.

Characteristics and risk factors for readmission in HIV-infected patients with Talaromyces marneffei infection.

OBJECTIVES: Talaromyces marneffei (T. marneffei) is an opportunistic fungal infection (talaromycosis), which is common in subtropical regions and is a leading cause of death in HIV-1-infected patients. This study aimed to determine the characteristics and risk factors associated with hospital readmissions in HIV patients with T. marneffei infection in order to reduce readmissions. METHODS: We conducted a retrospective study of admitted HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from 2012 to 2019. Kaplan-Meier analyses and Principal component analysis (PCA) were used to evaluate the effects of T. marneffei infection on patient readmissions. Additionally, univariate and multifactorial analyses, as well as Propensity score matching (PSM) were used to analyze the factors associated with patient readmissions. RESULTS: HIV/AIDS patients with T. marneffei-infected had shorter intervals between admissions and longer lengths of stay than non-T. marneffei-infected patients, despite lower readmission rates. Compared with non-T. marneffei-infected patients, the mortality rate for talaromycosis patients was higher at the first admission. Among HIV/AIDS patients with opportunistic infections, the mortality rate was highest for T. marneffei at 16.2%, followed by cryptococcus at 12.5%. However, the readmission rate was highest for cryptococcus infection (37.5%) and lowest for T. marneffei (10.8%). PSM and Logistic regression analysis identified leukopenia and elevated low-density lipoprotein (LDL) as key factors in T.marneffei-infected patients hospital readmissions. CONCLUSIONS: The first admission represents a critical window to intervene in the prognosis of patients with T. marneffei infection. Leukopenia and elevated LDL may be potential risk factors impacting readmissions. Our findings provide scientific evidence to improve the long-term outcomes of HIV patients with T. marneffei infection.

Prognostic value of sarcopenic visceral obesity in hepatocellular carcinoma treated with TACE.

Although Transartial chemoembolization (TACE) is one of the recommended treatments for hepatocellular carcinoma (HCC), there is always a dispute on the selection of the best beneficiary for treatment. We studied the prognostic value of nutritional markers, obesity, visceral obesity and sarcopenia on survival outcomes under single and different combinations. In a retrospective cohort of 235 patients with HCC at different stages, more accurate comprehensive prognostic factors were obtained by combining and comparing the multifactor hazard ratios (HR) of various parameters, including skeletal muscle index (SMI) and visceral fat index (VFI) obtained by computer tomography, laboratory index albumin-to-globulin (A/G) ratio, anthropometric body mass index (BMI) and other parameters. The study cohort was dominated by men (73.6%), with a median age of 54 years. According to the survival outcome of HCC patients, we obtained the ideal sex cutoff value of VFI: ≥40.54 cm 2 /m 2 for males (the receiver operating characteristic curve [ROC] = 0.764, P  < .001) and ≥ 43.19 cm 2 /m 2 for females (ROC = 0.718, P  < .05). According to the results of multifactor analysis, sarcopenic visceral obesity (HR = 8.35, 95% confidence intervals [CI] = [4.96, 14.05], P  < .001) is more effective than any single or combined prognosis assessment, including sarcopenic dystrophy (HR = 2.70, 95% CI = [1.85, 3.95], P  < .001), sarcopenic obesity (HR = 5.23, 95% CI = [3.41, 8.02], P  < .001), sarcopenia (HR = 5.74, 95% CI = [3.61, 9.11], P  < .001) and visceral obesity (HR = 3.44, 95% CI = [2.24, 5.27], P  < .001). Sarcopenic visceral obesity, defined by SMI and VFI, is a more objective and accurate prognostic indicator of HCC.

3D-printed gelatin/sodium alginate/58S bioactive glass scaffolds promote osteogenesis in vitro and in vivo.

Three-dimensional (3D)-printed scaffolds are a new strategy to fabricate biomaterials for treating bone defects. Here, using a 3D-printing technique, we fabricated scaffolds consisting of gelatin (Gel), sodium alginate (SA), and 58S bioactive glass (58S BG). To evaluate mechanical properties and biocompatibility of Gel/SA/58S BG scaffolds, the degradation test, compressive strength test, and cytotoxicity test were performed. The effect of the scaffolds on cell proliferation in vitro was determined by 4',6-diamidino-2-phenylindole (DAPI) staining. To evaluate osteoinductive properties, rBMSCs were cultured on the scaffolds for 7, 14, and 21 days and the expression of osteogenesis-related genes was analyzed using qRT-PCR. To examine the bone healing properties of Gel/SA/58S BG scaffolds in vivo, we used a rat mandibular critical-size defect bone model. The scaffolds were implanted into the defect area of rat mandible and bone regeneration and new tissue formation were assessed using microcomputed tomography (microCT) and hematoxylin and eosin (H&E) staining. The results showed that Gel/SA/58S BG scaffolds had appropriate mechanical strength as a filling material for bone defects. Furthermore, the scaffolds could be compressed within certain limits and then could recover their shape. The extract of the Gel/SA/58S BG scaffold showed no cytotoxicity. In vitro, the expression levels of Bmp2, Runx2, and OCN were increased in rBMSCs cultured on the scaffolds. In vivo, microCT and H&E staining demonstrated that scaffolds induced the formation of new bone at the mandibular defect area. These results indicated that Gel/SA/58S BG scaffolds have excellent mechanical characteristics, biocompatibility, and osteoinductive properties, suggesting that it could be a promising biomaterial for the repair of bone defects.

Spectrum and mortality of opportunistic infections among HIV/AIDS patients in southwestern China.

We describe the opportunistic infections (OIs) of HIV/AIDS to understand the spectrum, mortality, and frequency of multiple coinfected OIs among HIV/AIDS patients in southern China, where OIs are severe. We carried out a retrospective cohort study of hospitalized HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China, from Jan. 2011 to May. 2019. The chi-square test was used to analyze cross-infection; the Kaplan‒Meier analysis was used to compare mortality. A total of 12,612 HIV-infected patients were admitted to this cohort study. Among them, 8982 (71.2%) developed one or more OIs. The overall in-hospital mortality rate was 9.0%. Among the patients, 35.6% coinfected one OI, and 64.4% coinfected more than two OIs simultaneously. Almost half of the patients (60.6%) had CD4 + T-cell counts < 200 cells/µL. Pneumonia (39.8%), tuberculosis (35.3%), and candidiasis (28.8%) were the most common OIs. Coinfected cryptococcal meningitis and dermatitis are the most common combined OIs. The rate of anaemia (17.0%) was highest among those common HIV-associated complications. Multiple OIs are commonly found in hospitalized HIV/AIDS patients in southwestern China, which highlights the need for improved diagnosis and treatment.

Multiresidue Pesticide Analysis in Tea Using GC-MS/MS to Determine 12 Pesticide Residues (GB 2763-2021).

Pesticides are widely used on tea plants, and pesticide residues are of significant concern to consumers. The National Food Safety Standard Maximum Residue Limits for Pesticides in Food (GB 2763-2021) was recently amended. However, detection methods for pesticides newly added to the list of residues in beverages have not yet been established. For that reason, this study developed a solid-phase extraction (SPE) and gas chromatography-tandem mass spectrometry (GC-MS/MS) method for determining the residues of 12 pesticides, including four newly added, in black and green tea. Sample preparation processes (sample extraction, SPE clean-up, elution solvent, and elution volume) were optimized to monitor these residues reliably. Multiple reaction monitoring (MRM) was used for GC-MS/MS electron impact (EI) mode determination. Finally, satisfactory recoveries (70.7-113.0% for green tea and 72.0-99.1% for black tea) were achieved at three concentrations (10 µg/kg, 20 µg/kg, and 100 µg/kg). The LOQs were 0.04-8.69 µg/kg, and the LODs were 0.01-3.14 µg/kg. This study provides a reliable and sensitive workflow for determining 12 pesticide residues in tea, filling a gap in the newly revised National Standards.

Effect and Mechanism of Cotrimoxazole Against Talaromyces marneffei in vitro.

BACKGROUND: Talaromyces marneffei (formerly Penicillium marneffei) is an important thermally dimorphic fungus endemic which is characterized by one of the most frequent opportunistic infections in HIV/AIDS patients, mainly prevalent in Southeast Asia, southern China, and northeastern India. Cotrimoxazole(CTX) inhibits folic acid synthesis which is important for the survival of many bacteria, protozoa, and fungi, thereby commonly used to prevent several opportunistic infections among HIV/AIDS patients. In addition to preventing other HIV-associated opportunistic infections, CTX prophylaxis are considered to have the potential to prevent T. marneffei infection in HIV/AIDS patients receiving antiretroviral therapy (ART). However, the effect of cotrimoxazole towards T. marneffei fungus in vitro remains unclear. METHODS: Human THP-1 macrophages were used as cell model in vitro to explore the effect and mechanism of cotrimoxazole resistance towards T. marneffei. Cell viability assay and drug sensitivity colony forming units (CFU) experiments were conducted to determine the minimum inhibitory concentration (MIC) of cotrimoxazole inside and outside THP-1 macrophages respectively. Enzyme-linked immunosorbent assay (Elisa) was used to measure the concentration of Dihydropteroic acid synthetase (DHPS), Dihydrofolate synthetase (DHFS) and Dihydrofolate reductase (DHFR) between T. marneffei adding TMP/SMX and without adding TMP/SMX group respectively. Real-time fluorescence quantitative PCR(qPCR) was performed to detect the mRNA expression levels in Dectin-1 mediated signaling pathway and downstream inflammatory cytokines including IL-6, IL-10, IL-23A, CXCL8 and TNF-α released by T. marneffei-infected macrophages between adding TMP/SMX and without adding TMP/SMX group respectively. RESULTS: Cotrimoxazole can inhibit the proliferation of T. marneffei within safe concentration inside and outside THP-1 macrophages. Drug susceptibility results showed the minimal inhibit concentration(MIC) of 1:5 TMP/SMX was ranging from 14/70 to 68/340 µg/ml. The MIC of SMX was ranging from 100 to 360 µg/ml. The MIC of TMP was ranging from 240 to 400 µg/ml outside macrophages. The MIC of TMP/SMX was ranging from 36/180 to 68/340 µg/ml. The MIC of SMX was ranging from 340 to 360 µg/ml. The MIC of TMP was ranging from 320 to 400 µg/ml inside macrophages. The synergistic interaction of 1:5 TMP/SMX was more effective in inhibiting T. marneffei than separate SMX and TMP. DHPS, DHFS and DHFR can be inhibited by cotrimoxazole within safe and effective concentration. Dectin-1 expression is increased following T. marneffei infection, leading to the increase of IL-6, IL-10, IL-23A and the decrease of CXCL8 and TNF-α. Conversely, cotrimoxazole decrease the levels of Dectin-1, IL-6, IL-10, IL-23A and increase the levels of CXCL8 and TNF-α, thereby enhancing the intracellular killing-T. marneffei capacity of macrophages. CONCLUSIONS: Our findings indicated that cotrimoxazole directly inhibited T. marneffei growth by blocking DHPS, DHFS and DHFR and indirectly inhibited T. marneffei growth perhaps by regulating the Dectin-1 signaling pathway, which may effectively interfere with the defense ability of the host against T. marneffei infection.

Research on the osteogenesis and biosafety of ECM-Loaded 3D-Printed Gel/SA/58sBG scaffolds.

Employing scaffolds containing cell-derived extracellular matrix (ECM) as an alternative strategy for the regeneration of bone defects has shown prominent advantages. Here, gelatin (Gel), sodium alginate (SA) and 58s bioactive glass (58sBG) were incorporated into deionized water to form ink, which was further fabricated into composite scaffolds by the 3D printing technique. Then, rat aortic endothelial cells (RAOECs) or rat bone mesenchymal stem cells (RBMSCs) were seeded on the scaffolds. After decellularization, two kinds of ECM-loaded scaffolds (RAOECs-ECM scaffold and RBMSCs-ECM scaffold) were obtained. The morphological characteristics of the scaffolds were assessed meticulously by scanning electron microscopy (SEM). In addition, the effects of scaffolds on the proliferation, adhesion, and osteogenic and angiogenic differentiation of RBMSCs were evaluated by Calcein AM staining and reverse transcription polymerase chain reaction (RT-PCR). In vivo, full-thickness bone defects with a diameter of 5 mm were made in the mandibles of Sprague-Dawley (SD) rats to assess the bone regeneration ability and biosafety of the scaffolds at 4, 8 and 16 weeks. The osteogenic and angiogenic potential of the scaffolds were investigated by microcomputed tomography (Micro-CT) and histological analysis. The biosafety of the scaffolds was evaluated by blood biochemical indices and histological staining of the liver, kidney and cerebrum. The results showed that the ECM-loaded scaffolds were successfully prepared, exhibiting interconnected pores and a gel-like ECM distributed on their surfaces. Consistently, in vitro experiments demonstrated that the scaffolds displayed favourable cytocompatibility. In vitro osteogenic differentiation studies showed that scaffolds coated with ECM could significantly increase the expression of osteogenic and angiogenic genes. In addition, the results from mandibular defect repair in vivo revealed that the ECM-loaded scaffolds effectively promoted the healing of bone defects when compared to the pure scaffold. Overall, these findings demonstrate that both RAOECs-ECM scaffold and RBMSCs-ECM scaffold can greatly enhance bone formation with good biocompatibility and thus have potential for clinical application in bone regeneration.

MicroRNA-145-5p modulates Krüppel-like factor 5 and inhibits cell proliferation, migration, and invasion in nasopharyngeal carcinoma.

BACKGROUND: In several human cancers, Krüppel-like factor 5 (KLF5), a zinc finger transcription factor, can contribute to both tumor progression or suppression; however, the precise role of KLF5 in nasopharyngeal carcinoma (NPC) remains poorly understood. In this study, the association between KLF5 and microRNA-145-5p (miR-145-5p) in NPC cells was elucidated. RESULTS: Our results showed that KLF5 expression was up-regulated in NPC group compared to normal group. We found that KLF5 exhibited an oncogenic role in NPC cells. The upregulation of miR-145-5p inhibited the proliferation, migration, and invasion of NPC cells. It was observed that miR-145-5p could down-regulate the mRNA and protein expression of KLF5 in NPC cell lines. Additionally, the activity of focal adhesion kinase (FAK), a migration marker, was regulated by miR-145-5p and KLF5 in NPC cells. CONCLUSIONS: The results of this study indicated that miR-145-5p could repress the proliferation, migration, and invasion of NPC cells via KLF5/FAK regulation, and could be a potential therapeutic target for patients with NPC.

Quantitative Proteomics of Chromochloris zofingiensis Reveals the Key Proteins Involved in Cell Growth and Bioactive Compound Biosynthesis.

Glucose metabolism regulates cell growth and affects astaxanthin accumulation in the green algae Chromochloris zofingiensis. Hub gene functioning in this bioactive compound has been illustrated at the genome, transcriptome and metabolome level, but is rather limited from a proteome aspect. Microalgal cell produce an enhanced biomass (8-fold higher) but decreased lipid and astaxanthin content (~20% less) in the glucose condition compared to the control. Here, we investigate the proteomic response of C. zofingiensis grown with and without glucose using an LC-MS/MS-based Tandem Mass Tag (TMT) approach. The proteomic analysis demonstrated that glucose supplementation triggers the upregulation of 105 proteins and downregulation of 151 proteins. Thus, the carbon and energy flux might flow to cell growth, which increased the associated protein abundance, including DNA polymerase, translation initiation factor, 26S proteasome regulatory subunits, and the marker enzyme of the TCA cycle ribosomal protein. Moreover, the glucose supplement triggered the downregulation of proteins mainly involved in photosynthesis, chloroplasts, valine, leucine and isoleucine biosynthesis, 2-oxocarboxylic acid metabolism, and pantothenate and CoA biosynthesis pathways. This proteomic analysis is likely to provide new insights into algal growth and lipid or astaxanthin accumulation upon glucose supplementation, providing a foundation for further development of C. zofingiensis as oleaginous microalga for bioengineering applications.

Critical roles of mitochondrial fatty acid synthesis in tomato development and environmental response.

Plant mitochondrial fatty acid synthesis (mtFAS) appears to be important in photorespiration based on the reverse genetics research from Arabidopsis (Arabidopsis thaliana) in recent years, but its roles in plant development have not been completely explored. Here, we identified a tomato (Solanum lycopersicum) mutant, fern-like, which displays pleiotropic phenotypes including dwarfism, yellowing, curly leaves, and increased axillary buds. Positional cloning and genetic and heterozygous complementation tests revealed that the underlying gene FERN encodes a 3-hydroxyl-ACP dehydratase enzyme involved in mtFAS. FERN was causally involved in tomato morphogenesis by affecting photorespiration, energy supply, and the homeostasis of reactive oxygen species. Based on lipidome data, FERN and the mtFAS pathway may modulate tomato development by influencing mitochondrial membrane lipid composition and other lipid metabolic pathways. These findings provide important insights into the roles and importance of mtFAS in tomato development.

Machine learning-based in-hospital mortality prediction of HIV/AIDS patients with Talaromyces marneffei infection in Guangxi, China.

OBJECTIVE: Talaromycosis is a serious regional disease endemic in Southeast Asia. In China, Talaromyces marneffei (T. marneffei) infections is mainly concentrated in the southern region, especially in Guangxi, and cause considerable in-hospital mortality in HIV-infected individuals. Currently, the factors that influence in-hospital death of HIV/AIDS patients with T. marneffei infection are not completely clear. Existing machine learning techniques can be used to develop a predictive model to identify relevant prognostic factors to predict death and appears to be essential to reducing in-hospital mortality. METHODS: We prospectively enrolled HIV/AIDS patients with talaromycosis in the Fourth People's Hospital of Nanning, Guangxi, from January 2012 to June 2019. Clinical features were selected and used to train four different machine learning models (logistic regression, XGBoost, KNN, and SVM) to predict the treatment outcome of hospitalized patients, and 30% internal validation was used to evaluate the performance of models. Machine learning model performance was assessed according to a range of learning metrics, including area under the receiver operating characteristic curve (AUC). The SHapley Additive exPlanations (SHAP) tool was used to explain the model. RESULTS: A total of 1927 HIV/AIDS patients with T. marneffei infection were included. The average in-hospital mortality rate was 13.3% (256/1927) from 2012 to 2019. The most common complications/coinfections were pneumonia (68.9%), followed by oral candida (47.5%), and tuberculosis (40.6%). Deceased patients showed higher CD4/CD8 ratios, aspartate aminotransferase (AST) levels, creatinine levels, urea levels, uric acid (UA) levels, lactate dehydrogenase (LDH) levels, total bilirubin levels, creatine kinase levels, white blood-cell counts (WBC) counts, neutrophil counts, procaicltonin levels and C-reactive protein (CRP) levels and lower CD3+ T-cell count, CD8+ T-cell count, and lymphocyte counts, platelet (PLT), high-density lipoprotein cholesterol (HDL), hemoglobin (Hb) levels than those of surviving patients. The predictive XGBoost model exhibited 0.71 sensitivity, 0.99 specificity, and 0.97 AUC in the training dataset, and our outcome prediction model provided robust discrimination in the testing dataset, showing an AUC of 0.90 with 0.69 sensitivity and 0.96 specificity. The other three models were ruled out due to poor performance. Septic shock and respiratory failure were the most important predictive features, followed by uric acid, urea, platelets, and the AST/ALT ratios. CONCLUSION: The XGBoost machine learning model is a good predictor in the hospitalization outcome of HIV/AIDS patients with T. marneffei infection. The model may have potential application in mortality prediction and high-risk factor identification in the talaromycosis population.

Acceptance of COVID-19 vaccination and influencing factors among people living with HIV in Guangxi, China: a cross-sectional survey.

BACKGROUND: Vaccination has been proven to be an effective approach against the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to determine the acceptance rate and factors influencing acceptance of COVID-19 vaccination among people living with HIV (PLWH) in Guangxi, China. METHODS: A cross-sectional survey was carried out in five cities in Guangxi, China from May 7 to June 1, 2021. Questionnaires on the acceptance of COVID-19 vaccination and the related factors were conducted among PLWH recruited by simple random sampling. Univariate and multivariate logistic regression analyses were performed to identify factors associated with acceptance of COVID-19 vaccination. RESULTS: Of all valid respondents (n = 903), 72.9% (n = 658) were willing to receive COVID-19 vaccination. Fear of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the main reason for being willing to receive vaccination (76.0%), while the main reasons for not willing were the concerns about vaccine safety (54.7%) and the vaccination's effect on antiretroviral therapy (ART) (50.6%). The most important factors influencing acceptance were the perception that vaccination is unsafe for HIV-infected people (aOR = 0.082, 95% CI = 0.024-0.282) and the poor efficacy in preventing SARS-CoV-2 infection in HIV-infected people (aOR = 0.093, 95% CI = 0.030-0.287). Other factors associated with acceptance included Zhuang ethnicity (aOR = 1.653, 95% CI = 1.109-2.465), highest education level of middle school, high school or above (aOR = 1.747, 95% CI = 1.170-2.608; aOR = 2.492, 95% CI = 1.326-4.682), and the vaccination having little effect on ART efficacy (aOR = 2.889, 95% CI = 1.378-6.059). CONCLUSIONS: Acceptance rate of the COVID-19 vaccination is relatively low among PLWH compared to the general population in China, although some patients refused vaccination due to concerns about vaccine safety and vaccination affecting ART efficacy. More research is needed to investigate the impact of the COVID-19 vaccines on ART efficacy and the effectiveness in preventing SARS-CoV-2 infection among PLWH.

The Role of Innate Immunity in Natural Elite Controllers of HIV-1 Infection.

The natural process of human immunodeficiency virus type 1(HIV-1) infection is characterized by high viral load, immune cell exhaustion, and immunodeficiency, which eventually leads to the stage of acquired immunodeficiency syndrome (AIDS) and opportunistic infections. Rapidly progressing HIV-1 individuals often die of AIDS several years after infection without treatment. The promotion of ART greatly prolongs the survival time of HIV-infected persons. However, some patients have incomplete immune function reconstruction after ART due to latent storage of HIV-infected cells. Therefore, how to achieve a functional cure has always been the focus and hot spot of global AIDS research. Fortunately, the emergence of ECs/LTNPs who can control virus replication naturally has ignited new hope for realizing a functional cure for AIDS. Recently, a special category of infected individuals has attracted attention that can delay the progression of the disease more rigorously than the natural progression of HIV-1 infection described above. These patients are characterized by years of HIV-1 infection, long-term asymptomatic status, and normal CD4+T cell count without ART, classified as HIV-infected long-term nonprogressors (LTNPs) and elite controllers (ECs). Numerous studies have shown that the host and virus jointly determine the progression of HIV-1 infection, in which the level of innate immunity activation plays an important role. As the first line of defense against pathogen invasion, innate immunity is also a bridge to induce adaptive immunity. Compared with natural progressors, innate immunity plays an antiviral role in HIV-1 infection by inducing or activating many innate immune-related factors in the natural ECs. Learning the regulation of ECs immunity, especially the innate immunity in different characteristics, and thus studying the mechanism of the control of disease progression naturally, will contribute to the realization of the functional cure of AIDS. Therefore, this review will explore the relationship between innate immunity and disease progression in ECs of HIV-1 infection from the aspects of innate immune cells, signaling pathways, cytokines, which is helpful to provide new targets and theoretical references for the functional cure, prevention and control of AIDS, and development of a vaccine.

Association Between CD4/CD8 Ratio Recovery and Chronic Kidney Disease Among Human Immunodeficiency Virus-Infected Patients Receiving Antiretroviral Therapy: A 17-Year Observational Cohort Study.

BACKGROUND: CD4/CD8 ratio is considered as an emerging biomarker for human immunodeficiency virus (HIV)-related diseases. However, the relationship of CD4/CD8 ratio recovery and chronic kidney disease (CKD), and whether cumulative antiretroviral therapy (ART) is effective in the CD4/CD8 ratio recovery and in reducing CKD incidence among HIV patients remain unclear. METHODS: A 17-year observational cohort study was conducted on all HIV-infected patients receiving ART in Guangxi, China. Kaplan-Meier analysis was used to investigate the cumulative CKD incidence. Cox regression and propensity score matching (PSM) were used to evaluate the association between CD4/CD8 ratio recovery and CKD incidence, and the effect of ART regimens on CD4/CD8 ratio recovery and CKD incidence. RESULTS: A total of 59,268 eligible individuals contributing 285,143 person-years of follow-up, with an overall CKD incidence of 9.65%. After ART, patients who developed CKD showed higher mortality than those with normal kidney function (12.48 vs. 7.57%, p < 0.001). Patients whose CD4/CD8 ratio did not recover to 0.7 had a higher CKD incidence than the patients who recovered (aHR = 2.84, 95% CI 2.63-3.07), similar to the PSM analysis (aHR = 3.13, 95% CI 2.85-3.45). Compared with the PI-based and INSTI-based regimens, NNRTI-based regimen had a better CD4/CD8 ratio recovery rate (27.04, 16.16, and 29.66%, respectively) and a lower CKD incidence (17.43, 16.16, and 7.31%, respectively). CONCLUSION: This large-scale real-world setting provide new evidence that the CD4/CD8 ratio recovery is associated with lower CKD incidence in HIV-infected patients receiving ART. NNRTI-based is a better choice for CD4/CD8 ratio recovery and reducing the risk of CKD.

Structure Based Affinity Maturation and Characterizing of SARS-CoV Antibody CR3022 against SARS-CoV-2 by Computational and Experimental Approaches.

The COVID-19 epidemic is raging around the world. Neutralizing antibodies are powerful tools for the prevention and treatment of SARS-CoV-2 infection. Antibody CR3022, a SARS-CoV neutralizing antibody, was found to cross-react with SARS-CoV-2, but its affinity was lower than that of its binding with SARS-CoV, which greatly limited the further development of CR3022 against SARS-CoV-2. Therefore, it is necessary to improve its affinity to SARS-CoV-2 in vitro. In this study, the structure-based molecular simulations were utilized to virtually mutate the possible key residues in the complementarity-determining regions (CDRs) of the CR3022 antibody. According to the criteria of mutation energy, the mutation sites that have the potential to impact the antibody affinity were then selected. Then optimized CR3022 mutants with the enhanced affinity were further identified and verified by enzyme-linked immunosorbent assay (ELISA), surface plasma resonance (SPR) and autoimmune reactivity experiments. Finally, molecular dynamics (MD) simulation and binding free energy calculation (MM/PBSA) were performed on the wild-type CR3022 and its two double-site mutants to understand in more detail the contribution of these sites to the higher affinity. It was found that the binding affinity of the CR3022 antibody could be significantly enhanced more than ten times after the introduction of the S103F/Y mutation in HCDR-3 and the S33R mutation in LCDR-1. The additional hydrogen-bonding, hydrophobic interactions, as well as salt-bridges formed between the modified double-site mutated antibody and SARS-CoV-2 RBD were identified. The computational and experimental results clearly demonstrated that the affinity of the modified antibody has been greatly enhanced. This study indicates that CR3022 as a neutralizing antibody recognizing the conserved region of RBD against SARS-CoV with cross-reactivity with SARS-CoV-2, a different member in a large family of coronaviruses, could be improved by the computational and experimental approaches which provided insights for developing antibody drugs against SARS-CoV-2.