Effects of heat waves and cold spells on blood parameters: a cohort study of blood donors in Tianjin, China.

BACKGROUND: With the increasing occurrence of extreme temperature events due to climate change, the attention has been predominantly focused on the effects of heat waves and cold spells on morbidity and mortality. However, the influence of these temperature extremes on blood parameters has been overlooked. METHODS: We conducted a cohort study involving 2,752 adult blood donors in Tianjin, China, between January 18, 2013, and June 25, 2021. The generalized additive mixed model was used to investigate the effects and lagged effects of heat waves and cold spells on six blood parameters of blood donors, including alanine aminotransferase (ALT), white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HB), hematocrit (HCT), and platelet count (PLT). Subgroup analyses were stratified by sex, age, and BMI. RESULTS: Heat waves and cold spells are associated with changes in blood parameters, particularly HB and PLT. Heat waves increased HB and PLT, while cold spells increased HB and decreased PLT. The effect of heat waves is greater than that of cold spells. The largest effect of heat waves on HB and PLT occurred at lag1 with 2.6 g/L (95% CI: 1.76 to 3.45) and lag7 with 9.71 × 10^9/L (95% CI: 6.26 to 13.17), respectively, while the largest effect of cold spells on HB and PLT occurred at lag0 with 1.02 g/L (95% CI: 0.71 to 1.33) and lag2 with -3.85 × 10^9/L (95% CI: -5.00 to -2.70), respectively. In subgroup analysis, the effect of cold spells on ALT was greater in the 40-49 age group. CONCLUSION: We indicated that heat waves and cold spells can impact hemoglobin and platelet counts in the human body. These findings provide evidence linking heat waves or cold spells to diseases and may reduce health risks caused by extreme temperature events.

Betulinic acid attenuates T-2 toxin-induced lung injury by activating Nrf2 signaling pathway and inhibiting MAPK/NF-κB signaling pathway.

T-2 toxin, a type-A trichothecene mycotoxin, exists ubiquitously in mildewed foods and feeds. Betulinic acid (BA), a pentacyclic triterpenoid derived from plants, has the effect of relieving inflammation and oxidative stress. The purpose of this study was to investigate whether BA mitigates lung impairment caused by T-2 toxin and elucidate the underlying mechanism. The results indicated that T-2 toxin triggered the inflammatory cell infiltration, morphological alterations and cell apoptosis in the lungs. It is gratifying that BA ameliorated T-2 toxin-caused lung injury. The protein expression of nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway and the markers of antioxidative capability were improved in T-2 toxin induced lung injury by BA mediated protection. Simultaneously, BA supplementation could suppress T-2 toxin-induced mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB)-dependent inflammatory response and mitochondrial apoptotic pathway. Therefore, T-2 toxin gave rise to pulmonary toxicity, but these changes were moderated by BA administration through regulation of the Nrf2/MAPK/NF-κB pathway, which maybe offer a viable alternative for mitigating the lung impairments caused by the mycotoxin.

Local membrane source gathering by p62 body drives autophagosome formation.

Autophagosomes are double-membrane vesicles generated intracellularly to encapsulate substrates for lysosomal degradation during autophagy. Phase separated p62 body plays pivotal roles during autophagosome formation, however, the underlying mechanisms are still not fully understood. Here we describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation. Mass spectrometry-based proteomics reveals significant enrichment of vesicle trafficking components within p62 body. Combining cellular experiments and biochemical reconstitution assays, we confirm the gathering of ATG9 and ATG16L1-positive vesicles around p62 body, especially in Atg2ab DKO cells with blocked lipid transfer and vesicle fusion. Interestingly, p62 body also regulates ATG9 and ATG16L vesicle trafficking flux intracellularly. We further determine the lipid contents associated with p62 body via lipidomic profiling. Moreover, with in vitro kinase assay, we uncover the functions of p62 body as a platform to assemble ULK1 complex and invigorate PI3KC3-C1 kinase cascade for PI3P generation. Collectively, our study raises a membrane-based working model for multifaceted p62 body in controlling autophagosome biogenesis, and highlights the interplay between membraneless condensates and membrane vesicles in regulating cellular functions.

Silicon Nitride Bioceramics Sintered by Microwave Exhibit Excellent Mechanical Properties, Cytocompatibility In Vitro, and Anti-Bacterial Properties.

Silicon nitride is a bioceramic with great potential, and multiple studies have demonstrated its biocompatibility and antibacterial properties. In this study, silicon nitride was prepared by a microwave sintering technique that was different from common production methods. SEM and pore distribution analysis revealed the microstructure of microwave-sintered silicon nitride with obvious pores. Mechanical performance analysis shows that microwave sintering can improve the mechanical properties of silicon nitride. The CCK-8 method was used to demonstrate that microwave-sintered silicon nitride has no cytotoxicity and good cytocompatibility. From SEM and CLSM observations, it was observed that there was good adhesion and cross-linking of cells during microwave-sintered silicon nitride, and the morphology of the cytoskeleton was good. Microwave-sintered silicon nitride has been proven to be non-cytotoxic. In addition, the antibacterial ability of microwave-sintered silicon nitride against Staphylococcus aureus and Escherichia coli was tested, proving that it has a good antibacterial ability similar to the silicon nitride prepared by commonly used processes. Compared with silicon nitride prepared by gas pressure sintering technology, microwave-sintered silicon nitride has excellent performance in mechanical properties, cell compatibility, and antibacterial properties. This indicates its enormous potential as a substitute material for manufacturing bone implants.

Association of chromosomal abnormalities with prenatal exposure to heavy metals: A nested case-control study in high-risk pregnant women in China.

Prenatal exposure to heavy metals causes multiple hazards to fetal growth and development. Epidemiological studies on the association between heavy metals and fetal chromosomal abnormalities (CAs) are lacking. We conducted a nested case-control study in a cohort of high-risk pregnant women in China from September 2018 to June 2021. A total of 387 participants were diagnosed with fetal CAs in the case group and 699 were diagnosed with a normal karyotype in the control group. Amniotic fluid concentrations of 10 metals (barium, cobalt, antimony, manganese, ferrum, copper, selenium, strontium, vanadium, and chromium) were measured using inductively coupled plasma-mass spectrometry. We applied quantile g-computation and weighted quantile sum regression to assess the overall effect of metal mixtures and identify metals with significant weight. Logistic and Poisson regression analyses were used to estimate the effects of metals on CAs and CAs subtypes. Our results showed that the metal mixture concentrations were positively associated with the risk of fetal CAs. In adjusted logistic models, Sb was associated with fetal CAs (OR=1.15, 95% CI: 1.02-1.30), and revealed a linear dose-response relationship between Sb level and the risk of fetal CAs. Additionally, the exploratory analysis revealed that Sb levels were associated with Klinefelter syndrome (OR=1.452, 95% CI: 1.063-1.984) and Turner syndrome (OR=1.698; 95% CI,1.048-2.751). Our study revealed that metal mixtures are associated with a higher risk of fetal CAs and that this association may be driven primarily by Sb. Moreover, we provide a genetic perspective on the effects of heavy metals on sexual development in humans.

Differential genome-wide associated variants and enriched pathways of ECG parameters among people with versus without HIV.

OBJECTIVES: People with HIV (PWH) are more likely to develop ECG abnormalities. Substantial evidence exists for genetic contribution to ECG parameters among general population. However, whether and how would host genome associate with ECG parameters among PWH is unclear. Our research aims to analyze and compare genetic variants, mapped genes, and enriched pathways of ECG parameters among PWH and HIV-negative controls. DESIGN: A cross-sectional study. METHOD: We performed a large original genome-wide association study (GWAS) of ECG parameters among PWH ( n  = 1730) and HIV-negative controls ( n =  3746). Genome-wide interaction analyses were also conducted. RESULTS: A total of 18 novel variants were detected among PWH, six for PR interval including rs76345397 at ATL2 , 11 for QRS duration including rs10483994 at KCNK10 and rs2478830 at JCAD , and one for QTc interval (rs9815364). Among HIV-negative controls, we identified variants located at previously reported ECG-related genes ( SCN5A , CNOT1 ). Genetic variants had a significant interaction with HIV infection ( P  < 5 × 10 -8 ), implying that HIV infection and host genome might jointly influence ECG parameters. Mapped genes for PR interval and QRS duration among PWH were enriched in the biological process of viral genome replication and host response to virus, respectively, whereas enriched pathways for PR interval among HIV-negative controls were in the cellular component of voltage-gated sodium channel complex. CONCLUSION: The present GWAS indicated a distinctive impact of host genome on quantitative ECG parameters among PWH. Different from HIV-negative controls, host genome might influence the cardiac electrical activity by interfering with HIV viral infection, production, and latency among PWH.

Perfluoroalkyl substances promote breast cancer progression via ERα and GPER mediated PI3K/Akt and MAPK/Erk signaling pathways.

Perfluoroalkyl substances (PFASs) are a classic environmental endocrine disruptor with carcinogenic risk. Epidemiological studies have shown that PFASs contamination is associated with breast cancer development, but the mechanism remains largely unknown. This study first obtained complex biological information about PFASs-induced breast cancer through the comparative toxicogenomics database (CTD). The Protein-Protein Interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis were utilized to investigate molecular pathways. The ESR1 and GPER expression levels at different pathological stages and the prognosis of Breast Cancer patients were confirmed using the Cancer Genome Atlas (TCGA) database. Furthermore, we verified this by cellular experiments and the results showed breast cancer cell migration and invasion were promoted by PFOA. Two estrogen receptors (ER), ERα and G protein-coupled estrogen receptor (GPER), mediated the promoting effects of PFOA by activating MAPK/Erk and PI3K/Akt signaling pathways. These pathways were regulated by ERα and GPER in MCF-7 cells or independently by GPER in MDA-MB-231 cells. Overall, our study provides a better overview of the mechanisms associated with PFASs-induced breast cancer development and progression.

Impacts of heatwaves and cold spells on glaucoma in rural China: a national cross-sectional study.

China faces increasing health risks from climate change. The structure and function of the eye and vision were affected by extreme heat and cold. The study aimed to evaluate the impacts of heatwaves and cold spells on glaucoma. A national cross-sectional study of the Rural Epidemiology for Glaucoma (REG-China) was conducted in ten provinces of China, and 36,081 adults aged 40 years or more were included. Glaucoma signs were assessed via a standard examination. A total of 15 heatwave definitions, based on intensity (95th to 99th percentiles of temperature distribution) and duration (≥2 days, 3 days, and 4 days), were used to quantify heatwave effects, and 6 cold spell definitions were defined based on threshold temperature percentile (5th and 10th) and duration (3 days, 5 days, and 9 days). Multivariable-adjusted logistic regression models paired with interaction analysis were performed to investigate the impacts of heatwaves and cold spells on glaucoma, and the dose-response relationships were assessed using a restricted cubic spline (RCS) model. Subgroup analysis was conducted stratified by gender, age, smoking status, occupation, and family history of glaucoma. The overall prevalence of glaucoma was 2.1% (95% CI 1.94-2.25%). Higher heatwaves were significantly correlated with higher OR of glaucoma, with the OR (95% CI) ranging from 1.014 (1.009, 1.018) to 1.090 (1.065, 1.115) by different definitions. Glaucoma was affected by heatwaves more strongly than by cold spells. The effects of both heatwaves and cold spells were higher in males than females and in smokers than nonsmokers. These results of the present study evoked the attention of prospective research to elucidate the relationship between extreme temperatures and eye diseases.

Joint effects of meteorological factors and PM2.5 on age-related macular degeneration: a national cross-sectional study in China.

BACKGROUND: Weather conditions are a possible contributing factor to age-related macular degeneration (AMD), a leading cause of irreversible loss of vision. The present study evaluated the joint effects of meteorological factors and fine particulate matter (PM2.5) on AMD. METHODS: Data was extracted from a national cross-sectional survey conducted across 10 provinces in rural China. A total of 36,081 participants aged 40 and older were recruited. AMD was diagnosed clinically by slit-lamp ophthalmoscopy, fundus photography, and spectral domain optical coherence tomography (OCT). Meteorological data were calculated by European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis and were matched to participants' home addresses by latitude and longitude. Participants' individual PM2.5 exposure concentrations were calculated by a satellite-based model at a 1-km resolution level. Multivariable-adjusted logistic regression models paired with interaction analysis were performed to investigate the joint effects of meteorological factors and PM2.5 on AMD. RESULTS: The prevalence of AMD in the study population was 2.6% (95% CI 2.42-2.76%). The average annual PM2.5 level during the study period was 63.1 ± 15.3 µg/m3. A significant positive association was detected between AMD and PM2.5 level, temperature (T), and relative humidity (RH), in both the independent and the combined effect models. For PM2.5, compared with the lowest quartile, the odds ratios (ORs) with 95% confidence intervals (CIs) across increasing quartiles were 0.828 (0.674,1.018), 1.105 (0.799,1.528), and 2.602 (1.516,4.468). Positive associations were observed between AMD and temperature, with ORs (95% CI) of 1.625 (1.059,2.494), 1.619 (1.026,2.553), and 3.276 (1.841,5.830), across increasing quartiles. In the interaction analysis, the estimated relative excess risk due to interaction (RERI) and the attributable proportion (AP) for combined atmospheric pressure and PM2.5 was 0.864 (0.586,1.141) and 1.180 (0.768,1.592), respectively, indicating a synergistic effect between PM2.5 and atmospheric pressure. CONCLUSIONS: This study is among the first to characterize the coordinated effects of meteorological factors and PM2.5 on AMD. The findings warrant further investigation to elucidate the relationship between ambient environment and AMD.

The association between physical frailty and injurious falls and all-cause mortality as negative health outcomes in people living with HIV: A systematic review and meta-analysis.

OBJECTIVES: Physical frailty is one of the major concerns among older people living with HIV (PLWH). This meta-analysis aimed to explore the association between physical frailty and negative health outcomes among PLWH. METHODS: We systematically searched six electronic databases including PubMed, Embase, Web of Science, the Cochrane Library, and Chinese databases up to April 10, 2022, for studies examining the association between physical frailty and risk of negative health outcomes among PLWH. Risk ratios (RRs), odds ratios, and hazard ratios with 95% CIs were extracted, and meta-analyses were conducted by using a fixed or random-effects model. RESULTS: In total, 10 studies incorporating 7755 HIV-seropositive patients (mean age 49.4 years) were included in the meta-analysis. Overall, five studies with 3434 participants reported the effect of physical frailty on falls. Results showed that physical frailty in HIV-seropositive individuals demonstrated a higher risk of future falls (pooled RR 3.74, 95% CI 1.42-9.86) compared with robust HIV-seropositive patients. In addition, a meta-analysis of five studies (4321 participants) reporting the frailty-mortality association showed that physical frailty was significantly associated with a higher risk of all-cause mortality (RR 1.70, 95% CI 1.32-2.19) among PLWH. CONCLUSION: Physical frailty is a significant risk factor for negative health outcomes in PLWH, including falls and all-cause mortality, underscoring the need for routine screening and early intervention of physical frailty among PLWH.

Breast adipose metabolites mediates the association of tetrabromobisphenol a with breast cancer: A case-control study in Chinese population.

Studies exploring the association of tetrabromobisphenol A (TBBPA) with breast cancer and related mechanisms are limited. To investigate the relationship between TBBPA levels in breast adipose and breast cancer, we carried out case-control research. As well as further examine the mediating role of adipose metabolites between TBBPA and breast cancer using the metabolomics approach. In this study, the concentration of TBBPA was determined utilizing ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) after a solid phase extraction (SPE) pretreatment. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was employed to analyze adipose metabolomics. Evaluation of metabolites linked to TBBPA exposure and breast cancer was performed utilizing mediation analysis. With an estimated OR (95%CI) of 1.153 (1.023, 1.299), TBBPA was firmly linked with breast cancer. We also used propensity score matching analysis and sensitivity analysis to reduce the effect of confounding factors on the results. Metabolomics of adipose suggested significant perturbation in the linoleic acid metabolism pathway. In addition, for PC (16:0/16:0) as phospholipids, a mediation effect on the associations of TBBPA exposure with breast cancer risks was observed (estimated mediation percentage: 56.58%). Understanding the relationship between TBBPA exposure and the risk of breast cancer may be facilitated by the findings, which point to potential mediation metabolites.

The Tandem of Liquid Chromatography and Network Pharmacology for the Chemical Profiling of Pule'an Tablets and the Prediction of Mechanism of Action in Treating Prostatitis.

Prostatitis, a prevalent urinary tract disorder in males, has a complex etiology that leads to severe clinical discomfort. Pule'an Tablets, a classic single-component formulation primarily based on rapeseed pollen, have been clinically proven to have a beneficial therapeutic effect on both prostatitis and benign prostatic hyperplasia. However, there is currently a lack of research on the chemical composition and mechanisms of action of Pule'an Tablets in treating prostatitis. In this study, using liquid chromatography-mass spectrometry (LC-MS), a total of 53 compounds in Pule'an Tablets were identified, including flavonoids, phenylpropionamides, lipids, glucosinolates, and nucleic acids. Subsequently, through a network pharmacology analysis, potential target genes and their mechanisms of action were predicted accordingly. The results suggested that genes such as LPAR5, LPAR6, LPAR4, LPAR3, LPAR2, LPAR1, F2, ENPP2, MMP9, and TNF, along with pathways like prostate cancer, endocrine resistance, bladder cancer, and the IL-17 signaling pathway, may represent potential pathways involved in the therapeutic effects of Pule'an Tablets. This study represents the first systematic investigation into the chemical composition of Pule'an Tablets, shedding light on the potential mechanisms underlying their efficacy in treating prostatitis. These findings could serve as a valuable reference for future pharmacological research on Pule'an Tablets.

Metal Exposure-Related Welder's Pneumoconiosis and Lung Function: A Cross-Sectional Study in a Container Factory of China.

Long-term inhalation of welding fume at high exposure can cause welder's pneumoconiosis, and metals in welding dust are associated with respiratory dysfunction. This cross-sectional study, which contains 384 Chinese male workers who were or had been working in a container factory, aimed to assess the potential risk of haemal and urinary metal content in welder's pneumoconiosis. Further, we investigated their effects on lung function parameters. Metal content and lung function were measured using inductively coupled plasma-mass spectrometry (ICP-MS) and spirometer, respectively. The concentration and metal content of respirable dust as well as total dust were collected at this container factory. Lung function of cases with welder's pneumoconiosis was significantly worse, as indicated by lower values of FVC, FVC% predicted, FEV1, FEV1% predicted, MEF25% predicted, and MMEF% predicted (p < 0.05). Results of logistic regression models showed that haemal Cr and Zn were risk factors of welder's pneumoconiosis (OR = 4.98, 95%CI: 1.73-21.20, p = 0.009 for Cr; OR = 5.23, 95%CI: 1.56-41.08, p = 0.033 for Zn) after adjusted with age, BMI, working years, welding dust exposure years, and smoking status. Multiple linear regression models showed that several metals (haemal Cd and Pb; urinary Cd and Fe) were significantly associated with different lung function indices in the welder's pneumoconiosis group. Compared to non-welders, welders were exposed to considerably higher levels of respirable dust, total dust, and six kinds of metals (p < 0.05). In conclusion, haemal Cr and Zn are positively related to welder's pneumoconiosis. Meanwhile, Cd and Pb might worsen lung function in welder's pneumoconiosis.

Genome-wide associated variants of subclinical atherosclerosis among young people with HIV and gene-environment interactions.

BACKGROUND: Genome-wide association studies (GWAS) have identified some variants associated with subclinical atherosclerosis (SCA) in general population but lacking sufficient validation. Besides traditional risk factors, whether and how would genetic variants associate with SCA among people with HIV (PWH) remains to be elucidated. METHOD: A large original GWAS and gene-environment interaction analysis of SCA were conducted among Chinese PWH (n = 2850) and age/sex-matched HIV-negative controls (n = 5410). Subgroup analyses by age and functional annotations of variants were also performed. RESULTS: Different from HIV-negative counterparts, host genome had a greater impact on young PWH rather than the elders: one genome-wide significant variant (rs77741796, P = 2.20 × 10-9) and eight suggestively significant variants (P < 1 × 10-6) were identified to be specifically associated with SCA among PWH younger than 45 years. Seven genomic loci and 15 genes were mapped to play a potential role on SCA among young PWH, which were enriched in the biological processes of atrial cardiac muscle cell membrane repolarization and molecular function of protein kinase A subunit binding. Furthermore, genome-wide interaction analyses revealed significant HIV-gene interactions overall as well as gene-environment interactions with alcohol consumption, tobacco use and obesity among PWH. The identified gene-environment interaction on SCA among PWH might be useful for discovering high-risk individuals for the prevention of SCA, particularly among those with tobacco use and alcohol consumption. CONCLUSION: The present study provides new clues for the genetic contribution of SCA among young PWH and is the starting point of precision intervention targeting HIV-related atherosclerosis.

Machine learning models including insulin resistance indexes for predicting liver stiffness in United States population: Data from NHANES.

Background: Prevention and treatment of liver fibrosis at an early stage is of great prognostic importance, whereas changes in liver stiffness are often overlooked in patients before the onset of obvious clinical symptoms. Recognition of liver fibrosis at an early stage is therefore essential. Objective: An XGBoost machine learning model was constructed to predict participants' liver stiffness measures (LSM) from general characteristic information, blood test metrics and insulin resistance-related indexes, and to compare the fit efficacy of different datasets for LSM. Methods: All data were obtained from the National Health and Nutrition Examination Survey (NHANES) for the time interval January 2017 to March 2020. Participants' general characteristics, Liver Ultrasound Transient Elastography (LUTE) information, indicators of blood tests and insulin resistance-related indexes were collected, including homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR). Three datasets were generated based on the above information, respectively named dataset A (without the insulin resistance-related indexes as predictor variables), dataset B (with METS-IR as a predictor variable) and dataset C (with HOMA-IR as a predictor variable). XGBoost regression was used in the three datasets to construct machine learning models to predict LSM in participants. A random split was used to divide all participants included in the study into training and validation cohorts in a 3:1 ratio, and models were developed in the training cohort and validated with the validation cohort. Results: A total of 3,564 participants were included in this study, 2,376 in the training cohort and 1,188 in the validation cohort, and all information was not statistically significantly different between the two cohorts (p > 0.05). In the training cohort, datasets A and B both had better predictive efficacy than dataset C for participants' LSM, with dataset B having the best fitting efficacy [±1.96 standard error (SD), (-1.49,1.48) kPa], which was similarly validated in the validation cohort [±1.96 SD, (-1.56,1.56) kPa]. Conclusions: XGBoost machine learning models built from general characteristic information and clinically accessible blood test indicators are practicable for predicting LSM in participants, and a dataset that included METS-IR as a predictor variable would improve the accuracy and stability of the models.

Detraque: Dynamic execution tracing techniques for automatic fault localization of hardware design code.

In an error-prone development process, the ability to localize faults is a crucial one. Generally speaking, detecting and repairing errant behavior at an early stage of the development cycle considerably reduces costs and development time. The debugging of the Verilog program takes much time to read the waveform and capture the signal, and in many cases, problem-solving relies heavily on experienced developers. Most existing Verilog fault localization methods utilize the static analysis method to find faults. However, using static analysis methods exclusively may result in some types of faults being inevitably ignored. The use of dynamic analysis could help resolve this issue. Accordingly, in this work, we propose a new fault localization approach for Verilog, named Detraque. After obtaining dynamic execution through test cases, Detraque traces these executions to localize faults; subsequently, it can determine the likelihood of any Verilog statement being faulty and sort the statements in descending order by suspicion score. Through conducting empirical research on real Verilog programs with 61 faulty versions, Detraque can achieve an EXAM score of 18.3%. Thus, Detraque is verified as able to improve Verilog fault localization effectiveness when used as a supplement to static analysis methods.

Expression, purification, characterization and direct electrochemistry of two HiPIPs from Acidithiobacillus caldus SM-1.

High-potential iron-sulfur proteins (HiPIPs) from extremely acidophilic chemolithotrophic non-photosynthetic Acidithiobacillus commonly play a crucial role in ferrous or sulfurous biooxidation. Acidithiobacillus exhibit important industrial applications for bioleaching valuable metals from sulfide ores. In this study, two HiPIP genes from thermophilic Acidithiobacillus caldus SM-1 were cloned and successfully expressed, and their proteins were purified. The proteins displayed a brownish color with an optical absorbance peak at approximately 385 nm and an electronic paramagnetic resonance (EPR) g value of approximately 2.01, which confirmed that the iron-sulfur cluster was correctly inserted into the active site when the proteins were generated in E. coli. The proteins were more thermostable than HiPIPs from mesophilic Acidithiobacillus. The direct electron transfer (DET) between HiPIPs and electrode was achieved by the 2-mercaptopyrimidine (MP) surface-modified gold electrodes; the redox potentials of the HiPIP1 and HiPIP2 measured by cyclic voltammetry were approximately 304.5 mV and 400.5 mV, respectively. The electron transfer rate constant was estimated to be 0.75 s-1 and 0.66 s-1, respectively. The MP/Au electrode and Au electrode showed consistent differences in heterogeneous electron transfer rates and electron transfer resistances. Bioinformatics and molecular simulations further explained the direct electron transfer between the proteins and surface-modified electrode.

Untargeted Plasma Metabolomics Reveals Extensive Metabolic Alterations Among Treatment-Naive Human Immunodeficiency Virus/Hepatitis C Virus Co-Infected Patients with Liver Disease Progression.

Both human immunodeficiency virus (HIV) and hepatitis C virus (HCV) may induce metabolic disorders and cause liver complications. Therefore, we aim to analyze the metabolite differences among treatment-naive HIV/HCV co-infected patients with versus without liver disease progression (LDP) and HIV mono-infected patients. A cross-sectional study was conducted in 65 HIV/HCV co-infected patients (22 with LDP and 43 without) and 65 HIV mono-infected patients in Dehong prefecture of Yunnan province, China. Plasma metabolomics were measured by gas chromatography-mass spectrometry (MS) and liquid chromatography-MS. Discrimination analysis, pathway enrichment analysis, generalized linear model with binomial distribution, and area under the receiver-operating characteristic curve (AUC) were conducted to identify bilateral differences in metabolites and pathways in different comparison groups. A total of 10,831 with 673 named and 10,158 unnamed metabolites were detected. Compared with HIV/HCV co-infected patients without LDP, phenylalanine, tyrosine, and tryptophan biosynthesis pathway with the increased level of tyrosine were significantly altered among HIV/HCV co-infected patients with LDP. Compared with HIV mono-infected patients, the decreased level of glutamine and increased levels of glutamic acid, arachidonic acid, and its derivatives were identified among HIV/HCV co-infected patients. Metabolite panels adjusted for baseline information had a higher accuracy than baseline model (without metabolite information) in distinguishing HIV/HCV co-infected patients with versus without LDP (AUC 0.951 vs. 0.849, p = .027) and HIV/HCV co-infected patients from HIV mono-infected patients (AUC 0.889 vs. 0.766, p < .001). A novel set of metabolites were found to discriminate HIV/HCV co-infected patients with versus without LDP, and from HIV mono-infected patients, which may have mechanistic and interventional implications.

Microbial translocation is associated with advanced liver fibrosis among people with HIV.

BACKGROUND: The prevalence of liver complications is increasing among people living with HIV, and microbial translocation (MT) might play a vital role. We conducted a prospective cohort study to evaluate the association between plasma biomarkers of MT and liver fibrosis (LF) among people living with HIV in southwest China. METHOD: A total of 665 people living with HIV were enrolled at baseline and had at least one follow-up visit during the 3-year study period. We calculated the Liver Fibrosis Index (FIB-4) to evaluate LF and measured plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) as surrogate biomarkers for MT. We used ordinal logistic regression to investigate correlates of LF at baseline and used a linear mixed model to examine the association between dynamic changes in MT biomarkers and LF. RESULTS: Of the participants, 61 (9.17%) had advanced LF (FIB-4 >3.25), and 193 (29.02%) had moderate LF (1.45 ≤ FIB-4 ≤ 3.25). Patients with advanced LF had higher plasma levels of sCD14 and LBP than those with moderate or no LF, both at baseline and at follow-up. The following factors were significantly associated with advanced LF: the highest quartile of LBP (adjusted odds ratio [aOR] = 1.69; 95% confidence interval [CI] 1.02~2.81), current intravenous drug use (aOR = 1.82; 95% CI 1.06~3.12), baseline CD4 <200 cells/µl (aOR = 3.25; 95% CI 2.13~4.95), hepatitis C virus coinfection (aOR = 2.52; 95% CI 1.41~4.51) and age >50 years (aOR = 32.66; 95% CI 15.89~66.36). LF progression (increasing FIB-4) was significantly associated with increasing sCD14 level (ß = 1.11; 95% CI 0.97~1.26; p < 0.001) with covariate adjustment. CONCLUSION: The significant relationship between MT and LF may reveal pathogenic mechanisms and potential intervention targets of liver complications among people living with HIV in China.

Health-care access and utilization among HIV-infected men who have sex with men in two Chinese municipalities with or without lockdown amidst early COVID-19 pandemic.

City lockdown is critical to successfully contain the COVID-19 pandemic. The impact of lockdown and COVID-19 pandemic on healthcare among vulnerable population has yet to be explicated. A cross-sectional survey was conducted among HIV-infected men who have sex with men (MSM) in Wuhan with city lockdown and Shanghai without lockdown, and healthcare interruptions were evaluated and compared. A logistic regression analysis was employed to examine associates of HIV-related healthcare interruptions and compromised mental health. Compared to participants in Shanghai (N = 440), HIV-infected MSM in Wuhan (N = 503) had significantly higher proportion of untimely availability of antiretroviral drugs (ARVs) (20.6% vs. 8.4%), obtaining ARVs from outside institutions (29.1% vs. 8.1%), postponed non-AIDS treatment (6.4% vs. 2.8%) and untimely follow-up appointments (33.4% vs. 14.5%). HIV-related healthcare interruptions were positively associated with lockdown (OR = 4.89, 95% CI: 3.49-6.85) and non-local residence (OR = 1.91, 95% CI: 1.37-2.64). Compromised mental health, including insomnia and generalized anxiety disorders, was associated with non-local residence (OR = 1.35, 95% CI: 1.01-1.81) and healthcare interruptions (OR = 1.34, 95% CI: 1.01-1.79). HIV-infected MSM are vulnerable to healthcare interruptions and mental health problems during the COVID-19 pandemic, underscoring the need for tailored intervention strategies to minimize deleterious health consequences.