HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy.

BACKGROUND: The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear. METHODS AND RESULTS: RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson's analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM. CONCLUSIONS: The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.

Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

S100A4 Is a Key Facilitator of Thoracic Aortic Dissection.

Background: Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Methods: Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to ß-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. Results: S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Conclusions: Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.

Transmitted drug resistance and transmission clusters among ART-naïve HIV-1-infected individuals from 2019 to 2021 in Nanjing, China.

Background: Transmitted drug resistance (TDR) is an increasingly prevalent problem worldwide, which will significantly compromise the effectiveness of HIV treatments. However, in Nanjing, China, there is still a dearth of research on the prevalence and transmission of TDR among ART-naïve HIV-1-infected individuals. This study aimed to understand the prevalence and transmission of TDR in Nanjing. Methods: A total of 1,393 participants who were newly diagnosed with HIV-1 and had not received ART between January 2019 and December 2021 were enrolled in this study. HIV-1 pol gene sequence was obtained by viral RNA extraction and nested PCR amplification. Genotypes, TDR and transmission cluster analyses were conducted using phylogenetic tree, Stanford HIV database algorithm and HIV-TRACE, respectively. Univariate and multivariate logistic regression analyses were performed to identify the factors associated with TDR. Results: A total of 1,161 sequences were successfully sequenced, of which CRF07_BC (40.6%), CRF01_AE (38.4%) and CRF105_0107 (6.3%) were the main HIV-1 genotypes. The overall prevalence of TDR was 7.8%, with 2.0% to PIs, 1.0% to NRTIs, and 4.8% to NNRTIs. No sequence showed double-class resistance. Multivariate logistic regression analysis revealed that compared with CRF01_AE, subtype B (OR = 2.869, 95%CI: 1.093-7.420) and female (OR = 2.359, 95%CI: 1.182-4.707) were risk factors for TDR. Q58E was the most prevalent detected protease inhibitor (PI) -associated mutation, and V179E was the most frequently detected non-nucleoside reverse transcriptase inhibitor (NNRTI) -associated mutation. A total of 613 (52.8%) sequences were segregated into 137 clusters, ranging from 2 to 74 sequences. Among 44 individuals with TDR (48.4%) within 21 clusters, K103N/KN was the most frequent TDR-associated mutation (31.8%), followed by Q58E/QE (20.5%) and G190A (15.9%). Individuals with the same TDR-associated mutations were usually cross-linked in transmission clusters. Moreover, we identified 9 clusters in which there was a transmission relationship between drug-resistant individuals, and 4 clusters in which drug-resistant cases increased during the study period. Conclusion: The overall prevalence of TDR in Nanjing was at a moderate level during the past 3 years. However, nearly half of TDR individuals were included in the transmission clusters, and some drug-resistant individuals have transmitted in the clusters. Therefore, HIV drug-resistance prevention, monitoring and response efforts should be sustained and expanded to reduce the prevalence and transmission of TDR in Nanjing.

TREM2 Insufficiency Protects against Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization.

Rationale Idiopathic pulmonary fibrosis (IPF) is a lung disease with high mortality, limited treatment options and an unknown aetiology. M2 macrophages play a critical role in the pathological process of IPF. Triggering receptor expressed on myeloid cells-2 (TREM2) participates in the regulation of macrophages, although its role in IPF remains elusive. METHODS: This study examined the role of TREM2 in macrophage regulation using a well-established bleomycin (BLM)-induced pulmonary fibrosis (PF) mouse model. TREM2 insufficiency was induced by intratracheal treatment with TREM2-specific siRNA. The effects of TREM2 on IPF were evaluated using histological staining and molecular biological methods. RESULTS: TREM2 expression levels were significantly elevated in the lungs of IPF patients and mice with BLM-induced pulmonary fibrosis mice. Bioinformatics analysis revealed that IPF patients with higher TREM2 expression had a shorter survival time, and that TREM2 expression was closely associated with fibroblasts and M2 macrophages. Gene Ontology (GO) enrichment analysis showed that found TREM2-related differentially expressed genes (DEGs) were associated with inflammatory responses, extracellular matrix (ECM) and collagen formation. Single-cell RNA sequencing analysis revealed that TREM2 was predominantly expressed in macrophages. TREM2 insufficiency inhibited BLM-induced pulmonary fibrosis and M2 macrophage polarization. Mechanistic studies showed that TREM2 insufficiency suppressed the activation of STAT6 and the expression of fibrotic factors such as Fibronectin (Fib), Collagen I (Col I) and α- smooth muscle actin (α-SMA). CONCLUSION: Our study showed that TREM2 insufficiency might alleviate pulmonary fibrosis possibly through macrophage polarization regulation via STAT6 activation, providing a promising macrophage-related approach for the clinical therapy of pulmonary fibrosis.

Carnosol Inhibits the Proliferation, Migration, and Invasion of Hepatocellular Carcinoma Cells in vitro by Regulating the AMPK Signaling Pathway.

Background: Hepatocellular carcinoma (HCC) is one of the most malignant cancers in the world, and its 5- year survival rate is low. At present, for advanced primary liver cancer, the clinical treatment often adopts the systemic method, but there is no effective targeted treatment. The average survival time of patients with liver cancer after drug treatment is only 3-5 months. Therefore, it is of great clinical significance to find new and effective drugs for the treatment of HCC. Carnosol (CA) is a bioactive diterpene compound present in Lamiaceae spp., which has been demonstrated to have antioxidant, anti-inflammatory, and anticancer properties. Aim: In this study, we aimed to reveal the effect of carnosol on HCC and provide new possibilities for the drug therapy of HCC. Obejective: The objective of this study is to observe the effect of carnosol on the tumor phenotype and signaling pathway of HCC cells. Methods: We treated two different human HCC cells, HepG2 and Huh7, with carnosol. The cells were analyzed using the CCK-8 assay for viability and proliferation. The cell migration and invasion were detected by Transwell assay. The molecular markers of cell proliferation, apoptosis, migration, invasion, and signaling pathways were detected by RTPCR and WB. In addition, we performed rescue experiments with inhibitors to verify the affected signaling pathway. Results: The results showed that carnosol could significantly inhibit HCC cell viability, effort, colony formation, migration, and invasion. Moreover, Carnosol promoted the apoptosis of HCC cells. Mechanically, carnosol activated the AMPK-p53 pathway. Conclusion: To conclude, our study demonstrated that carnosol could inhibit proliferation, migration, invasion, and promote apoptosis via activating AMPK-p53 in HCC cells.

SAA1 deficiency alleviates cardiac remodeling by inhibiting NF-κB/p38/JNK and TGFß/Smad pathways.

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid-binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1-deficient (SAA1-/- ), and wild-type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1-/- mice displayed a lower level of cardiac fibrosis than wild-type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild-type-sham and knockout-sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.

SWAP70 Overexpression Protects Against Pathological Cardiac Hypertrophy in a TAK1-Dependent Manner.

Background Pathological cardiac hypertrophy is regarded as a critical precursor and independent risk factor of heart failure, and its inhibition prevents the progression of heart failure. Switch-associated protein 70 (SWAP70) is confirmed important in immunoregulation, cell maturation, and cell transformation. However, its role in pathological cardiac hypertrophy remains unclear. Methods and Results The effects of SWAP70 on pathological cardiac hypertrophy were investigated in Swap70 knockout mice and Swap70 overexpression/knockdown cardiomyocytes. Bioinformatic analysis combined with multiple molecular biological methodologies were adopted to elucidate the mechanisms underlying the effects of SWAP70 on pathological cardiac hypertrophy. Results showed that SWAP70 protein levels were significantly increased in failing human heart tissues, experimental transverse aortic constriction-induced mouse hypertrophic hearts, and phenylephrine-stimulated isolated primary cardiomyocytes. Intriguingly, phenylephrine treatment decreased the lysosomal degradation of SWAP70 by disrupting the interaction of SWAP70 with granulin precursor. In vitro and in vivo experiments revealed that Swap70 knockdown/knockout accelerated the progression of pathological cardiac hypertrophy, while Swap70 overexpression restrained the cardiomyocyte hypertrophy. SWAP70 restrained the binding of transforming growth factor ß-activated kinase 1 (TAK1) and TAK1 binding protein 1, thus blocking the phosphorylation of TAK1 and downstream c-Jun N-terminal kinase/P38 signaling. TAK1 interacted with the N-terminals (1-192) of SWAP70. Swap70 (193-585) overexpression failed to inhibit cardiac hypertrophy when the TAK1-SWAP70 interaction was disrupted. Either inhibiting the phosphorylation or suppressing the expression of TAK1 rescued the exaggerated cardiac hypertrophy induced by Swap70 knockdown. Conclusions SWAP70 suppressed the progression of cardiac hypertrophy, possibly by inhibiting the mitogen-activated protein kinases signaling pathway in a TAK1-dependent manner, and lysosomes are involved in the regulation of SWAP70 expression level.

TBC1D25 alleviates nonalcoholic steatohepatitis by inhibiting abnormal lipid accumulation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is a strong stimulant of cardiovascular diseases, affecting one-quarter of the world's population. TBC1 domain family member 25 (TBC1D25) regulates the development of myocardial hypertrophy and cerebral ischemia-reperfusion injury; however, its effect on NAFLD/nonalcoholic steatohepatitis (NASH) has not been reported. In this study, we demonstrated that TBC1D25 expression is upregulated in NASH. TBC1D25 deficiency aggravated hepatic steatosis, inflammation, and fibrosis in NASH. In vitro tests revealed that TBC1D25 overexpression restrained NASH responses. Subsequent mechanistic validation experiments demonstrated that TBC1D25 interfered with NASH progression by inhibiting abnormal lipid accumulation and inflammation. TBC1D25 deficiency significantly promoted NASH occurrence and development. Therefore, TBC1D25 may potentially be used as a clinical therapeutic target for NASH treatment.

Multi-scale analysis of nickel ion tolerance mechanism for thermophilic Sulfobacillus thermosulfidooxidans in bioleaching.

Bioleaching is intensively investigated for recovering valuable metals such as Li, Co, Ni and Cu. Nickel ion stress threatens the health of microorganisms when Ni2+ starts to accumulate in the leachate during the bioleaching of materials that are rich in Ni, such as spent lithium-ion batteries. The possible mechanisms underlying the response of S. thermosulfidooxidans to nickel ion stress were analyzed using a multi-scale approach. Under the condition of nickel ion stress, high concentrations of nickel ions were immobilized by extracellular polymeric substances, while concentrations of nickel ions inside the cells remained low. The intracellular adenosine triphosphate (ATP) concentration and H+-ATPase activity increased to maintain normal cell growth and metabolic activities. Scavenging abilities of S. thermosulfidooxidans for hydrogen peroxide and superoxide anion were enhanced to reduce oxidative damage induced by nickel ion stress. There were 734 differentially expressed genes identified by RNA-seq under nickel ion stress. Most of them were involved in oxidative phosphorylation, glutathione metabolism and genetic information processing, responsible for intracellular energy utilization, intracellular antioxidant capacity and DNA damage repair, respectively. The results of this study are of major significance for in-depth understanding of the mechanisms of acidophilic microorganisms' resistance to metal ions.

Advances in bioleaching of waste lithium batteries under metal ion stress.

In modern societies, the accumulation of vast amounts of waste Li-ion batteries (WLIBs) is a grave concern. Bioleaching has great potential for the economic recovery of valuable metals from various electronic wastes. It has been successfully applied in mining on commercial scales. Bioleaching of WLIBs can not only recover valuable metals but also prevent environmental pollution. Many acidophilic microorganisms (APM) have been used in bioleaching of natural ores and urban mines. However, the activities of the growth and metabolism of APM are seriously inhibited by the high concentrations of heavy metal ions released by the bio-solubilization process, which slows down bioleaching over time. Only when the response mechanism of APM to harsh conditions is well understood, effective strategies to address this critical operational hurdle can be obtained. In this review, a multi-scale approach is used to summarize studies on the characteristics of bioleaching processes under metal ion stress. The response mechanisms of bacteria, including the mRNA expression levels of intracellular genes related to heavy metal ion resistance, are also reviewed. Alleviation of metal ion stress via addition of chemicals, such as spermine and glutathione is discussed. Monitoring using electrochemical characteristics of APM biofilms under metal ion stress is explored. In conclusion, effective engineering strategies can be proposed based on a deep understanding of the response mechanisms of APM to metal ion stress, which have been used to improve bioleaching efficiency effectively in lab tests. It is very important to engineer new bioleaching strains with high resistance to metal ions using gene editing and synthetic biotechnology in the near future.

Survival and risk factors associated with mortality in people living with HIV from 2005 to 2018 in Nanjing, China.

Background: Although the introduction of antiretroviral therapy (ART) decreased the mortality of people living with Human Immunodeficiency Virus (PLHIV), substantially, hundreds of thousands of people are dying of AIDS each year. The accurate survival patterns and factors related to death among PLHIV were rarely reported. In this study, we evaluated survival status and identified factors associated with death among PLHIV in Nanjing. Methods: We conducted a retrospective analysis of PLHIV followed-up in Nanjing and registered to the national HIV/AIDS comprehensive management information system from 2005 to 2018. We used the life table to calculate the cumulative survival rates. We applied the Kaplan-Meier to calculate median survival times and employed cox hazard proportional regression to analyze the associated factors related to death. Results: The median survival time of PLHIV was 11.8 (95%CI:11.6-11.9) years from 2005 to 2018. Among 4,235 PLHIV included in this study, 7.5% had died of AIDS-related disease and the AIDS-related mortality rate was 2.0/100 PYs. The cumulative proportion surviving at the end of the interval was 95.2% over the 1st year, 94.0% over the 2nd year, 91.8% over the 5th year, and 85.4% over the 10th year, respectively. PLHIV who unaccepted ART showed a greater risk of death compared to those who accepted ART (AHR = 16.2, 95%CI:11.9~22.2). For baseline CD4 count, compared to CD4 < 200 cell/µL, higher CD4 count was demonstrated as a protective factor, with AHR = 0.2 (95%CI: 0.1~0.3) for ≥500 cell/µL, AHR = 0.3 (95%CI:0.2~0.4) for 350~499 cell/µL, AHR = 0.4 (95%CI:0.3~0.6 for 200~349 cell/µL). In addition, we observed a higher death risk in PLHIV who were screened through outpatient (AHR = 1.6, 95%CI: 1.1~2.2) and inpatient (AHR = 1.6, 95%CI: 1.1~2.5) compared to through VCT; the age of diagnosis was ≥50 years old (AHR = 9.5, 95%CI: 3.7~24.1) and 25~49 years old (AHR = 5.0, 95%CI: 2.0~12.3) compared to ≤ 24 years old; educated from junior and below (AHR = 3.4, 95%CI: 2.3~5.1) and Senior high school (AHR = 1.7, 95%CI: 1.1~2.7) compared to college and above. Conclusion: The AIDS-related mortality among PLHIV in Nanjing was relatively low. A higher risk for AIDS-related deaths were observed among PLHIV who unaccepted ART, whose baseline CD4 cell count was<200 cell/µL, older age, and lower educated.

Non-invasive diagnosis and surveillance of bladder cancer with driver and passenger DNA methylation in a prospective cohort study.

BACKGROUND: State-of-art non-invasive diagnosis processes for bladder cancer (BLCA) harbour shortcomings such as low sensitivity and specificity, unable to distinguish between high- (HG) and low-grade (LG) tumours, as well as inability to differentiate muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). This study investigates a comprehensive characterization of the entire DNA methylation (DNAm) landscape of BLCA to determine the relevant biomarkers for the non-invasive diagnosis of BLCA. METHODS: A total of 304 samples from 224 donors were enrolled in this multi-centre, prospective cohort study. BLCA-specific DNAm signature discovery was carried out with genome-wide bisulfite sequencing in 32 tumour tissues and 12 normal urine samples. A targeted sequencing assay for BLCA-specific DNAm signatures was developed to categorize tumour tissue against normal urine, or MIBC against NMIBC. Independent validation was performed with targeted sequencing of 259 urine samples in a double-blinded manner to determine the clinical diagnosis and prognosis value of DNAm-based classification models. Functions of genomic region harbouring BLCA-specific DNAm signature were validated with biological assays. Concordances of pathology to urine tumour DNA (circulating tumour DNA [ctDNA]) methylation, genomic mutations or other state-of-the-art diagnosis methods were measured. RESULTS: Genome-wide DNAm profile could accurately classify LG tumour from HG tumour (LG NMIBC vs. HG NMIBC: p = .038; LG NMIBC vs. HG MIBC, p = .00032; HG NMIBC vs. HG MIBC: p = .82; Student's t-test). Overall, the DNAm profile distinguishes MIBC from NMIBC and normal urine. Targeted-sequencing-based DNAm signature classifiers accurately classify LG NMIBC tissues from HG MIBC and could detect tumours in urine at a limit of detection of less than .5%. In tumour tissues, DNAm accurately classifies pathology, thus outperforming genomic mutation or RNA expression profiles. In the independent validation cohort, pre-surgery urine ctDNA methylation outperforms fluorescence in situ hybridization (FISH) assay to detect HG BLCA (n = 54) with 100% sensitivity (95% CI: 82.5%-100%) and LG BLCA (n = 26) with 62% sensitivity (95% CI: 51.3%-72.7%), both at 100% specificity (non-BLCA: n = 72; 95% CI: 84.1%-100%). Pre-surgery urine ctDNA methylation signature correlates with pathology and predicts recurrence and metastasis. Post-surgery urine ctDNA methylation (n = 61) accurately predicts recurrence-free survival within 180 days, with 100% accuracy. CONCLUSION: With the discovery of BLCA-specific DNAm signatures, targeted sequencing of ctDNA methylation outperforms FISH and DNA mutation to detect tumours, predict recurrence and make prognoses.

Strategies for anti-oxidative stress and anti-acid stress in bioleaching of LiCoO2 using an acidophilic microbial consortium.

High metal ion concentrations and low pH cause severely inhibit the activity of an acidophilic microbial consortium (AMC) in bioleaching. This work investigated the effects of exogenous spermine on biofilm formation and the bioleaching efficiency of LiCoO2 by AMC in 9K medium. After the addition of 1 mM spermine, the activities of glutathione peroxidase and catalase increased, while the amount of H2O2, intracellular reactive oxygen species (ROS) and malondialdehyde in AMC decreased. These results indicated that the ability of AMC biofilm to resist oxidative stress introduced by 3.5 g/L Li+ and 30.1 g/L Co2+ was improved by spermine. The activity of glutamate decarboxylase was promoted to restore the intracellular pH buffering ability of AMC. Electrochemical measurements showed that the oxidation rate of pyrite was increased by exogenous spermine. As a result, high bioleaching efficiencies of 97.1% for Li+ and 96.1% for Co2+ from a 5.0% (w v-1) lithium cobalt oxide powder slurry were achieved. This work demonstrated that Tafel polarization can be used to monitor the AMC biofilm's ability of uptaking electrons from pyrite during bioleaching. The corrosion current density increased with 1 mM spermine, indicating enhanced electron uptake by the biofilm from pyrite.

Trends in HIV Prevalence and HIV-Related Risk Behaviors Among Male Students Who Have Sex With Men From 2016 to 2020 in Nanjing, China: Consecutive Cross-Sectional Surveys.

Background: The growing HIV epidemic among student men who have sex with men (MSM) necessitates immediate attention from public health. In China, male students who have sex with men (SMSM) were also at an increasing risk of HIV transmission. The aim of this study was to investigate the trends in HIV prevalence, HIV-related risk behaviors, and HIV testing, as well as analyze the factors associated with HIV infection among SMSM in Nanjing. Methods: Data were collected through face-to-face questionnaire interviews and laboratory testing in Nanjing. The participants were recruited among SMSM by snowball sampling and internet-recruited convenience sampling annually from 2016 to 2020. The self-report data primarily included demographics, HIV knowledge, HIV-related behaviors, and HIV testing, while the laboratory test results of HIV and syphilis were collected. Linear-by-linear chi-square test was used to analyze the trends of HIV/syphilis prevalence and its risk behaviors. The binary logistic regression model was used to explore the factors associated with HIV infection. Results: During the 5 years from 2016 to 2020, a total of 775 SMSM were recruited in our survey (220, 112, 171, 142, and 120, respectively). The HIV prevalence was 5.2, 6.3, 5.3, 7.0, and 8.3%, without a significant increasing trend (P = 0.277). Syphilis prevalence fluctuated from 5.7% in 2016 to 4.2% in 2020, without a significant decreasing trend (P = 0.318). The proportion of consistent condom use in anal intercourse (48.5 to 56.2%, P < 0.05), and HIV testing in the past 12 months (51.0 to 59.2%, P < 0.05) were increasing. A remarkable growing trend has been reported in the percentage of MSM with more than one male sex partner (46.2 to 59.2%, P < 0.05). Multivariate analysis showed that HIV testing in the past 12 months was a protective factor against HIV infection. MSM who had unprotected anal intercourse (UAI) in the past 6 months, recreational drug use, and currently syphilis infection were risk factors for HIV infection. Conclusions: We observed stable HIV/ syphilis prevalence, increasing consistent condom use, increasing HIV testing rate, and increasing multiple male sex partners dramatically among SMSM in China. The original comprehensive intervention measures should be continuously strengthened for the subgroup. To satisfy the current HIV prevention requirements, new biological interventions should be introduced and carried out as major components of combination prevention programs.

The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac Hypertrophy.

BACKGROUND: Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif-containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidativestress. However, the role of Trim16 in cardiac hypertrophy is unknown. METHODS: We generated cardiac-specific knockout mice and adeno-associated virus serotype 9-Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function. RESULTS: We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomic analyses clearly demonstrated that Trim16 deficiency markedly exacerbated cardiomyocyte enlargement in vitro and in transverse aortic constriction-induced cardiac hypertrophy mouse model, whereas Trim16 overexpression attenuated cardiac hypertrophy and remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) is an essential target of Trim16 in cardiac hypertrophy. We found that Trim16 interacts with Prdx1 and inhibits its phosphorylation, leading to a robust enhancement of its downstream Nrf2 (nuclear factor-erythroid 2-related factor 2) pathway to block cardiac hypertrophy. Trim16-blocked Prdx1 phosphorylation was largely dependent on a direct interaction between Trim16 and Src and the resultant Src ubiquitinational degradation. Notably, Prdx1 knockdown largely abolished the anti-hypertrophic effects of Trim16 overexpression. CONCLUSIONS: Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.

Switch-associated protein 70 protects against nonalcoholic fatty liver disease through suppression of TAK1.

BACKGROUND AND AIMS: NAFLD is a progressive disease without known effective drug treatments. Switch-associated protein 70 (SWAP70) is a guanine nucleotide exchange factor that participates in the regulation of many cellular processes. However, the role of SWAP70 in NAFLD remains unclear. This study aimed to identify the function and mechanism of SWAP70 in NAFLD. APPROACH AND RESULTS: The results showed that the expression of SWAP70 was significantly increased in mice and hepatocytes after metabolic stimulation. Overexpression of SWAP70 in hepatocytes suppressed lipid deposition and inflammation, and SWAP70 knockdown created the inverse effect. Using hepatocyte-specific Swap70 knockout and overexpression mice fed a high-fat, high-cholesterol diet, we demonstrated that SWAP70 suppressed the progression of nonalcoholic steatohepatitis by inhibiting lipid accumulation, inflammatory response, and fibrosis. Mechanically, RNA sequencing analysis and immunoprecipitation assays revealed that SWAP70 inhibited the interaction between transforming growth factor ß-activated kinase 1 (TAK1) binding protein 1 and TAK1 and sequentially suppressed the phosphorylation of TAK1 and subsequent c-Jun N-terminal kinase/P38 signaling. Inhibition of TAK1 activation blocked hepatocyte lipid deposition and inflammation caused by SWAP70 knockdown. CONCLUSIONS: SWAP70 is a protective molecule that can suppress the progression of NAFLD by inhibiting hepatic steatosis and inflammation. SWAP70 may be important for mitigating the progression of NAFLD.

Effects of cadmium sulfide nanoparticles on sulfate bioreduction and oxidative stress in Desulfovibrio desulfuricans.

Sulfate-containing wastewater has a serious threat to the environment and human health. Microbial technology has great potential for the treatment of sulfate-containing wastewater. It was found that nano-photocatalysts could be used as extracellular electron donors to promote the growth and metabolic activity of non-photosynthetic microorganisms. However, nano-photocatalysts could also induce oxidative stress and damage cells. Therefore, the interaction mechanism between photosynthetic nanocatalysts and non-photosynthetic microorganisms is crucial to determine the regulatory strategies for microbial wastewater treatment technologies. In this paper, the mechanism and regulation strategy of cadmium sulfide nanoparticles (CdS NPs) on the growth of sulfate-reducing bacteria and the sulfate reduction process were investigated. The results showed that the sulfate reduction efficiency could be increased by 6.4% through CdS NPs under light conditions. However, the growth of Desulfovibrio desulfuricans C09 was seriously inhibited by 55% due to the oxidative stress induced by CdS NPs on cells. The biomass and sulfate reduction efficiency could be enhanced by 6.8% and 5.9%, respectively, through external addition of humic acid (HA). At the same time, the mechanism of the CdS NPs strengthening the sulfate reduction process by sulfate bacteria was also studied which can provide important theoretical guidance and technical support for the development of microbial technology combined with extracellular electron transfer (EET) for the treatment of sulfate-containing wastewater.

Tumor stemness and immune infiltration synergistically predict response of radiotherapy or immunotherapy and relapse in lung adenocarcinoma.

Cancer stem cells (CSCs) have been shown to accelerate tumor recurrence, radiotherapy, and chemotherapy resistance. Immunotherapy is a powerful anticancer treatment that can significantly prolong the overall survival of patients with lung adenocarcinoma (LUAD). However, little is known about the function of genes related to tumor stemness and immune infiltration in LUAD. After integrating the tumor stemness index based on mRNA expression (mRNAsi), immune score, mRNA expression, and clinical information from the TCGA database, we screened 380 tumor stemness and immune (TSI)-related genes and constructed a five TSI-specific-gene (CPS1, CCR2, NT5E, ANLN, and ABCC2) signature (TSISig) using a machine learning method. Survival analysis indicated that TSISig could stably predict the prognosis of patients with LUAD. Comparison of mRNAsi and immune score between high- and low-TSISig groups suggested that TSISig characterized tumor stemness and immune infiltration. In addition, enrichment of immune subpopulations showed that the low-TSISig group held more immune subpopulations. GSEA revealed that TSISig had a strong association with the cell cycle and human immune response. Further analysis revealed that TSISig not only had a good predictive ability for prognosis but could also serve as an excellent predictor of tumor recurrence and response to radiotherapy and immunotherapy in LUAD patients. TSISig might regulate the development of LUAD by coordinating tumor stemness and immune infiltration. Finally, a connectivity map (CMap) analysis demonstrated that the HDAC inhibitor could target TSISig.

Salidroside Activates the AMP-Activated Protein Kinase Pathway to Suppress Nonalcoholic Steatohepatitis in Mice.

BACKGROUND AND AIMS: NASH is becoming a leading cause of liver cirrhosis and HCC. Salidroside (p-hydroxyphenethyl-ß-D-glucoside; SAL) has various biological and pharmacological activities, including anti-inflammatory, -oxidant, and -cancer activities. However, the therapeutic effect and underlying molecular mechanism of SAL in NASH remain to be further clarified. METHODS AND RESULTS: In this study, we found that SAL alleviated lipid accumulation and inflammatory response in primary hepatocytes after palmitic acid/oleic acid (PO) stimulation. In addition, SAL effectively prevented high-fat/high-cholesterol (HFHC)-diet-induced NASH progression by regulating glucose metabolism dysregulation, insulin resistance, lipid accumulation, inflammation, and fibrosis. Mechanistically, integrated RNA-sequencing and bioinformatic analysis showed that SAL promoted AMPK-signaling pathway activation in vitro and in vivo, and this finding was further verified by determining the phosphorylation levels of AMPK. Furthermore, the protective effects of SAL on lipid accumulation and inflammation in hepatocytes and livers induced by PO or HFHC stimulation were blocked by AMPK interruption. CONCLUSIONS: Our studies demonstrate that SAL protects against metabolic-stress-induced NASH progression through activation of AMPK signaling, indicating that SAL could be a potential drug component for NASH therapy.