THOC7-AS1/OCT1/FSTL1 axis promotes EMT and serves as a therapeutic target in cutaneous squamous cell carcinoma.

BACKGROUND: THOC7-AS1 and FSTL1 expression are frequently upregulated in cutaneous squamous cell carcinoma (cSCC). However, their molecular biological mechanisms remain elusive and their potential as therapeutic targets needs urgent exploration. METHODS: Human tissue samples were used to evaluate clinical parameters. In vitro and in vivo experiments assessed biological functions. Quantitative PCR, western blot, immunohistochemistry, immunocytochemistry, immunoprecipitation, RNA fluorescence in situ hybridization, RNA pull-down, RNA immunoprecipitation, silver staining, chromatin immunoprecipitation, dual luciferase reporter assays etc. were utilized to explore the molecular biological mechanisms. RESULTS: We found FSTL1 is an oncogene in cSCC, with high expression in tumor tissues and cells. Its elevated expression closely associates with tumor size and local tissue infiltration. In vitro and in vivo, high FSTL1 expression promotes cSCC proliferation, migration and invasion, facilitating malignant behaviors. Mechanistically, FSTL1 interacts with ZEB1 to promote epithelial-to-mesenchymal transition (EMT) in cSCC cells. Exploring upstream regulation, we found THOC7-AS1 can interact with OCT1, which binds the FSTL1 promoter region and promotes FSTL1 expression, facilitating cSCC progression. Finally, treating tumors with THOC7-AS1 antisense oligonucleotides inhibited cSCC proliferative and migratory abilities, delaying tumor progression. CONCLUSIONS: The THOC7-AS1/OCT1/FSTL1 axis regulates EMT and promotes tumor progression in cSCC. This study provides clues and ideas for cSCC targeted therapy.

Predictive models of recurrent implantation failure in patients receiving ART treatment based on clinical features and routine laboratory data.

STUDY QUESTION: The objective was to construct a model for predicting the probability of recurrent implantation failure (RIF) after assisted reproductive technology (ART) treatment based on the clinical characteristics and routine laboratory test data of infertile patients. A model was developed to predict RIF. The model showed high calibration in external validation, helped to identify risk factors for RIF, and improved the efficacy of ART therapy. WHAT IS KNOWN ALREADY: Research on the influencing factors of RIF has focused mainly on embryonic factors, endometrial receptivity, and immune factors. However, there are many kinds of examinations regarding these aspects, and comprehensive screening is difficult because of the limited time and economic conditions. Therefore, we should try our best to analyse the results of routine infertility screenings to make general predictions regarding the occurrence of RIF. STUDY DESIGN, SIZE, DURATION: A retrospective study was conducted with 5212 patients at the Reproductive Center of the First Affiliated Hospital of USTC from January 2018 to June 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included 462 patients in the RIF group and 4750 patients in the control group. The patients' basic characteristics, clinical treatment data, and laboratory test indices were compared. Logistic regression was used to analyse RIF-related risk factors, and the prediction model was evaluated by receiver operating characteristic (ROC) curves and the corresponding areas under the curve (AUCs). Further analysis of the influencing factors of live births in the first cycle of subsequent assisted reproduction treatment in RIF patients was performed, including the live birth subgroup (n = 116) and the no live birth subgroup (n = 200). MAIN RESULTS AND THE ROLE OF CHANCE: (1) An increased duration of infertility (1.978; 95% CI, 1.264-3.097), uterine cavity abnormalities (2.267; 95% CI, 1.185-4.336), low AMH levels (0.504; 95% CI, 0.275-0.922), insulin resistance (3.548; 95% CI, 1.931-6.519), antinuclear antibody (ANA)-positive status (3.249; 95% CI, 1.20-8.797) and anti-ß2-glycoprotein I antibody (A-ß2-GPI Ab)-positive status (5.515; 95% CI, 1.481-20.536) were associated with an increased risk of RIF. The area under the curve of the logistic regression model was 0.900 (95% CI, 0.870-0.929) for the training cohort and 0.895 (95% CI, 0.865-0.925) for the testing cohort. (2) Advanced age (1.069; 95% CI, 1.015-1.126) was a risk factor associated with no live births after the first cycle of subsequent assisted reproduction treatment in patients with RIF. Blastocyst transfer (0.365; 95% CI = 0.181-0.736) increased the probability of live birth in subsequent cycles in patients with RIF. The area under the curve of the logistic regression model was 0.673 (95% CI, 0.597-0.748). LIMITATIONS, REASONS FOR CAUTION: This was a single-centre regression study, for which the results need to be evaluated and verified by prospective large-scale randomized controlled studies. The small sample size for the analysis of factors influencing pregnancy outcomes in subsequent assisted reproduction cycles for RIF patients resulted in the inclusion of fewer covariates, and future studies with larger samples and the inclusion of more factors are needed for assessment and validation. WIDER IMPLICATIONS OF THE FINDINGS: Prediction of embryo implantation prior to transfer will facilitate the clinical management of patients and disease prediction and further improve ART treatment outcomes. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the General Project of the National Natural Science Foundation of China (Nos. 82,201,792, 82,301,871, 81,971,446, and 82,374,212) and the Natural Science Foundation of Anhui Province (No. 2208085MH206). There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This study was registered with the Chinese Clinical Trial Register (Clinical Trial Number: ChiCTR1800018298 ).

Improving the level of the cytidine biosynthesis in E. coli through atmospheric room temperature plasma mutagenesis and metabolic engineering.

AIMS: Cytidine, as an important commercial precursor in the chemical synthesis of antiviral and antitumor drugs, is in great demand in the market. Therefore, the purpose of this study is to build a microbial cell factory with high cytidine production. METHODS AND RESULTS: A mutant E. coli NXBG-11-F34 with high tolerance to uridine monophosphate structural analogs and good genetic stability was obtained by atmospheric room temperature plasma (ARTP) mutagenesis combined with high-throughput screening. Then, the udk and rihA genes involved in cytidine catabolism were knocked out by CRISPR/Cas9 gene editing technology, and the recombinant strain E. coli NXBG-13 was constructed. The titer, yield, and productivity of cytidine fermented in a 5 l bioreactor were 15.7 g l-1, 0.164 g g-1, and 0.327 g l-1 h-1, respectively. Transcriptome analysis of the original strain and the recombinant strain E. coli NXBG-13 showed that the gene expression profiles of the two strains changed significantly, and the cytidine de novo pathway gene of the recombinant strain was up-regulated significantly. CONCLUSIONS: ARTP mutagenesis combined with metabolic engineering is an effective method to construct cytidine-producing strains.

Nurse-led sequential multiple assignment randomized trial of nudging intervention for early antiretroviral therapy initiation among patients with HIV/AIDS: Implementation study protocol.

AIMS: In China, more than 30% of patients have not initiated treatment within 30 days of HIV diagnosis. Delayed initiation has a detrimental influence on disease outcomes and increases HIV transmission. The study aims to evaluate the effectiveness of a nurse-led antiretroviral therapy initiation nudging intervention for people newly diagnosed with HIV in China to find the optimal intervention implementation strategy. METHODS: A Hybrid Type II sequential multiple assignment randomized trial will be conducted at four Centers for Disease Control and Prevention in Hunan, China. This study will recruit 447 people newly diagnosed with HIV aged ≥18 years and randomly assign them into two intervention groups and one control group. On top of the regular counselling services and referrals, intervention groups will receive a 4-week, 2-phase intervention based on the dual-system theory and the nudge theory. The control group will follow the currently recommended referral procedures. The primary outcomes are whether treatment is initiated, as well as the length of time it takes. The study outcomes will be measured at the baseline, day 15, day 30, week 12, week 24 and week 48. Generalized estimating equations and survival analysis will be used to compare effectiveness and explore factors associated with antiretroviral therapy initiation. Both qualitative and quantitative information will be collected to assess implementation outcomes. DISCUSSION: Existing strategies mostly target institutional-level factors, with little consideration given to patients' decision-making. To close this gap, we aim to develop an effective theory-driven nudging strategy to improve early ART initiation. IMPACT: This nurse-led study will help to prevent delayed initiation by employing implementation science strategies for people newly diagnosed with HIV. This study contributes to the United Nations' objective of ending the AIDS pandemic by 2030. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300070140. The trial was prospectively registered before the first participant was recruited. PATIENT AND PUBLIC INVOLVEMENT: The nudging intervention was finalized through the Nominal Group Technique where we invited five experts in the related field and five people living with HIV to participate.

The effects of medication therapy management on medication utilization among Medicare beneficiaries with HIV/AIDS.

BACKGROUND: Medicare Part D plans are required to provide medication therapy management (MTM) programs to eligible beneficiaries to optimize medication utilization. MTM programs' effects on medication utilization among older persons living with HIV/AIDS (PLWHs) remain unclear. OBJECTIVE: This study examined the effects of the Medicare MTM programs on medication utilization among PLWHs. METHODS: This study analyzed 2017 Medicare databases linked to the Area Health Resources Files. Recipients and nonrecipients of the MTM services were compared on their medication utilization: adherence to antiretroviral medications, drug-drug interactions (DDI), and concurrent use of opioids and benzodiazepines. The intervention group comprised recipients of the MTM services, and the control group was nonrecipients meeting the eligibility criteria. A propensity score with a ratio of 1:2 between the intervention and control groups was used to identify study groups with balanced characteristics. A logistic regression was used to control for patient/community characteristics. RESULTS: After matching, the intervention and comparison groups comprised 3298 and 6596 beneficiaries for the antiretroviral adherence measure, 809 and 1618 for the DDI measure, and 691 and 1382 for the concurrent use of opioids and benzodiazepines measure. The intervention was associated with higher odds of adherence to antiretroviral medications (adjusted odds ratio = 1.15, 95% CI = 1.04-1.26), and no concurrent use of opioids and benzodiazepines (adjusted odds ratio = 1.255, 95% CI = 1.005-1.568). The study groups did not differ on no DDI (adjusted odds ratio = 0.95, 95% CI = 0.74-1.20). CONCLUSIONS: Medicare MTM programs effectively improved medication utilization among PLWHs. Future studies should explore the long-term effects of the program.

De novo transcriptome profiling reveals the patterns of gene expression in plum fruits with bud mutations.

Bud mutation is a common technique for plant breeding and can provide a large number of breeding materials. Through traditional breeding methods, we obtained a plum plant with bud mutations (named "By") from an original plum variety (named "B"). The ripening period of "By" fruit was longer than that of "B" fruit, and its taste was better. In order to understand the characteristics of these plum varieties, we used transcriptome analysis and compared the gene expression patterns in fruits from the two cultivars. Subsequently, we identified the biological processes regulated by the differentially expressed genes (DEGs). Gene ontology (GO) analysis revealed that these DEGs were highly enriched for "single-organism cellular process" and "transferase activity". KEGG analysis demonstrated that the main pathways affected by the bud mutations were plant hormone signal transduction, starch and sucrose metabolism. The IAA, CKX, ARF, and SnRK2 genes were identified as the key regulators of plant hormone signal transduction. Meanwhile, TPP, the beta-glucosidase (EC3.2.1.21) gene, and UGT72E were identified as candidate DEGs affecting secondary metabolite synthesis. The transcriptome sequencing (RNA-seq) data were also validated using RT-qPCR experiments. The transcriptome analysis demonstrated that plant hormones play a significant role in extending the maturity period of plum fruit, with IAA, CKX, ARF, and SnRK2 serving as the key regulators of this process. Further, TPP, beta-glucosidase (EC3.2.1.21), and UGT72E appeared to mediate the synthesis of various soluble secondary metabolites, contributing to the aroma of plum fruits. The expression of BAG6 was upregulated in "B" as the fruit matured, but it was downregulated in "By". This indicated that "B" may have stronger resistance, especially fungal resistance. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01472-3.

Phosphorylcholine/Heparin Composite Coatings on Artificial Lung Membrane for Enhanced Hemo-compatibility.

As the key component of extracorporeal membrane oxygenation (ECMO), artificial lung membranes have low gas permeability and plasma leakage problems, and the contact between membrane materials and blood can cause coagulation, leading to the blockage of medical equipment and seriously threatening the safety of human life. In our work, poly(4-methyl-1-pentene) hollow fiber membranes (PMP HFMs) were prepared by the thermally induced phase separation (TIPS) method, the redox method was adopted for the surface hydroxylation of PMP HFMs, and then, heparin (Hep) and 2-(methacryloyloxy)ethyl(2-(trimethylammonio)ethyl) phosphate (MPC) were grafted to the surface of PMP HFMs to prepare anticoagulant coatings. The gas permeability and hemo-compatibility of the coatings were investigated by various characterization methods, such as gas flow meter, scanning electron microscope, extracorporeal circulation experiment, etc. The results show that PMP HFMs possess a bicontinuous pore structure with a dense surface layer, which could maintain good gas permeability with an oxygen permeance of 0.8 mL/bar·cm2·min and stable gas selectivity. Furthermore, the whole blood circulation of rabbit indicated that a composite surface of bioactive Hep and biopassive MPC might be used as artificial lung membranes without the formation of thrombosis within 21 days.

Virologic failure and all-cause mortality among older people living with HIV/AIDS in South China.

This retrospective cohort study investigated older people living with HIV/AIDS (PLWHA) characteristics, HIV care, and treatment outcomes among all cases between 1996 and 2019 in Guangxi, China. Secondary data were extracted from two national surveillance databases. Older (≥50 years old) and younger (18-49 years old) PLWHA were compared regarding demographic and behavioral characteristics, HIV care, virologic failure, and all-cause mortality. Older PLWHA accounted for 41.6% of all HIV cases (N = 144,952) between 1996 and 2019. The proportion of older cases increased from 10.4% to 64.8% for men and from 2.4% to 66.7% for women between 2002 and 2019. Heterosexual contact accounted for 96.0% of older adults. Moreover, older PLWHA had a lower median CD4 count at the HIV diagnosis (193 vs. 212 cells/µL, p < 0.0001) and were less likely to receive antiretroviral therapy (ART) than younger adults (72.1% vs. 86.1%, p < 0.001). The all-cause mortality risk of older PLWHA was 2.87 times of younger adults [adjusted hazard ratio (AHR) 2.87; 95% confidence interval (CI) 2.76-2.98]. In addition, older PLWHA reported an 18% increase in odds for virologic failure than younger adults (AOR 1.18; 95% CI 1.08-1.30). Therefore, enhanced HIV prevention and care are urgently needed in older people.

Transcriptome analysis reveals the mechanism of different fruit appearance between apricot (Armeniaca vulgaris Lam.) and its seedling.

BACKGROUND: Apricot fruit has great economic value. In the process of apricot breeding using traditional breeding methods, we obtained a larger seedling (named Us) from the original variety (named U). And Us fruit is larger than U, taste better. Therefore, revealing its mechanism is very important for Apricot breeding. METHODS: In this study, de novo assembly and transcriptome sequencing (RNA-Seq) was used to screen the differently expressed genes (DEGs) between U and Us at three development stages, including young fruits stage, mid-ripening stage and mature fruit stage. RESULTS: The results showed that there were 6,753 DEGs at different sampling time. "Cellulose synthase (UDP-forming) activity" and "cellulose synthase activity" were the key GO terms enriched in GO, of which CESA and CSL family played a key role. "Photosynthesis-antenna proteins" and "Plant hormone signal transduction" were the candidate pathways and lhca, lhcb, Aux/IAA and SAUR were the main regulators. CONCLUSION: The auxin signaling pathway was active in Us, of which Aux/IAAs and SAUR were the key fruit size regulators. The low level of lhca and lhcb in Us could reveal the low demand for exogenous carbon, but they increased at mature stage, which might be due to the role of aux, who was keeping the fruit growing. Aux and photosynthesis maight be the main causes of appearance formation of Us fruits. Interestingly, the higher expression of CESA and CSL proved that Us entered the hardening process earlier than U. The advanced developmental progress might also be due to the role of Aux.

Advances in the study of genetic factors and clinical interventions for fertilization failure.

Fertilization failure refers to the failure in the pronucleus formation, evaluating 16-18 h post in vitro fertilization or intracytoplasmic sperm injection. It can be caused by sperm, oocytes, and sperm-oocyte interaction and lead to great financial and physical stress to the patients. Recent advancements in genetics, molecular biology, and clinical-assisted reproductive technology have greatly enhanced research into the causes and treatment of fertilization failure. Here, we review the causes that have been reported to lead to fertilization failure in fertilization processes, including the sperm acrosome reaction, penetration of the cumulus and zona pellucida, recognition and fusion of the sperm and oocyte membranes, oocyte activation, and pronucleus formation. Additionally, we summarize the progress of corresponding treatment methods of fertilization failure. This review will provide the latest research advances in the genetic aspects of fertilization failure and will benefit both researchers and clinical practitioners in reproduction and genetics.

DAD3 targets ACE2 to inhibit the MAPK and NF-κB signalling pathways and protect against LPS-induced inflammation in bovine mammary epithelial cells.

The protective arm of the renin-angiotensin system (RAS), the ACE 2/Ang-(1-7)/MasR axis, has become a new anti-inflammatory target. As a specific activator of ACE2, diminazene aceturate (DA) can promote anti-inflammatory effects by regulating the ACE2/Ang-(1-7)/MasR axis. However, due to the reported toxicity of DA, its application has been limited. In the current study, we synthesized a low toxicity DA derivative 3 (DAD3) and sought to determine whether DAD3 can also activate ACE2 in bovine mammary epithelial cells (BMEC) and regulate the RAS system to inhibit inflammation. We found that both DA and DAD3 can activate and promote ACE2 expression in BMEC. iRNA-mediated knockdown of ACE2 demonstrated that DAD3 activates the ACE2/Ang-(1-7)/MasR axis and plays an anti-inflammatory role in BMEC. Furthermore, the inhibitory effects of DA and DAD3 on the protein phosphorylation of MAPK and NF-κB pathways were reduced in ACE2-silenced BMEC. Our findings show that ACE2 is a target of DAD3, which leads to inhibition of the MAPK and NF-κB signalling pathways and protects against LPS-induced inflammation in BMEC. Thus, DAD3 may provide a new strategy to treat dairy cow mastitis.

Reviving chloroquine for anti-SARS-CoV-2 treatment with cucurbit[7]uril-based supramolecular formulation.

The wide-spreading SARS-CoV-2 virus has put the world into boiling water for more than a year, however pharmacological therapies to act effectively against coronavirus disease 2019 (COVID-19) remain elusive. Chloroquine (CQ), an antimalarial drug, was found to exhibit promising antiviral activity in vitro and in vivo at a high dosage, thus CQ was approved by the FDA for the emergency use authorization (EUA) in the fight against COVID-19 in the US, but later was revoked the EUA status due to the severe clinical toxicity. Herein, we show that supramolecular formulation of CQ by a macrocyclic host, curcurbit[7]uril (CB[7]), reduced its non-specific toxicity and improved its antiviral activity against coronavirus, working in synergy with CB[7]. CB[7] was found to form 1:1 host-guest complexes with CQ, with a binding constant of ∼104 L/mol. The CQ-CB[7] formulation decreased the cytotoxicity of CQ against Vero E6 and L-02 cell lines. In particular, the cytotoxicity of CQ (60 µmol/L) against both Vero E6 cell line and L-02 cell lines was completely inhibited in the presence of 300 µmol/L and 600 µmol/L CB[7], respectively. Furthermore, the CB[7] alone showed astonishing antiviral activity in SARS-CoV-2 infected Vero E6 cells and mouse hepatitis virus strain A59 (MHV-A59) infected N2A cells, and synergistically improved the antiviral activity of CQ-CB[7], suggesting that CB[7]-based CQ formulation has a great potential as a safe and effective antiviral agent against SARS-CoV-2 and other coronavirus.

Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumor.

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2 O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified ß-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2 O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2 O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.

Trends of Human Immunodeficiency Virus, Syphilis, and Hepatitis C Infections Among Men Who Have Sex With Men in Chongqing, China: A Serial Cross-sectional Survey From 2011 to 2018.

BACKGROUND: Human immunodeficiency virus (HIV) prevalence and incidence rates have expeditiously increased among Chongqing men who have sex with men (MSM) over the past decade. This study investigated the trends of HIV, syphilis, and hepatitis C virus (HCV) infections and behavioral attributes of Chongqing MSM. METHODS: Chongqing MSM who were 18 years or older were recruited annually from 2011 to 2018. Interviewer-administered paper-pencil interviews were used to collect demographics, behavioral information, and sexually transmitted diseases history. Blood samples were collected for the tests of HIV, syphilis, and HCV. A stepwise regression model was conducted to assess the associations of demographics, behaviors, and syphilis and HCV infections with HIV infection. RESULTS: A total of 4900 MSM participated in the study. The average HIV, syphilis, and HCV prevalence over 8 years were 15.4%, 4.0%, and 0.3%, respectively. The HIV prevalence ranged from 13.5% to 16.4%. Syphilis and HCV were generally low and stable across years. An increased proportion of participants received HIV counseling, testing, and condoms. Multivariable regression indicated that HIV-positive MSM were more likely to be older, married, and less educated, and they were more likely to perform unprotected anal intercourse with male partners in the past 6 months, have syphilis, and less likely to receive HIV counseling, testing, condoms, and peer education in the past year. CONCLUSIONS: The HIV counseling, testing, and peer education programs showed a negative association with HIV-positive status among Chongqing MSM. The HIV prevalence is still high. More programs must be implemented to effectively curb the HIV epidemic.

Trends of HIV, hepatitis C virus and syphilis seroprevalence among injection and non-injection drug users in southwestern China, 2010-2017.

BACKGROUND: The primary risk of HIV transmission in China has shifted from injecting drug use (IDU) to sexual contact since 2006. We evaluated the prevalence trends of HIV, hepatitis C virus (HCV), syphilis, and sexual and drug use behaviors among drug users. Methods: People who use drugs participated in any of four rounds of cross-sectional surveys during 2010-2017 in Chongqing. Participants were tested for HIV, HCV, and syphilis. Questionnaire interviewing was conducted to collect behavioral information. Chi-square and trend tests were employed to assess the changes in diseases and behaviors over time. Results: A total of 8,171 people who inject drugs (PWID) and 5,495 non-injection drug users (NIDU) were included in the analyses. HIV prevalence among PWID in four rounds of the survey in 2010-11, 2012-13, 2014-15, and 2016-17 was 11.5%, 9.7%, 6.5%, and 6.9%, and among NIDU, 2.4%, 1.4%, 2.1% and 2.6%, respectively. HCV prevalence among PWID was 83.5%, 85.2%, 67.1% and 79.7% (P < 0.001), and among NIDU, 22.2%, 10.8%, 13.4% and 14.8%, (P < 0.001). Conclusions: The declining HIV and HCV prevalence among PWID is coincident with declining risky drug use behaviors. Tailored disease prevention and interventions targeting PWID and NIDU are needed.

Matrine and baicalin inhibit apoptosis induced by Panton-Valentine leukocidin of Staphylococcus aureus in bovine mammary epithelial cells.

It was previously thought that the Panton-Valentine leukocidin (PVL) toxin of Staphylococcus aureus (S. aureus) was not the main cause of cow mastitis. However, in recent years, detection of the gene encoding PVL has been increasing in dairy cow mastitis, which implies that PVL may be related to bovine mastitis. Therefore, we wanted to search for drugs inhibiting PVL or PVL-induced apoptosis. In this report, we investigated the apoptosis mechanism of PVL in bovine mammary epithelial cells (BMEC) and the inhibition mechanism of matrine and baicalin on PVL-induced apoptosis of BMEC. The results demonstrated that BMEC were damaged and underwent apoptosis by a standard PVL-producing strain of S. aureus (ATCC 49775), a PVL knockout mutant Δpvl 49775, complemented mutant C-Δpvl 49775, or recombinant (r)PVL in vitro. The rates of apoptosis and necrosis induced by S. aureus ATCC 49775 and C-Δpvl 49775 were significantly higher than those induced by Δpvl 49775, demonstrating that BMEC apoptosis and necrosis were associated with PVL. In addition, this research found matrine and baicalin could inhibit the apoptosis of BMEC induced by PVL-producing S. aureus and by rPVL. Matrine downregulated protein expression levels of endogenous and exogenous cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9, and the effect was pronounced at a concentration of 50 µg/mL. Baicalin downregulated the expression of cleaved caspase-9. These results suggested that matrine and baicalin may have potential value against cow mastitis caused by the toxin PVL.

Interventions to improve the HIV continuum of care in China.

PURPOSE OF REVIEW: To describe HIV epidemic and interventions for improving HIV continuum of care in China. RECENT FINDINGS: The reported HIV epidemic has been continuously increasing, partially due to the expansion of active HIV testing campaign. Public health intervention programs have been effective in containing HIV spread among former plasma donors and people who inject drugs (PWID), but more infections occur among heterosexual men and women and young men who have sex with men. Of 1.25 million Chinese people are living with HIV, one-third do not know their status. About two-thirds of diagnosed individuals have used antiretroviral therapy (ART) and two-thirds of those on ART have achieved viral suppression, but some risk groups such as PWID have lower rates. The national free ART program has reduced adult and pediatric mortality and reduced heterosexual transmission. China faces great challenges to reduce HIV sexual transmission, improve the HIV continuum of care, and close the gaps to the UNAIDS Three "90" Targets.

Risk Prediction Score for HIV Infection: Development and Internal Validation with Cross-Sectional Data from Men Who Have Sex with Men in China.

Receptive anal intercourse, multiple partners, condomless sex, sexually transmitted infections (STIs), and drug/alcohol addiction are familiar factors that correlate with increased human immunodeficiency virus (HIV) risk among men who have sex with men (MSM). To improve estimation to HIV acquisition, we created a composite score using questions from routine survey of 3588 MSM in Beijing, China. The HIV prevalence was 13.4%. A risk scoring tool using penalized maximum likelihood multivariable logistic regression modeling was developed, deploying backward step-down variable selection to obtain a reduced-form model. The full penalized model included 19 sexual predictors, while the reduced-form model had 12 predictors. Both models calibrated well; bootstrap-corrected c-indices were 0.70 (full model) and 0.71 (reduced-form model). Non-Beijing residence, short-term living in Beijing, illegal drug use, multiple male sexual partners, receptive anal sex, inconsistent condom use, alcohol consumption before sex, and syphilis infection were the strongest predictors of HIV infection. Discriminating higher-risk MSM for targeted HIV prevention programming using a validated risk score could improve the efficiency of resource deployment for educational and risk reduction programs. A valid risk score can also identify higher risk persons into prevention and vaccine clinical trials, which would improve trial cost-efficiency.

Yeast Microcapsule-Mediated Targeted Delivery of Diverse Nanoparticles for Imaging and Therapy via the Oral Route.

Targeting of nanoparticles to distant diseased sites after oral delivery remains highly challenging due to the existence of many biological barriers in the gastrointestinal tract. Here we report targeted oral delivery of diverse nanoparticles in multiple disease models, via a "Trojan horse" strategy based on a bioinspired yeast capsule (YC). Diverse charged nanoprobes including quantum dots (QDs), iron oxide nanoparticles (IONPs), and assembled organic fluorescent nanoparticles can be effectively loaded into YC through electrostatic force-driven spontaneous deposition, resulting in different diagnostic YC assemblies. Also, different positive nanotherapies containing an anti-inflammatory drug indomethacin (IND) or an antitumor drug paclitaxel (PTX) are efficiently packaged into YC. YCs containing either nanoprobes or nanotherapies may be rapidly endocytosed by macrophages and maintained in cells for a relatively long period of time. Post oral administration, nanoparticles packaged in YC are first transcytosed by M cells and sequentially endocytosed by macrophages, then transported to neighboring lymphoid tissues, and finally delivered to remote diseased sites of inflammation or tumor in mice or rats, all through the natural route of macrophage activation, recruitment, and deployment. For the examined acute inflammation model, the targeting efficiency of YC-delivered QDs or IONPs is even higher than that of control nanoprobes administered at the same dose via intravenous injection. Assembled IND or PTX nanotherapies orally delivered via YCs exhibit remarkably potentiated efficacies as compared to nanotherapies alone in animal models of inflammation and tumor, which is consistent with the targeting effect and enhanced accumulation of drug molecules at diseased sites. Consequently, through the intricate transportation route, nanoprobes or nanotherapies enveloped in YC can be preferentially delivered to desired targets, affording remarkably improved efficacies for the treatment of multiple diseases associated with inflammation.