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Objectives: This study aims to investigate the association between CD4+ T cell count and combined antiretroviral therapy (cART) with the prevalence of anal human papillomavirus (HPV) infection among HIV-positive male cohort in China.Methods: A survey was conducted in men from a HIV cohort in Taizhou, China between 2016 and 2019. A face-to-face questionnaire interview was administered, and an anal-canal swab was collected for HPV genotyping.Results: A total of 766 HIV-positive men were recruited. The HPV prevalence was lower among those with increased CD4+ T cell count than those with decreased or unchanged (46.5 vs. 56.6%, p = 0.033) from baseline. In multivariable models, having the current CD4+ T cell count of 350-499 cells/µL (aOR 0.28, 95% CI 0.13-0.64), and of ≥ 500 cells/µL (aOR 0.26, 95% CI 0.11-0.60) were associated with lower prevalence of any type HPV infection compared with those with < 200 cells/µL. Having taken NVP + 3TC + AZT was inversely associated with any high-risk (HR)-HPV (aOR 0.47, 95% CI 0.25-0.90) and any low-risk (LR)-HPV infection (aOR 0.40, 95% CI 0.18-0.88), compared with those taking EFV + 3TC + TDF.Conclusions: Increased CD4+ T cell count at follow-up was significantly associated with lower prevalence of anal HPV infection. Inverse associations between NVP + 3TC + AZT and HR-HPV or LR-HPV infecton were observed. [ABSTRACT FROM AUTHOR]

Matriptase is an epithelia‐specific membrane‐anchored serine protease, and its dysregulation is highly related to the progression of a variety of cancers. Hepatocyte growth factor activator inhibitor‐1 (HAI‐1) inhibits matriptase activity through forming complex with activated matriptase. The balance of matriptase activation and matriptase/HAI‐1 complex formation determines the intensity and duration of matriptase activity. 3‐Cl‐AHPC, 4‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐3‐chlorocinnamic acid, is an adamantly substituted retinoid‐related molecule and a ligand of retinoic acid receptor γ (RARγ). 3‐Cl‐AHPC is of strong anti‐cancer effect but with elusive mechanisms. In our current study, we show that 3‐Cl‐AHPC time‐ and dose‐ dependently induces matriptase/HAI‐1 complex formation, leading to the suppression of activated matriptase in cancer cells and tissues. Furthermore, 3‐Cl‐AHPC promotes matriptase shedding but without increasing the activity of shed matriptase. Moreover, 3‐Cl‐AHPC inhibits matriptase‐mediated cleavage of pro‐HGF through matriptase/HAI‐1 complex induction, resulting in the suppression of pro‐HGF‐stimulated signalling and cell scattering. Although 3‐Cl‐AHPC binds to RARγ, its induction of matriptase/HAI‐1 complex is not RARγ dependent. Together, our data demonstrates that 3‐Cl‐AHPC down‐regulates matriptase activity through induction of matriptase/HAI‐1 complex formation in a RARγ‐independent manner, providing a mechanism of 3‐Cl‐AHPC anti‐cancer activity and a new strategy to inhibit abnormal matriptase activity via matriptase/HAI‐1 complex induction using small molecules. [ABSTRACT FROM AUTHOR]

Background: Cancer‐targeted T‐cell receptor T (TCR‐T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer‐reactive TCR‐T cells have been unsuccessful. Methods: Here, we developed a novel strategy to screen for cancer‐targeted TCR‐T cells using a special humanized mouse model with person‐specific immune fingerprints. Rare steady‐state circulating hematopoietic stem and progenitor cells were expanded via three‐dimensional culture of steady‐state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T‐cell subsets, and cytokines. To fully stimulate the immune response and to obtain B‐cell precursor NAML‐6‐ and triple‐negative breast cancer MDA‐MB‐231‐targeted TCR‐T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR β‐chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated. Results: The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V–J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice. Conclusions: We constructed a personalized humanized mouse model to screen cancer‐targeted TCR‐T pools. Our platform provides an effective source of cancer‐targeted TCR‐T cells and allows for the design of patient‐specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment. [ABSTRACT FROM AUTHOR]

Jade artifacts produced in prehistoric China continue to generate extensive scholarly interest. In the absence of textual data, inferring how works functioned in Jade Age communities remains challenging. This paper focuses on Hongshan 红山 culture (4500–3000 BCE) jades, a distinctively styled corpus primarily recovered from late fourth millennium BCE graves in northeastern China. Recent finds within and beyond the Hongshan core zone have enriched the jade inventory and expanded the known scope of its stylistic variations. The analysis sheds light on enigmatic types, reveals the complex representational nature of this corpus, and clarifies the mimetic intentions that resulted in the soft rounded forms characteristic of the style. Most objects examined were unearthed at Hongshan ceremonial centers and have sound excavation pedigrees. Their study relies on contextual archaeological data and comparative visual analysis and draws on the broader Hongshan material world. Further considerations include environment, funerary practices, materiality, cognition, and human anatomy. Ultimately, the paper uncovers new paradigms of figural representation that should open fresh investigative avenues for specialists of early China. Preliminary evaluation of jades unearthed further south at Lingjiatan 凌家滩 and Liangzhu 良渚 sites suggests that some late Neolithic societies adopted Hongshan practices. Current evidence hints at members of prehistoric communities attempting, through jade works, to rationalize their physical circumstances and assert their social power by symbolically fusing with elements of their environments. [ABSTRACT FROM AUTHOR]

Intraperitoneal injection of dihydromyricetin (DMY) has shown promising potential in the treatment of alcoholism. However, its therapeutic effect is limited due to its low solubility, poor stability, and high gut-liver first-pass metabolism, resulting in very low oral bioavailability. In this study, we developed a DMY-loaded self-emulsifying drug delivery system (DMY-SEDDS) to enhance the oral bioavailability and anti-alcoholism effect of DMY. DMY-SEDDS improved the oral absorption of DMY by facilitating lymphatic transport. The area under the concentration-time curve (AUC) of DMY in the DMY-SEDDS group was 4.13-fold higher than in the DMY suspension group. Furthermore, treatment with DMY-SEDDS significantly enhanced the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in the liver of mice (p < 0.05). Interestingly, DMY-SEDDS also increased ADH activity in the stomach of mice with alcoholism (p < 0.01), thereby enhancing ethanol metabolism in the gastrointestinal tract and reducing ethanol absorption into the bloodstream. As a result, the blood alcohol concentration of mice with alcoholism was significantly decreased after DMY-SEDDS treatment (p < 0.01). In the acute alcoholism mice model, compared to saline treatment, DMY-SEDDS prolonged the onset of LORR (loss of righting reflex) (p < 0.05) and significantly shortened the duration of LORR (p < 0.01). Additionally, DMY-SEDDS treatment significantly reduced gastric injury in acute alcoholism mice. Collectively, these findings demonstrate the potential of DMY-SEDDS as a treatment in the treatment of alcoholism. [ABSTRACT FROM AUTHOR]

STUDY QUESTION What is the association between late bedtime, night sleep duration, and lifetime cardiovascular disease (CVD) risk in women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among women with PCOS. WHAT IS KNOWN ALREADY Previous studies indicated that sleep disturbances, including altered sleep duration and staying up late (SUL), occurred more frequently among women with PCOS compared to women without PCOS. Studies have shown that both PCOS and sleep disturbances are associated with deterioration in cardiometabolic health in the longer term. However, there are limited data regarding the possible association between sleep disturbances and CVD risk among reproductive-aged women with PCOS. STUDY DESIGN, SIZE, DURATION From the original 393 women identified at our center, a total of 213 women with PCOS aged 18–40 years were enrolled in a cross-sectional study between March 2020 and July 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS Bedtime and night sleep duration were obtained from a standardized self-administered questionnaire. The prediction for atherosclerotic CVD risk in the China risk model was applied to estimate the lifetime CVD risk in the PCOS population. Restricted cubic spline regression was applied to explore the non-linear association between sleep duration and lifetime CVD risk in a series of models. Multivariable logistic regression analyses were performed to determine the association between bedtime, night sleep duration, and lifetime CVD risk. MAIN RESULTS AND THE ROLE OF CHANCE In our study, we found that the proportion of SUL was 94.25% and the mean (±SD) of night sleep duration was 7.5 ± 1.1 h in women with PCOS. Restricted cubic spline regression analysis showed a U-shaped relation between sleep duration and lifetime CVD risk. After adjusting for occasional drinking, fasting insulin, triglyceride, low-density lipoprotein cholesterol, and testosterone in multivariable logistic analyses, compared with going to bed at 23–24 o'clock, those who went to bed after 1 o'clock were independently associated with high-lifetime CVD risk [odds ratio (OR) = 3.87, 95% CI: 1.56–9.62]; compared with optimal sleep duration (7–8 h/night), short sleep (<7 h/night) was also independently associated with high-lifetime CVD risk (OR = 2.46, 95% CI: 1.01–5.97). LIMITATIONS, REASONS FOR CAUTION Inferring causality is limited owing to the cross-sectional design. All sleep variables data were obtained from a standardized self-administered questionnaire rather than measurements using objective approaches. Even after adjusting for potential confounders, we still cannot completely rule out the possibility of residual confounding from unmeasured factors such as socioeconomic status. Future studies with larger sample sizes are needed to further explore the relation between long sleep duration and lifetime CVD risk. Although these findings are not generalizable to non-SUL PCOS populations, they could be used for guiding multidimensional treatment. Lastly, there is no non-PCOS group in the current cross-sectional study, which limits the interpretation of the findings from the PCOS group. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to report that both late bedtime (≥1:00) and short sleep duration (<7 h/night) were independently associated with a high-lifetime CVD risk among reproductive-aged women with PCOS, in a sample of Chinese adults. Predicting cardiovascular risk and examining the association between sleep disturbances and predicted CVD risk among women with PCOS help to highlight the need for early interventions on sleep to improve their cardiovascular outcomes. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Natural Science Foundation of Fujian Province (No. 2020J011242), the Fujian provincial health technology project (No. 2022CXB016), the Joint Research Projects of Health and Education Commission of Fujian Province (No. 2019-WJ-39), and the Medical and Health project of Xiamen Science & Technology Bureau (No. 3502Z20214ZD1001). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Aims: The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism‐based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag. Methods: Nonlinear mixed‐effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness‐of‐fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study. Results: The pharmacokinetic data of hetrombopag were well described by a modified target‐mediated drug disposition (TMDD) model with dual sequential first‐order absorption. Mean parameter estimates (interindividual variability) were CL/F 7.66 L/h (63.5%), Vc/F 30.0 L (77.2%) and Kdeg 0.693/h (87.1%). The pharmacodynamic profile was well described by a five‐compartment lifespan model with four‐transit and one‐platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once‐daily hetrombopag would able to achieve an ideal platelet count level (50‐200 × 109/L). Conclusion: TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once‐daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag. [ABSTRACT FROM AUTHOR]

Sensing electrodes with two different materials (precursor Bi2W2O9 and the tungsten oxide) were synthesized. The tungsten oxide with high specific surface area (78 m2 g−1) was prepared by acid leaching of Bi2W2O9 under microwave processing and the ultrasonic exfoliation reaction. The structure and morphology of the precursor Bi2W2O9 and the tungsten oxide were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and the Brunauer–Emmett–Teller method. The mixed potential NO2 sensors based on yttria-stabilized zirconia and sensing electrodes with the two materials were fabricated and compared and then their sensing properties were examined. All sensors showed good response to 30–500 ppm NO2 at their best operation temperature. The sensor equipped with exfoliated tungsten oxide exhibited the better sensing performance than the sensor equipped with precursor Bi2W2O9, which shows the sensitivity of 64.61 mV decade−1 to NO2 at the minimum operation temperature of 450 °C. In addition, the stability, repeatability, and cross-sensitivity of the two sensors were analyzed in details. Furthermore, the mixed potential sensing mechanism of NO2 for the tungsten oxide was also discussed. [ABSTRACT FROM AUTHOR]

Objective. The present study was designed to determine whether dexmedetomidine (DEX) exerts cardioprotection against myocardial I/R injury in diabetic hearts and the mechanisms involved. Methods. A total of 30 diabetic rats induced by high-glucose-fat diet and streptozotocin (STZ) were randomly assigned to five groups: diabetic sham-operated group (DM-S), diabetic I/R group (DM-I/R), diabetic DEX group (DM-D), diabetic DEX + Wort group (DM-DW), and diabetic Wort group (DM-W). Another 12 age-matched male normal SD rats were randomly divided into two groups: sham-operated group (S) and I/R group (I/R). All rats were subjected to 30 min myocardial ischemia followed by 120 min reperfusion except sham groups. Plasmas were collected to measure the malondialdehyde (MDA), creatine kinase isoenzymes (CK-MB), and lactate dehydrogenase (LDH) levels and superoxide dismutase (SOD) activity at the end of reperfusion. Pathologic changes in myocardial tissues were observed by H-E staining. The total and phosphorylated form of Akt and GSK-3β protein expressions were measured by western blot. The ratio of Bcl-2/Bax at mRNA level was detected by reverse transcription-polymerase chain reaction (RT-PCR). Results. DEX significantly reduced plasma CK-MB, MDA concentration, and LDH level and increased SOD activity caused by I/R. The phosphorylation of Akt and GSK-3β was increased, Bcl-2 mRNA and the Bcl-2/Bax ratio was increased, and Bax mRNA was decreased in the DEX group as compared to the I/R group, while posttreatment with Wort attenuated the effects induced by DEX. Conclusion. The results of this study suggest that DEX postconditioning may increase the phosphorylation of GSK-3β by activating the PI3K/Akt signaling pathway and may inhibit apoptosis and oxidative stress of the myocardium, thus exerting protective effects in diabetic rat hearts suffering from I/R injury. [ABSTRACT FROM AUTHOR]