Dexmedetomidine attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18-23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

The association of depressive symptoms with adverse clinical outcomes in hypertension: Data from SPRINT randomized trail.

OBJECTIVE: This study intends to explore the effect of depressive symptoms on adverse clinical outcomes in middle-aged and elderly hypertensive patients. METHODS: This post hoc analysis was conducted using data from the Systolic Blood Pressure Intervention Trial (SPRINT), and we used cox proportional risk regression to examine the relationship between depressive symptoms and adverse clinical outcomes (primary outcome, all-cause mortality, cardiovascular disease(CVD) mortality, heart failure(HF), myocardial infarction(MI), non-myocardial infarction acute coronary syndrome(non-MI ACS)). RESULTS: In a follow-up study of 9259 participants, we found that depression symptoms was significantly and positively associated with the primary outcome (HR 1.03, 95%CI 1.01-1.05; p for trend = 0.0038), all-cause mortality (HR 1.03, 95%CI 1.01-1.05; p for trend = 0.0308), HF(HR 1.05, 95%CI 1.01-1.08; p for trend = 0.0107), and non-MI ACS(HR 1.06, 95%CI 1.01-1.10; p for trend = 0.0120). Kaplan-Meier survival curves for depression symptoms severity (none, mild, moderate, and above) and adverse clinical outcomes suggested that for all but primary clinical outcomes, the cumulative risk of adverse clinical outcomes increased with increasing depression symptoms severity. CONCLUSION: For middle-aged and elderly hypertensive patients, depression symptoms exacerbates the risk of adverse clinical outcomes (primary outcome, all-cause mortality, CVD death, MI, HF, and non-MI ACS), and the risk increases with the severity of depression symptoms.

Comparison of laser versus cold knife visual internal urethrotomy in the treatment of urethral stricture (stricture length <2 cm): A systematic review and meta-analysis.

PURPOSE: There is still controversy regarding the safety and efficacy of cold knife visual internal urethrotomy and laser incisions for the treatment of urethral stricture. This study aims to compare the results of postoperative long-term and short-term maximum urinary flow rates (Qmax), surgical time, postoperative complications, and 1-year recurrence rates between the cold knife and laser surgery. METHODS: We searched databases including Embase, PubMed, Cochrane, and Clinical Trials.gov to identify relevant literature published in English up to September 2023. We used Stata to compare various parameters. This study is registered in PROSPERO (CRD42023471634). Nine comparative experiments were conducted, involving a total of 659 participants. RESULTS: The laser group showed significantly better results compared to the cold knife group in terms of postoperative 12-month maximum urinary flow rate (mean differences [MD] 2.131; 95% [1.015, 3.249], P < .0001), postoperative bleeding (RR 0.277, 95% [0.079, 0.977], P = .046), and 1-year recurrence rate (RR 0.667, 95% [0.456, 0.976], P = .037). However, there were no significant differences in postoperative 6-month and 3-month Qmax, surgical time, urethral leakage complications, overall complications, and Visual Analog Scale (VAS) scores. CONCLUSION: The current study results suggest that laser urethral incision has greater advantages in the long-term (12 months), 1-year recurrence rate, and bleeding complications compared to cold knife urethral incision in the treatment of urethral stricture (<2 cm). Therefore, laser urethral incision may be a better choice for patients with urethral stricture.

Homozygous variant in DRC3 (LRRC48) gene causes asthenozoospermia and male infertility.

Human infertility affects 10-15% of couples. Asthenozoospermia accounts for 18% of men with infertility and is a common male infertility phenotype. The nexin-dynein regulatory complex (N-DRC) is a large protein complex in the sperm flagellum that connects adjacent doublets of microtubules. Defects in the N-DRC can disrupt cilia/flagellum movement, resulting in primary ciliary dyskinesia and male infertility. Using whole-exome sequencing, we identified a pathological homozygous variant of the dynein regulatory complex subunit 3 (DRC3) gene, which expresses leucine-rich repeat-containing protein 48, a component of the N-DRC, in a patient with asthenozoospermia. The variant ENST00000313838.12: c.644dup (p. Glu216GlyfsTer36) causes premature translational arrest of DRC3, resulting in a dysfunctional DRC3 protein. The patient's semen count, color, and pH were normal according to the reference values of the World Health Organization guidelines; however, sperm motility and progressive motility were reduced. DRC3 protein was not detected in the patient's sperm and the ultrastructure of the patient's sperm flagella was destroyed. More importantly, the DRC3 variant reduced its interaction with other components of the N-DRC, including dynein regulatory complex subunits 1, 2, 4, 5, 7, and 8. Our data not only revealed the essential biological functions of DRC3 in sperm flagellum movement and structure but also provided a new basis for the clinical genetic diagnosis of male infertility.

Effects of natural extract interventions in prostate cancer: A systematic review and network meta-analysis.

BACKGROUND: Over years, there has been a widespread quest for effective dietary patterns and natural extracts to mitigate prostate cancer risk. However, despite numerous experimental studies conducted on various natural extracts, the evidence substantiating their efficacy remains largely insufficient. This dearth of compelling evidence presents a significant challenge in advocating for their widespread use as preventive measures against prostate cancer. OBJECTIVE: Our study endeavors to undertake a network meta-analysis to evaluate the influence of natural extracts on prostate cancer. METHODS: Researchers systematically searched through Embase, PubMed, Cochrane Library, and Web of Science databases until December 2023. The main focus was on assessing primary outcomes comprising prostate-specific antigen (PSA), insulin-like growth factor-binding protein-3 (IGFBP-3), insulin-like growth factor-1 (IGF-1). We conducted data analysis utilizing StataMP 15.0 software. Therapeutic effects were ranked based on the probability values derived from Surface Under the Cumulative Ranking curve (SUCRA). Additionally, cluster analysis was employed to assess the impacts of natural extracts on three distinct outcomes. RESULTS: Following screening procedures, the 28 eligible studies were incorporated, the selected studies encompassed 1,566 prostate cancer patients and evaluated 16 different natural extract treatments. Specifically, 24 trials included PSA indicators, 10 included IGF-1 indicators, and 8 included IGFBP-3 indicators. The findings revealed that, based on the SUCRA values, the combined therapy of silybin with selenium (74%) appears to be the most effective approach for reducing serum PSA levels. Simultaneously, silybin alone (84.6%) stands out as the most promising option for decreasing serum IGF-1 levels. Lastly, concerning IGFBP-3, silybin alone (67.7%) emerges as the optimal choice. Twelve studies provided comprehensive information on adverse drug reactions/events (ADR/ADE), whereas five articles did not report any significant ADR/ADE. CONCLUSION: The NMA suggests that, compared to placebo, utilizing silybin either alone or in combination with selenium has been shown to enhance therapeutic effects, offering potential benefits to patients with prostate cancer. This study can offer valuable insights for prostate patients considering natural extract treatments. Further evidence is required to confirm the safety profile of these treatments.

Suitability of reduced dose glucocorticoids therapy regimen for antibody-associated vasculitis patients with TB: a retrospective study.

INTENTION: Immunosuppressive therapy is the major treatment approach for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Due to impaired cellular immunological function and the use of glucocorticoids and immunosuppressants, AAV patients are predisposed to opportunistic infections, including tuberculosis (TB). This retrospective study aims to analyze the clinical characteristics of patients with AAV and TB and explore suitable glucocorticoid regimens for them. So as to provide a basis for future clinical guidelines and have important value for guiding clinical treatment. METHODS: This study retrospectively reviewed 58 AAV patients (18-80 years old) with TB admitted to Changsha Central Hospital Affiliated with the University of South China from 2016.1 to 2023.4 Patients were divided into standard-dose and reduced-dose glucocorticoid groups before retrospectively analyzing their medical records. RESULTS: A total of 58 AAV patients with TB were enrolled, with 15 dying throughout the monitoring period. Through analysis data, compared with the standard-dose group, the reduced group had less proteinuria and hematuria. In survival analysis, the reduced-dose glucocorticoid group had lower mortality than the standard-dose group (P = 0.03); however, no significant difference was noted in the use of immunoglobulin (P = 0.39), tuberculosis activity (P = 0.64), and age stratification (P = 0.40). The BVAS score before treatment and 6 months post-treatment suggest that the two regimens cause the same risk of ESKD (P > 0.05). CONCLUSION: In conclusion, the reduced glucocorticoid dose group can achieve the same curative effect as the standard dose group and has less damage to the kidney in hematuria and proteinuria. Therefore, the reduced glucocorticoid dose treatment regimen may be more suitable for AAV patients with TB.

Cyanotic Nephropathy in an Adult Patient with Eisenmenger Syndrome: A Case Report and Literature Review.

INTRODUCTION: Cyanotic nephropathy, a rare disease characterized by proteinuria, decreased estimated glomerular filtration rate, thrombocytopenia, polycythemia, and hyperuricemia, may occasionally be secondary to cyanotic congenital heart disease (CHD). There are currently no detailed diagnostic criteria or treatments for cyanotic nephropathy, owing to its extremely low incidence. Eisenmenger syndrome (ES) was initially defined by Paul Wood in pathophysiologic terms as "pulmonary hypertension (PH) at the systemic level, caused by a high pulmonary vascular resistance, with a reversed or bidirectional shunt at the aorto-pulmonary, ventricular, or atrial level." It typically develops in the presence of large, unrepaired atrial or ventricular septal defects, arterial shunts, or complex forms of CHD and is the most severe hemodynamic phenotype of pulmonary arterial hypertension associated with CHD. This study aimed to outline the case of an ES patient who developed cyanotic nephropathy and successfully achieved clinical remission through primary disease treatment and symptomatic management. Overall, this case expands our understanding of cyanotic nephropathy and lays a theoretical reference for the treatment of ES. CASE PRESENTATION: A 33-year-old Chinese female attended the outpatient department with abnormal urine test results over the past two and a half years. Following a comprehensive medical history collection, she underwent the necessary tests. Cardiac color ultrasound displayed a significant widening of the pulmonary artery and PH (severe), as well as mild tricuspid regurgitation and patent ductus arteriosus. The results of the kidney biopsy, combined with clinical findings, suggested a high risk of polycythemia-related kidney disease. She was eventually diagnosed with cyanotic nephropathy and ES. Her symptoms were relieved following symptomatic treatment, such as the administration of ambrisentan, febuxostat, and home oxygen therapy. Her follow-up visit at 6 months demonstrated improvements in hyperuricemia and a significant increase in physical strength. CONCLUSION: Cyanotic nephropathy is a rare condition in adults. Kidney biopsy remains the gold standard of diagnosis for various nephropathies. Active treatment of CHD and alleviating hypoxia may be pivotal for the treatment of cyanotic nephropathy.

Structure-based design of non-hypertrophic apelin receptor modulator.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the ß-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Effectiveness of human immunodeficiency virus prevention strategies by mapping the geographic dispersion pattern of human immunodeficiency virus prevalence in Nanning, China.

BACKGROUND: The Guangxi government initiated two rounds of the Guangxi AIDS Conquering Project (GACP) in 2010 (Phase I) and 2015 (Phase II) to control human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemics. However, the effectiveness of GACP in HIV prevention and treatment has rarely been reported. This study aimed to assess the effectiveness of the GACP implemented in Guangxi, China and provide data for strategy and praxis improvements to achieve Joint United Nations Programme on HIV/AIDS (UNAIDS) 95-95 targets. METHODS: We used spatial approaches to trace the spatiotemporal distribution properties, epidemic trends, and correlation between macroscopic factors and HIV incidence using data from the Chinese HIV/AIDS case reporting system to explore the effects of the GACP. RESULTS: During the GACP era, the HIV epidemic stabilized in urban centers, showing a downward trend in the Hengzhou and Binyang Counties in the eastern region, whereas it continued to increase in rural areas of the northwest region, such as the Long'an, Mashan, Shanglin, and Wuming Districts. The linear directional mean (LDM) of HIV infection reported cases displayed a southeast-northwest direction, with an LDM value of 12.52°. Compared with that in Phase I, Hengzhou withdrew from the high-high clustering area, and the west-north suburban counties pulled out the low-low clustering area during Phase II. Significant HIV clusters were identified in the eastern region during Phase I, whereas these clusters emerged in the northwestern areas during Phase II. Regarding HIV, socioeconomic status, population mobility, and medical care levels were the key social drivers of heterogeneous spatial distribution. CONCLUSIONS: The GACP assisted in effectively managing the HIV epidemic in urban and eastern areas of Nanning City. However, prevention and control efforts in rural regions, particularly those located in the northwest, may not have yielded comparable outcomes. To address this disparity, allocating additional resources and implementing tailored intervention measures for these rural areas are imperative.

Dietary Shifts in the Adaptation to Changing Marine Resources: Insights from a Decadal Study on Greater Lizardfish (Saurida tumbil) in the Beibu Gulf, South China Sea.

Understanding dietary behavior during the individual development of marine predators and its temporal variations elucidates how species adapt to changes in marine resources. This is crucial for predicting marine predators' habitat selection and the natural population's responses to environmental changes. The authors conducted a comparative analysis of dietary shift strategies and trophic level variations in Greater lizardfish (Saurida tumbil) in the Beibu Gulf during two distinct periods (2010 and 2020) using stomach content and stable isotope analysis methods. Possible driving factors for these changes were also explored. Changes in the fishery community structure and the decline in the abundance of primary prey resources have led the S. tumbil population to diversify their prey species, utilize alternative resources, and expand their foraging space. However, the species' foraging strategy, characterized by chasing and preying on schooling and pelagic prey, promoted stability in their feeding behavior across spatial and temporal scales. The main prey items remained demersal and pelagic fish species, followed by cephalopods and crustaceans. Similar to other generalist fish species, ontogenetic dietary shifts (ODSs) indicated a partial transition towards larger prey items. However, the timing and magnitude of the ODSs varied between the two periods, reflecting life-history variations and adaptive adjustments to environmental changes. In comparison to 2010, the population's mean body length (BL) increased in 2020, and the proportion of the population feeding on pelagic-neritic prey significantly increased. However, the δ15N values were lower, indicating that the shift in the ecological niche of preferred prey from demersal to pelagic-neritic was the primary cause of the decrease in trophic levels. In the future, we will conduct further quantitative research integrating the spatiotemporal data of both predators and prey to clarify the relationships between marine predators' feeding behavior, trophic levels, and changes in prey community structure.

Early endovascular approaches for treating acute mesenteric arterial occlusive disease in hemodialysis patients.

BACKGROUND: Among hemodialysis patients, acute superior mesenteric artery (SMA) thrombosis a condition with a high mortality rate. Very few larger case series have been reported. METHOD: We reviewed eight hemodialysis patients with diabetes mellitus and SMA thrombosis managed with endovascular therapy in our institution. Demographic, clinical, and radiological data were described. The patency of the SMA was assessed by computed tomography angiography (CTA) at one month after the endovascular procedure. At the last visit, clinical symptoms and check of mortality were recorded. RESULTS: Multidetector CTA scan revealed severe stenosis of SMA in 6 patients and SMA occlusion in the other two patients. The severe stenosis of SMA were verified by angiography. Balloon angioplasty without stenting was performed to obtain satisfactory patency of SMA. Seven of eight patients achieved resolution of abdominal pain after the endovascular procedure. One patient died of suspected intestinal necrosis after 6 days of balloon angioplasty. All seven surviving patients did not experience a recurrence of symptoms with a median follow-up of 2 years. No significant residual stenotic or occlusive lesions were noted in follow-up CTA at one month after the endovascular procedure. CONCLUSION: SMA thrombosis should be systematically suspected in hemodialysis patients experiencing abdominal pain. Prompt diagnosis of SMA thrombosis as soon as possible and early endovascular therapy are required to obtain a favorable prognosis in the hemodialysis patient with SMA thrombosis.

Willingness to accept monkeypox vaccine and its correlates among men who have sex with men in Southern China: a web-based online cross-sectional study.

Background: The May 2022 global outbreak of monkeypox (MPX) poses a threat to the health of men who have sex with men. However, there is limited data on the willingness of MSM to receive monkeypox vaccination in Southern China. This study aimed to assess the knowledge of MPX, concerns regarding MPX, and willingness to receive monkeypox vaccination, as well as their correlates, among MSM in China. Methods: We conducted a Web-based online survey of MSM in Southern China from August to September 2022. Data were collected on the socio-demographic characteristics, knowledge, worries, concerns regarding MPX and willingness to receive monkeypox vaccination. Multivariate logistic regression was employed to explore the factors associated with willingness to receive monkeypox vaccination. Results: A total of 1903 participants completed the survey. Among them, approximately 69.9% reported being aware of MPX awareness, 94.1% of the participants supported the promotion of monkeypox vaccination. The majority of participants (91.4%) expressed their willingness to receive monkeypox vaccination. Participants who considered monkeypox vaccination safe [adjusted odds ratio (aOR) = 4.82, 95% CI: 1.35-17.18], agreed on the necessity of government promotion of monkeypox vaccination in China (aOR = 6.03, 95% CI: 1.07-33.93), believed in prioritizing monkeypox vaccination for MSM (aOR = 5.01, 95% CI: 1.10-22.71), and had friends or sexual partners who had already received the monkeypox or smallpox vaccination (aOR = 10.37, 95% CI: 2.11-50.99) are more likely to be vaccinated. Conversely, married individuals (aOR = 0.13, 95% CI: 0.03-0.47), those engaging in anal sex 4-6 times per week in the past 3 months (aOR = 0.26, 95% CI: 0.09-0.77) expressed hesitancy toward monkeypox vaccination. Conclusion: There was a high willingness to receive monkeypox vaccination among MSM in China. The hesitancy toward the monkeypox vaccine can be effectively mitigated by addressing concerns about its safety and potential adverse reactions. Moreover, increasing acceptance of the monkeypox vaccination among MSM and their peers is crucial, as social influence significantly impacts vaccine attitudes and behaviors.

Conformational transitions and activation of the adhesion receptor CD97.

Adhesion G protein-coupled receptors (aGPCRs) are evolutionarily ancient receptors involved in a variety of physiological and pathophysiological processes. Modulators of aGPCR, particularly antagonists, hold therapeutic promise for diseases like cancer and immune and neurological disorders. Hindered by the inactive state structural information, our understanding of antagonist development and aGPCR activation faces challenges. Here, we report the cryo-electron microscopy structures of human CD97, a prototypical aGPCR that plays crucial roles in immune system, in its inactive apo and G13-bound fully active states. Compared with other family GPCRs, CD97 adopts a compact inactive conformation with a constrained ligand pocket. Activation induces significant conformational changes for both extracellular and intracellular sides, creating larger cavities for Stachel sequence binding and G13 engagement. Integrated with functional and metadynamics analyses, our study provides significant mechanistic insights into the activation and signaling of aGPCRs, paving the way for future drug discovery efforts.

Predicting current and future potential distributions of the greater bandicoot rat (Bandicota indica) under climate change conditions.

BACKGROUND: Rodent infestation is a global problem. Rodents cause huge harm to agriculture, forestry, and animal husbandry around the world and spread various zoonoses. In this study, we simulated the potentially suitable habitats of Bandicota indica and predicted the impact of future climate change on its distribution under different socio-economic pathway scenarios of CMIP6 using a parameter-optimized maximum entropy (MaxEnt) model. RESULTS: The average area under the receiver operating characteristic curve (AUC) value (0.958 ± 0.006) after ten repetitions proved the high accuracy of the MaxEnt model. Model results show that the annual mean temperature (≥ 15.93 °C), isothermality (28.52-80.49%), annual precipitation (780.13-3863.13 mm), precipitation of the warmest quarter (≥ 204.37 mm), and nighttime light (≥ 3.38) were important limiting environmental variables for the distribution of B. indica. Under current climate conditions, the projected potential suitable habitats for B. indica were mainly in India, China, Myanmar, Thailand, and Vietnam, which cover a total area of 301.70 × 104 km2 . The potentially suitable areas of B. indica in the world will expand under different future climate change scenarios by 1.61-17.65%. CONCLUSIONS: These results validate the potential influence of climate change on the distribution of B. indica and aid in understanding the linkages between B. indica niches and the relevant environment, thereby identifying urgent management areas where interventions may be necessary to develop feasible early warning and prevention strategies to protect against this rodent's spread. © 2023 Society of Chemical Industry.

CD4/CD8 Ratio Recovered as a Predictor of Decreased Liver Damage in Adults Infected With HIV: 16-Year Observational Cohort Study.

BACKGROUND: As the life expectancy of individuals infected with HIV continues to increase, vigilant monitoring of non-AIDS-related events becomes imperative, particularly those pertaining to liver diseases. In comparison to the general population, patients infected with HIV experience a higher frequency of liver-related deaths. The CD4/CD8 ratio is emerging as a potential biomarker for non-AIDS-related events. However, few existing studies have been specially designed to explore the relationship between the CD4/CD8 ratio and specific types of non-AIDS-related events, notably liver damage. OBJECTIVE: This study aimed to investigate the potential association between the CD4/CD8 ratio and the development of liver damage in a sizable cohort of patients infected with HIV receiving antiretroviral treatment (ART). Additionally, the study sought to assess the effectiveness of 3 antiretroviral drugs in recovering the CD4/CD8 ratio and reducing the occurrence of liver damage in this population. METHODS: We conducted an observational cohort study among adults infected with HIV receiving ART from 2004 to 2020 in Guangxi, China. Propensity score matching, multivariable Cox proportional hazard, and Fine-Gray competing risk regression models were used to determine the relationship between the CD4/CD8 ratio recovered and liver damage. RESULTS: The incidence of liver damage was 20.12% among 2440 eligible individuals during a median follow-up period of 4 person-years. Patients whose CD4/CD8 ratio did not recover to 1.0 exhibited a higher incidence of liver damage compared to patients with a CD4/CD8 ratio recovered (adjusted hazard ratio 7.90, 95% CI 4.39-14.21; P<.001; subdistribution hazard ratio 6.80, 95% CI 3.83-12.11; P<.001), findings consistent with the propensity score matching analysis (adjusted hazard ratio 6.94, 95% CI 3.41-14.12; P<.001; subdistribution hazard ratio 5.67, 95% CI 2.74-11.73; P<.001). The Efavirenz-based regimen exhibited the shortest time for CD4/CD8 ratio recovery (median 71, IQR 49-88 months) and demonstrated a lower prevalence of liver damage (4.18/100 person-years). CONCLUSIONS: Recovery of the CD4/CD8 ratio was associated with a decreased risk of liver damage in patients infected with HIV receiving ART, adding evidence for considering the CD4/CD8 ratio as a potential marker for identifying individuals at risk of non-AIDS-related diseases. An efavirenz-based regimen emerged as a recommended choice for recovering the CD4/CD8 ratio and mitigating the risk of liver damage.

Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.

Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via Gi and ß-arrestin signaling pathways. However, the lack of understanding of the mechanism of ß-arrestin-1 (ßarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-ßarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the Gi protein complex. ßarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the Gi-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.

External quality assessment scheme for sperm DNA fragmentation: a pilot study in China.

BACKGROUND: The aim of this article is to establish an external quality assessment (EQA) scheme for sperm Deoxyribonucleic acid (DNA) fragmentation (SDF) detection, and to assess the feasibility of the scheme. In addition, this article provides some case analysis of abnormal results in order to really help improve the performance of the laboratory. RESULTS: In 2021 and 2022, 10 and 28 laboratories in China volunteered to participate in the EQA program respectively. Two samples were selected for EQA each year, a large spread of results was obtained for the four samples, and the highest values were 13.7, 4.2, 8.0 and 4.0 times the lowest respectively. The coefficients of variation (CVs) were very high for the four samples, at 46.6%, 30.1%, 26.7% and 30.3%, respectively. The CVs of the samples with high SDF values were lower than those of the samples with low SDF values. There was no significant difference between the results of sperm chromatin structure assay (SCSA) and sperm chromatin dispersion (SCD). For the 10 laboratories that participated in EQA in 2021 and 2022, the CVs of low SDF value samples and high SDF value samples decreased from 46.6% and 30.1% in 2021 to 32.5% and 22.7% in 2022, respectively. CONCLUSION: This is the first study to evaluate the EQA program on SDF, which involved a number of laboratories and was demonstrated to be feasible. It is recommended that all laboratories participate in the EQA of SDF to ensure the accuracy of the results.

RéSUMé: CONTEXTES: L'objectif de cet article est d'établir un système externe d'évaluation de la qualité (EEQ) pour la détection de la fragmentation de l'ADN des spermatozoïdes (SDF) et d'évaluer la faisabilité de ce système. En outre, cet article fournit une analyse de cas de résultats anormaux afin d'aider réellement à améliorer les performances du laboratoire. RéSULTATS: En 2021 et 2022, respectivement 10 et 28 laboratoires en Chine se sont portés volontaires pour participer au programme EEQ. Deux échantillons ont été sélectionnés chaque année pour l'EEQ ; un large éventail de résultats a été obtenu pour les quatre échantillons, et les valeurs les plus élevées étaient respectivement de 13,7, 4,2, 8,0 et 4,0 fois les plus faibles. Les coefficients de variation (CV) étaient très élevés pour les quatre échantillons, soit respectivement 46,6 %, 30,1 %, 26,7 % et 30,3 %. Les CV des échantillons avec des valeurs de SDF élevées étaient inférieurs à ceux des échantillons avec de faibles valeurs de SDF. Il n'y avait pas de différence significative entre les résultats du test de structure de la chromatine des spermatozoïdes (SCSA) et ceux de la dispersion de la chromatine des spermatozoïdes (SCD). Pour les 10 laboratoires qui ont participé à l'EEQ en 2021 et 2022, les CV des échantillons à faible valeur de SDF et ceux des échantillons à valeur élevée de SDF ont diminué, passant respectivement de 46,6 % et 30,1 % en 2021 à 32,5 % et 22,7 % en 2022. CONCLUSIONS: Il s'agit de la première étude à évaluer le programme externe d'évaluation de la qualité (EEQ) de l'analyse de la SDF, qui a impliqué un certain nombre de laboratoires, et qui s'est avéré réalisable. Il est recommandé que tous les laboratoires participent à l'EEQ de la SDF afin d'en assurer l'exactitude des résultats.

Bifunctional TiO2 Nanoflower-Induced H4TCBPE Aggregation Enhanced Electrochemiluminescence for an Ultrasensitive Assay of Organophosphorus.

In this work, the aggregation-induced emission ligand 1,1,2,2-tetra(4-carboxylbiphenyl)ethylene (H4TCBPE) was rigidified in the Ti-O network to form novel electrochemiluminescence (ECL) emitter H4TCBPE-TiO2 nanospheres, which acted as an effective ECL emitter to construct an "on-off" ECL biosensor for ultrasensitive detection of malathion (Mal). H4TCBPE-TiO2 exhibited excellent ECL responses due to the Ti-O network that can restrict the intramolecular free motions within H4TCBPE and then reduce the nonradiative relaxation. Moreover, TiO2 can act as an ECL co-reaction accelerator to promote the generation of sulfate radical anion (SO4•-), which interacts with H4TCBPE in the Ti-O network to produce enhanced ECL response. In the presence of Mal, numerous ligated probes (probe 1 to probe 2, P1-P2) were formed and released by copper-free click nucleic acid ligation reaction, which then hybridized with hairpin probe 1 (H1)-modified H4TCBPE-TiO2-based electrode surface. The P1-P2 probes can initiate the target-assisted terminal deoxynucleoside transferase (TdTase) extended reaction to produce long tails of deoxyadenine with abundant biotin, which can load numerous streptavidin-functionalized ferrocenedicarboxylic acid polymer (SA-PFc), causing quenching of the ECL signal. Thus, the ultrasensitive ECL biosensor based on H4TCBPE-TiO2 ECL emitter and click chemistry-actuated TdTase amplification strategy presents a desirable range from 0.001 to 100 ng/mL and a detection limit low to 9.9 fg/mL. Overall, this work has paved an avenue for the development of novel ECL emitters, which has opened up new prospects for ECL biosensing.

Fluorofenidone alleviates liver fibrosis by inhibiting hepatic stellate cell autophagy via the TGF-ß1/Smad pathway: implications for liver cancer.

Objectives: Liver fibrosis is a key stage in the progression of various chronic liver diseases to cirrhosis and liver cancer, but at present, there is no effective treatment. This study investigated the therapeutic effect of the new antifibrotic drug fluorofenidone (AKF-PD) on liver fibrosis and its related mechanism, providing implications for liver cancer. Materials and Methods: The effects of AKF-PD on hepatic stellate cell (HSC) autophagy and extracellular matrix (ECM) expression were assessed in a carbon tetrachloride (CCl4)-induced rat liver fibrosis model. In vitro, HSC-T6 cells were transfected with Smad2 and Smad3 overexpression plasmids and treated with AKF-PD. The viability and number of autophagosomes in HSC-T6 cells were examined. The protein expression levels of Beclin-1, LC3 and P62 were examined by Western blotting. The Cancer Genome Atlas (TCGA) database was used for comprehensively analyzing the prognostic values of SMAD2 and SMAD3 in liver cancer. The correlation between SMAD2, SMAD3, and autophagy-related scores in liver cancer was explored. The drug prediction of autophagy-related scores in liver cancer was explored. Results: AKF-PD attenuated liver injury and ECM deposition in the CCl4-induced liver fibrosis model. In vitro, the viability and number of autophagosomes in HSCs were reduced significantly by AKF-PD treatment. Meanwhile, the protein expression of FN, α-SMA, collagen III, Beclin-1 and LC3 was increased, and P62 was reduced by the overexpression of Smad2 and Smad3; however, AKF-PD reversed these effects. SMAD2 and SMAD3 were hazardous factors in liver cancer. SMAD2 and SMAD3 correlated with autophagy-related scores in liver cancer. Autophagy-related scores could predict drug response in liver cancer. Conclusions: AKF-PD alleviates liver fibrosis by inhibiting HSC autophagy via the transforming growth factor (TGF)-ß1/Smadpathway. Our study provided some implications about how liver fibrosis was connected with liver cancer by SMAD2/SMAD3 and autophagy.

Uptake of HIV testing and its correlates among sexually experienced college students in Southwestern, China: a Web-Based online cross-sectional study.

BACKGROUND: The prevalence of human immunodeficiency virus (HIV) is becoming more common among college students in China. However, latest data on the prevalence and correlates of HIV testing among sexually experienced college students is rarely. METHODS: An online survey was conducted among college students aged 18 years or older using multistage stratified cluster sampling from 16 colleges. Data on socio-demographic, HIV testing, HIV-related awareness, attitudes, sexual education and behaviors were collected. Propensity score matching (PSM) and logistic regression model were used to identify factors associated with HIV testing. RESULT: A total of 108,987 students participated the survey, of which 13,201 sexually experienced college students were included in this study. 1,939 (14.69%) college students with sexual experience reported uptake of HIV testing in the preceding year. The uptake of HIV testing increased for college students with a rising HIV knowledge score and sexual health knowledge. Being awareness of HIV-related knowledge (aOR = 1.15, 95%CI: 1.01-1.30), accepting one-night stands (aOR = 1.16, 95%CI:1.03-1.32), obtaining satisfactory sexual interpretation from parent(s) (aOR = 1.24, 95%CI: 1.07-1.43), ever had unintended pregnancy (aOR = 1.78, 95%CI: 1.32-2.38), ever had received HIV-related preventive service(s) (aOR = 1.37, 95%CI: 1.10-1.70), ever had participated HIV-related preventive services (aOR = 3.76, 95%CI: 2.99-4.75) and ever had anal sex (aOR = 2.66, 95%CI: 2.11-3.34) were positively associated with uptake of HIV testing. However, accepting premarital sex (aOR = 0.76, 95%CI: 0.66-0.88), accepting cohabitation (aOR = 0.75, 95%CI: 0.61-0.92), occasionally discussing sex with parent(s) (aOR = 0.68, 95%CI: 0.50-0.91), and being with moderate satisfaction of school sex courses (aOR = 0.74, 95%CI: 0.58-0.95) were negatively associated with uptake of HIV testing. CONCLUSION: The prevalence of HIV testing was relatively low. Participation in HIV-related services and high-risk sexual behaviors were important enablers for testing. Improving sex education for students, increasing HIV preventive services on campus, and improving family sex education are necessary to increase HIV testing among college sexually experienced students.