Thiazolidine Deprotection Using an Organic Solvent Extractable Aldehyde Scavenger for One-Pot Four-Segment Ligation.

We report a simple and convenient N-terminal thiazolidine (Thz) deprotection strategy and its application in one-pot multisegment ligation. In this strategy, O-benzylhydroxylamine (O-BHA) is used to efficiently and rapidly convert Thz into N-terminal cysteine. O-BHA can be easily separated from the ligation buffer by organic solvent extraction, avoiding the degradation of the peptide thioester by O-BHA. The utility of the O-BHA-based one-pot ligation strategy has been demonstrated in the assembly of CC chemokine ligand-2.

Induced pluripotent stem cell-derived mesenchymal stem cells enhance acellular nerve allografts to promote peripheral nerve regeneration by facilitating angiogenesis.

Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells. However, adult tissue-derived mesenchymal stem cells encounter various obstacles, including limited tissue sources, invasive acquisition methods, cellular heterogeneity, purification challenges, cellular senescence, and diminished pluripotency and proliferation over successive passages. In this study, we used induced pluripotent stem cell-derived mesenchymal stem cells, known for their self-renewal capacity, multilineage differentiation potential, and immunomodulatory characteristics. We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury. Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation. Furthermore, the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats. Additionally, our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization. Collectively, our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats, offering promising therapeutic strategies for clinical translation.

Cross-correlation and multifractality analysis of the Chinese and American stock markets based on the MF-DCCA model.

Objective: To compare the multifractal features and factors of the Chinese and American stock markets and their correlation, complexity and uncertainty. Methods: The paper analyzes the CSI 300 and S&P 500 indices from March 2018 to March 2023 using the MF-DCCA model and removes the long-term memory and nonlinear effects by random reshuffling and phase processing methods. Results: The paper shows that (1) CSI 300 and S&P 500 have multifractal features, with different long-term memory, complexity and irregularity at different scales; (2) The markets are fractal movements influenced by investors' irrationality and expectations, not efficient markets; (3) Long-term memory and nonlinear effects cause the multifractal features. The paper offers a new perspective and method for the market investors and regulators.

DcMYB62, a transcription factor from carrot, enhanced cadmium tolerance of Arabidopsis by inducing the accumulation of carotenoids and hydrogen sulfide.

Cadmium (Cd) is a significant heavy metal contaminant within the environment, carrying a notable level of toxicity that presents a substantial hazard to both plant and human. Carrot (Daucus carota), a significant root vegetable crop globally, have evolved multiple transcriptional regulatory mechanisms to cope with Cd stress, with a crucial involvement of the myeloblastosis (MYB) transcription factor. In this study, the DcMYB62 gene encoding 288 amino acids, localized in the nucleus and demonstrated transcription activation property, was isolated from carrot (cv. 'Kuroda'). There was a positive relationship observed between the levels of DcMYB62 expression and the accumulation patterns of carotenoids in two distinct carrot cultivars. Further investigation revealed that the expression of DcMYB62 improved Cd tolerance of Arabidopsis by increasing seed germination rate, root length, and overall survival rate. The levels of carotenoids in DcMYB62 transgenic Arabidopsis surpassed those in wild type, accompanied by elevated expression levels of 15-cis-phytoene desaturase, zeta-carotene desaturase, and carotenoid isomerase. Meanwhile, the heterologous expression of DcMYB62 promoted the biosynthesis of abscisic acid (ABA) and hydrogen sulfide (H2S), which in turn suppressed the formation of hydrogen peroxide and superoxide anion, while also stimulating stomatal closure. Furthermore, the heterologous expression of DcMYB62 increased the transcription of genes associated with heavy metal resistance in Arabidopsis, notably nicotianamine synthase. Overall, this study contributes to understanding how DcMYB62 promote Cd stress resistance of plants by regulating the biosynthesis pathways of carotenoids, ABA, and H2S, which offers valuable insights into the regulatory mechanism connecting DcMYBs with Cd stress response of carrot.

Investigating the impact of dietary guidelines transition on cardiometabolic risk profile: a forensic analysis using diet quality metrics.

Evaluating dietary guidelines using diet quality (DQ) offers valuable insights into the healthfulness of a population's diet. We conducted a forensic analysis using DQ metrics to compare the Malaysian Dietary Guidelines (MDG-2020) with its former version (MDG-2010) in relation to cardiometabolic risk (CMR) for an adult Malaysian population. A DQ analysis of cross-sectional data from the Malaysia Lipid Study (MLS) cohort (n = 577, age: 20-65yrs) was performed using the healthy eating index-2015 (HEI-2015) framework in conformation with MDG-2020 (MHEI2020) and MDG-2010 (MHEI2010). Of 13 dietary components, recommended servings for whole grain, refined grain, beans and legumes, total protein, and dairy differed between MDGs. DQ score associations with CMR, dietary patterns and sociodemographic factors were examined. Out of 100, total DQ scores of MLS participants were 'poor' for both MHEI2020 (37.1 ± 10.3) and MHEI2010 (39.1 ± 10.4), especially among young adults, males, Malays, and those frequently 'eating out' as well as those with greatest adherence to Sugar-Sweetened Beverages pattern and lowest adherence to Food Plant pattern. Both metrics shared similar correlations with CMR markers, with MHEI2020 exhibiting stronger correlations with WC, BF%, TG, insulin, HOMA2-IR, and smallLDL than MHEI2010, primarily attributed to reduced refined grain serving. Notably, participants with the highest adherence to MHEI2020 scores exhibited significantly reduced odds for elevated TG (AOR 0.44, 95% CI 0.21-0.93, p = 0.030), HOMA2-IR (AOR 0.44, 95% CI 0.21-0.88, p = 0.022), and hsCRP (AOR 0.54, 95% CI 0.31-0.96, p = 0.040, compared to those with the lowest adherence. Each 5-unit increase in MHEI2020 scores reduced odds for elevated BMI (- 14%), WC (- 9%), LDL-C (- 32%), TG (- 15%), HOMA2-IR (- 9%) and hsCRP (- 12%). While MHEI2020 scores demonstrated better calibration with CMR indicators, the overall sub-optimally 'poor' DQ scores of this population call for health promotion activities to target the public to achieve adequate intake of healthful fruits, non-starchy vegetables and whole grain, and moderate intake of refined grain, added sugar and saturated fat.

Fully automated hybrid approach on conventional MRI for triaging clinically significant liver fibrosis: A multi-center cohort study.

Establishing reliable noninvasive tools to precisely diagnose clinically significant liver fibrosis (SF, ≥F2) remains an unmet need. We aimed to build a combined radiomics-clinic (CoRC) model for triaging SF and explore the additive value of the CoRC model to transient elastography-based liver stiffness measurement (FibroScan, TE-LSM). This retrospective study recruited 595 patients with biopsy-proven liver fibrosis at two centers between January 2015 and December 2021. At Center 1, the patients before December 2018 were randomly split into training (276) and internal test (118) sets, the remaining were time-independent as a temporal test set (96). Another data set (105) from Center 2 was collected for external testing. Radiomics scores were built with selected features from Deep learning-based (ResUNet) automated whole liver segmentations on MRI (T2FS and delayed enhanced-T1WI). The CoRC model incorporated radiomics scores and relevant clinical variables with logistic regression, comparing routine approaches. Diagnostic performance was evaluated by the area under the receiver operating characteristic curve (AUC). The additive value of the CoRC model to TE-LSM was investigated, considering necroinflammation. The CoRC model achieved AUCs of 0.79 (0.70, 0.86), 0.82 (0.73, 0.89), and 0.81 (0.72-0.91), outperformed FIB-4, APRI (all p < 0.05) in the internal, temporal, and external test sets and maintained the discriminatory power in G0-1 subgroups (AUCs range, 0.85-0.86; all p < 0.05). The AUCs of joint CoRC-LSM model were 0.86 (0.79-0.94), and 0.81 (0.72-0.90) in the internal and temporal sets (p = 0.01). The CoRC model was useful for triaging SF, and may add value to TE-LSM.

Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury.

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet. In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion. We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m6A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI. By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.

Simultaneous imaging and element differentiation by energy-resolved x-ray absorption ghost imaging.

Based on the x-ray absorption edges of different elements, we simultaneously image and distinguish the composition of three differently shaped components of an object by using energy-resolved x-ray absorption ghost imaging (GI). The initial x-ray beam is spatially modulated by a series of Hadamard matrix masks, and the object is composed of three pieces of Mo, Ag, and Sn foil in the shape of a triangle, square, and circle, respectively. The transmitted x-ray intensity is measured by an energy-resolved single-pixel detector with a spectral resolution better than 0.8 keV. Through correlation of the transmission spectra with the corresponding Hadamard patterns, the spectral image of the sample is reconstructed, with a spatial resolution of 108 µm. Our experiment demonstrates a practical application of spectral ghost imaging, which has important potential for the noninvasive analysis of material composition and distribution in biology, medical science, and many other fields.

Gender-Specific Pathways in Violent Crime: Investigating the Role of Demographic and Mental Health Factors Using Mixed Graphical Models and Bayesian Networks.

This research aims to uncover gender-specific relationships and pathways that contribute to the perpetration of violent crimes, using sophisticated analytical tools to analyze the complex interactions between various factors. Employing Mixed Graphical Models and Bayesian networks, the study analyzes a sample of 1,254 prisoners (61.64% males and 38.36% females) to investigate the relationships among demographic factors, mental health issues, and violent crime. The study utilizes comprehensive measures, including the Beck Depression Inventory, Beck Anxiety Inventory, and Childhood Trauma Questionnaire, to assess participants' mental health status.Key findings reveal significant gender differences in the pathways to violent crime. For males, incomplete parental marriages strongly correlate with criminal behavior severity, while marriage status emerges as a significant factor, with married males less likely to commit violent crimes. In contrast, these relationships are not significant for females. Bayesian network analysis indicates that living in urban areas differently influences education and emotional expression across genders, emphasizing the importance of contextual factors. The study highlights the need for gender-specific considerations in criminal justice policies and interventions. It underscores the complex interplay of demographic and mental health factors in influencing violent crime pathways, providing insights for developing more effective prevention strategies. Despite its cross-sectional design and reliance on self-reported data, the research significantly contributes to understanding the gendered dimensions of criminal behavior.

Role of TRPC6 in apoptosis of skeletal muscle ischemia/reperfusion injury.

BACKGROUND: Skeletal muscle ischaemia-reperfusion injury (IRI) is a prevalent condition encountered in clinical practice, characterised by muscular dystrophy. Owing to limited treatment options and poor prognosis, it can lead to movement impairments, tissue damage, and disability. This study aimed to determine and verify the influence of transient receptor potential canonical 6 (TRPC6) on skeletal muscle IRI, and to explore the role of TRPC6 in the occurrence of skeletal muscle IRI and the signal transduction pathways activated by TRPC6 to provide novel insights for the treatment and intervention of skeletal muscle IRI. METHODS: In vivo ischaemia/reperfusion (I/R) and in vitro hypoxia/reoxygenation (H/R) models were established, and data were comprehensively analysed at histopathological, cellular, and molecular levels, along with the evaluation of the exercise capacity in mice. RESULTS: By comparing TRPC6 knockout mice with wild-type mice, we found that TRPC6 knockout of TRPC6 could reduced skeletal muscle injury after I/R or H/R, of skeletal muscle, so as therebyto restoringe some exercise capacity inof mice. TRPC6 knockdown can reduced Ca2+ overload in cells, therebyo reducinge apoptosis. In additionAdditionally, we also found that TRPC6 functionsis not only a key ion channel involved in skeletal muscle I/R injury, but also can affects Ca2+ levels and then phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signalling pathway. by knocking downTherefore, knockdown of TRPC6, so as to alleviated the injury inducedcaused by skeletal muscle I/R or and H/R. CONCLUSIONS: These findingsdata indicate that the presence of TRPC6 exacerbatescan aggravate the injury of skeletal muscle injury after I/Rischemia/reperfusion, leading towhich not only causes Ca2+ overload and apoptosis., Additionally, it impairsbut also reduces the self- repair ability of cells by inhibiting the expression of the PI3K/Akt/mTOR signalling pathway. ETo exploringe the function and role of TRPC6 in skeletal muscle maycan presentprovide a novelew approachidea for the treatment of skeletal muscle ischemia/reperfusion injury.

Acute kidney injury with intravenous colistin sulfate compared with polymyxin B in critically ill patients: A real-world, retrospective cohort study.

BACKGROUND: Polymyxins have re-emerged as a last-resort therapeutic option for infections caused by carbapenem-resistant gram-negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. METHODS: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30-day all-cause mortality. Additionally, the risk factors of polymyxins-induced AKI and 30-day all-cause mortality were identified by Cox proportional hazard regression analysis. RESULTS: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30-day all-cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin-induced AKI. CONCLUSIONS: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30-day all-cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings.

Physical exercise-related manifestations of long COVID: A systematic review and meta-analysis.

Objective: This study aims to systematically assess physical exercise-related symptoms of post-acute sequelae of SARS-CoV-2 infection (PASC or long COVID) in coronavirus disease 2019 (COVID-19) survivors. Methods: Eight databases were systematically searched on March 03, 2024. Original studies that compared physical exercise-related parameters measured by exercise testing between COVID-19 survivors who recovered from SARS-CoV-2 infection over 3 months and non-COVID-19 controls were included. A random-effects model was utilized to determine the mean differences (MDs) or standardized MDs in the meta-analysis. Results: A total of 40 studies with 6241 COVID-19 survivors were included. The 6-min walk test, maximal oxygen consumption (VO2max), and anaerobic threshold were impaired in COVID-19 survivors 3 months post-infection compared with non-COVID-19 controls in exercise testing, while VO2 were comparable between the two groups at rest. In contrast, no differences were observed in SpO2, heart rate, blood pressure, fatigue, and dyspnea between COVID-19 survivors and non-COVID-19 controls in exercise testing. Conclusion: The findings suggest an underestimation of the manifestations of PASC. COVID-19 survivors also harbor physical exercise-related symptoms of PASC that can be determined by the exercise testing and are distinct from those observed at rest. Exercise testing should be included while evaluating the symptoms of PASC in COVID-19 survivors.

Global Prevalence, Clinical Characteristics, Surveillance, Treatment Allocation, and Outcomes of Alcohol-Associated Hepatocellular Carcinoma.

BACKGROUND: Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS: Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS: Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes. CONCLUSIONS: Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.

Sex-based Disparities in Liver Transplantation for Hepatocellular Carcinoma and the Impact of the Growing Burden of NASH.

Background: The cause of liver disease is changing, but its impact on liver transplantation (LT) for hepatocellular carcinoma (HCC) in women and men is unclear. We performed a nationwide study to assess the prevalence and posttransplant survival outcomes of the various causes of liver disease in women and men with HCC. Methods: Data were obtained from the United Network for Organ Sharing database from 2000 to 2022. Data related to the listing, transplant, waitlist mortality, and posttransplant mortality for HCC were extracted. The proportion of HCC related to the various causes of liver disease among LT candidates and recipients and posttransplant survival were compared between women and men. Results: A total of 51 721 individuals (39 465 men, 12 256 women) with HCC were included. From 2000 to 2022, nonalcoholic steatohepatitis (NASH) was the fastest-growing cause of liver disease among female LT candidates with HCC (P < 0.01), followed by alcohol-associated liver disease. NASH overtook chronic hepatitis C as the leading cause of liver disease in 2020 and 2022 among waitlisted women and men with HCC, respectively. Female patients with HCC spent a significantly longer time on the LT waitlist compared with male patients (ß: 8.73; 95% confidence interval [CI], 2.91-14.54). Female patients with HCC from alcohol-associated liver disease also have a lower probability of receiving LT (subdistribution hazard ratio: 0.90; 95% CI, 0.82-0.99). Among transplant recipients with NASH HCC, female sex was associated with lower posttransplant mortality compared with male sex (hazard ratio: 0.79; 95% CI, 0.70-0.89; P < 0.01). Conclusions: Women have a significantly longer waitlist duration compared with men. NASH is now the leading cause of liver disease among both female and male LT candidates and recipients with HCC.

Sex and Race-Ethnic Disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis of 40,166 Individuals.

BACKGROUND: To overcome the limitations of the term "non-alcoholic fatty liver disease" (NAFLD), the term metabolic-associated steatotic liver disease (MASLD) was introduced. While epidemiologic studies have been conducted on MASLD, there is limited evidence on its associated sex and ethnic variations. AIMS: This study assesses the differences across sex and race-ethnicity on the prevalence, associated risk factors and adverse outcomes in individuals with MASLD. METHODS: Data retrieved from the National Health and Nutrition Examination Survey between 1999 to 2018 was analyzed. Prevalence, clinical characteristics, and outcomes were evaluated according to sex and race-ethnicity. Adverse outcomes and mortality events were analyzed using multivariate analyses. RESULTS: Of 40,166 individuals included, 37.63% had MASLD. There was a significant increase in MASLD prevalence from 1999 to 2018 among Mexican Americans (Annual Percentage Change [APC] + 1.889%, p < 0.001), other Hispanics (APC + 1.661%, p = 0.013), NH Whites (APC + 1.084%, p = 0.018), NH Blacks (APC + 1.108%, p = 0.007), and females (APC + 0.879%, p = 0.030), but not males. Females with MASLD were at lower risk of all-cause (HR: 0.766, 95%CI 0.711 to 0.825, p < 0.001), cardiovascular disease-related (CVD) (SHR: 0.802, 95% CI 0.698 to 0.922, p = 0.002) and cancer-related mortality (SHR: 0.760, 95% CI 0.662 to 0.873, p < 0.001). Significantly, NH Blacks have the highest risk of all-cause and CVD-related mortality followed by NH Whites then Mexican Americans. CONCLUSION: There has been an increase in prevalence in most race-ethnicities over time. While the change in definition shows no significant differences in previous associations found in NAFLD, the increased mortality in NH Whites relative to Mexican Americans remains to be explored.

"Ion-imprinting" strategy towards metal sulfide scavenger enables the highly selective capture of radiocesium.

Highly selective capture of radiocesium is an urgent need for environmental radioactive contamination remediation and spent fuel disposal. Herein, a strategy is proposed for construction of "inorganic ion-imprinted adsorbents" with ion recognition-separation capabilities, and a metal sulfide Cs2.33Ga2.33Sn1.67S8·H2O (FJSM-CGTS) with "imprinting effect" on Cs+ is prepared. We show that the K+ activation product of FJSM-CGTS, Cs0.51K1.82Ga2.33Sn1.67S8·H2O (FJMS-KCGTS), can reach adsorption equilibrium for Cs+ within 5 min, with a maximum adsorption capacity of 246.65 mg·g-1. FJMS-KCGTS overcomes the hindrance of Cs+ adsorption by competing ions and realizes highly selective capture of Cs+ in complex environments. It shows successful cleanup for actual 137Cs-liquid-wastes generated during industrial production with removal rates of over 99%. Ion-exchange column filled with FJMS-KCGTS can efficiently treat 540 mL Cs+-containing solutions (31.995 mg·L-1) and generates only 0.12 mL of solid waste, which enables waste solution volume reduction. Single-crystal structural analysis and density functional theory calculations are used to visualize the "ion-imprinting" process and confirm that the "imprinting effect" originates from the spatially confined effect of the framework. This work clearly reveals radiocesium capture mechanism and structure-function relationships that could inspire the development of efficient inorganic adsorbents for selective recognition and separation of key radionuclides.

Cellular mechanism underlying leptin-induced anion secretion of rat epididymal epithelial cells.

BACKGROUND: A large number of studies have shown that leptin plays an important role in the regulation of fertility via the hypothalamus-pituitary-gonad axis. However, its peripheral function in epididymis was still elusive. OBJECTIVE: The purpose of this study was to determine the pro-secretion effect of leptin on the rat epididymal epithelium. MATERIALS AND METHODS: In the present study, real-time quantitative polymerase chain reaction, western blot, and immunohistochemical analysis were employed to detect the expression pattern of leptin receptors in rat epididymis. The pro-secretion effect of leptin on epididymal epithelial cells was measured by short-circuit current, and the prostaglandin E2 and cyclic adenosine monophosphate level was evaluated by enzyme-linked immunosorbent assay. RESULTS: We verified that the leptin receptor was located on the epididymal epithelium, with a relatively high expression level in corpus and cauda epididymis. Ussing chamber experiments showed that leptin stimulated a significant rise of the short-circuit current in rat epididymal epithelial cells, which could be abolished by the specific leptin receptor antagonist peptide Allo-aca, or by removing the ambient Cl- and HCO3 -. Furthermore, the leptin-stimulated short-circuit current response could be abrogated by blocking the apical cystic fibrosis transmembrane regulator or the basolateral Na+-K+-2Cl- cotransporter. Our pharmacological experiments manifested that interfering with the prostaglandin H synthase-2-prostaglandin E2-EP2/EP4-adenylate cyclase pathways could significantly blunt the cystic fibrosis transmembrane regulator-mediated anion secretion induced by leptin. The enzyme-linked immunosorbent assay demonstrated that leptin could induce a substantial increase in prostaglandin E2 release and cyclic adenosine monophosphate synthesis of primary cultured rat cauda epididymal epithelial cells. Our data also suggested that JAK2, ERK, and PI3K-dependent phosphorylation may be involved in the activation of prostaglandin H synthase-2 and the subsequent prostaglandin E2 production. CONCLUSIONS: The present study demonstrated the pro-secretion function of leptin in rat epididymal epithelium via the activation of cystic fibrosis transmembrane regulator and Na+-K+-2Cl- cotransporter, which was dependent on the paracrine/autocrine prostaglandin E2 stimulated EP2/EP4-adenylate cyclase pathways, and thus contributed to the formation of an appropriate microenvironment essential for sperm maturation.

The discovery of a novel pyrrolo[2,3-b]pyridine as a selective CDK8 inhibitor offers a new approach against psoriasis.

Currently, the drugs used in clinical to treat psoriasis mainly broadly suppress cellular immunity. However, these drugs can only provide temporary and partial symptom relief, they do not cure the condition and may lead to recurrence or even serious toxic side effects. In this study, we describe the discovery of a novel potent CDK8 inhibitor as a treatment for psoriasis. Through structure-based design, compound 46 was identified as the most promising candidate, exhibiting a strong inhibitory effect on CDK8 (IC50 value of 57 nM) along with favourable inhibition against NF-κB. Additionally, it demonstrated a positive effect in an in vitro psoriasis model induced by TNF-α. Furthermore, this compound enhanced the thermal stability of CDK8 and exerted evident effects on the biological function of CDK8, and it had favourable selectivity across the CDK family and tyrosine kinase. This compound showed no obvious inhibitory effect on CYP450 enzyme. Further studies confirmed that compound 46 exhibited therapeutic effect on IMQ-induced psoriasis, alleviated the inflammatory response in mice, and enhanced the expression of Foxp3 and IL-10 in the dorsal skin in vivo. This discovery provides a new strategy for developing selective CDK8 inhibitors with anti-inflammatory activity for the treatment of psoriasis.

Gradient gyroid Ti6Al4V scaffolds with TiO2 surface modification: Promising approach for large bone defect repair.

Large bone defects, particularly those exceeding the critical size, present a clinical challenge due to the limited regenerative capacity of bone tissue. Traditional treatments like autografts and allografts are constrained by donor availability, immune rejection, and mechanical performance. This study aimed to develop an effective solution by designing gradient gyroid scaffolds with titania (TiO2) surface modification for the repair of large segmental bone defects. The scaffolds were engineered to balance mechanical strength with the necessary internal space to promote new bone formation and nutrient exchange. A gradient design of the scaffold was optimized through Finite Element Analysis (FEA) and Computational Fluid Dynamics (CFD) simulations to enhance fluid flow and cell adhesion. In vivo studies in rabbits demonstrated that the G@TiO2 scaffold, featuring a gradient structure and TiO2 surface modification, exhibited superior healing capabilities compared to the homogeneous structure and TiO2 surface modification (H@TiO2) and gradient structure (G) scaffolds. At 12 weeks post-operation, in a bone defect representing nearly 30 % of the total length of the radius, the implantation of the G@TiO2 scaffold achieved a 27 % bone volume to tissue volume (BV/TV) ratio, demonstrating excellent osseointegration. The TiO2 surface modification provided photothermal antibacterial effects, enhancing the scaffold's biocompatibility and potential for infection prevention. These findings suggest that the gradient gyroid scaffold with TiO2 surface modification is a promising candidate for treating large segmental bone defects, offering a combination of mechanical strength, bioactivity, and infection resistance.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.