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Abstract Background Melanoma is a highly aggressive form of skin cancer. The existence of cancer stem cells (CSCs) and tumor immune evasion are two major causes of melanoma progression, but no effective treatment has been found at present. Astragalus polysaccharide (APS) is a principal active component derived from Astragalus membranaceus, showing anti-tumor effects in various tumors including melanoma. However, the underlying mechanism is still unclear. Methods The regulation of APS on self-renewal ability and CSC markers expression in melanoma stem cells (MSCs) was measured by tumor sphere formation and tumorigenicity assays, RT-qPCR, and western blot. Flow cytometry was conducted to evaluate the activation of immune system by APS in melanoma mice. Further, the mechanism was explored based on PD-L1 overexpression and knock-down B16 cells. Results APS attenuated the tumor sphere formation of MSCs in vitro as well as the tumorigenicity in vivo. It also decreased the expression of CD133, BMI1 and CD47. Based on the PD-L1 overexpression and knock-down B16 cells, it was confirmed that APS inhibited the induction of MSCs by down-regulating PD-L1 expression. Meanwhile, APS increased the infiltration of CD4+ and CD8+T cells in tumor tissues because of its inhibitory effect on PD-L1. Conclusions APS inhibited MSC induction and overcame tumor immune evasion through reducing PD-L1 expression. This study provided compelling evidence that APS could be a prospective therapeutic agent for treating melanoma.

Abstract Background Accumulating evidence suggests that cardiovascular diseases and breast cancer share a number of common risk factors, however, evidence on the association between cardiovascular health (CVH) and breast cancer is limited. The present study aimed to assess the association of CVH, defined by Life’s Essential 8 (LE8) and genetic risk with breast cancer incidence and mortality among premenopausal and postmenopausal women. Methods We used data from the UK Biobank and conducted the multivariate Cox proportional-hazards models to examine associations of LE8 score and genetic risk with breast cancer incidence and mortality. Date on LE8 score was collected between 2006 and 2010 and composed of eight components, including behavioral metrics (diet, tobacco or nicotine exposure, physical activity, and sleep health), and biological metrics (body mass index, blood lipids, blood glucose, and blood pressure). The polygenic risk score (PRS) was calculated as the sum of effect sizes of individual genetic variants multiplied by the allele dosage. Results A total of 150,566 premenopausal and postmenopausal women were included. Compared to postmenopausal women with low LE8 score, those with high LE8 score were associated with 22% lower risk of breast cancer incidence (HR: 0.78, 95% CI: 0.70–0.87) and 43% lower risk of breast cancer mortality (HR: 0.57, 95% CI: 0.36–0.90). By contrast, we did not observe the significant association among premenopausal women. Further analyses stratified by PRS categories showed that high LE8 score was associated with 28% and 71% decreased risk of breast cancer incidence (HR: 0.72, 95% CI: 0.60–0.87) and mortality (HR: 0.29, 95% CI: 0.10–0.83) compared to low LE8 score among high genetic risk groups, but no significant associations were found among low genetic risk groups. Furthermore, compared with postmenopausal women with high LE8 score and low genetic risk, those with low LE8 score and high genetic risk were associated with increased risk of breast cancer incidence (HR: 6.26, 95% CI: 4.43–8.84). Conclusions The present study suggests that better CVH is a protective factor for both breast cancer incidence and mortality among postmenopausal women. Moreover, the risk of developing breast cancer caused by high genetic susceptibility could be largely offset by better CVH.

Water is the important medium of the tea infusions, which plays a crucial role in the development of tea quality. Tooma sinensis (TS) fermented tea was brewed with tap water, mineral water and purified water. The physicochemical indexes, biochemical components, antioxidant activity and flavor compounds of three types tea infusions were analyzed using ultraviolet spectrophotometer, electronic tongue and gas chromatography-mass spectrometry (GC-MS) to elucidate the influence of different brewing water on the quality of TS fermented tea infusions. The results demonstrated that the quality and antioxidant activity of TS fermented tea infusions were significant influenced by different brewing water (P

Abstract Peripheral arterial diseases (PAD) have been reported to be the leading cause for limb amputations, and the current therapeutic strategies including antiplatelet medication or intervene surgery are reported to not clinically benefit the patients with high-grade PAD. To this respect, revascularization based on angiogenetic vascular endothelial growth factor (VEGF) gene therapy was attempted for the potential treatment of critical PAD. Aiming for transcellular delivery of VEGF-encoding plasmid DNA (pDNA), we proposed to elaborate intriguing virus-like DNA condensates, wherein the supercoiled rigid micrometer-scaled plasmid DNA (pDNA) could be regulated in an orderly fashion into well-defined nano-toroids by following a self-spooling process with the aid of cationic block copolymer poly(ethylene glycol)-polylysine at an extraordinary ionic strength (NaCl: 600 mM). Moreover, reversible disulfide crosslinking was proposed between the polylysine segments with the aim of stabilizing these intriguing toroidal condensates. Pertaining to the critical hindlimb ischemia, our proposed toroidal VEGF-encoding pDNA condensates demonstrated high levels of VEGF expression at the dosage sites, which consequently contributed to the neo-vasculature (the particularly abundant formation of micro-vessels in the injected hindlimb), preventing the hindlimb ischemia from causing necrosis at the extremities. Moreover, excellent safety profiles have been demonstrated by our proposed toroidal condensates, as opposed to the apparent immunogenicity of the naked pDNA. Hence, our proposed virus-like DNA condensates herald potentials as gene therapy platform in persistent expressions of the therapeutic proteins, and might consequently be highlighted in the management of a variety of intractable diseases.

Abstract Triple negative breast cancer (TNBC) has the characteristics of low immune cell infiltration, high expression of tumor programmed death ligand 1 (PD-L1), and abundant cancer stem cells. Systemic toxicity of traditional chemotherapy drugs due to poor drug selectivity, and chemotherapy failure due to tumor drug resistance and other problems, so it is particularly important to find new cancer treatment strategies for TNBC with limited treatment options. Both the anti-tumor natural drugs curcumin and ginsenoside Rg3 can exert anti-tumor effects by inducing immunogenic cell death (ICD) of tumor cells, reducing PD-L1 expression, and reducing cancer stem cells. However, they have the disadvantages of poor water solubility, low bioavailability, and weak anti-tumor effect of single agents. We used vinyl ether bonds to link curcumin (Cur) with N-O type zwitterionic polymers and at the same time encapsulated ginsenoside Rg3 to obtain hyperbranched zwitterionic drug-loaded micelles OPDEA-PGED-5HA@Cur@Rg3 (PPH@CR) with pH response. In vitro cell experiments and in vivo animal experiments have proved that PPH@CR could not only promote the maturation of dendritic cells (DCs) and increase the CD4+ T cells and CD8+ T cells by inducing ICD in tumor cells but also reduce the expression of PD-L1 in tumor tissues, and reduce cancer stem cells and showed better anti-tumor effects and good biological safety compared with free double drugs, which is a promising cancer treatment strategy.

Abstract Background To evaluate a novel intraoperative localization technique utilizing temporary pulmonary arteriovenous occlusion for enhancing the precision of sublobar resections in early‐stage NSCLC. Methods Conducted from January to November 2023, this study involved 140 patients. During the surgery, key pulmonary vessels were identified using preoperative three‐dimensional (3D) imaging and temporarily occluded with noninvasive clamps to isolate the target lung segment. Following vascular occlusion, indocyanine green (ICG) was administered intravenously to precisely delineate the resection margins. After visually confirming the marked areas, the clamps were released, and a targeted partial resection was performed on the delineated segment. Surgical data, including operation times, surgical margins, and hospitalization costs, were collected and compared with those from a historical control group of 110 patients who underwent traditional pulmonary wedge resections. Results In the study group, the median surgical margin achieved was 16 mm, which was statistically significant compared to 15 mm in the control group (p

Abstract Background Multidrug-resistant organisms (MDRO) pose a significant threat to public health. Intensive Care Units (ICU), characterized by the extensive use of antimicrobial agents and a high prevalence of bacterial resistance, are hotspots for MDRO proliferation. Timely identification of patients at high risk for MDRO can aid in curbing transmission, enhancing patient outcomes, and maintaining the cleanliness of the ICU environment. This study focused on developing a machine learning (ML) model to identify patients at risk of MDRO during the initial phase of their ICU stay. Methods Utilizing patient data from the First Medical Center of the People’s Liberation Army General Hospital (PLAGH-ICU) and the Medical Information Mart for Intensive Care (MIMIC-IV), the study analyzed variables within 24 h of ICU admission. Machine learning algorithms were applied to these datasets, emphasizing the early detection of MDRO colonization or infection. Model efficacy was evaluated by the area under the receiver operating characteristics curve (AUROC), alongside internal and external validation sets. Results The study evaluated 3,536 patients in PLAGH-ICU and 34,923 in MIMIC-IV, revealing MDRO prevalence of 11.96% and 8.81%, respectively. Significant differences in ICU and hospital stays, along with mortality rates, were observed between MDRO positive and negative patients. In the temporal validation, the PLAGH-ICU model achieved an AUROC of 0.786 [0.748, 0.825], while the MIMIC-IV model reached 0.744 [0.723, 0.766]. External validation demonstrated reduced model performance across different datasets. Key predictors included biochemical markers and the duration of pre-ICU hospital stay. Conclusions The ML models developed in this study demonstrated their capability in early identification of MDRO risks in ICU patients. Continuous refinement and validation in varied clinical contexts remain essential for future applications.

AbstractAs a processed product of traditional Chinese medicine Curcumae Radix, Curcumae Radix Carbonisata (CRC) has been widely used in the treatment of liver diseases in ancient medical books. In this study, novel carbon dots (CDs) extending from 1.0 to 4.5 nm were separated from fluid extricates of CRC. Meanwhile, a liver fibrosis model induced by carbon tetrachloride (CCl4) was utilized to determine the inhibitory effects of CRC-CDs against liver fibrosis. The results exhibited the CRC-CDs with a quantum yield of 1.34% have a significant inhibitory effect on CCl4-induced liver fibrosis, as demonstrated by improving hepatocyte degeneration and necrosis, inflammatory cell infiltration and fibrotic tissue hyperplasia, downregulating the levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), triglyceride (TG), tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in the serum, upregulating the contents of superoxide dismutase (SOD), reduced glutathione (GSH), and downregulating the concentration of malondialdehyde (MDA), which lays an important foundation for the development of CRC-CDs as a novel drug for the treatment of liver fibrosis, and provide a certain experimental basis for the clinical application of CRC-CDs in the future.

AbstractChinese herbs contain substances that regulate female hormones. Our study confirmed that Zingiberis rhizoma carbonisata contains Zingiberis rhizoma-based carbon dots (ZR-CDs), which exert regulatory effects on serum oestradiol and FSH in mice and show impacts on endometrial growth and follicular development that potentially affect the ability of female fertility. ZR-CDs were characterized to clarify the microstructure, optical features, and functional group characteristics. It shows that ZR-CDs are spherical carbon nanostructures ranging from 0.97 to 2.3 nm in diameter, with fluorescent properties and a surface rich in functional groups. We further investigated the impact of ZR-CDs on oestradiol and FSH in serum, growth, and the development of ovarian and uterine using normal female mice and exogenous oestradiol intervention model. It was observed that ZR-CDs accelerated oestrogen metabolism and attenuated oestradiol-induced endometrial hyperplasia. Simultaneously, ZR-CDs triggered an increase in FSH, even in the presence of high-serum oestradiol that inhibits FSH secretion. Our findings suggest that ZR-CDs could be a potential therapeutic treatment for anovulatory menstruation.

The cuticular wax, acting as the ultimate defense barrier, is essential for the normal morphogenesis of plant organs. Despite this importance, the connection between wax composition and leaf development has not been thoroughly explored. In this study, we characterized a new maize mutant, ragged leaf4 (rgd4), which exhibits crinkled and ragged leaves starting from the sixth leaf stage. The phenotype of rgd4 is conferred by ZmCER1, which encoding an aldehyde decarbonylase involved in wax biosynthesis. ZmCER1 function deficient mutant displayed reduced cuticular wax density and disordered bulliform cells (BCs), while ZmCER1 overexpressing plants exhibited the opposite effects, indicating that ZmCER1 regulates cuticular wax biosynthesis and BCs development. Additionally, as the density of cuticular wax increased, the water loss rate of detached leaf decreases, suggesting that ZmCER1 is positively correlated with plant drought tolerance.

Abstract Helicobacter pylori (H. pylori), together with its CagA, has been implicated in causing DNA damage, cell cycle arrest, apoptosis, and the development of gastric cancer. Although lncRNA H19 is abundantly expressed in gastric cancer and functions as a pro-oncogene, it remains unclear whether lncRNA H19 contributes to the oncogenic process of H. pylori CagA. This study investigates the role of H19 in the DNA damage response and malignancy induced by H. pylori. It was observed that cells infected with CagA+ H. pylori strain (GZ7/cagA) showed significantly higher H19 expression, resulting in increased γH2A.X and p-ATM expression and decreased p53 and Rad51 expression. Faster cell migration and invasion was also observed, which was reversed by H19 knockdown in H. pylori. YWHAZ was identified as an H19 target protein, and its expression was increased in H19 knockdown cells. GZ7/cagA infection responded to the increased YWHAZ expression induced by H19 knockdown. In addition, H19 knockdown stimulated cells to enter the G2-phase and attenuated the effect of GZ7/cagA infection on the cellular S-phase barrier. The results suggest that H. pylori CagA can upregulate H19 expression, participate in the DNA damage response and promote cell migration and invasion, and possibly affect cell cycle arrest via regulation of YWHAZ.

Abstract Sysmex DI-60 enumerates and classifies leukocytes. Limited research has evaluated the performance of Sysmex DI-60 in abnormal samples, and most focused on leukopenic samples. We evaluate the efficacy of DI-60 in determining white blood cell (WBC) differentials in normal and abnormal samples in different WBC count. Peripheral blood smears (n = 166) were categorised into normal control and disease groups, and further divided into moderate and severe leucocytosis, mild leucocytosis, normal, mild leukopenia, and moderate and severe leukopenia groups based on WBC count. DI-60 preclassification and verification and manual counting results were assessed using Bland–Altman and Passing–Bablok regression analyses. The Kappa test compared the concordance in the abnormal cell detection between DI-60 and manual counting. DI-60 exhibited notable overall sensitivity and specificity for all cells, except basophils. The correlation between the DI-60 preclassification and manual counting was high for segmented neutrophils, band neutrophils, lymphocytes, and blasts, and improved for all cell classes after verification. The mean difference between DI-60 and manual counting for all cell classes was significantly high in moderate and severe leucocytosis (WBC > 30.0 × 109/L) and moderate and severe leukopenia (WBC

Abstract The mid-Piacenzian warm period (MPWP, ~3.264–3.025 Ma) has gained widespread interest due to its partial analogy with future climate. However, quantitative data–model comparison of East Asian Summer Monsoon (EASM) precipitation during the MPWP is relatively rare, especially due to problems in decoding the imprint of physical processes to climate signals in the records. In this study, pollen-based precipitation records are reconstructed and compared to the multi-model ensemble mean of the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2). We find spatially consistent precipitation increase in most simulations but a spatially divergent change in MPWP records. We reconcile proxy data and simulation by decomposing physical processes that control precipitation. Our results 1) reveal thermodynamic control of an overall enhancement of EASM precipitation and 2) highlight a distinct control of thermodynamic and dynamical processes on increases of tropical and subtropical EASM precipitation, reflecting the two pathways of water vapor supply that enhance EASM precipitation, respectively.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is a common disease in the urinary system, with a high incidence and poor prognosis in advanced stages. Although γ-interferon-inducible protein 16 (IFI16) has been reported to play a role in various tumors, its involvement in ccRCC remains poorly documented, and the molecular mechanisms are not yet clear. Methods We conducted bioinformatics analysis to study the expression of IFI16 in ccRCC using public databases. Additionally, we analyzed and validated clinical specimens that we collected. Subsequently, we explored the impact of IFI16 on ccRCC cell proliferation, migration, and invasion through in vitro and in vivo experiments. Furthermore, we predicted downstream molecules and pathways using transcriptome analysis and confirmed them through follow-up experimental validation. Results IFI16 was significantly upregulated in ccRCC tissue and correlated with poor patient prognosis. In vitro, IFI16 promoted ccRCC cell proliferation, migration, and invasion, while in vivo, it facilitated subcutaneous tumor growth and the formation of lung metastatic foci. Knocking down IFI16 suppressed its oncogenic function. At the molecular level, IFI16 promoted the transcription and translation of IL6, subsequently activating the PI3K/AKT signaling pathway and inducing epithelial-mesenchymal transition (EMT). Conclusion IFI16 induced EMT through the IL6/PI3K/AKT axis, promoting the progression of ccRCC.

Abstract Background The cumulative live birth rate (CLBR) has been regarded as a key measure of in vitro fertilization (IVF) success after a complete treatment cycle. Women undergoing IVF face great psychological pressure and financial burden. A predictive model to estimate CLBR is needed in clinical practice for patient counselling and shaping expectations. Methods This retrospective study included 32,306 complete cycles derived from 29,023 couples undergoing IVF treatment from 2014 to 2020 at a university-affiliated fertility center in China. Three predictive models of CLBR were developed based on three phases of a complete cycle: pre-treatment, post-stimulation, and post-treatment. The non-linear relationship was treated with restricted cubic splines. Subjects from 2014 to 2018 were randomly divided into a training set and a test set at a ratio of 7:3 for model derivation and internal validation, while subjects from 2019 to 2020 were used for temporal validation. Results Predictors of pre-treatment model included female age (non-linear relationship), antral follicle count (non-linear relationship), body mass index, number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, tubal factor, male factor, and scarred uterus. Predictors of post-stimulation model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), number of previous IVF attempts, number of previous embryo transfer failure, type of infertility, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. Predictors of post-treatment model included female age (non-linear relationship), number of oocytes retrieved (non-linear relationship), cumulative Day-3 embryos live-birth capacity (non-linear relationship), number of previous IVF attempts, scarred uterus, stimulation protocol, as well as endometrial thickness, progesterone and luteinizing hormone on trigger day. The C index of the three models were 0.7559, 0.7744, and 0.8270, respectively. All models were well calibrated (p = 0.687, p = 0.468, p = 0.549). In internal validation, the C index of the three models were 0.7422, 0.7722, 0.8234, respectively; and the calibration P values were all greater than 0.05. In temporal validation, the C index were 0.7430, 0.7722, 0.8234 respectively; however, the calibration P values were less than 0.05. Conclusions This study provides three IVF models to predict CLBR according to information from different treatment stage, and these models have been converted into an online calculator ( https://h5.eheren.com/hcyc/pc/index.html#/home ). Internal validation and temporal validation verified the good discrimination of the predictive models. However, temporal validation suggested low accuracy of the predictive models, which might be attributed to time-associated amelioration of IVF practice.

Beef is rich in nutrients and is one of the favored meats among consumers. Market price, consumer willingness to buy and satisfaction are affected by the quality of beef, so it is important to test the quality of beef. At present, traditional beef quality testing methods have the problems of time-consuming, sample damage and complex operation. Recently, non-destructive testing technology has been widely used in beef quality testing because of its advantages of rapidity, high efficiency, non-destructive and environment-friendly. This paper summarises the progress of non-destructive testing technology in beef quality analysis (sensory quality, nutritional quality and other quality), and systematically describes the principles of non-destructive testing techniques such as near-infrared spectroscopy, Raman spectroscopy, hyperspectral imaging, E-tongue and E-nose. The progress of non-destructive testing techniques in beef quality analysis within the last five years is discussed in detail. The existing problems of non-destructive testing technology in beef quality analysis are put forward, and the future application prospect is prospected. It hopes to provide a reference for the research and application of non-destructive testing technology for beef quality.

The capabilities of 23 global climate models (GCMs) from the Coupled Model Intercomparison Project Phase 6 were evaluated for six extreme precipitation indices from 1961 to 2010 using interannual variability and Taylor skill scores in the Yellow River Basin and its eight subregions. The temporal variations and spatial distributions of extreme precipitation indices were projected from 2021 to 2050 under the shared socioeconomic pathway scenarios (SSP2–4.5 and SSP5–8.5). The results show that most GCMs perform well in simulating extreme values (1-day maximum precipitation (RX1day) and 5-day maximum precipitation (RX5day)), duration (consecutive dry days), and intensity index (simple daily intensity index (SDII)), and perform poor in simulating the threshold indices (precipitation on very wet days (R95p) and number of heavy precipitation days (R10mm)). The projected changes in extreme precipitation indicate that under the SSP2-4.5 scenario, future extreme precipitation will increase by 15.7% (RX1day), 15.8% (RX5day), 30.3% (R95p), 1d (R10mm), and 6.6% (SDII), respectively, decrease by 2.1d (CDD). The aforementioned changes are further enhanced under the SSP5-8.5 scenario. Extreme precipitation changes widely in Hekou Town to Longmen, in the northeastern part of the region from Longmen to Sanmenxia, below Huayuankou, and in the interflow basin. HIGHLIGHTS The study evaluated the biases of 23 global climate models (GCMs) from observations and the spatial distribution of the biases.; Interannual variability score, Taylor diagram, and Taylor skill score were used to evaluate CMIP6 GCMs.; The future changes of the Yellow River Basin and its subregions extreme precipitation under SSP2-4.5 and SSP5-8.5 scenarios were projected by using six ETCCDI indices.;

Abstract Multi-generational asexual reproduction of Gastrodia elata Bl. will cause seedling species degeneration. Sexual reproduction of Gastrodia elata Bl. seed is an effective method to solve the problem of degeneration. The development of Gastrodia elata Bl. seeds cannot be separated from the germination fungus. However, there are few strains of germination fungus in production, and there is also the problem of species degradation in application for many years. It is very important for the sexual reproduction of Gastrodia elata Bl. to isolate more new strains of excellent germination fungus from the origin. This study used the Gastrodia elata Bl. f. glauca S. chow seeds germination vegetative propagation corms capture method to isolate its symbiotic germination fungus, and comprehensively identified the species of germination fungus by colony morphology, ITS, sporocarps regeneration and germination function, and compared the growth characteristics and germination ability with other germination fungus (Mycena purpureofusca, Mycena dendrobii and Mycena osmundicola). The germination fungus was isolated from the vegetative propagation corms of Gastrodia elata Bl. f. glauca S. chow seeds and named GYGL-1. After comprehensive identification, GYGL-1 was Mycetinis scorodonius. Compared with other germination fungus, GYGL-1 has fast germination speed, vigorous growth, and high germination ability for Gastrodia elata Bl. f. glauca S. chow seeds. Innovated the isolation method of Gastrodia elata Bl. seeds germination fungus, obtained the regenerated sporocarps of the germination fungus, and discovered that Mycetinis scorodonius has a new function of germinating Gastrodia elata Bl. f. glauca S. chow seeds, enriching the resource library of Gastrodia elata Bl. germination fungus.

Abstract Introduction Atopic dermatitis (AD) is a chronic immuno-inflammatory skin disease. Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor approved for the treatment of mild to moderate AD. This post hoc analysis assesses the efficacy and safety of crisaborole in Chinese patients aged ≥ 2 years with mild to moderate AD. Methods We evaluated the efficacy and safety of crisaborole in Chinese patients from the vehicle-controlled, phase 3 CrisADe CLEAR study. Patients were randomly assigned 2:1 to receive crisaborole or vehicle twice daily, respectively, for 28 days. The primary endpoint was percent change from baseline in Eczema Area and Severity Index (EASI) total score at day 29. Key secondary endpoints were improvement in Investigator’s Static Global Assessment (ISGA), ISGA success, and change from baseline in weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score. Adverse events were documented. Results Of 391 patients in the overall study, 237 were from China, 157 assigned to crisaborole and 80 assigned to vehicle. A greater reduction in percent change from baseline in EASI total score at day 29 was shown in the crisaborole vs. vehicle group (least squares mean [LSM]: −66.34 [95% (confidence interval) CI −71.55 to −61.12] vs. −50.18 [95% CI −58.02 to −42.34]). Response rates for achievement of ISGA improvement (43.2% [95% CI 35.4–51.1] vs. 33.4% [95% CI 22.5–44.2]) and ISGA success (31.7% [95% CI 24.3–39.0] vs. 21.5% [95% CI 12.1–30.9]) at day 29 were higher in the crisaborole vs. vehicle group. A greater reduction in change from baseline in weekly average PP-NRS score at week 4 was observed in the crisaborole vs. vehicle group (LSM: −1.98 [95% CI −2.34 to −1.62] vs. −1.08 [95% CI −1.63 to −0.53]). No new safety signals were observed. Conclusion Crisaborole was effective and well tolerated in Chinese patients aged ≥ 2 years with mild to moderate AD. Trial Registration ClinicalTrials.gov, NCT04360187.

Abstract Background Knowledge of pharmacovigilance (PV) and adverse drug reactions (ADRs) are the core competencies that healthcare students should acquire during their studies. The objective of this study was to assess attitudes towards and knowledge of PV and ADRs among healthcare students in China. Methods An online, cross-sectional survey was conducted nationally among healthcare students in China from April through October 2023. Knowledge of PV and ADRs was assessed using a questionnaire based on current PV guidelines. We performed logistic regression analysis to determine the potential factors related to knowledge of and attitudes towards PV and ADRs. Results A total of 345 students were included in the analysis. Among the healthcare students who participated in the survey, 225 (65.22%) students correctly defined PV, while only 68 (19.71%) had a correct understanding of ADRs. Among all respondents included in the analysis, only 71 (20.58%) reported having taken a PV course. Pharmacy students were more likely to have taken PV courses at a university and to demonstrate superior knowledge compared to other healthcare students. The logistic regression model revealed that the significant predictors of a higher level of PV knowledge were being female (odds ratio [OR]: 1.76; 95% confidence interval (CI): 1.06–2.92; P value: 0.028) and having previously taken PV-related courses (OR: 2.00; 95% CI: 1.06–3.80; P value: 0.034). Conclusions This study revealed that healthcare students’ knowledge of PV and ADRs is unsatisfactory. However, there were a limited number of universities providing PV education. Given the vital role of healthcare professionals in identifying and reporting ADRs, our findings raise significant concerns. Hence, more efforts should be made to enhance PV education for future healthcare professionals.

Adenosine exerts its dual functions of homeostasis and neuromodulation in the brain by acting at mainly 2 G-protein coupled receptors, called A1 and A2A receptors. The adenosine A2A receptor (A2AR) antagonists have been clinically pursued for the last 2 decades, leading to final approval of the istradefylline, an A2AR antagonist, for the treatment of OFF-Parkinson's disease (PD) patients. The approval paves the way to develop novel therapeutic methods for A2AR antagonists to address 2 major unmet medical needs in PD and traumatic brain injury (TBI), namely neuroprotection or improving cognition. In this review, we first consider the evidence for aberrantly increased adenosine signaling in PD and TBI and the sufficiency of the increased A2AR signaling to trigger neurotoxicity and cognitive impairment. We further discuss the increasing preclinical data on the reversal of cognitive deficits in PD and TBI by A2AR antagonists through control of degenerative proteins and synaptotoxicity, and on protection against TBI and PD pathologies by A2AR antagonists through control of neuroinflammation. Moreover, we provide the supporting evidence from multiple human prospective epidemiological studies which revealed an inverse relation between the consumption of caffeine and the risk of developing PD and cognitive decline in aging population and Alzheimer's disease patients. Collectively, the convergence of clinical, epidemiological and experimental evidence supports the validity of A2AR as a new therapeutic target and facilitates the design of A2AR antagonists in clinical trials for disease-modifying and cognitive benefit in PD and TBI patients.

Abstract Based on the theory of empty hole effect of cutting blasting, the Hopkinson effect and Saint–Venant principle are integrated to establish a two-dimensional calculation model of dynamic stress evolution of the holes wall, and then the dynamic fracture mechanism and damage distribution mode of the rock mass in the cutting area under the action of longitudinal waves are predicted. The results of the calculation and numerical simulation are verified by experiments, and the results show that: The time-varying stress function of the circular cavity wall conforms to the periodic dynamic evolution of the trigonometric function, and the theoretical calculation is consistent with the simulation results. Through the calculation of the round holes cut model and the square empty hole cut model, the change of the shape of the holes in the cut area changes the failure form of the surrounding rock mass. The circular empty hole wall is affected by the stress wave to produce "interval ring" destruction, and the effect of the reflected stretch wave is inhibited. The large range of rock mass in the square empty hole wall produces tensile and shear failure, and the rock mass collapses inward under the influence of the second stage stress. Among them, the empty space utilization rate of the square empty hole model is about 8.5 times that of the circular holes model. Vibration monitoring in the center of the cutting area shows that the vibration effect of the circular empty hole is larger than that of the square empty hole, and the proportion of rock breaking energy is lower.

Abstract Molecular recognition of proteins is key to their biological functions and processes such as protein–protein interactions (PPIs). The large binding interface involved and an often relatively flat binding surface make the development of selective protein-binding materials extremely challenging. A general method is reported in this work to construct protein-binding polymeric nanoparticles from cross-linked surfactant micelles. Preparation involves first dynamic covalent chemistry that encodes signature surface lysines on a protein template. A double molecular imprinting procedure fixes the binding groups on the nanoparticle for these lysine groups, meanwhile creating a binding interface complementary to the protein in size, shape, and distribution of acidic groups on the surface. These water-soluble nanoparticles possess excellent specificities for target proteins and sufficient affinities to inhibit natural PPIs such as those between cytochrome c (Cytc) and cytochrome c oxidase (CcO). With the ability to enter cells through a combination of energy-dependent and -independent pathways, they intervene apoptosis by inhibiting the PPI between Cytc and the apoptotic protease activating factor-1 (APAF1). Generality of the preparation and the excellent molecular recognition of the materials have the potential to make them powerful tools to probe protein functions in vitro and in cellulo.

Abstract Background Accumulating evidence suggests a pivotal role of vitamin B2 in the pathogenesis and progression of prostate cancer (PCa). Vitamin B2 intake has been postulated to modulate the screening rate for PCa by altering the concentration of prostate-specific antigen(PSA). However, the relationship between vitamin B2 and PSA remains indeterminate. Hence, we conducted a comprehensive evaluation of the association between vitamin B2 intake and PSA levels, utilizing data from the National Health and Nutrition Examination Survey (NHANES) database. Methods From a pool of 20,371 participants in the NHANES survey conducted between 2003 and 2010, a cohort of 2,323 participants was selected for the present study. The male participants were classified into four distinct groups based on their levels of vitamin B2 intake. We employed a multiple linear regression model and a non-parametric regression method to investigate the relationship between vitamin B2 and PSA levels. Results The study cohort comprised of 2,323 participants with a mean age of 54.95 years (± 11.73). Our findings revealed a statistically significant inverse correlation between vitamin B2 intake (mg) and PSA levels, with a reduction of 0.13 ng/ml PSA concentration for every unit increase in vitamin B2 intake. Furthermore, we employed a fully adjusted model to construct a smooth curve to explore the possible linear relationship between vitamin B2 intake and PSA concentration. Conclusions Our study in American men has unveiled a notable inverse association between vitamin B2 intake and PSA levels, potentially posing a challenge for the identification of asymptomatic prostate cancer. Specifically, our findings suggest that individuals with higher vitamin B2 intake may be at a greater risk of being diagnosed with advanced prostate cancer in the future, possibly indicating a detection bias. These results may offer a novel explanation for the observed positive correlation between vitamin B2 intake and prostate cancer.

Bread wheat (Triticum aestivum) is a staple food crop worldwide. The genetic dissection of important nutrient traits is essential for the biofortification of wheat to meet the nutritional needs of the world’s growing population. Here, 45,298 single-nucleotide polymorphisms (SNPs) from 55K chip arrays were used to genotype a panel of 768 wheat cultivars, and a total of 154 quantitative trait loci (QTLs) were detected for eight traits under three environments by genome-wide association study (GWAS). Three QTLs (qMn-3B.1, qFe-3B.4, and qSe-3B.1/qFe-3B.6) detected repetedly under different environments or traits were subjected to subsequent analyses based on linkage disequilibrium decay and the P-values of significant SNPs. Significant SNPs in the three QTL regions formed six haplotypes for qMn-3B.1, three haplotypes for qFe-3B.4, and three haplotypes for qSe-3B.1/qFe-3B.6. Phenotypic analysis revealed significant differences among haplotypes. These results indicated that the concentrations of several nutrient elements have been modified during the domestication of landraces to modern wheat. Based on the QTL regions, we identified 15 high-confidence genes, eight of which were stably expressed in different tissues and/or developmental stages. TraesCS3B02G046100 in qMn-3B.1 and TraesCS3B02G199500 in qSe-3B.1/qFe-3B.6 were both inferred to interact with metal ions according to the Gene Ontology (GO) analysis. TraesCS3B02G199000, which belongs to qSe-3B.1/qFe-3B.6, was determined to be a member of the WRKY gene family. Overall, this study provides several reliable QTLs that may significantly affect the concentrations of nutrient elements in wheat grain, and this information will facilitate the breeding of wheat cultivars with improved grain properties.

Abstract. Background:. Patients who undergo coronary artery bypass grafting (CABG) are known to be at a significant risk of experiencing long-term adverse events, emphasizing the importance of regular assessments. Evaluating health-related quality of life (HRQoL) serves as a direct method to gauge prognosis. Our objective is to ascertain the prognostic significance of consecutive HRQoL assessments using the Physical Component Summary (PCS) and Mental Component Summary (MCS) derived from the Short-Form 36 (SF-36) health survey in CABG patients. Methods:. The study population consisted of 433 patients who underwent isolated elective CABG at Fuwai Hospital between 2012 and 2013. SF-36 assessments were conducted during both the hospitalization period and follow-up. The primary endpoint of the study was all-cause mortality, while the secondary outcome was a composite measure including death, myocardial infarction, stroke, and repeat revascularization. We assessed the relationships between the PCS and MCS at baseline, as well as their changes during the first 6 months after the surgery (referred to as ΔPCS and ΔMCS, respectively), and the observed outcomes. Results:. The patients were followed for an average of 6.28 years, during which 35 individuals (35/433, 8.1%) died. After adjusting for clinical variables, it was observed that baseline MCS scores (hazard ratio [HR] for a 1-standard deviation [SD] decrease, 1.57; 95% confidence interval [CI], 1.07–2.30) and ΔMCS (HR for a 1-SD decrease, 1.67; 95% CI, 1.09–2.56) were associated with all-cause mortality. However, baseline PCS scores and ΔPCS did not exhibit a significant relationship with all-cause mortality. Notably, there was a dose-response relationship observed between ΔMCS and the likelihood of all-cause mortality (HRs for the 2nd, 3rd and 4th quartiles compared to the 1st quartile, 0.33, 0.45 and 0.11, respectively). Conclusions:. Baseline MCS and changes in MCS were independent predictors for long-term mortality of CABG. Better mental health status and recovery indicated better prognosis.

Abstract Background Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles. Methods A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS. Results Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P

Abstract This article presents a millimetre‐wave (MMW) wideband multibeam antenna array with a pillbox transition using multilayer low‐temperature cofired ceramic (LTCC) technology. The mushroom structure with dual resonant modes offers wideband performance for radiating array, while an integrated pillbox reflector achieves multibeam scheme. To reduce the design complexity of electrically large pillbox system, two popular pillbox transitions are investigated with a unit model method. The proposed unit model can be used to predict the transmission performance of pillbox reflector in any incident angle. Moreover, the mushroom antenna array and power divider fed by quasi‐TEM wave are also designed using unit model, greatly simplifying the design of electrically large pillbox antenna array. In the final design, the long‐slot pillbox transition, rather than multi‐slot transition, is selected due to its ultrawideband performance and simple structure. The proposed LTCC prototype is analysed and fabricated, obtaining a good agreement between simulation and measurement. The measured results show a −10 dB impedance bandwidth of 17.6% from 31 to 37 GHz, and five beams with ±45° scanning range is achieved with sidelobe level lower than −10 dB.

Abstract Background Chemoresistance and immunosuppression are two major obstacles in the current anti-cancer treatments. This study investigates the involvements of a CCAAT enhancer binding protein delta (CEBPD)/vesicle associated membrane protein 3 (VAMP3) axis in paclitaxel (PTX) resistance and immune evasion in triple-negative breast cancer (TNBC). Methods PTX resistance-related genes were screened by bioinformatics. CEBPD and VAMP3 expression in clinical TNBC samples was examined by immunohistochemistry. Three PTX-resistant TNBC cell lines (MDA-MB-231/PTX, MDA-MB-468/PTX and MDA-MB-453/PTX) were generated, and their drug resistance was analyzed. Autophagy of cells was analyzed by immunofluorescence staining. Interaction between CEBPD and VAMP3 promoter was identified by immunoprecipitation and luciferase assays. The extracellular expression of programmed cell death-ligand 1 (PD-L1) in TNBC cells was detected. Extracellular vesicles (EVs) from TNBC cells were isolated to examine their effects on CD8+ T cell exhaustion. Results CEBPD and VAMP3 were upregulated in chemo-resistant tissue samples and in PTX-resistant TNBC cells. The CEBPD downregulation enhanced PTX sensitivity of cells. However, further upregulation of VAMP3 in cells restored PTX resistance, which was likely due to the activation of autophagy, as the autophagy antagonist chloroquine enhanced PTX sensitivity of cells. CEBPD was found to bind to the VAMP3 promoter to activate its transcription. The CEBPD/VAMP3 axis also increased the PD-L1 expression in the conditioned medium of TNBC cells. The TNBC cell-derived EVs increased the exhaustion of co-cultured CD8+ T cells. Conclusion This study provides novel evidence that CEBPD plays a key role in enhancing PTX resistance in TNBC cells across various subtypes through VAMP3-mediated autophagy activation. Additionally, the CEBPD/VAMP3 axis also increases extracellular PD-L1 level, delivered by cancer cell-derived EVs, to suppress CD8+ T cell-mediated anti-tumor immune response. These significant observations may provide new insights into the treatment of TNBC, suggesting CEBPD and VAMP3 as promising targets to overcome treatment resistance.

Summary: Stapokibart (CM310) is a humanized IL-4Rα monoclonal antibody currently undergoing phase 3 trials for type 2 inflammatory diseases. In contrast to dupilumab, which bound exclusively to human IL-4Rα, stapokibart demonstrated cross-species reactivity to IL-4Rα from human, cynomolgus monkey, and rat. Stapokibart exhibited comparable blocking activity to dupilumab. Epitope mapping revealed that stapokibart bound to distinct sites on IL-4Rα compared to dupilumab. In vitro assays showed that stapokibart was comparable or numerically superior in blocking IL-4Rα-mediated signaling compared to dupilumab. In vivo studies further demonstrated that stapokibart effectively inhibited the progression of type 2 inflammation. Pharmacokinetic studies revealed a circulating half-life of approximately 298–351 h in cynomolgus monkeys and 55–142 h in rats for stapokibart. Toxicity studies indicated a favorable safety profile in cynomolgus monkeys and rats. The preclinical evaluation of stapokibart supports its clinical development.

Ulcerative colitis (UC) is a chronic non-specific inflammatory disease involving the mucosa and submucosa of the rectum and colon. Lindera aggregate (Sims) Kosterm is a traditional Chinese herb used for thousands of years in the treatment of gastrointestinal diseases. Previously, we have demonstrated that the extracts of Lindera aggregate have good anti-UC effects, but their pharmacodynamic active components have not been fully clarified. Therefore, we explored the therapeutic effect of Linderanine C (LDC), a characteristic component of Lindera aggregata, on UC and its mechanism in this study. Firstly, we found that LDC could significantly reduce the disease activity index of UC and improve shortened colon and pathological changes in vivo. Colon tissue transcriptomics suggested that the anti-UC effect of LDC might be related to its anti-inflammatory activity. Cellular experiments revealed that LDC could inhibit the expression of the M1 cell marker CD86 in RAW264.7 cells, reduce the production of inflammatory mediators such as IL-6 and TNF-α, and have good anti-inflammatory activity in vitro. Cellular transcriptomics reveal the potential involvement of the MAPK signaling pathway in the anti-inflammatory effect of LDC. The co-culture assay confirmed that LDC could significantly reduce inflammation-mediated intestinal epithelial cell injury. In conclusion, LDC was able to inhibit macrophage M1 polarization and reduce inflammatory mediator production by inhibiting the MAPK signaling pathway, effectively improving UC.

Abstract Negative Air Ions (NAIs), essential for environmental and human health, facilitate air purification and offer antimicrobial benefits. Our study achieves hourly estimations of NAIs using a machine learning framework, developed from a multi‐layer selection pipeline of over 200 variables, to identify the key determinants critical for adapting to high‐resolution NAIs dynamics. Addressing site sparsity and NAIs volatility, we introduced a hybrid stacking incorporating pseudo sites generated from Kriging Spatiotemporal Augmentation (KSTA) to mitigate spatial overfitting. Our approach, validated in Zhejiang, China, demonstrates exceptional accuracy, achieving R2 values of 0.90 (sample‐based), 0.85 (temporal‐based), and 0.79 (site‐based). This work not only sheds light on NAIs behavior in relation to diurnal shifts, land use, and environmental events, but also integrates a health grading system, enhancing public health strategies through precise air quality assessment.

BackgroundTransmission-blocking vaccines (TBVs) can effectively prevent the community’s spread of malaria by targeting the antigens of mosquito sexual stage parasites. At present, only a few candidate antigens have demonstrated transmission-blocking activity (TBA) potential in P. vivax. Quiescin-sulfhydryl oxidase (QSOX) is a sexual stage protein in the rodent malaria parasite Plasmodium berghei and is associated with a critical role in protein folding by introducing disulfides into unfolded reduced proteins. Here, we reported the immunogenicity and transmission-blocking potency of the PvQSOX in P. vivax.Methods and findingsThe full-length recombinant PvQSOX protein (rPvQSOX) was expressed in the Escherichia coli expression system. The anti-rPvQSOX antibodies were generated following immunization with the rPvQSOX in rabbits. A parasite integration of the pvqsox gene into the P. berghei pbqsox gene knockout genome was developed to express full-length PvQSOX protein in P. berghei (Pv-Tr-PbQSOX). In western blot, the anti-rPvQSOX antibodies recognized the native PvQSOX protein expressed in transgenic P. berghei gametocyte and ookinete. In indirect immunofluorescence assays, the fluorescence signal was detected in the sexual stages, including gametocyte, gamete, zygote, and ookinete. Anti-rPvQSOX IgGs obviously inhibited the ookinetes and oocysts development both in vivo and in vitro using transgenic parasites. Direct membrane feeding assays of anti-rPvQSOX antibodies were conducted using four field P. vivax isolates (named isolates #1–4) in Thailand. Oocyst density in mosquitoes was significantly reduced by 32.00, 85.96, 43.52, and 66.03% with rabbit anti-rPvQSOX antibodies, respectively. The anti-rPvQSOX antibodies also showed a modest reduction of infection prevalence by 15, 15, 20, and 22.22%, respectively, as compared to the control, while the effect was insignificant. The variation in the DMFA results may be unrelated to the genetic polymorphisms. Compared to the P.vivax Salvador (Sal) I strain sequences, the pvqsox in isolate #1 showed no amino acid substitution, whereas isolates #2, #3, and #4 all had the M361I substitution.ConclusionsOur results suggest that PvQSOX could serve as a potential P. vivax TBVs candidate, which warrants further evaluation and optimization.

Abstract Background As the leading cause of end‐stage liver disease, nonalcoholic fatty liver disease (NAFLD) is mainly induced by lipid dyshomeostasis. The translation of endogenous circular RNAs (circRNAs) is closely related to the progression of various diseases, but the involvement of circRNAs in NAFLD has not been determined. Methods Combined high‐throughput circRNA profiles were used to identify circRNAs with translational potential. The underlying molecular mechanisms were investigated by RNA sequencing, pull‐down/MS and site‐specific mutagenesis. Results In this study, we focused on circ‐SLC9A6, an abnormally highly expressed circRNA in human and mouse liver tissue during NAFLD development that exacerbates metabolic dyshomeostasis in hepatocytes by encoding a novel peptide called SLC9A6‐126aa in vivo and in vitro. YTHDF2‐mediated degradation of m6A‐modified circ‐SLC9A6 was found to be essential for the regulation of SLC9A6‐126aa expression. We further found that the phosphorylation of SLC9A6‐126aa by AKT was crucial for its cytoplasmic localization and the maintenance of physiological homeostasis, whereas high‐fat stress induced substantial translocation of unphosphorylated SLC9A6‐126aa to the nucleus, resulting in a vicious cycle of lipid metabolic dysfunction. Nuclear SLC9A6‐126aa promotes transcriptional activation of the target gene CD36 and enhances its occupancy of the CD36 promoter locus by regulating MOF‐mediated histone H4K16 acetylation. Hepatic CD36 depletion significantly ameliorated hyperactivated MAPK signalling and lipid disturbance in SLC9A6‐126aa transgenic mice. Clinically, increasing levels of SLC9A6‐126aa were observed during NAFLD progression and were found to be positively correlated with the CD36 and MAPK cascades. Conclusion This study revealed the role of circ‐SLC9A6‐derived SLC9A6‐126aa in the epigenetic modification‐mediated regulation of lipid metabolism. Our findings may provide promising therapeutic targets for NAFLD and new insights into the pathological mechanisms of metabolic diseases. Highlights Under normal circumstances, driven by m6A modification, YTHDF2 directly recognizes and degrades circ‐SLC9A6, thereby inhibiting the translation of SLC9A6‐126aa. Additionally, AKT1 phosphorylates and inhibits the nuclear translocation of SLC9A6‐126aa. In NAFLD, lipid overload leads to YTHDF2 and AKT1 deficiency, ultimately increasing the expression and nuclear import of SLC9A6‐126aa. Nuclear SLC9A6‐126aa binds directly to the CD36 promoter and initiates CD36 transcription, which induces lipid dyshomeostasis.

The giant panda (Ailuropoda melanoleuca) is recognized worldwide as an icon for wildlife conservation. The Qinling subspecies (Ailuropoda melanoleuca qinlingensis) inhabiting the Qinling Mountains is more endangered. Previous studies have indicated that Qinling pandas are potentially at risk from environmental pollutants, which they are exposed to via food and drinking water. However, there is little information about the surface water quality in the Qinling Mountains, and it is unknown whether drinking water is an important pollutant source for pandas. Water samples were collected from five different nature reserves in Qinling, each of which is home to a population of pandas. The samples were analyzed for five essential metals of copper (Cu), zinc (Zn), manganese (Mn), chromium (Cr), and nickel (Ni) and four non-essential metals of lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg). The concentrations of all heavy metals (HMs) were higher in buffer zones than in the core areas and were highest in Foping and Niuweihe nature reserves. The concentrations of mercury exceeded the water quality standard in the core zone of three reserves, suggesting that NWH (Niuweihe), THS (Tianhuashan), and PHL (Pingheliang) giant panda populations were at risk from mercury toxicity. The accumulation of other elements over time could also pose a serious risk to pandas. Three main sources of pollution were identified: coal combustion, waste incineration, and fertilizer use; traffic-related activities; and metal mining. Environmental pollution is compromising the efforts to conserve the giant panda, and measures need to be put in place to control pollution sources.

Background and objectiveThe rupture risk of intracranial aneurysms (IAs) is related to their arterial origin, but whether the different segments of the artery have different risks and act as independent risk factors is still unknown. Our study aimed to investigate the rupture risk of IAs in different arterial segments in a large Chinese cohort.MethodsImaging and clinical data of consecutive patients with IAs diagnosed by Computed Tomography angiography (CTA) from January 2013 to December 2022 were collected. Two neuroradiologists independently identified ruptured and unruptured IAs based on imaging and medical records. The internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA), vertebral artery (VA), and posterior cerebral artery (PCA) were segmented according to the Bouthillier and Fischer segmentation methods. Stenoses of the proximal parent vessel were evaluated and documented. The Institutional Review Board (IRB) at Beijing Tiantan Hospital approved this retrospective study.ResultsA total of 3,837 aneurysms {median size 3.5 mm [interquartile range (IQR) 2.6–5.1 mm]; 532 ruptured} were included in this study from 2,968 patients [mean age: 57 years (IQR 50–64); male patients: 1,153]. Ruptured aneurysms were most commonly located in the posterior inferior cerebellar artery (PICA) (52.9%), anterior communicating artery (ACoA) (33.8%), other locations (33.3%), ACA (22.4%), and basilar artery (BA) (21.4%). The locations with the highest likelihood of rupture were the C7 ICA (21.3%), M2 MCA (24.0%), distal MCA (25.0%), and A2 ACA (28.1%). IAs originating from the C7 (p < 0.001), dM1 (p = 0.022), and dA1 (p = 0.021) segments were independent risk factors for rupture. IAs without stenosis of the proximal parent vessel were associated with a higher risk of rupture (p = 0.023).ConclusionThere are unique associations between the origins of aneurysms from various arterial segments. Aneurysms originating from the anterior communicating artery (ACoA), BA, PICA, A2, dA, C7, and M2 indicate a higher risk of rupture. Aneurysms originating from C4, C5, and C6 indicate a lower risk of rupture. C7 IAs, ACoA IAs, and PICA IAs seem to be independent risk factors.

IntroductionThe prevalence of male infertility has been increasing globally, necessitating the search for safe and nontoxic active compounds to alleviate reproductive dysfunction. Although the precise mechanism remains unknown, Cynomorium songaricum Rupr. (CS) extract has protective effects on the reproductive system. The effect of C. songaricum Rupr. flavonoids (CSF) on reproductive injury and testicular mesenchymal stem cell viability in male mice and TM3 cells was investigated.MethodsWe explored the possible association between these effects and the testosterone (T) synthesis pathway. Mice were administered cyclophosphamide to induce reproductive damage, followed by CSF administration. Body mass and organ index were recorded. Pathological changes in T and the epididymis were observed using hematoxylin-eosin staining. ELISA measured the serum levels of T, luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and estradiol (E2) in mice. Fructose and zinc ion levels in the seminal plasma were measured. TM3 cells were treated with Bisphenol A (BPA) and different concentrations of CSF, followed by proliferative evaluations using the CCK-8 assay and T and LH level assessments using ELISA. Furthermore, the expression of steroidogenic enzyme genes and proteins was investigated using western blotting and RT-PCR.ResultsCSF exhibited a notable reduction in reproductive damage and improved pathological changes in testicular and epididymal tissues. CSF group demonstrated substantially higher levels of seminal plasma fructose and zinc ions; markedly elevated serum levels of T, LH, GnRH, and FSH; and lower levels of E2 than those of the model group. Intracellular T content and secretion of T and LH increase with CSF while effectively mitigating BPA-induced damage to TM3 cells. CSF group exhibited substantially higher gene and protein expression of steroidogenic enzymes than those of the model group, both in vivo and in vitro. CSF ameliorates reproductive impairment by enhancing the expression of pivotal enzymes involved in synthesizing T.DiscussionCSF ameliorates cyclophosphamide-induced reproductive impairment and bisphenol A-induced TM3 cell damage in mice by regulating sex hormone levels in the Hypothalamic-Pituitary-Gonadal Axis (HPG axis) and upregulating the expression of steroidogenic enzymes. Therefore, CS is a potential treatment for male reproductive impairment.

ObjectiveIt has been recognized that there is a nexus among Trisomy 8 (T8), Behcet's disease (BD), and myelodysplastic syndrome (MDS). We reported a series of inflammatory features in 2 children with T8 without hematological involvement.Methods2 children with trisomy 8 who were excluded from MDS were retrospectively collected from the Department of Rheumatology and Immunology, Children's Hospital of Nanjing Medical University, Nanjing.ResultsPatients developed a range of inflammatory manifestations before a diagnosis of T8. The clinical manifestations of T8 patients vary from normal to severely disabled. Glucocorticoids and thalidomide can effectively relieve inflammation in patients with T8.ConclusionThe early clinical manifestations of T8 in children lack specificity, and the diagnosis is mainly based on karyotype analysis, gastrointestinal endoscopy and bone marrow aspiration findings. Active and effective immunoregulatory therapy and long-term follow-up can improve the prognosis of patients with T8.

Sewage with a low carbon-to-nitrogen (C/N) ratio can be effectively treated using high-rate algal ponds (HRAPs), consisting of a combined symbiotic system of algae and bacteria. However, HRAPs have been predominantly used in laboratories, but their application in wastewater treatment plants is yet to be realized. Herein, laboratory and pilot-scale experimental studies were conducted using wetland effluent from the Baitabao estuary and effluent from the ecological wastewater treatment plant in Liaozhong County. The ammonia nitrogen (NH4+–N) and chemical oxygen demand (COD) concentrations in the effluent treated using the lab-scale system decreased to

Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 (CYP81A9), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo. Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9, thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.

BackgroundThis study aimed to identify the predictive factors for prolonged length of stay (LOS) in elderly type 2 diabetes mellitus (T2DM) patients suffering from cerebral infarction (CI) and construct a predictive model to effectively utilize hospital resources.MethodsClinical data were retrospectively collected from T2DM patients suffering from CI aged ≥65 years who were admitted to five tertiary hospitals in Southwest China. The least absolute shrinkage and selection operator (LASSO) regression model and multivariable logistic regression analysis were conducted to identify the independent predictors of prolonged LOS. A nomogram was constructed to visualize the model. The discrimination, calibration, and clinical practicality of the model were evaluated according to the area under the receiver operating characteristic curve (AUROC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC).ResultsA total of 13,361 patients were included, comprising 6,023, 2,582, and 4,756 patients in the training, internal validation, and external validation sets, respectively. The results revealed that the ACCI score, OP, PI, analgesics use, antibiotics use, psychotropic drug use, insurance type, and ALB were independent predictors for prolonged LOS. The eight-predictor LASSO logistic regression displayed high prediction ability, with an AUROC of 0.725 (95% confidence interval [CI]: 0.710–0.739), a sensitivity of 0.662 (95% CI: 0.639–0.686), and a specificity of 0.675 (95% CI: 0.661–0.689). The calibration curve (bootstraps = 1,000) showed good calibration. In addition, the DCA and CIC also indicated good clinical practicality. An operation interface on a web page (https://xxmyyz.shinyapps.io/prolonged_los1/) was also established to facilitate clinical use.ConclusionThe developed model can predict the risk of prolonged LOS in elderly T2DM patients diagnosed with CI, enabling clinicians to optimize bed management.

Puerarin, a monomer of traditional Chinese medicine, is a key component of Pueraria radix. Both clinical and experimental researches demonstrated that puerarin has therapeutic effects on Parkinson's disease (PD). Puerarin's pharmacological mechanisms include: 1) Anti-apoptosis. Puerarin inhibits cell apoptosis through the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) signaling pathways. Puerarin also exerts a hormone-like effect against cell apoptosis; 2) Anti-oxidative stress injury. Puerarin inhibits the Nrf2 nuclear exclusion through the GSK-3β/Fyn pathway to promote the Nrf2 accumulation in the nucleus, and then promotes the antioxidant synthesis through the Nrf2/ARE signaling pathway to protect against oxidative stress; 3) Neuroprotective effects by intervening in the ubiquitin-proteasome system (UPS) and autophagy-lysosomal pathway (ALP). Puerarin significantly enhances the activity of chaperone-mediated autophagy (CMA), which downregulates the expression of α-synuclein, reduces its accumulation, and thus improves the function of damaged neurons. Additionally, puerarin increases proteasome activity and decreases ubiquitin-binding proteins, thereby preventing toxic accumulation of intracellular proteins; 4) Alleviating inflammatory response. Puerarin inhibits the conversion of microglia to the M1 phenotype while inducing the transition of microglia to the M2 phenotype. Furthermore, puerarin promotes the secretion of anti-inflammatory factor and inhibits the expression of pro-inflammatory factors; 5) Increasing the levels of dopamine and its metabolites. Puerarin could increase the levels of dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum; 6) Promoting neurotrophic factor expression and neuronal repair. Puerarin increases the expression of glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), thereby exerting a neuroprotective effect. Moreover, the regulation of the gut microbiota by puerarin may be a potential mechanism for the treatment of PD. The current review discusses the molecular mechanisms of puerarin, which may provide insight into the active components of traditional Chinese medicine in the treatment of PD.

Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNA (sncRNA) molecules derived from tRNA, including tRNA derived fragments (tRFs) and tRNA halfs (tiRNAs). tsRNAs can affect cell functions by participating in gene expression regulation, translation regulation, intercellular signal transduction, and immune response. They have been shown to play an important role in various human diseases, including cardiovascular diseases (CVDs). Targeted regulation of tsRNAs expression can affect the progression of CVDs. The tsRNAs induced by pathological conditions can be detected when released into the extracellular, giving them enormous potential as disease biomarkers. Here, we review the biogenesis, degradation process and related functional mechanisms of tsRNAs, and discuss the research progress and application prospects of tsRNAs in different CVDs, to provide a new perspective on the treatment of CVDs.

Infection with Plasmodium falciparum is often deadly when it results in cerebral malaria, which is associated with neuropathology described as an overwhelming inflammatory response and mechanical obstruction of cerebral microvascular. PI3Kγ is a critical component of intracellular signal transduction and plays a central role in regulating cell chemotaxis, migration, and activation. The purpose of this study was to examine the relationship between inhibiting the PI3Kγ pathway and the outcome of experimental cerebral malaria (ECM) in C57BL/6J mice infected with the mouse malaria parasite, Plasmodium berghei ANKA. We observed that oral administration of the PI3Kγ inhibitor IPI549 after infection completely protected mice from ECM. IPI549 treatment significantly dampened the magnitude of inflammatory responses, with reduced production of pro-inflammatory factors, decreased T cell activation, and altered differentiation of antigen-presenting cells. IPI549 treatment protected the infected mice from neuropathology, as assessed by an observed reduction of pathogenic T cells in the brain. Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria.

In this paper, non-woven fabric and glass fiber fabric were used to prepare resin-based absorbing composite. The thermal expansion coefficient and the microwave absorbing properties of the absorbing composites with different glass fiber volume fraction were studied. The results show that the simulation results of the thermal expansion coefficient calculated by Schapery model are inconsistent with the experimental results, the metallographic results were studied to reveal that it is the added absorbent in the composite that partially replaced the resin at the interface between resin and fiber bundle causes the parameters of the material substituted in the Schapery model to be improper. A different simulation model was proposed to introduce a set of different parameters of the material to reduce the error between simulation and experiment results and the simulation results show that the error is reduced from a maximum of 53 % to a minimum of 3 %. Meanwhile the microwave absorbing properties show that the absorbing peaks of the composite materials move to low frequency with the increasing glass fiber volume fraction and the minimum reflection loss (RL) first increase and then decrease. The metallographic results show that the different distribution of absorbent in the composites within different reinforced fibers causes the movement of the absorbing peaks and the change of its minimum RL. Those research results lay a foundation for the further popularization and application of the absorbing composites.

We present measurements of the 2p-3d transition opacity of a hot molybdenum–scandium sample with nearly half-vacant molybdenum M-shell configurations. A plastic-tamped molybdenum–scandium foil sample is radiatively heated to high temperature in a compact D-shaped gold Hohlraum driven by ∼30 kJ laser energy at the SG-100 kJ laser facility. X rays transmitted through the molybdenum and scandium plasmas are diffracted by crystals and finally recorded by image plates. The electron temperatures in the sample in particular spatial and temporal zones are determined by the K-shell absorption of the scandium plasma. A combination of the IRAD3D view factor code and the MULTI hydrodynamic code is used to simulate the spatial distribution and temporal behavior of the sample temperature and density. The inferred temperature in the molybdenum plasma reaches a average of 138 ± 11 eV. A detailed configuration-accounting calculation of the n = 2–3 transition absorption of the molybdenum plasma is compared with experimental measurements and quite good agreement is found. The present measurements provide an opportunity to test opacity models for complicated M-shell configurations.

An improved understanding of the Plasmodium vivax populations in the Great Mekong Subregion (GMS) is needed to monitor the progress of malaria elimination. This study aimed to use a P. vivax single nucleotide polymorphism (SNP) barcode to evaluate the population dynamics and explore the gene flow among P. vivax parasite populations in the western GMS (China, Myanmar and Thailand). A total of 315 P. vivax patient samples collected in 2011 and 2018 from four regions of the western GMS were genotyped for 42 SNPs using the high-throughput MassARRAY SNP genotyping technology. Population genetic analysis was conducted to estimate the genetic diversity, effective population size, and population structure among the P. vivax populations. Overall, 291 samples were successfully genotyped at 39 SNPs. A significant difference was observed in the proportion of polyclonal infections among the five P. vivax populations (P = 0.0012, Pearson Chi-square test, χ2 = 18.1), with western Myanmar having the highest proportion (96.2%, 50/52) in 2018. Likewise, the average complexity of infection was also highest in western Myanmar (1.31) and lowest in northeast Myanmar (1.01) in 2018. The older samples from western China in 2011 had the highest pairwise nucleotide diversity (π, 0.388 ± 0.046), expected heterozygosity (He, 0.363 ± 0.02), and the largest effective population size. In comparison, in the neighboring northeast Myanmar, the more recent samples in 2018 showed the lowest values (π, 0.224 ± 0.036; He, 0.220 ± 0.026). Furthermore, the 2018 northeast Myanmar parasites showed high and moderate genetic differentiation from other populations with FST values of 0.162-0.252, whereas genetic differentiation among other populations was relatively low (FST ≤ 0.059). Principal component analysis, phylogeny, and STRUCTURE analysis showed that the P. vivax population in northeast Myanmar in 2018 substantially diverged from other populations. Although the 42 SNP barcode is a valuable tool for tracking parasite origins of worldwide parasite populations, a more extended barcode with additional SNPs is needed to distinguish the more related parasite populations in the western GMS.