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Abstract To improve the utilization rates of soda residue (SR) and fly ash (FA), reduce environmental pollution, and enhance the mechanical properties of marine clay (MC), this study proposes mixing SR, FA, and MC with cement and /or lime to prepare soda residue-fly ash stabilized soil (SRFSS). Using an orthogonal design for the proportions, the study analyzes the compaction performance, unconfined compressive strength (UCS), and shear strength of SRFSS. The influence of various factors on the mechanical properties of SRFSS was investigated through range and variance analyses. The mechanical mechanism was revealed from the perspectives of grading and cementation. The results indicate that SR and FA significantly impact the mechanical properties of SRFSS. The range and variance analysis results are consistent: SR content of 30% and 70% has the most significant impact on compaction performance and UCS, respectively, while 20% FA content has the greatest effect on shear strength. The recommended base proportion is 70% SR + 20% FA + 10% MC. The gradation and cementitious properties jointly influence the mechanical performance and microstructure of SRFSS, G8 has the lowest planar porosity, at only 0.89%. The calcium (Ca) content in SRFSS specimens with different proportions shows significant variation, from 5.0 to 53.6 wt%, while the silicon (Si)/Al ratio (0.76–2.73) shows relatively small fluctuations. The primary hydration products include calcium hydroxide (Ca(OH)2), calcium silicate hydrate (C-S-H), and ettringite (AFt).

Abstract Background Selpercatinib, a highly selective tyrosine kinase inhibitor, has emerged as an excellent treatment option for patients with rearranged during transfection-altered cancer. However, there is limited comprehensive safety information available for selpercatinib through large-scale post-marketing monitoring. Methods This study conducted a comprehensive analysis of selpercatinib-related adverse events (AEs) using the FDA Adverse Event Reporting System database. Four disproportionality methods were employed to identify potential AEs associated with selpercatinib. Specifically, this study investigated the differences in AEs of selpercatinib with respect to reporter continent, indication, sex, age, weight, dose, frequency, and onset time. Results A total of 464 reports and 1,007 selpercatinib-related AEs were identified. Three new significant AEs were discovered, including dysphagia, pericardial effusion, and hemiparesis. Notably, Asia reported hepatic function abnormal more frequently, especially in patient administered doses exceeding 160 mg. Furthermore, hypersensitivity was reported more frequently by Asia and in individuals weighing less than 50 kg. Conclusions It is paramount to stay vigilant concerning the potential emergence of three newly identified AEs. Significant differences were found in selpercatinib-related AEs concerning reporter continent, sex, weight, dose, frequency, and onset time, which deserved clinical attention. These findings contribute to a broader understanding of the AE profiles of selpercatinib.

Abstract Background Impoverished students constitute a group that cannot be overlooked in higher education. It is crucial for pharmaceutical universities worldwide to implement financial assistance programs that promote the development and success of students from poor families. Chinese universities have carried out active exploration of subsidized education, and made important achievements, but there are also problems, which are worth learning from. This study proposed a strategy to improve the core literacy of impoverished pharmaceutical students under the development-oriented funding system. Methods The study centers on clinical pharmacy students from a pharmaceutical college as the research subjects. A sequential explanatory mixed-methods approach was employed, with quantitative data collected through a survey questionnaire, supplemented by qualitative data collected through in-depth interviews. Data gathered from these two levels were integrated and subjected to statistical analysis. Results The quantitative survey yielded a total of 397 valid samples, most of whom were females (73.8%), mainly at undergraduate level (89.67%), and from non-urban area (73.81%). Five of them participated in further qualitative interviews. The combined data identified: (a) financial aid—most students were highly satisfied with the financial support; (b) psychological support—most of the students interviewed reported that the scholarship significantly improved their self-confidence and motivation; (c) academic guidance—funded students had clear expectations for career development and academic guidance, demonstrating a strong need for further professional study; and (d) employment assistance—most students wanted career guidance and career planning support. Conclusions The financial assistance in pharmaceutical colleges and universities should be enriched to resolve the worries of impoverished clinical pharmacy students through economic assistance, improve the moral cultivation with psychological assistance, strengthen their cultural and scientific literacy, and improve their knowledge and practical ability through academic assistance. Through the integration of pharmacy education, the vocational competence of clinical pharmacy students can be improved by employment assistance, and the reform of higher pharmacy education can be further promoted to improve the training quality of pharmaceutical talents.

Abstract Lower-grade gliomas (LGGs) exhibit diverse clinical behaviors and varying immune infiltration levels. Mitochondria have been implicated in numerous cancer pathogenesis and development, including LGGs. However, the precise biological functions of mitochondrial genes in shaping the immune landscape and the prognostic significance of LGGs remain elusive. Utilizing the Mito-Carta3.0 database, we curated a total of 1136 genes implicated in mitochondrial functions. By leveraging the expression profiles of 1136 genes related to mitochondria, we successfully categorized LGGs into four distinctive mitochondria-related transcriptome (MRT) subtypes. Our thorough analysis conclusively demonstrated that these subtypes exhibited marked disparities. To enable a personalized and integrated evaluation of LGG patients, we developed a prognostic signature known as MRT-related prognostic signature (MTRS). MTRS demonstrated correlation with mitochondria-related transcriptome (MRT) subtypes, allowing the assessment of patients’ prognosis and immune microenvironment. We conducted a detailed exploration of the single-cell distribution of MTRS in lower-grade gliomas and verified the core genes of MTRS within the spatial transcriptome of these tumors. Furthermore, our study pinpointed MGME1 as the pivotal gene in the model, functioning as an oncogene that exerts influence on cell proliferation and migration capabilities. Our research highlights the importance of mitochondrial transcriptomic features in LGGs, offering paths for tailored therapies.

Abstract Purpose This study aimed to comprehensively assess the safety of rimegepant administration in real-world clinical settings. Methods Data from the Food and Drug Administration Adverse Event Reporting System (FAERS) spanning the second quarter of 2020 through the first quarter of 2023 were retrospectively analyzed in this pharmacovigilance investigation. This study focuses on employing subgroup analysis to monitor rimegepant drug safety. Descriptive analysis was employed to examine clinical characteristics and concomitant medication of adverse event reports associated with rimegepant, including report season, reporter country, sex, age, weight, dose, and frequency, onset time, et al. Correlation analysis, including techniques such as violin plots, was utilized to explore relationships between clinical characteristics in greater detail. Additionally, four disproportionality analysis methods were applied to assess adverse event signals associated with rimegepant. Results A total of 5,416,969 adverse event reports extracted from the FAERS database, 10, 194 adverse events were identified as the “primary suspect” (PS) drug attributed to rimegepant. Rimegepant-associated adverse events involved 27 System Organ Classes (SOCs), and the significant SOC meeting all four detection criteria was “general disorders and administration site conditions” (SOC: 10018065). Additionally, new significant adverse events were discovered, including “vomiting projectile” (PT: 10047708), “eructation” (PT: 10015137), “motion sickness” (PT: 10027990), “feeling drunk” (PT: 10016330), “reaction to food additive” (PT: 10037977), etc. Descriptive analysis indicated that the majority of reporters were consumers (88.1%), with most reports involving female patients. Significant differences were observed between female and male patients across age categories, and the concomitant use of rimegepant with other medications was complex. Conclusion This study has preliminarily identified potential new adverse events associated with rimegepant, such as those involving the gastrointestinal system, nervous system, and immune system, which warrant further research to determine their exact mechanisms and risk factors. Additionally, significant differences in rimegepant-related adverse events were observed across different age groups and sexes, and the complexity of concomitant medication use should be given special attention in clinical practice.

Abstract Osteoporosis (OP) is a chronic disease characterized by diminished bone mass and structural deterioration, ultimately leading to compromised bone strength and an increased risk of fractures. Diagnosis primarily relies on medical imaging findings and clinical symptoms. This study aims to explore an adjunctive diagnostic technique for OP based on surface-enhanced Raman scattering (SERS). Serum SERS spectra from the normal, low bone density, and osteoporosis groups were analyzed to discern OP-related expression profiles. This study utilized partial least squares (PLS) and support vector machine (SVM) algorithms to establish an OP diagnostic model. The combination of Raman peak assignments and spectral difference analysis reflected biochemical changes associated with OP, including amino acids, carbohydrates, and collagen. Using the PLS-SVM approach, sensitivity, specificity, and accuracy for screening OP were determined to be 77.78%, 100%, and 88.24%, respectively. This study demonstrates the substantial potential of SERS as an adjunctive diagnostic technology for OP.

Summary: Background: Sepsis is a significant health burden on a global scale. Timely identification and treatment of sepsis can greatly improve patient outcomes, including survival rates. However, time-consuming laboratory results are often needed for screening sepsis. We aimed to develop a quick sepsis screening tool (qSepsis) based on patients’ non-laboratory clinical data at the emergency department (ED) using machine learning (ML), and compare its performance with established clinical scores. Methods: This retrospective study included patients admitted to the ED of Zhongnan Hospital of Wuhan University (Wuhan, China) from 1/1/2015 to 5/31/2022. Patients who were under 18 years of age, had cardiopulmonary arrest upon arrival at the ED, or had missing and abnormal medical record data were excluded. The qSepsis was derived by three ML algorithms, including logistic regression (LR), random forest (RF), and extreme gradient boosting (XGB). To benchmark the existing clinical tools for assessing the risk of sepsis in the ED, qSepsis was compared with the Systemic Inflammatory Response Syndrome (SIRS), the Quick Sepsis-Related Organ Failure Assessment (qSOFA), and the Modified Early Warning Score (MEWS). The external validation was performed with the Medical Information Mart for Intensive Care IV ED database (United States), and adopted the same inclusion and exclusion criteria. The predictive power of qSepsis and other clinical scores was measured using the area under the receiver operating characteristic curve (AUROC). The primary outcome of the study was the diagnosis of sepsis in the ED based on the Sepsis 3.0 criteria, which served as the basis for developing the qSepsis tool. Findings: A total of 414,864 patients were finally included in the cohort (median ([IQR]) patient age, 43 (29, 60) years; 202,730 (48.87%) females, 212,134 (51.13%) males), and 200,089 in the external testing cohort (median (SD) patient age, 57 (39, 71) years; 107,427 (53.69%) females, 92,663 (46.31%) males). For internal testing, LR outperformed RF and XGB with an AUROC of 0.862 (95% CI, 0.855–0.869). In external testing, the AUROC decreased to 0.766 (95% CI, 0.758–0.774) for LR, 0.725 (95% CI, 0.717–0.733) for RF, and 0.735 (95% CI, 0.728–0.742) for XGB. In addition, the AUROC for the qSOFA, MEWS, and SIRS scores in external validation cohort were 0.579 (95% CI, 0.563–0.596), 0.600 (95% CI, 0.578–0.622), and 0.704 (95% CI, 0.683–0.725), respectively. The area under the precision–recall curve (AUPRC) for the qSepsis model was 0.213 (95% CI: 0.204–0.222). The AUPRC values for the other scores were as follows: SIRS, 0.071 (95% CI: 0.013–0.099); qSOFA, 0.096 (95% CI: 0.003–0.186); and MEWS, 0.083 (95% CI: 0.063–0.111). Interpretation: This retrospective study demonstrated that qSepsis had better predictive performance in terms of AUROC and area under the precision–recall curve (AUPRC) compared to existing assessment scores. It has the potential to be used in pre-hospital settings with limited access to laboratory tests and in the ED for quick screening of patients with sepsis. However, due to its low positive predictive value (PPV), the false alarms may increase in actual clinical practice. Funding: Transformation of Scientific and Technological Achievements Fund Project of Zhongnan Hospital of Wuhan University.

Background The objective of the present study is to examine the total phenolic and flavonoid content of an ethanol extract of Sanghuangporus sanghuang and to evaluate its phytochemical properties, antioxidant activity, and capacity to protect DNA from damage. This pharmaceutical/food resource mushroom may serve as a novel substitute functional food for health-conscious consumers, given its promising source of phenolics and flavonoids. Methods S. sanghuang ethanol extract (SEE) was evaluated for total phenolic and flavonoid contents, while UPLC-MS analysis was used for terpenoids, phenylpropanoid, flavonoids, steroidal, phenols identification, and function prediction. Antioxidant and anti-DNA damage activities were tested in vitro using ferric reducing antioxidant power (FRAP), 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis-3-ethylbenzotiazolin-6-sulfonic acid (ABTS), and DNA damage protection assay. Results and Conclusion Total phenolic content (TPC) in SEE was 385.38 ± 1.36 mg GA/g extract, while total flavonoid content (TFC) was 298.22 ± 2.38 mg QE/g extract. The extracts exhibited high antioxidant and free radical scavenging activities with relatively stronger free radical scavenging activity. A total of 491 metabolites were investigated by Ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Most of the top 20 compounds were predicted to have various functions like antioxidant, anti-cancer and anti-inflammatory. This study highlighted S. sanghuang was a beneficial source of phenolics and flavonoids. It contains potential natural antioxidant that could be used as a lead contender in the development of antioxidant medicines for the treatment of a wide range of oxidative stress-related illnesses.

BackgroundArtificial intelligence (AI) has been widely adopted for the prediction of latent shock occurrence in critically ill patients in intensive care units (ICUs). However, the usefulness of an ICU-based model to predict latent shock risk in an emergency department (ED) setting remains unclear. This study aimed to develop an AI model to predict latent shock risk in patients admitted to EDs.MethodsMultiple regression analysis was used to compare the difference between Medical Information Mart for Intensive Care (MIMIC)-IV-ICU and MIMIC-IV-ED datasets. An adult noninvasive model was constructed based on the MIMIC-IV-ICU v3.0 database and was externally validated in populations admitted to an ED. Its efficiency was compared with efficiency of testing with noninvasive systolic blood pressure (nSBP) and shock index.ResultsA total of 50,636 patients from the MIMIC-IV-ICU database was used to develop the model, and a total of 2,142 patients from the Philips IntelliSpace Critical Care and Anesthesia (ICCA)-ED and 425,087 patients from the MIMIC-IV-ED were used for external validation. The modeling and validation data revealed similar non-invasive feature distributions. Multiple regression analysis of the MIMIC-IV-ICU and MIMIC-IV-ED datasets showed mostly similar characteristics. The area under the receiver operating characteristic curve (AUROC) of the noninvasive model 10 min before the intervention was 0.90 (95% CI: 0.84–0.96), and the diagnosis accordance rate (DAR) was above 80%. More than 80% of latent shock patients were identified more than 70 min earlier using the noninvasive model; thus, it performed better than evaluating shock index and nSBP.ConclusionThe adult noninvasive model can effectively predict latent shock occurrence in EDs, which is better than using shock index and nSBP.

Summary: Mental stress-induced myocardial ischemia (MSIMI) is linked to a 2-fold increase in cardiovascular events, but its underlying myocardial blood flow (MBF) mechanisms remain underexplored. Using nitrogen-13-ammonia cardiac positron emission tomography-computed tomography (PET-CT) assessing myocardial perfusion defect and MBF under resting, mental stress (MS), adenosine stress (AS) conditions, angina with no obstructive coronary artery disease (ANOCA) women showed a significantly higher prevalence of MSIMI compared to age-matched healthy controls (36/84 vs. 1/42, p

Abstract Background The binary diagnosis of Metabolic Syndrome(MetS) fails to accurately evaluate its severity, and the association between MetS severity and frailty progression remains inadequately elucidated. This study aims to clarify the relationship between the severity of MetS and the progression of frailty among the middle-aged and elderly population in China. Method Participants from the 2011–2018 China Health and Retirement Longitudinal Study(CHARLS) were included for a longitudinal analysis. The study employs a frailty index(FI) based on 32 health deficits to diagnose frailty and to assess FI trajectories. An age-sex-ethnicity-specific MetS scoring model (MetS score) was used to assess metabolic syndrome severity in Chinese adults. The Cumulative MetS score from 2012 to 2015 was calculated using the formula: (MetS score in wave 1 + MetS score in wave 3) / 2 × time(2015 - 2012). The association between MetS score, Cumulative MetS score, and the risk and trajectory of frailty were evaluated using Cox regression/logistic regression, and linear mixed models. Restricted Cubic Splines(RCS) models were utilized to detect potential non-linear associations. Results A higher MetS score was significantly associated with an increased risk of frailty(HR per 1 SD increase = 1.205; 95%CI: 1.14 to 1.273) and an accelerated FI trajectory(β per 1 SD increase = 0.113 per year; 95%CI: 0.075 to 0.15 per year). Evaluating changes in MetS score using a Cumulative MetS score indicated that each 1 SD increase in the Cumulative MetS score increased the risk of frailty by 22.2%(OR = 1.222; 95%CI: 1.133 to 1.319) and accelerated the rate of increase in FI(β = 0.098 per year; 95%CI: 0.058 to 0.138 per year). RCS model results demonstrated a dose-response curve relationship between MetS score and Cumulative MetS score with frailty risk. Stratified analysis showed consistency across subgroups. The interaction results indicate that in males and individuals under aged 60, MetS score may accelerate the increase in FI, a finding consistent across both models. Conclusions Our findings underscore the positive correlation between the severity of MetS and frailty progression in the middle-aged and elderly, highlighting the urgent need for early identification of MetS and targeted interventions to reduce the risk of frailty.

Abstract To improve the thermal health state of workers in mines facing heat hazards and enhance cooling capacity utilization efficiency of mine ventilation, this study proposes a suitable air distribution for mine workers’ local cooling, taking into account the characteristics of long-narrow underground space and workers. The suggested air distribution involves harnessing underground cold air jets along with the mine’s crossflow (mainstream ventilation) to create a localized safeguard airflow around the worker’s head-neck, known as jet ventilation in crossflow (JVIC). The flow visualization experiment identified five flow patterns within a confined space. The study explores the impact of the velocity ratio (R) and confinement scale (C) on the evolution of JVIC flow patterns and presents a parametric description of the resulting flow field. Drawing on the microclimate control scope around mine workers’ head-neck, the study defines the effective cooling zone and the ineffective cooling zone as the boundaries for controlling JVIC air distribution within confined mine spaces. This clarifies the applicability of the air distribution form and introduces an evaluation model for assessing the cooling effect and the efficiency of cooling capacity utilization to manage the non-uniform underground environment.

Abstract In this study, a machine vision method is proposed to characterize 3D roughness of the textured surface on cylinder liner processed by plateau honing. The least absolute value (L∞) regression robust algorithm and Levenberg-Marquardt (LM) algorithm are employed to reconstruct image reference plane. On this basis, a single-hidden layer feedforward neural network (SLFNN) based on the extreme learning machine (ELM) is employed to model the relationship between high frequency information and 3D roughness. The characteristic parameters of Abbott-Firestone curve and 3D roughness measured by a confocal microscope are used to construct ELM-SLFNN prediction model for 3D roughness. The results indicate that the proposed method can effectively characterize 3D roughness of the textured surface of cylinder liner.

Abstract An arc is the high‐temperature discharge plasma produced in the opening process of mechanical switches, which directly affects the breaking capability of a hybrid DC circuit breaker. According to the physical mechanism of an electric arc, the construction of an arc model for simulation analysis is an important technical means in the electrical field. In this study, based on the theory of magneto hydrodynamics (MHD), a gas mechanical switch model of a natural commutation DC circuit breaker with a compound gap is established. The arc motion process under different conditions is simulated and calculated. The influence of different initial pressures, different opening speeds, and different striking currents on the arc voltage characteristics is analysed. The results show that the larger the gas pressure, the smaller the arc volume and the higher the arc voltage. The faster the opening speed, the longer the arc and the higher the arc voltage; with the increase of the current, the arc voltage increases rapidly at a low current, while the arc voltage increases slowly at a high current.

Background: The extensive community of gut microbiota significantly influences various biological functions throughout the body, making its characterization a focal point in biomedicine research. Over the past few decades, studies have revealed a potential link between specific gut bacteria, their associated metabolic pathways, and influenza. Bacterial metabolites can communicate directly or indirectly with organs beyond the gut via the intestinal barrier, thereby impacting the physiological functions of the host. As the microbiota increasingly emerges as a ‘gut signature’ in influenza, gaining a deeper understanding of its role may offer new insights into its pathophysiological relevance and open avenues for novel therapeutic targets. In this Review, we explore the differences in gut microbiota between healthy individuals and those with influenza, the relationship between gut microbiota metabolites and influenza, and potential strategies for preventing and treating influenza through the regulation of gut microbiota and its metabolites, including fecal microbiota transplantation and microecological preparations. Methods: We utilized PubMed and Web of Science as our search databases, employing keywords such as “influenza,” “gut microbiota,” “traditional Chinese medicine,” “metabolites,” “prebiotics,” “probiotics,” and “machine learning” to retrieve studies examining the potential therapeutic connections between the modulation of gut microbiota and its metabolites in the treatment of influenza. The search encompassed literature from the inception of the databases up to December 2023. Results: Fecal microbiota transplantation (FMT), microbial preparations (probiotics and prebiotics), and traditional Chinese medicine have unique advantages in regulating intestinal microbiota and its metabolites to improve influenza outcomes. The primary mechanism involves increasing beneficial intestinal bacteria such as Bacteroidetes and Bifidobacterium while reducing harmful bacteria such as Proteobacteria. These interventions act directly or indirectly on metabolites such as short-chain fatty acids (SCFAs), amino acids (AAs), bile acids, and monoamines to alleviate lung inflammation, reduce viral load, and exert anti-influenza virus effects. Conclusion: The gut microbiota and its metabolites have direct or indirect therapeutic effects on influenza, presenting broad research potential for providing new directions in influenza research and offering references for clinical prevention and treatment. Future research should focus on identifying key strains, specific metabolites, and immune regulation mechanisms within the gut microbiota to accurately target microbiota interventions and prevent respiratory viral infections such as influenza.

Acute lung injury (ALI) has multiple causes and can easily progress to acute respiratory distress syndrome (ARDS) if not properly treated. Nuclear factor κB (NF-κB) is a key pathway in the treatment of ALI/ARDS. By exploring the relevance of NF-κB and the pathogenesis of this disease, it was found that this disease was mainly associated with inflammation, dysfunction of the endothelial barrier, oxidative stress, impaired clearance of alveolar fluid, and coagulation disorders. Traditional Chinese medicine (TCM) has the characteristics of multitargeting, multipathway effects, and high safety, which can directly or indirectly affect the treatment of ALI/ARDS. This article summarizes the mechanism and treatment strategies of TCM in recent years through intervention in the NF-κB-related signaling pathways for treating ALI/ARDS. It provides an overview from the perspectives of Chinese herbal monomers, TCM couplet medicines, TCM injections, Chinese herbal compounds, and Chinese herbal preparations, offering insights into the prevention and treatment of ALI/ARDS with TCM.

Abstract Capmatinib is a potent selective mesenchymal-epithelial transition inhibitor approved in 2020 for the treatment of metastatic non-small cell lung cancer. As real-world evidence is very limited, this study evaluated capmatinib-induced adverse events through data mining of the FDA Adverse Event Reporting System database. Four disproportionality analysis methods were employed to quantify the signals of capmatinib-related adverse events. The difference in capmatinib-associated adverse event signals was further investigated with respect to sex, age, weight, dose, onset time, continent, and concomitant drug. A total of 1518 reports and 4278 adverse events induced by capmatinib were identified. New significant adverse event signals emerged, such as dysphagia, dehydration, deafness, vocal cord paralysis, muscle disorder, and oesophageal stenosis. Notably, higher risk of alanine aminotransferase and aspartate aminotransferase increases were observed in females, especially when capmatinib was combined with immune checkpoint inhibitors. Compared with Europeans and Asians, Americans were more likely to experience peripheral swelling, especially in people > 65 years of age. Renal impairment and increased blood creatinine were more likely to occur with single doses above 400 mg and in Asians. This study improves the understanding of safety profile of capmatinib.

Abstract The increasing depth of mine excavation presents greater challenges in mine ventilation and in managing cooling energy consumption. Therefore, there is an urgent need for comprehensive research on jet ventilation influenced by low-speed crossflows. This study investigated the impact of flow velocity ratios (R) and jet exit diameters (d) on flow-field distribution and flow characteristics through velocity measurements and smoke flow visualization experiments. The results of the study revealed two distinct types of air lakes formed by jet ventilation in crossflow (JVIC), with one being wall-attached and the other suspended. Notably, a significant secondary flow phenomenon was observed in the near-field near the upper wall. Additionally, the deflection angle (θ j) of JVIC decreases as R and d/D increase, leading to the formation and movement of a semi-confined point (SP) and a confined point (CP) in the -x direction. Moreover, the wall confinement effect diminishes the jet’s diffusion and deflection ability in the -z direction, leading to increased penetration in the x direction. Before the formation of the SP, the deflection section of the jet lengthens, followed by a rapid shortening upon its formation. Finally, the study further developed empirical equations for the jet axial trajectory and diffusion width.

The scattering of reinforcement plays a crucial role in the microstructure and properties of metal matrix composites. In this study, an aluminum matrix composite (AMC) was reinforced by 10 wt% TiO2 (Al-10TiO2), with an average particle size of a submicron, combined with a different content of graphitic carbon nitride (g-C3N4), which was fabricated by shift-speed ball milling (SSBM) combined with multi-pass friction stir processing (FSP). In addition to the high hardness of TiO2, g-C3N4 has functional groups to promote in situ reactions. SSBM improves the distribution of reinforcement, refines grain size, and reduces the structural destruction of g-C3N4. The in situ reaction was achieved after multi-pass FSP at a high rotational speed and low travel speeds, which can promote uniform dispersion and grain refinement. Moreover, the g-C3N4 shows the efficient enhancement of strength while maintaining the elongation of AMC. Because the exfoliation of g-C3N4 under the effect of processing reduces the agglomeration of TiO2, boosts the flattening of Al, and enhances interface integration with the base metal. In situ phases can reduce the generation of coarse phases and improve interfacial bonding ability to enhance mechanical properties. The maximum tensile strength has been found at about 172.5 MPa in the Al-10TiO2 containing 1 wt% g-C3N4, which was enhanced by 34% compared to that of the Al-10TiO2. The tensile strength increases when the g-C3N4 content increases from 0 to 1 wt%, but then reduces with a further increase of content. The hardness was increased by 50.2%, 60.2%, and 35% with a g-C3N4 content of 0.5, 1, and 2 wt% compared to AMCs without reinforcement, respectively. According to the test, the enhancement mechanism is mainly attributed to Orowan, grain refinement strengthening, and load transfer of scattered reinforcement. In summary, the utilization of hybrid reinforcements successfully enhances the microstructure and mechanical properties.

BackgroundPercutaneous left atrial appendage closure (LAAC) serves as an alternative prophylactic strategy for patients with non-valvular atrial fibrillation (AF) who cannot undergo anti-coagulation therapy. Proper management of associated complications is crucial to enhancing the procedure's success rate and mitigating perioperative risks and adverse events during follow-up.AimsThis study aims to summarize our center's experience and strategies in managing procedural-related complications encountered in 512 cases of LAAC with or without ablation for AF conducted from January 2020 to December 2023.ResultsWe identified 11 significant intervention-requiring complications associated with LAAC with or without Ablation procedure. These included three cases of intraoperative thrombosis, three instances of pericardial effusion or tamponade, one case of device-related thrombosis, one peri-device leak, one systemic embolism, one bleeding episode, and one additional device-related complication. The categorization of intraoperative thrombosis was as follows: one patient exhibited heparin resistance; one experienced thrombosis due to prolonged device implantation during the LAAC with ablation procedure; and one had unexplained intraoperative thrombosis. The pericardial effusion or tamponade likely resulted from damage to the atrial appendage during LAAC device insertion. Two patients encountered device-related thrombosis and systemic embolism events possibly caused by non-standard postoperative antithrombotic medication use; one patient's peri-device leak may have resulted from incomplete endothelialization of the occluder post-surgery; one patient experienced postoperative bladder bleeding; and one patient's device-related complications occurred due to a dislodged strut frame that damaged the left atrial appendage, leading to pericardial effusion. Our proactive interventions enabled all patients with these surgical-related complications to be safely discharged, with subsequent follow-ups showing no adverse events.ConclusionImplementing targeted interventions for immediate procedural-related complications during the LAAC with or without ablation procedures enhances procedural success rates, diminishes postoperative mortality and patient disability, and bolsters stroke prevention efforts. This approach underscores the importance of a strategic response to complications, affirming the procedure's viability and safety in managing non-valvular AF in patients contraindicated for anticoagulation.

Background: Cefuroxime has played a crucial role in the prevention and treatment of bacterial infections. However, the differences in adverse events across formulations and routes remain unclear. Objectives: This study aimed to investigate the post-marketing safety of cefuroxime, particularly concerning formulations and routes. Design: A retrospective pharmacovigilance study of cefuroxime was conducted using the data from Food and Drug Administration Adverse Event Reporting System database. Methods: The clinical characteristics and concomitant drugs reported with cefuroxime were investigated. Adverse event signals of cefuroxime were identified based on four disproportionality algorithms. The signal differences of cefuroxime across formulations and routes were further examined. Results: A total of 1810 adverse event reports associated with cefuroxime were identified, and 181 cefuroxime-associated signals were detected. Compared with tablets, injections were more likely to cause preferred terms ‘blood pressure decreased’ and ‘anaphylactic shock’. In addition, system organ class ‘eye disorders’ significantly increased when cefuroxime was administered intraocularly, underscoring the importance of exercising caution regarding ocular toxicity. Conclusion: The adverse events associated with cefuroxime were significantly different across formulations and routes, which deserve special attention in clinical use.

Background: In December 2015, the World Health Organization, the World Animal Health Organization, and the Food and Agriculture Organization of the United Nations convened the International Congress on the elimination of rabies in Geneva. How to use epidemiological factors of post-exposure prophylaxis to prevent rabies has become the focus of attention. Objective: To analyze the epidemiological characteristics of 9772 patients with rabies in a four-year period in one hospital, to clarify the outbreak law of rabies and to explore the corresponding prevention and control strategies. Methods: The epidemiological data of rabies patients were collected from the infectious disease reporting information management system of the hospital from July 2018 to June 2022. The distributional characteristics of 13 influencing factors were analyzed using the chi-square test and linear regression. Results: There was a significant correlation between the number of wounds and age, and the numbers of female and male patients were close. People over the age of 44 were more likely to get bites or scratches on their lower extremity (P

Abstract Purpose Cytokines regulate the interaction between the immune system and malignant tumors. Among them, interleukin-10 (IL-10) is a multifunctional anti-inflammatory cytokine mainly produced by immune cells. The correlation between gastric cancer and T/C single nucleotide polymorphism (SNP) of interleukin-10 (IL-10) promoter−819(rs1800871)was opaque and remained to be determined. We aim to explore the pertinence of gastric cancer and SNP of interleukin 10–819 by meta-analysis via five statistical models. Methods Databases including PubMed, Cochrane Library, Embase, the Scopus, and Google Scholars were comprehensively retrieved for the eligible studies on the related topic from inception to March 2022. Odds ratios (ORs) were generated for dichotomous variants by meta-analysis in each model via STATA 17.0 MP. The statistical models comprised recessive model, over-dominant model, allele model, co-dominant model and dominant model. Subgroup analysis was performed to investigate the difference across races as well as the source of heterogeneity if necessary. Results Eventually a total of 15 articles reporting 7779 patients were enrolled in our study. There were 2383 patients and 5396 controls, collectively. There was no correlation between gastric cancer and IL-10 819 in recessive model, co-dominant model or dominant model, and subgroup analysis showed that Asian, Latin American and Caucasian had no correlation with the risk of gastric cancer. In the allelic model, there was significant correlation between gastric cancer and IL-10 819 (OR = 3.96%, 95%CI: 3.28 to 3.78). In the over-dominant model, there is no correlation between gastric cancer and IL-10 819, but subgroup analysis uncovered significant vulnerability of Asian people with regard to gastric cancer. Conclusions In our study, both Asians, Latin Americans, and Europeans showed an increased risk of gastric cancer in the allelic model, whereas only Asians showed significant susceptibility in the super dominant model. Of course, more large cohort studies are needed to confirm our results.

Abstract Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) are blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupts the behavioral effects of ketamine. Ketamine treatment rapidly increases levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolishes both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.

With the rapid development of deep learning, convolutional neural networks have achieved milestones in synthetic aperture radar (SAR) image object detection. However, object detection in SAR images is still a great challenge due to the difficulty in distinguishing targets from complex backgrounds. At the same time, most of the targets in SAR images are small and unevenly distributed, which makes it challenging to extract sufficient feature information. To solve these issues mentioned above, an efficient object detection network for SAR images based on Swin transformer and YOLOv7 is proposed in this article. First, we design a novel feature aggregation module Petty-specialized feature aggregation (PS-FPN) to enrich small targets’ semantic and spatial features while keeping the model lightweight. PS-FPN module uses the fusion of deep and shallow features by using cross-layer feature aggregation and single-branch feature aggregation to enhance the detection of small targets. Second, a novel attention mechanism strategy mix-attention is proposed to find more attention regions. Finally, we add one more prediction head to extract shallow features that effectively preserve small targets’ feature information. To verify the effectiveness of the proposed algorithm, extensive experiments are carried out on several challenging SAR image datasets. The results show that, compared with other state-of-the-art detectors, the proposed method can achieve significant performance based on lightweight detection.

Grain weight is one of the key components of wheat (Triticum aestivum L.) yield. Genetic manipulation of grain weight is an efficient approach for improving yield potential in breeding programs. A recombinant inbred line (RIL) population derived from a cross between W7268 and Chuanyu 12 (CY12) was employed to detect quantitative trait loci (QTLs) for thousand-grain weight (TGW), grain length (GL), grain width (GW), and the ratio of grain length to width (GLW) in six environments. Seven major QTLs, QGl.cib-2D, QGw.cib-2D, QGw.cib-3B, QGw.cib-4B.1, QGlw.cib-2D.1, QTgw.cib-2D.1 and QTgw.cib-3B.1, were consistently identified in at least four environments and the best linear unbiased estimation (BLUE) datasets, and they explained 2.61 to 34.85% of the phenotypic variance. Significant interactions were detected between the two major TGW QTLs and three major GW loci. In addition, QTgw.cib-3B.1 and QGw.cib-3B were co-located, and the improved TGW at this locus was contributed by GW. Unlike other loci, QTgw.cib-3B.1/QGw.cib-3B had no effect on grain number per spike (GNS). They were further validated in advanced lines using Kompetitive Allele Specific PCR (KASP) markers, and a comparison analysis indicated that QTgw.cib-3B.1/QGw.cib-3B is likely a novel locus. Six haplotypes were identified in the region of this QTL and their distribution frequencies varied between the landraces and cultivars. According to gene annotation, spatial expression patterns, ortholog analysis and sequence variation, the candidate gene of QTgw.cib-3B.1/QGw.cib-3B was predicted. Collectively, the major QTLs and KASP markers reported here provide valuable information for elucidating the genetic architecture of grain weight and for molecular marker-assisted breeding in grain yield improvement.

Abstract Background Metabolic syndrome (MetS) is a pathological condition characterized by the abnormal clustering of several metabolic components and has become a major public health concern. We aim to investigate the potential link of Systemic immunity-inflammation index (SII) on MetS and its components. Methods and result Weighted multivariable logistic regression was conducted to assess the relationship between SII and MetS and its components. Restricted cubic spline (RCS) model and threshold effect analysis were also performed. A total of 6,999 U.S. adults were enrolled. Multivariate model found that SII were positively associated with MetS (OR = 1.18;95CI%:1.07–1.30) and hypertension (OR = 1.22; 95CI%:1.12–1.34) in a dose-dependent manner. When SII was converted into a categorical variable, the risk of MetS increased by 36% and the risk of hypertension increased by 53% in the highest quantile of SIIs. The RCS model confirmed linear associations between SII and MetS, as well as a non-linear association between SII and certain components of MetS, including hypertension, hyperglycemia, low HDL, and hyperlipidemia. Meanwhile, the relationship between SII and hypertension presents a J-shaped curve with a threshold of 8.27, above which the risk of hypertension increases. Furthermore, in MetS and hypertension, age, sex, body mass index (BMI), and race were not significantly associated with this positive association based on subgroup analyses and interaction tests(p for interaction > 0.05). Conclusions The present study indicated that there was a higher SII association with an increased risk of MetS and hypertension in adults. However, further prospective cohort studies are required to establish a causal relationship between SII and MetS, as well as its components.

Compared with large-scale ships, small-scale ships occupy few pixels and have low contrast, so it poses a great challenge to detect multiscale ships in synthetic aperture radar (SAR) images. In order to improve the accuracy of multiscale ship detection in SAR images, this article designs a general multiscale pyramid attention module (MPAM), which is a plug-and-play lightweight module that can adapt to many ship detection networks. In the MPAM, a deep feature extraction submodule is first designed to use the multiscale pyramid structure to divide the feature map into different levels, extracting rich features with resolution and semantic information for multiscale ship detection. The channel multilayer attention fusion submodule and spatial multilayer attention fusion submodule are then designed to fuse the channel and spatial attention blocks on different level feature maps, which could better learn the dependent features from the channel and spatial dimensions, to enhance the feature representation. Finally, the fused feature map is input into the existing ship detection networks to obtain the detection result. Experiments on SAR datasets containing multiscale ships show that the effectiveness of the MPAM in improving the accuracy of the existing ship detection networks.

The integration of the Crop Growth Model (CGM), Radiative Transfer Model (RTM), and Machine Learning Algorithm (MLA) for estimating crop traits represents a cutting-edge area of research. This integration requires in-depth study to address RTM limitations, particularly of similar spectral responses from multiple input combinations. This study proposes the integration of CGM and RTM for crop trait retrieval and evaluates the performance of CGM output-based RTM spectra generation for multiple crop traits estimation without biased sampling using machine learning models. Moreover, PROSAIL spectra as training against Harmonized Landsat Sentinel-2 (HLS) as testing was also compared with HLS data only as an alternative. It was found that satellite data (HLS, 80:20) not only consistently performed better, but PROSAIL (train) and HLS (test) also had satisfactory results for multiple crop traits from uniform training samples in spite of differences in simulated and real data. PROSAIL-HLS has an RMSE of 0.67 for leaf area index (LAI), 5.66 µg/cm2 for chlorophyll ab (Cab), 0.0003 g/cm2 for dry matter content (Cm), and 0.002 g/cm2 for leaf water content (Cw) against the HLS only, with an RMSE of 0.40 for LAI, 3.28 µg/cm2 for Cab, 0.0002 g/cm2 for Cm, and 0.001 g/cm2 for Cw. Optimized machine learning models, namely Extreme Gradient Boost (XGBoost) for LAI, Support Vector Machine (SVM) for Cab, and Random Forest (RF) for Cm and Cw, were deployed for temporal mapping of traits to be used for wheat productivity enhancement.

The performance of the anode varies from the impurity ions in the copper electrowinning process. This work focused on the variation of the electrochemical behavior of the Pb-0.06%Ca-1.2%Sn anode as the Fe ions (Fe3+ and/or Fe2+) existed in the electrolyte by electrochemical characterization. Copper electrodeposition experiments were conducted under a current density of 300 A/m2, with the Fe ion concentration in the electrolyte controlled within the range of 0 to 20 g/L and the Cu ion concentration maintained at 45 g/L at a temperature of 45 °C. The variation in the corrosion resistance, catalytic activity, and structural composition of the anode film layer was analyzed in-depth according to the presence of Fe ions. The results show that the structure of PbO2 on the surface of the film was changed as Fe ions doped into the anode film, and the oxygen evolution activity of the anode was also improved. However, the corrosion resistance decreased with increasing Fe3+ concentration. Furthermore, the addition of 2 g/L Fe2+ in the electrolyte containing 2 g/L Fe3+ led to an elevation in the corrosion resistance of the anode to some extent and further increased the oxygen evolution activity.

Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive scarring interstitial lung disease with an unknown cause. Some patients may experience acute exacerbations (AE), which result in severe lung damage visible on imaging or through examination of tissue samples, often leading to high mortality rates. However, the etiology and pathogenesis of AE-IPF remain unclear. AE-IPF patients exhibit diffuse lung damage, apoptosis of type II alveolar epithelial cells, and an excessive inflammatory response. Establishing a reliable animal model of AE is critical for investigating the pathogenesis. Recent studies have reported a variety of animal models for AE-IPF, each with its own advantages and disadvantages. These models are usually established in mice with bleomycin-induced pulmonary fibrosis, using viruses, bacteria, small peptides, or specific drugs. In this review, we present an overview of different AE models, hoping to provide a useful resource for exploring the mechanisms and targeted therapies for AE-IPF.

Abstract The surface organs mainly comprise the superficial layers of various parts of the mammalian body, including the skin, eyes, and ears, which provide solid protection against various threats to the entire body. Damage to surface organs could lead to many serious diseases or even death. Currently, despite significant advancements in this field, there remain numerous enigmas that necessitate expeditious resolution, particularly pertaining to diagnostic and therapeutic objectives. The advancements in nanomedicine have provided a significant impetus for the development of novel approaches in the diagnosis, bioimaging, and therapy of superficial organs. The aggregation‐induced emission (AIE) phenomenon, initially observed by Prof. Ben Zhong Tang, stands out due to its contrasting behavior to the aggregation‐caused quenching effect. This discovery has significantly revolutionized the field of nanomedicine for surface organs owing to its remarkable advantages. In this review of literature, we aim to provide a comprehensive summary of recent advances of AIE lumenogen (AIEgen)‐based nanoplatforms in the fields of detection, diagnosis, imaging, and therapeutics of surface organ‐related diseases and discuss their prospects in the domain. It is hoped that this review will help attract researchers’ attention toward the utilization of this field for the exploration of a wider range of biomedical and clinical applications.

Abstract Accurate cell type identification is a key and rate-limiting step in single-cell data analysis. Single-cell references with comprehensive cell types, reproducible and functionally validated cell identities, and common nomenclatures are much needed by the research community for automated cell type annotation, data integration, and data sharing. Here, we develop a computational pipeline utilizing the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples to construct LungMAP single-cell reference (CellRef) for both normal human and mouse lungs. CellRefs define 48 human and 40 mouse lung cell types catalogued from diverse anatomic locations and developmental time points. We demonstrate the accuracy and stability of LungMAP CellRefs and their utility for automated cell type annotation of both normal and diseased lungs using multiple independent methods and testing data. We develop user-friendly web interfaces for easy access and maximal utilization of the LungMAP CellRefs.

Abstract Objective Non-suicidal self-injury (NSSI) behaviors are prevalent in adolescents and have adverse effects on physical and mental health. However, little is known about the relationship between NSSI and alexithymia, or the underlying mechanisms that could explain this relationship. This study aimed to elucidate the current status of NSSI in adolescent depression, and analyze the relationship between alexithymia, loneliness, resilience, and adolescent depression with NSSI, so as to provide a theoretical basis for psychotherapeutic interventions. Method The study sample involved inpatients and outpatients from 12 hospitals across China and adolescents with depression who met the DSM-5 diagnostic criteria for depression episode. The following scales were used: The Functional Assessment of Self-Mutilation, Toronto Alexithymia Scale, UCLA Loneliness Scale, and Connor Davidson Resilience Scale. Results The detection rate of NSSI in adolescents with depression from 2021.01.01-2022.01.01 was 76.06% (1782/2343). Spearman’s correlation analysis revealed a significant correlation between alexithymia, loneliness, resilience and NSSI in depressed adolescents, and the results of the non-parametric test showed that the differences between the two groups for each factor were statistically significant. Binary logistic regression results showed that alexithymia (B = 0.023, p = 0.003, OR = 1.023, 95% CI: 1.008–1.038) and depression (B = 0.045, p

Flowering is critical to the success of plant propagation. The MYB family transcription factor CIRCADIAN CLOCK-ASSOCIATED1 (CCA1) is an essential component of the core loop of the circadian clock and plays a crucial role in regulating plant flowering time. In this study, we found that photoperiod affects the expression pattern and expression level of BcCCA1, which is delayed flowering time under short-day conditions in Pak-choi [Brassica campestris (syn. Brassica rapa) ssp. chinensis]. We detected overexpression and silencing of BcCCA1 in Pak-choi, resulting in delayed and promoted flowering time, respectively. Furthermore, we also discovered that FLOWERING LOCUS C (BcFLC) and SUPPRESSOR OF CONSTANS1 (BcSOC1) were expressed significantly differently in BcCCA1 overexpression and silencing plants compared with control plants. Therefore, we further investigated the interaction relationship between BcCCA1, BcFLC, and BcSOC1, and the results showed that BcCCA1 and BcFLC as a complex interacted with each other. Moreover, both BcCCA1 and BcFLC can directly bind to the promoter of BcSOC1 and repress its transcription, and BcCCA1 can form a complex with BcFLC to enhance the transcriptional inhibition of BcSOC1 by BcFLC. This study reveals a new mechanism by which the circadian clock regulates flowering time.

In the relay intercropping system of maize/sweet potato, the growth of the sweet potatoes is seriously limited by weak light stress in the early stage due to shade from maize plants. However, it is not clear how the weak light affects sweet potatoes and causes tuberous root loss. By setting two light intensity levels (weak light = 30% transmittance of normal light), this study evaluated the responses of two sweet potato cultivars with different tolerances to weak light in a field-based experiment and examined the divergence of gene expression related to light and photosynthesis in a pot-based experiment. The results showed that under weak light, the anatomic structure of functional leaves changed, and the leaf thickness decreased by 39.98% and 17.32% for Yuhongxinshu-4 and Wanshu-7, respectively. The ratio of S/R increased, and root length, root superficial area, and root volume all decreased. The photosynthetic enzyme rubisco was weakened, and the net photosynthetic rate (Pn) declined as well. The level of gene expression in Wanshu-7 was higher than that of Yuhongxinshu-4. The KEGG analysis showed that differentially expressed genes from the two cultivars under weak-light stress used the same enrichment pathway, mainly via glutathione metabolism and flavonoid biosynthesis. After full light levels were restored, the differentially expressed genes were all enriched in pathways such as photosynthesis, photosynthetic pigment synthesis, and carbon metabolism. These findings indicated that weak light changed the plant morphology, photosynthetic physiology and gene expression levels of sweet potatoes, which eventually caused losses in the tuberous root yield. The more light-sensitive cultivar (Wanshu-7) had stronger reactions to weak light. This study provides a theoretical basis and strategy for breeding low-light-tolerant varieties and improving relay intercropping production in sweet potatoes.

IntroductionIdiopathic pulmonary fibrosis (IPF) is characterized by progressive lung dysfunction due to excessive collagen production and tissue scarring. Despite recent advancements, the molecular mechanisms remain unclear.MethodsRNA sequencing identified 475 differentially expressed genes (DEGs) in the TGF-β1-induced primary lung fibrosis model. Gene expression chips GSE101286 and GSE110147 from NCBI gene expression omnibus (GEO) database were analyzed using GEO2R, revealing 94 DEGs in IPF lung tissue samples. The gene ontology (GO) and pathway enrichment, Protein-protein interaction (PPI) network construction, and Maximal Clique Centrality (MCC) scoring were performed. Experimental validation included RT-qPCR, Immunohistochemistry (IHC), and Western Blot, with siRNA used for gene knockdown. A co-expression network was constructed by GeneMANIA.ResultsGO enrichment highlighted significant enrichment of DEGs in TGF-β cellular response, connective tissue development, extracellular matrix components, and signaling pathways such as the AGE-RAGE signaling pathway and ECM-receptor interaction. PPI network analysis identified hub genes, including FN1, COL1A1, POSTN, KIF11, and ECT2. CALD1 (Caldesmon 1), CDH2 (Cadherin 2), and POSTN (Periostin) were identified as dysregulated hub genes in both the RNA sequencing and GEO datasets. Validation experiments confirmed the upregulation of CALD1, CDH2, and POSTN in TGF-β1-treated fibroblasts and IPF lung tissue samples. IHC experiments probed tissue-level expression patterns of these three molecules. Knockdown of CALD1, CDH2, and POSTN attenuated the expression of fibrotic markers (collagen I and α-SMA) in response to TGF-β1 stimulation in primary fibroblasts. Co-expression analysis revealed interactions between hub genes and predicted genes involved in actin cytoskeleton regulation and cell-cell junction organization.ConclusionsCALD1, CDH2, and POSTN, identified as potential contributors to pulmonary fibrosis, present promising therapeutic targets for IPF patients.

Abstract Pitolisant, a novel histamine H3‐receptor antagonist, holds significant promise for treating narcolepsy. However, a petition, which highlighted that pitolisant was associated with deaths during clinical trials, has propelled it into the spotlight of widespread societal attention on April 3, 2023. Till now, the clinical safety of pitolisant remains a heatedly debated topic. This study aimed to offer a comprehensive assessment of the safety profile of pitolisant in real‐world clinical settings. Adverse event reports where pitolisant was the primary suspect drug were extracted from the FDA Adverse Event Reporting System database. The clinical characteristics and concomitant drugs of the pitolisant‐associated adverse events were analyzed. The potential adverse event signals of pitolisant were explored using four disproportionality analysis methods. Furthermore, the difference in pitolisant‐associated adverse event signals was investigated concerning sex, age, weight, and dose. A total of 526 reports and 1695 adverse events with pitolisant as the primary suspected drug were identified. The most significant adverse event signals were generally mild and of short duration. The concomitant drugs of pitolisant were highly intricate, mainly included drugs for treating narcolepsy as well as antidepressants. Seven new significant adverse event signals emerged. The safety profile of pitolisant exhibited no significant differences across age and dose groups, although slight variations were observed in relation to sex and weight. The findings from reports of death and life‐threatening outcomes underscore the importance of enhanced monitoring for cardiac and respiratory adverse reactions when utilizing pitolisant. This study provided a broader understanding of the safety profile of pitolisant.

Abstract Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2‐deoxyglucose (2‐DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2‐addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS–MS) analytical methods for 2‐DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein‐cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug–drug interactions. The data demonstrated a rapid and complete separation of 2‐DG from common monosaccharides by HPLC‐MS–MS multi‐reaction monitoring. Application of the HPLC‐MS–MS 2‐DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax) for 2‐DG of 0.5 h after 2‐DG alone or with HCQ and identical post‐peak half‐life of approximately 1 h. With a seemingly bi‐modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax) and area under the curve (AUC0‐4h) of 2‐DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0‐8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0‐∞) of each drug, the combination affected the apparent volume of distribution (Vd) and clearance (CL) of 2‐DG, and CL for HCQ without affecting its Vd. We observed significant negative PK interactions, probably at the intestinal absorption level, between 2‐DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.

Abstract Protein aggregate species play a pivotal role in the pathology of various degenerative diseases. Their dynamic changes are closely correlated with disease progression, making them promising candidates as diagnostic biomarkers. Given the prevalence of degenerative diseases, growing attention is drawn to develop pragmatic and accessible protein aggregate species detection technology. However, the performance of current detection methods is far from satisfying the requirements of extensive clinical use. In this review, we focus on the design strategies, merits, and potential shortcomings of each class of detection methods. The review is organized into three major parts: native protein sensing, seed amplification, and intricate program, which embody three different but interconnected methodologies. To the best of our knowledge, no systematic review has encompassed the entire workflow, from the molecular level to the apparatus organization. This review emphasizes the feasibility of the methods instead of theoretical detection limitations. We conclude that high selectivity does play a pivotal role, while signal compilation, multilateral profiling, and other patient‐oriented strategies (i.e. less invasiveness and assay speed) are also important.

Osteoarthritis (OA) is a joint disease in which cartilage degradation is the hallmark pathological change. In this study, we investigated the anti-osteoarthritic effects of DHEA in rabbit chondrocytes. Polymerase chain reaction was performed to evaluate the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, aggrecan and collagen type 2. In addition, ERK1/2 signaling pathway components were analyzed by Western blotting. In IL-1β-induced chondrocytes, the phosphorylation of ERK1/2 was enhanced, and the downstream catabolic genes, including ADAMTS-4 and ADAMTS-5, were upregulated, while the anabolic genes aggrecan and collagen type 2 were downregulated. DHEA administration restored the IL-1β-induced imbalance in anabolic and catabolic gene expression. In addition, the phosphorylation of ERK1/2 was suppressed by DHEA. Then, PD98059 was used to block the ERK1/2 signaling pathway. The protective effect of DHEA was significantly increased when ERK1/2 signaling was inactivated. DHEA may exert its protective effect by suppressing ADAMTS in an ERK1/2-dependent manner in rabbit chondrocytes.

Grain number per spike (GNS) is a crucial component of grain yield and plays a significant role in improving wheat yield. To identify quantitative trait loci (QTL) associated with GNS, a recombinant inbred line (RIL) population derived from the cross of Zhongkemai 13F10 and Chuanmai 42 was employed to conduct QTL mapping across eight environments. Based on the bulked segregant exome sequencing (BSE-Seq), genomic regions associated with GNS were detected on chromosomes 5A and 6A. According to the constructed genetic maps, two major QTL QGns.cib-5A (LOD = 4.35–8.16, PVE = 8.46–14.43%) and QGns.cib-6A (LOD = 3.82–30.80, PVE = 5.44–12.38%) were detected in five and four environments, respectively. QGns.cib-6A is a QTL cluster for other seven yield-related traits. QGns.cib-5A and QGns.cib-6A were further validated using linked Kompetitive Allele Specific PCR (KASP) markers in different genetic backgrounds. QGns.cib-5A exhibited pleiotropic effects on productive tiller number (PTN), spike length (SL), fertile spikelet number per spike (FSN), and ratio of grain length to grain width (GL/GW) but did not significantly affect thousand grain weight (TGW). Haplotype analysis revealed that QGns.cib-5A and QGns.cib-6A were the targets of artificial selection during wheat improvement. Candidate genes for QGns.cib-5A and QGns.cib-6A were predicted by analyzing gene annotation, spatiotemporal expression patterns, and orthologous and sequence differences. These findings will be valuable for fine mapping and map-based cloning of genes underlying QGns.cib-5A and QGns.cib-6A.

ObjectivesAstragaloside IV (AS-IV) is a natural triterpenoid saponin compound with a variety of pharmacological effects, and several studies have clarified its anti-inflammatory effects, which may make it an effective alternative treatment against inflammation. In the study, we aimed to investigate whether AS-IV could attenuate the inflammatory response to acute lung injury and its mechanisms.MethodsDifferent doses of AS-IV (20mg·kg-1, 40mg·kg-1, and 80mg·kg-1) were administered to the ALI rat model, followed by collection of serum and broncho alveolar lavage fluid (BALF) for examination of the inflammatory response, and HE staining of the lung and colon tissues, and interpretation of the potential molecular mechanisms by quantitative real-time PCR (qRT-PCR), Western blotting (WB). In addition, fecal samples from ALI rats were collected and analyzed by 16S rRNA sequencing.ResultsAS-IV decreased the levels of TNF-α, IL-6, and IL-1β in serum and BALF of mice with Acute lung injury (ALI). Lung and colon histopathology confirmed that AS-IV alleviated inflammatory infiltration, tissue edema, and structural changes. qRT-PCR and WB showed that AS-IV mainly improved inflammation by inhibiting the expression of PI3K, AKT and mTOR mRNA, and improved the disorder of intestinal microflora by increasing the number of beneficial bacteria and reducing the number of harmful bacteria.ConclusionAS-IV reduces the expression of inflammatory factors by inhibiting the PI3K/AKT/mTOR pathway and optimizes the composition of the gut microflora in AIL rats.

ABSTRACTAs an important part of water splitting, the oxygen evolution reaction (OER) requires efficient, low-cost, and stable catalysts to overcome its sluggish kinetic barrier. In this study, based on previously reported OER catalyst materials of boron monosulfide mixed with graphene (r-BS+G), nickel foam (NF) is introduced as a supporting material for an r-BS+G electrocatalyst. The resulting r-BS+G-NF exhibits a very low overpotential at 10 (245 mV), 100 (308 mV), and 500 (405 mV) mA cm−2, with a low Tafel slope (56 mV dec−1). In addition, r-BS+G-NF exhibits high durability and can maintain high activity for more than 100 h at 100 mA cm−2. This is in sharp contrast to the catalyst without graphene (r-BS+NF), which shows lower durability. The results suggest that the unique morphology of the NF provides a large electrochemically active area and exposes more active sites on the surface of the prepared electrocatalyst, while the flexible graphene sheets play an important role as a support for effectively combining r-BS and NF. Consequently, the self-supporting structure can improve the OER performance as well as stability. Therefore, this study provides a promising strategy for use as an efficient and stable OER catalyst at high current densities.

Abstract Background Ferroptosis has been linked to tumor progression and resistance to antineoplastic therapy. Long noncoding RNA (lncRNA) exerts a regulatory role in various biological processes of tumor cells, while the function and molecular mechanism of lncRNA in ferroptosis are yet to be clarified in glioma. Methods Both gain-of-function and loss-of-function experiments were employed to investigate the effects of SNAI3-AS1 on the tumorigenesis and ferroptosis susceptibility of glioma in vitro and in vivo. Bioinformatics analysis, Bisulfite sequencing PCR, RNA pull-down, RIP, MeRIP and dual-luciferase reporter assay were performed to explore the low expression mechanism of SNAI3-AS1 and the downstream mechanism of SNAI3-AS1 in ferroptosis susceptibility of glioma. Results We found that ferroptosis inducer erastin downregulates SNAI3-AS1 expression in glioma by increasing the DNA methylation level of SNAI3-AS1 promoter. SNAI3-AS1 functions as a tumor suppressor in glioma. Importantly, SNAI3-AS1 enhances the anti-tumor activity of erastin by promoting ferroptosis both in vitro and in vivo. Mechanistically, SNAI3-AS1 competitively binds to SND1 and perturbs the m6A-dependent recognition of Nrf2 mRNA 3’UTR by SND1, thereby reducing the mRNA stability of Nrf2. Rescue experiments confirmed that SND1 overexpression and silence can rescue the gain- and loss-of-function ferroptotic phenotypes of SNAI3-AS1, respectively. Conclusions Our findings elucidate the effect and detailed mechanism of SNAI3-AS1/SND1/Nrf2 signalling axis in ferroptosis, and provide a theoretical support for inducing ferroptosis to improve glioma treatment.

Grain size and weight are key components of wheat yield. Exploitation of major underlying quantitative trait loci (QTL) can improve yield potential in wheat breeding. A recombinant inbred line (RIL) population was constructed to detect QTL for thousand-grain weight (TGW), grain length (GL) and grain width (GW) across eight environments. Genomic regions associated with grain size and grain weight were identified on chromosomes 4A and 6A using bulked segregant exome sequencing (BSE-Seq) analysis. After constructing genetic maps, six major QTL detected in at least four individual environments and in best linear unbiased estimator (BLUE) datasets, explained 7.50%–23.45% of the phenotypic variation. Except for QGl.cib-4A, the other five QTL were co-located in two regions, namely QTgw/Gw.cib-4A and QTgw/Gw/Gl.cib-6A. Interactions of these QTL were analyzed. Unlike QTgw/Gw/Gl.cib-6A, QTgw/Gw.cib-4A and QGl.cib-4A had no effect on grain number per spike (GNS). The QTL were validated in a second cross using Kompetitive Allele Specific PCR (KASP) markers. Since QTgw/Gw.cib-4A was probably a novel locus, it and the KASP markers reported here can be used in wheat breeding. TraesCS4A03G0191200 was predicted to be potential candidate gene for QTgw/Gw.cib-4A based on the sequence differences, spatiotemporal expression patterns, gene annotation and haplotype analysis. Our findings will be useful for fine mapping and for marker-assisted selection in wheat grain yield improvement.

Abstract Objectives To explore the diagnostic accuracy of ultrasound measurement of optic nerve sheath diameter (ONSD) and optic disc height (ODH) in detecting intracranial hypertension in non‐small‐cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM). Methods Seventy‐two patients with NSCLC‐LM and 65 patients with NSCLC were enrolled. The ONSD, ODH, eyeball transverse diameter (ETD), and eyeball vertical diameter (EVD) were measured by ultrasound. Subsequently, lumbar puncture was performed in NSCLC‐LM patients to measure cerebrospinal fluid pressure (CSFP), and intrathecal chemotherapy was regularly implemented. Pearson's correlation analysis was used to analyze the relationship between CSFP and ultrasound findings. The diagnostic accuracy of ONSD, ODH, and combined ONSD and ODH was evaluated by receiver operating characteristic (ROC) curve analysis and the corresponding area under the ROC curve (AUC). Results The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were higher in the NSCLC‐LM group (all p 280 mmH2O were 0.787 (95% CI: 0.64–0.93, sensitivity 68.75%, specificity 91.07%), 0.885 (95% CI: 0.81–0.96, sensitivity 100%, specificity 69.64%), 0.765 (95% CI: 0.64–0.89, sensitivity 81.25%, specificity 64.29%), and 0.788 (95% CI: 0.64–0.93, sensitivity 56.25%, specificity 91.07%), respectively. When ONSD was combined with ODH, the AUC was 0.913 (95% CI: 0.83–0.99, sensitivity 87.85%, specificity 85.70%). Furthermore, intrathecal chemotherapy was associated with a downtrend in CSFP and ultrasound findings. Conclusion There are important advantages of using bedside ultrasonography for detecting elevated CSFP in NSCLC‐LM patients. Further research should be performed to evaluate the clinical significance of an enlarged ONSD and increased ODH in NSCLC‐LM.

Abstract Background Evading apoptosis by overexpression of anti-apoptotic Bcl-2 family proteins is a hallmark of cancer cells and the Bcl-2 selective inhibitor venetoclax is widely used in the treatment of hematologic malignancies. Mcl-1, another anti-apoptotic Bcl-2 family member, is recognized as the primary cause of resistance to venetoclax treatment. However, there is currently no Mcl-1 inhibitor approved for clinical use. Methods Paired parental and Mcl-1 knockout H1299 cells were used to screen and identify a small molecule named MI-238. Immunoprecipitation (IP) and flow cytometry assay were performed to analyze the activation of pro-apoptotic protein Bak. Annexin V staining and western blot analysis of cleaved caspase 3 were employed to measure the cell apoptosis. Mouse xenograft AML model using luciferase-expressing Molm13 cells was employed to evaluate in vivo therapeutic efficacy. Bone marrow samples from newly diagnosed AML patients were collected to evaluate the therapeutic potency. Results Here, we show that MI-238, a novel and specific Mcl-1 inhibitor, can disrupt the association of Mcl-1 with BH3-only pro-apoptotic proteins, selectively leading to apoptosis in Mcl-1 proficient cells. Moreover, MI-238 treatment also potently induces apoptosis in acute myeloid leukemia (AML) cells. Notably, the combined treatment of MI-238 with venetoclax exhibited strong synergistic anti-cancer effects in AML cells in vitro, MOLM-13 xenografts mouse model and AML patient samples. Conclusions This study identified a novel and selective Mcl-1 inhibitor MI-238 and demonstrated that the development of MI-238 provides a novel strategy to improve the outcome of venetoclax therapy in AML.

Abstract Background Hypertensive patients with depression have a higher mortality rate and a worse prognosis compared with hypertensive only. Depression may reduce medication adherence in hypertension patients. Methods This study includes respondents in the National Health and Nutritional Examination Survey (NHANES) database from 2005 to 2018 who had previously been diagnosed with hypertension. Medication adherence was defined as taking medication as recommended by a physician. The depressive state was assessed using the patient health questionnaire (PHQ)-9. Results Nine thousand one hundred eighty-six respondents were included in the analysis. Medication adherence was associated with depression (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.26 to1.75) and depression score (OR: 1.04 per each point increase, 1.03 to 1.05) in the unadjusted analyses. After adjusting for clinical and socioeconomic/demographic factors, there were significant statistical correlations between depression score and medication adherence (aOR: 1.02 per each point increase, 1.00 to 1.03, p 0.05). It was still statistically significant relationships between sex, age, body mass index (BMI), race, marital status, and health insurance with medication adherence after adjusted socioeconomic/demographic factors. Conclusion Depression was marginally associated with poor medication adherence in hypertensive patients, and the correlation increased with depression degree. Moreover, socioeconomic/demographic factors have an independent impact on medication adherence including sex, age, BMI, race, marital status, and health insurance.