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Abstract Background As cardiovascular disease (CVD) morbidity and mortality increase yearly, this study aimed to explore the potential of the weight-adjusted-waist index (WWI) and its relation to long-term mortality in patients with CVD. Methods The diagnosis of CVD was based on standardized medical condition questionnaires that incorporated participants’ self-reported physician diagnoses. WWI (cm/√kg) is a continuous variable and calculated as waist circumference (WC, cm) divided by square root of body weight (kg). For analysis purposes, the participants were divided into four groups based on the quartiles (Q1 – Q4) of the WWI. The study’s primary outcome was all-cause mortality in patients with CVD, with cardiovascular mortality as the secondary outcome, and sample weights and complex survey designs were used to ensure reliable, accurate results. Results The final analysis included 4,445 study participants. In the fully adjusted model, the highest quartile (WWI > 12.05 cm/√ kg) showed a higher all-cause mortality rate compared with the lowest quartile (WWI 0.05); WWI was nonlinearly associated with the risk of all-cause mortality in patients with coronary heart disease and angina (P-overall

Abstract Background Molecular-clinical prognostic models for Myelodysplastic syndromes (MDS) offer more accurate prognosis predictions, yet existing models often overlook the heterogeneity of mutational profiles against the cytogenetic background. Moreover, how to apply these models in regions where large panel NGS is unaffordable remains a significant challenge to be addressed. Methods A total of 237 NK MDS patients from our center were used as the training set to screen for key variables and develop a prognostic model with overall survival (OS) as the endpoint. The C-index was used as the main evaluation metric to assess the model’s performance. The IWG-PM cohort (n = 691) was used as an external independent validation set to evaluate the generalizability of the model. Results We developed a seven-parameter molecular-clinical prognostic model, the Molecular Prognostic Scoring System for NK MDS (NK-PSS-M), which only incorporates three gene mutations as parameters. The NK-PSS-M can reliably predict OS and leukemia-free survival (LFS). The performance of NK-PSS-M was comparable to that of the Molecular International Prognostic Scoring System (IPSS-M), and it significantly outperformed the Revised International Prognostic Scoring System for MDS (IPSS-R). Conclusions The NK-PSS-M model improved the risk stratification of non-molecular models and provided a reliable alternative to the IPSS-M. This strategy provides insights into how resource-scarce regions can apply molecular-clinical models.

The tea plant cultivar ‘Zhonghuang 2’ (ZH2) possesses albino-induced yellow leaves that contain low levels of catechins but high contents of amino acids. However, the molecular mechanism underlying the yellow leaf phenotype of ZH2 has not been elucidated clearly. In the current research, the yellow shoots (ZH2-Y) and naturally converted green shoots (ZH2-G) of ZH2 were studied using metabolic and proteomic profiling for a better understanding of the mechanism underlying phenotype formation. In total, 107 differentially changed metabolites (DCMs) were identified from the GC‒MS-based metabolomics, and 189 differentially accumulated proteins (DAPs) were identified from the tandem mass tag (TMT)-based quantitative proteomics. Subsequently, integrated analysis revealed that ‘porphyrin and chlorophyll metabolism’, ‘carbon fixation in photosynthetic organisms’, and ‘phenylpropanoid biosynthesis’ pathways were commonly enriched for DAPs and DCMs. We further found that the inhibition of chlorophyll biosynthesis, the deficiency of photosynthetic proteins and the imbalance of the ROS-scavenging system were the crucial reasons responsible for the chlorosis, chloroplast abnormality and photooxidative damage of ZH2 leaves. Altogether, our research combines metabolomics and proteomics approaches to uncover the molecular mechanism leading to the yellow leaf phenotype of tea plants.

Abstract Blended care therapy (BCT), which augments live, video-based psychotherapy sessions with asynchronous digital tools, has the potential to increase access to evidence-based treatments for posttraumatic stress disorder (PTSD). However, its effectiveness in diverse, real-world settings is not well-understood. This evaluation aimed to assess clinical outcomes of a BCT program for PTSD symptoms. A retrospective cohort analysis was conducted of 199 adults who received an employer-offered BCT program for PTSD symptoms that delivered either cognitive processing therapy or prolonged exposure. PTSD symptom severity was regularly assessed using the PTSD Checklist for DSM-5 (PCL-5). Growth curve models were used to evaluate the trajectory of PTSD symptoms over the course of care, and an interaction term was added to assess outcomes by baseline PTSD symptom severity (i.e., PCL-5 ≥ 31 versus PCL-5

Abstract WNT/β-catenin signaling plays key roles in development and cancer1,2. ZNRF3/RNF43 modulates Frizzleds through ubiquitination, dampening WNT/β-catenin signaling. Conversely, RSPO1-4 binding to LGR4-6 and ZNRF3/RNF43 enhances WNT/β-catenin signaling3–5. Here, we elucidate the overall landscape of architectures in multiple LGR4, RSPO2, and ZNRF3 assemblies, showcasing varying stoichiometries and arrangements. These structures reveal that LGR4 and RSPO2 capture distinct states of ZNRF3. The intrinsic heterogeneity of the LGR4-RSPO2-ZNRF3 assembly is influenced by LGR4 content. Particularly, in the assembly complex with a 2:2:2 ratio, two LGR4 protomers induce and stabilize the inactive state of ZNRF3, characterized by a wide inward-open conformation of two transmembrane helices (TM helices). This specific assembly promotes a stable complex, facilitating LGR4-induced endocytosis of ZNRF3. In contrast, the active dimeric ZNRF3, bound by a single LGR4, adopts a coiled-coil TM helices conformation and dimerization of RING domains. Our findings unveil how LGR4 content mediates diverse assemblies, leading to conformational rearrangements in ZNRF3 to regulate WNT/β-catenin signaling, and provide a structural foundation for drug development targeting Wnt-driven cancers.

Abstract Prenylation modifications of natural products play essential roles in chemical diversity and bioactivities, but imidazole modification prenyltransferases are not well investigated. Here, we discover a dimethylallyl tryptophan synthase family prenyltransferase, AuraA, that catalyzes the rare dimethylallylation on the imidazole moiety in the biosynthesis of aurantiamine. Biochemical assays validate that AuraA could accept both cyclo-(L-Val-L-His) and cyclo-(L-Val-DH-His) as substrates, while the prenylation modes are completely different, yielding C2-regular and C5-reverse products, respectively. Cryo-electron microscopy analysis of AuraA and its two ternary complex structures reveal two distinct modes for receptor binding, demonstrating a tolerance for altered orientations of highly similar receptors. The mutation experiments further demonstrate the promiscuity of AuraA towards imidazole-C-dimethylallylation. In this work, we also characterize a case of AuraA mutant-catalyzed dimethylallylation of imidazole moiety, offering available structural insights into the utilization and engineering of dimethylallyl tryptophan synthase family prenyltransferases.

Abstract We explore the decay of bound neutrons in the JUNO liquid scintillator detector into invisible particles (e.g., $$n\rightarrow 3 \nu $$ n → 3 ν or $$nn \rightarrow 2 \nu $$ n n → 2 ν ), which do not produce an observable signal. The invisible decay includes two decay modes: $$ n \rightarrow { inv} $$ n → inv and $$ nn \rightarrow { inv} $$ n n → inv . The invisible decays of s-shell neutrons in $$^{12}\textrm{C}$$ 12 C will leave a highly excited residual nucleus. Subsequently, some de-excitation modes of the excited residual nuclei can produce a time- and space-correlated triple coincidence signal in the JUNO detector. Based on a full Monte Carlo simulation informed with the latest available data, we estimate all backgrounds, including inverse beta decay events of the reactor antineutrino $${\bar{\nu }}_e$$ ν ¯ e , natural radioactivity, cosmogenic isotopes and neutral current interactions of atmospheric neutrinos. Pulse shape discrimination and multivariate analysis techniques are employed to further suppress backgrounds. With two years of exposure, JUNO is expected to give an order of magnitude improvement compared to the current best limits. After 10 years of data taking, the JUNO expected sensitivities at a 90% confidence level are $$\tau /B( n \rightarrow { inv} ) > 5.0 \times 10^{31} \, \textrm{years}$$ τ / B ( n → inv ) > 5.0 × 10 31 years and $$\tau /B( nn \rightarrow { inv} ) > 1.4 \times 10^{32} \, \textrm{years}$$ τ / B ( n n → inv ) > 1.4 × 10 32 years .

Abstract Background The association between glycemic control and short-, and long-term lung health remains controversial. This study aimed to investigate the relationship between glucose control and overall lung health in a national cohort. Methods The analysis included 5610 subjects from NHANES 2007–2012. We assessed the correlation of glycemic status with respiratory symptoms (cough, sputum, wheeze, and exertional dyspnea), lung function (forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC)), and obstructive or restrictive lung disease (RLD). Furthermore, we determined all-cause mortality in patients with restrictive lung disease by linking data to the National Mortality Index records up to December 31, 2019. Results The study involved the examination of respiratory symptoms, pulmonary function tests, and mortality analyses encompassing 3714, 3916, and 173 subjects, respectively. Multifactorial regression analyses revealed that a 1% increase in blood glucose was associated with a reduction in effect sizes (β) for FVC and FEV1 by -1.66% (-2.47%, -0.86%) and -1.94% (-2.65%, -1.23%), respectively. This increase also exhibited correlations with an elevated risk of exertional dyspnoea, restrictive ventilation dysfunction, and all-cause mortality, presenting odds ratios (ORs) of 1.19 (1.06, 1.33), 1.22 (1.10, 1.36), and 1.61 (1.29, 2.01), respectively. Regarding glycemic control, patients with improved control demonstrated stronger associations with early lung damage, significantly correlating with reduced FVC (β -10.90%, [-14.45%, -7.36%]) and FEV1 (β -9.38%, [-12.90%, -5.87%]). Moreover, they experienced a notably higher risk of exertional dyspnoea (adjusted OR 2.09, [1.35- 3.24]), while the diabetic group with poorer glycemic control showed more significant connections with advanced lung damage. This group exhibited significant associations with an increased risk of restrictive ventilatory dysfunction (adjusted OR, 2.56, [1.70–3.86]) and all-cause mortality (hazard ratios [HRs] 2.65, [1.05–6.67]), all compared to the reference group with normal glycemic metabolism. Conclusions Elevated blood glucose exhibited an inverse correlation with both long-term and short-term lung health. A negative L-shaped relationship was observed between glycemic control and early lung injury, along with a linearly negative association concerning late-stage lung damage. Given the cross-sectional nature of this study, a longitudinal investigation is needed to validate our findings.

Abstract Atrial fibrillation (AF) is the most prevalent arrhythmia in clinical practice, and obesity serves as a significant risk factor for its development. The underlying mechanisms of obesity-related AF remain intricate and have yet to be fully elucidated. We have identified FPR2 as a potential hub gene involved in obesity-related AF through comprehensive analysis of four transcriptome datasets from AF patients and one transcriptome dataset from obese individuals, and its expression is up-regulated in both AF and obese individuals. Interestingly, ANXA1, the endogenous ligand of FPR2, was found to exhibit differential expression with AF and obesity. Specifically, it was observed to be down-regulated in AF patients but up-regulated in obese individuals. The susceptibility to AF in obese mice induced by high-fat diet (HFD) was increased following with the FPR2 blocker Boc-2.The administration of exogenous ANXA1 active peptide chain Ac2-26 can mitigate the susceptibility to AF in obese mice by attenuating atrial fibrosis, lipid deposition, oxidative stress injury, and myocardial cell apoptosis. However, this protective effect against AF susceptibility is reversed by AAV9-shAMPK-mediated AMPK specific knockdown in the myocardium. The vitro experiments demonstrated that silencing ANXA1 exacerbated lipid deposition, oxidative stress injury, and apoptosis induced by palmitic acid (PA) in cardiomyocytes. Additionally, Ac2-26 effectively mitigated myocardial lipid deposition, oxidative stress injury, and apoptosis induced by PA. These effects were impeded by FPR2 inhibitors Boc-2 and WRW4. The main mechanism involves the activation of AMPK by ANXA1 through FPR2 in order to enhance fatty acid oxidation in cardiomyocytes, thereby ultimately leading to a reduction in lipid accumulation and associated lipotoxicity. Our findings demonstrate that the ANXA1-FPR2 axis plays a protective role in obesity-associated AF by alleviating metabolic stress in the atria of obese mice, thereby emphasizing its potential as a promising therapeutic target for AF.

Abstract Background Toxoplasma gondii is an obligate protozoan parasite capable of infecting a wide range of warm-blooded animals and humans. Current treatment options, primarily pyrimethamine and sulfadiazine, have limitations, such as high recurrence rates, long treatment durations, and limited effectiveness against T. gondii. There is an unmet need for novel, safe, low-toxicity, and highly effective treatments. This study aimed to evaluate the anti-T. gondii effects of glabridin, a natural compound derived from the roots of a widely used medicinal plant. Methods The cytotoxicity of glabridin in Vero cells was assessed using a CCK-8 cell viability assay. Quantitative polymerase chain reaction (qPCR) targeting the Tg-529 gene was developed to quantify T. gondii and assess the inhibitory effects of glabridin on parasite proliferation. Ultrastructural changes in T. gondii after treatment were examined using electron microscopy. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (ΔΨm) were examined to assess the effects of glabridin on ROS levels and ΔΨm in T. gondii tachyzoites. Additionally, metabolomics and transcriptomics analyses were conducted to investigate the mechanisms underlying glabridin’s anti-T. gondii effects. Results Glabridin exhibited low toxicity to host cells and effectively inhibited T. gondii invasion and proliferation in vitro in a time-dependent manner. Glabridin-treated tachyzoites exhibited significant structural alterations, along with increased ROS production and a reduction in ΔΨm. Metabolomic analysis indicated that glabridin significantly affected amino acid metabolism pathways in T. gondii. In vivo, glabridin treatment significantly improved survival rates in T. gondii-infected BALB/c mice at a dosage of 100 mg/kg. Conclusions This study demonstrates that glabridin has potent anti-T. gondii effects in vitro and in vivo, likely through disruption of amino acid metabolism in the parasite. These findings highlight glabridin’s potential as a promising therapeutic agent for toxoplasmosis. Graphical abstract

Abstract Introduction Chronic kidney disease is a significant public health issue. Dapagliflozin has been shown to improve the quality of life for patients with chronic kidney disease. This review aimed to systematically assess the cost-effectiveness of adding dapagliflozin to standard care compared with standard care alone for treating chronic kidney disease. Methods The relevant studies were searched in PubMed, Web of Science, Scopus, Embase, and Cochrane from the inception date to June 1, 2024. The titles, abstracts, and full texts were independently evaluated and screened by two authors. Additionally, the economic evaluation studies were assessed independently by two authors using the consolidated health economic evaluation reporting standards checklist. Results 14 studies were included which were about the economic evaluations of adding dapagliflozin in the treatment of chronic kidney disease. The minimum consolidated health economic evaluation reporting standards score for the studies was 0.77, indicating very good quality. Adding dapagliflozin to the standard of care would be more effective and cost-saving in Mexico, Malaysia, Canada, Thailand, and China. The highest incremental cost-effectiveness ratio of dapagliflozin ($67962.75/QALY) originated from the USA. According to the available studies, adding dapagliflozin to standard of care for the treatment of chronic kidney disease is considered cost-effectiveness from both the healthcare system and the payer’s perspective. Conclusion Adding dapagliflozin to standard care in the treatment of chronic kidney disease is cost-effective from both the healthcare system and the payer’s perspective in well-developed countries.

Abstract Background Remimazolam is a benzodiazepine sedative that is indicated for induction and maintenance during general anaesthesia. Remimazolam is also used for sedation in outpatient surgery; however, most reports have focused on nonelderly patients, whereas only a few studies have reported the use of remimazolam for elderly patients when receiving regional nerve block anaesthesia. Aim The aim of this study was to evaluate the effects of different doses of remimazolam in elderly patients when specifically related to regional nerve block anaesthesia. Methods This study was conducted at a university hospital between February 2022 and March 2023. We included 80 patients aged 65 years or older under regional nerve block anaesthesia. After the effects of anaesthesia were determined, patients were intravenously administered different doses of the test drug, i.e. 4, 4.5, 5, 5.5, or 6 mg, which were named the R1, R2, R3, R4, and R5 groups, respectively. The primary outcome was the loss of consciousness time. The secondary outcomes included the maintenance time and the number of assisted ventilators needed. The exceptional response of patients in terms of loss of consciousness maintenance time, the mean arterial pressure (MAP), heart rate (HR), respiratory rate (RR), SpO2, and modified observers assessment of alertness/sedation (MOAA/S) scores were recorded at baseline (T0), 3 min after the injection of the test drug (T1), 6 min after the injection of the test drug (T2), 9 min after the injection of the test drug (T3), 12 min after the injection of the test drug (T4), 15 min after the injection of the test drug (T5), 18 min after the injection of the test drug (T6), 21 min after the injection of the test drug (T7), and 24 min after the injection of the test drug (T8). Results We included 80 patients according to the inclusion and exclusion criteria, with 16 patients in each group. There were no significant differences in sex, age, and BMI amongst the 5 groups. The loss of consciousness time was significantly greater in the R2 group than in the R3, R4, and R5 groups (p

Background and aims: Antiviral therapy is essential for hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). No data are available on the long-term prognosis or safety of tenofovir alafenamide (TAF), tenofovir disoproxil fumarate (TDF), or entecavir (ETV) in treating HBV-ACLF globally. This study was conducted to investigate the long-term efficacy and safety of the three nucleos(t)ide analogs in the treatment of HBV-ACLF. Methods: In this prospective, real-world cohort study, patients with HBV-ACLF were assigned to the TAF, TDF, and ETV groups. A total of 199 patients completed the 144-week follow-up. After propensity score matching (PSM), 44 patients remained in each group for further analysis of survival status, incidence of hepatocellular carcinoma (HCC), virological response, and liver and renal function indicators. Results: In the original cohort, HCC developed in one patient in each group. No serious drug-related adverse events were observed. In the PSM cohort, the 144-week survival rates were 56.82%, 75.00%, and 59.09% in the TAF, TDF, and ETV groups, respectively (P = 0.118). When stratified into noncirrhosis and cirrhosis subgroups at baseline, the survival rate of the ETV group was slightly lower than that of the TAF and TDF group in noncirrhosis patients (P = 0.338), and the survival rate of the TAF group was slightly lower than that of the TDF and ETV group in cirrhosis patients (P = 0.052), but the differences were not statistically significant. The long-term overall survival rates in the TAF, TDF, and ETV groups were comparable. After 144 weeks, no significant difference in the virological response rate or liver or renal function indicators was found among the three groups, except for the level of aspartate aminotransferase, which was significantly higher in the TDF group than in the ETV group at week 144 (P = 0.001). Conclusions: There were no significant differences in the survival rate, incidence of HCC, efficacy or safety associated with the use of these three nucleos(t)ide analogs in treating HBV-ACLF. Trial registration: ClinicalTrials.gov NCT03920618.

Abstract The fibrids in aramid insulation paper exhibit good adhesion ability. However, the effects of fibrids morphology on the mechanical and electrical properties of aramid insulation paper remains poorly understood. Aramid fibrids with different morphological structures were prepared by modifying the preparation process, and then they were used to fabricate aramid composite insulation paper under the same condition. The results showed that increasing the shear rate and aramid solution concentration affected the magnitude of the shear force and double diffusion process, thus affecting the average length, specific surface area, and crystallinity of the fibrids. When the rotor frequency is 25–30 Hz and the solution concentration is 15%, the fibrid has a large specific surface area while ensuring high crystallinity, which is beneficial to the improvement of breakdown strength. When the average length of fibrids is 0.8–1.4 mm, the fine content is 1.3%–2.3%, specific surface area is 57.5–62 m2 g−1, and crystallinity is 18.5%–27%, the aramid composite insulation paper has the optimal mechanical and electrical properties. Combined with the micromorphology test results, the influence mechanism of fibrids properties on the mechanical properties, dielectric properties, and AC and DC breakdown strength of aramid composite insulation paper was obtained. The result is of great theoretical significance and practical value for the preparation and application of high‐performance aramid composite insulation paper.

Abstract Aims/Introduction To investigate the related risk factors of retinopathy in young and middle-aged diabetic patients in order to improve the prognosis of patients. Materials and Methods Using clinical practice data from a cohort study at our two research centers, we developed a bivariate logistic regression model to investigate the frightening risk factors potentially for retinopathy in young and middle-aged patients with diabetes, including diabetes type, physical activity level, treatment-related characteristics and laboratory tests. Results A total of 453 patients with diabetes were investigated, 197 (43.5%) developed retinopathy. The risk of retinopathy was closely related to place of residence (OR: 0.275, 95% CI: 0.093–0.814), education level (OR: 0.522, 95% CI: 0.363–0.749), medical payment method (OR: 2.152, 95% CI: 1.308–3.539), BMI (OR: 1.187, 95% CI: 1.091–1.291), disease course (OR: 1.072, 95% CI: 1.028–1.118), hyperlipidemia (OR: 2.547, 95% CI: 1.260–5.150), physical activity level (OR: 0.312, 95% CI: 0.220–0.443), and dietary compliance (OR 0.871, 95% CI: 0.806–0.940). The area under the receiver operator characteristic curve was 0.915. Goodness of fit (Hosmer–Lemeshow) was 0.658. Conclusions The risk of young and middle-aged patients with increased as a result of certain patient characteristics and complications, especially lower dietary compliance and physical activity level.

Abstract To address the challenges related to active power dissipation and node voltage fluctuation in the practical transformation of power grids in the field of new energy such as wind and photovoltaic power generation, an improved Dung Beetle Optimization Algorithm Based on a Hybrid Strategy of Levy Flight and Differential Evolution (LDEDBO) is proposed. This paper systematically addresses this issue from three aspects: firstly, optimizing the DBO algorithm using Chebyshev chaotic mapping, Levy flight strategy, and differential evolution algorithm; secondly, validating the algorithm’s feasibility through real-time network reconfiguration at random time points within a 24-h period; and finally, applying the LDEDBO to address the dynamic reconfiguration problems of the IEEE-33 and IEEE-69 node bus. The simulation indicates that the power dissipation of the IEEE-33 node bus is decreased by 28.94% and the minimum node voltage is elevated from 0.9273 p.u to 0.9447 p.u after the reconstruction with LDEDBO. The power dissipation of the IEEE-69 node bus is reduced by 36.45%, and the minimum node voltage is increased from 0.9224 p.u to 0.9481 p.u. The LDEDBO enhances both the pace of convergence and the precision of the optimization model, leading to a superior solution for the switching combination.

Abstract Aims We aim to investigate the association between vitamin A intake and depression among patients with heart failure (HF). Methods and results In this cross‐sectional study, data of HF patients were extracted from the National Health and Nutrition Examination Survey (NHANES) 2007–2020. The independent variable was vitamin A intake, and the dependent variable was depression. Weighted univariate and multivariate logistic regression models were performed to explore the association of vitamin A intake with depression in HF patients. A total of 999 HF patients were included, with a mean age of 66.19 (0.51) years, and 566 (52.49%) were male. And 197 patients have depression. Vitamin A intake ≥731.38 mcg was associated with lower incidence of depression [odds ratio (OR) = 0.37; 95% confidence interval (CI): 0.18–0.76] in HF patients. Similarly, the relationship between high vitamin A intake and lower odds of depression were also observed in subgroups of those aged >65 years (OR = 0.16; 95% CI: 0.04–0.55), males (OR = 0.35; 95% CI: 0.14–0.86), without hypertension (OR = 0.25; 95% CI: 0.11–0.58), without diabetes (OR = 0.30; 95% CI: 0.11–0.78), with hyperlipidaemia (OR = 0.23; 95% CI: 0.09–0.64), and with chronic kidney disease (CKD) (OR = 0.32; 95% CI: 0.13–0.80). Conclusions High vitamin A intake was associated with lower odds of depression in HF patients. Appropriate vitamin A supplementation may have potential benefit to the prevention of depression in HF patients. Additional prospective large‐scale studies are required to confirm whether or not vitamin A could lead to decrease in depression symptoms.

Abstract To optimize the magnetic fluid seal design, the single-factor method is usually used to study the effect of the rectangular pole teeth structure parameters on the sealing capacity of the magnetic fluid seal by current research, and the design formula is obtained. However, the supporting data is too few to make the results universalizable. In this paper, to obtain a wider range of applicable design formulas, a large number of modeling and simulation experiments are conducted using the co-simulation analysis experimental method of MATLAB and COMSOL. The influence of structure parameters of rectangular pole teeth and the coupling effects of the structure parameters on the sealing capacity of sealing devices has been studied under different lengths of pole piece (L p ) and seal gap (L g ). The results explain the influences of tooth height (L h ), tooth width (L t ), groove width (L s ), and their coupling effects on the theoretical sealing capacity of magnetic fluid seals, and more widely applicable design formulas for pole teeth structure parameters are given. The design formulas can help to obtain good design parameters directly or reduce the optimization range when the magnetic fluid seals need to be optimized to meet the miniaturization and lightweight requirements of magnetic fluid sealing devices or improve the sealing capacity under the same seal size.

While the relationship among land price, transportation cost, and urban sprawl under the condition of local governments monopolizing land supply has been rarely discussed in the literature, this paper addresses this gap by hypothesizing based on the monocentric city model. The hypothesis suggests that due to increasing land prices and decreasing transportation costs, urban fringes are more likely to be developed, leading residents to move away from the city center and altering the demographic pattern of urban sprawl. An empirical analysis is conducted using panel data from 104 cities in China, including remote sensing data of urban land construction areas. The results show that high land prices and low transportation costs drive urban sprawl, with varying impacts across cities. The coupling coordination analysis indicates increasing influence of urban sprawl on land prices and transportation costs. These findings suggest the government should address the effects of unplanned urban expansion on these factors. The findings suggest that the government should pay more attention to the effects of unplanned urban expansion on land prices and transportation costs. Understanding the role of local governments in urban planning is crucial for comprehending China's urbanization strategy and its implications on social exclusion, gentrification, high housing prices, and other urban issues.

Abstract Background Nursing is crucial for delivering healthcare services; however, nursing shortages pose a significant global challenge, which the high turnover rate of junior nurses is expected to exacerbate. Enhancing nurses’ professional identities is likely to be an effective strategy for reducing turnover rates. Methods We recruited 865 junior clinical nurses from three tertiary hospitals in Henan Province, China. The participants completed a demographic questionnaire along with the Reflective Ability Scale for Clinical Nurses, the Nursing Profession Self-efficacy Scale, the Nursing Staff Self-learning Ability Evaluation Scale, and the Professional Identity Scale for Nurses. The relationships between reflective ability, self-directed learning, self-efficacy, and professional identity were evaluated using SPSS26.0, with PROCESS version 3.5 used to construct a chain-mediation model. Results Positive correlations were found between reflective ability, self-directed learning, self-efficacy, and professional identity. Chain mediation model analysis showed that reflective ability, self-directed learning, and self-efficacy directly and positively affected professional identity (β = 0.22, β = 0.30, β = 0.66, all p

Abstract Background Failure of systemic corticosteroid therapy is common in patients with newly diagnosed acute graft-versus-host disease (aGVHD) above grade II. Mesenchymal stem cells (MSCs) have been used as a tolerable and potentially effective second-line therapy for steroid-refractory aGVHD (SR-aGVHD); however, well-designed, prospective, controlled studies are lacking. Methods This multicentre, randomized, double-blind, placebo-controlled, exploratory phase 2 study enrolled patients with SR-aGVHD above grade II from 7 centres. Patients were randomized 1:1 to receive umbilical cord-derived MSCs or placebo added to one centre’s choice of second-line agents (except for ruxolitinib). The agents were infused twice weekly. Patients with complete response (CR), no response (NR), or progression of disease (PD) at d28 received 8 infusions, and those with partial response (PR) received the above infusions for another 4 weeks. The per-protocol population consisted of patients who received ≥ 8 infusions. The primary endpoint was the overall response rate (ORR, CR + PR) at d28, analyzed in the per-protocol and intention-to-treat populations. Results Seventy-eight patients (median age 38, range 13–62) were enrolled: 40 in the MSC group and 38 in the control. Patients in the MSC group received a median of 8 doses, with a median response time of 14 days. In intention-to-treat analysis, ORR at d28 was 60% for MSC group and 50% for control group (p = 0.375). The 2-year cumulative incidence of moderate to severe cGVHD was marginally lower in the MSC group than in the control (13.8% vs. 39.8%, p = 0.067). The 2-year failure-free survival was similar between the MSC and control groups (52.5% vs. 44.4%, p = 0.43). In per-protocol analysis (n = 62), ORR at d28 was significantly greater in the MSC group than in the control group (71.9% vs. 46.7%, p = 0.043). Among patients with gut involvement, ORR at d28 was significantly greater in the MSC group than in the control (66.7% vs. 33.3%, p = 0.031). The adverse events incidences were similar between groups. Conclusions In this exploratory study, there was no superior ORR at d28 demonstrated in the MSC group compared with the control. However, MSCs showed a gradual treatment effect at a median of 2 weeks. Patients who completed 8 infusions may benefit from adding MSCs to one conventional second-line agent, especially those with gut involvement. MSCs was well tolerated in patients with SR-aGVHD. Trial registration chictr.org.cn ChiCTR2000035740.

Abstract This research explored the link between teacher-student relationships and learning engagement, considering perceived social support as a mediator and academic self-efficacy as a moderator. A total of 930 college students completed the Academic Self-Efficacy Scale, Teacher-Student Relationships Questionnaire, Multidimensional Scale of Perceived Social Support, and College Student Learning Engagement Questionnaire. Mediating and moderating effects were investigated using SPSS19.0 and one of its process plugins 3.5. The findings indicated (1) teacher-student relationships positively predicted learning engagement; (2) perceived social support mediated the link between teacher-student relationships and learning engagement; and (3) academic self-efficacy moderated the initial phase of the pathway to the mediating role of perceived social support. Moreover, the mediating effect was more significant at elevated academic self-efficacy levels. Establishing harmonious relationships between teachers and students, nurturing students’ confidence in their academic abilities , and expanding students’ access to social support were essential to boosting the educational involvement of college students. The study findings will help educators enhance college students’ engagement in learning and provide recommendations for educators to conduct educational and teaching activities.

Abstract Despite advancements, the prevalence of HIV-associated neurocognitive impairment remains at approximately 40%, attributed to factors like pre-cART (combination antiretroviral therapy) irreversible brain injury. People with HIV (PWH) treated with cART do not show significant neurocognitive changes over relatively short follow-up periods. However, quantitative neuroimaging may be able to detect ongoing subtle microstructural changes. In this study, we hypothesized that tensor-valued diffusion encoding metrics would provide greater sensitivity than conventional diffusion tensor imaging (DTI) metrics in detecting HIV-associated brain microstructural injury. We further hypothesized that tensor-valued metrics would exhibit stronger associations with blood markers of neuronal and glial injury, such as neurofilament light chain (NFL) and glial fibrillary acidic protein (GFAP), as well as with cognitive performance. Using MRI at 3T, 24 PWH and 31 healthy controls underwent cross-sectional examination. The results revealed significant variations in tensor-valued diffusion encoding metrics across white matter regions, with associations observed between these metrics, cognitive performance, NFL and GFAP. Moreover, a significant interaction between HIV status and imaging metrics in gray and white matter was observed, particularly impacting total cognitive scores. Of interest, DTI metrics were less likely to be associated with HIV status than tensor-valued diffusion metrics. These findings suggest that tensor-valued diffusion encoding metrics offer heightened sensitivity in detecting subtle changes associated with axonal injury in HIV infection. Longitudinal studies are needed to further evaluate responsiveness of tensor-valued diffusion b-tensor encoding metrics in the contest HIV-associate mild chronic neuroinflammation.

Abstract A fungal effector that is toxic to plant cells was identified in Verticillium dahliae. The effector contains a non-canonical Common in several Fungal Extracellular Membrane proteins (CFEM) domain, a tandem repeat region consisting of four 14-amino acid repeats rich in proline, and a C-terminal region, thus is designated V. dahliae tetrapeptide repeat protein (VdTRP). The membrane targeting of VdTRP is vital for its cell toxicity. CFEM mediates the membrane targeting and the tandem repeat region exerts the toxic function upon cell membrane. The chitinase-like 1 (CTL1), an essential apoplastic protein of cotton, can redirect VdTRP from cell membrane to apoplast. Transgenic cotton overexpressing CTL1 greatly enhances cotton resistance to V. dahliae without affecting cotton growth and development, implicating its potential application in breeding cotton with high wilt resistance. Our data demonstrates that genetic manipulation of effector target constitutes potential strategy for improving crop resistance to fungal pathogens.

Abstract The regeneration of osteoporotic bone defects remains challenging as the critical stem cell function is impaired by inflammatory microenvironment. Synthetic materials that intrinsically direct osteo-differentiation versus self-renewal of recruited stem cell represent a promising alternative strategy for endogenous bone formation. Therefore, a microenvironmentally optimized polyurethane (PU) /n-HA scaffold to enable sustained delivery of gastrodin is engineered to study its effect on the osteogenic fate of stem cells. It exhibited interconnected porous networks and an elevated sequential gastrodin release pattern to match immune-osteo cascade concurrent with progressive degradation of materials. In a critical-sized femur defect model of osteoporotic rat, 5% gastrodin-PU/n-HA potently promoted neo-bone regeneration by facilitating M2 macrophage polarization and CD146+ host stem cell recruitment to defective site. The implantation time-dependently increased the bone marrow mesenchymal stem cell (BMSC) population, and further culture of BMSCs showed a robust ability of proliferation, migration, and mitochondrial resurgence. Of note, some of cell pairs produced one stemness daughter cell while the other committed to osteogenic lineage in an asymmetric cell division (ACD) manner, and a much more compelling ACD response was triggered when 5% gastrodin-PU/n-HA implanted. Further investigation revealed that one-sided concentrated presentation of aPKC and β-catenin in dividing cells effectively induced asymmetric distribution, which polarized aPKC biased the response of the daughter cells to Wnt signal. The asymmetric cell division in skeletal stem cells (SSCs) was mechanically comparable to BMSCs and also governed by distinct aPKC and β-catenin biases. Concomitantly, delayed bone loss adjacent to the implant partly alleviated development of osteoporosis. In conclusion, our findings provide insight into the regulation of macrophage polarization combined with osteogenic commitment of recruited stem cells in an ACD manner, advancing scaffold design strategy for endogenous bone regeneration. Graphical abstract

Abstract Postoperative pulmonary complications (PPCs) are common in patients undergoing general anesthesia, with atelectasis being a key contributor that increases postoperative mortality and prolongs hospitalization. Our research hypothesis is that ultrasound-guided individualized PEEP titration can reduce postoperative atelectasis. This single-center randomized controlled trial recruited elderly patients for laparoscopic surgery. Patients were randomly assigned to two group: the study group (individualized PEEP groups, PEEP Ind group) and the control group (Fixed PEEP group, PEEP 5 group). All patients in these two groups received volume-controlled ventilation during general anesthesia. Patients in the study group were given ultrasound-guided PEEP, while those in the control group were given a fixed 5 cmH2O PEEP. Bedside ultrasound assessed lung ventilation. The primary outcome was the severity of atelectasis within seven days post-surgery. Eighty-nine patients scheduled for elective laparoscopic radical surgery for colorectal cancer were enrolled in our study. Lung ultrasound scores (LUSs) in the study group during postoperative seven days was significantly decreased compared with that in the control group (P

Abstract Objectives To investigate whether the signal intensity (SI) ratio of residual fibroid (RF) to myometrium using Contrast-Enhanced Magnetic Resonance Imaging (CE-MRI) could predict fibroid regrowth after high-intensity focused ultrasound (HIFU) treatment. Materials and methods A retrospective analysis was conducted among 164 patients with uterine fibroids who underwent HIFU. To predict the RF regrowth, the SI perfusion parameters were quantified using the RF-myometrium SI ratio on CE-MRI on day 1 post-HIFU and then compared with the fibroid-myometrium SI ratio on the T2-weighted image (T2WI) and Funaki classification 1 year later. Thirty cases from another center were used as an external validation set to evaluate the performance of RF-myometrium SI ratio. Results The predictive performance of the RF-myometrium SI ratio on CE-MRI on day 1 post-HIFU (Area Under Curve, AUC: 0.869) was superior to that of the preoperative and postoperative fibroid-myometrium SI ratios on the T2WI (AUC: 0.724, 0.696) and Funaki classification (AUC: 0.663, 0.623). Multivariate analysis showed that the RF- myometrium SI ratio and RF thickness were independent factors. The RF-myometrium SI ratio reflects the long-term rate of re-intervention (r = 0.455, p

Abstract The relative risk and benefits of Laparoscopic liver resection (LLR) are still controversial. This study aimed to evaluate perioperative and survival outcomes for three primary malignant liver tumors related outcomes following LLR. Data from three Homogeneous-High-Volume-Expert-Centers were collected. Multivariable logistic regression analysis was performed for the association between LLR, and major complications defined as Clavien-Dindo Classification grade ≥ II. Multivariable Cox proportional hazards regression was used to explore the impact of LLR on primary malignant liver tumor survival. Overall, 5886 patients underwent liver resection, of which 1991 underwent LLR. After adjusting for covariables, LLR had significantly lower rate of CDC grade ≥ II (OR = 0.56, 95% CI: 0.48–0.67, P 0.05). LLR was associated with lower rate of major complications, especially in women, non-drinkers, those without a history of abdominal surgery, and those with normal platelet. For primary malignant liver tumors, the survival outcomes did not differ significantly between LLR and OLR.

Background: Data on SARSCoV-2 infection in children with hematological malignancies (HM) are limited. Here, we describe the clinical features of children with HM after SARS-CoV-2 infection and investigate the potential risk factors for disease severity. Methods: Children with HM and SARS-CoV-2 infection from five hospitals in five cities in Henan, China from October 2022 to January 2023 were retrospectively included. Clinical information and Coronavirus disease 2019 (COVID-19) vaccination status were collected for further analyses. Results: A total of 285 children with HM and SARS-CoV-2 infections were included. COVID-19 was asymptomatic in 3.2% of the patients (n = 9), mild in 89.1% (n = 254), moderate in 5.3% (n = 15), severe in 1.8% (n = 5), and critical in 0.7% (n = 2). Fever (92.4%) and cough (56.9%) were the most common symptoms. Most (249, 88.3%) children were managed at home during their COVID-19 illness. Of the 36 children admitted to the hospital, two required intensive care unit care, 11 required supplementary oxygen, and two non-invasive ventilation. A total of 283 (99.3%) children fully recovered and two (0.7%) died due to COVID-19. Significant risk factors for increased severity of infection in multivariable analyses were the presence of comorbidity (OR, 10.4; 95%CI, 2.8–38.7; p

Abstract The rapid advancement of spatial transcriptomics technologies has revolutionized our understanding of cell heterogeneity and intricate spatial structures within tissues and organs. However, the high dimensionality and noise in spatial transcriptomic data present significant challenges for downstream data analyses. Here, we develop GraphPCA, an interpretable and quasi-linear dimension reduction algorithm that leverages the strengths of graphical regularization and principal component analysis. Comprehensive evaluations on simulated and multi-resolution spatial transcriptomic datasets generated from various platforms demonstrate the capacity of GraphPCA to enhance downstream analysis tasks including spatial domain detection, denoising, and trajectory inference compared to other state-of-the-art methods.

The cardiac microenvironment profoundly restricts the efficacy of myocardial regeneration tactics for the treatment of myocardial infarction (MI). A prospective approach for MI therapeutics encompasses the combined strategy of scavenging reactive oxygen species (ROS) to alleviate oxidative stress injury and facilitating macrophage polarization towards the regenerative M2 phenotype. In this investigation, we fabricated a ROS-sensitive hydrogel engineered to deliver our previously engineered IL-1β-VHH for myocardial restoration. In mouse and rat models of myocardial infarction, the therapeutic gel was injected into the pericardial cavity, effectively disseminated over the heart surface, forming an in situ epicardial patch. The IL-1β-VHH released from the hydrogel exhibited penetrative potential into the myocardium. Our results imply that this infarct-targeting gel can adhere to the damaged cardiac tissue and augment the quantity of anti-IL-1β antibodies. Moreover, the anti-IL-1β hydrogel safeguards cardiomyocytes from apoptosis by neutralizing IL-1β and inducing M2-type polarization within the myocardial infarction regions, thereby facilitating therapeutic cardiac repair. Our results emphasize the effectiveness of this synergistic comprehensive treatment modality in the management of MI and showcase its considerable potential for promoting recovery in infarcted hearts.

Sediment flux of many rivers has been significantly reduced due to human activities caused by economic development, leading to increasingly severe riverbed degradation. To prevent riverbed degradation, grade control structures (GCSs) have been widely applied in degrading channels. Existing studies have not provided a good understanding of the effects of GCSs on flow characteristics and bed morphology in degrading channels, limiting the management of degrading channels. A series of flume tests with no sediment supply are conducted to investigate the effects of GCSs on upstream water levels and riverbed morphology in degrading channels. The experimental results indicate that: (1) in the initial stage of degradation, the water surface slope in the backwater reach is linearly and negatively correlated with the GCS-height Froude number, based on the average flow velocity upstream of the backwater reach due to GCS and the height of GCS; (2) the effective protection bed length upstream of GCS is approximately equal to the length of the reach where the flow velocity is less than the critical velocity for sediment motion in the backwater zone; (3) for sequential GCSs, the effective protection bed length will decrease if GCS is located in the backwater reach of the downstream GCS. A semi-analytical calculation method of the effective protection length and equilibrium bed profile upstream of GCS in degrading channels is proposed based on the critical condition of sediment motion and weir flow formulas. The computed values by the proposed calculation method agree well with the experimental data of the present study.

The optimal extraction process of phytoglycogen (PG) from sweet corn by ultrasound-assisted method was studied, and the physicochemical properties and biological activities of PG were evaluated in this paper. The effects of solid-liquid ratio, ultrasonic power and ultrasonic time on the yield of PG were investigated and the process parameters were further optimized by orthogonal experiment. Furthermore, the physicochemical properties of PG obtained by ultrasound-assisted method were investigated. Meanwhile, the antioxidation, cytotoxicity, apoptosis and hemolysis of PG were evaluated in vitro. The results showed that the optimal extraction conditions were as follows: Solid-liquid ratio of 1:9 (g/mL), ultrasonic power of 160 W and ultrasonic time of 80 min, the actual yield was 14.31%±0.38%. The PG particle size obtained by ultrasound-assisted method was lower than that obtained by traditional water extraction and alcohol precipitation method. In vitro antioxidant experiment showed that PG had a certain antioxidant capacity, especially it was more sensitive to DPPH free radicals, and the clearance rate reached 54.58%±1.39% at 20 mg/mL. The results of biosafety evaluation showed that the survival rate of mouse fibroblasts (3T3) was higher than 95% after incubation with different concentrations of PG for 24 or 48 h. Meanwhile, PG had no obvious apoptotic effect on cells, and the apoptotic rate was lower than 7% at the maximum concentration. After 2 h of co-incubation, the hemolysis rate caused by PG on red blood cells was also much lower than the national standard (5%), which confirmed that PG had good biocompatibility with normal cells and red blood cells. Overall, this study showed that ultrasound-assisted method could improve the yield and physicochemical properties of PG, and also confirmed that PG was a non-toxic natural nanoparticle, which had great application potential in drug or food factor delivery.

Abstract Tumor draining lymph nodes (TDLN) represent a key component of the tumor-immunity cycle. There are few studies describing how TDLNs impact lymphocyte infiltration into tumors. Here we directly compare tumor-free TDLNs draining “cold” and “hot” human triple negative breast cancers (TDLNCold and TDLNHot). Using machine-learning-based self-correlation analysis of immune gene expression, we find unbalanced intranodal regulations within TDLNCold. Two gene pairs (TBX21/GATA3-CXCR1) with opposite correlations suggest preferential priming of T helper 2 (Th2) cells by mature dendritic cells (DC) within TDLNCold. This is validated by multiplex immunofluorescent staining, identifying more mature-DC-Th2 spatial clusters within TDLNCold versus TDLNHot. Associated with this Th2 priming preference, more IL4 producing mast cells (MC) are found within sinus regions of TDLNCold. Downstream, Th2-associated fibrotic TME is found in paired cold tumors with increased Th2/T-helper-1-cell (Th1) ratio, upregulated fibrosis growth factors, and stromal enrichment of cancer associated fibroblasts. These findings are further confirmed in a validation cohort and public genomic data. Our results reveal a potential role of IL4+ MCs within TDLNs, associated with Th2 polarization and reduced immune infiltration into tumors.

Abstract Purpose The essence of this scholarly work was to carefully outline the key factors intensifying the virulence and protracted contagion of COVID-19, particularly among individuals afflicted with hematologic malignancies (HM), in an epoch predominantly governed by the Omicron variant. Methods Adults with HM diagnosed with COVID-19 from November 2022 to February 2023 were monitored in this retrospective study. Patient blood samples yielded biochemical data, and COVID-19 was confirmed through RNA or antigen testing. The factors affecting severity and infection duration were examined using both univariate and multivariate logistic regression analyses. For calculating the overall survival probabilities, the Kaplan–Meier product limit approach was employed. Results In the examined cohort, 133 individuals diagnosed with HM and concomitantly infected with COVID-19 were scrutinized. Of the participants, 29.3% (39 patients) were classified as Severe/Critical, while the other 70.7% (94 patients) were categorized as Non-severe. A significant difference was observed in vaccination status: 61.7% of patients in the Non-severe group had received at least a two-dose vaccine regimen, whereas 61.5% of the Severe/Critical group had either minimal or only one dose of vaccination. The data analysis revealed that elevated C-reactive protein levels (≥ 100 mg/L) significantly raised the risk of severe/critical conditions in HM patients with COVID-19, as determined by advanced multivariate logistic regression. The odds ratio was 3.415 with a 95% confidence interval of 1.294–9.012 (p = 0.013). Patients who continued to have positive nucleic acid tests and ongoing symptoms beyond 30 days were categorized as having a persistent infection, whereas those who achieved infection control within this timeframe were categorized as having infection recovery. Of the HM cohort, 11 did not survive beyond 30 days after diagnosis. The results from a competing risk model revealed that increased interleukin-6 levels (HR: 2.626, 95% CI: 1.361–5.075; p = 0.004) was significantly associated with persistent infection. Conversely, receiving more than two vaccine doses (HR: 0.366, 95% CI: 0.158–0.846; p = 0.019), and having high IgG levels (≥ 1000 mg/dl) (HR: 0.364, 95% CI: 0.167–0.791; p = 0.011), were associated with infection recovery. There was a notable disparity in survival rates between patients with persistent infections and infection recovery, with those in the non-persistent group demonstrating superior survival outcomes (P

Abstract As an abundant agricultural and forestry biomass resource, hemicelluloses are hard to be effectively degraded and utilized by microorganisms due to the constraints of membrane and metabolic regulations. Herein, we report a synthetic extracellular metabolic pathway with hemicellulose-degrading-enzymes controllably displayed on Escherichia coli surface as engineered bacterial consortia members for efficient utilization of xylan, the most abundant component in hemicellulose. Further, we develop a hemicellulose/O2 microbial fuel cell (MFC) configuring of enzyme-engineered bacterial consortia based bioanode and bacterial-displayed laccase based biocathode. The optimized MFC exhibited an open-circuit voltage of 0.71 V and a maximum power density (P max) of 174.33 ± 4.56 µW cm−2. Meanwhile, 46.6% (w/w) α-ketoglutarate was produced in this hemicellulose fed-MFC. Besides, the MFC retained over 95% of the P max during 6 days’ operation. Therefore, this work establishes an effective and sustainable one-pot process for catalyzing renewable biomass into high-value products and electricity in an environmentally-friendly way.

Abstract Background Identifying modifiable risk factors is essential for the prevention of skin cancer; however, establishing causality can be challenging in conventional epidemiological studies. This study aimed to determine the causal associations of potentially modifiable risk factors with skin cancer using Mendelian randomization (MR). Methods Genetic instruments for 53 risk factors, including socioeconomic status, dietary and lifestyle factors, anthropometric measures, medication use, and comorbidities, were identified from previous genome-wide association studies. Two-sample MR analyses were performed using summary statistics for three major types of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Findings were verified using multiple MR methods under different assumptions and replication datasets. Results Genetic liability to sunburn occasions, actinic keratosis, and prior skin cancers was associated with a higher risk of all three types of skin cancer, whereas genetic liability to vitiligo was associated with a lower risk. For specific skin cancer types, genetically predicted higher nevus counts and occupational class were associated with an increased risk of melanoma. Genetic liability to rheumatoid arthritis, type 2 diabetes, and increased physical activity were associated with a lower risk of BCC. Genetically predicated body mass index showed a negative association with BCC, and a positive association with SCC. Conclusions Our study reaffirmed several previously established risk factors and identified novel potential risk factors for skin cancer. Further work is needed to unravel the biological pathways in different skin cancer types and translate our findings to inform public health policies.

Abstract Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.

Abstract Background Coronary artery bypass grafting is associated with a high occurrence of postoperative cardiopulmonary complications. Preliminary evidence suggested that enhanced recovery after surgery can effectively reduce the occurrence of postoperative cardiopulmonary complications. However, enhanced recovery after surgery with systematic integration of cardiopulmonary rehabilitation (ERAS-CaRe) into for Coronary artery bypass grafting has not been evaluated so far. We thus design the ERAS-CaRe randomized-controlled trial to evaluate possible superiority of embedding cardiopulmonary rehabilitation in ERAS over ERAS alone as well as to investigate effects of differential timing of cardiopulmonary rehabilitation within enhanced recovery after surgery (pre-, post-, perio-operative) on post-operative cardiopulmonary complications following Coronary artery bypass grafting surgery. Methods ERAS-CaRe is a pragmatic, randomized-controlled, parallel four-arm, clinical trial. Three hundred sixty patients scheduled for Coronary artery bypass grafting in two Chinese hospitals will be grouped randomly into (i) Standard enhanced recovery after surgery or (ii) pre-operative ERAS-CaRe or (iii) post-operative ERAS-CaRe or (iv) perio-operative ERAS-CaRe. Primary outcome is the occurrence of cardiopulmonary complications at 10 days after Coronary artery bypass grafting. Secondary outcomes include the occurrence of other individual complications including cardiac, pulmonary, stroke, acute kidney injury, gastrointestinal event, ICU delirium rate, reintubation rate, early drainage tube removal rate, unplanned revascularization rate, all-cause mortality, ICU readmission rate, plasma concentration of myocardial infarction-related key biomarkers etc. Discussion The trial is designed to evaluate the hypothesis that a cardiopulmonary rehabilitation based enhanced recovery after surgery program reduces the occurrence of cardiopulmonary complications following Coronary artery bypass grafting and to determine optimal timing of cardiopulmonary rehabilitation within enhanced recovery after surgery. The project will contribute to increasing the currently limited knowledge base in the field as well as devising clinical recommendations. Trial registration The trial was registered at the Chinese Clinical Trials Registry on 25 August 2023 (ChiCTR2300075125; date recorded: 25/8/2023, https://www.chictr.org.cn/ ).

Abstract Background Previous studies have shown that patients with pre-existing chronic obstructive pulmonary diseases (COPD) were more likely to be infected with coronavirus disease (COVID-19) and lead to more severe lung lesions. However, few studies have explored the severity and prognosis of COVID-19 patients with different phenotypes of COPD. Purpose The aim of this study is to investigate the value of the deep learning and radiomics features for the severity evaluation and the nucleic acid turning-negative time prediction in COVID-19 patients with COPD including two phenotypes of chronic bronchitis predominant patients and emphysema predominant patients. Methods A total of 281 patients were retrospectively collected from Hohhot First Hospital between October 2022 and January 2023. They were divided to three groups: COVID-19 group of 95 patients, COVID-19 with emphysema group of 94 patients, COVID-19 with chronic bronchitis group of 92 patients. All patients underwent chest computed tomography (CT) scans and recorded clinical data. The U-net model was pretrained to segment the pulmonary involvement area on CT images and the severity of pneumonia were evaluated by the percentage of pulmonary involvement volume to lung volume. The 107 radiomics features were extracted by pyradiomics package. The Spearman method was employed to analyze the correlation of the data and visualize it through a heatmap. Then we establish a deep learning model (model 1) and a fusion model (model 2) combined deep learning with radiomics features to predict nucleic acid turning-negative time. Results COVID-19 patients with emphysema was lowest in the lymphocyte count compared to COVID-19 patients and COVID-19 companied with chronic bronchitis, and they have the most extensive range of pulmonary inflammation. The lymphocyte count was significantly correlated with pulmonary involvement and the time for nucleic acid turning negative (r=-0.145, P

Abstract N6-methyladenosine (m6A) is the most prevalent modification found in eukaryotic RNA and played a significant role in various cancers. However, the mechanism by which m6A modification influences cervical cancer (CC) tumorigenesis remains unclear. Therefore, we aim to elucidate the role and mechanism of METTL3 in CC progression. In the present study, we observed a significant upregulation of METTL3 in CC tissues and cell lines. Knockdown of METTL3 resulted in reduced growth, migration, and invasion of CC cells, as well as affected apoptosis, while overexpression of METTL3 reversed these effects. Through a combined analysis of meRIP-seq and Ribo-seq data following METTL3 knockdown, NEK2 was identified as a key target of METTL3 in CC cells. Correlation analysis, MeRIP-qPCR, and luciferase reporter assay suggested that METTL3 regulates NEK2 expression through m6A modification. NEK2 synergized with METTL3 to mediate the malignant phenotype of CC cells. The METTL3-NEK2 axis promoted CC progression by activating the Wnt/β-catenin pathway and inhibiting the apoptosis pathway. In conclusion, METTL3 facilitated the malignant progression of CC and contributed to the formation of the METTL3-NEK2 regulatory axis in an m6A-dependent manner, which represented a potential target for CC therapy.

Abstract The Whale Optimization Algorithm (WOA) is regarded as a classic metaheuristic algorithm, yet it suffers from limited population diversity, imbalance between exploitation and exploration, and low solution accuracy. In this paper, we propose the Spiral-Enhanced Whale Optimization Algorithm (SEWOA), which incorporates a nonlinear time-varying self-adaptive perturbation strategy and an Archimedean spiral structure into the original WOA. The Archimedean spiral structure enhances the diversity of the solution space, aiding the algorithm in escaping local optima. The nonlinear time-varying self-adaptive optimization dynamic perturbation strategy improves the algorithm’s local search capability and enhances solution accuracy. The effectiveness of the proposed algorithm is validated from multiple perspectives using CEC2014 test functions, CEC2017 test functions, and 23 benchmark test functions. The experimental results demonstrate that the enhanced Whale Optimization Algorithm significantly improves population diversity, balances global and local search, and enhances solution accuracy. Additionally, SEWOA exhibits excellent performance in solving three engineering design problems, showcasing its value and wide range of potential applications.

Abstract In August 2022, Pakistan experienced unprecedented monsoon rains, leading to devastating floods and landslides affecting millions. While previous research has mainly focused on the contributions of seasonal and synoptic anomalies, this study elucidates the dominant influences of tropical and extratropical intraseasonal oscillations on both the occurrence and subseasonal prediction of this extreme rainfall event. Our scale-decomposed moisture budget analysis revealed that intense rainfall in Pakistan was triggered and sustained by enhanced vertical moisture transport anomalies, primarily driven by interactions between intraseasonal circulation anomalies and the prevailing background moisture field when tropical and mid-latitude systems coincided over Pakistan. Evaluation of subseasonal-to-seasonal prediction models further highlighted the critical role of tropical intraseasonal modes in causing this extreme rainfall event in Pakistan. Models that accurately predicted northward-propagating intraseasonal convection with a forecast lead time of 8–22 days demonstrated good skill in predicting the extreme event over Pakistan.

Abstract Clinical studies and meta-analyses have suggested a link between thyroid dysfunction and lens opacification. The objective of this study is to investigate the causal relationship between hyperthyroidism and the development of cataracts using the Mendelian randomization approach, with the aim of filling the gap in knowledge about the systemic effects of hyperthyroidism on ocular health. Leveraging genetic variants as instrumental variables, the analysis used extensive datasets from the UK Biobank and the FinnGen Database and employed three common approaches for causal inference (the Inverse Variance Weighted method, a regression based method the Weighted Median estimator, and MR-Egger regression) and accompanying sensitivity analyses to ensure robustness. The results demonstrate that there is a strong likely causal relationship, with hyperthyroidism increasing the risk of developing senile cataracts (OR = 361.09, 95%CI 5.024 to 2.60 × 104, P = 0.007). A sensitivity analysis provided no evidence of horizontal pleiotropy and no significant outliers, suggesting the results are robust. In conclusion, our study established a significant causal relationship between hyperthyroidism and increased risk of cataract development, underscoring the importance of considering the systemic effects of hyperthyroidism in clinical and public health interventions and policies. Future research should focus on elucidating the molecular mechanisms underlying this association, exploring the potential benefits of early intervention in hyperthyroidism to prevent cataract development, and investigating whether these findings translate across different ethnic populations. Additionally, further GWAS studies aimed at identifying genetic variants associated with both hyperthyroidism and cataracts are warranted to confirm and expand upon our results.

Abstract This paper proposes a method of impulse current generator modulated DC arc by combining the advantages of pulse and the RF to solve the low electron energy problem of direct current arc. Through experimental analyzing the electrical, spectral, and optical characteristics of the arc, the effect of impulse current generator (ICG) on improving electron energy is discussed. The results show that the ICG consumes more energy to enhance the strength of arc discharge, and therefore electron energy is increased in a microsecond scale. In addition, it is found that the electron energy of the arc discharge can be adjusted by varying inductance, capacitance, and discharge tube: increasing the inductance or capacitance can increase the electron energy firstly and then decrease it. In adjusting the three adjustable components, adjusting the inductor is the most effective method, followed by adjusting the capacitor, and adjusting the repetition frequency has the least effect. The reason is discussed, and it is believed that the results are related to leakage inductance and distributed capacitance.

Abstract Background The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This study was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non–small cell lung cancer (NSCLC) harboring EGFR mutations. Methods Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results From June 2019 to June 2021, 20 patients were enrolled in this study. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥ 3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4–35.6). the ORR was 95% (95% CI, 75.1-99.9%), the DCR was 100% (95% CI, 83.2-100%), and the median DOR was 26.4 months (95% CI, 18.9–33.9). The median OS has not been reached. Conclusion The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is manageable and tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.

Abstract Metabolic disorder significantly contributes to diabetic vascular complications, including diabetic retinopathy, the leading cause of blindness in the working-age population. However, the molecular mechanisms by which disturbed metabolic homeostasis causes vascular dysfunction in diabetic retinopathy remain unclear. O-GlcNAcylation modification acts as a nutrient sensor particularly sensitive to ambient glucose. Here, we observe pronounced O-GlcNAc elevation in retina endothelial cells of diabetic retinopathy patients and mouse models. Endothelial-specific depletion or pharmacological inhibition of O-GlcNAc transferase effectively mitigates vascular dysfunction. Mechanistically, we find that Yes-associated protein (YAP) and Transcriptional co-activator with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are O-GlcNAcylated in diabetic retinopathy. We identify threonine 383 as an O-GlcNAc site on YAP, which inhibits its phosphorylation at serine 397, leading to its stabilization and activation, thereby promoting vascular dysfunction by inducing a pro-angiogenic and glucose metabolic transcriptional program. This work emphasizes the critical role of the O-GlcNAc-Hippo axis in the pathogenesis of diabetic retinopathy and suggests its potential as a therapeutic target.

Abstract Digital technology has become crucial for the protection of cultural relics, enabling their acquisition, preservation, exhibition, and dissemination in a non-contact manner.At present, the three-dimensional(3D) visualization technology of cultural relics focuses on the research of non-true 3D visualization, which cannot provide continuous viewing angle and takes a long time to render. This paper focuses on the acquisition and reproduction of digital information related to cultural relics, and proposes to achieve the true 3D display of cultural relics from a continuous perspective based on integrated imaging(InIm). Building up on traditional InIm, an Element image array (EIA) generation algorithm based on local depth template matching is designed by using spatial geometry relation. Experimental results show that the algorithm not only enables naked-eye 3D visualization of cultural relics, but also the generation speed is more than twice that of the compared 3D display data source generation algorithm.

The arginine-vasopressin (AVP) hormone plays a pivotal role in regulating various physiological processes, such as hormone secretion, cardiovascular modulation, and social behavior. Recent studies have highlighted the V1a receptor as a promising therapeutic target. In-depth insights into V1a receptor-related pathologies, attained through in vivo imaging and quantification in both peripheral organs and the central nervous system (CNS), could significantly advance the development of effective V1a inhibitors. To address this need, we develop a novel V1a-targeted positron emission tomography (PET) ligand, [18F]V1A-2303 ([18F]8), which demonstrates favorable in vitro binding affinity and selectivity for the V1a receptor. Specific tracer binding in peripheral tissues was also confirmed through rigorous cell uptake studies, autoradiography, biodistribution assessments. Furthermore, [18F]8 was employed in PET imaging and arterial blood sampling studies in healthy rhesus monkeys to assess its brain permeability and specificity, whole-body distribution, and kinetic properties. Our research indicated [18F]8 as a valuable tool for noninvasively studying V1a receptors in peripheral organs, and as a foundational element for the development of next-generation, brain-penetrant ligands specifically designed for the CNS.