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Most speakers' first language (L1) in Hong Kong and Guangdong China is Cantonese. Even though the L1 of both Guangdong Cantonese speakers and Hong Kong Cantonese speakers is the same, their second languages (L2) belong to different language families. Previous studies have pointed out that L2 status in third language (L3) acquisition is a salient factor. This study aimed to: (1) examine Guangdong Cantonese speakers' pronunciation error patterns in their L2 Mandarin and L3 English and explore the language interaction patterns among these three languages; (2) compare the findings with those of Hong Kong Cantonese speakers whose L2 is English and L3 Mandarin in Chen and Han (2019. L3 phonology: contributions of L1 and L2 to L3 pronunciation learning by Hong Kong speakers. International Journal of Multilingualism, 16(4), 492-512. https://doi.org/10.1080/14790718.2019.1573901) to identify the roles of L1 and L2 in L3 acquisition. Results of the reading aloud tasks, a questionnaire survey and interview data show that the language interaction patterns among L1, L2 and L3 are influenced by learners' language proficiency.

Abstract Purpose The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. Methods Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. Results The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. Conclusion The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

Functional dyspepsia (FD) is a brain–gut interaction disorder located in the stomach and duodenum, which has complex pathophysiological mechanisms, and there is no effective treatment for FD. Acupuncture and moxibustion have been proven to have definite and significant efficacy on FD. Focusing on the affected area and combined with the potential pathophysiology of FD, here we discuss the possible mechanisms of acupuncture and moxibustion in treating FD to guide future clinical and experimental research. We argue that the pathological causes of FD can be roughly divided into gastrointestinal dysfunction, duodenal low-grade inflammation, visceral hypersensitivity, and duodenal intestinal barrier and microbial imbalance. Correspondingly, the possible mechanisms of acupuncture and moxibustion in treating FD are elucidated from the perspective of how they improve gastric accommodation, regulate gastrointestinal motility, reduce gastric visceral sensitivity, regulate eosinophil–mast cell axis, inhibit low-grade inflammatory responses, and possibly regulate intestinal microbial homeostasis and duodenal barrier function through the microbiota–gut–brain axis. Although some evidence is still lacking, acupuncture remains a promising treatment for FD. In the future, it is necessary to conduct additional clinical and experimental research on acupuncture and moxibustion in treating FD to further explore their effects and mechanisms.

Calcium imaging with protein-based indicators1,2 is widely used to follow neural activity in intact nervous systems, but current protein sensors report neural activity at timescales much slower than electrical signalling and are limited by trade-offs between sensitivity and kinetics. Here we used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators3-8. The resulting 'jGCaMP8' sensors, based on the calcium-binding protein calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (half-rise times of 2 ms) and the highest sensitivity for neural activity reported for a protein-based calcium sensor. jGCaMP8 sensors will allow tracking of large populations of neurons on timescales relevant to neural computation.

Objective To analyze the clinical and genetic characteristics of three children with congenital heart defects， dysmorphic facial features and intellectual developmental disorders（CHDFIDD）. Methods Three children presenting with CHDFIDD were enrolled. Genomic DNA was extracted from peripheral venous blood of the children and their parents. Whole-exome sequencing（WES） was performed using chip-capture high-throughput sequencing technology. Suspected causative mutations were verified by Sanger sequencing and bioinformatic analysis. Using “CDK13 gene” and “CDK13-related diseases” as search terms， literatures of CNKI and Wanfang database were retrieved until February 2024. Using “CDK13”， “CDK13-related disorder” and “CHDFIDD” as search terms， literatures from the establishment of PubMed database untio February 2024 was retrieved， and the relevant literature was reviewed. Results WES revealed heterozygous variants of the CDK13 gene in three children， including c.2572 C>T （p.Leu858Phe）， c.2579 G>A （p.Arg860Gln）， and c.2602C>T （p.Arg868Trp）， which were verified as de novo variants by Sanger sequencing.Combined with the clinical phenotype， all 3 children were diagnosed with CHDFIDD. However， the possibility that one of the affected children’s parents was a germline chimera for the mutation could not be excluded. According to the ACMG guidelines， all three mutation sites were classified as likely pathogenic. A total of 14 studies consisting of 108 cases were retrieved. Among them， c.2572C>T has not been reported. Conclusions The de novo variants of the CDK13 gene may be the genetic cause of developmental delay/intellectual disability in these three children. The findings in the present study expand the spectrum of CDK13 gene mutations， providing reference for the diagnosis of CHDFIDD.

Abstract Massive increases in the risks of depressive disorders and the ensuing suicide have become the overarching menace for children/adolescents. Despite global consensus to instigate psychological healthcare policy for these children/adolescents, their effects remain largely unclear neither from a small amount of official data nor from small-scale scientific studies. More importantly, in underprivileged children/adolescents in lower-middle-economic-status countries/areas, the data collection may not be as equally accessible as in developed countries/areas, thus resulting in underrepresented observations. To address these challenges, we released a large-scale and multi-center cohort dataset (n = 249,772) showing the effects of primary psychological healthcare on decreasing depression and suicidal ideation in these children/adolescents who were underrepresented in previous studies or current healthcare systems, including unattended children/adolescents, orphans, children/adolescents in especially difficult circumstances, and “left-behind” and “single-parenting” children/adolescents. We provided all individual data recording the depressive symptoms and suicide ideation that had been collected at baseline (Oct 2022) and half-year follow-up (May 2023) from practicing this psychological healthcare system.

Replacing ordinary concrete in partially encased concrete (PEC) columns with high-strength and durability reactive powder concrete (RPC) significantly improves their axial capacity and suppresses local buckling of the steel section. To study the axial mechanical performance of partially encased composite reactive powder concrete (PEC-RPC) columns after exposure to high temperatures, axial compression tests of eight PEC-RPC column specimens were designed and conducted. Thermal response, failure modes, axial load-vertical displacement curves, and strain-axial strain curves of different specimens were observed considering the effects of link spacing, cross-sectional dimensions, constant temperature duration, and cooling methods. Results indicate: PEC-RPC columns exhibited whitening on the surface of RPC after high-temperature exposure, specimens with the largest link spacing experienced RPC peeling due to concentrated thermal stress, exacerbated by spraying water, which created a stress difference between the surface and the interior, resulting in RPC peeling. The deeper the thermocouple was embedded, the lower the measured temperature. Additionally, due to the significantly lower thermal conductivity of RPC compared to steel, the temperature at measurement points within the RPC is much lower than that at the steel web. The failure mode of PEC-RPC columns after axial loading was characterized by the crushing of RPC and local buckling of section steel. The larger the link spacing, the more prone it was to multi-layer buckling, and columns with larger cross-sectional sizes tended to exhibit shear failure. The characteristic value of mechanical performance showed higher sensitivity to cross-sectional dimensions, but relatively lower sensitivity to link spacing and constant temperature duration. As the cross-sectional dimensions increased from 150×150 mm to 250×250 mm, the peak load, residual bearing capacity, stiffness, and ductility increased by 72.51–164.86 %, 89.8–173.6 %, 61.85–151.47 %, and 13.72–31.46 %, respectively. Finally, based on partition constraint theory and superposition principle, a simplified method for calculating the axial mechanical performance of PEC-RPC columns after exposure to high temperatures was proposed.

Vehicle Routing Problem with Uncertain Demands (VRPUD) is one of the research hotspots in the field of logistics scheduling. In this paper, a Discrete Jaya (DJaya) algorithm is presented for the VRPUD to minimize the total cost. A novel dividing-point-based coding scheme is designed to represent solutions with higher robustness. In addition, an efficient repair strategy is embedded into the decoding process to avoid the failure of producing feasible solutions. The best and worst solutions are employed to generate offspring solutions in DJaya. Several efficient local search methods are also presented to enhance the exploitation ability and increase the diversity of solutions. Based on the benchmark data sets of the VRPUD, numerical simulations are carried out for the proposed DJaya algorithm with uncertain demands. Computational results and comparisons with the state-of-the-art algorithms demonstrate the superiority of the proposed algorithm in solving VRPUD.

Purpose: Sleep disorders are common globally. Probiotics may improve human microbial diversity, offering potential benefits for sleep disturbances by enhancing sleep quality and reducing disorders. We aimed to use a population-based study to investigate the association between yogurt (a probiotic food) and probiotic consumption with sleep disturbances in US adults. Methods: A total of 49,693 adults from the 2009–2018 National Health and Nutrition Examination Survey (NHANES) were included in the analyses. Sleep disorders and sleep duration were assessed according to the Sleep Disorders Questionnaire. The Dietary Questionnaire evaluated yogurt and dietary supplements containing probiotic consumption. After adjusting for confounding factors, weighted multivariable logistic regression and subgroup analyses were used to assess the association between yogurt and probiotic consumption and sleep status. Results: Of the study cohort, 3535 (14.24 %) participants consumed yogurt and/or dietary supplements containing probiotics. The prevalence of sleep disorders was 16.22 %. Only 53.51 % of the participants achieved the recommended amount of sleep (7–9 h), with 6.10 % and 33.48 % having excessive and insufficient sleep duration, respectively. Weighted Logistic regression models indicated a significant association of probiotic intake with a decreased risk of sleep disturbances compared with those without yogurt or probiotic consumption after adjustments. (For sleep disorders: OR: 0.96, 95 % CI 0.94–0.98, P < 0.001; for sleep duration: OR: 0.98, 95 % CI 0.96–1.00, P = 0.081) Moreover, the effect size of the probiotic intake on sleep was especially significant in sex, race, and BMI subgroups. Conclusion: The present study first indicated that yogurt and probiotic consumption were associated with a reduced risk of sleep disturbances in US adults, particularly among males, whites, and those with a normal BMI. Incorporating yogurt or probiotics into the diet could serve as a public health strategy for improving sleep disturbances, though further investigation into the underlying mechanisms is needed.

ObjectiveAdverse events associated with dexmedetomidine were analyzed using data from the FDA’s FAERS database, spanning from 2004 to the third quarter of 2023. This analysis serves as a foundation for monitoring dexmedetomidine’s safety in clinical applications.MethodsData on adverse events associated with dexmedetomidine were standardized and analyzed to identify clinical adverse events closely linked to its use. This analysis employed various signal quantification analysis algorithms, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS).ResultsIn the FAERS database, dexmedetomidine was identified as the primary suspect in 1,910 adverse events. Our analysis encompassed 26 organ system levels, from which we selected 346 relevant Preferred Terms (PTs) for further examination. Notably, adverse drug reactions such as diabetes insipidus, abnormal transcranial electrical motor evoked potential monitoring, acute motor axonal neuropathy, and trigeminal cardiac reflex were identified. These reactions are not explicitly mentioned in the drug’s specification, indicating the emergence of new signals for adverse drug reactions.ConclusionData mining in the FAERS database has elucidated the characteristics of dexmedetomidine-related adverse drug reactions. This analysis enhances our understanding of dexmedetomidine’s drug safety, aids in the clinical management of pharmacovigilance studies, and offers valuable insights for refining drug-use protocols.

Abstract Background Body temperature (BT) is routinely measured and can be controlled in critical care settings. BT can impact patient outcome, but the relationship between BT and mortality has not been well-established. Methods A retrospective cohort study was conducted based on the MIMIC-IV (N = 43,537) and eICU (N = 75,184) datasets. The primary outcome and exposure variables were hospital mortality and first 48-h median BT, respectively. Generalized additive models were used to model the associations between exposures and outcomes, while adjusting for patient age, sex, APS-III, SOFA, and Charlson comorbidity scores, temperature gap, as well as ventilation, vasopressor, steroids, and dialysis usage. We conducted subgroup analysis according to ICU setting, diagnoses, and demographics. Results Optimal BT was 37 °C for the general ICU and subgroup populations. A 10% increase in the proportion of time that BT was within the 36–38 °C range was associated with reduced hospital mortality risk in both MIMIC-IV (OR 0.91; 95% CI 0.90–0.93) and eICU (OR 0.86; 95% CI 0.85–0.87). On the other hand, a 10% increase in the proportion of time when BT 38 °C was associated with increased mortality risk in both MIMIC-IV (OR 1.09; 95% CI 1.07–1.12) and eICU (OR 1.09; 95% CI 1.08–1.11). All patient subgroups tested consistently showed an optimal temperature within the 36–38 °C range. Conclusions A BT of 37 °C is associated with the lowest mortality risk among ICU patients. Further studies to explore the causal relationship between the optimal BT and mortality should be conducted and may help with establishing guidelines for active BT management in critical care settings.

Accurate prediction of short-term passenger flow in urban rail transit systems plays a crucial role in optimizing operations and enhancing passenger experience. This study presents a scientific approach to predict subway passenger flow by analyzing characteristic patterns, identifying key factors influencing passenger flow changes, and leveraging relevant data sources. The multi-source data used in this study are described and pre-processed to capture the spatial, temporal, and other factors that contribute to subway passenger flow distribution. Utilizing the extracted features as inputs, an improved Long Short-Term Memory (LSTM) method is employed for short-term passenger flow prediction. The performance of the improved LSTM method is compared and analyzed against traditional methods. The results demonstrate that the proposed approach outperforms traditional methods in terms of prediction accuracy for the same prediction target. Furthermore, the fusion of multi-source data and the inclusion of external factors significantly enhance the prediction accuracy. This research highlights the importance of considering various factors and data sources when forecasting short-term passenger flow in urban rail transit systems. By employing an improved LSTM method and integrating multiple data dimensions, the proposed approach offers superior prediction accuracy compared to traditional methods. The findings contribute to the development of efficient and reliable prediction models for optimizing urban rail transit operations and improving passenger services.

Abstract Aims We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. Methods and results Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7‐nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad‐shSDF‐1α into the infarcted heart. Cardiac tissue acetylcholine (ACh) and serum ACh, tumour necrosis factor α (TNF‐α), interleukin 1β (IL‐1β) and interleukin 6 (IL‐6) levels were detected by ELISA to determine whether VNS was successful. An inflammatory injury model in human coronary artery endothelial cells (HCAECs) was established by lipopolysaccharide and identified by evaluating TNF‐α, IL‐1β and IL‐6 levels and tube formation. Immunohistochemistry staining was performed to evaluate CD31‐positive vessel density and stromal cell‐derived factor‐l alpha (SDF‐1α) expression in the MI heart in vivo and the expression and distribution of SDF‐1α, C‐X‐C motif chemokine receptor 4 and CXCR7 in HCAECs in vitro. Western blotting was used to detect the levels of SDF‐1α, V‐akt murine thymoma viral oncogene homolog (AKT), phosphorylated AKT (pAKT), specificity protein 1 (Sp1) and phosphorylation of Sp1 in HCAECs. Left ventricular performance, including left ventricular systolic pressure, left ventricular end‐diastolic pressure and rate of the rise and fall of ventricular pressure, should be evaluated 28 days after VNS treatment. VNS was successfully established for MI therapy with decreases in serum TNF‐α, IL‐1β and IL‐6 levels and increases in cardiac tissue and serum ACh levels, leading to increased SDF‐1α expression in coronary endothelial cells of MI hearts, triggering angiogenesis of MI hearts with increased CD31‐positive vessel density, which was abolished by the m/nAChR inhibitors mecamylamine and atropine or knockdown of SDF‐1α by shRNA. ACh promoted SDF‐1α expression and its distribution along with the branch of the formed tube in HCAECs, resulting in an increase in the number of tubes formed in HCAECs. ACh increased the levels of pAKT and phosphorylation of Sp1 in HCAECs, resulting in inducing SDF‐1α expression, and the specific effects could be abolished by mecamylamine, atropine, the PI3K/AKT blocker wortmannin or the Sp1 blocker mithramycin. Functionally, VNS improved left ventricular performance, which could be abolished by Ad‐shSDF‐1α. Conclusions VNS promoted angiogenesis to repair the infarcted heart by inducing SDF‐1α expression and redistribution along new branches during angiogenesis, which was associated with the m/nAChR‐AKT‐Sp1 signalling pathway.

There are enormous differences in benzo[a]pyrene (BaP) acute toxicity tests on Daphnia magna, according to previous publications. The explanations of the reasons for this extreme variation are necessary. In this context, the acute toxicity tests of different experiment conditions (light/dark, culture medium, and solvent) were conducted on Daphnia magna with BaP as the toxicant of concern. Based on the experiments above, molecular dynamics (MD) simulations were employed to investigate the mechanisms of action. According to our results, the significant influence of light exposure on the acute toxicity test of BaP (p < 0.05) on D. magna was recorded. On the basis of the MD simulations, it was possible that BaP may not affect the normal operation of Superoxide Dismutase and Catalase directly, and it could be quickly transferred from the body through Glutathione S-transferase and Cytochromes P450. Therefore, when exposed to light, the oxidative stress process intensifies, causing damage to Daphnia magna. Apparently, the ecotoxicity tests based on inhibition for D. magna cannot adequately reflect the toxic effects of BaP.