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Abstract Stomach adenocarcinoma (STAD) is the most prevalent gastrointestinal malignancy and seriously threatens the life of the global population. Anoikis, a process of programmed cell death that occurs when cells detach from the extracellular matrix, is closely associated with tumor invasion and metastasis. In this study, we used the TCGA-STAD database to identify the expression patterns and prognostic relevance of anoikis-related genes (ARGs) in STAD. Functional enrichment analysis was used to explore the potential pathway. LASSO and Cox regression were used to construct anoikis-related prognostic signature. The anoikis risk score (ARS) incorporated 7 genes and stratified patients into highand low-risk subgroups by median value splitting. In addition, external validation was performed based on GSE66229, GSE15459, and GSE84437 cohorts. Nomograms were created based on risk characteristics in combination with clinical variants and the performance of the model was validated with time-dependent AUC, calibration curves, and decision curve analysis (DCA). The prognostic signature indicated that the low-risk subgroup had better outcomes and significant correlations with tumor microenvironment, immune landscape, immunotherapy response, and drug sensitivity. In addition, single-cell analysis displayed the cell types, the subcellular localization of prognostic genes, and the cellular interaction to reveal the potential molecular communication mechanism of anoikis resistance. Finally, in vitro experiments confirmed the critical role of CRABP2 in STAD. The results indicated that CRABP2 knockdown inhibited gastric cancer cell proliferation, migration and invasion, and promoted apoptosis. In summary, ARS can serve as a biomarker for predicting survival outcomes in STAD patients, providing new tools for personalized treatment decisions for STAD patients.

Abstract Atherosclerosis (AS) is a chronic vascular disease characterized by inflammation of the arterial wall and the formation of cholesterol plaques. Hashimoto’s thyroiditis (HT) is an autoimmune disorder marked by chronic inflammation and destruction of thyroid tissue. Although previous studies have identified common risk factors between AS and HT, the specific etiology and pathogenic mechanisms underlying these associations remain unclear. We obtained relevant datasets for AS and HT from the Gene Expression Omnibus (GEO). By employing the Limma package, we pinpointed common differentially expressed genes (DEGs) and discerned co-expression modules linked to AS and HT via Weighted Gene Co-expression Network Analysis (WGCNA). We elucidated gene functions and regulatory networks across various biological scenarios through enrichment and pathway analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Core genes were identified using Cytoscape software and further validated with external datasets. We also conducted immune infiltration analysis on these core genes utilizing the CIBERSORT method. Lastly, Single-cell analysis was instrumental in uncovering common diagnostic markers. Based on differential analysis and WGCNA, we identified 119 candidate genes within the cohorts for AS and HT. KEGG and GO enrichment analyses indicate that these genes are significantly involved in antigen processing and presentation, along with various immune-inflammatory pathways. Two pivotal genes, PTPRC and TYROBP, were identified using five algorithms from the cytoHubba plugin. Validation through external datasets confirmed their substantial diagnostic value for AS and HT. Moreover, the results of Gene Set Enrichment Analysis (GSEA) indicated that these core genes are significantly enriched in various receptor interactions and signaling pathways. Immune infiltration analysis revealed a strong association of lymphocytes and macrophages with the pathogenesis of AS and HT. Single-cell analysis demonstrated predominant expression of the core genes in macrophages, monocytes, T cells and Common Myeloid Progenitor (CMP). This study proposes that an aberrant immune response might represent a shared pathogenic mechanism in AS and HT. The genes PTPRC and TYROBP are identified as critical potential biomarkers and therapeutic targets for these comorbid conditions. Furthermore, the core genes and their interactions with immune cells could serve as promising targets for future diagnostic and therapeutic strategies.

Abstract Background Among hypertensive cohorts across different nations, the relationship between the triglyceride-glucose index (TyG) and its conjunction with obesity metrics in relation to cardiovascular disease (CVD) incidence and mortality remains to be elucidated. Methods This study enrolled 9,283, 164,357, and 5,334 hypertensives from the National Health and Nutrition Examination Survey (NHANES), UK Biobank (UKBB), and Shanghai Pudong cohort. The related outcomes for CVD were defined by multivariate Cox proportional hazards models, Generalized Additive Models and Mendelian randomization analysis. Mediation analysis explored the mediating role of inflammatory markers in the above relationships. Results Five measures of insulin resistance were linked to CVD and related death in a U-shaped pattern, with the highest group having different risk increases. Higher glucose triglyceride-waist height ratio (TyG-WHTR) was linked to higher all-cause mortality (UKBB: HR 1.21, 95%CI 1.16–1.26, NHANES: HR 1.17, 95%CI 1.00–1.36), CVD mortality (UKBB: HR 1.36, 95%CI 1.23–1.49, NHANES: HR 1.32, 95%CI 1.00–1.72) risks. In the China Pudong cohort, higher triglyceride/high-density lipoprotein-cholesterol (TG/HDL_C) ratio was associated with higher risks of CVD and stroke (HR 1.31, 95%CI 1.00–1.73 and 1.67, 1.06–2.63). Inflammation markers like systemic inflammatory response index (SIRI) and C-reactive protein (CRP) partially explained these links, with CRP having a stronger effect. Genetically predicted TyG was also linked to stroke (OR 1.26, 95%CI 1.10–1.45) risk. Conclusions An elevated TyG index and its related indices are significantly correlated with an increased risk of CVD and related mortality across three national cohorts. These indices are anticipated to serve as valid predictors of incident CVD and mortality in individuals with hypertension. Graphical abstract

ABSTRACT Background Previous studies reveal inconsistent associations between serum lipid traits and the risks of fractures and osteoporosis in the general population. Methods This prospective cohort study analysed data from 414 302 UK Biobank participants (223 060 women and 191 242 men, aged 37–73 years) with serum lipid measurements: apolipoprotein A (Apo A), apolipoprotein B (Apo B), total cholesterol (TC), high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), triglycerides (TG) and lipoprotein A (Lp(a)). Multivariable Cox proportional hazard models with penalized cubic splines were used to explore potential nonlinear associations of each lipid trait with the risks of fractures and osteoporosis. Subgroup analyses by age, sex, BMI categories and pre‐existing cardiovascular disease were conducted. Mediation analyses using the g‐formula were performed to quantify to which extent bone mineral density (BMD) may mediate the association between serum lipids and fracture risk. Results Over a median follow‐up period of 13.8 years, 25 918 (6.8%) of the 383 530 participants without prior fracture had incident fracture cases, and 7591 (4.1%) of the 184 919 participants with primary care data and without baseline osteoporosis were diagnosed with osteoporosis. TG had nonlinear associations with fractures and osteoporosis, whereas Apo B, TC and LDL‐C had linear associations. There were also nonlinear associations of Apo A and HDL‐C with fractures. Individuals in the highest quintiles for Apo A (fracture: HR 1.15 [95% CI 1.10, 1.21]; osteoporosis: HR 1.13 [1.02, 1.25]) and HDL‐C (fracture: HR 1.27 [1.20, 1.34]; osteoporosis: HR 1.31 [1.18, 1.46]) were associated with higher risks of fractures and osteoporosis. Conversely, those in the highest quintile for Apo B (fracture: HR 0.85 [0.81, 0.89]; osteoporosis: HR 0.86 [0.79, 0.94]), LDL‐C (fracture: HR 0.89 [0.85, 0.93]; osteoporosis: HR 0.91 [0.83, 1.00]) and TG (fracture: HR 0.78 [0.74, 0.82]; osteoporosis: HR 0.75 [0.68, 0.82]) were associated with lower risks. The associations of Apo A (ratio of HR [RHR] 1.05 [1.02, 1.09]) and HDL‐C (RHR 1.06 [1.03, 1.09]) with fracture risk were more pronounced in men compared to women. Except for TG and Lp(a), the associations between serum lipids and fractures appear to be partially mediated through BMD (mediation proportions: 5.30% to 40.30%), assuming causality. Conclusions Our study reveals a complex interplay between different lipid markers and skeletal health, potentially partially mediated through BMD. Routine lipid profile assessments, including HDL‐C and Apo A among other lipid traits, may be integrated into the strategies for fracture risk stratification.

Abstract Background Lung cancer is characterized by high morbidity and mortality due to the lack of practical early diagnostic and prognostic tools. The present study uses machine learning algorithms to construct a clinical predictive model for non-small cell lung cancer (NSCLC) patients. Methods Laboratory indices of the NSCLC patients at their initial visit were collected for quality control and exploratory analysis. By comparing the levels of the above indices between the survival and death groups, the statistically significant indices were selected for subsequent machine learning modeling. Ten machine learning algorithms were then employed to develop the predictive models with survival and recurrence as outcomes, respectively. Moreover, regression models were constructed using the random survival forest algorithm by incorporating the survival time dimension. Finally, critical variables in the optimal model were screened based on the interpretable algorithms to build a decision tree to facilitate clinical application. Results 682 patients were enrolled according to the inclusion and exclusion criteria. The preliminary comparison results revealed that except for fast blood glucose, CD3 +T cell proportion, NK cell proportion, and CA72-4, there were significant statistical differences in other tumor markers, inflammation, metabolism, and immune-related indices between the survival and death groups (p

Abstract Chronic gastritis (CG) is a common inflammatory disease of chronic inflammatory lesion of gastric mucosa and in the diagnosis of gastritis in traditional Chinese medicine (TCM), CG can be classified into Cold ZHENG (syndrome in TCM) and Hot ZHENG. However, the molecular features of Cold/Hot ZHENG in CG and the mechanism of Cold/Hot herbs in formulae for CG remained unclear. In this study, we collected a transcriptomics data including 35 patients of Cold/Hot ZHENG CG and 3 scRNA-seq CG samples. And 25 formulae for CG and 89 herbs recorded in these formulae were also collected. We conduct a comprehensive analysis based on the combination of transcriptomics datasets and machine learning algorithms, to discover biomarkers for Cold/Hot ZHENG CG. Then the target profiles of the collected formulae and Cold/Hot herbs were predicted to uncover the features and biomarkers of them against Cold/Hot ZHENG CG. These biomarkers suggest that Hot ZHENG CG might be characterized by over-inflammation and exuberant metabolism, and Cold ZHENG CG showed a trend of suppression in immune regulation and energy metabolism. Biomarkers and specific pathways of Hot herbs tend to regulate immune responses and energy metabolism, while those of Cold herbs are more likely to participate in anti-inflammatory effects. Finally, the findings were verified based on public transcriptomics datasets, as well as transcriptomics and ELISA detection, taking Jin Hong tablets as a case study. Biomarkers like leptin and IL-6 together with proportions of immune cells showed significant changes after the intervention. These findings might reflect the mechanism and build a bridge between macro and micro views of Cold/Hot ZHENG as well as Cold/Hot herbs. Graphical abstract

ABSTRACT Evidence suggests that approximately 63.0%–84.2% of stroke survivors have hypertension, yet there is currently no stroke prediction tool specifically designed for individuals with hypertension. Using data from 20 702 hypertensive patients from the China Stroke Primary Prevention Trial (CSPPT), we developed a 5‐year stroke risk prediction model. This prospective study collected treated blood pressure every 3 months, resulting in 22 measurements over the study period. The model was internally validated using bootstrap resampling, and its predictive performance was assessed with the C‐index and calibration curves. We also developed a random forest model to rank the variable importance. The 5‐year stroke risk prediction model for hypertensive individuals includes 10 risk factors, ranked by importance as follows: average systolic blood pressure during treatment, age, average diastolic blood pressure during treatment, baseline systolic blood pressure, history of diabetes, baseline total cholesterol level, baseline folate level, self‐reported stress, smoking, and folic acid supplementation or not. The C statistic of the equation was 0.74 and there were no significant differences by gender or treatment group. Calibration plots indicate good internal consistency between observed and predicted 5‐year stroke risk. We also developed an online calculator to assist clinicians and patients (https://zhouziyi.shinyapps.io/CSPPT/). Our study indicates that for patients with hypertension, long‐term posttreatment blood pressure is the primary predictor of stroke risk. Trial Registration: The CSPPT (clinicaltrials.gov Identifier: NCT00794885).

BackgroundExisting epidemiological studies investigated the association between a single vitamin and hypertension. However, the potential relationship between the level of circulating multivitamins and blood pressure has not been explored. We aimed to investigate the association between multiple fat-soluble vitamin levels and blood pressure.MethodsA total of 2052 participants with essential hypertension were sampled nationwide. The plasma concentrations of fat-soluble vitamins (A, E, D, and K) were assessed using liquid chromatography coupled with the mass spectrometry method. Participants were categorized into different co-exposure patterns using the unsupervised K-means clustering method. The multiple linear regression model was used for subsequent analyses.ResultsParticipants were classified into two co-exposure patterns of fat-soluble vitamins. The levels of vitamins were relatively low in pattern 1, compared to pattern 2. Participants in pattern 2 had no significantly different blood pressure levels compared to pattern 1. However, the plasma 25-hydroxyvitamin D3 (VD3) levels were negatively associated with SBP (logarithmic 10 transformed) (β = −0.002, 95% CI: −0.004, 0); participants in the fourth α-tocopherol quartile had mean SBP levels that were 1.02% (95% CI: 0.43, 1.61%) greater than those in the lowest quartile (p for trend

IntroductionArtificial vascular scaffolds can mimic the structure of natural blood vessels and replace the damaged vessels by implanting them at the injury site to perform the corresponding functions. Electrospinning technology can perfectly combine biological signals and topographical cues to synergistically induce directed cell migration and growth.MethodsIn this study, poly (caprolactone) (PCL) nanofibers, PCL nanofibers uniformly coated with the extracellular matrix derived from endothelial cells (ECd), and bi-directional linear gradient ECd-coated PCL nanofibers were prepared by electrospinning and electrospray techniques to evaluate their effects on the proliferation and migration of Human umbilical vein endothelial cells (HUVECs) and rapid endothelialization.ResultsThe results showed that HUVECs could successfully adhere to the surface of these three nanofibers and maintain high viability. The migration results indicated that the bidirectional linear gradient coating could accelerate the migration of HUVECs and the endothelialization process. On this basis, three types of bionic vascular scaffolds, including PCL vascular scaffold, uniform ECd-coated PCL vascular scaffold, and bi-directional linear gradient ECd-coated PCL vascular scaffold, were further prepared. The results showed that the topology and biological signal of the bi-directional linear gradient ECd-coated PCL vascular scaffold synergistically promoted the migration of HUVECs more effectively.DiscussionThis provides a new way to clinically promote the structural and functional recovery of damaged vessels and develop personalized or universal artificial vascular scaffolds, which is of great importance in cardiovascular regenerative medicine.

Abstract Protein language models (PLMs) play a dominant role in protein representation learning. Most existing PLMs regard proteins as sequences of 20 natural amino acids. The problem with this representation method is that it simply divides the protein sequence into sequences of individual amino acids, ignoring the fact that certain residues often occur together. Therefore, it is inappropriate to view amino acids as isolated tokens. Instead, the PLMs should recognize the frequently occurring combinations of amino acids as a single token. In this study, we use the byte-pair-encoding algorithm and unigram to construct advanced residue vocabularies for protein sequence tokenization, and we have shown that PLMs pre-trained using these advanced vocabularies exhibit superior performance on downstream tasks when compared to those trained with simple vocabularies. Furthermore, we introduce PETA, a comprehensive benchmark for systematically evaluating PLMs. We find that vocabularies comprising 50 and 200 elements achieve optimal performance. Our code, model weights, and datasets are available at https://github.com/ginnm/ProteinPretraining . Scientific contribution This study introduces advanced protein sequence tokenization analysis, leveraging the byte-pair-encoding algorithm and unigram. By recognizing frequently occurring combinations of amino acids as single tokens, our proposed method enhances the performance of PLMs on downstream tasks. Additionally, we present PETA, a new comprehensive benchmark for the systematic evaluation of PLMs, demonstrating that vocabularies of 50 and 200 elements offer optimal performance. Graphical Abstract

Abstract It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.

Abstract Accurately modeling the protein fitness landscapes holds great importance for protein engineering. Pre-trained protein language models have achieved state-of-the-art performance in predicting protein fitness without wet-lab experimental data, but their accuracy and interpretability remain limited. On the other hand, traditional supervised deep learning models require abundant labeled training examples for performance improvements, posing a practical barrier. In this work, we introduce FSFP, a training strategy that can effectively optimize protein language models under extreme data scarcity for fitness prediction. By combining meta-transfer learning, learning to rank, and parameter-efficient fine-tuning, FSFP can significantly boost the performance of various protein language models using merely tens of labeled single-site mutants from the target protein. In silico benchmarks across 87 deep mutational scanning datasets demonstrate FSFP’s superiority over both unsupervised and supervised baselines. Furthermore, we successfully apply FSFP to engineer the Phi29 DNA polymerase through wet-lab experiments, achieving a 25% increase in the positive rate. These results underscore the potential of our approach in aiding AI-guided protein engineering.

The soil environment is a primary destination for contaminants such as microplastics (MPs) and heavy metals (HMs), which are frequently detected simultaneously. The long-term coexistence of MPs and HMs in the soil necessitates unavoidable interactions, affecting their environmental chemical behavior and bioavailability. These co-contaminants pose potential threats to soil organism growth and reproduction, crop productivity, food security, and may jeopardize human health via the food chain. This paper summarizes the sources and trends of MPs in the soil environment, along with the mechanisms and current research status of MP adsorption or desorption of HMs. Additionally, this paper reviews factors affecting HM adsorption on MPs, including MP properties, HM chemical properties, and other environmental factors. Lastly, the effects of MPs and HMs on soil ecology and human health are summarized. The interaction mechanisms and potential biological effects of their co-contamination require further exploration. Future research should delve deeper into the ecotoxic effects of MP–HM co-contamination at cellular and molecular levels, to provide a comprehensive reference for understanding the environmental behavior of their co-contamination in soil.

The presence of particles leads to varying degrees of mass loss on a metal sealing surface, which severely affects the seal’s lifespan. Understanding the complex wear mechanism and optimizing the surface roughness morphology are particularly important in engineering. By characterizing the surface of the metal (SS 304) with different roughness parameters Ra, Rp, Rpk, Rpc and Rku, the variation mode of mass loss under abrasive wear conditions was revealed. Unlike traditional two-body wear, the involvement of abrasive particles significantly impacts surface Ra and other surface morphologies (asperity peak features). A contact model for metal rough surfaces, distinct from two-body contact, was established to clarify the changes in removal mechanisms. It was found that the change in the contact between the particle and the asperity peak led to a change in the mass loss and guided the appropriate metal roughness range: Ra 0.05 μm and Ra 0.6–0.8 μm. In addition, it was found that the removal of asperity peaks is holistic under low roughness, and only parts of asperity peaks are removed under high roughness. Notably, the metrological methods used in this study supplement existing roughness measurements. By exploring the complex removal mechanism of asperity peaks, micro-scale guidance for surface (texture) design, machining, and optimization is provided.

Abstract Background Hypertension and frailty often occur concurrently, exhibiting increasing prevalence in the older population. In this study, we analyzed the frailty status among older adults with hypertension and the impact of their interaction on death risk. Method This prospective cohort survey study included data from older people in an urban community in Beijing collected between 2009 and 2020 using the cluster random sampling method. The participants were older adults who were ≥ 60 years old at the time of investigation and had lived at the place of investigation for > 1 year. The survey variables comprised those related to health and frailty status assessed during the 2009 baseline survey, along with death-related information as outcome variables in 2020. Additionally, a frailty index (FI) model was used to examine the frailty status among the older adults at baseline. The effects of hypertension prevalence on the age-related frailty changes as well as on mortality for varying degrees of frailty were further analyzed. Lastly, Cox regression and Kaplan–Meier curves were applied to evaluate the impact of the interaction between hypertension and frailty on death risk. Results Ultimately, 1197 older individuals aged between 60 and 101 years(average age at baseline: 74.8 ± 8.6 years) were included .Among them, 475 individuals were men (mean age:74.8 ± 8.8 years), and 722 were women (mean age:74.8 ± 8.4 years).Frailty was identified in 151 individuals, leading to a prevalence rate of 12.6%(151/1197),while hypertension was detected in 593 (prevalence rate:49.5% [593/1197]).A total of 443 deaths were recorded by 2020, resulting in a mortality rate of 37.0% (443/1197).Moreover, FI values and mortality rates were higher at any age in older adults with hypertension compared with those without hypertension. Survival time analysis showed that the median survival time of older adults with hypertension and frailty was the shortest (39.0[95%CI: 35.6–42.3] months)when compared with that of older adults without hypertension but with frailty (52.9 [95%CI: 46.6-59.3] months), those with hypertension but without frailty (102.7 [95%CI: 98.7–106.8] months), and those without hypertension and frailty (127.9 [95%CI: 113.5–134.7] months),with log-rank x 2 = 999.686 and P

In this paper, a fully-discrete alternating direction implicit (ADI) difference method is proposed for solving three-dimensional (3D) fractional subdiffusion equations with variable coefficients, whose solution presents a weak singularity at $ t = 0 $. The proposed method is established via the L1 scheme on graded mesh for the Caputo fractional derivative and central difference method for spatial derivative, and an ADI method is structured to change the 3D problem into three 1D problems. Using the modified Grönwall inequality we prove the stability and $ \alpha $-robust convergence. The results presented in numerical experiments are in accordance with the theoretical analysis.

Blockchain has shown significant potential as a key enabler in privacy and security in the forthcoming 6G wireless network, due to its distributed and decentralized characteristics. Practical Byzantine fault tolerance (PBFT) emerges as a prominent technology for deployment in wireless networks due to its attributes of low latency, high throughput, and minimal computational requirements. However, the high complexity of communication is the bottleneck of PBFT for achieving high scalability. To tackle this problem, this paper proposes a novel framework of PBFT, where the inter-node communication during the normal case operation is completed through base stations. The uplink and downlink communication between the base station and nodes are modelled based on the signal-to-interference-plus-noise ratio (SINR) threshold. A novel ‘timeout’ mechanism is incorporated to reduce the communication complexity. The performance is evaluated by metrics including consensus success probability, communication complexity, view change delay, view change occurrence probability, consensus delay, consensus throughput and energy consumption. The numerical results show that the proposed scheme achieves higher consensus success probability and throughput, lower communication complexity and consensus delay compared to the conventional PBFT. The results of view change delay and view change occurrence probability and the optimal configuration provide analytical guidance for the deployment of wireless PBFT networks.

Abstract Background This study aimed to evaluate the association of triglyceride-glucose (TyG) index, an insulin resistance surrogate biomarker, with first stroke in a hypertensive population and to explore potential influencing factors. Methods This study, a cohort study among a rural Chinese hypertensive population, utilized data from the China Stroke Primary Prevention Trial (CSPPT). The TyG index was calculated as ln [fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2]. Multivariate analysis using Cox proportional hazards models was conducted. Results A total of 7569 hypertensive patients were included in this study. When TyG index was assessed as quartiles, compared with the reference group (Quartile 1), the hazard ratio of stroke was 1.04 in Quartile 2, 1.43 in Quartile 3, and 1.45 in Quartile 4, with a significant trend test (P = 0.013). When Quartiles 3 and 4 were combined (≥ 8.8), the hazard ratio was 1.41 compared with combined Quartiles 1 and 2 (

Practical Byzantine Fault Tolerance (PBFT) is one of the most popular consensus mechanisms for the consortium and private blockchain technology. It has been recognized as a candidate consensus mechanism for the Internet of Things networks as it offers lower resource requirements and high performance when compared with other consensus mechanisms such as proof of work. In this paper, by considering the blockchain nodes are wirelessly connected, we model the network nodes distribution and transaction arrival rate as Poisson point process and we develop a framework for evaluating the performance of the wireless PBFT network. The framework utilizes slotted ALOHA as its multiple access technique. We derive the end-to-end success probability of the wireless PBFT network which serves as the basis for obtaining other key performance indicators namely, the optimal transmission interval, the transaction throughput and delay, and the viable area. The viable area represents the minimum PBFT coverage area that guarantees the liveness, safety, and resilience of the PBFT protocol while satisfying a predefined end-to-end success probability. Results show that the transmission interval required to make the wireless PBFT network viable can be reduced if either the end-to-end success probability requirement or the number of faulty nodes is lowered.

This study aimed to assess the real-world effectiveness of vaccines and hybrid immunity in preventing infections during the Omicron prevalent period in Hong Kong. This study analyzed vaccination records and COVID-19 confirmed case records from 1 January 2022 to 28 January 2023 and included a total of 7,165,862 individuals with vaccination or infection records. This study found that an additional vaccine dose offered increased protection against Omicron BA.1/2 and BA.4 infections for individuals without prior infections in general. Hybrid immunity, acquired through vaccination and natural infection, was found to be significantly stronger than that provided by vaccines alone. The Comirnaty Original/Omicron BA.4/5 bivalent vaccine, introduced in December 2022, was associated with a lower risk of BA.4 infection when administered as a booster dose after three doses of CoronaVac. However, individuals with four doses of the CoronaVac vaccine did not exhibit a significantly lower risk of infection compared to those with three doses during the BA.4 dominant period. This study highlights the importance of promoting booster shot uptake and encouraging vaccination among those who have recovered from COVID-19 infections. The potential immune imprinting effect associated with the Comirnaty and CoronaVac vaccine underscores the need for continued surveillance and research to optimize vaccination strategies for emerging variants.

Abstract Glutamate, the major excitatory neurotransmitter in the central nervous system, has also been found to play a role in embryonic stem (ES) cells. However, the exact mechanism and function of glutamatergic signaling in ES cells remain poorly understood. In this study, we identified a glutamatergic transmission circuit in ES cells that operates through an autocrine mechanism and regulates cell proliferation. We performed biological analyses to identify the key components involved in glutamate biosynthesis, packaging for secretion, reaction, and reuptake in ES cells, including glutaminase, vesicular glutamate transporter, glutamate N-methyl-d-aspartate (NMDA) receptor, and cell membrane excitatory amino-acid transporter (EAAT). We directly quantified the released glutamate signal using microdialysis-high performance liquid chromatography-tandem mass spectrometry (MD–HPLC–MS–MS). Pharmacological inhibition of endogenous glutamate release and the resulting tonic activation of NMDA receptors significantly affected ES cell proliferation, suggesting that ES cells establish a glutamatergic autocrine niche via releasing and responding to the transmitter for their own regulation.

Abstract To investigate the fluorescein angiography (FA) findings and compare the extent of retinal vascularization in retinopathy of prematurity (ROP), recovered after intravitreal ranibizumab (IVR) monotherapy and those regressed spontaneously. Infants with a history of ROP who underwent FA between April 2018 and November 2021 were retrospectively included. The patients were divided into two groups based on whether they had received IVR (IVR group) or had ROP that regressed spontaneously without treatment (untreated group). The differences between the two groups in zone II ROP were also compared, to equalize the subgroups as much as possible in terms of disease severity. FA findings were recorded. The extent of vascularization was measured by the ratio of the distance from the center of the disk to the border of the vascularized zone (DB) and the distance from the center of the disk to the center of the fovea (DF). The width of the persistent avascular retina (PAR) was counted by disc diameters (DD). One hundred and ten eyes of 55 infants were included in the IVR group and 76 eyes of 38 babies in the untreated group. The ratio of abnormal shape of vessels was significantly higher in the IVR group than in the untreated group (50.9% vs. 35.5%; P = 0.038), while the linear choroidal filling pattern, tortuosity of vessels over the posterior pole, dye leakage, anomalous branching of vessels, circumferential vessels, arteriovenous shunt, abnormal capillary bed, and macular abnormalities were similarly. There was a smaller temporal DB/DF ratio (4.48 vs. 4.63; P = 0.003) and greater PAR (2.63 vs. 1.76; P

Abstract Background Although non-alcoholic fatty liver disease (NAFLD) is linked to inflammation, whether an inflammatory diet increases the risk of NAFLD is unclear. This study aimed to examine the association between the Energy-adjusted Diet Inflammatory Index (E-DII) score and severe NAFLD using UK Biobank. Methods This prospective cohort study included 171,544 UK Biobank participants. The E-DII score was computed using 18 food parameters. Associations between the E-DII and incident severe NAFLD (defined as hospital admission or death) were first investigated by E-DII categories (very/moderately anti-inflammatory [E-DII 1]) using Cox proportional hazard models. Nonlinear associations were investigated using penalised cubic splines fitted into the Cox proportional hazard models. Analyses were adjusted for sociodemographic, lifestyle and health-related factors. Results Over a median follow-up of 10.2 years, 1489 participants developed severe NAFLD. After adjusting for confounders, individuals in the very/moderately pro-inflammatory category had a higher risk (HR: 1.19 [95% CI: 1.03 to 1.38]) of incident severe NAFLD compared with those in the very/moderately anti-inflammatory category. There was some evidence of nonlinearity between the E-DII score and severe NAFLD. Conclusions Pro-inflammatory diets were associated with a higher risk of severe NAFLD independent of confounders such as the components of the metabolic syndrome. Considering there is no recommended treatment for the disease, our findings suggest a potential means to lower the risk of NAFLD.

BackgroundThere is growing concern regarding elevated levels of circulating unmetabolized folic acid (UMFA) due to excessive intake of folic acid (FA). However, no randomized clinical trial has been conducted to examine the FA-UMFA dose-response relationship.ObjectiveThis study aimed to investigate the FA-UMFA dose-response relationship in Chinese adults with hypertension and elevated homocysteine (H-type hypertension), a population with clear clinical indication for FA treatment.MethodsThe data for this study were derived from a randomized, double-blind, multicenter clinical trial of 8 FA dosages on efficacy of homocysteine (Hcy) lowering. The parent trial had three 3 stages: screening period (2–10 days), run-in period (0–2 weeks, baseline visit), and double-blind treatment period (8 weeks) with follow-up visits at the end of the 2nd, 4th, 6th, and 8th weeks of treatment. Participants were randomly assigned to 8 treatment groups corresponding to FA dosages of 0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0 mg to 2.4 mg.ResultsThis study included 1,567 Chinese adults aged ≥45 years with H-type hypertension. There was a positive but non-linear association between FA supplementation and UMFA levels in the dosage range of 0 mg to 2.4 mg. In the regression analysis, the coefficients for the linear and quadratic terms of FA dosage were both statistically significant (P < 0.001). Notably, the slope for UMFA was greater for FA dosages >0.8 mg (ß = 11.21, 95% CI: 8.97, 13.45) compared to FA dosages ≤0.8 mg (ß = 2.94, 95% CI: 2.59, 3.29). Furthermore, FA dosages higher than 0.8 mg did not confer additional benefits in terms of increasing 5-methyl tetrahydrofolic acid (5-MTHF, active form of folate) or reducing homocysteine (Hcy).ConclusionIn Chinese adults with H-type hypertension, this study showed a positive, non-linear, dosage-response relationship between FA supplementation ranging from 0 to 2.4 mg and circulating UMFA levels. It revealed that 0.8 mg FA is an optimal dosage in terms of balancing efficacy (increasing 5-MTHF and lowering Hcy) while minimizing undesirable elevation of UMFA.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03472508?term=NCT03472508&draw=2&rank=1, identifier NCT03472508.

The efficacy of different echinocandins is assessed by evaluating the in vitro activity of a novel antifungal, rezafungin, against invasive fungal isolates in comparison with anidulafungin and caspofungin. Using the broth microdilution (BMD) method, the susceptibility of 1000 clinical Candida isolates (including 400 C. albicans, 200 C. glabrata, 200 C. parapsilosis, 150 C. tropicalis and 50 C. krusei) and 150 Aspergillus isolates (100 A. fumigatus and 50 A. flavus) from the Eastern China Invasive Fungi Infection Group (ECIFIG) was tested for the antifungals including anidulafungin, rezafungin, caspofungin and fluconazole. The echinocandins showed strong activity against C. albicans that was maintained against fluconazole-resistant isolates. The GM MIC (geometric mean minimum inhibitory concentration) value of rezafungin was found to be comparable to that of anidulafungin or caspofungin against the five tested common Candida species. C. tropicalis exhibited higher resistance rates (about 8.67–40.67% in different antifungals) than the other four Candida species. Through the sequencing of FKS genes, we searched for mutations in echinocandin-resistant C. tropicalis isolates and found that all displayed alterations in FKS1 S654P. The determined MEC (minimal effective concentration) values against A. fumigatus and A. flavus for rezafungin (0.116 μg/mL, 0.110 μg/mL) are comparable to those of caspofungin (0.122 μg/mL, 0.142 μg/mL) but higher than for anidulafungin (0.064 μg/mL, 0.059 μg/mL). Thus, the in vitro activity of rezafungin appears comparable to anidulafungin and caspofungin against most common Candida and Aspergillus species. Rezafungin showed higher susceptibility rates against C. glabrata. Rezafungin indicates its potent activity for potential clinical application.

Semi-quantum secret sharing is an important research issue in quantum cryptography. In this paper, we propose a (t, n) threshold semi-quantum secret sharing protocol, which combines the practicality of semi-quantum secret sharing protocols and the flexibility of (t, n) threshold quantum secret sharing protocols. Participants prepare and transmit single particles in a circular way, and then any t out of n participants can recover the secret according to Shamir’s secret sharing scheme. As quantum resources, single particles are easy to prepare. Furthermore, classical participants only need to possess the capability to prepare and insert particles. The security analysis shows our protocol has security against most attacks. Except decoy particles, all particles are useful to carry the secret message, so the efficiency of the proposed protocol can achieve 100%.

Abstract We aimed to evaluate the prospective association of vitamin B5 with all‐cause mortality and explore its potential modifiers in Chinese adults with hypertension. A nested, case‐control study was conducted in the China Stroke Primary Prevention Trial, including 505 deaths of all causes and 505 matched controls. The median follow‐up duration was 4.5 years. The primary outcome measure in this investigation was all‐cause mortality, which encompassed deaths for any reason. The mean plasma vitamin B5 concentration for cases (43.7 ng/mL) was higher than that in controls (40.9 ng/mL) (p = .001). When vitamin B5 was further assessed as quintiles, compared with the reference group (Q1:

Abstract Manganese (Mn) is an essential trace metal element that is associated with diabetes; however, the results of previous studies are inconsistent. Furthermore, few studies have been conducted in a hypertensive population. The purpose of this study is to explore the relationship between manganese and diabetes in a population with hypertension. A cross‐sectional study was conducted, including 2575 hypertensive individuals from 14 provinces in China. Serum manganese concentrations were measured by the inductively coupled plasma mass spectrometry (ICP‐MS) method. And logistic regression models were used to analyze the association between serum manganese and the risk of diabetes. The prevalence of diabetes was 27.0% in this hypertensive population. In logistic regression models, the odds ratios (95% confidence interval) for diabetes in tertile subgroups were 1.40 (1.12, 1.76) and 1.32 (1.05, 1.65) for tertiles 1 and tertiles 3, respectively, compared to tertile 2 (reference). Additionally, an interaction between sex and manganese was observed. The odds ratios (95% confidence interval) for diabetes were 1.29 (0.95, 1.75) and 0.96 (0.70, 1.31) for tertiles 1 and tertiles 3 among males, and 1.44 (1.01, 2.04) and 1.81 (1.29, 2.55) for tertiles 1 and tertiles 3 among females, respectively, compared to tertile 2. In conclusion, a U‐shaped association between serum manganese and diabetes was observed in a Chinese population with hypertension, and the association was modified by sex.

Abstract Background and aims Clarifying the association between 5-methyltetrahydrofolate and homocysteine and the effect pattern of methylene tetrahydrofolate reductase (MTHFR C677T) may contribute to the management of homocysteine and may serve as a significant reference for a randomized controlled trial of 5-methyltetrahydrofolate intervention. This study aimed to reveal the association between these two biochemical indices. Methods Study population was drawn from the baseline data of the China Stroke Primary Prevention Trial (CSPPT), including 2328 hypertensive participants. 5-methyltetrahydrofolate and homocysteine were determined by stable-isotope dilution liquid chromatography-tandem mass spectrometry and automatic clinical analyzers, respectively. MTHFR C677T polymorphisms were detected using TaqMan assay. Multiple linear regression was performed to evaluate the association between serum 5-methyltetrahydrofolate and homocysteine. Results There was a significant inverse association between 5-methyltetrahydrofolate and homocysteine when 5-methyltetrahydrofolate was ≤ 10 ng/mL, and this association was modified by MTHFR C677T (per 1-ng/mL increment; All: β = − 0.50, P

Abstract Background Serum choline levels were associated with multiple chronic diseases. However, the association between serum choline and all-cause mortality in Chinese adults with hypertension remains unclear. The purpose of this study is to explore the association between serum choline concentrations and all-cause mortality risk in Chinese adults with hypertension, a high-risk population. Methods A nested, case–control study was conducted that included 279 patients with all-cause death, and 279 matched, living controls, derived from the China Stroke Primary Prevention Trial (CSPPT). Baseline serum choline concentrations were measured by liquid chromatography with tandem quadrupole mass spectrometry (LC–MS/MS). Multivariate logistic regression analysis was used to assess the association of serum choline levels and all-cause mortality risk, with adjustment of pertinent covariables, including folic acid and homocysteine. Results The median age of all participants was 64.13 years [interquartile range (IQR), 57.33–70.59 years]. The median serum choline concentration for cases (9.51 μg/mL) was higher than that in controls (7.80 μg/mL) (P = 0.009). When serum choline concentration was assessed as a continuous variable (per SD increased), there was a positive relation between serum choline levels and all-cause mortality risk [odds ratios (OR), 1.29; 95% confidence intervals (95%CI), 1.06–1.57; P = 0.010]. There was an increased all-cause mortality risk for participants in quartiles 2–4 (≥ 4.00 μg/mL; OR, 1.79; 95%CI, 1.15–2.78 compared with quartile 1 (

BackgroundFrailty and diabetes are two important health problems associated with aging in older individuals. This paper seeks to analyze the frailty in older adults suffering from diabetes and the combined effect of diabetes and frailty on mortality risk.MethodsThe frailty index (FI) model was employed when evaluating frailty among the older adults based on the baseline data conducted in 2009; and death as outcome variables collected in 2020 were analyzed. The influence of diabetes on age-related changes in frailty in the older adults and resulting mortality rates was analyzed. Cox regression and Kaplan-Meier curves were applied to evaluate the influence on the risk of death and the 11-year survival of the older adults with varying diabetes and frailty statuses.ResultsUltimately, 1,213 older people aged between 60 and 101, with an average age of (74.79 ± 8.58) at baseline, were included in the analysis. By 2020, there had been 447 deaths with mortality at 36.9% (447/1,213); there were 271 cases of diabetes, with a prevalence of 22.3% (271/1,213). The mean FI value for older adults with diabetes was higher than that of those without regardless of age, and the average annual relative growth rate of the FI value for older adults with diabetes was higher than that of those without diabetes (β = 0.039 vs. β = 0.035, t = 8.367, P < 0.001). For all FI value levels, the mortality rate among older adults with diabetes was higher than that of those without. The Cox Regression analysis showed that, compared with those suffering from neither diabetes nor frailty, older adults with both had the higher mortality risk (HR = 1.760. P < 0.001), followed by older adults suffering from frailty alone (HR = 1.594, P = 0.006), and then by older adults suffering from only diabetes (HR = 1.475, P = 0.033). The survival analysis showed that the median survival of those suffering from diabetes and frailty to be the shortest at just 57.23 (95% CI: 54.05 to 60.41) months, lower than the 83.78 (95% CI: 79.33 to 88.23) months in those suffering from frailty alone, and 119.93 (95% CI: 113.84 to 126.02) months in those with only diabetes, and 124.39 (95% CI: 119.76 to 129.02) months in older adults with neither diabetes nor frailty (P < 0.001).ConclusionFrailty is common among older adults suffering from diabetes, and there is an increased risk of poor health outcomes, such as death, among older adults suffering from diabetes and frailty. When diagnosing, treating, and dealing with older adults with diabetes, attention should be paid to screening and assessing frailty in hopes of identifying it early so that appropriate measures of intervention can be taken to avoid or delay the resulting adverse effects.

The interaction between electrospinning nanomaterials and stem cells to repair damaged tissue mainly focus on manipulating cell viability, proliferation, or paracrine by the materials and their specific topology. In particular, the paracrine products of stem cells influence the behavior of those repairable cells (i.e., epidermal cells, fibroblasts, and endothelial cells) to speed up the repair progress. In this study, a series of nanofiber-based meshes were fabricated by electrospinning and light-welding technology to investigate their impacts on the paracrine behaviors of adipose stem cells (ADSCs) and their performance in accelerating wound healing. We found that the nanofiber-based meshes with varied grid sizes and modified with gelatin nanofibers could regulate the paracrine of ADSCs. As a result, the migration of fibroblasts and endothelial cells as well as angiogenesis was all influenced in vitro. In vivo investigation using rat skin wound healing models also indicated that the nanofiber-based meshes could accelerate wound healing rate, increase the thickness of the regenerated epidermis, and promote type I collagen production and CD31-positive vessel formation in the dermis layer. Taken together, such nanofiber-based meshes provide effective and promising alternatives to design tissue-repair scaffolds involving manipulating stem cell paracrine and wound closure.

Due to their limitations, conventional electric and water film dust removal methods struggle to handle fine dust. This study presented information on and examined the electrostatic water film cyclone dust collector (EWFCDC). By using the variable control approach, the impacts of inlet flow speed, water film flow rate, and corona pole form on dust removal performance were investigated. At EWFCDC, an orthogonal test was carried out to improve the test design and operating parameters based on the single-factor experiment. The pressure loss in the cyclone cylinder, when there is no water film and no corona pole, is a quadratic function of the inlet flow speed, and it is 2418.10 Pa at a 21.25 m/s inlet flow speed. The effectiveness of dust removal may be increased by increasing the water film flow rate. The effectiveness of dust removal is greatly influenced by the type of corona pole used, and cage needling thread is the optimal type. The electrostatic water film cyclone’s multimechanism coupling significantly increases the effectiveness of dust removal.

The outer blood–retina barrier (oBRB), comprises tightly connected retinal pigment epithelium (RPE) cells, Bruch’s membrane, and choroid blood vessels, and is essential for retinal health and normal visual function. Disruption of the RPE barrier and its dysfunction can lead to retinal disorders such as age-related macular degeneration (AMD). In the present study, we investigated the essential role of choroid endothelial cells (ECs) in the RPE barrier formation process and its dysfunction. We discovered that ECs promoted RPE barrier formation through angiocrine signaling. Through blocking or activating endothelial Notch signaling and conducting experiments in vitro and in vivo, we confirmed that endothelial Notch signaling regulated the expression of heparin-binding epidermal growth factor (HBEGF) and consequently impacted the expression and activity of matrix metalloproteinases (MMP)-9 in RPE cells. This modulation influenced the RPE extracellular matrix deposition, tight junctions and RPE barrier function. In in vivo experiments, the intravitreal administration of recombinant HBEGF (r-HBEGF) alleviated the RPE barrier disruption induced by subretinal injection (SI) or laser treatment and also rescued RPE barrier disruption in endothelial Notch-deficient mice. Our results showed that the endothelial Notch signaling drove HBEGF expression through angiocrine signaling and effectively improved RPE barrier function by regulating the MMP-9 expression in RPE cells. It suggests that the modulation of Notch signaling in the choroidal endothelium may offer a novel therapeutic strategy for retinal degenerative diseases.

This paper proposes a distributed coordination scheme for connected vehicles, including automated vehicles (AVs) and manual vehicles (MVs), at signal-free intersections. The cooperation issue of vehicles at an intersection is formulated into a multi-objective optimization problem that aims to eliminate conflicts and improve traffic mobility and fuel economy. For this purpose, the future trajectories of AVs and MVs are predicted by the respective car-following models, and are shared with neighboring vehicles in conflict relationships. The proposed scheme optimizes the sum of the performance of AVs within the cooperative zone in a prediction horizon. A distributed optimization algorithm in the receding horizon is presented to obtain the local optimal solutions, and is tested in simulations with different demand levels and penetration rates of AVs. The results show that the proposed scheme reduces travel time by 29.7–45.5% and 34.5–49.2%, and decreases fuel consumption by 27.6–35.3% and 21.6–29.9% under 70–100% penetration rates of AVs, compared to the no-control operation and fixed-time signal control strategy. In addition, a comparison simulation with the strategy of jointly optimizing the vehicle trajectory and signal timing is conducted to evaluate the relative merits of the proposed scheme.

Abstract Composite rocks are easily encountered in a wide range of geotechnical construction projects. Understanding their mechanical properties and failure modes is very important to ensure project quality and safety. This study conducted a mechanical analysis to assess the stress distribution in composite rock with a horizontal interlayer and predicted the possible failure modes. Uniaxial compression tests were carried out on the composite rock samples to reveal their mechanical properties. It was concluded that a composite rock with a thick interlayer failed more easily than a composite rock with a thin interlayer. Four potential failure modes were related to the internal stress distribution under compression and the differences in deformation capacity and strength among the constituent components. The stress distribution derived from the mechanical analysis could explain the failure mechanism very well. These results verified the validity of the mechanical analysis results and improved understanding of the mechanical properties of composite rock with a horizontal interlayer.

BackgroundThe prospective association between plasma Se and stroke risk remains inconclusive. The relationship between Se and ischemic stroke among a low circulating Se status population deserves more attention, especially for Chinese people who were a high-risk group for Se deficiency.ObjectiveThe relationship between plasma Se concentration and ischemic stroke risk in a large-scale Chinese community-based population and any potential effect modifiers were investigated.MethodsA nested, case-control study, using data from the “China H-type Hypertension Registry Study” were conducted. A total of 1,904 first ischemic stroke cases and 1,904 controls matched for age, sex, and village were included in this study. The association between plasma Se and first ischemic stroke was evaluated by conditional logistic regression analyses.ResultsThe median value of plasma Se was 65.8 μg/L among total participants. Overall, a significant inverse relationship between plasma Se and first ischemic stroke risk was found (per SD increment; adjusted OR: 0.87; 95% CI: 0.80 and 0.95). Accordingly, a significantly lower risk of first ischemic stroke was found in participants in quartile 3 (65.8−

OTUD6A is a deubiquitinase that plays crucial roles in various human diseases. However, the precise regulatory mechanism of OTUD6A remains unclear. In this study, we found that OTUD6A significantly inhibited the production of type I interferon. Consistently, peritoneal macrophages and bone marrow-derived macrophages from Otud6a−/− mice produced more type I interferon after virus infection compared to cells from WT mice. Otud6a−/−− mice also exhibited increased resistance to lethal HSV-1 and VSV infections, as well as LPS attacks due to decreased inflammatory responses. Mechanistically, mass spectrometry results revealed that UBC13 was an OTUD6A-interacting protein, and the interaction was significantly enhanced after HSV-1 stimulation. Taken together, our findings suggest that OTUD6A plays a crucial role in the innate immune response and may serve as a potential therapeutic target for infectious disease.

Abstract Background To date, there is no clearly defined association between plasma selenium levels and first stroke. We aimed to investigate the association between baseline plasma selenium and first stroke risk in a community-based Chinese population. Methods Using a nested case-control study design, a total of 1255 first stroke cases and 1255 matched controls were analyzed. Participant plasma selenium concentrations were measured by inductively coupled plasma mass spectrometry (ICP-MS), and the association of plasma selenium with first stroke risk was estimated by conditional logistic regression models. Results Overall, a non-linear negative association between plasma selenium and first total stroke and first ischemic stroke risks was found in males but not in females. Compared with participants with lower selenium levels (tertile 1–2, < 94.1 ng/mL), participants with higher selenium levels (tertile 3, ≥ 94.1 ng/mL) had significantly lower risks of first total stroke (OR 0.63; 95% CI 0.48, 0.83) and first ischemic stroke (OR 0.61; 95% CI 0.45, 0.83) in males but not in females with first total stroke (OR 0.92; 95% CI 0.69, 1.22) and first ischemic stroke (OR 0.89; 95% CI 0.65, 1.22). Furthermore, a stronger association between plasma selenium and first total stroke was found in males with higher vitamin E levels (≥ 13.5 μg/mL vs. < 13.5 μg/mL P-interaction = 0.007). No significant association was observed between plasma selenium and first hemorrhagic stroke risk in either males or females. Conclusion Our study indicated a significant, non-linear, negative association between plasma selenium and first stroke in males but not in females. Trial registration ChiCTR1800017274 .

Abstract Background According to the Global Burden of Disease Study 2017, smoking is one of the leading four risk factors contributing to deaths in China. We aimed to evaluate the associations of smoking with all-cause mortality in a Chinese rural population. Methods Male participants over age 45 (n = 5367) from a large familial aggregation study in rural China, were included in the current analyses. A total of 528 former smokers and 3849 current smokers accounted for 10 and 71.7% of the cohort, respectively. Generalized Estimating Equations were used to evaluate the association between baseline smoking status and mortality, adjusting for pertinent covariates. Results There were 579 recorded deaths during the 15-year follow-up. Current smokers (odds ratio [OR],1.60; 95% CI,1.23–2.08) had higher all-cause mortality risks than nonsmokers. Relative to nonsmokers, current smokers of more than 40 pack-years ([OR],1.85; 95% CI,1.33–2.56) had a higher all-cause mortality risk. Compared to nonsmokers, current smokers who started smoking before age 20 ([OR],1.91; 95% CI,1.43–2.54) had a higher all-cause mortality risk, and former smokers in the lower pack-year group who quit after age 41 (median) ([OR],3.19; 95% CI,1.83–5.56) also had a higher risk of death after adjustment. Furthermore, former smokers who were also former drinkers had the highest significant risk of mortality than never smokers or drinkers. (P for interaction = 0.034). Conclusions This study provides evidence that current smokers and former smokers have a higher mortality risk than nonsmokers and would benefit from cessation at a younger age.

Cryptococcosis is an opportunistic and potentially lethal infection caused by Cryptococcus neoformans and Cryptococcus gattii complex, which affects both immunocompromised and immunocompetent people, and it has become a major public health concern worldwide. In this study, we characterized the molecular epidemiology and antifungal susceptibility of 133 C. neoformans isolates from East China Invasive Fungal Infection Group (ECIFIG), 2017–2020. Isolates were identified to species level by matrix-assisted laser desorption ionization-time of flight mass spectrometry and confirmed by IGS1 sequencing. Whole-genome sequencing (WGS) was conducted on three multidrug-resistant isolates. Among the 133 strains, 61 (45.86%) were isolated from HIV-positive patients and 72 (54.16%) were isolated from HIV-negative patients. In total, C. neoformans var. grubii accounted for 97.74% (130/133), while C. neoformans var. neoformans was rare (2.06%, 3/133). The strains were further classified into nine sequence types (STs) dominated by ST5 (90.23%, 120/133) with low genetic diversity. No association was observed between STs and HIV status. All strains were wild type to voriconazole, while high antifungal minimal inhibitory concentrations (MICs) above the epidemiological cutoff values (ECVs) were observed in C. neoformans strains, and more than half of isolates were non-wild-type to amphotericin B (89.15%, 109/133). Eight isolates were resistant to fluconazole, and eight isolates were non-wild type to 5-fluorocytosine. Furthermore, WGS has verified the novel mutations of FUR1 in 5-fluorocytosine-resistant strains. In one isolate, aneuploidy of chromosome 1 with G484S mutation of ERG11 was observed, inducing high-level resistance (MIC: 32 μg/ml) to fluconazole. In general, our data showed that there was no significant difference between HIV-positive and HIV-negative patients on STs, and we elucidate the resistant mechanisms of C. neoformans from different perspectives. It is important for clinical therapy and drug usage in the future.

BackgroundSerine plays a key role in numerous cellular processes, the levels and metabolism is therefore of critical importance. However, few data are available to illustrate the association of serine with long-term health effects, especially, the predictive value for long-term mortality.ObjectiveThis study was conducted to evaluate the relationship between serum serine levels and all-cause mortality in general hypertensive patients in a longitudinal cohort, and to examine the potential effect modifiers.MethodsA nested case-control (NCC) study was conducted utilizing 20702 hypertensive participants from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, actively controlled trial conducted from May 2008 to August 2013 in China. The current study included 291 cases of all-cause mortality and 291 controls matched on age (≤ 1 year), sex and treatment group. All-cause mortality was the main outcome in this analysis, which included death due to any reason.ResultsWith the increase in serum serine levels, the risk of all-cause mortality first increased before flattening. After adjusting for related variables, the risk of mortality increased significantly with the increase of serum serine levels. Compared with group Q1, the mortality risk of group Q2, Q3 and Q4 were significantly increased [ORs, 95% CI: Q2: 2.32, (1.32–4.07); Q3: 2.59, (1.48–4.54); and Q4: 1.85, (1.07–3.22)]. In the exploratory analysis, we observed three effect modifiers, total homocysteine, 5-Methyltetrahydrofolate, and estimated glomerular filtration rate significantly modified the serum serine and all-cause mortality association.ConclusionSerum serine levels were significantly associated with an increased risk of all-cause mortality in hypertensive patients. Our results and findings, if confirmed further, suggest that serum serine should be considered as a marker for screening risk factors of mortality.Clinical Trial Registration[https://www.clinicaltrials.gov/ct2/show/study/NCT00794885.], identifier [CSPPT, NCT00794885].

ObjectiveThe relationship between plasma copper concentration and prevalence of diabetes in adults with hypertension is unclear. We aimed to determine the association between plasma copper concentration and prevalence of diabetes in Chinese adults with hypertension.MethodsA total of 2,579 participants (697 cases and 1,882 controls) was included in this cross-sectional study. Plasma copper concentrations were determined by inductively coupled plasma mass spectrometry. Multivariable logistic regression model was used to determine the association between plasma copper concentration and prevalence of diabetes.ResultsAccording to the logistic regression analyses, the adjusted OR for the prevalence of diabetes in participants with plasma copper concentration ≥109.4 μg/dL was 1.26 (1.00, 1.58) compared with those with plasma copper concentration

This study proposes a Task and Motion Planning (TAMP) method with symbolic decisions embedded in a bilevel optimization. This TAMP method exploits the discrete structure of sequential manipulation for long-horizon and versatile tasks in dynamic environments. At the symbolic planning level, we propose a scalable decision-making method for long-horizon manipulation tasks using the Planning Domain Definition Language (PDDL) with causal graph decomposition. At the motion planning level, we devise a trajectory optimization (TO) approach based on the Differential Dynamic Programming (DDP) and Alternating Direction Method of Multipliers (ADMM), suitable for solving constrained, large-scale nonlinear optimization in a distributed manner. Distinct from conventional geometric motion planners, our approach generates highly dynamic manipulation motions by incorporating the full robot and object dynamics. Furthermore, in lieu of a hierarchical planning approach, we solve a holistically integrated bilevel optimization problem involving costs from both the low-level TO and the high-level search. Simulation and experimental results demonstrate dynamic manipulation for long-horizon object sorting tasks in clutter and on a moving conveyor belt.

BackgroundVitamin K plays a role in preventing vascular calcification and may have a synergetic influence with vitamin D on cardiovascular health. However, whether this relationship applies to stroke, especially in a high-risk population of hypertensive individuals, remains unclear. The present study aims to study the joint association of low vitamin K1 and D status with first stroke in general hypertensive adults.MethodsThis study used a nested, case–control design with data from the China Stroke Primary Prevention Trial. The analysis included 604 first total stroke patients and 604 matched controls from a Chinese population with hypertension. Odds ratios (ORs) and 95% confidence intervals were calculated using conditional logistic regression.ResultsThere was a non-linear negative association between plasma vitamin K1 and the risk of first total stroke or ischemic stroke in the enalapril-only group. Compared to participants in vitamin K1 quartile 1, a significantly lower risk of total stroke (OR = 0.58, 95% CI: 0.36, 0.91, P = 0.020) or ischemic stroke (OR = 0.34, 95% CI: 0.17, 0.63, P < 0.001) was found in participants in vitamin K1 quartile 2-4 in the enalapril-only group. When further divided into four subgroups by 25(OH)D and vitamin K1, a significantly higher risk of total stroke or ischemic stroke was observed in participants with both low vitamin K1 and 25(OH)D compared to those with both high vitamin K1 and 25(OH)D in the enalapril-only group. No increased risk was observed in the groups low in one vitamin only.ConclusionLow concentrations of both vitamin K1 and 25(OH)D were associated with increased risk of stroke.

BackgroundStroke is a major global health burden, and risk prediction is essential for the primary prevention of stroke. However, uncertainty remains about the optimal prediction model for analyzing stroke risk. In this study, we aim to determine the most effective stroke prediction method in a Chinese hypertensive population using machine learning and establish a general methodological pipeline for future analysis.MethodsThe training set included 70% of data (n = 14,491) from the China Stroke Primary Prevention Trial (CSPPT). Internal validation was processed with the rest 30% of CSPPT data (n = 6,211), and external validation was conducted using a nested case–control (NCC) dataset (n = 2,568). The primary outcome was the first stroke. Four received analysis methods were processed and compared: logistic regression (LR), stepwise logistic regression (SLR), extreme gradient boosting (XGBoost), and random forest (RF). Population characteristic data with inclusion and exclusion of laboratory variables were separately analyzed. Accuracy, sensitivity, specificity, kappa, and area under receiver operating characteristic curves (AUCs) were used to make model assessments with AUCs the top concern. Data balancing techniques, including random under-sampling (RUS) and synthetic minority over-sampling technique (SMOTE), were applied to process this unbalanced training set.ResultsThe best model performance was observed in RUS-applied RF model with laboratory variables. Compared with null models (sensitivity = 0, specificity = 100, and mean AUCs = 0.643), data balancing techniques improved overall performance with RUS, demonstrating a more satisfactory effect in the current study (RUS: sensitivity = 63.9; specificity = 53.7; and mean AUCs = 0.624. Adding laboratory variables improved the performance of analysis methods. All results were reconfirmed in validation sets. The top 10 important variables were determined by the analysis method with the best performance.ConclusionAmong the tested methods, the most effective stroke prediction model in targeted population is RUS-applied RF. From the insights, the current study revealed, we provided general frameworks for building machine learning-based prediction models.

Selenium (Se) is an essential trace element in selenoproteins biosynthesis for the human body and plays an important role in the prevention and control of subsequent cardiovascular disease in adults with hypertension. However, reports on Se status and its potential determinants in populations from different regions of China are limited, especially data on adults with hypertension, a high-risk group more vulnerable to oxidative stress. Thus, we conducted a cross-sectional study from February 2017 to May 2018 of 2,599 participants (1,389 men and 1,210 women) on middle-aged to elderly adults with hypertension with a mean age of 63.1 years (SD 13.3) from 14 provinces of China and aimed to examine the relationship of plasma Se status with demographic characteristics and lifestyles. Overall, the male participants (mean value 75.0 μg/L) tended to have higher plasma Se concentrations than the female participants (73.7 μg/L) when controlling for relevant factors. There were significant differences among regions, and in age and body mass index (BMI) in plasma Se distribution, and plasma Se concentrations were significantly lower among those in the regions with relatively lower Se, aged 60 years or older, and with BMI lower than 28 kg/m2. Moreover, a higher frequency of meat consumption (1–2 or ≥3 times/week vs.

It is important for chatbots to emotionally communicate with users. However, most emotional response generation models generate responses simply based on a specified emotion, neglecting the impacts of speaker’s personality on emotional expression. In this work, we propose a novel model named GERP to generate emotional responses based on the pre-defined personality. GERP simulates the emotion conversion process of humans during the conversation to make the chatbot more anthropomorphic. GERP adopts the OCEAN model to precisely define the chatbot’s personality. It can generate the response containing the emotion predicted based on the personality. Specifically, to select the most-appropriate response, a proposed beam evaluator was integrated into GERP. A Chinese sentiment vocabulary and a Chinese emotional response dataset were constructed to facilitate the emotional response generation task. The effectiveness and superiority of the proposed model over five baseline models was verified by the experiments.

The Prototheca alga is the only chlorophyte known to be involved in a series of clinically relevant opportunistic infections in humans and animals, namely, protothecosis. Most pathogenic cases in humans are caused by Prototheca wickerhamii. In order to investigate the evolution of Prototheca and the genetic basis for its pathogenicity, the genomes of two P. wickerhamii strains S1 and S931 were sequenced using Nanopore long-read and Illumina short-read technologies. The mitochondrial, plastid, and nuclear genomes were assembled and annotated including a transcriptomic data set. The assembled nuclear genome size was 17.57 Mb with 19 contigs and 17.45 Mb with 26 contigs for strains S1 and S931, respectively. The number of predicted protein-coding genes was approximately 5,700, and more than 96% of the genes could be annotated with a gene function. A total of 2,798 gene families were shared between the five currently available Prototheca genomes. According to the phylogenetic analysis, the genus of Prototheca was classified in the same clade with A. protothecoides and diverged from Chlorella ~500 million years ago (Mya). A total of 134 expanded genes were enriched in several pathways, mostly in metabolic pathways, followed by biosynthesis of secondary metabolites and RNA transport. Comparative analysis demonstrated more than 96% consistency between the two herein sequenced strains. At present, due to the lack of sufficient understanding of the Prototheca biology and pathogenicity, the diagnosis rate of protothecosis is much lower than the actual infection rate. This study provides an in-depth insight into the genome sequences of two strains of P. wickerhamii isolated from the clinic to contribute to the basic understanding of this alga and explore future prevention and treatment strategies.

BackgroundPrevious studies have shown an association of stroke and brachial ankle pulse wave velocity (baPWV). However, due to limitations on total population size and small numbers of stroke cases, lack of power has prevented further detection among subgroups such as age and laboratory testing.MethodsA total of 19217 participants including 660 incident stroke patients were pooled in the present study. Participants were divided to 2 groups, aged less than 65 years [56.0 (50.0, 61.0)] and aged 65 years or more [70.0 (67.0, 74.0)].ResultsAfter adjustment for demographic, anthropometric, and laboratory parameters, the incident stroke was positively associated to baPWV in the group aged less than 65 years (OR, 1.16; 95% CI, 1.05–1.28), but not in the older group aged 65 or more. When baPWV was assigned as quartiles, a significant, increased risk of new-onset stroke was found in quartiles 3-4 compared with quartile 1. In addition, the predictive value of baPWV for incident stroke was modified by fasting glucose in participants aged less than 65 years (P-interaction = 0.010). An increase in baPWV was strongly, positively associated to new-onset stroke in the subgroup of normal fasting glucose (< 5.6 mmol/L) (OR, 1.34; 95% CI, 1.15 - 1.57), but no effect was seen in the impaired fasting glucose (5.6-7.0 mmol/L) or diabetic fasting glucose (> 7.0 mmol/L) subgroups.ConclusionsIncreased baPWV was significantly associated with new-onset stroke in a hypertensive population aged less than 65 years. Particularly, it is of great importance to monitor baPWV for predicting incident stroke in “relatively healthy” hypertensive patients, i.e. aged less than 65 years with normal fasting glucose.