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Background: In China, as people's standard of living improves and the medical service system becomes more sophisticated, the demand for higher-quality and improved healthcare services is steadily rising. Inequality in health resource allocation (HRA) is more pronounced in ethnic minority areas (EMAs) than in developed regions. However, little research exists on high-quality medical resources (HQMRs) in China's EMAs. Hence, we examined the spatiotemporal dynamic evolution of HQMRs in China's EMAs from 2007 to 2021 and identified the main factors affecting their respective HQMR levels., Methods: We selected tertiary hospitals to represent the quality of healthcare resources. We employed descriptive statistical techniques to analyze changes in the distribution of HQMRs from 2007 to 2021. We used the Dagum Gini coefficient and kernel density approach to analyze the dynamic evolution of HQMRs in China's EMAs. We utilized the least squares dummy variable coefficient (LSDVC) to identify key factors affecting HQMR., Results: The number of HQMRs in each EMA has risen annually. The average number of tertiary hospitals increased from 175 in 2007 to 488 in 2021. The results of the Dagum Gini coefficient revealed that the differences in the HQMR level in China's EMAs have slowly declined, and intra-regional disparities have now become the primary determining factor influencing overall variations. The kernel density plot indicated that the HQMR level improved significantly during the study period, but bifurcation became increasingly severe. Using the LSDVC for analysis, we found that gross domestic product (GDP) per capita , the size of the resident population, and the number of students enrolled in general higher education exhibited a significant negative correlation with HQMR levels, while GDP and urbanization rate had a significant promoting effect., Conclusion: The HQMR level in EMAs has risen rapidly but remains inadequate. The differences in HQMR between regions have continued to narrow, but serious bifurcation has occurred. Policymakers should consider economic growth, education, and population size rather than simply increasing the number of HQMRs everywhere., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liang, Huang, Chen, Hao and Li.)

Down syndrome (DS), caused by an additional chromosome 21, has a high risk of congenital heart defects (CHD), one of the primary causes of mortality in DS newborns. To elucidate the pathogenetic mechanisms underlying this condition, we explored the role of RNA m6A methylation, regulated by METTL3, in DS cardiac development and its impact on the expression of SH3BGR, a gene located at Down syndrome congenital heart disease (DS-CHD) minimal region. We analyzed DS fetal cardiac tissues to assess RNA m6A methylation levels and identify potential contributors. RNA sequencing was performed to detect differentially expressed genes in the same tissues. To further understand METTL3's function in heart development, we inactivated Mettl3 in the developing mouse heart to mimic the significantly reduced METTL3 observed in DS cardiac development. Additionally, human cardiomyocyte AC16 cells were used to investigate the molecular mechanism by which METTL3 regulates SH3BGR expression. Apoptosis was analyzed to evaluate METTL3's effect on heart development through SH3BGR regulation. Reduced m6A modification and decreased METTL3 expression were observed in human DS fetal hearts, along with a significant increase of SH3BGR expression. METTL3, through m6A modification, was found to regulate SH3BGR expression, by influencing mRNA stability. METTL3-deficient mouse embryos exhibited heart malformation with increased apoptosis, emphasizing its role in heart development. In DS hearts, METTL3 downregulation and SH3BGR upregulation, potentially orchestrated by abnormal m6A modification, contribute to gene dysregulation and apoptosis. This study reveals novel insights into DS cardiac pathology, highlighting the intricate role of METTL3 in DS congenital heart defects and presenting the m6A modification of SH3BGR as a potential therapeutic target., (© 2024. The Author(s).)

Background: KIDINS220 encodes a transmembrane scaffold protein, kinase D-interacting substrate of 220 kDa, that regulates neurotrophin signaling. Variants in KIDINS220 have been linked to spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome or prenatal fatal cerebral ventriculomegaly and arthrogryposis (VENARG). This study aimed to investigate the genotype-phenotype correlation of pathogenic KIDINS220 variants., Methods: We performed whole-exome sequencing on a patient with SINO syndrome and epilepsy. Identified pathogenic variants were confirmed using Sanger sequencing and evaluated with in silico tools. A comprehensive literature review was conducted to analyze the genetic and phenotypic data of both the newly diagnosed patient and previously reported cases with KIDINS220 variants., Results: We identified novel compound heterozygous variants in KIDINS220 , c.1556C > T (p.Thr519Met) and c.2374C > T (p.Arg792*), in the patient. Our analysis revealed that biallelic loss-of-function variants in KIDINS220 are associated with VENARG or autosomal recessive SINO (AR-SINO), whereas carboxy-terminal truncated variants that escape nonsense-mediated mRNA decay and lack amino acid residues 1507-1529 are linked to autosomal dominant SINO (AD-SINO). Patients with AR-SINO exhibit more severe clinical features compared to those with AD-SINO., Conclusions: Our study expands the spectrum of KIDINS220 variants associated with AR-SINO and provides a valuable genotype-phenotype correlation for pathogenic KIDINS220 variants., Competing Interests: The authors declare that they have no competing interests to declare., (© 2024 The Authors.)

Flexible zinc-air batteries are leading power sources for next-generation smart wearable electronics. However, flexible zinc-air batteries suffer from the highly-corrosive safety risk and limited lifespan due to the absence of reliable solid-state electrolytes (SSEs). Herein, a single-anion conductive SSE with high-safety is constructed by incorporating a highly amorphous dual-cation ionomer into a robust hybrid matrix of functional carbon nanotubes and polyacrylamide polymer. The as-fabricated SSE obtains dual-penetrating ionomer-polymer networks and hierarchical ionic highways, which contribute to mechanical robustness with 1200 % stretchability, decent water uptake and retention, and superhigh ion conductivity of 245 mS ⋅ cm -1 and good Zn anode reversibility. Remarkably, the flexible solid-state zinc-air batteries delivers a high specific capacity of 764 mAh ⋅ g -1 and peak power density of 152 mW ⋅ cm -2 as well as sustains excellent cycling stability for 1050 cycles (350 hours). This work offers a new paradigm of OH - conductors and broadens the definition and scope of OH - conductors., (© 2024 Wiley-VCH GmbH.)

Glioblastoma (GBM) is the most common malignant brain tumor and has the poorest prognosis attributed to its chemoresistance to temozolomide (TMZ), the first-line drug for treating GBM. TMZ resistance represents a significant obstacle to successful GBM treatment, necessitating the development of new strategies to overcome this resistance and augment the chemosensitivity of GBM cells to TMZ. This study established a TMZ-resistant U251 (U251-TMZ) cell line by exposing it to increasing doses of TMZ in vitro. We focused on the DNA methyltransferase 3B (DNMT3B) gene, phosphorylated Akt (p-Akt), total Akt (t-Akt), phosphorylated PI3K (p-PI3K), and total PI3K (t-PI3K) protein expression. Results showed that the DNMT3B gene was significantly upregulated in the U251-TMZ cell line. The p-Akt and p-PI3K protein expression in U251-TMZ cells was also significantly elevated. Moreover, we found that DNMT3B downregulation was correlated with the increased chemosensitivity of GBM cells to TMZ. LY294002 suppressed the PI3K/Akt signaling pathway, leading to a notable inhibition of PI3K phosphorylation and a significant decrease in DNMT3B expression in U251-TMZ cells. Given that DNMT3B expression is mediated by the PI3K/Akt signaling pathway, its downregulation further increased the chemosensitivity of GBM cells to TMZ and therefore is a promising therapeutic for GBM treatment. Our results suggested that DNMT3B downregulation can inhibit the proliferation of GBM cells and induce GBM cell apoptosis in vitro. In addition, the PI3K/Akt signaling pathway plays an important role in the chemosensitivity of GBM cells to TMZ by regulating DNMT3B expression., (© 2024. The Author(s).)

The glycoprotein GP64 of alphabaculovirus is crucial for viral entry and fusion. Here, we investigated the N-glycosylation patterns of Bombyx mori nucleopolyhedrovirus (BmNPV) GP64 and its signal peptide (SP) cleaved form, SP Δn GP64, along with their impacts on viral infectivity and fusogenicity. Through deglycosylation assays, we confirmed N-glycosylation of BmNPV GP64 on multiple sites. Mutational analysis targeting predicted N-glycosylation sites revealed diverse effects on viral infectivity and cell fusion. Particularly noteworthy were mutations at sites 175, which resulted in complete loss of infectivity and fusion capacity. Furthermore, LC-MS/MS analysis uncovered unexpected non-classical N-glycosylation sites, including N252, N302, N367, and N471, with only N302 and N471 identified in SP Δn GP64. Subsequent investigation highlighted the critical roles of these residues in BmNPV amplification and fusion, underscoring the essentiality of N367 glycosylation for GP64 fusogenicity. Our findings provide valuable insights into the non-classical glycosylation landscape of BmNPV GP64 and its functional significance in viral biology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The rapid expansion of the biomedical literature challenges traditional review methods, especially during outbreaks of emerging infectious diseases when quick action is critical. Our study aims to explore the potential of ChatGPT to automate the biomedical literature review for rapid drug discovery., Materials and Methods: We introduce a novel automated pipeline helping to identify drugs for a given virus in response to a potential future global health threat. Our approach can be used to select PubMed articles identifying a drug target for the given virus. We tested our approach on two known pathogens: SARS-CoV-2, where the literature is vast, and Nipah, where the literature is sparse. Specifically, a panel of three experts reviewed a set of PubMed articles and labeled them as either describing a drug target for the given virus or not. The same task was given to the automated pipeline and its performance was based on whether it labeled the articles similarly to the human experts. We applied a number of prompt engineering techniques to improve the performance of ChatGPT., Results: Our best configuration used GPT-4 by OpenAI and achieved an out-of-sample validation performance with accuracy/F1-score/sensitivity/specificity of 92.87%/88.43%/83.38%/97.82% for SARS-CoV-2 and 87.40%/73.90%/74.72%/91.36% for Nipah., Conclusion: These results highlight the utility of ChatGPT in drug discovery and development and reveal their potential to enable rapid drug target identification during a pandemic-level health emergency., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To develop an Artificial Intelligence (AI)-based anomaly detection model as a complement of an "astute physician" in detecting novel disease cases in a hospital and preventing emerging outbreaks., Methods: Data included hospitalized patients (n = 120,714) at a safety-net hospital in Massachusetts. A novel Generative Pre-trained Transformer (GPT)-based clinical anomaly detection system was designed and further trained using Empirical Risk Minimization (ERM), which can model a hospitalized patient's Electronic Health Records (EHR) and detect atypical patients. Methods and performance metrics, similar to the ones behind the recent Large Language Models (LLMs), were leveraged to capture the dynamic evolution of the patient's clinical variables and compute an Out-Of-Distribution (OOD) anomaly score., Results: In a completely unsupervised setting, hospitalizations for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection could have been predicted by our GPT model at the beginning of the COVID-19 pandemic, with an Area Under the Receiver Operating Characteristic Curve (AUC) of 92.2 %, using 31 extracted clinical variables and a 3-day detection window. Our GPT achieves individual patient-level anomaly detection and mortality prediction AUC of 78.3 % and 94.7 %, outperforming traditional linear models by 6.6 % and 9 %, respectively. Different types of clinical trajectories of a SARS-CoV-2 infection are captured by our model to make interpretable detections, while a trend of over-pessimistic outcome prediction yields a more effective detection pathway. Furthermore, our comprehensive GPT model can potentially assist clinicians with forecasting patient clinical variables and developing personalized treatment plans., Conclusion: This study demonstrates that an emerging outbreak can be accurately detected within a hospital, by using a GPT to model patient EHR time sequences and labeling them as anomalous when actual outcomes are not supported by the model. Such a GPT is also a comprehensive model with the functionality of generating future patient clinical variables, which can potentially assist clinicians in developing personalized treatment plans., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An increasing number of studies have suggested that macrophages participate in sepsis-induced myocardial injury. Our study highlights the function and mechanism of the lncRNA Snhg14 in "M1" polarized macrophage-mediated myocardial cell damage. Lipopolysaccharide (LPS) was used to treat H9c2 cells to construct an in vitro myocardial injury model. M1 and M2 polarization of RAW264.7 cells were induced and the exosomes were obtained from the supernatant through ultracentrifugation. Moreover, cecal ligation and puncture (CLP) surgery was implemented to establish a mouse sepsis-induced myocardial injury model, and Snhg14 was knocked down with sh-Snhg14. The results showed that the conditioned medium (CM) and the exosomes (Exo) of M1 macrophages substantially augmented LPS-induced apoptosis and oxidative stress in myocardial cells. Notably, M1-CM and M1-Exo contributed to nearly 50 % of myocardial cell viability decline. Snhg14 was highly expressed in M1 macrophages and exosomes derived from M1-MΦ (M1-Exo). Snhg14 overexpression aggravated myocardial cell damage and increased 10 to 50 times expression of proinflammatory cytokines in MΦ. Snhg14 knockdown reversed M1-Exo-mediated myocardial cell damage and inhibited the production of proinflammatory cytokines (50 %-75 % decline) of MΦ. Moreover, Snhg14 targeted and inhibited miR-181a-5p expression. miR-181a-5p upregulation partly reversed Snhg4 overexpression-mediated myocardial cell damage and MΦ activation. In vivo , sh-Snhg14 dramatically ameliorated cardiac damage in septic mice by enhancing miR-181a-5p and inhibiting the HMGB1/NF-κB pathway. In conclusion, "M1" macrophage-derived exosomal Snhg14 aggravates myocardial cell damage by modulating the miR-181a-5p/HMGB1/NF-κB pathway., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

To investigate the effects of early administration of ciprofloxacin (CIP) on Xueshan chickens, in this study Xueshan chickens were measured for growth performance, tested for drug residues, evaluated for meat quality, and muscle metabolism changes were explored using a non-target metabolomics approach. Experimental findings revealed that early CIP use did not significantly impact the overall growth rate of Xueshan chickens ( p > 0.05). However, notable alterations in meat quality were observed: the CIP-treated group exhibited a significant decrease in muscle pH (pH 1 and pH 24 ) and a marked increase in drip loss and moisture content ( p > 0.05). No CIP residues were detected in muscle tissue. Untargeted metabolomics analyses unveiled significant alterations in the metabolic profile of market-age chickens following CIP treatment. Both functional enrichment and metabolic network analyses indicated significant effects on the ko01120 (microbial metabolism in diverse environments) and ko00350 (tyrosine metabolism) pathways, implying that CIP treatment may influence chicken meat quality by modulating microbial communities and amino acid metabolism. This study provides a crucial foundation for understanding the impact of antibiotics on meat quality and metabolism in poultry production, offering scientific insights for optimizing antibiotic-use strategies and safeguarding poultry product quality.

Aims: The utility of growth differentiation factor-15 (GDF-15) in predicting long-term adverse outcomes in heart failure (HF) patients is not well established. This study explored the relationship between GDF-15 levels and adverse outcomes in HF patients across various ejection fraction (EF) phenotypes associated with coronary heart disease (CHD) and evaluated the added prognostic value of incorporating GDF-15 into the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score-based model., Methods and Results: This single-centre cohort study included 823 HF patients, categorized into 230 (27.9%) reduced EF (HFrEF), 271 (32.9%) mid-range EF (HFmrEF), and 322 (39.1%) preserved EF (HFpEF) groups. The median age was 68.0 years (range: 56.0-77.0), and 245 (29.8%) were females. Compared with the HFrEF and HFmrEF groups, the HFpEF group had a higher GDF-15 concentration (P = 0.002) and a higher MAGGIC risk score (P < 0.001). We examined the associations between GDF-15 levels and the risks of all-cause mortality and HF rehospitalization using Cox regression models. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) metrics were employed to assess the incremental prognostic value. During the 9.4 year follow-up period, 425 patients died, and 484 were rehospitalized due to HF. Multivariate Cox regression analysis revealed that elevated GDF-15 levels were significantly associated with an increased risk of all-cause mortality [hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.20-1.54; P < 0.001] and HF rehospitalization (HR = 1.75, 95% CI: 1.57-1.95; P < 0.001) across all HF phenotypes. This association remained significant when GDF-15 was treated as a categorical variable (high GDF-15 group: all-cause death: HR = 1.73, 95% CI: 1.40-2.14; P < 0.001; HF rehospitalization: HR = 3.37, 95% CI: 2.73-4.15; P < 0.001). Inclusion of GDF-15 in the MAGGIC risk score-based model provided additional prognostic value for all HF patients (Δ C-index = 0.021, 95% CI: 0.002-0.041; IDI = 0.011, 95% CI: 0.001-0.025; continuous NRI = 0.489, 95% CI: 0.174-0.629) and HF rehospitalization (Δ C-index = 0.034, 95% CI: 0.005-0.063; IDI = 0.021, 95% CI: 0.007-0.032; continuous NRI = 0.307, 95% CI: 0.147-0.548), particularly in the HFpEF subgroup., Conclusions: GDF-15 is identified as an independent risk factor for adverse outcomes in HF patients across the entire EF spectrum in the context of CHD. Integrating GDF-15 into the MAGGIC risk score-based model enhances its prognostic capability for adverse outcomes in the general HF population. This incremental prognostic effect was observed specifically in the HFpEF subgroup and not in other subgroups., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Identification of individuals with mild cognitive impairment (MCI) who are at risk of developing Alzheimer's disease (AD) is crucial for early intervention and selection of clinical trials., Methods: We applied natural language processing techniques along with machine learning methods to develop a method for automated prediction of progression to AD within 6 years using speech. The study design was evaluated on the neuropsychological test interviews of n = 166 participants from the Framingham Heart Study, comprising 90 progressive MCI and 76 stable MCI cases., Results: Our best models, which used features generated from speech data, as well as age, sex, and education level, achieved an accuracy of 78.5% and a sensitivity of 81.1% to predict MCI-to-AD progression within 6 years., Discussion: The proposed method offers a fully automated procedure, providing an opportunity to develop an inexpensive, broadly accessible, and easy-to-administer screening tool for MCI-to-AD progression prediction, facilitating development of remote assessment., Highlights: Voice recordings from neuropsychological exams coupled with basic demographics can lead to strong predictive models of progression to dementia from mild cognitive impairment. The study leveraged AI methods for speech recognition and processed the resulting text using language models. The developed AI-powered pipeline can lead to fully automated assessment that could enable remote and cost-effective screening and prognosis for Alzehimer's disease., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We aimed to analyze the feasibility of endovascular treatment for brucellosis-related aorta-iliac artery pseudoaneurysm. We did a statistical analysis that among the 11 cases, the thoracic aorta was involved in 3 cases, the abdominal aorta was involved in 6 cases, and the iliac artery was involved in 2 cases. Five patients had a history of contact with cattle and sheep, 3 had a history of drinking raw milk, 10 patients had a fever before the operation, and 11 patients had positive serum agglutination test. Blood culture was positive in 2 patients. All patients were given anti-brucellosis treatment immediately after diagnosis. One died of aortic rupture 5 days after emergency endovascular gastrointestinal bleeding. Endovascular-covered stent implantation and active anti-brucellosis therapy were used to treat 10 patients. The follow-up period was 8 years without aortic complications or death for all patients. We think early diagnosis and a combination of anti-brucellosis drugs and endovascular therapy may be the first choice for treating the pseudoaneurysm caused by Brucella., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fearful, angry, and disgusted facial expressions are evolutionarily salient and convey different types of threat signals. However, it remains unclear whether these three expressions impact sensory perception and attention in the same way. The present ERP study investigated the temporal dynamics underlying the processing of different types of threatening faces and the impact of attentional resources employed during a perceptual load task. Participants were asked to judge the length of bars superimposed over faces presented in the center of the screen. A mass univariate statistical approach was used to analyze the EEG data. Behaviorally, task accuracy was significantly reduced following exposure to fearful faces relative to neutral distractors, independent of perceptual load. The ERP results revealed that the P1 amplitude over the right hemisphere was found to be enhanced for fearful relative to disgusted faces, reflecting the rapid and coarse detection of fearful cues. The N170 responses elicited by fearful, angry, and disgusted faces were larger than those elicited by neutral faces, suggesting the largely automatic and preferential processing of threats. Furthermore, the early posterior negativity (EPN) component yielded increased responses to fearful and angry faces, indicating prioritized attention to stimuli representing acute threats. Additionally, perceptual load exerted a pronounced influence on the EPN and late positive potential (LPP), with larger responses observed in the low perceptual load condition, indicating goal-directed cognitive processing. Overall, the early sensory processing of fearful, angry, and disgusted faces is characterized by differential sensitivity in capturing attention automatically, despite the importance of these facial signals for survival. Fearful faces produce a strong interference effect and are processed with higher priority than angry and disgusted ones., Competing Interests: Declaration of competing interest All authors declared that they had no conflict of interest concerning their authorship or the publication of this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development., (© 2024. The Author(s).)

Multicellularity was accompanied by the emergence of new classes of cell surface and secreted proteins. The nematode C. elegans is a favorable model to study cell surface interactomes, given its well-defined and stereotyped cell types and intercellular contacts. Here we report our C. elegans extracellular interactome dataset, the largest yet for an invertebrate. Most of these interactions were unknown, despite recent datasets for flies and humans, as our collection contains a larger selection of protein families. We uncover new interactions for all four major axon guidance pathways, including ectodomain interactions between three of the pathways. We demonstrate that a protein family known to maintain axon locations are secreted receptors for insulins. We reveal novel interactions of cystine-knot proteins with putative signaling receptors, which may extend the study of neurotrophins and growth-factor-mediated functions to nematodes. Finally, our dataset provides insights into human disease mechanisms and how extracellular interactions may help establish connectomes., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Since their discovery, the infinite-layer nickelates have been regarded as an appealing system for gaining deeper insights into high-temperature superconductivity (HTSC). However, the synthesis of superconducting samples has been proven to be challenging. Here, an ultrahigh vacuum (UHV) in situ ${\mathrm{\text{in situ}}}$ reduction method is developed using atomic hydrogen as a reducing agent and is applied in the lanthanum nickelate system. The reduction parameters, including the reduction temperature (T R ) and hydrogen pressure (P H ), are systematically explored. It is found that the reduction window for achieving superconducting transition is quite wide, reaching nearly 80°C in T R and three orders of magnitude in P H when the reduction time is set to 30 min. And there exists an optimal P H for achieving the highest T c if both T R and reduction time are fixed. More prominently, as confirmed by atomic force microscopy and scanning transmission electron microscopy, the atomically flat surface can be preserved during the in situ ${\mathrm{\text{in situ}}}$ reduction process, providing advantages over the ex situ ${\mathrm{\text{ex situ}}}$ CaH 2 method for surface-sensitive experiments., (© 2024 Wiley‐VCH GmbH.)

Objective: MicroRNAs (miRNAs) are endogenous non-coding RNAs that can play a role in the post-transcriptional regulation of mammalian preadipocyte differentiation. However, the precise functional mechanism of its regulation of fat metabolism is not fully understood., Methods: We identified bta-miR-365-3p, which specifically targets the 3' untranslated region (3'UTR) of the FK506-binding protein 5 (FKBP5), and verified its mechanisms for regulating expression and involvement in adipogenesis., Results: In this study, we found that the overexpression of bta-miR-365-3p significantly decreased the lipid accumulation and triglyceride content in the adipocytes. Compared to inhibiting bta-miR-36 5-3p group, overexpression of bta-miR-365-3p can inhibit the expression of adipocyte differentiation-related genes C/EBPα and PPARγ. The dualluciferase reporter system further validated the targeting relationship between bta-miR-365-3p and FKBP5. FKBP5 mRNA and protein expression were detected by quantitative real-time polymerase chain reaction and Western blot. Overexpression of bta-miR-365-3p significantly down-regulated FKBP5 expression, while inhibition of bta-miR-365-3p showed the opposite, indicating that bta-miR-365-3p negatively regulates FKBP5. Adenosine 5'-monophosphate (AMP)-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway is closely related to the regulation of cell growth and is involved in the development of bovine adipocytes. In this study, overexpression of bta-miR-365-3p significantly inhibited mRNA and protein expression of AMPK, mTOR, and SREBP1 genes, while the inhibition of bta-miR-365-3p expression was contrary to these results. Overexpression of FKBP5 significantly upregulated AMPK, mTOR, and SREBP1 gene expression, while inhibition of FKBP5 expression was contrary to the above experimental results., Conclusion: In conclusion, these results indicate that bta-miR-365-3p may be involved in the AMPK/mTOR signaling pathway in regulating Yanbian yellow cattle preadipocytes differentiation by targeting the FKBP5 gene.

Many countries and commercial organizations have shown great interest in constructing a Martian base. In situ resource utilization (ISRU) provides a cost-effective way to achieve this ambitious goal. In this article, we proposed to use Martian soil simulant to produce a fiber to satisfy material requirement for the construction of Martian base. The composition, melting behavior, and fiber forming process of the soil simulant was studied, and continuous fiber with maximum strength of 1320 MPa and elastic modulus of 99 GPa was obtained on a spinning facility. The findings of this study demonstrate the feasibility of ISRU to prepare Martian fiber from the soil on the Mars, offering a new way to obtain key materials for the construction of a Martian base., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Untethered miniature soft robots have significant application potentials in biomedical and industrial fields due to their space accessibility and safe human interaction. However, the lack of selective and forceful actuation is still challenging in revolutionizing and unleashing their versatility. Here, we propose a focused ultrasound-controlled phase transition strategy for achieving millimeter-level spatially selective actuation and Newton-level force of soft robots, which harnesses ultrasound-induced heating to trigger the phase transition inside the robot, enabling powerful actuation through inflation. The millimeter-level spatial resolution empowers single robot to perform multiple tasks according to specific requirements. As a concept-of-demonstration, we designed soft robot for liquid cargo delivery and biopsy robot for tissue acquisition and patching. Additionally, an autonomous control system is integrated with ultrasound imaging to enable automatic acoustic field alignment and control. The proposed method advances the spatiotemporal response capability of untethered miniature soft robots, holding promise for broadening their versatility and adaptability., (© 2024. The Author(s).)

Cucurbitacin IIa is a triterpenoid isolated exclusively from Hemsleya plants and a non-steroidal anti-inflammatory drug that functions as the main ingredient of prescription Hemslecin capsules and tablets in China. Synthetic biology provides new strategies for production of such valuable cucurbitacins at a large scale; however, the biosynthetic pathway of cucurbitacin IIa has been unknown, and the heterologous production of cucurbitacins in galactose medium has been expensive and low yielding. In this study, we characterized the functions of genes encoding two squalene epoxidases (HcSE1-2), six oxidosqualene cyclases (HcOSC1-6), two CYP450s (HcCYP87D20 and HcCYP81Q59), and an acyltransferase (HcAT1) in cucurbitacin IIa biosynthesis by heterologous expression in Saccharomyces cerevisiae and Nicotiana benthamiana. We achieved high-level production of the key cucurbitacin precursor 11-carbonyl-20β-hydroxy-Cuol from glucose in yeast via modular engineering of the mevalonate pathway and optimization of P450 expression levels. The resulting yields of 46.41 mg/l 11-carbonyl-20β-hydroxy-Cuol and 126.47 mg/l total cucurbitacin triterpenoids in shake flasks are the highest yields yet reported from engineered microbes. Subsequently, production of 11-carbonyl-20β-hydroxy-Cuol by transient gene expression in tobacco resulted in yields of 1.28 mg/g dry weight in leaves. This work reveals the key genes involved in biosynthesis of prescription cucurbitacin IIa and demonstrates that engineered yeast cultivated with glucose can produce high yields of key triterpenoid intermediates. We describe a low-cost and highly efficient platform for rapid screening of candidate genes and high-yield production of pharmacological triterpenoids., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Cardiovascular disease (CVD) is closely associated with the triglyceride glucose (TyG) index and its related indicators, particularly its combination with obesity indices. However, there is limited research on the relationship between changes in TyG-related indices and CVD, as most studies have focused on baseline TyG-related indices., Methods: The data for this prospective cohort study were obtained from the China Health and Retirement Longitudinal Study. The exposures were changes in TyG-related indices and cumulative TyG-related indices from 2012 to 2015. The K-means algorithm was used to classify changes in each TyG-related index into four classes (Class 1 to Class 4). Multivariate logistic regressions were used to evaluate the associations between the changes in TyG-related indices and the incidence of CVD., Results: In total, 3243 participants were included in this study, of whom 1761 (54.4%) were female, with a mean age of 57.62 years at baseline. Over a 5-year follow-up, 637 (19.6%) participants developed CVD. Fully adjusted logistic regression analyses revealed significant positive associations between changes in TyG-related indices, cumulative TyG-related indices and the incidence of CVD. Among these changes in TyG-related indices, changes in TyG-waist circumference (WC) showed the strongest association with incident CVD. Compared to the participants in Class 1 of changes in TyG-WC, the odds ratio (OR) for participants in Class 2 was 1.41 (95% confidence interval (CI) 1.08-1.84), the OR for participants in Class 3 was 1.54 (95% CI 1.15-2.07), and the OR for participants in Class 4 was 1.94 (95% CI 1.34-2.80). Moreover, cumulative TyG-WC exhibited the strongest association with incident CVD among cumulative TyG-related indices. Compared to the participants in Quartile 1 of cumulative TyG-WC, the OR for participants in Quartile 2 was 1.33 (95% CI 1.00-1.76), the OR for participants in Quartile 3 was 1.46 (95% CI 1.09-1.96), and the OR for participants in Quartile 4 was 1.79 (95% CI 1.30-2.47)., Conclusions: Changes in TyG-related indices are independently associated with the risk of CVD. Changes in TyG-WC are expected to become more effective indicators for identifying individuals at a heightened risk of CVD., (© 2024. The Author(s).)

Freestanding single-crystalline SrTiO 3 membranes, as high-κ dielectrics, hold significant promise as the gate dielectric in two-dimensional (2D) flexible electronics. Nevertheless, the mechanical properties of the SrTiO 3 membranes, such as elasticity, remain a critical piece of the puzzle to adequately address the viability of their applications in flexible devices. Here, we report statistical analysis on plane-strain effective Young's modulus of large-area SrTiO 3 membranes (5 × 5 mm 2 ) over a series of thicknesses (from 6.5 to 32.2 nm), taking advantage of a highly efficient buckling-based method, which reveals its evident thickness-dependent behavior ranging from 46.01 to 227.17 GPa. Based on microscopic and theoretical results, we elucidate these thickness-dependent behaviors and statistical data deviation with a bilayer model, which consists of a surface layer and a bulk-like layer. The analytical results show that the ∼3.1 nm surface layer has a significant elastic softening compared to the bulk-like layer, while the extracted modulus of the bulk-like layer shows a variation of ∼40 GPa. This variation is considered as a combined contribution from oxygen deficiency presenting in SrTiO 3 membranes, and the alignment between applied strain and the crystal orientation. Upon comparison of the extracted elastic properties and electrostatic control capability to those of other typical gate dielectrics, the superior performance of single-crystalline SrTiO 3 membranes has been revealed in the context of flexible gate dielectrics, indicating the significant potential of their application in high-performance flexible 2D electronics.

The transcription factors of WRKY genes play essential roles in plant growth, stress responses, and metabolite biosynthesis. Erigeron breviscapus , a traditional Chinese herb, is abundant in flavonoids and has been used for centuries to treat cardiovascular and cerebrovascular diseases. However, the WRKY transcription factors that regulate flavonoid biosynthesis in E. breviscapus remain unknown. In this study, a total of 75 EbWRKY transcription factors were predicted through comprehensive genome-wide characterization of E. breviscapus and the chromosomal localization of each EbWRKY gene was investigated. RNA sequencing revealed transient responses of 74 predicted EbWRKY genes to exogenous abscisic acid (ABA), salicylic acid (SA), and gibberellin 3 (GA3) after 4 h of treatment. In contrast, the expression of key structural genes involved in flavonoid biosynthesis increased after 4 h in GA3 treatment. However, the content of flavonoid metabolites in leaves significantly increased at 12 h. The qRT-PCR results showed that the expression patterns of EbWRKY11 , EbWRKY30 , EbWRKY31 , EbWRKY36 , and EbWRKY44 transcription factors exhibited a high degree of similarity to the 11 structural genes involved in flavonoid biosynthesis. Protein-DNA interactions were performed between the key genes involved in scutellarin biosynthesis and candidate WRKYs . The result showed that F7GAT interacts with EbWRKY11, EbWRKY36, and EbWRKY44, while EbF6H has a self-activation function. This study provides comprehensive information on the regulatory control network of flavonoid accumulation mechanisms, offering valuable insights for breeding E. breviscapus varieties with enhanced scutellarin content., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Song, Zhang, Li, Xiang, Zhao, Wei, Zhang, Yang and Hao.)

N 6 -Methyladenosine (m 6 A) is one of the most abundant modifications of eukaryotic mRNA, but its comprehensive biological functionality remains further exploration. In this study, we identified and characterized a new flowering-promoting gene, EARLY HEADING DATE6 (EHD6), in rice. EHD6 encodes an RNA recognition motif (RRM)-containing RNA binding protein that is localized in the non-membranous cytoplasm ribonucleoprotein (RNP) granules and can bind both m 6 A-modified RNA and unmodified RNA indiscriminately. We found that EHD6 can physically interact with YTH07, a YTH (YT521-B homology) domain-containing m 6 A reader. We showed that their interaction enhances the binding of an m 6 A-modified RNA and triggers relocation of a portion of YTH07 from the cytoplasm into RNP granules through phase-separated condensation. Within these condensates, the mRNA of a rice flowering repressor, CONSTANS-like 4 (OsCOL4), becomes sequestered, leading to a reduction in its protein abundance and thus accelerated flowering through the Early heading date 1 pathway. Taken together, these results not only shed new light on the molecular mechanism of efficient m 6 A recognition by the collaboration between an RNA binding protein and YTH family m 6 A reader, but also uncover the potential for m 6 A-mediated translation regulation through phase-separated ribonucleoprotein condensation in rice., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the effects of different induction agents on the incidence of post-induction hypotension (PIH) and its associated interventions during rapid sequence intubation (RSI) in the ED., Methods: A single centre retrospective study of patients intubated between 2018 and 2021 was conducted in a regional Australian ED. The impact of induction agent choice, in addition to demographic and clinical factors on the incidence of PIH were determined using descriptive statistics and a multivariate analysis presented as adjusted odds ratios (aORs) and their 95% confidence intervals (CIs)., Results: Ketamine and propofol, used either individually or in conjunction with fentanyl, were significantly associated with PIH (ketamine aOR 4.5, 95% CI 1.35-14.96; propofol aOR 4.88, 95% CI 1.46-16.29). Age >60 years was associated with a greater requirement for vasopressors (aOR 4.46, 95% CI 2.49-7.97) and a higher risk of mortality after RSI (aOR 4.2, 95% CI 1.87-9.40). Patients with a shock index >1.0 were significantly more likely to require vasopressors (aOR 5.13, 95% CI 2.35-11.2) and have a cardiac arrest within 15 min of RSI (aOR 3.56, 95% CI 1.07-11.8)., Conclusions: Exposure to both propofol and ketamine is significantly associated with PIH after RSI, alongside age and shock index. PIH is likely multifactorial in nature, and this data supports the sympatholytic effect of induction agents as the underlying cause of PIH rather than the choice of agent itself. Further prospective work including a randomised controlled trial between induction agents is justified to further clarify this important clinical question., (© 2023 Australasian College for Emergency Medicine.)

Baculovirus has been widely used for foreign protein expression in biomedical studies, and budded virus (BV) surface display has developed into an important research tool for heterogenous membrane protein studies. The basic strategy of surface display is to construct a recombinant virus where the target gene is fused with a complete or partial gp64 gene. In this study, we further investigate and develop this BV surface displaying strategy. We constructed stable insect cell lines to express the target protein flanking with different regions of signal peptide (SP) and GP64 transmembrane domain (TMD). Subsequently, recombinant BmNPV was used to infect the cell, and the integration of heterogeneous protein into BV was detected. The results indicated that deletion of the n-region of SP (SP Δn ) decreased the incorporation rate more than that of the full-length SP. However, the incorporation rate of the protein fused with h and c-region deletion of SP (SP Δh-c ) was significantly enhanced by 35-40 times compare to full-length SP. Moreover, the foreign protein without SP and TMD failed to display on the BV, while the integration of foreign proteins with GP64 TMD fusion at the c-terminal was significantly enhanced by 12-26 times compared to the control. Thus, these new strategies developed the BV surface display system further., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tumor immunotherapy brings new light and vitality to breast cancer patients, but low response rate and limitations of therapeutic targets become major obstacles to its clinical application. Recent studies have shown that CD24 is involved in an important process of tumor immune regulation in breast cancer and is a promising target for immunotherapy., Methods: In this study, singleR was used to annotate each cell subpopulation after t-distributed stochastic neighbor embedding (t-SNE) methods. Pseudo-time trace analysis and cell communication were analyzed by Monocle2 package and CellChat, respectively. A prognostic model based on CD24-related genes was constructed using several machine learning methods. Multiple quantitative immunofluorescence (MQIF) was used to evaluate the spatial relationship between CD24 + PANCK + cells and exhausted CD8 + T cells., Results: Based on the scRNA-seq analysis, 1488 CD24-related differential genes were identified, and a risk model consisting of 15 prognostic characteristic genes was constructed by combining the bulk RNA-seq data. Patients were divided into high- and low-risk groups based on the median risk score. Immune landscape analysis showed that the low-risk group showed higher infiltration of immune-promoting cells and stronger immune reactivity. The results of cell communication demonstrated a strong interaction between CD24 + epithelial cells and CD8 + T cells. Subsequent MQIF demonstrated a strong interaction between CD24 + PANCK + and exhausted CD8 + T cells with FOXP3 + in breast cancer. Additionally, CD24 + PANCK + and CD8 + FOXP3 + T cells were positively associated with lower survival rates., Conclusion: This study highlights the importance of CD24 + breast cancer cells in clinical prognosis and immunosuppressive microenvironment, which may provide a new direction for improving patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Multimodal and controllable locomotion in complex terrain is of great importance for practical applications of insect-scale robots. Robust locomotion plays a particularly critical role. In this study, a locomotion mechanism for magnetic robots based on asymmetrical friction effect induced by magnetic torque is revealed and defined. The defined mechanism overcomes the design constraints imposed by both robot and substrate structures, enabling the realization of multimodal locomotion on complex terrains. Drawing inspiration from human walking and running locomotion, a biped robot based on the mechanism is proposed, which not only exhibits rapid locomotion across substrates with varying friction coefficients but also achieves precise locomotion along patterned trajectories through programmed controlling. Furthermore, apart from its exceptional locomotive capabilities, the biped robot demonstrates remarkable robustness in terms of load-carrying and weight-bearing performance. The presented locomotion and mechanism herein introduce a novel concept for designing magnetic robots while offering extensive possibilities for practical applications in insect-scale robotics., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

Background: Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model., Methods: A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4-8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA)., Results: A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram's predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort., Conclusions: We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID., (© 2024. The Author(s).)

Significant water-related side reactions hinder the development of highly safe, low-cost aqueous zinc metal batteries (AZMBs) for grid-scale energy storage. Herein, by regulating the length of alkyl chains, we successfully adjust interstitial voids between the polymer chains of a metal soap interface between 1.48 Å (size of a zinc ion) and 4.0 Å (size of a water molecule). Therefore, water molecules are selectively "size-excluded," while smaller zinc ions are permitted to pass through. Consequently, water-related side reactions (including hydrogen evolution and corrosion) could be effectively inhibited. Furthermore, abundant zinc ion tunnels accompanied with zincophilic components facilitate the homogenization of the Zn 2+ flux, thus preventing dendrite growth. Therefore, the Zn symmetric cell shows a lifespan of approximately 10 000 cycles at 20 mA cm -2 and 1 mA h cm -2 , and the Zn//Na 5 V 12 O 32 (NVO) full cell delivers much better cycling stability with much higher capacity retention of around 93% after 2000 cycles at 2 A g -1 compared to its bare Zn counterpart (19%). This work provides valuable insights for the utilization of metal soap interfaces and regulation of their channel size between perpendicular alkyl chains to realize precise water shielding, which is not only applicable in ZMBs but also in other aqueous batteries., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The escalating demand for enhanced therapeutic efficacy and reduced adverse effects in the pharmaceutical domain has catalyzed a new frontier of innovation and research in the field of pharmacy: novel drug delivery systems. These systems are designed to address the limitations of conventional drug administration, such as abbreviated half-life, inadequate targeting, low solubility, and bioavailability. As the disciplines of pharmacy, materials science, and biomedicine continue to advance and converge, the development of efficient and safe drug delivery systems, including biopharmaceutical formulations, has garnered significant attention both domestically and internationally. This article presents an overview of the latest advancements in drug delivery systems, categorized into four primary areas: carrier-based and coupling-based targeted drug delivery systems, intelligent drug delivery systems, and drug delivery devices, based on their main objectives and methodologies. Additionally, it critically analyzes the technological bottlenecks, current research challenges, and future trends in the application of novel drug delivery systems.

Lysine post-translational modifications (PTMs) are widespread and versatile protein PTMs that are involved in diverse biological processes by regulating the fundamental functions of histone and non-histone proteins. Dysregulation of lysine PTMs is implicated in many diseases, and targeting lysine PTM regulatory factors, including writers, erasers, and readers, has become an effective strategy for disease therapy. The continuing development of mass spectrometry (MS) technologies coupled with antibody-based affinity enrichment technologies greatly promotes the discovery and decoding of PTMs. The global characterization of lysine PTMs is crucial for deciphering the regulatory networks, molecular functions, and mechanisms of action of lysine PTMs. In this review, we focus on lysine PTMs, and provide a summary of the regulatory enzymes of diverse lysine PTMs and the proteomics advances in lysine PTMs by MS technologies. We also discuss the types and biological functions of lysine PTM crosstalks on histone and non-histone proteins and current druggable targets of lysine PTM regulatory factors for disease therapy., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Background: The triglyceride glucose-body mass index (TyG-BMI) is recognized as a reliable surrogate for evaluating insulin resistance and an effective predictor of cardiovascular disease. However, the link between TyG-BMI index and adverse outcomes in heart failure (HF) patients remains unclear. This study examines the correlation of the TyG-BMI index with long-term adverse outcomes in HF patients with coronary heart disease (CHD)., Methods: This single-center, prospective cohort study included 823 HF patients with CHD. The TyG-BMI index was calculated as follows: ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. To explore the association between the TyG-BMI index and the occurrences of all-cause mortality and HF rehospitalization, we utilized multivariate Cox regression models and restricted cubic splines with threshold analysis., Results: Over a follow-up period of 9.4 years, 425 patients died, and 484 were rehospitalized due to HF. Threshold analysis revealed a significant reverse "J"-shaped relationship between the TyG-BMI index and all-cause mortality, indicating a decreased risk of all-cause mortality with higher TyG-BMI index values below 240.0 (adjusted model: HR 0.90, 95% CI 0.86-0.93; Log-likelihood ratio p = 0.003). A distinct "U"-shaped nonlinear relationship was observed with HF rehospitalization, with the inflection point at 228.56 (adjusted model: below: HR 0.95, 95% CI 0.91-0.98; above: HR 1.08, 95% CI 1.03-1.13; Log-likelihood ratio p < 0.001)., Conclusions: This study reveals a nonlinear association between the TyG-BMI index and both all-cause mortality and HF rehospitalization in HF patients with CHD, positioning the TyG-BMI index as a significant prognostic marker in this population., (© 2024. The Author(s).)

Salmonella infections pose a significant threat to animal and human health. Phytochemicals present a potential alternative treatment. Galla chinensis tannic acid (GCTA), a hydrolyzable polyphenolic compound, inhibits bacterial growth and demonstrates potential as an alternative or supplement to antibiotics to prevent Salmonella infections. However, little is known about the antimicrobial mechanism of GCTA against Salmonella. Here, we revealed 456 differentially expressed proteins upon GCTA treatment, impacting pathways related to DNA replication, repair, genomic stability, cell wall biogenesis, and lipid metabolism using TMT-labeled proteomic analysis. TEM analysis suggested altered bacterial morphology and structure post-treatment. A Salmonella-infected-mouse model indicated that GCTA administration improved inflammatory markers, alleviated intestinal histopathological alterations, and reduced Salmonella enterica serovar Enteritidis (S. Enteritidis) colonization in the liver and spleen of Salmonella-infected mice. The LD 50 of GCTA was 4100 mg/kg with an oral single dose, vastly exceeding the therapeutic dose. Thus, GCTA exhibited antibacterial and anti-infective activity against S. Enteritidis. Our results provided insight into the molecular mechanisms of these antibacterial effects, and highlights the potential of GCTA as an alternative to antibiotics., (© 2024. The Author(s).)

Social ties, either positive or negative, lead to signed network patterns, the subject of balance theory. For example, strong balance introduces cycles with even numbers of negative edges. The statistical significance of such patterns is routinely assessed by comparisons to null models. Yet, results in signed networks remain controversial. Here, we show that even if a network exhibits strong balance by construction, current null models can fail to identify it. Our results indicate that matching the signed degree preferences of the nodes is a critical step and so is the preservation of network topology in the null model. As a solution, we propose the STP null model, which integrates both constraints within a maximum entropy framework. STP randomization leads to qualitatively different results, with most social networks consistently demonstrating strong balance in three- and four-node patterns. On the basis our results, we present a potential wiring mechanism behind the observed signed patterns and outline further applications of STP randomization.

Understanding cellular coordination remains a challenge despite knowledge of individual pathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulated in cellular senescence. Utilizing an auxin-inducible system, we observed that RNA exosome depletion in embryonic stem cells significantly affects the transcriptome and proteome, causing pluripotency loss and pre-senescence onset. Mechanistically, exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-protein equilibrium. This disturbance limits nuclear protein availability and hinders polymerase initiation and engagement, reducing gene transcription. Concurrently, it promptly disrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resulting in a translational shutdown. Prolonged exosome depletion induces nuclear structural changes resembling senescent cells, including aberrant chromatin compaction, chromocenter disassembly, and intensified heterochromatic foci. These effects suggest that the dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemic functional decline, altering the cell state and promoting senescence., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bacteria develop tolerance after transient exposure to antibiotics, and tolerance is a significant driver of resistance. The purpose of this study is to evaluate the mechanisms underlying tolerance formation in vancomycin-intermediate Staphylococcus aureus (VISA) strains. VISA strains were cultured with sub-minimum inhibitory concentrations (sub-MICs) of vancomycin. Enhanced vancomycin tolerance was observed in VISA strains with distinct genetic lineages. Western blot revealed that the VISA protein succinylation (Ksucc) levels decreased with the increase in vancomycin exposure. Importantly, Ksucc modification, vancomycin tolerance, and cell wall synthesis were simultaneously affected after deletion of SacobB, which encodes a desuccinylase in S. aureus. Several Ksucc sites were identified in MurA, and vancomycin MIC levels of murA mutant and Ksucc-simulated (MurA(K69E) and MurA(K191E)) mutants were reduced. The vancomycin MIC levels of K65-MurA(K191E) in particular decreased to 1 mg/L, converting VISA strain K65 to a vancomycin-susceptible S. aureus strain. We further demonstrated that the enzymatic activity of MurA was dependent on Ksucc modification. Our data suggested the influence of vancomycin exposure on bacterial tolerance, and protein Ksucc modification is a novel mechanism in regulating vancomycin tolerance., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest to this work., (Copyright © 2024. Published by Elsevier GmbH.)

Weakly coupled mode-division multiplexing (MDM) transmission over legacy laid multimode fiber (MMF) has great economic efficiency and can enormously enhance the capacity of short-reach optical interconnections. In order to be compatible with cost-efficient intensity-modulation/direct-detection (IM/DD) transceivers, weakly coupled mode-group demultiplexers that can simultaneously receive each mode group of MMFs are highly desired. In this paper, we propose a scalable low-modal-crosstalk mode-group demultiplexer over MMF based on multiplane light conversion (MPLC). Multiple input Hermite-Gaussian (HG) modes of MMF are first converted to bridging modes that are composed of H G 00 modes distributed as a right-angle triangle in Cartesian coordinates, and then each H G 00 mode belonging to a degenerate mode group is mapped to different overlapped H G n 0 modes with vertical orientation for simultaneous detection. With the help of bridging modes, the MPLC-based mode-group demultiplexer can efficiently demultiplex all mode groups in standard MMFs with less than 20 phase masks. A nine-mode-group demultiplexer is further designed for demonstration, and simulation results show that the MPLC-based demultiplexer achieves low modal crosstalk of lower than -22.3 d B at 1550 nm and lower than -17.9 d B over the C-band for all the nine mode groups with only 16 phase masks.

Background: This study aimed to investigate the relationship between baseline soluble suppression of tumorigenesis-2 (sST2) concentration and the outcomes of heart failure (HF), atrial fibrillation (AF) or death in patients with coronary heart disease (CHD) with or without renal insufficiency (RI)., Methods: Between March 2011 and December 2015, 3454 patients with CHD from the Chinese PLA General Hospital were enrolled in this cohort study. The patients were followed up until October 2021. AF, HF, and death events were recorded. Associations between baseline sST2 concentrations and clinical outcomes were assessed using Kaplan-Meier (K-M) curves, and Cox regression and generalised additive models. Subgroup analysis were carried out between RI and non-RI groups., Results: Among the patients with CHD (61.5 ± 11.8 years; 78.6 % men), 415 (12.02 %) had RI. During a median follow-up of 8.37 years, HF and AF were reported in 216 (6.25 %) and 174 (5.04 %) patients, respectively, and 297 (8.60 %) died. The K-M curves indicated that patients in the higher quartiles of sST2 concentrations were correlated with a poor survival rate of HF, AF, or death (all Ps  < 0.001). Generalised additive model (GAM) demonstrated a nonlinear positive association between sST2 concentration and the risk of HF, AF, and death in CHD patients. The cut-off value of sST2 for predicting HF, AF and death were 32.1, 25.4 and 28.6 ng/mL, respectively. CHD patients with sST2 higher than the cut-off value had higher risks of HF (HR: 3.02, 95%CI: 2.24-4.05), AF (HR: 2.86; 95%CI: 2.10-3.90), and death (HR:2.11, 95%CI: 1.67-2.67). Furthermore, in patients with RI (12.02 %, n = 415), the prognostic value of sST2 over the cut-off value for HF and death remained unchanged (HR: 3.21 and 2.35; P  < 0.05). In patients with CHD with or without RI, sST2 improved the area under the curve (AUC) of traditional risk models for predicting clinical endpoint events., Conclusions: The biomarker sST2 may be useful for predicting HF, AF, and death in patients with CHD. The predicted value was not affected by renal function., Competing Interests: All authors disclosed no financial relationships relevant to this publication., (© 2024 The Authors.)

Calcium homeostasis imbalance is one of the important pathological mechanisms in heart failure. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), a calcium ATPase on the sarcoplasmic reticulum in cardiac myocytes, is a myocardial systolic-diastolic Ca2 + homeostasis regulating enzyme that is not only involved in cardiac diastole but also indirectly affects cardiac myocyte contraction. SERCA2a expression was found to be decreased in myocardial tissue in heart failure, however, there are few reports on serum SERCA2a expression in patients with heart failure, and this study was designed to investigate whether serum SERCA2a levels are associated with the occurrence of adverse events after discharge in patients hospitalized with heart failure. Patients with heart failure hospitalized in the cardiovascular department of the Second Affiliated Hospital of Guangdong Medical University, China, from July 2018 to July 2019 were included in this study, and serum SERCA2a concentrations were measured; each enrolled patient was followed up by telephone after 6 months (6 ± 1 months) for general post-discharge patient status. The correlation between serum SERCA2a levels and the occurrence of adverse events (death or readmission due to heart failure) after hospital discharge was assessed using multiple analysis and trend analysis. Seventy-one patients with heart failure were finally included in this study, of whom 38 (53.5%) were men and 33 (46.5%) were women (All were postmenopausal women). Multiple analysis revealed no correlation between serum SERCA2a levels and the occurrence of adverse events in the total study population and in male patients, but serum SERCA2a levels were associated with the occurrence of adverse outcome events after hospital discharge in female patients (OR = 1.02, P = .047). Further analysis using a trend analysis yielded a 4.0% increase in the risk of adverse outcomes after hospital discharge for each unit increase in SERCA2a in female patients (OR = 1.04; P = .02), while no significant difference was seen in men. This study suggests that serum SERCA2a levels at admission are associated with the occurrence of post-discharge adverse events in postmenopausal female patients hospitalized with heart failure., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Six oxidosqualene cyclases ( Ni OSC1- Ni OSC6) from Neoalsomitra integrifoliola were characterized for the biosynthesis of diverse triterpene scaffolds, including tetracyclic and pentacyclic triterpenes from the 2,3-oxidosqualene ( 1 ) and oxacyclic triterpenes from the 2,3:22,23-dioxidosqualene ( 2 ). Ni OSC1 showed high efficiency in the production of naturally rare (20 R )-epimers of oxacyclic triterpenes. Mutagenesis results revealed that the Ni OSC1-F731G mutant significantly increased the yields of (20 R )-epimers compared to the wild type. Homology modeling and molecular docking elucidated the origin of the (20 R )-configuration in the epoxide addition step.

Herein we describe the medicinal chemistry efforts that led to the discovery of the clinical-staged Syk inhibitor sovleplenib ( 41 ) via a structure-activity relationship investigation and pharmacokinetics (PK) optimization of a pyrido[3,4- b ]pyrazine scaffold. Sovleplenib is a potent and selective Syk inhibitor with favorable preclinical PK profiles and robust anti-inflammation efficacy in a preclinical collagen-induced arthritis model. Sovleplenib is now being developed for treating autoimmune diseases such as immune thrombocytopenic purpura and warm antibody hemolytic anemia as well as hematological malignancies., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Purpose: The purpose was to evaluate the clinical outcomes of a dedicated venous stent with the tripartite composite segments for the treatment of iliofemoral venous obstruction (IVO) in a mixed cohort of nonthrombotic iliac vein lesion (NIVL) and post-thrombotic syndrome (PTS) over a period of 12 months., Methods: The Grency Trial is a prospective, multicenter, single-arm, open-label, pivotal study, which was conducted at 18 large tertiary hospitals in China from August 2019 to October 2020. A total of 133 hospitalized patients were screened and 110 patients with clinical, etiology, anatomical, and pathophysiology clinical class (CEAP) clinical grade C>3 and iliac vein stenosis >50% or occlusion, including 72 patients with NIVL and 38 patients with PTS, were implanted with Grency venous stents. Primary endpoint was stent patency at 12 months follow-up, and secondary outcomes were technical success; improvement in venous clinical severity score (VCSS) at 3, 6, and 12 month follow-up; and rates of clinical adverse events., Results: Among 110 patients who were implanted with Grency venous stents, 107 patients completed the 12 month follow-up. All 129 stents were successfully implanted in 110 limbs. Twelve-month primary patency rate was 94.39% [95% confidence interval [CI]=88.19%-97.91%] overall, and 100% [94.94%-100%] and 83.33% [67.19%-93.63%] in the NIVL and PTS subgroups, respectively. Venous clinical severity score after iliac vein stenting improved significantly up to 12 months follow-up. There were 3 early major adverse events (1 intracerebral hemorrhage and 2 stent thrombosis events related to anticoagulation therapy), and 7 late major adverse events (1 cardiovascular death, 1 intracranial hemorrhage with uncontrolled hypertension, and 5 in-stent restenosis cases without stent fractures or migration)., Conclusions: The Grency venous stent system appeared excellent preliminary safe and effective for IVO treatment. Further large-scale studies with longer-term follow-up are needed to evaluate long-term patency and durability of stent., Clinical Impact: The design of venous stents for iliofemoral venous obstruction (IVO) must address engineering challenges distinct from those encountered in arterial stenting. The Grency venous stent, a nitinol self-expanding stent specifically tailored for IVO, features a composite structure designed to meet the stent requirements of various iliac vein segments. The Grency Trial is a prospective, multicenter, single-arm, open-label pivotal study aimed at evaluating the efficacy and safety of the Grency stent system. Following a 12-month follow-up period, the Grency venous stent system has demonstrated both safety and efficacy in treating iliofemoral venous outflow obstruction., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A series of hydrothermal liquefaction (HTL) experiments with two different samples of municipal sewage sludge (MSS) were conducted at 350 °C for 30 min residence time in a high pressure batch reactor. The main aim of the study was to explore the distribution and migration pathways of a broad range of metals and metalloids in the HTL products (bio-oil, char and aqueous phase) obtained in the presence of various homogeneous and heterogeneous catalysts (Na 2 CO 3 , Li 2 CO 3 , K 2 CO 3 , Ba(OH) 2 , Fe 2 O 3 , CeO 2 , NiMo/MoO 3 , MoS 2 , Ni/NiO, SnO 2 , FeS). The elements under study included 16 environmentally significant metals and metalloids (As, B, Ba, Cd, Co, Cr, Cu, Mn, Mo, Ni, Pb, Sb, Se, Sn, Zn and Hg). The study showed that the quantitative migration of the tested metals and metalloids to the particular HTL products, relative to their initial content in the raw sludge, is different for the individual elements. Most metals exhibited a particularly strong affinity to the solid fraction (biochar). In the obtained HTL bio-oils, all tested elements were identified, except of Cd. It was also found that B and As have high affinity to the aqueous phase. A direct effect of catalysts on the contents of some elements in the products was also proved by the study, e.g. increased concentration of Cr in the biochar when Fe 2 O 3 was used as a process catalyst. Due to the wide scope of the tested elements and broad range of catalyst used, the results obtained represent a unique and comprehensive set of environmental data compared to similar HTL studies previously conducted for MSS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: An increasing body of evidence suggests that serum albumin levels play a role in cardiovascular diseases. However, the specific causal relationship between serum albumin levels and cardiovascular disease remains partially unknown., Methods: Mendelian randomization (MR) was employed in this study to examine potential causal relationships between instrumental variables and cardiovascular diseases. Specifically, we utilized genetic variants of serum albumin levels within the reference range as our instrumental variables. To acquire data on genetic associations with cardiovascular diseases, we sourced information from renowned genome-wide association studies such as UK BioBank, EMBL-EBI, and FinnGen. Notably, our study leveraged summary statistics from large cohorts that have been previously described., Results: We explored the association between serum albumin levels and various conditions, including heart failure (HF), venous thromboembolism (VTE), stroke, atrial fibrillation (AF), coronary artery disease (CAD), type 2 diabetes (T2DM), and pulmonary heart disease (PHD). Genetically predicted serum albumin levels were associated with PHD (odds ratio = 0.737, 95% CI = 0.622 - 0.874, P < 0.001), AF (odds ratio = 0.922, 95% CI = 0.870 - 0.977, P = 0.006), VTE (odds ratio = 0.993, 95% CI = 0.991 - 0.995, P < 0.001), and Stroke (odds ratio = 0.997, 95% CI = 0.995 - 0.999, P = 0.002). However, genetically predicted serum albumin level traits were not associated with HF, CAD and T2DM., Conclusion: Our study demonstrates a significant association between serum albumin levels and cardiovascular disease, underscoring the crucial role of low serum albumin as a predictive factor in patients with cardiovascular disease., (© 2024. The Author(s).)

Background: Nitrogen (N) is an important macronutrient involved in the biosynthesis of primary and secondary metabolites in plants. However, the metabolic regulatory mechanism of low-N-induced triterpenoid saponin and flavonoid accumulation in rhizomatous medicinal Panax notoginseng (Burk.) F. H. Chen remains unclear., Methods: To explore the potential regulatory mechanism and metabolic basis controlling the response of P. notoginseng to N deficiency, the transcriptome and metabolome were analysed in the roots., Results: The N content was significantly reduced in roots of N 0 -treated P. notoginseng (0 kg·N·667 m -2 ). The C/N ratio was enhanced in the N-deficient P. notoginseng. N deficiency promotes the accumulation of amino acids (L-proline, L-leucine, L-isoleucine, L-norleucine, L-arginine, and L-citrulline) and sugar (arabinose, xylose, glucose, fructose, and mannose), thus providing precursor metabolites for the biosynthesis of flavonoids and triterpenoid saponins. Downregulation of key structural genes (PAL, PAL3, ACC1, CHS2, PPO, CHI3, F3H, DFR, and FGT), in particular with the key genes of F3H, involved in the flavonoid biosynthesis pathway possibly induced the decrease in flavonoid content with increased N supply. Notoginsenoside R 1 , ginsenoside Re, Rg 1 , Rd, F 1 , R 1  + Rg 1  + Rb 1 and total triterpenoid saponins were enhanced in the N 0 groups than in the N 15 (15 kg·N·667 m -2 ) plants. Higher phosphoenolpyruvate (an intermediate of glycolyticwith pathway metabolism) and serine (an intermediate of photorespiration) levels induced by N deficiency possibly promote saponin biosynthesis through mevalonic acid (MVA) and methylerythritol (MEP) pathways. Genes (MVD2, HMGS, HMGR1, HMGR2, DXR, and HMGR1) encoding the primary enzymes HMGS, HMGR, DXR, and MVD in the MVA and MEP pathways were significantly upregulated in the N 0 -treated P. notoginseng. The saponin biosynthesis genes DDS, DDS, CYP716A52, CYP716A47, UGT74AE2, and FPS were upregulated in the N-deficient plants. Upregulation of genes involved in saponin biosynthesis promotes the accumulation of triterpenoid saponins in the N 0 -grown P. notoginseng., Conclusions: N deficiency enhances primary metabolisms, such as amino acids and sugar accumulation, laying the foundation for the synthesis of flavonoids and triterpenoid saponins in P. notoginseng. F3H, DDS, FPS, HMGR, HMGS and UGT74AE2 can be considered as candidates for functional characterisation of the N-regulated accumulation of triterpenoid saponins and flavonoids in future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In response to the epochal demand for high-quality development in early childhood education in China, it is imperative and necessary to improve the competency level of early childhood educators. The study aims to investigate the relationship between psychological contracts and teacher competency, and to verify the mediating roles of job crafting and professional identity in the relationship between psychological contracts and teacher competency. This study employed validated measurement scales regarding psychological contracts, teachers' professional identity, job crafting, and teacher competency. Each of these scales has established internal consistency coefficients. Data were collected from 318 early childhood teachers in Sichuan, China. The results highlight the significant impact of psychological contracts on the prediction of teacher competency. It is worth mentioning that the psychological contracts, together with their distinct components such as normative responsibility and development responsibility, have a direct and favorable impact on teacher competency. This implies that developing the psychological contracts might be an effective technique for improving teacher competence. The individual mediation of job crafting and professional identity in the link between psychological contracts and teacher competency has been well-established. However, the combined or chain mediating influence of these factors provides a unique and valuable perspective on the phenomenon of job crafting leading to professional identity, which in turn impacts teacher competency. The study found that psychological contracts have a positive predictive effect on teacher competency, while job crafting and professional identity both have independent and chain mediating roles in the relationship between psychological contracts and teacher competency. Therefore, this study suggests a comprehensive enhancement of the psychological contracts level from aspects such as normative responsibility, interpersonal responsibility, and development responsibility. By stimulating job crafting and professional identity levels in both internal and external environments, we can improve the competency level of early childhood educators., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Due to molecular forces, biomacromolecules assemble into liquid condensates or solid aggregates, and their corresponding formation and dissolution processes are controlled. Protein homeostasis is disrupted by increasing age or environmental stress, leading to irreversible protein aggregation. Hypoxic pressure is an important factor in this process, and uncontrolled protein aggregation has been widely observed in hypoxia‑related conditions such as neurodegenerative disease, cardiovascular disease, hypoxic brain injury and cancer. Biomolecular condensates are also high‑order complexes assembled from macromolecules. Although they exist in different phase from protein aggregates, they are in dynamic balance under certain conditions, and their activation or assembly are considered as important regulatory processes in cell survival with hypoxic pressure. Therefore, a better understanding of the relationship between hypoxic stress, protein aggregation and biomolecular condensation will bring marked benefits in the clinical treatment of various diseases. The aim of the present review was to summarize the underlying mechanisms of aggregate assembly and dissolution induced by hypoxic conditions, and address recent breakthroughs in understanding the role of aggregates in hypoxic‑related diseases, given the hypotheses that hypoxia induces macromolecular assemblage changes from a liquid to a solid phase, and that adenosine triphosphate depletion and ATP‑driven inactivation of multiple protein chaperones play important roles among the process. Moreover, it is anticipated that an improved understanding of the adaptation in hypoxic environments could extend the overall survival of patients and provide new strategies for hypoxic‑related diseases.