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Abstract Prostate cancer (PCa) is the second leading cause of cancer-related mortality among men in the United States. While PCa initially responds to androgen deprivation therapy, a significant portion progresses to castration-resistant PCa. Approximately 20–25% of these cases acquire aggressive neuroendocrine (NE) features, ultimately leading to neuroendocrine prostate cancer (NEPC). In this study, we investigated the expression of stathmin 1 (STMN1) across PCa subtypes using bioinformatics, western blotting, and immunohistochemical staining analyses in human and murine models. We found that elevated STMN1 expression correlated with high Gleason Scores, increased cell proliferation, and poor clinical outcomes in PCa patients. Notably, STMN1 expression was significantly higher in NEPC compared to prostate adenocarcinoma, suggesting its role in NEPC progression. Findings from TRAMP tumors, a murine NEPC model, further supported these results. In conclusion, STMN1 expression is elevated in advanced PCa, particularly in NEPC, suggesting its involvement in the progression of aggressive forms of PCa. While STMN1 shows potential as a diagnostic and prognostic marker for aggressive PCa, further studies are necessary to establish its clinical utility.

Background: Prolonged bradycardia leads to inadequate pumping of the heart, causing myocardial ischemia, which in turn affects cardiac function. Depending on its clinical features, improving the AV node conduction block may be an important tool to inhibit the progression of the disease. Lingbao Huxin Dan, which consists of several traditional Chinese medicines, is used for conditions similar to bradycardia and may be a potential therapeutic agent for bradycardia. In this experiment, we investigated its therapeutic significance and possible therapeutic targets for sinus bradycardia. Methods: The bradycardia model of SD rats was prepared by using acetylcholine, propranolol, and verapamil respectively, and treated with Lingbao Huxin Dan for 3 weeks. At the end of treatment, the rats' ECG was recorded using a PV-LOOP heart rate recorder. The hearts and serum samples were collected to detect heart rate and related gene expression which were screened through network pharmacology analysis, as well as to evaluate the effect of Lingbao Huxin Dan on ion channels in the cardiac conduction system. Results: Lingbao Huxin Dan improved the heart rate in the bradycardia model of SD rats and inhibited AV node conduction block by targeting ion channel proteins in the cardiac conduction system. The underlying molecular mechanism may be the activation of the β-adrenergic receptor-dependent cAMP/PKA signaling pathway targeted to enhance the expression of the pacing channel HCN4. In addition, Lingbao Huxin Dan prevented the deterioration of bradycardia by promoting the production of the oxygen radical scavenger SOD and inhibiting the upregulation of LDH due to cardiomyocyte damage. Conclusions: Our study proved that Lingbao Huxin Dan alleviated bradycardia by downregulating CX45 and enhancing the expression of HCN4, ADRβ1, and TRPM7 to shorten the atrioventricular node induction period and improve sinoatrial node signaling. In addition, Lingbao Huxin Dan relieved myocardial injury induced by bradycardia by reducing the level of oxygen free radicals in the cardiac microenvironment.

Abstract Background Older adults with chronic diseases are at higher risk of depressive symptoms than those without. For the onset of depressive symptoms, the prediction ability of changes in common risk factors over a 2-year follow-up period is unclear in the Chinese older population. This study aimed to build risk prediction models (RPMs) to estimate the probability of incident 2-year depression using data from the China Health and Retirement Longitudinal Study (CHARLS). Methods Four ML algorithms (logistic regression [LR], AdaBoost, random forest [RF] and k-nearest neighbor [kNN]) were applied to develop RPMs using the 2011–2015 cohort data. These developed models were then validated with 2018–2020 survey data. We evaluated the model performance using discrimination and calibration metrics, including an area under the receiver operating characteristic curve (AUROC) and the precision-recall curve (AUPRC), accuracy, sensitivity and calibrations plot. Finally, we explored the key factors of depressive symptoms by the selected best predictive models. Results This study finally included 7,121 participants to build models to predict depressive symptoms, finding a 21.5% prevalence of depression. Combining the Synthetic Minority Oversampling Technique (SMOTE) with the logistic regression model (LR-SM) exhibited superior precision to predict depression than other models, with an AUROC and AUPRC of 0.612 and 0.468, respectively, an accuracy of 0.619 and a sensitivity of 0.546. In additiona, external validation of the LR-SM model using data from the 2018–2020 data also demonstrated good predictive ability with an AUROC of 0.623 (95% CI: 0.555– 0.673). Sex, self-rated health status, occupation, eyesight, memory and life satisfaction were identified as impactful predictors of depression. Conclusions Our developed models exhibited high accuracy, good discrimination and calibration profiles in predicting two-year risk of depression among older adults with chronic diseases. This model can be used to identify Chinese older population at high risk of depression and intervene in a timely manner.

Abstract Background Muscle atrophy can cause muscle dysfunction and weakness. Krüppel‐like factor 13 (KLF13), a central regulator of cellular energy metabolism, is highly expressed in skeletal muscles and implicated in the pathogenesis of several diseases. This study investigated the role of KLF13 in muscle atrophy, which could be a novel therapeutic target. Methods The effects of gene knockdown and pharmacological targeting of KLF13 on skeletal muscle atrophy were investigated using cell‐based and animal models. Clofoctol, an antibiotic and KLF13 agonist, was also investigated as a candidate for repurposing. The mechanisms related to skeletal muscle atrophy were assessed by measuring the expression levels and activation statuses of key regulatory pathways and validated using gene knockdown and RNA sequencing. Results In a dexamethasone‐induced muscle atrophy mouse model, the KLF13 knockout group had decreased muscle strength (N) (1.77 ± 0.10 vs. 1.48 ± 0.16, P

Abstract Time-varying metamaterials rely on large and fast changes of the linear permittivity. Beyond the linear terms, however, the effect of a non-perturbative modulation of the medium on harmonic generation remains largely unexplored. In this work, we study second harmonic generation at an optically pumped time-varying interface between air and a 310 nm Indium Tin Oxide film. We observe a modulation contrast at the second harmonic wavelength up to 93% for a pump intensity of 100 GW/cm2, leading to large frequency broadening and shift. We experimentally demonstrate that a significant contribution to the enhancement comes from the temporal modulation of the second order nonlinear susceptibility. Moreover, we show the frequency-modulated spectra resulting from single and double-slit time diffraction could be exploited for enhanced optical computing and sensing, enabling broadband time-varying effects on the harmonic signal and extending the application of Epsilon-Near-Zero materials to the visible range.

Abstract In patients with relapsed or refractory neuroblastoma (NB), the limited efficacy of conventional chemotherapies necessitates the exploration of new treatment options. Previous studies have highlighted the anti-tumor properties of arsenic trioxide (ATO) in high-risk NB (HR-NB). This study aims to assess the effectiveness and safety of ATO combined with salvage chemotherapy regimens, featuring cyclophosphamide and topotecan, as a foundational treatment for children with relapsed or refractory NB. Eleven patients (four relapsed, seven refractory NB) were retrospectively analyzed for efficacy and treatment relevance. Salvage treatments, incorporating ATO (0.18 mg/kg daily for 8 h intravenously on days 1 to 10), were administered upon disease progression or relapse, with assessments conducted every two cycles. Treatments had 63.6% efficacy, with six cases of partial response, one case of stable disease, and four cases of disease progression. The overall response rate was 54.5%, and the disease control rate was 63.6%. Importantly, the systemic toxicity experienced by patients following salvage chemotherapy with ATO was mild. Salvage chemotherapy regimens featuring ATO demonstrated potential for prolonging disease stabilization for relapsed or refractory HR-NB patients, exhibiting both favorable efficacy and safety profiles. This suggests further clinical exploration and promotion of this therapeutic approach in the treatment of NB.

Abstract Background Diabetic retinopathy (DR), the principal cause of acquired blindness among the working-age population, is the most frequent microvascular complication of diabetes. Although metabolic disorders are hypothesized to play a role in its pathogenesis, the underlying mechanism remains largely elusive. Methods To elucidate the mechanism, we initially compared metabolite profiles of vitreous fluid between 23 patients with DR and 12 non-diabetic controls using liquid chromatography/tandem mass spectrometry, identifying the distinct metabolite indoxyl sulfate (IS). Subsequently, streptozotocin (STZ)-induced diabetic and IS-injected rat models were established to examine the effects of IS on retinal microvasculature. RNA sequencing was conducted to identify potential regulatory mechanisms in IS-treated human retinal endothelial cells (HREC). Finally, target gene knockdown in HREC and treatment of IS-injected rats with inhibitors (targeting IS production or downstream regulators) were employed to elucidate the detailed mechanisms and identify therapeutic targets for DR. Results Metabolomics identified 172 significantly altered metabolites in the vitreous humor of diabetics, including the dysregulated tryptophan metabolite indoxyl sulfate (IS). IS was observed to breach the blood-retinal barrier and accumulate in the intraocular fluid of diabetic rats. Both in vivo and in vitro experiments indicated that elevated levels of IS induced endothelial apoptosis and disrupted cell junctions. RNA sequencing pinpointed prostaglandin E2 (PGE2) synthetase-cyclooxygenase 2 (COX-2) as a potential target of IS. Validation experiments demonstrated that IS enhanced COX-2 expression, which subsequently increased PGE2 secretion by promoting transcription factor EGR1 binding to COX-2 DNA following entry into cells via organic anion transporting polypeptides (OATP2B1). Furthermore, inhibition of COX-2 in vivo or silencing EGR1/OATP2B1 in HREC mitigated IS-induced microcapillary damage and the activation of COX-2/PGE2. Conclusion Our study demonstrated that indoxyl sulfate (IS), a uremic toxin originating from the gut microbiota product indole, increased significantly and contributed to retinal microvascular damage in diabetic retinopathy (DR). Mechanistically, IS impaired retinal microvascular integrity by inducing the expression of COX-2 and the production of PGE2. Consequently, targeting the gut microbiota or the PGE2 pathway may offer effective therapeutic strategies for the treatment of DR. Graphical Abstract

IntroductionSevere fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease discovered in China in 2009. SFTS monitoring has been carried out since 2010 in mainland China. In recent years, human infection with SFTS virus (SFTSV) has frequently been detected in Jiujiang of Jiangxi Province, Central China.MethodsSera of SFTS surveillance cases and samples collected from humans, animals and ticks surrounding the cases were used to detect SFTSV RNA by real-time RT-PCR. SFTSV-positive samples were further subjected to sequencing and analysis of the S, M, and L segments of SFTSV.ResultsFour patients were positive for SFTSV infection. However, the subjects like humans, animals and ticks around the cases were all detected as negative for the virus infection. Phylogenetic analysis of the partial segments revealed that SFTSVs in three patients from Jiujiang were clustered with genotype C4 and C5 on the L and M segment-established phylogenetic tree; however, phylogenetic analysis of the S segment showed that the strains were grouped into genotype J1. These results suggested that the S, M, and L segments of these strains underwent segmental reassortment, which was later supported by recombination signal detection. The reassortment event was detected by at least four methods with a significance level of p value

Abstract Background Despite improvement in treatment strategies for atrial fibrillation (AF), a significant proportion of patients still experience recurrence after ablation. This study aims to propose a novel algorithm based on Transformer using surface electrocardiogram (ECG) signals and clinical features can predict AF recurrence. Methods Between October 2018 to December 2021, patients who underwent index radiofrequency ablation for AF with at least one standard 10-second surface ECG during sinus rhythm were enrolled. An end-to-end deep learning framework based on Transformer and a fusion module was used to predict AF recurrence using ECG and clinical features. Model performance was evaluated using areas under the receiver operating characteristic curve (AUROC), sensitivity, specificity, accuracy and F1-score. Results A total of 920 patients (median age 61 [IQR 14] years, 66.3% male) were included. After a median follow-up of 24 months, 253 patients (27.5%) experienced AF recurrence. A single deep learning enabled ECG signals identified AF recurrence with an AUROC of 0.769, sensitivity of 75.5%, specificity of 61.1%, F1 score of 55.6% and overall accuracy of 65.2%. Combining ECG signals and clinical features increased the AUROC to 0.899, sensitivity to 81.1%, specificity to 81.7%, F1 score to 71.7%, and overall accuracy to 81.5%. Conclusions The Transformer algorithm demonstrated excellent performance in predicting AF recurrence. Integrating ECG and clinical features enhanced the models’ performance and may help identify patients at low risk for AF recurrence after index ablation.

Ultra-low-wear polyethylene (ULWPE) is a promising material for artificial joint implants, owing to its good biocompatibility and wear resistance. However, its molecular weight is almost an order of magnitude lower than that of Ultrahigh molecular weight polyethylene (UHMWPE). The mechanism between wear resistance and the structure of ULWPE is still unknown. This study analyzed their attributes from microstructure to macroscopic performance and revealed the wear resistance mechanisms of ULWPE by conducting an in-depth investigation of four types of polyethylene, including ULWPE, UHMWPE, and high-density polyethylene. Impact tests showed that ULWPE, with a molecular weight of 282 kg/mol, exhibited an impact energy of 110 kJ/m2, surpassing the 97 kJ/m2 recorded for UHMWPE (molecular weight over 5000 kg/mol). Furthermore, tribology tests indicated that the wear rate of the most anti-wear ULWPE was 4.479 ± 0.040 mm³/Mc, which was significantly lower than the 5.601 ± 0.456 mm³/Mc for UHMWPE. The excellent mechanical properties and wear resistance of ULWPE were derived from its unique structure. Dynamic rheological assessments and thermal classification techniques confirmed that ULWPE had long-branched chains. The long-branched chains markedly increased the proportion of the high entanglement and the tie molecules in the amorphous regions, endowing it with superior toughness. At the same time, the high crystallinity of ULWPE gives it sufficient hardness and strength. The combination of high crystallinity and high entanglement endowed ULWPE with a good balance between strength and toughness, leading to its exceptional mechanical properties and wear resistance. This study provided robust data for ULWPE's clinical use and theoretical insights for designing durable, implantable polymers.

Abstract Objective Endovascular therapy (EVT) is the most successful treatment for patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. However, futile recanalization (FR) seriously affects the prognosis of these patients. The aim of this study was to investigate predictors of FR after EVT in patients with AIS. Method Patients diagnosed with AIS due to anterior circulation LVO and receiving EVT between June 2020 and October 2022 were prospectively enrolled. FR after EVT was defined as a poor 90-day prognosis (modified Rankin Scale [mRS] score ≥ 3) despite achieving successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] classification of 2b-3). All included patients were categorized into control group (mRS score

Abstract Cognitive decline in Parkinson's disease (PD) varies widely. While models to predict cognitive progression exist, comparing traditional probabilistic models to deep learning methods remains understudied. This study compares sequential modeling techniques to identify cognitive progression in individuals with and without PD. Using data from the Parkinson's Progression Marker Initiative, shallow Markov, deep recurrent (long short‐term memory [LSTM]), and nonrecurrent (temporal fusion transformer [TFT]) models were compared to predict cognitive status over time. Cognitive status was categorized into normal cognition (NC), mild cognitive impairment (MCI), and dementia. Predictions were made annually for up to 3 years using clinical data, including demographics, cognitive assessments, PD severity, and medical history. Each approach was evaluated using inverse probability weighted (IPW‐) F1 scores. An ensemble method combined outputs from the Markov, LSTM, and TFT models. The dataset included 917 individuals (53% PD; 30% at risk for PD; 17% Healthy Controls). The TFT model outperformed others across all annual periods (IPW‐F1 = 0.468) compared to the Markov (IPW‐F1 = 0.349) and LSTM (IPW‐F1 = 0.414) models, with improved performance using an ensemble approach (IPW‐F1 = 0.502). For MCI and dementia predictions, which were rarer occurrences compared to NC status (ratios: 50:8:1), the TFT model consistently outperformed competing models, achieving IPW‐F1 scores of 0.496 and 0.533 for MCI and dementia, respectively. In conclusion, sequential deep learning models like TFT, which mitigate long‐term memory loss and can interpret complex, high‐dimensional data, perform best overall in predicting clinically important cognitive transitions. These methods should be further explored for predicting degenerative conditions.

TGF-β stimulates CCN2 expression which in turn amplifies TGF-β signaling. This process promotes extracellular matrix production and accelerates the pathological progression of fibrotic diseases. Alternative splicing plays an important role in multiple disease development, while U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential factor in the early steps of pre-mRNA splicing. However, the molecular mechanism underlying abnormal CCN2 expression upon TGF-β stimulation remains unclear. This study elucidates that SIRT4 acts as a master regulator for CCN2 expression in response to TGF-β by modulating U2AF2-mediated alternative splicing. Analyses of renal biopsy specimens from patients with CKD and mouse fibrotic kidney tissues revealed marked nuclear accumulation of SIRT4. The tubulointerstitial fibrosis was alleviated by global deletion or tubular epithelial cell (TEC)-specific knockout of Sirt4, and aggravated by adeno-associated virus-mediated SIRT4 overexpression in TECs. Furthermore, SIRT4 was found to translocate from the mitochondria to the cytoplasm through the BAX/BAK pore under TGF-β stimulation. In the cytoplasm, TGF-β activated the ERK pathway and induced the phosphorylation of SIRT4 at Ser36, which further promoted its interaction with importin α1 and subsequent nuclear translocation. In the nucleus, SIRT4 was found to deacetylate U2AF2 at K413, facilitating the splicing of CCN2 pre-mRNA to promote CCN2 protein expression. Importantly, exosomes containing anti-SIRT4 antibodies were found to effectively mitigate the UUO-induced kidney fibrosis in mice. Collectively, these findings indicated that SIRT4 plays a role in kidney fibrosis by regulating CCN2 expression via the pre-mRNA splicing.

Based on electrophysiological activity, neuroprostheses can effectively monitor and control neural activity. Currently, electrophysiological neuroprostheses are widely utilized in treating neurological disorders, particularly in restoring motor, visual, auditory, and somatosensory functions after nervous system injuries. They also help alleviate inflammation, regulate blood pressure, provide analgesia, and treat conditions such as epilepsy and Alzheimer’s disease, offering significant research, economic, and social value. Enhancing the targeting capabilities of neuroprostheses remains a key objective for researchers. Modeling and simulation techniques facilitate the theoretical analysis of interactions between neuroprostheses and the nervous system, allowing for quantitative assessments of targeting efficiency. Throughout the development of neuroprostheses, these modeling and simulation methods can save time, materials, and labor costs, thereby accelerating the rapid development of highly targeted neuroprostheses. This article introduces the fundamental principles of neuroprosthesis simulation technology and reviews how various simulation techniques assist in the design and performance enhancement of neuroprostheses. Finally, it discusses the limitations of modeling and simulation and outlines future directions for utilizing these approaches to guide neuroprosthesis design.

AimsHypoalbuminemia can lead to underestimations of the true anion gap levels. There are few data on albumin-corrected serum anion gap (ACAG) status and mortality in the diabetes. The study aimed to examine the association between ACAG and all-cause, cardiovascular, and cancer mortality in type 2 diabetes (T2D) patients.MethodsHerein, 8,161 diabetic adults were included in the National Health and Nutrition Examination Survey (NHANES) 1999-2018. National Mortality Index (NDI) data were used for determining mortality outcomes through 31 December 2019. Cox proportional hazards models were used to estimate the risk of all-cause, cardiovascular, and cancer mortality. We conducted a mediation analysis using the counterfactual framework method to estimate how ACAG may be indirectly associated with increased mortality risk through mediators.ResultsA total of 2,309 deaths were documented over 8,161 person-years of follow up, including 659 cardiovascular and 399 cancer deaths. In multivariate analyses, higher ACAG levels had a significant correlation with an increase in all-cause (HR, 1.58; 95% CI, 1.38-1.81; P=0.001), cardiovascular (HR, 1.34; 95% CI, 1.05-1.72; P=0.019), and cancer (HR, 1.41; 95% CI, 1.02-1.96; P=0.018) mortality rates than the controls. Results of the mediation analysis showed that altered levels of C-reactive protein and estimated glomerular filtration rate (eGFR) explained 7.867% and 7.669% of the relation between serum ACAG and all-cause mortality, respectively (all P

Abstract Though sterile diet, post‐transplantation surgery is a clinical strategy for patient care to prevent the infiltration of gut pathogens, less is known about its effects on the gut microbiome. Here, the gut microbiome dynamics of leukemia patients following a 120‐day “sterile‐normal” diet strategy posthematopoietic cell transplantation are examined. In contrast to the traditional idea, a sterile diet leads to the lowest gut microbiota diversity (p

The key to inrush water control engineering in coal mine lies in forming a water-resistant barrier through the pouring of aggregate, which achieves flow interception and reduction. In order to quantitatively describe the spatiotemporal evolution mechanism of aggregate accumulation, an analytical calculation method is proposed to divide the process of aggregate settling and stacking into the process of particle layers superposition with a certain thickness and theoretical formulas for the entire process from settlement to pile after aggregate pouring in a dynamic water environment about critical parameters (horizontal displacement of particle xd, dynamic repose angle ψ, flow velocity in the topping zone U, critical flow velocity for aggregate retention Ucr) are proposed. Based on this, a prediction model about the growth of aggregate accumulation is constructed. The distribution characteristics of the flow field and the differences in aggregate accumulation morphology during the pouring period are studied with CFD-DEM, and the rationality of the prediction model is verified. The study reveals that spatially, the location of the main sedimentary domain during the initial interception phase can be divided into three regions, depending on whether the initial flow velocity Us exceeds the incipient flow velocity for particles Uc or the critical flow velocity for aggregate retention Ucr. That is considered ineffective pouring if the main sedimentary domain lies in region ③. Temporally, the growth process of aggregate accumulation can be summarized into three stages: a height rapid increase stage, a synchronous growth stage in height and length, and a stage with only horizontal elongation. The presence of the first stage is determined by the initial flow velocity, while the duration of the first stage is predominantly governed by the pouring conditions (particle size, pouring rate). A critical criterion for pore clogging and aggregate retention is derived based on sediment transport rate and incipient flow velocity from sediment dynamics. The numerical simulation experimental results indicate that the prediction model effectively characterizes the growth law of aggregate accumulation because the relative error between the theoretical calculation values and the simulated experiment values is less than 10% after the aggregate stacking stabilizes.

In this paper, the hot deformation behavior of Ti65 alloy was investigated over the temperature range of 930–1110 °C with the strain rate of 0.001–1 s−1. According to the stress-strain curves, the constitutive equation was developed to describe the flow behavior of Ti65 alloy. The processing maps were constructed based on the dynastic materials model (DMM) and the perfect formability zone of Ti65 alloy is found under the temperature of 970–1020 °C and the strain rate of 0.001–0.1 s−1. In addition, a three-dimensional nonlinear transient thermo-mechanically coupled finite element model of the multi-dimensional forging (MDF) process of Ti65 alloy was developed. The effects of the forging temperature and forging speed, on the temperature rise, residual stress, and grain refinement were predicted. By analyzing the temperature and stress distribution, the optimum forging temperature and speed for Ti65 alloys were determined to be 1000 °C and 10 mm/s, respectively. Increasing the forging temperature or reducing the forging speed reduces the temperature rise and the maximum tensile stress, thus reducing the risk of cracking. Additionally, the equivalent strain increases as forging speed decreases. Simultaneously, the accumulated strain is more significant for the inside of the forgings. The results of this research are instructive for the optimization of the MDF process.

The target of rapamycin (TOR) serves as a central regulator of cell growth, coordinating anabolic and catabolic processes in response to nutrient availability, growth factors, and energy supply. Activation of TOR has been shown to promote photosynthesis, growth, and development in yeast, animals, and plants. In this study, the complete cDNA sequence of the Lst8 gene was obtained from Nannochloropsis gaditana. The structure of N. gaditana LST8 comprises a typical WD40 repeat sequence, exhibiting high sequence similarity to several known LST8 proteins. By overexpressing the Lst8 gene in N. gaditana, we constructed the NgLst8 transgenic algal strain and measured its photosynthetic activity and growth. We observed that an increase in LST8 abundance promotes the expression of TOR-related kinase, thereby enhancing photosynthetic growth. Transcriptome analysis further elucidated the response mechanism of elevated Lst8 abundance in relation to photosynthesis. Our findings indicate that increased Lst8 expression activates ABC transporter proteins and the MAPK signaling pathway, which regulate the transmembrane transport of sugars and other metabolites, integrate photosynthesis, sugar metabolism, and energy signaling, and modulate energy metabolism in algal cells through interactions with the TOR signaling pathway.

ObjectiveThis research aimed to investigate the association between the blood urea nitrogen-to-creatinine (BUN/Cr) ratio and the rate of in-hospital mortality in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF), who are also receiving care in intensive care unit (ICU).MethodsA retrospective study was conducted using the MIMIC-IV database. We collected data on BUN/Cr levels at admission for patients with AIS and concurrent AF. To assess the association between BUN/Cr and in-hospital mortality rate, statistical analysis was conducted employing multivariable logistic regression models and restricted cubic spline models. These models were utilized to investigate the potential relationship and provide insights into the impact of BUN/Cr on the likelihood of in-hospital mortality. Interaction and subgroup analyses were performed to evaluate the consistency of the correlation.ResultsThere were a total of 856 patients (age ≥ 18 years) with a median age of 78.0 years, of which 466 (54.4%) were female. Out of 856 patients, 182 (21.26%) died in the hospital. Upon controlling for confounding factors, the multivariable logistic regression analysis elucidated that patients falling within the third trisection (Q3 > 22.41 mg/dL) exhibited a noticeably increased susceptibility to in-hospital mortality when contrasted with their counterparts positioned in the second trisection (Q2: 17.2–22.41 mg/dL) (OR = 2.02, 95% CI: 1.26–3.26, p = 0.004). A non-linear J-shaped relationship was observed between BUN/Cr at ICU admission and in-hospital mortality rate (p = 0.027), with a turning point at 19.63 mg/dL. In the threshold analysis, there was a 4% rise in in-hospital mortality for each 1 mg/dL increase in BUN/Cr (OR: 1.04, 95% CI: 1.01–1.06, p = 0.012).ConclusionIn patients with AIS complicated by AF, BUN/Cr at admission shows a J-shaped correlation with in-hospital mortality rate. When BUN/Cr exceeds 19.63 mg/dL, the in-hospital mortality rate increases.

ABSTRACT Microbial immigration is an ecological process in natural environments; however, the ecological trade-off mechanisms that govern the balance between species extinction and migration are still lacking. In this study, we investigated the mechanisms underlying the migration of diazotrophic communities from soil to leaves across six natural mangrove habitats in southern China. The results showed that the diazotrophic alpha and beta diversity exhibited significant regional and locational variations. The diazotrophic species pool gradually increased from the leaves to nonrhizosphere soil at each site, exhibiting a vertical distribution pattern. Mantel test analyses suggested that climate factors, particularly mean annual temperature, significantly influenced the structure of the diazotrophic community. The diazotrophic community assembly was mainly governed by dispersal limitation in soil and root samples, whereas dispersal limitation and ecological drift were dominant in leaves. Partial least squares path modeling revealed that the species pool and soil properties, particularly the oxidation-reduction potential and pH, were closely linked to the species-immigration ratio of diazotrophic communities. Our study provides novel insights for understanding the ecological trait diversity patterns and spread pathways of functional microbial communities between below- and aboveground habitats in natural ecosystems.IMPORTANCEEnvironmental selection plays key roles in microbial transmission. In this study, we have provided a comprehensive framework to elucidate the driving patterns of the ecological trade-offs in diazotrophic communities across large-scale mangrove habitats. Our research revealed that Bradyrhizobium japonicum, Marinobacterium lutimaris, and Agrobacterium tumefaciens were more abundant in root-associated soil than in leaves by internal and external pathways. The nonrhizospheric and rhizospheric soil samples harbored the most core amplicon sequence variants, indicating that these dominant diazotrophs could adapt to broader ecological niches. Correlation analysis indicated that the diversities of the diazotrophic community were regulated by biotic and abiotic factors. Furthermore, this study found a lower species immigration ratio in the soil than in the leaves. Both species pool and soil properties regulate the species-immigration mechanisms of the diazotrophic community. These results suggest that substantial species immigration is a widespread ecological process, leading to alterations in local community diversity across diverse host environments.

Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development. In this study, we present an innovative, integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride (NC), a promising anti-tumor drug candidate. Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney, particularly within the inner cortex (IC) region, following single and repeated dose of NC. High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule. Employing spatial metabolomics based on AFADESI-MSI, we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure. These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters (organic cation transporters, multidrug and toxin extrusion, and organic cation transporter 2 (OCT2)), metabolic enzymes (protein arginine N-methyltransferase (PRMT) and nitric oxide synthase), mitochondria, oxidative stress, and inflammation in NC-induced nephrotoxicity. This study offers novel insights into NC-induced renal damage, representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.

ObjectiveAnaprazole, an innovative drug, has shown promise in initial clinical trials for patients with duodenal ulcers (DU) in China. This study aimed to evaluate the potential effects, safety, and cost-effectiveness of Anaprazole compared to Ilaprazole in the treatment of DU and the budgetary impact on the healthcare system.MethodsTwo multicentre, randomized controlled trials were used as data sources. The efficacy and safety of Anaprazole and Ilaprazole were compared using an anchored matching-adjusted indirect comparison (MAIC). A cost-utility analysis (CUA) was performed using a Markov model. A budget impact analysis (BIA) was conducted to evaluate the impact on the expenditure of the Chinese healthcare system. Deterministic and probabilistic sensitivity analyses were undertaken to test the uncertainty.ResultsThe study findings indicated that Anaprazole and Ilaprazole have similar efficacy and safety in treating DU (OR = 1.05; 95% CI, 0.94–1.01; p = 0.35; OR = 0.63; 95% CI, 0.39–1.08; p = 0.12). The ICUR was 2,995.41¥/QALY, which is below the WTP threshold. The CUA results showed that Anaprazole is a cost-effective intervention with a probability of 85% at a given threshold. The results demonstrated strong robustness in the sensitivity analysis. Anaprazole imposed a low burden on the Chinese healthcare budget in the BIA.ConclusionCompared with Ilaprazole, Anaprazole has similar efficacy, safety, and high cost-effectiveness, while also impacting the total expenditure of the healthcare system.Clinical Trial Registration:ClinicalTrials.gov, identifier NCT04215653 and NCT02847455

Abstract Treatment for anterior cruciate ligament (ACL) tears depends on the condition of the ligament. We aimed to identify different tear statuses from preoperative MRI using deep learning-based radiomics with sex and age. We reviewed 862 patients with preoperative MRI scans reflecting ACL status from Hunan Provincial People’s Hospital. Based on sagittal proton density-weighted images, a fully automated approach was developed that consisted of a deep learning model for segmenting ACL tissue (ACL-DNet) and a deep learning-based recognizer for ligament status classification (ACL-SNet). The efficacy of the proposed approach was evaluated by using the sensitivity, specificity and area under the receiver operating characteristic curve (AUC) and compared with that of a group of three orthopedists in the holdout test set. The ACL-DNet model yielded a Dice coefficient of 98% ± 6% on the MRI datasets. Our proposed classification model yielded a sensitivity of 97% and a specificity of 97%. In comparison, the sensitivity of alternative models ranged from 84 to 90%, while the specificity was between 86 and 92%. The AUC of the ACL-SNet model was 99%, demonstrating high overall diagnostic accuracy. The diagnostic performance of the clinical experts as reflected in the AUC was 96%, 92% and 88%, respectively. The fully automated model shows potential as a highly reliable and reproducible tool that allows orthopedists to noninvasively identify the ACL status and may aid in optimizing different techniques, such as ACL remnant preservation, for ACL reconstruction.

Abstract Selective-area p-type doping has been regarded as one of the primary challenges in vertical GaN junction-based power devices. Nickel oxide (NiO), serving as a natural p-type semiconductor without the requirement for sophisticated activation and enabling adjustable charge concentration, is potentially feasible to form pn hetero-junction in GaN power devices. In this work, a vertical GaN Schottky barrier diode (SBD) featuring hybrid p-NiO junction termination extension (HP-JTE) with fluorine (F)-implanted buried layer (FIBL) has been demonstrated. With FIBL incorporated underneath p-NiO in the termination region, the reverse leakage current can be effectively reduced by approximately 3 orders of magnitude. By virtue of photon emission microscopy measurements, it has also been verified that the light emission and leakage current through p-NiO termination region can be effectively suppressed by FIBL. Thanks to the HP-JTE structure as well as the nearly ideal Schottky interface, the vertical GaN SBD exhibits a high current swing of $\sim 10^{13}$ , a low ideality factor of $\sim 1.02$ , a low differential $R_{O N}$ of $\sim 0.89 \mathrm{~m} \Omega \cdot \mathrm{cm}^2$ , a low forward voltage drop of $\sim 0.8 \mathrm{~V}$ (defined at $100 \mathrm{~A} / \mathrm{cm}^2$ ), and a breakdown voltage of $\sim 780 \mathrm{~V}$ (defined at $0.1 \mathrm{~A} / \mathrm{cm}^2$ ). The characterizations and findings in this work can provide valuable insights into the p-NiO/GaN hetero-junction-based power devices.

Abstract Background The relationship between leukocyte telomere length (LTL) and mortality risk in individuals with metabolic syndrome (MetS) remains poorly understood. This study aimed to investigate the association between telomere length and long-term all-cause mortality, and cardiovascular disease (CVD) mortality, in individuals with MetS in the United States. Methods A total of 1980 participants with MetS aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (1999–2002) were included in this cohort study. Medical records review was used to identify the cause of deaths as of December 2018. We employed Kaplan-Meier curves, fitted curves, and Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD mortality, stratified by tertiles of LTL. Results Over a median follow-up of 17.75 years of participants with metabolic syndrome, 819 deaths occurred, including 231 cardiovascular deaths. After adjusting for multiple covariates, participants with shorter telomere length had a significantly higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.11–1.6) and CVD mortality (HR, 1.36; 95% CI, 0.96–1.93) compared with those in the highest tertile of telomere length. All-cause mortality (P

Abstract Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-β1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-β1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Diabetic cardiomyopathy (DCM) is a metabolic disease and a leading cause of heart failure among people with diabetes. Mass spectrometry imaging (MSI) is a versatile technique capable of combining the molecular specificity of mass spectrometry (MS) with the spatial information of imaging. In this study, we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity. We optimized the air flow-assisted desorption electrospray ionization (AFADESI)-MSI platform to detect a wide range of metabolites, and then used matrix-assisted laser desorption ionization (MALDI)-MSI for increasing metabolic coverage and improving localization resolution. AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections, respectively, while MALDI-MSI detected 61 metabolites in negative analysis. Our study revealed the heterogenous metabolic profile of the heart in a DCM model, with over 105 region-specific changes in the levels of a wide range of metabolite classes, including carbohydrates, amino acids, nucleotides, and their derivatives, fatty acids, glycerol phospholipids, carnitines, and metal ions. The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model. Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.

Abstract Background Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR‐92b on the upregulation of exercise training‐induced physical performance. Methods Adeno‐associated virus (AAV)‐mediated skeletal muscle miR‐92b overexpression in C57BLKS/J mice, and global knockout of miR‐92b mice were used to explore the function of miR‐92b in glycogen and lactate metabolism in skeletal muscle. AAV‐mediated UGP2 or MCT4 knockdown in WT or miR‐92 knockout mice was used to confirm whether miR‐92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results Global knockout of miR‐92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR‐92b (both miR‐92b‐3p and miR‐92b‐5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P

The multiprotein Target of Rapamycin (TOR) Complex 1 (TORC1) is a serine/threonine kinase that stimulates anabolic metabolism and suppresses catabolism. Deregulation of TORC1 is implicated in various human pathologies, including cancer, epilepsy, and neurodegenerative disorders. The Gap Activity Towards Rags (GATOR) complex contains two subcomplexes: GATOR1, which inhibits TORC1 activity; and GATOR2, which counteracts GATOR1s function. Structural and biochemical studies have elucidated how GATOR1 regulates TORC1 activity by acting as a GTPase activating protein for Rag GTPase. However, while cryogenic electron microscopy has determined that the structure of the multi-protein GATOR2 complex is conserved from yeast to humans, how GATOR2 inhibits GATOR1 remains unclear. Here, we describe recent whole-animal studies in Drosophila that have yielded novel insights into GATOR2 function, including identifying a novel role for the GATOR2 subunit WDR59, redefining the core proteins sufficient for GATOR2 activity, and defining a TORC1-independent role for GATOR2 in the regulation of the lysosomal autophagic endomembrane system. Additionally, the recent characterization of a novel methionine receptor in Drosophila that acts through the GATOR2 complex suggests an attractive model for the evolution of species-specific nutrient sensors. Research on GATOR2 function in Drosophila highlights how whole-animal genetic models can be used to dissect intracellular signaling pathways to identify tissue-specific functions and functional redundancies that may be missed in studies confined to rapidly proliferating cell lines.

Abstract Obese sarcopenia is a severe and prevalent disease in an aging society. Compared to sarcopenia alone, the development and advanced stage of obesity sarcopenia is faster and more severe. Diagnosis of the cause of adipocyte accumulation is also more complicated; however, no effective pharmacological treatment is available. Chronic inflammation is one of the causes of sarcopenia, and obese patients, who are more likely to develop chronic inflammation, may simultaneously suffer from obesity and sarcopenia. Mitochondrial metabolic disorders have been more easily observed in the tissue cells of patients with obesity and sarcopenia. Mitochondrial metabolic disorders include abnormal mtDNA release, mitochondrial autophagy, and dynamic mitochondrial disorders. Therefore, this review will reveal the mechanism of development of obesity myasthenia gravis from the perspective of mitochondria and discuss the currently existing small-molecule drugs.

Abstract Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin FS621G inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin FS621G also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin FS195R, and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.

Abstract Background The pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear. Methods This study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed. Results In this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that β-catenin and the downstream of Wnt/β-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated β-catenin protein in a concentration-dependent manner. However, overexpression of β-catenin did not affect RhoA-ROCK levels, suggesting that β-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of β-catenin and up-regulated β-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/β-catenin signaling. Overexpression of β-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment. Conclusion Our novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-β-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.

Abstract Background The autonomic nervous system can be responsible for the initiation and maintenance of arrhythmias. Low-level tragus stimulation (LLTS), a noninvasive form of autonomic neuromodulation, has been shown to be effective in treating atrial fibrillation. We intended to treat frequent premature ventricular complexes (PVCs) with LLTS. Methods and design The present study will be a prospective multicenter, double-blind, randomized, controlled trial to assess the antiarrhythmic effects of LLTS on frequent PVCs in patients without structured heart disease (SHD). A total of 100 patients with PVC burden > 10% will be randomly assigned to the active or sham LLTS in 1:1 fashion and receive the proposed intervention for 6 months. The primary outcome is PVC burden at 6 months as assessed by 10 days of continuous ambulatory electrocardiographic monitoring. Secondary outcomes include heart rate variability (HRV), quality of life, skin sympathetic nerve activity, and inflammatory markers. Adverse events will also be recorded. Discussion The present trial will be the first to evaluate the effect of LLTS on frequent PVCs on patients without SHD. LLTS may serve as a low-cost, minimal-risk, and non-invasive alternative to conventional antiarrhythmic therapy. Trial registration ClinicalTrial.gov NCT04909528. Registered on 17 June 2021. World health organization trial registration data set was shown in Supplementary Table 1.

Abstract Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.

Hot extrusion process can improve the mechanical properties of materials. However, due to the presence of SiC particles, SiCp/Al composites are prone to fracture damage in the extrusion process. To determine the optimal processing parameters, the processing maps of 17 vol.% SiCp/2009Al composite were established using power dissipation rate and Murty instability criterion. Furthermore, taking aluminum canning into consideration, a three-dimensional macroscopic hot extrusion finite element model of SiCp/Al composite was constructed. The influences of initial temperature, canning morphology and canning thickness on extrusion properties were predicted, and verified by comparison of processing maps and experiments. The optimal extrusion parameters for SiCp/2009Al composite are located within the window of temperature, 450–475 °C and strain rate, 0.001–0.004 s−1 or 0.6–1 s−1. Additionally, the properties of the SiCp/Al composite can be greatly improved by hot extrusion with a suitable canning. Of these, the half canning finish the extrusion task faster, but the extrusion properties under the bottom canning are the best. When the ratio of the canning thickness to the diameter of the workpiece is about 0.17, the effective stress, strain and damage are minimum. The work performed in this research, for the first time, provides quantitative evaluations of process parameters on the hot deformation of SiCp/Al composite, which enables to provide useful guides for hot extrusion parameters selection of SiCp/Al composite.

Missing data is unavoidable in longitudinal clinical trials, and outcomes are not always normally distributed. In the presence of outliers or heavy-tailed distributions, the conventional multiple imputation with the mixed model with repeated measures analysis of the average treatment effect (ATE) based on the multivariate normal assumption may produce bias and power loss. Control-based imputation (CBI) is an approach for evaluating the treatment effect under the assumption that participants in both the test and control groups with missing outcome data have a similar outcome profile as those with an identical history in the control group. We develop a robust framework to handle non-normal outcomes under CBI without imposing any parametric modeling assumptions. Under the proposed framework, sequential weighted robust regressions are applied to protect the constructed imputation model against non-normality in the covariates and the response variables. Accompanied by the subsequent mean imputation and robust model analysis, the resulting ATE estimator has good theoretical properties in terms of consistency and asymptotic normality. Moreover, our proposed method guarantees the analysis model robustness of the ATE estimation in the sense that its asymptotic results remain intact even when the analysis model is misspecified. The superiority of the proposed robust method is demonstrated by comprehensive simulation studies and an AIDS clinical trial data application.

Abstract Spinal cord injuries (SCI) are usually caused by mechanical trauma that leads to serious physical and psychological damage to the patient as well as a huge economic burden to the whole society. The prevention, treatment, and rehabilitation of spinal cord injuries have become a major issue for the medical community today due to the enormous social and economic expenditure induced via spinal cord injuries. Therefore, in-depth research into SCI is necessary. Microglia have been shown to be the key player in the immune inflammatory response after spinal cord injury, but the mechanisms of immune regulation at different time points after spinal cord injury remain unclear. To investigate the inflammatory biomarkers associated with microglia at different time points after SCI, we downloaded single-cell RNA sequencing data from mouse spinal cords 3- and 14-days after the injury and identified subpopulations associated with microglia. Further functional enrichment analysis also confirmed that microglia are associated with immune system regulation at different time points and that both can modulate cytokine production. As ferroptosis is a newly identified non-apoptotic programmed cell death, microglia establish a bridge between ferroptosis and CNS inflammation and may play an important role in spinal cord injury. We then screened for genes differentially expressed in microglia during 3- and 14-days after spinal cord injury and associated with iron death, named Stmn1 and Fgfbr1, respectively, and verified that these pivotal genes are closely related to the immune cells. Finally, we also screened for drug fractions associated with these pivotal genes. Our results predict key genes in the immune inflammatory process associated with microglia at different time points after spinal cord injury at the single-cell level and provide a molecular basis for better treatment of SCI.

Microorganisms, especially rare microbial species, are crucial in estuarine ecosystems for driving biogeochemical processes and preserving biodiversity. However, the understanding of the links between ecosystem multifunctionality (EMF) and the diversity of rare bacterial taxa in estuary ecosystems remains limited. Employing high-throughput sequencing and a variety of statistical methods, we assessed the diversities and assembly process of abundant and rare bacterioplankton and their contributions to EMF in a subtropical estuary. Taxonomic analysis revealed Proteobacteria as the predominant phylum among both abundant and rare bacterial taxa. Notably, rare taxa demonstrated significantly higher taxonomic diversity and a larger species pool than abundant taxa. Additionally, our findings highlighted that deterministic assembly processes predominantly shape microbial communities, with heterogeneous selection exerting a stronger influence on rare taxa. Further analysis reveals that rare bacterial beta-diversity significantly impacts to EMF, whereas alpha diversity did not. The partial least squares path modeling (PLS-PM) analysis demonstrated that the beta diversity of abundant and rare taxa, as the main biotic factor, directly affected EMF, while temperature and total organic carbon (TOC) were additional key factors to determine the relationship between beta diversity and EMF. These findings advance our understanding of the distribution features and ecological knowledge of the abundant and rare taxa in EMF in subtropical estuaries, and provide a reference for exploring the multifunctionality of different biospheres in aquatic environments.

Abstract Vibrio is a salt‐tolerant heterotrophic bacterium that occupies an important ecological niche in marine environments. However, little is known about the contribution of resource diversity to the marine Vibrio diversity and community stability. In this study, we investigated the association among resource diversity, taxonomic diversity, phylogenetic diversity, and community stability of marine Vibrio in the Beibu Gulf. V. campbellii and V. hangzhouensis were the dominant groups in seawater and sediments, respectively, in the Beibu Gulf. Higher alpha diversity was observed in the sediments than in the seawater. Marine Vibrio community assembly was dominated by deterministic processes. Pearson's correlation analysis showed that nitrite (NO2−‐N), dissolved inorganic nitrogen (DIN), ammonium (NH4+‐N), and pH were the main factors affecting marine Vibrio community stability in the surface, middle, and bottom layers of seawater and sediment, respectively. Partial least‐squares path models (PLS‐PM) demonstrated that resource diversity, water properties, nutrients, and geographical distance had important impacts on phylogenetic and taxonomic diversity. Regression analysis revealed that the impact of resource diversity on marine Vibrio diversity and community stability varied across different habitats, but loss of Vibrio diversity increases community stability. Overall, this study provided insights into the mechanisms underlying the maintenance of Vibrio diversity and community stability in marine environments.

Abstract Helical structures of liquid crystal elastomers (LCEs) hold promise in soft robotics for self‐regulated rolling motions. The understanding of their motion paths and potentials for terrain exploration remains limited. This study introduces a self‐adjusting, lateral‐rolling soft robot inspired by sidewinder snakes. The spring‐like LCE helical filaments (HFs) autonomously respond to thermal cues, demonstrating dynamic and sustainable locomotion with adaptive rolling along non‐linear paths. By fine‐tuning the diameter, pitch, and modulus of the LCE HFs, and the environmental temperature, the movements of the LCE HFs, allowing for exploration of diverse terrains over a 600 cm2 area within a few minutes, can be programmed. LCE HFs are showcased to navigate through over nine obstacles, including maze escaping, terrain exploration, target hunting, and successfully surmounting staircases through adaptable rolling.

Summary: Traditional loss functions such as cross-entropy loss often quantify the penalty for each mis-classified training sample without adequately considering its distance from the ground truth class distribution in the feature space. Intuitively, the larger this distance is, the higher the penalty should be. With this observation, we propose a penalty called distance-weighted Sinkhorn (DWS) loss. For each mis-classified training sample (with predicted label A and true label B), its contribution to the DWS loss positively correlates to the distance the training sample needs to travel to reach the ground truth distribution of all the A samples. We apply the DWS framework with a neural network to classify different stages of Alzheimer’s disease. Our empirical results demonstrate that the DWS framework outperforms the traditional neural network loss functions and is comparable or better to traditional machine learning methods, highlighting its potential in biomedical informatics and data science.

ObjectiveThis study aimed to evaluate the SpO2 (transcutaneous oxygen saturation) -mortality link in elderly T2DM (diabetes mellitus type 2) patients with cerebral infarction and identify their optimal SpO2 range.MethodsIn this investigation, we employed a comprehensive approach. Initially, we screened the MIMIC-IV database, identifying elderly T2DM patients with cerebral infarction, utilizing specific ICD-9 and ICD-10 codes. We then harnessed the power of restricted cubic splines to craft a visual representation of the correlation between SpO2 and 1-year mortality. To enhance our analysis, we harnessed Cox multivariate regression, allowing us to compute adjusted hazard ratios (HR) accompanied by 95% confidence intervals (CIs). Additionally, we crafted Cumulative Mortality Curve analyses, augmenting our study by engaging in rigorous subgroup analyses, stratifying our observations based on pertinent covariates.ResultsIn this study, 448 elderly T2DM patients with cerebral infarction were included. Within 1-year post-discharge, 161 patients (35.94%) succumbed. Employing Restricted Cubic Spline analysis, a statistically significant U-shaped non-linear relationship between admission ICU SpO2 levels and 1-year mortality was observed (P-value < 0.05). Further analysis indicated that both low and high SpO2 levels increased the mortality risk. Cox multivariate regression analysis, adjusting for potential confounding factors, confirmed the association of low (≤94.5%) and high SpO2 levels (96.5–98.5%) with elevated 1-year mortality risk, particularly notably high SpO2 levels (>98.5%) [HR = 2.06, 95% CI: 1.29–3.29, P-value = 0.002]. The cumulative mortality curves revealed the following SpO2 subgroups from high to low cumulative mortality at the 365th day: normal levels (94.5% < SpO2 ≤ 96.5%), low levels (SpO2 ≤ 94.5%), high levels (96.5% < SpO2 ≤ 98.5%), and notably high levels (>98.5%). Subgroup analysis demonstrated no significant interaction between SpO2 and grouping variables, including Sex, Age, Congestive heart failure, Temperature, and ICU length of stay (LOS-ICU; P-values for interaction were >0.05).ConclusionsStriking an optimal balance is paramount, as fixating solely on lower SpO2 limits or neglecting high SpO2 levels may contribute to increased mortality rates. To mitigate mortality risk in elderly T2DM patients with cerebral infarction, we recommend maintaining SpO2 levels within the range of 94.5–96.5%.

Previously, we demonstrated that the SCFcyclin F complex directly mediates the poly-ubiquitylation of TDP-43, raising the question of whether cyclin F can be used to enhance the turnover of TDP-43. A hurdle to the use of cyclin F, however, is that the overexpression of cyclin F can lead to the initiation of cell death pathways. Accordingly, the aim of this study was to identify and evaluate a less toxic variant of cyclin F. To do so, we first confirmed and validated our previous findings that cyclin F binds to TDP-43 in an atypical manner. Additionally, we demonstrated that mutating the canonical substrate region in cyclin F (to generate cyclin FMRL/AAA) led to reduced binding affinity to known canonical substrates without impacting the interaction between cyclin F and TDP-43. Notably, both wild-type and cyclin FMRL/AAA effectively reduced the abundance of TDP-43 in cultured cells whilst cyclin FMRL/AAA also demonstrated reduced cell death compared to the wild-type control. The decrease in toxicity also led to a reduction in morphological defects in zebrafish embryos. These results suggest that cyclin F can be modified to enhance its targeting of TDP-43, which in turn reduces the toxicity associated with the overexpression of cyclin F. This study provides greater insights into the interaction that occurs between cyclin F and TDP-43 in cells and in vivo.

Abstract Vitamin D plays a vital role in immunity and is related to susceptibility and the severity of pneumonia. The home confinement caused by the novel coronavirus disease (COVID‐19) decreased sunlight exposure derived from outdoor activities in children, thereby possibly exerting an influence on 25‐hydroxyvitamin D [25(OH)D] levels. The aim of this study is to quantify vitamin D level changes and trends among infants and toddlers with community‐acquired pneumonia (CAP) during and post the home confinement period. This study included children who were hospitalized in the respiratory department of the Children's Hospital of Chongqing Medical University with CAP between February 1 and July 31 from 2020 to 2022 (N = 397). We used propensity score matching to control the confounding bias. The levels and trends of the children's serum 25(OH)D concentrations overall and by age groups were compared between the different periods. The serum 25(OH)D concentration during the home confinement period was lower (p

Objective: To study the anti-fatigue effects of mulberry anthocyanins (AM) and discuss the mechanism in mice. Methods: After preparation and analysis, the the antioxidant activity AM was evaluated. The mice were randomly divided into the quiet group, the aerobic exercise group, the model group, the low, medium and high does groups (the AM dosage were 100, 200 and 400 mg/kg/d, respectively), and exhaustive swimming test were performed. After mouse were orally administered for 4 weeks, the fatigue-related biochemical indicators were measured to evaluate the anti-fatigue effect of AM, such as the levels of blood lactic acid (Lac), blood urea nitrogen (BUN) and malondialdehyde (MDA) the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Meanwhile, the anti-fatigue mechanism was explained by the relative expression levels of Nrf2 and HO-1 mRNA. Result: After enrichment and purification, the contents of active components in AM were increased, and showed the antioxidant capacity that equivalented to vitamin C. Compared with the model group, the low, medium and high does groups were significantly prolonged exhaustive swimming time (P

Background: Tuberculosis (TB) continues to be prevalent in China also among children and adolescents in China. We built a dynamic mathematical model for TB transmission in China, and applied it to compare the epidemic trends 2021–2030 under a range of screening interventions focusing on children and adolescents. Methods: We developed a dynamic mathematical model with a flexible structure. The model can be applied either stochastically or deterministically, and can encompass arbitrary age structure and resistance levels. In the present version, we used the deterministic version excluding resistance but including age structure with six groups: 0–5, 6–11, 12–14, 15–17, 18–64, and 65 years and above. We parameterized the model by literature data and fitting it to case and death estimates provided by the World Health Organization. We compared the new TB cases and TB-related deaths in each age group over the period 2021–2030 in 10 scenarios that involved intensified screening of particular age groups of children, adolescents, or young adults, or decreased or increased diagnostic accuracy of the screening. Results: Screening the entire age class of 18-year-old persons would prevent 517,000 TB cases and 14,600 TB-related deaths between years 2021 and 2030, corresponding to 6.6% and 5.5% decrease from the standard of care projection, respectively. Annual screening of children aged 6–11 and, to a lesser extent, 0–5 years, also reduced TB incidence and mortality, particularly among children of the respective ages but also in other age groups. In contrast, intensified screening of adolescents did not have a major impact. Screening with a simpler and less accurate method resulted in worsened outcomes, which could not be offset by more intensive screening. More accurate screening and better sensitivity to detect latent TB could prevent 2.3 million TB cases and 68,500 TB deaths in the coming 10 years. Conclusion: Routine screening in schools can efficiently reduce the burden of TB in China. Screening should be intensified particularly among children in primary school age.