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Abstract Background The prevention of catheter-related bloodstream infections (CRBSI) is a critical priority in the clinical management of central venous catheters (CVCs). This meta-analysis aims to evaluate the efficacy of chlorhexidine gluconate antibacterial dressings in the context of CVC care. Methods A systematic literature search was performed in PubMed, Web of Science, Embase et al. databases up to May 28, 2024. The search targeted randomized controlled trials (RCTs) that investigated the impact of chlorhexidine gluconate antibacterial dressings on CVC-related outcomes. The meta-analysis was conducted using RevMan 5.3 software. Results The final analysis included 14 RCTs involving a total of 8920 patients with CVCs, with participants divided into a chlorhexidine antibacterial dressing group (n = 4731) and a control group (n = 4189). The chlorhexidine dressing group demonstrated a statistically significant reduction in the incidence of CRBSI compared to the control group, with a relative risk (RR) of 0.48, 95% confidence interval (CI) 0.36–0.64, P 0.05). Conclusions There is a notable reduction in the incidence of CRBSI and bacterial colonization in patients with CVCs through the application of chlorhexidine gluconate dressings. Given the compelling evidence, the integration of these dressings into standard nursing care protocols for the management of CVCs is advocated.

Objective To explore the role and mechanism of pumilio homolog 1 （PUM1） in hypoxia/reoxygenation induced cell injury in human renal tubular epithelial cells （HK-2）. Methods A hypoxia/reoxygenation （H/R） model of HK-2 cells was established in vitro. PUM1 expression was knocked down through small interfering RNA （siRNA）. Cells were randomized into three groups of control， hypoxia/reoxygenation （H/R） and H/R+siRNA. Western blot （WB） method was used for detecting the expression level of PUM1 protein. Cell Count Kit 8 （CCK-8） was employed for detecting cell viability. Hydrogen peroxide （H2O2）， malondialdehyde （MDA） and superoxide dismutase （SOD） were used for evaluating the levels of oxidative stress. Flow cytometry was utilized for detecting the level of cell apoptosis. Results As compared with control group， protein expression level of PUM1 in H/R 3 h group （1.76 ± 0.11 vs 0.98 ± 0.05）， H/R 6 h group （2.89 ± 0.14 vs 0.98 ± 0.05） and H/R 12 h group （3.78 ± 0.08 vs 0.98 ± 0.05） gradually spiked with the prolongation of hypoxic time. As compared with H/R group， knocking down the expression of PUM1 significantly improved the cell viability （73.67 ± 3.42 vs 29.60 ± 2.94）， oxidative stress [H2O2:（13.53 ± 0.85）μmol/L vs （22.43 ± 1.12）μmol/L， MDA: （16.03 ± 0.70）μmol/L vs （31.20 ± 1.50）μmol/L， SOD: （34670 ± 1800）U/L vs （5730 ± 1220）U/L] and apoptotic level [（14.89 ± 1.65）% vs （39.71 ± 1.94）%] after H/R in H/R+si-PUM1 group. Conclusion PUM1 is up-regulated in H/R induced HK-2 cells and its inhibition may alleviate H/R injury through reducing oxidative stress and lowering cell apoptosis levels.

Abstract Background The histone-lysine N-methyltransferase SMYD1, which is specific to striated muscle, plays a crucial role in regulating early heart development. Its deficiency has been linked to the occurrence of congenital heart disease. Nevertheless, the precise mechanism by which SMYD1 deficiency contributes to congenital heart disease remains unclear. Methods We established a SMYD1 knockout pluripotent stem cell line and a doxycycline-inducible SMYD1 expression pluripotent stem cell line to investigate the functions of SMYD1 utilizing an in vitro-directed myocardial differentiation model. Results Cardiomyocytes lacking SMYD1 displayed drastically diminished differentiation efficiency, concomitant with heightened proliferation capacity of cardiac progenitor cells during the early cardiac differentiation stage. These cellular phenotypes were confirmed through experiments inducing the re-expression of SMYD1. Transcriptome sequencing and small molecule inhibitor intervention suggested that the GSK3β/β-catenin&ERK signaling pathway was involved in the proliferation of cardiac progenitor cells. Chromatin immunoprecipitation demonstrated that SMYD1 acted as a transcriptional activator of GSK3β through histone H3 lysine 4 trimethylation. Additionally, dual-luciferase analyses indicated that SMYD1 could interact with the promoter region of GSK3β, thereby augmenting its transcriptional activity. Moreover, administering insulin and Insulin-like growth factor 1 can enhance the efficacy of myocardial differentiation in SMYD1 knockout cells. Conclusions Our research indicated that the participation of SMYD1 in the GSK3β/β-catenin&ERK signaling cascade modulated the proliferation of cardiac progenitor cells during myocardial differentiation. This process was partly reliant on the transcription of GSK3β. Our research provided a novel insight into the genetic modification effect of SMYD1 during early myocardial differentiation. The findings were essential to the molecular mechanism and potential interventions for congenital heart disease. Graphical abstract

Abstract Background Stroke is a leading cause of death worldwide, with oxidative stress and calcium overload playing significant roles in the pathophysiology of the disease. Ozone, renowned for its potent antioxidant properties, is commonly employed as an adjuvant therapy in clinical settings. Nevertheless, it remains unclear whether ozone therapy on parthanatos in cerebral ischemia–reperfusion injury (CIRI). This study aims to investigate the impact of ozone therapy on reducing parthanatos during CIRI and to elucidate the underlying mechanism. Methods Hydrogen peroxide (H2O2) was utilized to mimic the generation of reactive oxygen species (ROS) in SH-SY5Y cell reperfusion injury in vitro, and an in vivo ischemic stroke model was established. Ozone saline was introduced for co-culture or intravenously administered to mice. Apoptosis and oxidative stress were assessed using flow cytometry and immunofluorescence. Western blotting was utilized to examine the expression of parthanatos signature proteins. The mechanism by which ozone inhibits parthanatos was elucidated through inhibiting PPARg or Nrf2 activity. Results The findings demonstrated that ozone mitigated H2O2-induced parthanatos by either upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) or activating peroxisome proliferator-activated receptorg (PPARg). Furthermore, through the use of calcium chelators and ROS inhibitors, it was discovered that ROS directly induced parthanatos and facilitated intracellular calcium elevation. Notably, a malignant feedback loop between ROS and calcium was identified, further amplifying the induction of parthanatos. Ozone therapy exhibited its efficacy by increasing PPARg activity or enhancing the Nrf2 translation, thereby inhibiting ROS production induced by H2O2. Concurrently, our study demonstrated that ozone treatment markedly inhibited parthanatos in stroke-afflicted mice. Additionally, ozone therapy demonstrated significant neuroprotective effects on cortical neurons, effectively suppressing parthanatos. Conclusions These findings contribute valuable insights into the potential of ozone therapy as a therapeutic strategy for reducing parthanatos during CIRI, highlighting its impact on key molecular pathways associated with oxidative stress and calcium regulation.

High-pressure waterjet-assisted tunnel boring machine (WTBM) is an efficient method for improving the tunneling performance of a tunnel boring machine (TBM) and reducing the wear of its disc cutters in hard rock with high geostresses. Confining pressure directly affects the efficiency of rock breaking and the configuration of the disc cutters. In this study, we evaluated the effect of confining pressure on WTBM rock breaking by developing a self-designed and manufactured experimental system, including confining pressure loading, TBM disc-cutter penetration, and high-pressure waterjet. The macro fracture, acoustic emission (AE), peak normal force drop, and specific energy (SE) were analyzed for four different confining pressures (10, 20, 30, and 35 MPa). The results showed that the cutting depth of the waterjet increased linearly as the waterjet pressure increased and decreased with the gradual increase in the nozzle moving speed. The expansion and development of cracks formed rock debris, and the size of the rock fragments decreased with an increase in confining pressure. When the waterjet pressure was 280 MPa, the nozzle moving velocity was 800 mm/min and the kerf space was 75 mm, which indicated that the confining pressure, which was 23.16 MPa, minimized the cutting SE under this condition. However, regardless of the confining pressure, the maximum normal force of WTBM was less than that of a TBM, whereas the SE of WTBM was less than that of complete TBM cutting mode (CTCM). The average force drop and average drop rate of SE were approximately 25%, and 80%, respectively. The results of this study can inspire the design and mechanism of a TBM assisted by a high-pressure waterjet.

Autophagy is a kind of “self-eating” phenomenon that is ubiquitous in eukaryotic cells. It mainly manifests in the damaged proteins or organelles in the cell being wrapped and transported by the autophagosome to the lysosome for degradation. Many factors cause autophagy in cells, and the mechanism of nutrient-deficiency-induced autophagy has been a research focus. It has been reported that amino-acid-deficiency-induced cellular autophagy is mainly mediated through the mammalian rapamycin target protein complex 1 (mTORC1) signaling pathway. In addition, some researchers also found that non-mTORC1 signaling pathways also regulate autophagy, and the mechanism of autophagy occurrence induced by the deficiency of different amino acids is not precisely the same. Therefore, this review aims to summarize the process of various amino acids regulating cell autophagy and provide a narrative review on the molecular mechanism of amino acids regulating autophagy.

Abstract Grain boundary plays a vital role in thermoelectric transports, leading to distinct properties between single crystals and polycrystals. Manipulating the grain boundary to realize good thermoelectric properties in polycrystals similar as those of single crystals is a long-standing task, but it is quite challenging. Herein, we develop a liquid-phase sintering strategy to successfully introduce Mg2Cu nano-sintering-aid into the grain boundaries of Mg3(Bi, Sb)2-based materials. The nano-aid helps to enlarge the average grain size to 23.7 μm and effectively scatter phonons, leading to excellent electrical transports similar as those of single crystals and ultralow lattice thermal conductivity as well as exceptional thermoelectric figure of merit (1.5 at 500 K) and conversion efficiency (7.4% under temperature difference of 207 K). This work provides a simple but effective strategy for the fabrication of high-performance polycrystals for large-scale applications.

Abstract Background Patients with skeletal angle Class III malocclusion usually have inadequate hard and soft tissue volume at the mandibular anterior teeth. The labial proclination at the teeth may lead to gingival recession. The purpose of this study was to explore whether periodontal phenotype modification therapy with soft tissue augmentation (PhMT-s) can prevent gingival recession in these patients. Methods Four patients with skeletal Class III malocclusion and a thin periodontal phenotype underwent surgical-orthodontic treatment. Prior to tooth movement, they underwent a minimally invasive vestibular incision with subperiosteal tunnel access combined with autogenous connective tissue grafts for periodontal phenotype modification with soft tissue augmentation (PhMT-s). The labial gingival thickness of the anterior mandibular teeth was measured at three distinct levels: at the cementoenamel junction (GT0), 3 mm apical to the CEJ (GT3), and 6 mm apical to the CEJ (GT6). These measurements were taken at baseline, three months following PhMT-s, and after tooth decompensation. Additionally, a biopsy sample was obtained from the PhMT-s site of one patient. All sections were subsequently stained using hematoxylin and eosin, Masson trichrome, Sirius Red, and immunohistochemistry. Results The thickness of the labial gingiva was increased about 0.42 to 2.00 mm after PhMT-s. At the end of pre-orthognathic surgical orthodontic treatment, the thickness of the labial gingiva was increased about − 0.14 to 1.32 mm compared to the baseline and no gingival recession occurred after the pre-orthognathic surgical orthodontic treatment. The histologic results demonstrated that the grafts obtained from the PhMT-s site exhibited increased deposition of collagen fibers. Moreover, the proportion of type III collagen increased and the grafts displayed significantly reduced positive expression of CD31 and OCN. Conclusions PhMT-s increased the thickness of the soft tissue, stabilizing the gingival margin for teeth exhibiting a thin periodontal phenotype and undergoing labial movement. This is attributed to the increased deposition of collagen fibers.

Abstract Background Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. Methods This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. Results The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. Conclusion This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

Abstract Colorectal cancer (CRC) stands as a major contributor to cancer-related fatalities within China. There is an urgent need to identify accurate biomarkers for recurrence predicting in CRC. Reduced representation bisulfite sequencing was used to perform a comparative analysis of methylation profiles in tissue samples from 30 recurrence to 30 non-recurrence patients with CRC. Least absolute shrinkage and selection operator method was performed to select the differential methylation regions (DMRs) and built a DNA methylation classifier for predicting recurrence. Based on the identified top DMRs, a methylation classifier was built and consisted of eight hypermethylated DMRs in CRC. The DNA methylation classifier showed high accuracy for predicting recurrence with an area under the receiver operator characteristic curve of 0.825 (95% CI 0.680–0.970). The Kaplan–Meier survival analysis demonstrated that CRC patients with high methylation risk score, evaluated by the DNA methylation classifier, had poorer survival than low risk score (Hazard Ratio 4.349; 95% CI 1.783–10.61, P = 0.002). And only CRC patients with low methylation risk score could acquire benefit from adjuvant therapy. The DNA methylation classifier has been proved as crucial biomarkers for predicting recurrence and exhibited promising prognostic value after curative surgery in patients with CRC.

Abstract In this paper, we investigate the relationship between the indicators for COVID-19 monitoring and the dynamic of jumps across six major financial markets including China, France, Italy, Germany, the UK, and the US. First, this paper finds that jumps occurred more frequently in the index returns during the COVID-19 pandemic. Second, the empirical findings suggest that the anxiety stemming from potential future control measures, which were prompted by updates in COVID-19 briefings, plays a significant role in explaining the jumps in index returns within financial markets. The strategies of ‘zero tolerance for COVID-19’, ‘maximum healthcare capacity’, and ‘less tolerance for restriction’ were carried out by China, European countries, and the US respectively. These diverse approaches to managing COVID-19 have a significant and varied impact on the market’s sudden price movements.

Abstract Background Compared with multiple daily insulin injections (MDI), continuous subcutaneous insulin infusion (CSII) is significantly more expensive and has not been widely used in Chinese type 1 diabetes mellitus (T1DM) patients. So there are still significant knowledge gaps regarding clinical and patient-reported outcomes in China. Aims This study aims to compare the glycated hemoglobin (HbA1C), insulin therapy related quality of life (ITR-QOL), fear of hypoglycemia (FOH) of adult T1DM patients treated with MDI and CSII based on propensity score matching in real-world conditions in China. Methods Four hundred twenty adult T1DM patients who were treated with MDI or CSII continuously for more than 12 months in a national metabolic center from June 2021 to June 2023 were selected as the study subjects. Their QOL and FOH were evaluated with Insulin Therapy Related Quality of Life Measure Questionnaire-Chinese version (ITR-QOL-CV) and the Chinese Version Hypoglycemia Fear Survey-Worry Scale (CHFSII-WS), and their HbA1C were collected at the same time. Potential confounding variables between the two groups were matched using propensity score matching. Results Of the 420 patients included in the study, 315 were in MDI group and 105 were in CSII group. 102 pairs were successfully matched. After matching, the total score of ITR-QOL-CV scale in CSII group was significantly higher than that in MDI group (87.08 ± 13.53 vs. 80.66 ± 19.25, P = 0.006). Among them, the dimensions of daily life, social life, and psychological state were all statistically different (P

Abstract Background Many randomized controlled trials (RCTs) and network meta-analyses have demonstrated that the progression-free survival (PFS) and overall survival (OS) of advanced non-small cell lung cancer (NSCLC) patients can be improved through combination immunotherapy or monotherapies. However, time-dependent analysis of the treatment effect is currently lacking. Thus, we aimed to evaluate the efficacy of first-line immunotherapy, and establish a hazard ratio function to reflect the time-varying progression or mortality risk of patients with NSCLC. Methods Seventeen clinical trials were selected based on search strategy. Baseline characteristics, including the age, sex, smoking status, geographical region, and Eastern Cooperative Oncology Group (ECOG) performance status of patients, were balanced, resulting in ten immunotherapies from nine appropriate clinical trials to conduct treatment effect comparison. Results We found that nivolumab plus ipilimumab (nivo + ipi) improved the PFS and OS over time. The hazard ratio of nivo + ipi, relative to that of pembrolizumab, decreased from 1.11 to 0.36 for PFS, and from 0.93 to 0.49 for OS over a 10-year period. In terms of the response to immunotherapy in patients with different PD-L1 expression levels, patients with PD-L1 > = 50% experienced lower rates of progression and a reduced mortality risk over time. The hazard ratio of patients with PD-L1 > = 50% relative to all of the patients decreased from 0.73 to 0.69 for PFS, and from 0.78 to 0.67 for OS. Conclusions Based on the fact that time-dependent progression and mortality risk existed during the treatment duration, physicians should select a suitable treatment regimen for patients based on the hazard ratio.

ABSTRACT Bombyx mori cypovirus (BmCPV), a member of the Reoviridae family, is a well-established research model for double-stranded RNA (dsRNA) viruses with segmented genomes. Despite its small genome size, the coding potential of BmCPV remains largely unexplored. In this study, we identified a novel small open reading frame within the S10 dsRNA genome, encoding a small viral peptide (VSP59) with 59 amino acid residues. Functional characterization revealed that VSP59 acts as a negative regulator of viral replication. VSP59 predominantly localizes to the cytoplasm, where it interacts with prohibitin 2 (PHB2), an inner membrane mitophagy receptor. This interaction targets mitochondria and triggers caspase 3-dependent apoptosis. Transient expression of vsp59 in BmN cells suppressed viral replication, an effect that was reversed by silencing PHB2 expression. Moreover, recombinant BmCPV with a mutated vsp59 exhibited reduced replication. Our findings demonstrate that VSP59 interacts with PHB2 on mitochondria, inducing apoptosis and thereby diminishing viral replication. This study expands our understanding of the genetic information encoded by the BmCPV genome and highlights the role of novel small peptides in host-virus interactions.IMPORTANCEA novel small open reading frame (sORF) from the viral genome was identified and characterized. The sORF could encode a small viral peptide (VSP59) that targeted mitochondria and induced prohibitin 2-related apoptosis, further attenuating Bombyx mori cypovirus replication.

Background: Cardiovascular disease (CVD) remains a leading cause of mortality globally. Environmental pollutants, specifically volatile organic compounds (VOCs), have been identified as significant risk factors. This study aims to develop a machine learning (ML) model to predict CVD risk based on VOC exposure and demographic data using SHapley Additive exPlanations (SHAP) for interpretability. Methods: We utilized data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2018, comprising 5098 participants. VOC exposure was assessed through 15 urinary metabolite metrics. The dataset was split into a training set (70 %) and a test set (30 %). Six ML models were developed, including Random Forest (RF), Light Gradient Boosting Machine (LightGBM), Decision Tree (DT), Extreme Gradient Boosting (XGBoost), Multi-Layer Perceptron (MLP), and Support Vector Machines (SVM). Model performance was evaluated using the Area Under the Receiver Operating Characteristic Curve (AUROC), accuracy, balanced accuracy, F1 score, J-index, kappa, Matthew's correlation coefficient (MCC), positive predictive value (PPV), negative predictive value (NPV), sensitivity (sens), specificity (spec) and SHAP was applied to interpret the best-performing model. Results: The RF model exhibited the highest predictive performance with an ROC of 0.8143. SHAP analysis identified age and ATCA as the most significant predictors, with ATCA showing a protective effect against CVD, particularly in older adults and those with hypertension. The study found a significant interaction between ATCA levels and age, indicating that the protective effect of ATCA is more pronounced in older individuals due to increased oxidative stress and inflammatory responses associated with aging. E-values analysis suggested robustness to unmeasured confounders. Conclusions: This study is the first to utilize VOC exposure data to construct an ML model for predicting CVD risk. The findings highlight the potential of combining environmental exposure data with demographic information to enhance CVD risk prediction, supporting the development of personalized prevention and intervention strategies.

Objectives: Respiratory infections are among the most common infectious diseases, resulting in significant morbidity and mortality. C-reactive protein (CRP), serum amyloid A (SAA), procalcitonin (PCT), and interleukin-6 (IL-6) are advantageous for diagnosing respiratory tract infections. This study assessed the analytical performance and accuracy of new kits for Eu3+-based CRP/SAA and PCT/IL-6 lateral flow immunoassay and its diagnostic value in respiratory tract infections. Methods: This study evaluated the detection performance of a test kit using guidelines from the Center for Medical Device Evaluation (CMDE) and the Clinical and Laboratory Standards Institute (CLSI). The test results were compared to those of the commercial kits (CRP: Mindray; SAA: Norman; PCT: Shanghai Upper; IL-6: Wantai BioPharm). A total of 156 patients with respiratory tract infections (53 with bacterial infections (Bac group); 50 with viral infections (Vir group); and 53 with co-infections (Bac + Vir group)) were enrolled, along with 50 healthy controls (HC group). Venous blood samples were collected to measure levels of SAA, PCT, CRP, and IL-6 using both the test and commercial kits. The diagnostic value of these biomarkers was assessed using receiver operating characteristic (ROC) curves. Results: Correlation analysis demonstrated a strong concordance between the test kits and commercial kits (CRP: r = 0.9396, P

Summary: Background: The worldwide geographical and temporal variation in the prevalence of diabetes represents a challenge, but also an opportunity for gaining etiological insights. Encompassing the bulk of East Asians, a large and distinct proportion of the world population, China can be a source of valuable epidemiological insights for diabetes, especially in early life, when pathophysiology begins. We carried out a nationwide, epidemiological survey of Prevalence and Risk of Obesity and Diabetes in Youth (PRODY) in China, from 2017 to 2019, to estimate the population-based prevalence of diagnosed pediatric diabetes and screen for undiagnosed pediatric type 2 diabetes (T2D). Methods: PRODY was a nation-wide, school population-based, cross-sectional, multicenter survey by questionnaire, fasting urine glucose test and simple oral glucose tolerance test (s-OGTT), among a total number of 193,801 general-population children and adolescents (covered a pediatric population of more than 96.8 million), aged 3–18, from twelve provinces across China. The prevalence of the self-reported pediatric diabetes, the proportion of subtypes, the crude prevalence of undiagnosed T2D and prediabetes in general juvenile population and the main risk factors of type 1 (T1D) and type 2 (T2D) diabetes had been analyzed in the study. Findings: The prevalence of all self-reported pediatric diabetes was estimated at 0.62/1000 (95% CI: 0.51–0.74), with T1D at 0.44/1000 (95% CI: 0.35–0.54) and T2D at 0.18/1000 (95% CI: 0.13–0.25). For undiagnosed T2D, the crude prevalence was almost ten-fold higher, at 1.59/1000, with an estimated extra 28.45/1000 of undiagnosed impaired glucose tolerance (IGT) and 53.74/1000 of undiagnosed impaired fasting glucose (IFG) by s-OGTT screening. Maternal diabetes history is the major risk factors for all subtypes of pediatric diabetes in China. Interpretation: The PRODY study provides the first population-based estimate of the prevalence of pediatric diabetes China and reveals a magnitude of the problem of undiagnosed pediatric T2D. We propose a practical screening strategy by s-OGTT to address this serious gap. Funding: The National Key Research and Development Programme of China, Key R&D Program of Zhejiang, the National Natural Science Foundation of China and the Zhejiang Provincial Key Disciplines of Medicine, Key R&D Program Projects in Zhejiang Province.

BackgroundOrbital decompression surgery is a treatment option for Thyroid-associated Ophthalmopathy (TAO). However, its effects on visual function and macular perfusion status remain unclear. This study examined how orbital decompression surgery affects visual acuity and macular blood flow in TAO patients and the variation between these two factors.MethodsThis study involved cross-sectional and longitudinal analyses of 54 TAO patients, who were categorized into a normal vision group (n = 40) and an impaired vision group (n = 14) based on the presence of visual impairment before surgery (LogMAR BCVA >0.097). Among the participants, 20 underwent orbital decompression surgery (normal vision group: n = 13, impaired vision group: n = 7). BCVA and IOP were assessed at baseline in patients with TAO, and macular retinal blood perfusion indices were measured using OCTA. One month post-operatively, changes in these indices were compared between the two groups, and the correlation between visual acuity and macular perfusion indices was analyzed.ResultsThe LogMar BCVA in the visual impairment group was significantly worse than that in the normal vision group (p

Abstract Infection by bacteria leads to tissue damage and inflammation, which need to be tightly controlled by host mechanisms to avoid deleterious consequences. It is previously reported that TMEM16F, a calcium‐activated lipid scramblase expressed in various immune cell types including T cells and neutrophils, is critical for the control of infection by bacterium Listeria monocytogenes (Lm) in vivo. This function correlated with the capacity of TMEM16F to repair the plasma membrane (PM) damage induced in T cells in vitro, by the Lm toxin listeriolysin O (LLO). However, whether the protective effect of TMEM16F on Lm infection in vivo is mediated by an impact in T cells, or in other cell types, is not determined. Herein, the immune cell types and mechanisms implicated in the protective effect of TMEM16F against Lm in vivo are elucidated. Cellular protective effects of TMEM16F correlated with its capacity of lipid scrambling and augment PM fluidity. Using cell type‐specific TMEM16F‐deficient mice, the indication is obtained that TMEM16F expressed in liver Kupffer cells (KCs), but not in T cells or B cells, is key for protection against Listeria in vivo. In the absence of TMEM16F, Listeria induced PM rupture and fragmentation of KCs in vivo. KC death associated with greater liver damage, inflammatory changes, and dysregulated liver metabolism. Overall, the results uncovered that TMEM16F expressed in Kupffer cells is crucial to protect the host against Listeria infection. This influence is associated with the capacity of Kupffer cell‐expressed TMEM16F to prevent excessive inflammation and abnormal liver metabolism.

ObjectiveHIV drug resistance (HIVDR) has become a threat to the elimination of the AIDS epidemic due to the global scale-up of antiretroviral therapy (ART) for HIV-infected individuals. This study aims to investigate the epidemiological dynamics and molecular characterization of HIV pretreatment drug resistance (PDR) and acquired drug resistance (ADR) in Hangzhou, a developed region in China.MethodsAn epidemiological survey combined with a molecular transmission network and Bayesian analysis was conducted. A total of 3,596 individuals with newly confirmed HIV infections (from 2020 to 2023) and 164 individuals with ART failure (from 2021 to 2023) were included. The molecular transmission network was used to identify key drug-resistant transmission clusters, while the Bayesian analysis was utilized to trace the origins and spread of these clusters.ResultsThe overall prevalence of PDR was found to be 8.4% (303/3596). Among these cases, PDR to non-nucleoside reverse transcriptase inhibitors (NNRTIs) accounted for 4.7% (170/3596), significantly higher than the resistance observed for protease inhibitors (PIs; 2.8%, p

BackgroundLaparoscopic pyeloplasty is a minimally invasive approach for the therapy of infant ureteropelvic junction obstruction (UPJO), reliant on CO2 pneumoperitoneum insufflation. While the impact of CO2 insufflation on adult and older pediatric populations has been studied, its effects on infants remain less explored.MethodsThis prospective randomized controlled trial included infants with UPJO undergoing laparoscopic pyeloplasty. Patients were allocated to low pneumoperitoneum pressure (LPP, 5 mmHg) or high pneumoperitoneum pressure (HPP, 8 mmHg) groups. Surgical parameters, postoperative complications, acid-base balance, stress markers, inflammatory cytokines, and oxidative stress markers were evaluated and compared.ResultsA total of 116 infants were analyzed. Preoperative characteristics were comparable between LPP and HPP groups. No significant differences in blood loss, operation time, or hospitalization time were observed. Postoperative complications were similar between groups. Acid-base balance analysis revealed a decrease in pH after pneumoperitoneum in both groups, with greater reductions in actual base excess and standard base excess in the HPP group. Stress markers, cytokines, and oxidative stress markers increased postoperatively in both groups, with higher levels in the HPP group.ConclusionHPP leads to more pronounced physiological responses, including acid-base alterations, stress reactions, and inflammatory cytokine elevations.

Abstract Large and complex workpieces are core components in fields, such as aerospace, shipbuilding, and other industrial applications. However, the main challenge of curved plate processing comes from the difficulty in determining the nonlinear rebound features with structural design parameters. An intelligent method framework is proposed for 3D surface manufacturing in cloud‐edge collaboration environment. With the construction of an intelligent generation method for machining parameters, a unified data model is effectively integrated with various discrete data, and an intelligent processing mechanism based on 3D point clouds is constructed. In particular, a prediction method for curved panel rebound is constructed to reduce the manual dependency of the manufacturing process. Finally, a related case study is conducted to verify the framework, and the result shows accuracy, interpretability and reusability advantages over other similar methods.

SHA-3, the latest hash standard from NIST, is utilized by numerous cryptographic algorithms to handle sensitive information. Consequently, SHA-3 has become a prime target for side-channel attacks, with numerous studies demonstrating successful breaches in unprotected implementations. Masking, a countermeasure capable of providing theoretical security, has been explored in various studies to protect SHA-3. However, masking for hardware implementations may significantly increase area costs and introduce additional delays, substantially impacting the speed and area of higher-level algorithms. In particular, current low-latency first-order masked SHA-3 hardware implementations require more than four times the area of unprotected implementations. To date, the specific structure of SHA-3 has not been thoroughly analyzed for exploitation in the context of masking design, leading to difficulties in minimizing the associated area costs using existing methods. We bridge this gap by conducting detailed leakage path and data dependency analyses on two-share masked SHA-3 implementations. Based on these analyses, we propose a compact and low-latency first-order SHA-3 masked hardware implementation, requiring only three times the area of unprotected implementations and almost no fresh random number demand. We also present a complete theoretical security proof for the proposed implementation in the glitch+register-transition-robust probing model. Additionally, we conduct leakage detection experiments using PROLEAD, TVLA and VerMI to complement the theoretical evidence. Compared to state-of-theart designs, our implementation achieves a 28% reduction in area consumption. Our design can be integrated into first-order implementations of higher-level cryptographic algorithms, contributing to a reduction in overall area costs.

Evidence from epidemiological studies suggests that hearing loss is associated with an accelerated decline in cognitive function, but the underlying pathophysiological mechanism remains poorly understood. Studies using auditory tasks have suggested that degraded auditory input increases the cognitive load for auditory perceptual processing and thereby reduces the resources available for other cognitive tasks. Attention-related networks are among the systems overrecruited to support degraded auditory perception, but it is unclear how they function when no excessive recruitment of cognitive resources for auditory processing is needed. Here, we implemented an EEG study using a nonauditory visual attentional selection task in 30 individuals with age-related hearing loss (ARHLs, 60–73 years) and compared them with aged (N = 30, 60–70 years) and young (N = 35, 22–29 years) normal-hearing controls. Compared with their normal-hearing peers, ARHLs demonstrated a significant amplitude reduction for the posterior contralateral N2 component, which is a well-validated index of the allocation of selective visual attention, despite the comparable behavioral performance. Furthermore, the amplitudes were observed to correlate significantly with hearing acuities (pure tone audiometry thresholds) and higher-order hearing abilities (speech-in-noise thresholds) in aged individuals. The target-elicited alpha lateralization, another mechanism of visuospatial attention, demonstrated in control groups was not observed in ARHLs. Although behavioral performance is comparable, the significant decrease in N2pc amplitude in ARHLs provides neurophysiologic evidence that may suggest a visual attentional deficit in ARHLs even without extra-recruitment of cognitive resources by auditory processing. It supports the hypothesis that constant degraded auditory input in ARHLs has an adverse impact on the function of cognitive control systems, which is a possible mechanism mediating the relationship between hearing loss and cognitive decline.

Abstract In this article, we read with great attention the correspondence by Bullement et al., regarding our published study on cost-effectiveness of first-line immunotherapy combinations with or without chemotherapy for advanced non-small cell lung cancer. We referred to a few the most important comments from Bullement et al. in our opinion, including proportional hazard (PH) assumption, accelerated failure time (AFT) model, and health utility, and made some explanations.

Background: Acute kidney injury (AKI) poses a significant concern in elderly patients undergoing laparoscopic abdominal surgery due to increased vulnerability arising from aging, comorbidities, and surgery-related factors. Early detection and intervention are crucial for mitigating short- and long-term consequences. This study aims to investigate the correlation between preoperative Geriatric Nutritional Risk Index (GNRI), neutrophil-to-lymphocyte ratio (NLR), and the occurrence of postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery, as well as to assess the predictive value of their combined detection for postoperative AKI. Methods: A retrospective study involving 347 elderly patients (aged 60 years or older) undergoing laparoscopic abdominal surgery explored the relationship between preoperative GNRI, NLR, and postoperative AKI. GNRI was calculated based on serum albumin and body weight ratios, while NLR was derived from preoperative blood tests. Results: The combined GNRI and NLR test demonstrated superior predictive value (area under the curve [AUC] = 0.87) compared to individual markers. Multivariate logistic analysis identified age, American Society of Anesthesiologists (ASA) grade, comorbidities, preoperative GNRI, and NLR as independent risk factors for AKI. Correlation analysis affirmed a negative correlation between preoperative GNRI and AKI severity, and a positive correlation between preoperative NLR and AKI severity. Conclusion: The preoperative GNRI and NLR have clinical values in predicting postoperative AKI in elderly patients undergoing laparoscopic abdominal surgery.

Abstract Background Previously identified phenotypes of acute respiratory distress syndrome (ARDS) could not reveal the dynamic change of phenotypes over time. We aimed to identify novel clinical phenotypes in ARDS using trajectories of fluid balance, to test whether phenotypes respond differently to different treatment, and to develop a simplified model for phenotype identification. Methods FACTT (conservative vs liberal fluid management) trial was classified as a development cohort, joint latent class mixed models (JLCMMs) were employed to identify trajectories of fluid balance. Heterogeneity of treatment effect (HTE) for fluid management strategy across phenotypes was investigated. We also constructed a parsimonious probabilistic model using baseline data to predict the fluid trajectories in the development cohort. The trajectory groups and the probabilistic model were externally validated in EDEN (initial trophic vs full enteral feeding) trial. Results Using JLCMM, we identified two trajectory groups in the development cohort: Class 1 (n = 758, 76.4% of the cohort) had an early positive fluid balance, but achieved negative fluid balance rapidly, and Class 2 (n = 234, 24.6% of the cohort) was characterized by persistent positive fluid balance. Compared to Class 1 patients, patients in Class 2 had significantly higher 60-day mortality (53.5% vs. 17.8%, p

Abstract Background To determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC). Methods We reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors. Results EGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861–0.978, p

Abstract Background Gastric cancer represents a highly lethal malignancy with an elevated mortality rate among cancer patients, coupled with a suboptimal postoperative survival prognosis. Nectin-4, an overexpressed oncological target for various cancers, has been exploited to create antibody-drug conjugates (ADCs) to treat solid tumors. However, there is limited research on Nectin-4 ADCs specifically for gastric cancer, and conventional immunoglobulin G (IgG)-based ADCs frequently encounter binding site barriers. Based on the excellent tumor penetration capabilities inherent in nanobodies (Nbs), we developed Nectin-4-targeting Nb drug conjugates (NDCs) for the treatment of gastric cancer. Results An immunized phage display library was established and employed for the selection of Nectin-4-specific Nbs using phage display technology. Subsequently, these Nbs were engineered into homodimers to enhance Nb affinity. To prolong in vivo half-life and reduce immunogenicity, we fused an Nb targeting human serum albumin (HSA), resulting in the development of trivalent humanized Nbs. Further, we site-specifically conjugated a monomethyl auristatin E (MMAE) at the C-terminus of the trivalent Nbs, creating Nectin-4 NDC (huNb26/Nb26-Nbh-MMAE) with a drug-to-antibody ratio (DAR) of 1. Nectin-4 NDC demonstrated excellent in vitro cell-binding activities and cytotoxic efficacy against cells with high Nectin-4 expression. Subsequent administration of Nectin-4 NDC to mice bearing NCI-N87 human gastric cancer xenografts demonstrated rapid tissue penetration and high tumor uptake through in vivo imaging. Moreover, Nectin-4 NDC exhibited noteworthy dose-dependent anti-tumor efficacy in in vivo studies. Conclusion We have engineered a Nectin-4 NDC with elevated affinity and effective tumor uptake, further establishing its potential as a therapeutic agent for gastric cancer. Graphical abstract

Abstract The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint–liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

Abstract Background Pneumocystis pneumonia is an uncommon precipitant of acute respiratory distress syndrome and is associated with high mortality. Prone positioning ventilation has been proven to reduce mortality in patients with moderate–severe acute respiratory distress syndrome. We investigated the effect of prone positioning on oxygenation and mortality in intubated patients with pneumocystis pneumonia comorbid with moderate–severe acute respiratory distress syndrome. Methods In this single-center, retrospective, observational, cohort study, eligible patients were enrolled at West China Hospital of Sichuan University from January 1, 2017, to December 31, 2021. Data on demographics, clinical features, ventilation parameters, arterial blood gas, and outcomes were collected. Patients were assigned to the prone cohort or supine cohort according to whether they received prone positioning ventilation. The main outcome was 28-day mortality. Findings A total of 79 patients were included in the study. Sixty-three patients were enrolled in the prone cohort, and 16 patients were enrolled in the supine cohort. The 28-day mortality was 61.9% in the prone cohort and 68.8% in the supine cohort (P = 0.26), and 90-day mortality was 66.7% in the prone cohort and 68.8% in the supine cohort (P = 0.55). Patients in the supine cohort had fewer invasive mechanical ventilation days and more ventilator-free days. The incidence of complications was higher in the prone cohort than in the supine cohort. Conclusions In patients with pneumocystis pneumonia and moderate–severe acute respiratory distress syndrome, prone positioning did not decrease 28-day or 90-day mortality. Trial registration ClinicalTrials.gov number, ChiCTR2200063889. Registered on 20 September 2022, https://www.chictr.org.cn/showproj.html?proj=174886 .

Abstract Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.

Abstract Biallelic mutations in the coenzyme Q7 (COQ7) encoding gene were recently identified as a genetic cause of distal hereditary motor neuropathy. Here, we explored the clinical, electrophysiological, pathological, and genetic characteristics of a Chinese patient with spastic paraplegia associated with recessive variants in COQ7. This patient carried a novel c.322C>A (p.Pro108Thr) homozygous variant. Sural biopsy revealed mild mixed axonal and demyelinating degeneration. Immunoblotting showed a significant decrease in the COQ7 protein level in the patient's fibroblasts. This study confirmed that COQ7 variant as a genetic cause of HSP, and further extended spastic paraplegia to the phenotypic spectrum of COQ7‐related disorders.

Abstract Defence against pathogens relies on intracellular nucleotide-binding, leucine-rich repeat immune receptors (NLRs) in plants. Hormone signaling including abscisic acid (ABA) pathways are activated by NLRs and play pivotal roles in defence against different pathogens. However, little is known about how hormone signaling pathways are activated by plant immune receptors. Here, we report that a plant NLR Sw-5b mimics the behavior of the ABA receptor and directly employs the ABA central regulator PP2C-SnRK2 complex to activate an ABA-dependent defence against viral pathogens. PP2C4 interacts with and constitutively inhibits SnRK2.3/2.4. Behaving in a similar manner as the ABA receptor, pathogen effector ligand recognition triggers the conformational change of Sw-5b NLR that enables binding to PP2C4 via the NB domain. This receptor-PP2C4 binding interferes with the interaction between PP2C4 and SnRK2.3/2.4, thereby releasing SnRK2.3/2.4 from PP2C4 inhibition to activate an ABA-specific antiviral immunity. These findings provide important insights into the activation of hormone signaling pathways by plant immune receptors.

Abstract Riemerella anatipestifer infection is characterized by meningitis with neurological symptoms in ducklings and has adversely affected the poultry industry. R. anatipestifer strains can invade the duck brain to cause meningitis and neurological symptoms, but the underlying mechanism remains unknown. In this study, we showed that obvious clinical symptoms, an increase in blood‒brain barrier (BBB) permeability, and the accumulation of inflammatory cytokines occurred after intravenous infection with the Yb2 strain but not the mutant strain Yb2ΔsspA, indicating that Yb2 infection can lead to cerebrovascular dysfunction and that the type IX secretion system (T9SS) effector SspA plays a critical role in this pathological process. In addition, we showed that Yb2 infection led to rapid degradation of occludin (a tight junction protein) and collagen IV (a basement membrane protein), which contributed to endothelial barrier disruption. The interaction between SspA and occludin was confirmed by coimmunoprecipitation. Furthermore, we found that SspA was the main enzyme mediating occludin and collagen IV degradation. These data indicate that R. anatipestifer SspA mediates occludin and collagen IV degradation, which functions in BBB disruption in R. anatipestifer-infected ducks. These findings establish the molecular mechanisms by which R. anatipestifer targets duckling endothelial cell junctions and provide new perspectives for the treatment and prevention of R. anatipestifer infection.

Objective To investigate the relationship between grip strength and physical mobility and bone mineral density(BMD) in elderly hospitalized patients. Methods 235 elderly patients(≥ 60 years) treated in the Department of Geriatrics of the Second Affiliated Hospital of Dalian Medical University from October 2020 to October 2021 were selected to assess their grip strength and physical mobility(gait speed, 5 sitting up test time, and up-and-go test time) and analyze their correlation with BMD. Results Univariate analysis showed that grip strength and gait speed were positively correlated with BMD, and up-and-go test time and 5 sitting up test time were negatively correlated with BMD, and this correlation was present in patients of both genders(P

In this work, we are concerned with the order preservation problem for multidimensional neutral type stochastic differential equations of infinite delay with jumps under non-Lipschitz conditions. By using a truncated Euler-Maruyama scheme and adopting an approximation argument, we have developed the well-posedness of solutions for a class of stochastic functional differential equations which allow the length of memory to be infinite, and the coefficients to be non-Lipschitz and even unbounded. Moreover, we have extended some existing conclusions on order preservation for stochastic systems to a more general case. A pair of examples have been constructed to demonstrate that the order preservation need not hold whenever the diffusion term contains a delay term, although the jump-diffusion coefficient could contain a delay term.

Abstract Three-dimensional phase change memory (3D PCM), possessing fast-speed, high-density and nonvolatility, has been successfully commercialized as storage class memory. A complete PCM device is composed of a memory cell and an associated ovonic threshold switch (OTS) device, which effectively resolves the leakage current issue in the crossbar array. The OTS materials are chalcogenide glasses consisting of chalcogens such as Te, Se and S as central elements, represented by GeTe6, GeSe and GeS. Among them, GeSe-based OTS materials are widely utilized in commercial 3D PCM, their scalability, however, has not been thoroughly investigated. Here, we explore the miniaturization of GeSe OTS selector, including functional layer thickness scalability and device size scalability. The threshold switching voltage of the GeSe OTS device almost lineally decreases with the thinning of the thickness, whereas it hardly changes with the device size. This indicates that the threshold switching behavior is triggered by the electric field, and the threshold switching field of the GeSe OTS selector is approximately 105 V/μm, regardless of the change in film thickness or device size. Systematically analyzing the threshold switching field of Ge–S and Ge–Te OTSs, we find that the threshold switching field of the OTS device is larger than 75 V/μm, significantly higher than PCM devices (8.1–56 V/μm), such as traditional Ge2Sb2Te5, Ag–In–Sb–Te, etc. Moreover, the required electric field is highly correlated with the optical bandgap. Our findings not only serve to optimize GeSe-based OTS device, but also may pave the approach for exploring OTS materials in chalcogenide alloys.

Abstract Medium-sized-ring compounds have been recognized as challenging synthetic targets in organic chemistry. Especially, the difficulty of synthesis will be augmented if an E-olefin moiety is embedded. Recently, photo-induced dearomative cycloaddition reactions that proceed via energy transfer mechanism have witnessed significant developments and provided powerful methods for the organic transformations that are not easily realized under thermal conditions. Herein, we report an intramolecular dearomative [5 + 4] cycloaddition of naphthalene-derived vinylcyclopropanes under visible-light irradiation and a proper triplet photosensitizer. The reaction affords dearomatized polycyclic molecules possessing a nine-membered-ring with an E-olefin moiety in good yields (up to 86%) and stereoselectivity (up to 8.8/1 E/Z). Detailed computational studies reveal the origin behind the favorable formation of the thermodynamically less stable isomers. Diverse derivations of the dearomatized products have also been demonstrated.

Abstract Background Albuminuria, the presence of excess of protein in urine, is a well-known risk factor for early kidney damage among diabetic/prediabetic patients. There is a complex interaction between physical activity (PA) and albuminuria. However, the relationship of specific-domain PA and albuminuria remained obscure. Methods Albuminuria was defined as urinary albumin/creatinine ratio (ACR) > 30 mg/g. PA was self-reported by participants and classified into transportation-related PA (TPA), occupation-related PA (OPA), and leisure-time PA (LTPA). Weighted logistic regression was conducted to compute the odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate the dose–response of PA domains with the risk of albuminuria. Results A total of 6739 diabetic/prediabetic patients (mean age: 56.52 ± 0.29 years) were enrolled in our study, including 3181 (47.20%) females and 3558 (52.80%) males. Of them, 1578 (23.42%) were identified with albuminuria, and 5161(76.58%) were without albuminuria. Diabetic/prediabetic patients who adhered the PA guidelines for total PA had a 22% decreased risk of albuminuria (OR = 0.78, 95%CI 0.64–0.95), and those met the PA guidelines for LTPA had a 28% decreased of albuminuria (OR = 0.72, 95%CI 0.57–0.92). However, OPA and TPA were both not associated with decreased risk of albuminuria. RCS showed linear relationship between the risk of albuminuria with LTPA. Conclusions Meeting the PA guideline for LTPA, but not OPA and TPA, was inversely related to the risk of albuminuria among diabetic/prediabetic patients. Additionally, achieving more than 300 min/week of LTPA conferred the positive effects in reducing albuminuria among diabetic/prediabetic patients.

The vast majority of data obtained from sequence analysis of influenza A viruses (IAVs) have revealed that nonstructural 1 (NS1) proteins from H1N1 swine, H3N8 equine, H3N2 avian and the correspondent subtypes from dogs have a conserved four C-terminal amino acid motif when independent cross-species transmission occurs between these species. To test the influence of the C-terminal amino acid motifs of NS1 protein on the replication and virulence of IAVs, we systematically generated 7 recombinants, which carried naturally truncated NS1 proteins, and their last four C-terminal residues were replaced with PEQK and SEQK (for H1N1), EPEV and KPEI (for H3N8) and ESEV and ESEI (for H3N2) IAVs. Another recombinant was generated by removing the C-terminal residues by reverse genetics. Remarkably, the ESEI and KPEI motifs circulating in canines largely contributed efficient replication in cultured cells and these had enhanced virulence. In contrast, the avian ESEV motif was only responsible for high pathogenicity in mice. We examined the effects of these motifs upon interferon (IFN) induction. The 7 mutant viruses replicated in vitro in an IFN-independent manner, and the canine SEQK motif was able to induced higher levels of IFN-β in human cell lines. These findings shed further new light on the role of the four C-terminal residues in replication and virulence of IAVs and suggest that these motifs can modulate viral replication in a species-specific manner.

ABSTRACTMyotonia congenita (MC) is a rare hereditary muscle disease caused by variants in the CLCN1 gene. Currently, the correlation of phenotype-genotype is still uncertain between dominant-type Thomsen (TMC) and recessive-type Becker (BMC). The clinical data and auxiliary examinations of MC patients in our clinic were retrospectively collected. Electromyography was performed in 11 patients and available family members. Whole exome sequencing was conducted in all patients. The clinical and laboratory data of Chinese MC patients reported from June 2004 to December 2022 were reviewed. A total of 11 MC patients were included in the study, with a mean onset age of 12.64 ± 2.73 years. The main symptom was muscle stiffness of limbs. Warm-up phenomenon and percussion myotonia were found in all patients. Electromyogram revealed significant myotonic charges in all patients and two asymptomatic carriers, while muscle MRI and biopsy showed normal or nonspecific changes. Fourteen genetic variants including 6 novel variants were found in CLCN1. Ninety-eight Chinese patients were re-analyzed and re-summarized in this study. There were no significant differences in the demographic data, clinical characteristics, and laboratory findings between 52 TMC and 46 BMC patients. Among the 145 variants in CLCN1, some variants, including the most common variant c.892 G>A, could cause TMC in some families and BMC in others. This study expanded the clinical and genetic spectrum of Chinese patients with MC. It was difficult to distinguish between TMC and BMC only based on the clinical, laboratory, and genetic characteristics.

AbstractThe structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o-methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model (R2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Abstract Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D‐P‐Ak (polydopamine‐PLGA‐akermanite), designed to fit within the defect site while minimizing injury. The D‐P‐Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene‐related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo‐inductive biomaterials with potential for further clinical applications.

Plant spotted leaf (spl) mutants are useful to reveal the regulatory mechanisms of immune responses. Thus, in crop plants, their agronomic traits, especially the grain quality are usually ignored. Here, we characterized a rice spl mutant named spl-A (spotted leaf mutant from A814) that shows autoimmunity, broad-spectrum disease resistance and growth deterioration including decreased rice quality. A single nucleotide mutation of C1144T, which leads to change of the 382nd proline to serine, in the gene encoding the ATPases associated with diverse cellular activities (AAA)-type ATPase LRD6-6 is responsible for the phenotype of the spl-A mutant. Mechanistically, this mutation impairs LRD6-6 ATPase activity and disrupts its interaction with endosomal sorting complex required for transport (ESCRT)-III subunits OsSNF7.1/7.2/7.3. And thus, leading to compromise of multivesicular bodies (MVBs)-mediated vesicle trafficking and accumulation of ubiquitinated proteins in both leaves and seeds of spl-A. Therefore, the immune response of spl-A is activated, and the growth and grain quality are deteriorated. Our study identifies a new amino acid residue that important for LRD6-6 and provides new insight into our understanding of how MVBs-mediated vesicle trafficking regulates plant immunity and growth, including grain quality in rice.

Rice-wheat and maize-wheat rotations are major cropping systems in the middle and lower reaches of Yangtze River in China, where high nitrogen (N) inputs and low N efficiency often exacerbate resource waste and environmental pollution. Due to the changes in factors such as soil properties and moisture content, the N fate and the N utilization characteristics of wheat in different rotations are significantly different. Efficient N management strategies are thus urgently required for promoting maximum wheat yield in different rotation systems while reducing N loss. A 2-year field experiment using isotopic (15N) tracer technique was conducted to evaluate the fate of 15N-labeled urea in wheat fields and the distribution characteristics of N derived from different sources. The wheat yield and N use efficiency under various N rates (180 and 240 kg ha−1, abbreviated as N180 and N240) and preceding crops (rice and maize, abbreviated as R-wheat and M-wheat) were also investigated. The results showed that N240 increased N uptake and grain yield by only 8.77−14.97% and 2.51−4.49% compared with N 180, but decreased N agronomic efficiency (NAE) and N physiological efficiency (NPE) by 14.78−18.79% and 14.06−31.35%. N240 also decreased N recovery in plants by 2.8% on average compared with N180, and increased N residue in soil and N loss to the environment. Compared with that of basal N, the higher proportion of topdressing N was absorbed by wheat rather than lost to the environment. In addition, the accumulation of topdressing N in grain was much higher than that of basal N. Compared with that in R-wheat treatment, plants in M-wheat treatment trended to absorb more 15N and reduce unaccounted N loss, resulting in higher yield potential. Moreover, the M-wheat treatment increased N recovery in 0−20 cm soil but decreased 80−100 cm soil compared with R-wheat treatment, indicating a lower risk of N loss in deeper soil. Collectively, reducing N application rate and increasing the topdressing ratio is an effective way to balance sustainable crop yield for a secure food supply and environmental benefit, which is more urgent in rice-wheat rotation.

BackgroundSnijders Blok-Campeau syndrome (SNIBCPS) is a rare genetic disorder characterized by facial abnormalities, hypotonia, macrocephaly, and global developmental delay (GDD) caused by mutations in CHD3 gene. There is limited information on SNIBCPS and few studies on its pathogenic gene CHD3.MethodsWe utilized whole-exome sequencing, in vitro minigene splicing assay analysis, and construction of protein models to validate the suspected pathogenic mutation. In addition, the PubMed database was searched using the keywords “Snijders Blok-Campeau syndrome,” “CHD3,” or “SNIBCPS” to summarize the gene mutations and clinical phenotypic characteristics of children with SNIBCPS.ResultsWe identified a non-frameshift variant c.3592_c.3606delGCCAAGAGAAAGATG, a splice site variant c.1708-1G>T, and two missense variants, c. 2954G>C (p.Arg985Pro) and c.3371C>T (p.A1124V), in CHD3 variants with SNIBCPS. Importantly, the c.3592_c.3606delGCCAAGAGAAAGATG, c.1708-1G>T, and c.3371C > T (p.A1124V) loci were not reported, and the children in this study also had phenotypic features of unibrow, transverse palmar creases, tracheal bronchus, and hypomelanosis of Ito (HI). The c.1708-1G>T classical splicing mutation leads to abnormal shearing of mRNA, forming a truncated protein that ultimately affects gene function.ConclusionOur findings have expanded the spectrum of genetic variants and clinical features in children with SNIBCPS. Splicing analysis of CHD3 is an important method to understand the pathogenesis of spliced cells.

Pyroptosis, a form of caspase-1-dependent cell death, also known as inflammation-dependent death, plays a crucial role in diseases such as stroke, heart disease, or tumors. Since its elucidation, pyroptosis has attracted widespread attention from various sectors. Reactive oxygen species (ROS) can regulate numerous cellular signaling pathways. Through further research on ROS and pyroptosis, the level of ROS has been revealed to be pivotal for the occurrence of pyroptosis, establishing a close relationship between the two. This review primarily focuses on the molecular mechanisms of ROS and pyroptosis in tumors and inflammatory diseases, exploring key proteins that may serve as drug targets linking ROS and pyroptosis and emerging fields targeting pyroptosis. Additionally, the potential future development of compounds and proteins that influence ROS-regulated cell pyroptosis is anticipated, aiming to provide insights for the development of anti-tumor and anti-inflammatory drugs.

The motor temperature distribution characteristics help to understand the working condition of the unit, thus improving efficiency. Currently, the motors are gradually being used at high altitudes. However, the plateau region has low air pressure, thin air and large differences in humidity. There is a lack of research on the effect of its complex and special working environment on motor temperature. Therefore, in this study, the numerical analysis of the motor temperature field is carried out from the novel perspective of plateau characteristics. In this paper, the finite volume method is used to analyse the flow-heat-solid coupling of a 20 MW motor. By comparing and verifying the experimental data with the simulation data, it is found that the error between the two is within 5 %. In order to have a more comprehensive picture of the motor's operation in the plateau environment, the temperature effects of different air pressure, air intake and relative humidity on the motor were investigated. The results of the study show that air pressure changes have a large effect on the temperature of the stator structure. The temperature decreases when the air pressure increases and the temperature difference decreases gradually with the increase of air pressure. The largest temperature difference in the stator structure occurs when the air pressure increases from 10 kPa to 40 kPa. The change in air intake has a positive effect on the stator structure temperature, which decreases when the air intake increases. After simulation calculations, it was found that the best heat dissipation effect was achieved in the range of air intake between 3.5 m/s and 4.5 m/s. Relative humidity has a minimal effect on the stator structure temperature. The conclusions of this paper can provide certain theoretical reference for the temperature change law of the motor under plateau operation, which is of great significance to improve the comprehensive hydraulic performance.