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Abstract To explore the relationship between morphological and hemodynamic parameters, baseline characteristics, and long-term outcomes in patients with moyamoya disease (MMD) using a computational fluid dynamics model. We retrospectively reviewed 129 patients at Beijing Tiantan hospital between July 2020 and December 2021. Perioperative clinical variables and Suzuki stage were recorded. Logistic regression analysis was employed to identify the risk factors for unfavorable long-term outcomes. The association between morphological, CT perfusion parameters, hemodynamic parameters and the Suzuki stage, clinical variables of MMD was also analyzed. Patients with high relative Wall Shear Stress (rWSS) were older and had more cases with higher Suzuki stage and worse follow-up mRS scores (p

Abstract Understanding Pd effects on NOx storage and release is crucial for designing passive NOx adsorber (PNA) to control NOx emissions during diesel cold-starts. Herein, we report two oxidation states of Pd species on CexZr1-xO2 regulated by metal-support interaction. Pdδ+ (0

Abstract CRISPR/Cas12a is a highly promising detection tool. However, detecting single nucleotide variations (SNVs) remains challenging. Here, we elucidate Cas12a specificity through crRNA engineering and profiling of single- and double-base mismatch tolerance across three targets. Our findings indicate that Cas12a specificity depends on the number, type, location, and distance of mismatches within the R-loop. We also find that introducing a wobble base pair at position 14 of the R-loop does not affect the free energy change when the spacer length is truncated to 17 bp. Therefore, we develop a new universal specificity enhancement strategy via iterative crRNA design, involving truncated spacers and a wobble base pair at position 14 of the R-loop, which tremendously increases specificity without sacrificing sensitivity. Additionally, we construct a PAM-free one-pot detection platform for SARS-CoV-2 variants, which effectively distinguishes SNV targets across various GC contents. In summary, our work reveals new insights into the specificity mechanism of Cas12a and demonstrates significant potential for in vitro diagnostics.

Abstract Increasing evidence supports the crucial role of Epithelial-Mesenchymal Transition (EMT) in cancer invasion and metastasis. N-acetylglucosaminyltransferase V (MGAT5), which is associated with multiantenna glycosylation, can contribute to tumorigenesis, yet its specific role in promoting colorectal cancer (CRC) metastasis remains unclear. Bioinformatics analysis of CRC datasets revealed that elevated MGAT5 expression was associated with EMT and a poor prognosis. In vitro experiments confirmed the pivotal role of MGAT5 as an EMT regulator in CRC cells. MGAT5 overexpression stimulated cell proliferation and migration, while MGAT5 knockdown had the opposite effect. Mechanistically, MGAT5 promoted EMT through multiantenna glycosylation of ZO-1, promoting its ubiquitination and reducing its expression. Clinically, MGAT5 upregulation in the CRC TMA correlated negatively with ZO-1 expression, which is indicative of malignancy and a poor prognosis. This study revealed that MGAT5 promotes EMT in CRC via interactions between multiple antenna glycosylation products and ZO-1 ubiquitination/degradation, indicating that MGAT5 could serve as a promising therapeutic target for CRC. Graphical Abstract

Microvascular changes are considered key factors in the process of intervertebral disk degeneration (IDD). Microvascular invasion and growth into the nucleus pulposus (NP) and cartilaginous endplates are unfavorable factors that trigger IDD. In contrast, the rich distribution of microvessels in the bony endplates and outer layers of the annulus fibrosus is an important safeguard for the nutrient supply and metabolism of the intervertebral disk (IVD). In particular, the adequate supply of microvessels in the bony endplates is the main source of the nutritional supply for the entire IVD. Microvessels can affect the progression of IDD through a variety of pathways. Many studies have explored the effects of microvessel alterations in the NP, annulus fibrosus, cartilaginous endplates, and bony endplates on the local microenvironment through inflammation, apoptosis, and senescence. Studies also elucidated the important roles of microvessel alterations in the process of IDD, as well as conducted in‐depth explorations of cytokines and biologics that can inhibit or promote the ingrowth of microvessels. Therefore, the present manuscript reviews the published literature on the effects of microvascular changes on IVD to summarize the roles of microvessels in IVD and elaborate on the mechanisms of action that promote or inhibit de novo microvessel formation in IVD.

Abstract To evaluate the impact of the CD4 count on ESAT6-CFP10 (EC) skin test, QuantiFERON-TB Gold In-tube test (QFT) and tuberculin skin test (TST) in a large prison and communities in Jiangsu Province among people living with HIV (PLHIV). Participants in communities were tested with the QFT and EC skin test and in prison were tested with the QFT, TST and EC skin test. A 4-knotted restricted cubic spline fitted for Logistic models was used to explore the cutoff point of CD4 count and the associations between changes in CD4 count and Mycobacterium tuberculosis (M.tb) infection. Among 1,815 PLHIV included, 19.3% (350) were from prisons and 80.7% (1465) were identified through community screenings. M.tb infection rates were 12.2% and 8.3% through QFT and EC tests, respectively. Odd Ratios (ORs) for infection increased with CD4 counts, peaking at 618 cells/mm3 for EC, 392 cells/mm3 for QFT, then plateaued. However, the pattern differed for EC between prison and screening scenarios. In prison settings, M.tb infection increased with CD4 count from 0 to 350 cells/mm3, plateaued until 500 cells/mm3, and then persistently increased. Conversely, for community, ORs decreased until 300 cells/mm3, followed by an increase between 300 and 729 cells/mm3, after which they continued to rise persistently. Our cross-sectional study among PLHIV revealed a higher rate of M.tb infection in prison compared to the community. The relationship between CD4 count and infection became negative after a certain threshold. This pivotal point differed with detection methods, with QFT showing lower CD4 thresholds than EC.

Abstract We present SpliceTransformer (SpTransformer), a deep-learning framework that predicts tissue-specific RNA splicing alterations linked to human diseases based on genomic sequence. SpTransformer outperforms all previous methods on splicing prediction. Application to approximately 1.3 million genetic variants in the ClinVar database reveals that splicing alterations account for 60% of intronic and synonymous pathogenic mutations, and occur at different frequencies across tissue types. Importantly, tissue-specific splicing alterations match their clinical manifestations independent of gene expression variation. We validate the enrichment in three brain disease datasets involving over 164,000 individuals. Additionally, we identify single nucleotide variations that cause brain-specific splicing alterations, and find disease-associated genes harboring these single nucleotide variations with distinct expression patterns involved in diverse biological processes. Finally, SpTransformer analysis of whole exon sequencing data from blood samples of patients with diabetic nephropathy predicts kidney-specific RNA splicing alterations with 83% accuracy, demonstrating the potential to infer disease-causing tissue-specific splicing events. SpTransformer provides a powerful tool to guide biological and clinical interpretations of human diseases.

Hydrogels, which are three-dimensional networks of crosslinked hydrophilic polymers, have become crucial for various advanced applications owing to their exceptional water absorption and swelling properties. This review explores the applications of hydrogels based on their unique swelling properties, beyond their application in traditional drug delivery, focusing on atmospheric water harvesting, hydrogel actuator, expansion microscopy (ExM), and 3D nanofabrication through controlled deswelling. We first discuss the factors influencing hydrogel swelling, such as network size and polymer properties. Next, we explore the mechanisms underlying hydrogel swelling, emphasizing the interplay between various forces. Hydrogel swelling enables ExM for super-resolution imaging of biological tissues, while controlled deswelling of hydrogels facilitates the creation of intricate 3D structures with nanoscale precision—a breakthrough for additive manufacturing techniques. Despite these advantages, challenges still remain. We conclude this review by emphasizing the need for interdisciplinary research to address these limitations and unlock the full potential of the hydrogel technology. The future of hydrogel research holds promise for revolutionary contributions to environmental science, robotics, and biomedical imaging.

Abstract Purpose Low-fat dietary (LFD) pattern refers to a dietary structure with reduced fat intake. The aim was to investigate the association between LFD pattern and risk of head and neck cancer (HNC). Methods Data were derived from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. LFD score was used to assess adherence to an LFD pattern, with higher scores indicating greater adherence. Cox regression was used to evaluate the association between LFD score and risk of HNC and its subtypes. To visualize the trend in risk of HNC and its subtypes with changing LFD score, restricted cubic spline plots were utilized. A series of subgroup analyses were conducted to identify potential confounders. Sensitivity analyses were performed to assess the robustness of the results. Results Among 98,459 participants of PLCO trial, 268 cases with HNC were identified during an average of 8.8 years of follow-up. In the fully adjusted model, participants in the highest compared with the lowest quartiles of LFD score had a lower risk of HNC (HR Q4 vs. Q1: 0.60; 95% CI: 0.40–0.90; P for trend = 0.026) and larynx cancer (HRQ4 vs. Q1: 0.46; 95% CI: 0.22–0.96; P for trend = 0.039). The restricted cubic spline plots demonstrated a linear dose-response relationship between the LFD score and the risk of HNC and its subtypes (all P for nonlinearity > 0.05). The primary association remained robust in the sensitivity analysis. Conclusion Our findings suggest that adherence to an LFD pattern may lower the risk of HNC in the US population.

Abstract Background Homocysteine (HCY) is a sulfur-containing amino acid that is an independent or important risk factor for the occurrence of many chronic diseases and is one of the most important indicators for determining health risks. However, existing HCY detection methods do not meet the requirements of clinical diagnosis. Therefore, there is an urgent need to establish new detection methods to meet the needs of clinical detection. Results In this study, we used the principle of competitive method to establish a new method for the determination of HCY in human serum using a chemiluminescent enzyme immunoassay in conjunction with a chemiluminescent assay instrument that uses magnetic microparticles as the solid phase of the immunoreaction. The established method achieved satisfactory results in terms of minimum detection limit, specificity, accuracy, and clinical application. The limit of detection was 0.03 ng/mL. The intra-assay coefficient of variation (CV) was 1.94–5.05%, the inter-assay CV was 2.29–6.88%, and the recovery rate was 88.60–93.27%. Cross-reactivity with L-cysteine ranged from 0.0100 to 0.0200 μmol/L, and cross-reactivity with glutathione ranged from 0.0100 to 0.200 μmol/L, all of which were less than the limit of detection (LoD) of this method. The linear factor R of this method was greater than 0.99. Conclusions In summary, the developed method showed a good correlation with the product from Abbott. A total of 996 clinical patients with cardiovascular diseases were evaluated using the method developed in this study.

Objective: To analyze the hotspots, patterns, and distribution of research on the safety and risk of antibody preparations in the past 20 years. It also seeks to summarize the current status and trends of research on the safety and risk control of antibody preparations. Methods: Taking “antibody preparation”, “safety” and “risk” as keywords, relevant articles were searched in the databases Web of Science. CiteSpace was utilized to analyze the annual number of publications, countries, authors, institutions, highly cited literature and keywords of the screened literature, and the relevant maps were drawn and the results were analyzed. Results: A total of 1693 articles were included. The annual number of publications in the field of antibody preparation safety has shown stable growth followed by a rapid increase between 2002 and 2022. Among the countries, the United States accounted for 36.7% of the total publications, ranking first in the world. Large foreign pharmaceutical companies, research institutions, comprehensive university and their affiliated hospitals were the most high-yield institutions. Current hot topics in the field of antibody preparation safety research include “ADC”, “monoclonal antibody”, “anti-tumor activity”, “immunotherapy”, etc. Conclusion: Over the past 20 years, research on antibody formulations has garnered increasing attention both domestically and internationally, with a focus mainly on efficacy and safety. There has been relatively little research on risk control. In the future, more in-depth research is needed on the mechanisms of adverse reactions in antibody formulations to provide more effective strategies for risk control.

Abstract Background Catheter-related bladder discomfort (CRBD) commonly occurs in patients who have indwelling urinary catheters while under general anesthesia. And moderate-to-severe CRBD can lead to significant adverse events and negatively impact patient health outcomes. However, current screening studies for patients experiencing moderate-to-severe CRBD after waking from general anesthesia are insufficient. Constructing predictive models with higher accuracy using multiple machine learning techniques for early identification of patients at risk of experiencing moderate-to-severe CRBD during general anesthesia resuscitation. Methods Eight hundred forty-six patients with indwelling urinary catheters who were resuscitated in a post-anesthesia care unit (PACU). Trained researchers used the CRBD 4-level assessment method to evaluate the severity of a patient’s CRBD. They then inputted 24 predictors into six different machine learning algorithms. The performance of the models was evaluated using metrics like the area under the curve (AUC). Results The AUCs of the six models ranged from 0.82 to 0.89. Among them, the RF model displayed the highest predictive ability, with an AUC of 0.89 (95%CI: 0.87, 0.91). Additionally, it achieved an accuracy of 0.93 (95%CI: 0.91, 0.95), 0.80 sensitivity, 0.98 specificity, 0.94 positive predictive value (PPV), 0.92 negative predictive value (NPV), 0.87 F1 score, and 0.07 Brier score. The logistic regression (LR) model has achieved good results (AUC:0.87) and converted into a nomogram. Conclusions The study has successfully developed a machine learning prediction model that exhibits excellent predictive capabilities in identifying patients who may develop moderate-to-severe CRBD after undergoing general anesthesia. Furthermore, the study also presents a nomogram, which serves as a valuable tool for clinical healthcare professionals, enabling them to intervene at an early stage for better patient outcomes.

Abstract Mitochondrial dysfunction is a significant contributor to podocyte injury in diabetic kidney disease (DKD). While previous studies have shown that PVT1 might play a vital role in DKD, the precise molecular mechanisms are largely unknown. By analyzing the plasma and kidney tissues of DKD patients, we observed a significant upregulation of PVT1 expression, which exhibited a positive correlation with albumin/creatinine ratios and serum creatinine levels. Then, we generated mice with podocyte-specific deletion of PVT1 (Nphs2-Cre/Pvt1 flox/flox ) and confirmed that the deletion of PVT1 suppressed podocyte mitochondrial dysfunction and inflammation in addition to ameliorating diabetes-induced podocyte injury, glomerulopathy, and proteinuria. Subsequently, we cultured podocytes in vitro and observed that PVT1 expression was upregulated under hyperglycemic conditions. Mechanistically, we demonstrated that PVT1 was involved in mitochondrial dysfunction by interacting with TRIM56 post-transcriptionally to modulate the ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission. Additionally, the release of mtDNA and mtROS from damaged mitochondria triggered inflammation in podocytes. Subsequently, we verified the important role of TRIM56 in vivo by constructing Nphs2-Cre/Trim56flox/flox mice, consistently with the results of Nphs2-Cre/Pvt1 flox/flox mice. Together, our results revealed that upregulation of PVT1 could promote mitochondrial dysfunction and inflammation of podocyte by modulating TRIM56, highlighting a potential novel therapeutic target for DKD.

Abstract Background Dental caries is still a major disease that affect the oral health of people in China. First permanent molars (FPMs) are the most caries-susceptible teeth among school-aged children. The aim of this study was to investigate the eruption and caries status of first permanent molars in children aged 6–7 years in Shijingshan District, Beijing, China, to provide information for oral health promotion. Methods The study was a cross-sectional survey conducted in 6-7-year-old first grade children from public elementary schools in Shijingshan District, Beijing. Participants were invited to receive a clinical oral examination. The eruption status and caries experience of FPMs were recorded. Questionnaires assessing children’s sociodemographic information and oral health-related behaviors were completed by the children’s parents or guardians. Results A total of 3,176 children, including 1,644 boys (51.8%) and 1,532 girls (48.2%) were included in the oral examination and questionnaire. Eruption status of FPMs was as follows: 37.5% fully erupted, 28.3% partially erupted, 34.2% not erupted. Girls had more erupted FPMs than boys (70.1% VS 61.8%, P

A transgenic protein is frequently expressed as different homologous variants in genetically modified crops due to differential processing of targeting peptides or optimization of activity and specificity. The aim of this study was to develop a science-based approach for risk assessment of homologous protein variants using dicamba mono-oxygenase (DMO) as a case study. In this study, DMO expressed in the next-generation dicamba-tolerant maize, sugar beet and soybean crops exhibited up to 27 amino acid sequence differences in the N-terminus. Structure modeling using AlphaFold, ESMFold and OpenFold demonstrates that these small N-terminal extensions lack an ordered secondary structure and do not disrupt the DMO functional structure. Three DMO variants were demonstrated to have equivalent immunoreactivity and functional activity ranging from 214 to 331 nmol/min/mg. Repeated toxicity studies using each DMO variant found no test substance-related adverse effects. These results support that homologous protein variants, which have demonstrated physicochemical and functional equivalence, can leverage existing safety data from one variant without requiring additional de novo safety assessments.

With the rapid advancement and wide application of microwave technology, it enhances convenience while potentially endangering health. The immune system, as a vital shield, is an important protective barrier and also one of the sensitive targets of microwave radiation. The immune system is particularly affected by microwave radiation via innate and adaptive immune responses, which is supported by both population surveys and experimental studies; however, the precise mechanism of immunotoxicity of microwave radiation remains under investigation. In light of recent scientific advances in the correlation between microwave radiation and the immune system, the deleterious impact of microwave radiation on innate immunity was delineated. Microwave radiation can induce irregular innate immune function by damaging macrophages, neutrophils, natural killer cells, and dendritic cells. The effects of microwave radiation on adaptive immunity were also elucidated. Microwave radiation can impair cellular immune response by influencing T cell proliferation, maturation and activation, and distribution of T cell subpopulation, and also hinder humoral immune function by influencing B lymphocyte protein expression, maturation during development, and number of B cells. Disparity in the immune function of the body can precipitate the onset of various immune-associated diseases, so the immunotoxic effects of microwave radiation and associated protection need considerable attention and detailed investigation. This article reviewed the shortcomings of existing studies, and suggested that future experimental studies should use experimental parameters that are more similar to the actual scene of life and work, pay more attention to the biological effects of combined multi-frequency microwave exposure on the immune system, use standardized and unified experimental methods, and incorporate more sophisticated experimental technologies to further elucidate the laws of damage effect and exact mechanism of microwave radiation on the immune system, so as to provide a scientific basis for potent protection against the damage effect of microwave radiation on the immune system.

Abstract In thrombotic diseases, coagulation, anticoagulation, and fibrinolysis are three key physiological processes that interact to maintain blood in an appropriate state within blood vessels. When these processes become imbalanced, such as excessive coagulation or reduced anticoagulant function, it can lead to the formation of blood clots. Genetic factors play a significant role in the onset of thrombotic diseases and exhibit regional and ethnic variations. The decision of whether to initiate prophylactic anticoagulant therapy is a matter that clinicians must carefully consider, leading to the development of various thrombotic risk assessment scales in clinical practice. Given the considerable heterogeneity in clinical diagnosis and treatment, researchers are exploring the application of artificial intelligence in medicine, including disease prediction, diagnosis, treatment, prevention, and patient management. This paper reviews the research progress on various genetic factors involved in thrombotic diseases, analyzes the advantages and disadvantages of commonly used thrombotic risk assessment scales and the characteristics of ideal scoring scales, and explores the application of artificial intelligence in the medical field, along with its future prospects.

Abstract DNA polymerase ζ (Pol ζ) plays an essential role in replicating damaged DNA templates but contributes to mutagenesis due to its low fidelity. Therefore, ensuring tight control of Pol ζ’s activity is critical for continuous and accurate DNA replication, yet the specific mechanisms remain unclear. This study reveals a regulation mechanism of Pol ζ activity in human cells. Under normal conditions, an autoinhibition mechanism keeps the catalytic subunit, REV3L, inactive. Upon encountering replication stress, however, ATR-mediated phosphorylation of REV3L’s S279 cluster activates REV3L and triggers its degradation via a caspase-mediated pathway. This regulation confines the activity of Pol ζ, balancing its essential role against its mutations causing potential during replication stress. Overall, our findings elucidate a control scheme that fine tunes the low-fidelity polymerase activity of Pol ζ under challenging replication scenarios.

Abstract Recent advances in computer vision and deep learning techniques have facilitated significant progress in video scene understanding, thus helping film and television practitioners achieve accurate video editing. However, so far, publicly available semantic segmentation datasets are mostly limited to indoor scenes, city streets, and natural images, often ignoring example objects in action movies, which is a research gap that needs to be urgently filled. In this paper, we introduce a large-scale, high-precision semantic segmentation dataset of props in Chinese martial arts movie clips, named ChineseMPD. Specifically, this dataset first establishes segmentation rules and general review criteria for audiovisual data, and then provides semantic segmentation annotations for six weapon props (Gun, Sword, Stick, Knife, Hook, and Arrow) with a summary of 32,992 objects.To the best of our knowledge, this dataset is the largest semantic segmentation dataset for movie props to date. ChineseMPD dataset not only significantly expands the application of traditional tasks of computer vision such as object detection and scene understanding, but also opens up new avenues for interdisciplinary research.

Abstract Endoscopic submucosal dissection (ESD) of fibrotic colorectal lesions is difficult and has a high complication rate. There are only a few reports on the utility of orthodontic rubber band (ORB) traction in reducing the difficulty of this procedure. This study aimed to investigate the risk factors for perforation when applying ORB traction during ESD of fibrotic colorectal lesions. We continuously collected the clinical data of 119 patients with fibrotic colorectal lesions who underwent ESD with ORB and clip traction between January 2019 and January 2024. Possible risk factors for perforation were analyzed. The median ORB-ESD operative time was 40 (IQR 28–62) min, and the en bloc and R0 resection rates were 94.1% and 84.0%, respectively. Perforation occurred in 16 of 119 patients (13.4%). The lesion size, lesion at the right half of the colon or across an intestinal plica, the degree of fibrosis, operation time, and the surgeon’s experience were associated with perforation during ORB-ESD (P

Abstract Background Alström syndrome (AS) is a rare autosomal recessive disorder that leads to multiple organ fibrosis and failure. Precise diagnosis from the clinical symptoms is challenging due to its highly variabilities and its frequent confusion with other ciliopathies and genetic diseases. Currently, mutations in the ALMS1 gene have been reported as a major cause of AS, thus, it is crucial to focus on the detection and discovery of ALMS1 mutations. Case presentation We present a case of a 13-year-old Chinese boy weighing 70 kg and standing 168 cm tall. He has two younger brothers. Their parents hail from different ancestral homes in eastern and northern China. The patient’s primary clinical findings included visual impairment at the age of four and progressive hearing loss starting at the age of ten. Subsequently, at the age of twelve, the patient developed hyperlipidaemia and hyperinsulinemia. Ultrasonographic findings indicated the presence of gallstones and mild fatty liver. His Body Mass Index (BMI) significantly increased to 25 kg/m2 (ref: 18.5–23.9 kg/m2). Additionally, echocardiography revealed mild mitral and tricuspid regurgitation. Ultimately, Whole Exome Sequencing (WES) identified a new missense mutation in the ALMS1 gene (NG_011690.1 (NM_015120): c.9536G > A (p.R3179Q)). This missense mutation generated an aberrant splicer and disrupted the stability and hydrophobicity of proteins, which preliminarily determined as “ likely pathogenic”. Therefore, considering all the above symptoms and molecular analysis, we deduced that the patient was diagnosed with AS according to the guidelines. We recommended that he continue wearing glasses and undergo an annual physical examination. Conclusion In this case report, we report a novel homozygous ALMS1 mutation associated with AS in the Chinese population, which expands the mutation spectrum of ALMS1. Genetic testing indeed should be incorporated into the diagnosis of syndromic deafness, as it can help avoid misdiagnoses of AS. While there is no specific treatment for AS, early diagnosis and intervention can alleviate the progression of some symptoms and improve patients’ quality of life.

Abstract Background Despite the known association between chronic inflammation and reduced muscle mass, there is a gap in research regarding the association between the systemic immune-inflammation index (SII) and sarcopenic obesity (SO). This study aims to assess the relationship between SII and SO in middle-aged and elderly adults and the mediating role of triglyceride-glucose index (TyG). Methods This cross-sectional study involved 2,719 participants aged 45–90 years who underwent health check-ups. SO was evaluated by combining sarcopenia [assessed by handgrip strength and appendicular skeletal muscle index (ASMI)] with obesity (determined by body fat percentage). Association between SII and SO, sarcopenia, and obesity in middle-aged and elderly individuals was examined using multivariable logistic regression, restricted cubic spline analysis, and subgroup analysis. Bidirectional mediation analysis was conducted to determine the direct and indirect effects through SII and TyG. Results The study included 2,719 participants, of which 228 had SO (8.4%). SO prevalence increased as the SII quartiles rose (P for trend 0.05). Conclusions Elevated levels of SII were associated with an increased risk of SO in middle-aged and elderly adults, especially in the elderly population, and elevated TyG levels played a role in this relationship.

Abstract Purpose Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. Methods and materials Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. Results A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11–81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02–52.36, p = 0.005]). Conclusion Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Abstract Background Continuing care is needed for the growing number of chronically ill patients who struggle with health problems after discharge. This study aims to elucidate the development process, functionalities, service protocols, and utilization of an Internet Plus Care (IPC) platform devised by our hospital to offer healthcare services to discharged patients. Methods This was a mixed study. After describing the development process, function and usage of IPC platform, we retrospectively collect data such as the general information of service recipients and service providers, service items, and service prices through the IPC platform from January 2021 to September 2023 to characterize these services. Results 69 nurses delivered a total of 788 services to 211 patients through the IPC platform. The majority of services (N = 652, 82.7%) were delivered offline, with almost half of the recipients (N = 384, 48.7%) being elderly individuals. 46.4% of nurses provided services ≥ 3 times. Furthermore, 26.5% of patients received services three or more times. Notably, patients’ care requirements exhibited variations across age groups, with wound care (n = 243, 63.3%), pressure injuries care (n = 50, 13.0%), and replacement of indwelling nasogastric tubes (n = 20, 5.2%) emerging as the top three services favored by the elderly. Conclusions The IPC platform demonstrates potential in delivering diverse health services to patients; however, the involvement of nurses and patients needs to be enhanced. It is necessary to implement relevant safeguard policies to promote the effective use of IPC platform for health management of discharged patients in the future. What does this paper contribute to the wider global clinical community? The prevalence of chronic diseases is on the rise, and patients with chronic diseases continue to struggle with health problems after discharge and require extended treatment and rehabilitation. Our study proves that IPC platform presents a promising avenue for addressing these challenges. It is anticipated that governmental authorities will undertake comprehensive policy, legislative, and medical insurance reforms to facilitate the extensive adoption of IPC platform-based services.

Abstract Diabetic nephropathy (DN) is a critical inflammatory condition linked to diabetes, affecting millions worldwide. This study employs Mendelian randomization (MR) to explore the causal relationship between immune cell signatures and DN, analyzing over 731 immune signatures and incorporating data from 1400 metabolites to investigate potential mediators. Despite no statistically significant influence of DN on immunophenotypes after FDR correction, some phenotypes with unadjusted low P-values warranted mention, including CD34 on Hematopoietic Stem Cell (Myeloid cell Panel), CD45 on CD33− HLA DR− (Myeloid cell Panel). Furthermore, three immunophenotypes were identified to have a significant impact on DN risk: CD16−CD56 on HLA DR+ NK (TBNK Panel), CD45 on HLA DR+ T cell (TBNK Panel), and CD33dim HLA DR+ CD11b+ AC (Myeloid cell Panel). Our findings underscore the critical role of immune cells in DN, highlighting potential mediators and offering new insights into its underlying mechanisms.

Abstract Integrin αvβ6 holds promise as a therapeutic target for organ fibrosis, yet targeted therapies are hampered by concerns over inflammatory-related side effects. The role of αvβ6 in renal inflammation remains unknown, and clarifying this issue is crucial for αvβ6-targeted treatment of chronic kidney disease (CKD). Here, we revealed a remarkable positive correlation between overexpressed αvβ6 in proximal tubule cells (PTCs) and renal inflammation in CKD patients and mouse models. Notably, knockout of αvβ6 not only significantly alleviated renal fibrosis but also reduced inflammatory responses in mice, especially the infiltration of pro-inflammatory macrophages. Furthermore, conditional knockout of αvβ6 in PTCs in vivo and co-culture of PTCs with macrophages in vitro showed that depleting αvβ6 in PTCs suppressed the migration and pro-inflammatory differentiation of macrophages. Screening of macrophage activators showed that αvβ6 in PTCs activates macrophages via secreting IL-34. IL-34 produced by PTCs was significantly diminished by αvβ6 silencing, and reintroduction of IL-34 restored macrophage activities, while anti-IL-34 antibody restrained macrophage activities enhanced by αvβ6 overexpression. Moreover, RNA-sequencing of PTCs and verification experiments demonstrated that silencing αvβ6 in PTCs blocked hypoxia-stimulated IL-34 upregulation and secretion by inhibiting YAP expression, dephosphorylation, and nuclear translocation, which resulted in the activation of Hippo signaling. While application of a YAP agonist effectively recurred IL-34 production by PTCs, enhancing the subsequent macrophage migration and activation. Besides, reduced IL-34 expression and YAP activation were also observed in global or PTCs-specific αvβ6-deficient injured kidneys. Collectively, our research elucidates the pro-inflammatory function and YAP/IL-34/macrophage axis-mediated mechanism of αvβ6 in renal inflammation, providing a solid rationale for the use of αvβ6 inhibition to treat kidney inflammation and fibrosis.

Abstract Background Cerebral ischemic disease is a common cerebrovascular disease, especially ischemic stroke. Exercise has protective functions on brain tissues following cerebral ischemia‐reperfusion injury (CIRI), but its preventive effects and mechanisms in CIRI remain unclear. We aimed to investigate the effects and mechanisms of exercise preconditioning on CIRI. Methods The middle cerebral artery occlusion (MCAO) operation was prepared to establish CIRI rats. All rats were randomized into the MCAO, exercise (exercise preconditioning plus MCAO operation), vector (exercise preconditioning, MCAO operation plus intraventricular injection of empty vector), and tissue inhibitor of metalloprotease 1 overexpression (OE‐TIMP1, exercise preconditioning, MCAO operation plus intraventricular injection of OE‐TIMP1) groups. Results The results indicated that exercise preconditioning suppressed approximately 66.67% of neurological deficit scores and 73.79% of TIMP1 mRNA expression in MCAO rats, which were partially offset by OE‐TIMP1. The protective effects of exercise against neuron death status and cerebral infarction size in MCAO rats were reversed by OE‐TIMP1. It also confirmed that exercise weakened apoptosis and oxidative stress damage, with notable increases of B‐cell lymphoma‐2, superoxide dismutase, and glutathione peroxidase production, and evident decreases of BCL2‐associated X, caspase 3, and malondialdehyde in MCAO rats, while these effects were partially reversed by OE‐TIMP1. Additionally, the inhibitory effects of exercise on the protein levels of TIMP1, hypoxia‐inducible factor‐alpha, vascular endothelial growth factor receptor 2, vascular endothelial growth factor, and neurogenic locus notch homolog protein 1 in MCAO rats were partially reversed by OE‐TIMP1. Conclusion Altogether, exercise preconditioning had protective effects on CIRI by restraining TIMP1, which provided new therapeutic strategies for preventing CIRI.

Background: Closed-loop electronic medication management systems are effective measures for preventing medication errors (MEs). However, there is limited evidence supporting this, and few studies have evaluated the long-term effects of these systems on safe medication. Objective: To evaluate the long-term effects of implementing a closed-loop medication order executive system on the safe clinical use of medications. Design: A quasi-experimental design. Method: Data from 2017 to 2023 were extracted and retrospectively analyzed. The primary outcome indicator was the ME rate. Secondary outcome indicators were the accuracy of order verification and patient identification and the implementation rate of fresh medicine dispensing. The autoregressive integrated moving average (ARIMA) model in time-series analysis was used to evaluate the level and trend changes in ME rates using SPSS 25.0 before and after system implementation. Root cause analysis and descriptive statistics were used to assess changes in types, stages, and causes of ME rates. The independent samples t -test was used to analyze secondary outcomes. Results: Overall, 295 MEs were reported with a mean of 0.26 ± 0.26 ME rates per month during 2017–2023. The ARIMA model showed a decrease in the average level of ME rates after system implementation, with no statistically significant decrease in the long term, and a significant drop in the ME rate in the short and medium term ( p

Amaryllidaceae alkaloids (AAs) are complex plant secondary metabolites possessing a wide range of biological activities. 4′-O-methylnorbelladine (4OMN) is the branchpoint intermediate for the entire AAs, and was the last common intermediate before AA pathway branches diverge. The cyclization of 4OMN by C-C oxidative coupling, which can afford para-para′, ortho-para′, and para-ortho′ scaffold, was catalyzed by cytochrome P450 96T (CYP96T) family enzymes. To clarify the mechanisms involved in this controversial step, four CYP96T homologs (LauCYP96T1, LauCYP96T1-like-1, LauCYP96T1-like-2 and LauCYP96T1-like-3) were cloned from the full-length transcriptome of Lycoris aurea. All the four LauCYP96T are localized to endoplasmic reticulum. Functional analysis reveals that LauCYP96T1 and LauCYP96T1-like proteins display inverted regioselectivity for oxidative coupling of 4OMN, in which LauCYP96T1 and LauCYP96T1-like-2 dominantly afford para-para′ scaffold, and LauCYP96T1-like-1 and LauCYP96T1-like-3 are responsible for para-ortho′ scaffold formation. Using molecular homology modeling and docking studies, we predicted models for the binding of 4OMN to LauCYP96T, and identified two amino acid residues that might be responsible for the dominant changes in generated products of para-ortho′ and para-para′ oxidative coupling. Our results highlight the functional diversity and promiscuity of LauCYP96T enzymes and might provide valuable information for Amaryllidaceae alkaloid production.

BackgroundCupping therapy has been indicated effective in reducing muscle fatigue after 24 h based on the spectral analyses of surface electromyography (sEMG). However, there is no sufficient evidence showing changes of sEMG nonlinear indexes at more time points after cupping therapy. Furthermore, it is unclear whether the intervention timings of cupping therapy affect the recovery from muscle fatigue. The purpose of this study was to use the sEMG nonlinear analysis to assess the difference of time response of cupping therapy between different intervention timings after muscle fatigue.Materials and methodsThis randomized controlled trial recruited 26 healthy volunteers. Cupping therapy (−300 mmHg pressure for 5 min by the 45 mm-diameter cup) was applied before (i.e., pre-condition) or after (i.e., post-condition) muscle fatigue induced by performing repeated biceps curls at 75% of the 10 repetitions of maximum (RM) on the non-dominant upper extremity. Subjects were randomly allocated to the pre-condition group or the post-condition group. The sEMG signals during the maximal voluntary isometric contractions (MVC) of the biceps were recorded at four time points (i.e., baseline; post 1: immediate after cupping-fatigue/fatigue-cupping interventions; post 2: 3 h after cupping-fatigue/fatigue-cupping interventions; post 3: 6 h after cupping-fatigue/fatigue-cupping interventions). Two nonlinear sEMG indexes (sample entropy, SampEn; and percent determinism based on recurrence quantification analysis, %DET) were used to evaluate the recovery from exercise-introduced muscle fatigue. The Friedman test followed by the Nemenyi test and the Mann-Whitney U test were applied in statistics.ResultsThe SampEn and %DET change rate did not show any significant differences at four time points in the pre-condition group. However, there were significant delayed effects instead of immediate effects on improving muscle fatigue in the post-condition group (SampEn change rate: baseline 0.0000 ± 0.0000 vs. post 2 0.1105 ± 0.2253, p < 0.05; baseline 0.0000 ± 0.0000 vs. post 3 0.0627 ± 0.4665, p < 0.05; post 1–0.0321 ± 0.2668 vs. post 3 0.0627 ± 0.4665, p < 0.05; and %DET change rate: baseline 0.0000 ± 0.0000 vs. post 2–0.1240 ± 0.1357, p < 0.01; baseline 0.0000 ± 0.0000 vs. post 3 0.0704 ± 0.6495, p < 0.05; post 1 0.0700 ± 0.3819 vs. post 3 0.0704 ± 0.6495, p < 0.05). Moreover, the SampEn change rate of the post-condition group (0.1105 ± 0.2253) was significantly higher than that of the pre-condition group (0.0006 ± 0.0634, p < 0.05) at the post 2 time point. No more significant between-groups difference was found in this study.ConclusionThis is the first study demonstrating that both the pre-condition and post-condition of cupping therapy are useful for reducing muscle fatigue. The post-condition cupping therapy can e ffectively alleviate exercise-induced muscle fatigue and there is a significant delayed effect, especially 3 h after the interventions. Although the pre-condition cupping therapy can not significantly enhance muscle manifestations, it can recover muscles into a non-fatigued state.

The tympanic membrane (TM) is constantly in a state of vibrating. However, there is currently a lack of drug-delivery scaffolds suitable for the dynamic environment of TM perforation. In this study, a mechano-responsive tough hydrogel was developed. It consists of basic fibroblast growth factor (bFGF)-loaded sodium alginate (SA) microspheres, polysulfobetaine methacrylate (polySBMA), and gelatin methacrylate (GelMA). This hydrogel was designed to serve as a TM scaffold to promote perforation healing under dynamic conditions. bFGF was encapsulated in SA microspheres, which were then incorporated into polySBMA-GelMA hydrogels through photo-initiated free radical polymerization. The mechanical properties, tissue adhesiveness, swelling properties, and degradation of the hydrogels were evaluated before and after microsphere incorporation. It was observed that incorporating bFGF-loaded SA microspheres did not significantly impact the adhesion and degradation mechanisms of the hydrogel. The compressive strength and tensile strength of the microsphere-incorporated hydrogel were up to 6.6 MPa and 64.1 kPa, respectively, suitable for a TM scaffold. The release behavior of bFGF from the hydrogel could be controlled by vibration stimulation without significantly affecting the hydrogel's mechanical properties, indicating a mechano-responsive nature of the hydrogel. The in vitro cytotoxicity assay demonstrated that the hydrogels showed no cytotoxic effects. Moreover, cell culture assays demonstrated that vibration stimulation could enhance the release of bFGF, significantly promoting cell proliferation and migration. The results demonstrate the significant potential of the mechano-responsive hydrogel as a scaffold for repairing TM perforations.

Soil water content (SWC) is an essential index that reflects water conditions in the soil surface during drought, and changes in SWC are critical in guiding agricultural irrigation management. Remote sensing is a crucial means of monitoring SWC, and the red and near-infrared bands of optical remote sensing data are often used to monitor SWC through remote sensing retrieval. With the development of remote sensing technology, red-edge band has also been used to retrieve SWC. It exhibits higher sensitivity to changes in vegetation and SWC, relatively more precise differentiation between vegetation and soil, and more accurate SWC detection. However, there has been relatively little research regarding the use of the red-edge band for retrieving SWC. In this study, we developed a novel method, based on the principle of spectral space and the calculation of modified perpendicular drought index, to calculate the soil water index using the red-edge band of the Gaofen-6 (GF-6) satellite by comparing the retrieval accuracy of GF-6 using different combinations of red, near-infrared, and red-edge bands. Based on the measured SWC in the Shijin Irrigation District of Hebei Province, an SWC retrieval model was established using linear regression. Moreover, the new method was used to retrieve SWC from GF-6 and Sentinel-2 with the same central wavelength, and the reliability of the new method was compared and analyzed. The results revealed that the combination of red band and red-edge band 2 with a central wavelength of 0.74 μm substantial. improved the retrieval accuracy of SWC. Our study provides a new method for retrieving SWC using optical remote sensing, which can effectively improve retrieval accuracy and provide data support for agricultural irrigation monitoring and water management.

Abstract Ionic conductive hydrogels (ICHs) have recently gained prominence in biosensing, indicating their potential to redefine future biomedical applications. However, the integration of these hydrogels into sensor technologies and their long‐term efficacy in practical applications pose substantial challenges, including a synergy of features, such as mechanical adaptability, conductive sensitivity, self‐adhesion, self‐regeneration, and microbial resistance. To address these challenges, this study introduces a novel hydrogel system using an imidazolium salt with a ureido backbone (UL) as the primary monomer. Fabricated via a straightforward one‐pot copolymerization process that includes betaine sulfonate methacrylate (SBMA) and acrylamide (AM), the hydrogel demonstrates multifunctional properties. The innovation of this hydrogel is attributed to its robust mechanical attributes, outstanding strain responsiveness, effective water retention, and advanced self‐regenerative and healing capabilities, which collectively lead to its superior performance in various applications. Moreover, this hydrogel exhibited broad‐spectrum antibacterial activity. Its potential for biomechanical monitoring, especially in tandem with contact and noncontact electrocardiogram (ECG) devices, represents a noteworthy advancement in precise real‐time cardiac monitoring in clinical environments. In addition, the conductive properties of the hydrogel make it an ideal substrate for electrophoretic patches aimed at treating infected wounds and consequently enhancing the healing process.

BackgroundDespite the increased accessibility and availability of technology in recent years, equality and access to health-related technology remain limited to some demographics. In particular, patients who are older or from rural communities represent a large segment of people who are currently underusing mobile health (mHealth) solutions. System usability continues to hinder mHealth adoption among users with nontraditional digital literacy. ObjectiveThis study aims to investigate if state-of-the-art mobile app interfaces from open-source libraries provide sufficient usability for rural patients with cancer, with minimal design changes and forgoing the co-design process. MethodsWe developed Assuage (Network Reconnaissance Lab) as a research platform for any mHealth study. We conducted a pilot study using Assuage to assess the usability of 4 mobile user interfaces (UIs) based on open-source libraries from Apple’s ResearchKit and CareKit. These UIs varied in complexity for reporting distress symptoms. Patients with cancer were recruited at the Markey Cancer Center, and all research procedures were conducted in person. Participants completed the distress assessment using a randomly selected UI in Assuage with little to no assistance. Data were collected on participant age, location, mobile app use, and familiarity with mHealth apps. Participants rated usability with the System Usability Scale (SUS), and usability issues were documented and compared. A one-way ANOVA was used to compare the effect of the UIs on the SUS scores. ResultsWe recruited 30 current or postsurgery patients with cancer for this pilot study. Most participants were aged >50 years (24/30, 80%), from rural areas (25/30, 83%), had up to a high school education (19/30, 63%), and were unfamiliar with mHealth apps (21/30, 70%). General mobile app use was split, with 43% (14/30) of the patients not regularly using mobile apps. The mean SUS score across the UIs was 75.8 (SD 22.2), with UI 3 and UI 4 achieving an SUS score ≥80, meeting the industry standard for good usability of 80. Critical usability issues were related to data input and navigation with touch devices, such as scale-format questions, vertical scrolling, and traversing multiple screens. ConclusionsThe findings from this study show that most patients with cancer (20/30, 67%) who participated in this study rated the different interfaces of Assuage as above-average usability (SUS score >68). This suggests that Apple’s ResearchKit and CareKit libraries can provide usable UIs for older and rural users with minimal interface alterations. When resources are limited, the design stage can be simplified by omitting the co-design process while preserving suitable usability for users with nontraditional technical proficiency. Usability comparable to industry standards can be achieved by considering heuristics for interface and electronic survey design, specifically how to segment and navigate surveys, present important interface elements, and signal gestural interactions.

Benzo(a)pyrene (BaP) or benzo (a) pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE) exposure causes trophoblast cell dysfunctions and induces miscarriage, which is generally epigenetically regulated. Homologous recombination (HR) repair of DNA double strand break (DSB) plays a crucial role in maintenance of genetic stability and cell normal functions. However, whether BaP/BPDE might suppress HR repair in human trophoblast cells to induce miscarriage, as well as its epigenetic regulatory mechanism, is largely unclear. In this study, we find that BaP/BPDE suppresses HR repair of DSB in trophoblast cells and eventually induces miscarriage by up-regulating lnc-HZ08. In mechanism, lnc-HZ08 (1) down-regulates the expression levels of FOXA1 (forkhead box A1) and thus suppresses FOXA1-mediated mRNA transcription of BRCA1 (Breast cancer susceptibility gene 1) and CtIP (CtBP-interacting protein), (2) impairs BRCA1 and CtIP protein interactions by competitive binding with CtIP through lnc-HZ08-1 fragment, and also (3) suppresses BRCA1-mediated CtIP ubiquitination without affecting CtIP stability, three of which eventually suppress HR repair in human trophoblast cells. Supplement with murine Ctip could efficiently restore (i.e. increase) HR repair and alleviate miscarriage in BaP-exposed mouse model. Collectively, this study not only reveals the association and causality among BaP/BPDE exposure, the defective HR repair, and miscarriage, but also discovers novel mechanism in lnc-HZ08-regulated BRCA1/CtIP-mediated HR repair, bridging epigenetic regulation and genetic instability and also providing an efficient approach for treatment against BaP/BPDE-induced unexplained miscarriage.

The aim of this report was to evaluate the efficacy of nasal reconstruction using auricular cartilage combined with auricular full-thickness skin graft and a local flap from the right nasal ala for correcting complex nasal defects, and its impact on the patient's quality of life and psychological well-being. We present the case of a 50-year-old female with a severe nasal deformity due to a car accident, characterized by a missing right alar flap and an exposed right nostril. The patient underwent nasal reconstructive surgery using auricular cartilage combined with an auricular full-thickness skin graft and a local flap from the right nasal ala. Detailed records of the patient's postoperative recovery, surgical outcomes, and satisfaction were made at follow-up. The survival rate of the grafted skin and flaps on the nasal ala, septum, and dorsum was high. The reconstructed right nasal ala closely resembled the left, and the patient was very satisfied. In patients with complex nasal deformities, nasal reconstruction using ear cartilage combined with auricular full-thickness skin grafts and local flaps can achieve satisfactory aesthetic and functional outcomes. The high level of postoperative satisfaction suggests that this technique significantly improves patients’ quality of life and psychological well-being.

PurposeCough and sputum are the most common clinical symptoms of acute respiratory tract infection. Ambroxol is a mucolytic expectorant commonly used in clinical practice. This study aimed to evaluate the efficacy, safety, and compliance of ambroxol hydrochloride spray (Luo Runchang ®) for the treatment of acute respiratory tract diseases in children.MethodsThis was a multicenter, open-labeled, randomized controlled study. The experimental group received ambroxol hydrochloride oral sprays, and the control group received ambroxol hydrochloride oral solutions. The primary endpoint was the change in cough symptom scores from baseline. Secondary endpoints include changes in cough severity score, quality of life, adherence, and adverse events.ResultsA total of 154 subjects were randomized and included in the analysis. The mean change of total cough symptom score of the spray group at the end of treatment was −4.7 (1.54) compared to −4.2 (1.62) in the solution group (P = 0.0005). The mean change of cough severity score was −5.7 (2.09) in the spray group compared to −5.2(2.04) in the solution group (P = 0.012). Quality of life scores significantly improved in the spray group (P

Background: Age-related mandibular osteoporosis frequently causes loose teeth, difficulty eating, and disfiguration in elders. Bmi1−/− mice displaying accelerated skeletal aging represent a useful model for testing interventions against premature jaw bone loss. As an anti-aging agent, metformin may ameliorate molecular dysfunction driving osteoporosis pathogenesis. We explored the mechanisms of mandibular osteopenia in Bmi1−/− mice and prevention by metformin treatment. Methods: Three mouse groups were utilized: wild-type controls, untreated Bmi1−/−, and Bmi1−/− receiving 1 g/kg metformin diet. Mandibular bone phenotype was assessed by X-ray, micro-CT, histology, and immunohistochemistry. AMPK-mTOR pathway analysis, senescence markers, osteoblast and osteoclast gene expression were evaluated in jaw tissue. Osteoclast differentiation capacity and associated signaling molecules were examined in cultured Bmi1−/− bone marrow mononuclear cells ± metformin. Results: Bmi1 loss reduced mandible bone density concomitant with decreased AMPK activity, increased mTOR signaling and cellular senescence in jaw tissue versus wild-type controls. This was accompanied by impaired osteoblast function and upregulated osteoclastogenesis markers. Metformin administration normalized AMPK-mTOR balance, oxidative stress and senescence signaling to significantly improve mandibular bone architecture in Bmi1−/− mice. In culture, metformin attenuated excessive osteoclast differentiation from Bmi1−/− marrow precursors by correcting dysregulated AMPK-mTOR-p53 pathway activity and suppressing novel pro-osteoclastogenic factor Stfa1. Conclusions: Our study newly demonstrates metformin prevents accelerated jaw bone loss in a premature aging murine model by rectifying molecular dysfunction in cellular energy sensors, redox state, senescence and osteoclastogenesis pathways. Targeting such age-associated mechanisms contributing to osteoporosis pathogenesis may help maintain oral health and aesthetics in the growing elderly population. Translational potential: The pronounced mandibular osteopenia exhibited in Bmi1−/− mice represents an accelerated model of jaw bone deterioration observed during human aging. Our finding that metformin preserves mandibular bone integrity in this progeroid model has important clinical implications. As an inexpensive oral medication already widely used to manage diabetes, metformin holds translational promise for mitigating age-related osteoporosis. The mandible is essential for chewing, swallowing, speech and facial structure, but progressively loses bone mass and strength with advancing age, significantly impacting seniors' nutrition, physical function and self-image. Our results suggest metformin's ability to rectify cellular energy imbalance, oxidative stress and osteoclast overactivity may help maintain jaw bone health into old age. Further research is still needed given metformin's multifaceted biology and bone regulation by diverse pathways. However, this preclinical study provides a strong rationale for clinical trials specifically examining mandibular outcomes in elderly subjects receiving standard metformin treatment for diabetes or prediabetes. Determining if metformin supplementation can prevent or delay oral disability and disfigurement from senescent jaw bone loss in the growing aged population represents an important public health priority. In summary, our mechanistic findings in a genetic mouse model indicate metformin merits investigation in rigorous human studies for alleviating morbidity associated with age-related mandibular osteoporosis.

Abstract Background Due to the high mortality and disability rate of intracranial hemorrhage, headache is not the main focus of research on cerebral arteriovenous malformation (AVM), so research on headaches in AVM is still scarce, and the clinical understanding is shallow. This study aims to delineate the risk factors associated with headaches in AVM and to compare the effectiveness of various intervention treatments versus conservative treatment in alleviating headache symptoms. Methods This study conducted a retrospective analysis of AVMs who were treated in our institution from August 2011 to December 2021. Multivariable logistic regression analysis was employed to assess the risk factors for headaches in AVMs with unruptured, non-epileptic. Additionally, the effectiveness of different intervention treatments compared to conservative management in alleviating headaches was evaluated through propensity score matching (PSM). Results A total of 946 patients were included in the analysis of risk factors for headaches. Multivariate logistic regression analysis identified that female (OR 1.532, 95% CI 1.173–2.001, p = 0.002), supply artery dilatation (OR 1.423, 95% CI 1.082–1.872, p = 0.012), and occipital lobe (OR 1.785, 95% CI 1.307–2.439, p

Abstract Moyamoya disease (MMD) is a cerebrovascular narrowing and occlusive condition characterized by progressive stenosis of the terminal portion of the internal carotid artery and the formation of an abnormal network of dilated, fragile perforators at the base of the brain. However, the role of PANoptosis, an apoptotic mechanism associated with vascular disease, has not been elucidated in MMD. In our study, a total of 40 patients’ genetic data were included, and a total of 815 MMD-related differential genes were screened, including 215 upregulated genes and 600 downregulated genes. Among them, DNAJA3, ESR1, H19, KRT18 and STK3 were five key genes. These five key genes were associated with a variety of immune cells and immune factors. Moreover, GSEA (gene set enrichment analysis) and GSVA (gene set variation analysis) showed that the different expression levels of the five key genes affected multiple signaling pathways associated with MMD. In addition, they were associated with the expression of MMD-related genes. Then, based on the five key genes, a transcription factor regulatory network was constructed. In addition, targeted therapeutic drugs against MMD-related genes were obtained by the Cmap drug prediction method: MST-312, bisacodyl, indirubin, and tropanyl-3,5-dimethylbenzoate. These results suggest that the PANoptosis-related genes may contribute to the pathogenesis of MMD through multiple mechanisms.

Abstract The interaction between programmed cell death ligand 1 (PD-L1), which is expressed on the surface of tumor cells, and programmed cell death 1 (PD-1), which is expressed on T cells, impedes the effective activation of tumor antigen-specific T cells, resulting in the evasion of tumor cells from immune-mediated killing. Blocking the PD-1/PD-L1 signaling pathway has been shown to be effective in preventing tumor immune evasion. PD-1/PD-L1 blocking antibodies have garnered significant attention in recent years within the field of tumor treatments, given the aforementioned mechanism. Furthermore, clinical research has substantiated the efficacy and safety of this immunotherapy across various tumors, offering renewed optimism for patients. However, challenges persist in anti-PD-1/PD-L1 therapies, marked by limited indications and the emergence of drug resistance. Consequently, identifying additional regulatory pathways and molecules associated with PD-1/PD-L1 and implementing judicious combined treatments are imperative for addressing the intricacies of tumor immune mechanisms. This review briefly outlines the structure of the PD-1/PD-L1 molecule, emphasizing the posttranslational modification regulatory mechanisms and related targets. Additionally, a comprehensive overview on the clinical research landscape concerning PD-1/PD-L1 post-translational modifications combined with PD-1/PD-L1 blocking antibodies to enhance outcomes for a broader spectrum of patients is presented based on foundational research.

Abstract Background Little is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy. Methods Patients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding. Results Among 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events. Conclusions This study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH. Trial registration ISRCTN65203415.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is associated with a high prevalence of cancer-related deaths. The survival rates of patients are significantly lower in late-stage ccRCC than in early-stage ccRCC, due to the spread and metastasis of late-stage ccRCC, surgery has not reached the goal of radical cure, and the effect of traditional radiotherapy and chemotherapy is poor. Thus, it is crucial to accurately assess the prognosis and provide personalized treatment at an early stage in ccRCC. This study aims to develop an efficient nomogram model for stratifying and predicting the survival of ccRCC patients based on tumor stage. Methods We first analyzed the microarray expression data of ccRCC patients from the Gene Expression Omnibus (GEO) database and categorized them into two groups based on the disease stage (early and late stage). Subsequently, the GEO2R tool was applied to screen out the genes that were highly expressed in all GEO datasets. Finally, the clinicopathological data of the two patient groups were obtained from The Cancer Genome Atlas (TCGA) database, and the differences were compared between groups. Survival analysis was performed to evaluate the prognostic value of candidate genes (PSAT1, PRAME, and KDELR3) in ccRCC patients. Based on the screened gene PSAT1 and clinical parameters that were significantly associated with patient prognosis, we established a new nomogram model, which was further optimized to a single clinical variable-based model. The expression level of PSAT1 in ccRCC tissues was further verified by qRT-PCR, Western blotting, and immunohistochemical analysis. Results The datasets GSE73731, GSE89563, and GSE150404 identified a total of 22, 89, and 120 over-expressed differentially expressed genes (DEGs), respectively. Among these profiles, there were three genes that appeared in all three datasets based on different stage groups. The overall survival (OS) of late-stage patients was significantly shorter than that of early-stage patients. Among the three candidate genes (PSAT1, PRAME, and KDELR3), PSAT1 was shown to be associated with the OS of patients with late-stage ccRCC. Multivariate Cox regression analysis showed that age, tumor grade, neoadjuvant therapy, and PSAT1 level were significantly associated with patient prognosis. The concordance indices were 0.758 and 0.725 for the 3-year and 5-year OS, respectively. The new model demonstrated superior discrimination and calibration compared with the single clinical variable model. The enhancer PSAT1 used in the new model was shown to be significantly overexpressed in tissues from patients with late-stage ccRCC, as demonstrated by the mRNA level, protein level, and pathological evaluation. Conclusion The new prognostic prediction nomogram model of PSAT1 and clinicopathological variables combined was thus established, which may provide a new direction for individualized treatment for different-stage ccRCC patients.

Abstract We present the gluon distribution functions of the pion and kaon in small-x and large-x regions, and compare them with the results obtained from lattice QCD and continuum Schwinger function methods. Whether in the small-x region or the large-x region, our gluon distribution of the pion is consistent with the results of lattice QCD and continuum Schwinger function methods. We also calculate the first four moments of gluon distributions of the pion and kaon at different $$Q^{2}$$ Q 2 scales. In addition, we present the mass decomposition of the pion and kaon with the dynamical parton distribution functions calculated by the DGLAP equation with parton–parton recombination corrections. The mass structures of the pion and kaon are completely different from that of the proton.

Abstract Background Early water intake has gained widespread attention considering enhanced recovery after surgery (ERAS). In the present systematic evaluation and meta-analysis, we assessed the effects of early water intake on the incidence of vomiting and aspiration in adult patients who received general anaesthesia on regaining consciousness during the resuscitation period. Objective To systematically analyse the results of randomised controlled trials on early postoperative water intake in patients who underwent different types of surgery under general anaesthesia, both at home and abroad, to further explore the safety and application of early water intake and provide an evidence-based foundation for clinical application. Design Systematic review and meta-analysis. Methods To perform the systematic evaluation and meta-analysis, we searched the Web of Science, CINAHL, Embase, PubMed, Cochrane Library, Sinomed, China National Knowledge Infrastructure (CNKI), Wanfang, and Vipshop databases to identify randomised controlled trial studies on early water intake in adult patients who received general anaesthesia. Results Herein, we included 10 publications with a total sample size of 5131 patients. Based on statistical analysis, there was no statistically significant difference in the incidence of vomiting (odds ratio [OR] = 0.81; 95% confidence interval [CI] [0.58–1.12]; p = 0.20; I-squared [I2] = 0%) and aspiration (OR = 0.78; 95%CI [0.45–1.37]; p = 0.40; I2 = 0%) between the two groups of patients on regaining consciousness post-general anaesthesia. Conclusion Based on the available evidence, early water intake after regaining consciousness post-anaesthesia did not increase the incidence of adverse complications when compared with traditional postoperative water abstinence. Early water intake could effectively improve patient thirst and facilitate the recovery of gastrointestinal function.

Background: Colon cancer is one of the most prevalent digestive cancers worldwide. Results of epidemiological, experimental, and clinical studies suggest that aspirin inhibits the development of colon cancer. This study aimed to systematically elucidate the molecular mechanisms by which aspirin prevents colon carcinogenesis. Methods: We determined the global protein expression profiles of colorectal cancer and aspirin-treated cells using quantitative proteomic analysis. We analyzed the proteomic results using bioinformatics (including differential proteins, protein annotation, Kyoto Encyclopedia of Genes and Genomes [KEGG] pathways, and protein–protein interaction [PPI] network). The viability of the colon cancer cell line and HT29 ​cells treated with aspirin was determined using the cell counting kit-8 assay. The differentially expressed proteins, such as p53 and cyclin-dependent kinase 1 (CDK1), were quantified using real-time polymerase chain reaction (PCR) and Western blotting. We measured cell cycle distribution and apoptosis in HT29 ​cells exposed to aspirin using fluorescence-activated cell sorting (FACS). Results: We found that 552 proteins were significantly dysregulated, of which 208 and 334 were upregulated and downregulated, respectively, in colon cancer cells exposed to 10 ​mmol/L of aspirin (95% confidence interval [CI]: -1.269 to -0.106, P ​

Abstract Introduction Transthyretin amyloidosis (ATTR) is a progressive, heterogeneous rare disease manifesting as ATTR polyneuropathy (ATTR-PN), ATTR cardiomyopathy (ATTR-CM), or a mixed phenotype. Tafamidis meglumine (20 mg po qd) is approved in some markets to delay neurologic progression in ATTR-PN, while high-dose tafamidis (80/61 mg po qd) is approved worldwide to reduce cardiovascular mortality and cardiovascular-related hospitalization in ATTR-CM. The objective of this study was to assess the real-world benefit of high-dose tafamidis for delaying neurologic progression in patients with mixed-phenotype variant ATTR-CM (ATTRv-CM). Methods This exploratory, retrospective, observational cohort study evaluated anonymized electronic medical records and included adult patients with mixed-phenotype ATTRv-CM treated with high-dose tafamidis for at least 6 months. Neurologic assessments included the Medical Research Council (MRC) Scale for Muscle Strength, Neuropathy Impairment Score (NIS) muscle weakness subscale, and Polyneuropathy Disability (PND) instrument. Modified body mass index (mBMI) was also assessed. Results Patients (N = 10) started tafamidis treatment an average of 3.8 months after diagnosis, with an average treatment duration of 20.8 months. Seven of 10 patients demonstrated normal muscle strength on the MRC scale throughout the study, and 9 of 10 patients had no decline in muscle strength during the post-treatment period. The NIS muscle weakness subscale score was ≤ 60 for all patients in the study at all time points, suggesting normal function to mild impairment. Six of 10 patients had no change in walking capacity as measured by the PND instrument at pre- and post-assessments, while one-third of patients had a decrease in PND stage (signaling improvement) from pre- to post-assessment. mBMI remained relatively stable throughout the study. Conclusion This is the first real-world study to demonstrate the potential value of high-dose tafamidis for delaying neurologic disease progression in patients with mixed-phenotype ATTRv-CM. The findings underscore the importance of multidisciplinary assessment for patients with ATTR amyloidosis. Trial registration ClinicalTrials.gov: NCT05139680.