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Author(s): Paul J Emmerson [1]; Feng Wang [2]; Yong Du [2]; Qian Liu [2]; Richard T Pickard [1]; Malgorzata D Gonciarz [1]; Tamer Coskun [1]; Matthew J Hamang [1]; Dana [...]

Adiponectin, encoded by the Adipoq gene, is emerging as a protein hormone with insulin-sensitizing, anti-inflammatory and antiapoptotic functions. However, the underlying mechanistic basis for these pleiotropic actions are unknown. Adiponectin [...], The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)-independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

Author(s): Silvana Obici [1]; Bei B. Zhang [2]; George Karkanias [1]; Luciano Rossetti (corresponding author) [1] Increased glucose production (GP) is the major cause of fasting hyperglycemia in patients with [...]

Large language models (LLMs) have the potential to enhance evidence synthesis efficiency and accuracy. This study assessed LLM-only and LLM-assisted methods in data extraction and risk of bias assessment for 107 trials on complementary medicine. Moonshot-v1-128k and Claude-3.5-sonnet achieved high accuracy (≥95%), with LLM-assisted methods performing better (≥97%). LLM-assisted methods significantly reduced processing time (14.7 and 5.9 min vs. 86.9 and 10.4 min for conventional methods). These findings highlight LLMs' potential when integrated with human expertise., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Gastric cancer (GC) is a prevalent malignant tumor of the digestive system that is often diagnosed at advanced stages owing to inconspicuous early symptoms and a lack of specific examination methods. Effective treatment of advanced stages remains challenging, emphasizing the need for new therapeutic targets. Metabolic reprogramming, a hallmark of tumors, plays a pivotal role in tumor progression, immune evasion, and immune surveillance. DNA damage-regulated autophagy modulator 1 (DRAM1) encodes a hexameric transmembrane protein that is predominantly located in lysosomes and induces autophagy; however, its mechanism of action in gastric cancer remains unclear. Our study found that elevated DRAM1 expression in patients with GC correlated with survival and prognosis. DRAM1 knockdown suppressed energy metabolism in GC cells through the PI3K/AKT/mTOR signaling pathway, thereby mitigating GC progression. Atorvastatin, a focus of recent tumor research, significantly enhanced apoptosis levels in DRAM1 knockdown GC cells compared to the control group. Therefore, through metabolic reprogramming, DRAM1 may serve as a potential therapeutic target for GC prevention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Morality and ethics: The Medical Ethics Committee of Drum Tower Hospital, Nanjing University Medical School approved this study. The feasibility of tissue sampling in the experiment is strictly adhered to and standardized ethically according to the Helsinki Declaration. Each patient signed a document requesting their informed consent, ensuring their understanding and agreement. Animal experiments were conducted in Nanjing, and all animal experimental methods were carried out in accordance with the ARRIVE principles., (© 2025. The Author(s).)

Overexpression of uridine-cytidine kinase 2 (UCK2), a key enzyme in the pyrimidine salvage pathway, is implicated in human cancer development, while its regulation under nutrient stress remains to be investigated. Here, we show that under glucose limitation, AMPK phosphorylates glycinamide ribonucleotide formyltransferase (GART) at Ser440, and this modification facilitates its interaction with UCK2. Through its binding to UCK2, GART generates tetrahydrofolate (THF) and thus inhibits the activity of integrin-linked kinase associated phosphatase (ILKAP) for removing AKT1-mediated UCK2-Ser254 phosphorylation under glucose limitation, in which dephosphorylation of UCK2-Ser254 tends to cause Trim21-mediated UCK2 polyubiquitination and degradation. In this way, both UCK2 binding ability and THF producing catalytic activity of GART protect protein stability of UCK2 and pyrimidine salvage synthesis, and sustain tumor cell growth under glucose limitation. In addition, UCK2-Ser254 phosphorylation level displays a positive relationship with GART-Ser440 phosphorylation level and its enhancement is correlated with poor prognosis of human hepatocellular carcinoma (HCC) patients. These findings reveal a non-canonical role of GART in regulating pyrimidine salvage synthesis under nutrient stress, and raise the potential for alternative treatments in targeting pyrimidine salvage-dependent tumor growth., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. This study was reviewed and approved by Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (KY2024-152-B) with written informed consents from all the patients., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

To enhance the safety of coal mining operations and improve the efficiency of gas extraction, hydraulic flushing technology has been widely used in low permeability coal seams. This study aims to investigate the mechanism of hydraulic flushing by conducting experiments focusing on four aspects: sample strength, punching pressure, punching position and vibration direction. The results show that an increase in hydraulic flushing pressure leads to a deeper impact groove, whereas higher sample strength results in a shallower groove. Additionally, the amplitude of stress wave is positively correlated with the density of the sample, with low-strength samples exhibiting extensive stress wave propagation and minimal attenuation. The stress wave vibration is multi-directional, which can maximize the instability and destruction of the internal structure of the coal body. To validate the practical efficacy of hydraulic flushing, a field test was conducted at the Yuwu Coal Mine in Changzhi City, Shanxi Province. The field trial shows that the effective influence radius of hydraulic flushing can reach 4 m, with a significantly lower gas flow attenuation coefficient compared to ordinary borehole. Notably, the permeability of coal seam in hydraulic flushing area is close to twice that of ordinary drilling area., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The scope of neck lymph node dissection remains controversial for unilateral papillary thyroid carcinoma (UPTC) patients with no clinical evidence of lymph node metastasis (cN0). This study aims to build and validate a model for predicting central lymph node metastasis (CLNM) in UPTC patients through preoperative basic information and intraoperative rapid frozen pathology results. Retrospective analysis covered 1928 patients with PTC from the Wuhan Union Hospital database (2010-2020), randomly split into training and validation sets in a 7:3 ratio. Univariate and multivariate logistic regression analyses were performed to assess the risk factors for ipsilateral CLNM and contralateral CLNM in UPTC patients with cN0. Identified six risk factors for ipsilateral CLNM and seven risk factors for contralateral CLNM in cN0 UPTC patients. Two separate nomograms were constructed to visualize the results. The C-index for predicting ipsilateral and contralateral CLNM nomograms is 0.746 (95% CI 0.723-0.768) and 0.712 (95% CI 0.679-0.744), respectively. The calibration curves presented good agreement between prediction by nomograms and actual observation. The clinical decision curves suggest a net benefit from this model. UPTC patients can use these two nomograms to predict the probability of ipsilateral CLNM and contralateral CLNM separately, enabling risk stratification and aiding in surgical decision-making., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The study follows the 2013 revised Helsinki Declaration and has been approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Approval No. 0304-01). This is an observational study that does not involve collecting personal information of patients, therefore the ethics committee of our institution eliminates the need for obtaining informed consent., (© 2025. The Author(s).)

Land ecological security (LES) is crucial for human well-being and sustainable development, especially in areas like the Lower Yellow River Flood Plain (LYRFP), which faces flood threats, economic challenges, and ecological fragility. This study introduces a "Quality-Structure-Function" framework for evaluating LYRFP's LES, incorporating ecological baselines and the impacts of land use changes on human well-being for a comprehensive assessment. Using the Optimal Parameter Geographic Detector (OPGD) model, we analyzed agricultural, industrial, and socio-economic factors as potential LES drivers. The findings indicate a gradual improvement in LES over the past two decades, with spatial variations-higher in upstream and estuarine areas and lower in the middle. Significant enhancements post-2010 were observed in Shandong Province, unlike the modest gains in Henan. Spatial heterogeneity in LES was evident across floodplain segments, with Jitai Beach witnessing the most decline, Dongying Beach the most improvement, and Zhengkai Beach the largest internal disparities. Economic growth and reduced agricultural activities positively impacted LES, while population growth-related human activities contributed to its decline. This study suggested land use safety improvements in LYRFP by considering spatiotemporal and influencing factors for regional ecological protection and development., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)

The current mortality rates for breast cancer underscore the need for better prognostic tools; moreover, LIM and calponin homology domain 1 (LIMCH1), which is a protein with dual roles in cancer, is a promising candidate for investigation. This study employed an integrative approach combining bioinformatics analysis of The Cancer Genome Atlas (TCGA) cohort and clinical immunohistochemistry (IHC) cohort data. We analysed LIMCH1 expression patterns, its associations with clinicopathological features and prognosis, and its impact on the tumour immune microenvironment (TIME). Functional annotations and single-cell RNA sequencing (scRNA-seq) data were used to explore the underlying molecular mechanisms. Our analysis revealed that high LIMCH1 expression in breast cancer patients was significantly associated with unfavourable clinical outcomes and served as an independent prognostic indicator. The functional annotations revealed pathways related to carcinogenesis and metabolic reconfiguration, thus suggesting the role of LIMCH1 in tumour progression. Additionally, LIMCH1 expression was correlated with an immunosuppressive TIME characterized by increased numbers of M2 macrophages and reduced numbers of CD8 + T cells and NK cells. Finally, we developed a nomogram incorporating LIMCH1 expression for predicting overall survival rates, thus providing a clinically applicable tool. Our research elucidates the diverse functions of LIMCH1 in the pathogenesis of breast cancer, thus highlighting its potential utility as both a prognostic indicator and a therapeutic intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical declaration and consent to participate: This article does not contain any studies with animals performed by any of the authors. The studies involving human participants were reviewed and approved by The Ethics Committee of Renmin Hospital of Wuhan University (No. WDRY2021-KS009). Written informed consent was obtained from the individual(s) for the publication of any data included in this article., (© 2025. The Author(s).)

Previous studies on the correlation between serum selenium and hypertension have yielded inconsistent results. Our previous analysis of participants from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 indicated that elevated serum selenium concentrations were associated with an increased risk of metabolic abnormalities in obese individuals, with the primary effect being on blood pressure in males. The aim of this study was to further elucidate the relationship between serum selenium and the risk of hypertension in obese males. In this study, we examined the correlation between serum selenium concentrations and hypertension in 2,585 male participants with a body mass index (BMI) ≥ 30 kg/m 2 aged between 20 and 80 years from the 2011-2018 NHANES database. The associations between serum selenium levels and hypertension were evaluated through weighted generalized linear regression analyses. To examine the saturation threshold effect between serum selenium and hypertension, a generalized additive model (GAM) and a two-piecewise linear regression model were employed. Furthermore, the saturation threshold effect was evaluated separately in subgroups stratified by BMI and age. The weighted prevalence of hypertension (51.84%) was slightly higher than that of nonhypertension (48.16%) in the participants included in this study. After rigorous adjustment for sociodemographic, physical, and laboratory test covariates, the weighted odds ratio (OR) of hypertension increased by 103% for every 1 standard deviation (SD) increase (approximately 24.41 µg) in the serum selenium concentration in participants assigned to the highest serum selenium group (weighted OR = 2.03; 95% CI = 1.24-3.32; P = 0.013). A calculation was subsequently performed to determine the saturation threshold effect of selenium on hypertension among participants in the medium and highest selenium concentration subgroups. The findings indicated that participants with serum selenium concentrations exceeding the saturation threshold (2.56 µM) demonstrated an elevated risk of developing hypertension (weighted OR = 9.58; 95% CI = 2.74-33.46; P = 0.000) in comparison to those with serum selenium concentrations below the threshold. Subgroup analyses demonstrated that serum selenium concentrations exceeding the saturation threshold were associated with an increased risk of hypertension in participants with a BMI ≤ 35 kg/m 2 (weighted OR = 9.11; 95% CI = 1.43-58.24; P = 0.030) or those aged less than 55 years or younger (weighted OR = 8.37; 95% CI = 1.71-40.94; P = 0.014). For obese adult males who require additional selenium supplementation to enhancing their overall health and well-being, it is strongly recommended that the serum selenium concentrations be monitored throughout the course of supplementation to ensure that they remain within the relatively safe range (approximately less than 215.75 µg/L)., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Chronic kidney disease (CKD) is a worldwide public health problem. Podocyte damage is a hallmark of glomerular diseases including focal segmental glomerulosclerosis (FSGS) and one of the leading causes of CKD. Lysine methylation is a crucial post-translational modification. Beyond epidemic regulation, various lysine methyltransferases have been recently reported to participate in disease progression, including cancers and kidney diseases. Among them, Methyltransferase-like 10 (METTL10), is recognized as a gene associated with estimated glomerular filtration rate (eGFR) and CKD risk. However, its role in podocyte damage remains unclear. We identified the differentially expressed genes(DEGs)in podocyte injury by bioinformatics analysis. Patients diagnosed as idiopathic FSGS by renal biopsy were enrolled. Mouse model was established by Adriamycin(ADR) and urinary albumin/ creatinine ratio(UACR) was detected. Murine podocyte cell line was stimulated with ADR. We determined METTL10 was one of the significantly downregulated genes in damaged podocytes, confirmed the decreased glomerular expression of METTL10 in patients with idiopathic FSGS and in mice with ADR-induced nephrosis, respectively. Moreover, we found a negative correlation between glomerular METTL10 levels and UACR in mice. METTL10 was reduced in ADR-treated podocytes, accompanied by podocyte dedifferentiation (loss of synaptopodin, podocin, nephrin, WT-1) and acquisition of mesenchymal cell markers (snail, desmin, pax2). Knockdown of METTL10 promoted their dedifferentiation. METTL10 regulates podocyte dedifferentiation under damaging stimuli and protects podocytes., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to declare., (© 2024. The Author(s).)

The Insulated Gate Bipolar Transistor (IGBT) is a crucial power semiconductor device, and the integrity of its internal structure directly influences both its electrical performance and long-term reliability. However, the precise semantic segmentation of IGBT ultrasonic tomographic images poses several challenges, primarily due to high-density noise interference and visual distortion caused by target warping. To address these challenges, this paper constructs a dedicated IGBT ultrasonic tomography (IUT) dataset using Scanning Acoustic Microscopy (SAM) and proposes a lightweight Multi-Scale Fusion Network (LMFNet) aimed at improving segmentation accuracy and processing efficiency in ultrasonic images analysis. LMFNet adopts a deep U-shaped encoder-decoder architecture, with the backbone designed using inverted residual blocks to optimize feature transmission while maintaining model compactness. Additionally, we introduce two flexible, plug-and-play modules: the Context Feature Fusion (CFF) module, which effectively integrates multi-scale contextual information at skip connection layers, and the Multi-Scale Perception Aggregation (MPA) module, which focuses on extracting and fusing multi-scale features at bottleneck layers. Experimental results demonstrate that LMFNet performs exceptionally well on the IUT dataset, significantly outperforming existing methods in terms of segmentation accuracy and model lightweighting performance., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

This study used ultra-widefield swept-source optical coherence tomography angiography (UWF SS-OCTA) to analyze and compare choroidal blood flow and anatomical changes in eyes affected by central serous chorioretinopathy (CSC), pachychoroid neovasculopathy (PNV), and uncomplicated pachychoroid (UCP). The findings revealed distribution patterns of vortex veins across the three patient groups and provided initial findings insights into the origin of choroidal neovascularization (CNV) in PNV. A total of 44 patients with CSC, 38 with PNV, and 46 with UCP were included in the analysis. Three-dimensional data were obtained from scans measuring 20 mm vertically by 24 mm horizontally with a scan depth of 6 mm, covering nine subfields. The results showed that CSC groups exhibited significantly higher choroidal vessel volume per unit area (mCVV/a), choroidal vascularity index (CVI), and choroidal thickness (CT) compared to the PNV and UCP groups. While the PNV and UCP groups shared similar choroidal vascular characteristics, the PNV group exhibited slightly higher choroidal vessel volume and notably the lowest foveal choriocapillaris density. These findings suggest that PNV and CSC may represent a continuous pathological spectrum, while UCP might be considered a precursor to CSC or a stage following its resolution. Additionally, further analysis indicated that CNV in PNV could be attributed to choriocapillaris occlusion and ischemia resulting from mechanical compression by hypertrophic choroidal vessels. These findings enhance our understanding of choroidal structure and hemodynamics within pachychoroid spectrum diseases (PSD), shedding light on shared etiological mechanisms and advancing the characterization of their pathophysiology., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of General Hospital of Central Theater Commandand with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study., (© 2024. The Author(s).)

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We developed a novel "two-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57Bl6/NJ mice fed a high-fat diet (HFD) for > 10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d. HFD-Renin (aka "HFpEF") mice demonstrated obesity and insulin resistance, moderate left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by echocardiographic measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to human HFpEF. Treatment with empagliflozin, an effective but incompletely understood HFpEF therapy, improved multiple endpoints. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Additional preclinical HFpEF models allow for orthogonal studies to increase validity in assessment of interventions., Competing Interests: Declarations. Competing interests: DPK is a consultant for Pfizer Inc. YS, KT, XC, MM, RK, DH-S, RM, BBZ, RJRF are employees of Pfizer Inc. or were employees at the time the research was conducted. Multiple Pfizer authors own Pfizer stock. The other authors declare no competing interests., (© 2024. The Author(s).)

Annexin A5 (ANXA5) is a small calcium-dependent protein that binds specifically to negatively charged phosphatidylserine as a marker of apoptosis. Previous studies have shown that ANXA5 expression is elevated in hypertensive patients and is closely related to left ventricular systolic function in hypertensive patients, but its specific mechanism of action has not been clarified. GEO database analysis showed that ANXA5 expression was significantly upregulated in hypertensive myocardial hypertrophy. The expression of ANXA5 protein and mRNA was overexpressed, and knockdown of ANXA5 can effectively attenuate cardiomyocyte apoptosis and inflammatory response, ameliorate myocardial hypertrophy and cardiac dysfunction in ALD-induced hypertrophic cardiomyocytes and in SHR hypertrophic hearts. Mechanistically, ANXA5 has synergistic effect with intracellular calciumion level. In the meantime, ANXA5 knockdown inhibited cell apoptosis along with a decrease of Bax/Bcl-2 ratio, and induction of PI3K/AKT activation. It should be noted that LY290004 (PI3K/Akt signaling pathway inhibitor) can weaken the inhibitory effect of knockdown ANXA5 on cardiomyocyte apoptosis and myocardial protection. Therefore, ANXA5 knockdown improves hypertensive myocardial hypertrophy and cardiac function by inhibiting apoptosis and inflammatory response and activating PI3K/AKT/Bcl-2 pathway, ANXA5 may be a potential therapeutic direction for the treatment of hypertensive myocardial hypertrophy., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All animal experiments were approved by the Animal Ethics Committee of the Guizhou Medical University (Permit No.1900572). Consent for publication: Not applicable., (© 2024. The Author(s).)

To observe the structural changes of retina and choroid in patients with different degrees of myopia. We recruited 219 subjects with different degrees of myopia for best corrected visual acuity, computer refraction, intraocular pressure, axial length (AL), optical coherence tomography (OCT) imaging, and other examinations. Central macular retinal thickness (CRT), subfoveal choroidal thickness (SFCT), nasal retinal thickness (NRT), temporal retinal thickness (TRT), nasal choroidal thickness (NCT) and temporal choroidal thickness (TCT) were measured by optical coherence tomography. ImageJ software was used to measure the retinal area and choroidal area (CA), and Niblack was used to binarize all OCT images to measure the choroidal vessel area (CVA) and choroidal matrix area (CMA). We found that CRT, SFCT, NRT, TRT, NCT, TCT, CA, CVA, and CMA were significantly reduced in the pathological myopia (PM) group. AL was negatively correlated with NRT, SFCT, CMA, CVA and choroidal stromal index. There was a significant positive correlation between AL and choroidal vascular index. The choroidal vascular index in the PM group was significantly increased compared with the other groups. We established a univariate receiver operating curve to analyze the diagnostic value of all parameters for PM. Spherical equivalent, AL, SFCT, TCT, NCT, CA, CVA, and CMA had high diagnostic value for PM, among which CMA had the highest accuracy. There are changes in choroidal structure in adults with different degrees of myopia. Choroidal thickness, CVA and CMA decrease significantly with the increase of myopia, and are correlated with AL. The decrease of CMA has higher diagnostic value in myopia., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: This study followed the tenets of the Declaration of Helsinki and was approved by the Ethical Committee of Jinshan Hospital of Fudan University. Consent to participate: In addition, all studies were conducted with the consent of the subjects and signed the informed consent form., (© 2024. The Author(s).)

Although intermittent hypoxia training (IHT) and methazolamide (MTZ) alone can prevent high-altitude cerebral edema (HACE) to varying degrees, their efficacy and dispersion remain limited. However, only a handful of trials have explored the effectiveness of the IHT and MTZ combination in preventing HACE. Rats were first exposed to hypobaric hypoxia (5000 m, 54.02 kPa, 10.8% fraction of inspired oxygen (FiO 2 )) with simultaneous exhaustive exercise (EE) for different durations to determine the ideal condition for establishing a rat model of HACE. Rats receiving various courses of IHT were subjected to this condition, and changes in behaviour, brain water content (BWC), pathology and brain protein expression were evaluated. Meanwhile, rats received different doses of MTZ before and during hypoxia exposure with simultaneous EE. Finally, rats receiving the IHT and MTZ combination were then exposed to hypoxia with simultaneous EE. Systemic inflammation and mild cerebral edema developed in rats after 6 h of hypobaric hypoxia with simultaneous EE. Rats showed severe impairment of spatial and memory functions after 2 days of hypobaric hypoxia with simultaneous EE, and the pathology of their brain showed significant dilated perivascular spaces, cell swelling, vacuolar degeneration and reduced neuron count. BWC, serum inflammatory factors and expression of vascular endothelial growth factor (VEGF) and aquaporin 4 (AQP4) proteins in the hippocampus increased significantly. Both IHT and MTZ differentially counteracted hypobaric hypoxia-induced spatial and memory function impairments and increased BWC, pathological changes and expression of AQP4 and VEGF proteins in the hippocampus. Among these, the long-course IHT (BID, 14 d) combined with MTZ (200 mg/kg/d) showed the most significant improvement, restoring the rats' indices to normal levels. Continuous hypobaric hypoxia with simultaneous EE for 2 days resulted in significant HACE in rats, which may be used to establish a rat model of HACE. Both IHT and MTZ alleviated HACE in rats to varying degrees, among which long-course IHT (BID, 14 d) combined with MTZ (200 mg/kg/d) effectively prevented HACE in rats., Competing Interests: Declaration. Competing interests: The authors declare no competing interests. Ethics approval: This study was approved by the Institutional Review Board of Beijing Shijitan Hospital, Capital Medical University, Approval No: sjtkyll-lx-2023(010). This study is reported in accordance with ARRIVE guidelines., (© 2024. The Author(s).)

Renal ischemia-reperfusion injury (IRI) is an important cause of acute kidney injury (AKI). However, the pathophysiological changes and mechanisms during IRI-AKI progression remain unclear. This study aims toinvestigate the potential mechanisms in the progression of IRI-AKI by integrating metabolomics and transcriptomics data, providing a reference for the subsequent identification of biomarkers and therapeutic targets. IRI-AKI rat models with 30 min of ischemia and 24-72 h of reperfusion surgery simulating the progression of AKI were established. Compared to the control group underwent sham surgery (NC group), most of the differentially expressed metabolites (DEMs) in IRI-AKI 24 h and IRI-AKI 72 h decreased, mainly including amino acids, organic acids, and carnitines. Additionally, we found that DEMs were mainly enriched in amino acid-related pathways, among which valine, leucine, and isoleucine biosynthesis were dramatically altered in all comparisons. Transcriptomics revealed that differentially expressed genes (DEGs) were primarily involved in amino acid, lipid, and fatty acid metabolism. By integrating metabolomics and transcriptomics, we found valine, leucine, and isoleucine biosynthesis play key roles in IRI-AKI development. Our findings concluded that valine, leucine, and isoleucine pathways are hubs that potentially connect transcriptomes to metabolomes, providing new insights regarding the pathogenesis of IRI-AKI and its potential biomarkers and therapeutic strategies., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma, often exhibits resistance to tyrosine kinase inhibitors (TKIs) when used as monotherapy. However, the integration of PD-1 blockade with TKIs has significantly improved patient survival, making it a leading therapeutic strategy for ccRCC. Despite these advancements, the efficacy of this combined therapy remains suboptimal, necessitating a deeper understanding of the underlying regulatory mechanisms. Through comprehensive analyses, including mass spectrometry, RNA sequencing, lipidomic profiling, immunohistochemical staining, and ex vivo experiments, we explored the interaction between PTPRZ1 and RNF26 and its impact on ccRCC cell behavior. Our results revealed a unique interaction where PTPRZ1 stabilized RNF26 protein expression by dephosphorylating it at the Y432 site. The modulation of RNF26 levels by PTPRZ1 was found to be mediated through the proteasome pathway. Additionally, PTPRZ1, via its interaction with RNF26, activated the TNF/NF-κB signaling pathway, thereby promoting cell proliferation, angiogenesis, and lipid metabolism in ccRCC cells. Importantly, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was attenuated when RNF26 was simultaneously knocked down. These findings highlight the critical role of the PTPRZ1-RNF26 axis in ccRCC and suggest that combining PTPRZ1 inhibitors with current TKIs and PD-1 blockade therapies could significantly improve treatment outcomes for ccRCC patients., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya hospital, Central South University. Consent to publication: All subjects have written informed consent., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The study investigated the impact of varicocele on male infertility by analyzing sperm samples from 42 varicocele patients and 22 healthy individuals. Basic sperm parameters such as concentration and vitality were assessed, along with the DNA Fragmentation Index (DFI) using the SCSA method. Additionally, the mean number of sperm DNA breaks (MDB) and free DNA fragments amount in seminal plasma (fDFA) were analyzed using the TDT-Strand Displacement Probe Technique. Results showed higher levels of DFI, MDB, and fDFA in varicocele-related infertility cases. Combining MDB and fDFA proved more effective in predicting fertility compared to individual assessments or the DFI alone. While these findings suggest a potential role for MDB and fDFA as predictors of male fertility, further rigorous studies are needed to validate their application in varicocele-related male infertility., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Consent for publication: Not applicable., (© 2024. The Author(s).)

In the general population, there is limited evidence for the associations between hand eczema (HE) and lifestyle factors, and between the severity of HE and quality of life. This study aimed to estimate the risk factors for the incidence of HE in the general population and the risk factors for the severity of HE. A cross-sectional questionnaire was administered to 121 HE patients in a hospital from December 2018 to December 2019 in Wuhan. The severity of HE was significantly associated with working with wet hands more than 5 h per day and chapped skin. Sixty-seven patients have positive patch test results. Working with wet hands for more than 5 h per day and chapped skin were the most common and significant risk factors for HE. Working hours with wet hands per day was an independent risk factor for the hand eczema severity index and dermatology life quality index, and there was a significant positive correlation between chapped skin and the severity of hand eczema and higher transepidermal water loss (TEWL). The results also revealed a significant positive correlation between the severity of HE and the impact on quality of life and the severity of TEWL. Prolonged wet hand work can lead to a higher rate of severe hand eczema in the general population. HE can be relieved by reducing the wet hand working time and hand moisturizing., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Distant metastasis is the leading cause of cancer-related mortality, and achieving survival benefits through advancements in systemic therapy remains challenging. Mast cells play a dual role in shaping the tumor microenvironment (TME) and influencing distant metastasis, underscoring the significant research value of targeting mast cells for systemic therapy in advanced cancer. We investigated variations in mast cell infiltration levels in primary and metastatic malignancies using immunocyte infiltration analysis. Mast cell subsets were identified from pan-cancer distant metastasis single-cell sequencing data through dimensionality reduction clustering and cell type annotation, combined with cell trajectory and communication network analyses. A prognostic model was established using WGCNA and 12 machine learning algorithms to identify potential mast cell targets. Drug sensitivity and Mendelian randomization analyses were conducted to select potential drugs targeting mast cells, and their effects on epithelial-mesenchymal transition (EMT) were validated through in vitro experiments, including wound healing, transwell, and western blot assays. Results revealed that activated mast cells show increased infiltration in metastatic tumors, correlating with poor survival duration. XBP1+ mast cells were identified as key components of the inhibitory TME, potentially involved in EMT activation. Simvastatin was identified as a potential drug, reversing EMT induced by XBP1+ mast cells in pan-cancer. Aberrant activation of MEK/ERK signaling in XBP1+ mast cells can stimulate cancer cell EMT by modulating degranulation, while Simvastatin can inhibit EMT by suppressing degranulation., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The data utilized in this study is exclusively obtained from publicly available sources and commercial human cell line, eliminating the need for ethical scrutiny. Consent for publication: Not applicable., (© 2024. The Author(s).)

This study aimed to systematically review the clinical efficacy of probiotics or synbiotics supplementation in the treatment of chemotherapy-induced complications and gut microbiota dysbiosis in patients with gastrointestinal cancer. A literature search was performed systematically using PubMed, Embase, Cochrane, Web of Science, Wanfang Data, and CNKI for randomized controlled trials of probiotics or synthetic supplementation on chemotherapy-induced complications and gut microbiota dysbiosis in gastrointestinal cancer up to December 2023. The outcome measures included chemotherapy-related complications and the the incidence of gut microbiotas. Fifteen studies were finally eligible for meta-analysis, involving 1356 patients. Meta-analysis results showed that the the incidence rates of chemotherapy-related complications such as nausea and vomiting [RR = 0.61, 95% CI (0.46,0.82), P = 0.0008] and diarrhea [RR = 0.47, 95% CI (0.32,0.68), P < 0.001] were significantly reduced after probiotic intervention. The number of intestinal flora changed significantly after intervention, such as bifidobacterium [SMD = 1.33, 95% CI (0.52,2.31), P = 0.001], Escherichia coli [SMD = -0.82, 95% CI (-1.26, -0.38), P = 0.0003], and the difference was statistically significant. Probiotics or synbiotics supplementation can reduce chemotherapy-induced complications in patients with gastrointestinal cancer and regulate the number of gut microbiotas to balance the intestinal microecology of the body., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The primary objective of this study was to identify the factors associated with the development of depressive symptoms in elderly breast cancer (BC) patients and to construct a nomogram model for predicting these symptoms. We recruited 409 patients undergoing BC treatment in the breast departments of two tertiary-level hospitals in Jiangsu Province from November 2023 to April 2024 as our study cohort. Participants were categorized into depressed and non-depressed groups based on their clinical outcomes. Univariate and multivariate logistic regression analyses were employed to identify independent risk factors for depression among BC patients. Multivariate analysis revealed that monthly income, pain score, family support score, and physical activity score significantly influenced the onset of depression in older BC patients (P < 0.05).The risk prediction model, constructed using these identified factors, demonstrated excellent discriminatory power, as evidenced by an area under the ROC curve (AUC) of 0.824. The maximum Youden index was 0.627, with a sensitivity of 90.60%, specificity of 72.10%, and a diagnostic threshold value of 1.501. The results of the Hosmer-Lemeshow goodness-of-fit test (χ² = 3.181, P = 0.923) indicated that the model fit the data well. The calibration curve for the model closely followed the ideal curve, suggesting a strong fit and high predictive accuracy. Our nomogram model exhibited superior predictive performance, enabling healthcare professionals to identify high-risk patients early and implement preventative measures to mitigate the development of depressive symptoms. This study is a cross-sectional study that lacks longitudinal data and has a small sample size. Future research could involve larger samples, multicenter studies, and prospective designs to build better clinical predictive models., (© 2024. The Author(s).)

Green and sustainable development is unstoppable. The digital economy has driven great changes in production methods and has become a key strength in reshaping global economic structure and achieving sustainable development. Cities are both the mainstay of economic growth and the main source of various environmental pollution problems. Therefore, studying the relationship between urban digital economy and urban green total factor productivity is of great significance. Based on panel data from 252 cities in China 2011-2019, a two-way fixed effects model was used to examine the impact of urban digital economy on urban green total factor productivity. The empirical results indicate that: (1) Urban digital economy has a significant positive impact on urban green total factor productivity. (2) Urban technological-innovation-level and human-capital-structure of play a mediating role in the impact. (3) This impact has regional heterogeneity and resource-based type heterogeneity. The research conclusions are not only valuable supplements to previous research, but also providing reliable instructions for implementing a flexible digital economy policy., (© 2024. The Author(s).)

Intestinal microbiota imbalance plays an important role in the progression of obstructive sleep apnea (OSA), and is considered to be the main mediator that triggers metabolic comorbidities. Here, we analyzed the changes in intestinal microbiota in patients with different severities of OSA based on apnea hypopnea index (AHI) classification, and explored the role of intestinal microbiota in the severity of OSA. This study included 19 healthy volunteers and 45 patients with OSA [5 ≤ AHI < 15 (n = 14), 15 ≤ AHI < 30 (n = 13), AHI ≥ 30 (n = 18)]. Relevant sleep monitoring data and medical history data were collected, and microbial composition was analyzed using 16S rRNA high-throughput sequencing technology. The diversity analysis of intestinal microbiota among different groups of people was conducted, including alpha diversity, beta diversity, species diversity, and marker species as well as differential functional metabolic pathway prediction analysis. With the increase of AHI classification, the alpha diversity in patients with OSA significantly decreased. The results revealed that the severity of OSA is associated with differences in the structure and composition of the intestinal microbiota. The abundance of bacteria producing short-chain fatty acids (such as Bacteroides, Ruminococcacea, and Faecalibacterium) in severe OSA is significantly reduced and a higher ratio of Firmicutes to Bacteroidetes. Random forest analysis showed that Parabacteroides was a biomarker genus with important discriminatory significance. The differential metabolic pathway prediction function shows that the main function of maintaining intestinal microbiota homeostasis is biosynthetic function. Our results show that the differences in the composition of intestinal microbiota in patients with different severities of OSA are mainly related to short-chain fatty acid-producing bacteria. These changes may play a pathological role in OSA combined with metabolic comorbidities., (© 2024. The Author(s).)

The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons 1-3 . It is a pharmacological target for various antidepressants and analgesic drugs 4,5 . Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlA EM ), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na + and Cl - undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlA EM provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to explore the relationship between shift-working nurses' social jetlag and body mass index (BMI) and provide a theoretical basis for nursing managers to develop appropriate health interventions. Shift work is unavoidable in nursing and is associated with circadian rhythm disorders. Social jetlag is prevalent in shift-working nurses and is associated with adverse health outcomes (particularly metabolism-related indicators). BMI is a significant metabolic indicator, and research has demonstrated its effectiveness in predicting the formation of metabolic syndrome. The relationship between social jetlag and BMI can be explained by considering physiological, psychological, and behavioral factors. However, most studies on social jetlag and health status are focused on non-shift nurse populations, with fewer studies on shift workers. Five tertiary hospitals located at similar latitudes in Southwest China were selected for the study. We surveyed 429 shift-working nurses using sociodemographic data, the Munich Chronotype Questionnaire for Shift Workers, and BMI. The restricted cubic spline model was used to analyze the relationship between social jetlag and BMI among shift-working nurses, and segmented linear regression was performed around the inflection point using multiple linear regression analysis. The results revealed that social jetlag (82.0 [85.0] min) was experienced by 64.6% of the shift-working nurses. After controlling for confounding variables, the model with seven knots had the lowest accepted Akaike information criterion value, and there was a U-shaped relationship between shift-working nurses' BMI and social jetlag in this model; its inflection (lowest) point of 20.7 was considered the cut-off point. Segmented regression showed that for BMI < 20.7, BMI was significantly negative with standardized social jetlag; whereas with BMI > 20.7, BMI was significantly positive with standardized social jetlag. BMI has a U-shaped relationship with social jetlag, and attention should be paid to overweight or underweight shift-working nurses to detect early circadian rhythm disorder. Shift-working nurses with high social jetlag tended to have higher/lower BMI, which should be further investigated in the future, to minimize metabolic diseases among them., (© 2024. The Author(s).)

The traceability of groundwater nitrate pollution is crucial for controlling and managing polluted groundwater. This study integrates hydrochemistry, nitrate isotope (δ 15 N-NO 3 - and δ 18 O-NO 3 - ), and self-organizing map (SOM) and end-member mixing (EMMTE) models to identify the sources and quantify the contributions of nitrate pollution to groundwater in an intensive agricultural region in the Sha River Basin in southwestern Henan Province. The results indicate that the NO 3 - -N concentration in 74% (n = 39) of the groundwater samples exceeded the WHO standard of 10 mg/L. According to the results of EMMTE modeling, soil nitrogen (68.4%) was the main source of nitrate in Cluster-1, followed by manure and sewage (16.5%), chemical fertilizer (11.9%) and atmospheric deposition (3.3%). In Cluster-2, soil nitrogen (60.1%) was the main source of nitrate, with a significant increase in the contribution of manure and sewage (35.5%). The considerable contributions of soil nitrogen may be attributed to the high nitrogen fertilizer usage that accumulated in the soil in this traditional agricultural area. Moreover, it is apparent that most Cluster-2 sampling sites with high contributions of manure and sewage are located around residential land. Therefore, the arbitrary discharge and leaching of domestic sewage may be responsible for these results. Therefore, this study provides useful assistance for the continuous management and pollution control of groundwater in the Sha River Basin., (© 2024. The Author(s).)

External ventricular drainage (EVD) is a common procedure in neurosurgical practice. Presently, the three methods used most often include direct EVD (dEVD), long-tunneled external ventricular drains (LTEVDs), and EVD via the Ommaya reservoir (EVDvOR). But they possess drawbacks such as limited duration of retention, vulnerability to iatrogenic secondary infections, and challenges in regulating drainage flow. This study aimed to explore the use of a modified ventriculoperitoneal shunt (mVPS)-the abdominal end of the VPS device was placed externally-as a means of temporary EVD to address the aforementioned limitations. This retrospective cohort study, included 120 cases requiring EVD. dEVD was performed for 31 cases, EVDvOR for 54 cases (including 8 cases with previously performed dEVD), and mVPS for 35 cases (including 6 cases with previously performed EVDvOR). The one-time success rate (no need for further other EVD intervention) for dEVD, EVDvOR, and mVPS were 70.97%, 88.89%, and 91.42%, dEVD vs EVDvOR (P < 0.05), dEVD vs mVPS (P < 0.05), EVDvOR vs mVPS (P > 0.05). Puncture needle displacement or detachment was observed in nearly all cases of EVDvOR, while no such complications have been observed with mVPS. Apart from this complication, the incidence of postoperative complications was 35.48%, 14.81%, and 8.5%, dEVD vs EVDvOR (P < 0.05), dEVD vs mVPS (P < 0.05), EVDvOR vs mVPS (P > 0.05). Mean postoperative retention for EVD was 14.68 ± 9.50 days, 25.96 ± 15.14 days, and 82.43 ± 64.45 days, respectively (P < 0.001). In conclusion, mVPS significantly extends the duration of EVD, which is particularly beneficial for patients requiring long-term EVD., (© 2024. The Author(s).)

Tobacco smoke exposure has been demonstrated to impede bone remodeling and diminish bone density, yet research regarding its correlation with parathyroid hormone (PTH) remains limited. This study aims to investigate the relationship between tobacco smoke exposure and serum PTH levels in adults aged 20 years and older. This study included 7,641 participants from two cycles of the National Health and Nutrition Examination Survey (NHANES, United States, 2003- 2006). Reflect tobacco smoke exposure through serum cotinine levels, and use an adjusted weighted multivariate linear regression model to test the independent linear relationship between serum cotinine and PTH. Stratified analysis was conducted to validate the sensitivity of the conclusions. Smooth curve fitting and threshold effect analysis were performed to assess the non-linear relationship. After comprehensive adjustment using weighted multivariate regression analysis, a negative correlation was found between serum cotinine and PTH levels. The interaction p-values in subgroup analyses were all greater than 0.05. Moreover, smooth curve fitting indicated a non-linear relationship between serum cotinine and PTH, with a turning point observed. Our research indicates that tobacco smoke exposure is negatively correlated and independent of serum parathyroid hormone levels, indicating that long-term tobacco smoke exposure may lead to parathyroid dysfunction in adults., (© 2024. The Author(s).)

Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1-4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient's response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP's response to biological therapy., (© 2024. The Author(s).)

Inflammatory bowel disease (IBD) is characterized by persistent damage to the intestinal barrier and excessive inflammation, leading to increased intestinal permeability. Current treatments of IBD primarily address inflammation, neglecting epithelial repair. Our previous study has reported the therapeutic potential of notoginsenoside R1 (NGR1), a characteristic saponin from the root of Panax notoginseng, in alleviating acute colitis by reducing mucosal inflammation. In this study we investigated the reparative effects of NGR1 on mucosal barrier damage after the acute injury stage of DSS exposure. DSS-induced colitis mice were orally treated with NGR1 (25, 50, 125 mg·kg -1 ·d -1 ) for 10 days. Body weight and rectal bleeding were daily monitored throughout the experiment, then mice were euthanized, and the colon was collected for analysis. We showed that NGR1 administration dose-dependently ameliorated mucosal inflammation and enhanced epithelial repair evidenced by increased tight junction proteins, mucus production and reduced permeability in colitis mice. We then performed transcriptomic analysis on rectal tissue using RNA-sequencing, and found NGR1 administration stimulated the proliferation of intestinal crypt cells and facilitated the repair of epithelial injury; NGR1 upregulated ISC marker Lgr5, the genes for differentiation of intestinal stem cells (ISCs), as well as BrdU incorporation in crypts of colitis mice. In NCM460 human intestinal epithelial cells in vitro, treatment with NGR1 (100 μM) promoted wound healing and reduced cell apoptosis. NGR1 (100 μM) also increased Lgr5 + cells and budding rates in a 3D intestinal organoid model. We demonstrated that NGR1 promoted ISC proliferation and differentiation through activation of the Wnt signaling pathway. Co-treatment with Wnt inhibitor ICG-001 partially counteracted the effects of NGR1 on crypt Lgr5 + ISCs, organoid budding rates, and overall mice colitis improvement. These results suggest that NGR1 alleviates DSS-induced colitis in mice by promoting the regeneration of Lgr5 + stem cells and intestinal reconstruction, at least partially via activation of the Wnt/β-Catenin signaling pathway. Schematic diagram of the mechanism of NGR1 in alleviating colitis. DSS caused widespread mucosal inflammation epithelial injury. This was manifested by the decreased expression of tight junction proteins, reduced mucus production in goblet cells, and increased intestinal permeability in colitis mice. Additionally, Lgr5 + ISCs were in obviously deficiency in colitis mice, with aberrant down-regulation of the Wnt/β-Catenin signaling. However, NGR1 amplified the expression of the ISC marker Lgr5, elevated the expression of genes associated with ISC differentiation, enhanced the incorporation of BrdU in the crypt and promoted epithelial restoration to alleviate DSS-induced colitis in mice, at least partially, by activating the Wnt/β-Catenin signaling pathway., (© 2024. The Author(s).)

Fungal diseases, such as powdery mildew and rusts, significantly affect the quality and yield of wheat. Pyramiding diverse types of resistance genes into cultivars represents the preferred strategy to combat these diseases. Moreover, achieving collaborative improvement between diseases resistance, abiotic stress, quality, and agronomic and yield traits is difficult in genetic breeding. In this study, the wheat cultivar, Guinong 29 (GN29), showed high resistance to powdery mildew and stripe rust at both seedling and adult plant stages, and was susceptible to leaf rust at the seedling stage but slow resistance at the adult-plant stage. Meanwhile, it has elite agronomic and yield traits, indicating promising coordination ability among multiple diseases resistance and other key breeding traits. To determine the genetic basis of these elite traits, GN29 was tested with 113 molecular markers for 98 genes associated with diseases resistance, stress tolerance, quality, and adaptability. The results indicated that two powdery mildew resistance (Pm) genes, Pm2 and Pm21, confirmed the outstanding resistance to powdery mildew through genetic analysis, marker detection, genomic in situ hybridization (GISH), non-denaturing fluorescence in situ hybridization (ND-FISH), and homology-based cloning; the stripe rust resistance (Yr) gene Yr26 and leaf rust resistance (Lr) genes Lr1 and Lr46 conferred the stripe rust and slow leaf rust resistance in GN29, respectively. Meanwhile, GN29 carries dwarfing genes Rht-B1b and Rht-D1a, vernalization genes vrn-A1, vrn-B1, vrn-D1, and vrn-B3, which were consistent with the phenotypic traits in dwarf characteristic and semi-winter property; carries genes Dreb1 and Ta-CRT for stress tolerance to drought, salinity, low temperature, and abscisic acid (ABA), suggesting that GN29 may also have elite stress-tolerance ability; and carries two low-molecular-weight glutenin subunit genes Glu-B3b and Glu-B3bef which contributed to high baking quality. This study not only elucidated the genetic basis of the elite traits in GN29 but also verified the capability for harmonious improvement in both multiple diseases resistance and other comprehensive traits, offering valuable information for breeding breakthrough-resistant cultivars., (© 2024. The Author(s).)

Recent research in computational imaging largely focuses on developing machine learning (ML) techniques for image recognition in the medical field, which requires large-scale and high-quality training datasets consisting of raw images and annotated images. However, suitable experimental datasets for cervical spine X-ray are scarce. We fill the gap by providing an open-access Cervical Spine X-ray Atlas (CSXA), which includes 4963 raw PNG images and 4963 annotated images with JSON format (JavaScript Object Notation). Every image in the CSXA is enriched with gender, age, pixel equivalent, asymptomatic and symptomatic classifications, cervical curvature categorization and 118 quantitative parameters. Subsequently, an efficient algorithm has developed to transform 23 keypoints in images into 77 quantitative parameters for cervical spine disease diagnosis and treatment. The algorithm's development is intended to assist future researchers in repurposing annotated images for the advancement of machine learning techniques across various image recognition tasks. The CSXA and algorithm are open-access with the intention of aiding the research communities in experiment replication and advancing the field of medical imaging in cervical spine., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the most common fatal cancers worldwide, and the identification of novel treatment targets and prognostic biomarkers is urgently needed because of its unsatisfactory prognosis. Regulator of G-protein signaling 19 (RGS19) is a multifunctional protein that regulates the progression of various cancers. However, the specific function of RGS19 in HCC remains unclear. The expression of RGS19 was determined in clinical HCC samples. Functional and molecular biology experiments involving RGS19 were performed to explore the potential mechanisms of RGS19 in HCC. The results showed that the expression of RGS19 is upregulated in HCC tissues and is significantly associated with poor prognosis in HCC patients. RGS19 promotes the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, RGS19, via its RGS domain, stabilizes the MYH9 protein by directly inhibiting the interaction of MYH9 with STUB1, which has been identified as an E3 ligase of MYH9. Moreover, RGS19 activates β-catenin/c-Myc signaling via MYH9, and RGS19 is also a transcriptional target gene of c-Myc. A positive feedback loop formed by RGS19, MYH9, and the β-catenin/c-Myc axis was found in HCC. In conclusion, our research revealed that competition between RGS19 and STUB1 is a critical mechanism of MYH9 regulation and that the RGS19/MYH9/β-catenin/c-Myc feedback loop may represent a promising strategy for HCC therapy., (© 2024. The Author(s).)

RNA isoforms influence cell identity and function. However, a comprehensive brain isoform map was lacking. We analyze single-cell RNA isoforms across brain regions, cell subtypes, developmental time points and species. For 72% of genes, full-length isoform expression varies along one or more axes. Splicing, transcription start and polyadenylation sites vary strongly between cell types, influence protein architecture and associate with disease-linked variation. Additionally, neurotransmitter transport and synapse turnover genes harbor cell-type variability across anatomical regions. Regulation of cell-type-specific splicing is pronounced in the postnatal day 21-to-postnatal day 28 adolescent transition. Developmental isoform regulation is stronger than regional regulation for the same cell type. Cell-type-specific isoform regulation in mice is mostly maintained in the human hippocampus, allowing extrapolation to the human brain. Conversely, the human brain harbors additional cell-type specificity, suggesting gain-of-function isoforms. Together, this detailed single-cell atlas of full-length isoform regulation across development, anatomical regions and species reveals an unappreciated degree of isoform variability across multiple axes., (© 2024. The Author(s).)

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA., (© 2024. The Author(s).)

Interferon Gamma Inducible Protein 16 (IFI16) belongs to the HIN-200 protein family and is pivotal in immunological responses. Serving as a DNA sensor, IFI16 identifies viral and aberrant DNA, triggering immune and inflammatory responses. It is implicated in diverse cellular death mechanisms, such as pyroptosis, apoptosis, and necroptosis. Notably, these processes are integral to the emergent concept of PANoptosis, which encompasses cellular demise and inflammatory pathways. Current research implies a significant regulatory role for IFI16 in PANoptosis, particularly regarding cardiac pathologies. This review delves into the complex interplay between IFI16 and PANoptosis in heart diseases, including atherosclerosis, myocardial infarction, heart failure, and diabetic cardiomyopathy. It synthesizes evidence of IFI16's impact on PANoptosis, with the intention of providing novel insights for therapeutic strategies targeting heart diseases., (© 2024. The Author(s).)

Immunotherapy had shown good antitumor activity in a variety of solid tumors, but low benefit in CRC, so there was an urgent need to explore new biomarkers. We evaluated the role of KMT2C using publicly available data from the Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC). In addition, further analysis was performed in an internal cohort. Moreover, the mutant profiles of KMT2C was analyzed in a large CRC cohort. The relationship between clinical pathologic features and KMT2C were analyzed with using the two-sided chi-squared test or the Fisher exact test. Clinicopathologic characteristics associated with overall survival using Cox regression and the Kaplan-Meier method. We found that KMT2C-mutated CRC patients in the immunotherapy cohort had significantly improved OS compared with KMT2C WT patients (P = 0.013). However, this phenomenon did not exist in non-immunotherapy cohort. Our cohort validated the value of KMT2C mutations in predicting better clinical outcomes, including ORR (P < 0.0001) and OS (P = 0.010). Meanwhile, KMT2C mutation was associated with higher tumor mutation burden, MSI score, higher levels of immune-associated T cells, neutrophil, and M1-type macrophages. Our study suggested that KMT2C mutation might be a potential positive predictor for CRC immunotherapy., (© 2024. The Author(s).)

Teratozoospermia is a significant cause of male infertility, but the pathogenic mechanism of acephalic spermatozoa syndrome (ASS), one of the most severe teratozoospermia, remains elusive. We previously reported Spermatogenesis Associated 6 (SPATA6) as the component of the sperm head-tail coupling apparatus (HTCA) required for normal assembly of the sperm head-tail conjunction, but the underlying molecular mechanism has not been explored. Here, we find that the co-chaperone protein BAG5, expressed in step 9-16 spermatids, is essential for sperm HTCA assembly. BAG5-deficient male mice show abnormal assembly of HTCA, leading to ASS and male infertility, phenocopying SPATA6-deficient mice. In vivo and in vitro experiments demonstrate that SPATA6, cargo transport-related myosin proteins (MYO5A and MYL6) and dynein proteins (DYNLT1, DCTN1, and DNAL1) are misfolded upon BAG5 depletion. Mechanistically, we find that BAG5 forms a complex with HSPA8 and promotes the folding of SPATA6 by enhancing HSPA8's affinity for substrate proteins. Collectively, our findings reveal a novel protein-regulated network in sperm formation in which BAG5 governs the assembly of the HTCA by activating the protein-folding function of HSPA8., (© 2024. The Author(s).)

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109)., (© 2024. The Author(s).)

In a previous study, we discovered that the level of lnc-TSPAN12 was significantly elevated in hepatocellular carcinoma (HCC) and correlated with a low survival rate. However, the function and mechanism of lnc-TSPAN12 in modulating epithelial-mesenchymal transition (EMT) and metastasis in HCC remains poorly understood. This study demonstrates that lnc-TSPAN12 positively influences migration, invasion, and EMT of HCC cells in vitro and promotes hepatic metastasis in vivo. The modification of N6-methyladenosine, driven by METTL3, is essential for the stability of lnc-TSPAN12, which may partially contribute to the upregulation of lnc-TSPAN12. Mechanistically, lnc-TSPAN12 exhibits direct interactions with EIF3I and SENP1, acting as a scaffold to enhance the SENP1-EIF3I interaction. As a result, the SUMOylation of EIF3I is inhibited, preventing its ubiquitin-mediated degradation. Ultimately, this activates the Wnt/β-catenin signaling pathway, stimulating EMT and metastasis in HCC. Our findings shed light on the regulatory mechanism of lnc-TSPAN12 in HCC metastasis and identify the lnc-TSPAN12-EIF3I/SENP1 axis as a novel therapeutic target for HCC., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study analyzed the effects of the Dark Tetrad (narcissism, Machiavellianism, psychopathy, sadism) and self-concealment on social appearance anxiety. Empirical investigations on which personality traits influence social appearance anxiety are yet missing. In this study, a sample of N = 1186 Chinese students performed a questionnaire-based survey assessing different personality facets and social appearance anxiety tendencies. Measures included the Narcissistic Personality Inventory, the Levenson Self-Report Psychopathy Scale, the Machiavellian Personality Scale, the Short Sadistic Impulse Scale, the Self-concealment Scale, and the Social Appearance Anxiety Scale. The results of the multiple regression analysis showed that psychopathy, Machiavellianism, sadism, and self-concealment positively predicted social appearance anxiety and narcissism negatively predicted social appearance anxiety. Machiavellianism, psychopathy, sadism, and self-concealment were positive predictors of social appearance anxiety, whereas narcissism was a negative predictor. These findings provide insight into the complex nature of the Dark Tetrad and their influence on social appearance anxiety., (© 2024. The Author(s).)