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Abstract The acidic tumor microenvironment, a hallmark of many solid tumors, is primarily induced by the high glycolytic rate of tumor cells. To avoid acidosis, tumor cells ingeniously maintain an acidic extracellular pH while keeping a relatively alkaline intracellular pH. Overturning the unique pH gradient of tumor cells has exhibited to be a viable approach for cancer therapy. In this review, the formation and regulatory mechanisms of the acidic microenvironment in solid tumors will be firstly outlined. Subsequently, we will comprehensively summarize the latest advancements in anti-tumor therapy via using nanomedicines to manipulate the tumor pH gradient, including acidifying intracellular environment and alkalizing extracellular environment. Following this, we will discuss the future potential of strategies employing nanomedicines to reverse tumor pH gradient. This review aims to foster research on therapeutic approaches targeting the pH regulation of solid tumors and holds an optimistic outlook for the future development of this field.

Abstract Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)’s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31–0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27–0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3–5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.

Abstract Objective Several studies have discussed the relationship between cholesterol and gallstones, and high-density lipoprotein cholesterol (HDL-C) as a representative of this has been addressed in various diseases. The metric neutrophil to high-density lipoprotein cholesterol ratio (NHR) derived from HDL-C has attracted much attention. The purpose of this article is to examine the relationship between NHR and gallstones in a population of American adults. Methods This study investigated the correlation between NHR and gallstone prevalence among US adults using population-based data from the 2017–2020 National Health and Nutrition Examination Survey (NHANES). NHR was derived by dividing the neutrophil count by HDL-C. Data were analyzed using a variety of statistical techniques, such as univariate analysis, multivariate analysis, and subgroup analysis. In addition, a receiver operating characteristic curve (ROC) was used to determine the predictive power of the index for the risk of gallstone prevalence. Results The trial enrolled 6,954 subjects, among whom 746 patients were diagnosed with gallstones. By fully adjusted multivariate logistic regression analysis in the Model 3 section observed a significant positive association between NHR and gallstones with an odds ratio (OR) of 1.05 and a 95% confidence interval (CI) of (1.01, 1.10). The restricted cubic curve (RCS) had a P-Nonlinear = 0.481, suggesting that the relationship was a near-linear one. The area under the curve (AUC) of the ROC curve was 0.550, indicating that NHR has a predictive value for the development of gallstones. Conclusion This study demonstrated a near-linear correlation between NHR and increased susceptibility to gallstones, and the ROC curve is evidence that NHR has some predictive value for the risk of gallstones, albeit with weak predictive power relative to NPAR (Neutrophil percentage/albumin) and NAR (Neutrophils/albumin). Of course, to confirm these findings, more extensive prospective studies are needed to thoroughly validate the role of NHR in the development of gallstones.

Abstract Background In humans and other mammals, the process of oogenesis initiates asynchronously in specific ovarian regions, leading to the localization of dormant and growing follicles in the cortex and medulla, respectively; however, the current understanding of this process remains insufficient. Results Here, we integrate single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) to comprehend spatial–temporal gene expression profiles and explore the spatial organization of ovarian microenvironments during early oogenesis in pigs. Projection of the germ cell clusters at different stages of oogenesis into the spatial atlas unveils a “cortical to medullary (C-M)” distribution of germ cells in the developing porcine ovaries. Cross-species analysis between pigs and humans unveils a conserved C-M distribution pattern of germ cells during oogenesis, highlighting the utility of pigs as valuable models for studying human oogenesis in a spatial context. RNA velocity analysis with ST identifies the molecular characteristics and spatial dynamics of granulosa cell lineages originating from the cortical and medullary regions in pig ovaries. Spatial co-occurrence analysis and intercellular communication analysis unveils a distinct cell–cell communication pattern between germ cells and somatic cells in the cortex and medulla regions. Notably, in vitro culture of ovarian tissues verifies that intercellular NOTCH signaling and extracellular matrix (ECM) proteins played crucial roles in initiating meiotic and oogenic programs, highlighting an underappreciated role of ovarian microenvironments in orchestrating germ cell fates. Conclusions Overall, our work provides insight into the spatial characteristics of early oogenesis and the regulatory role of ovarian microenvironments in germ cell fate within a spatial context.

Abstract Gestational diabetes mellitus (GDM), a common pregnancy disease, has long-term negative effects on offspring health. Epigenetic changes may have important contributions to that, but the underlying mechanisms are not well understood. Here, we report the influence of GDM on DNA methylation of offspring (GDF1) oocytes and the possible mechanisms. Our results show that GDM induces genomic hyper-methylation of offspring oocytes, and at least a part of the altered methylation is inherited by F2 oocytes, which may be a reason for the inheritance of metabolic disorders. We further find that GDM exposure increases the expression of Ezh2 in oocytes. Ezh2 regulates DNA methylation via DNMT1, and Ezh2 knockdown reduces the genomic methylation level of GDF1 oocytes. These results suggest that GDM may induce oocyte genomic hyper-methylation of offspring via enhancing the Ezh2 expression recruiting more DNMT1 into nucleus.

Abstract Objective This study aimed to determine the therapeutic efficacy of tacrolimus (TAC) with mycophenolate mofetil (MMF) or cyclophosphamide (CYC) on the renal response in systemic lupus erythematosus (SLE) patients. Methods A retrospective cohort study based on medical data was conducted among SLE patients who took at least one of the following medicines in 2010–2021: TAC, MMF and CYC. The odds ratio (OR) and 95% confidence interval (CI) were calculated, and the synergistic interaction was estimated using logistic regression models. Results Among 793 SLE patients, 27.9% patients (221 cases) achieved CR after at least 3 months. The TAC use was positively associated with CR with an adjusted OR (95% CI) of 2.82 (1.89, 4.22) overall and in subgroups of SLE patients with SLEDAI scores > 12, moderate or severe urinary protein and comorbidities. The dose-response effect on CR was also observed at TAC doses greater than 4 mg/d and more than 180 days, with adjusted ORs (95% CIs) of 5.65 (2.35, 13.55) and 3.60 (2.02, 6.41), respectively. Moreover, the combined effect of TAC with MMF or CYC was better than that of monotherapy, there was significant synergistic interactions with adjusted ORs (95% CIs) of 2.43 (1.20, 4.92) and 3.14 (1.49, 6.64), respectively, and similar results were observed for the combination of different doses of TAC with MMF or CYC. Conclusion TAC can effectively alleviate the condition of patients with SLE and may interact with MMF or CYC, which suggests that the combination therapy of TAC with MMF or CYC may produce greater benefits for patients with SLE. Trial registration This is a purely observational study that does not require registration.

Background and aims: Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma (HCC). However, the tumor-protective functions of growth differentiation factors (GDFs) in HCC are yet to be clarified. In this study, we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC. Methods: The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues. A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression. Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC. Results: The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors (P

Abstract Topologically associating domains (TADs) are essential units of genome architecture, influencing transcriptional regulation and diseases. Despite numerous methods proposed for TAD identification, it remains challenging due to complex background and nested TAD structures. We introduce HTAD, a human-in-the-loop TAD caller that combines machine learning with human supervision to achieve high accuracy. HTAD begins with feature extraction for potential TAD border pairs, followed by an interactive labeling process through active learning. Performance assessments using public curation and synthetic datasets demonstrate HTAD’s superiority over other state-of-the-art methods and reveal highly hierarchical TAD structures, offering a human-in-the-loop solution for detecting complex genomic patterns.

Abstract Development of large-scale alkaline seawater electrolysis requires robust and corrosion-resistant anodes. Here we propose engineering NiFe layered double hydroxide (LDH)-based anodes by incorporating a series of anions into the LDH interlayers. The most optimal NiFe LDH anode with intercalated phosphates demonstrates stable operation at a high current density of 1.0 A cm−2 for over 1000 hours in a 2 W-scale alkaline seawater electrolyzer (ASWE). Fundamental studies indicate that the basicity, indicated by pK a values, of the intercalated anions in NiFe LDH governs its oxygen evolution reaction activity and corrosion resistance. Highly basic anions (i.e., phosphates) securely anchor Fe sites and facilitate proton transfer to boost both durability and activity. Notably, we demonstrate the proof-of-concept for the NiFe anode in an industrial 1 kW-scale ASWE stack (1,081.2 cm2 anode area in total). This unit achieves a stable operating current density of 0.5 A cm−2 at about 2.0 V, twice that of the commercial alkaline pure water electrolyzer, contributing to an economically competitive hydrogen production cost of US$ 1.96 kgH2 −1.

Abstract In current studies for testing Bell inequalities at colliders, the reconstruction of spin correlations from scattering cross-sections relies on the bilinear form of the spin correlations, but not all local hidden variable models (LHVMs) have such a property. To demonstrate that a general LHVM cannot be rule out via scattering cross-section data, we propose a specific LHVM, which can exactly duplicate the same scattering cross-section for particle production and decay as the standard quantum theory, making it indistinguishable at colliders in principle. Despite of this, we find that reconstructing spin correlations through scattering cross-sections can still exclude a broad class of LHVMs, e.g., those models employing classical spin correlations as a surrogate for quantum spin correlations.

Abstract Objectives Delirium is a prominent symptom of sepsis-associated encephalopathy (SAE) and is highly prevalent in septic patients hospitalized in the intensive care unit, being closely connected with raised mortality rates. Acute hyperglycemia (AH) has been recognized as a separate risk factor for delirium and a worse prognosis in critically sick patients. Nevertheless, the exact contribution of AH to the advancement of SAE is still unknown. Methods This research retrospectively evaluated the connection between blood glucose levels (BGLs) and the incidence of delirium and death rates in septic patients in the ICU of a tertiary comprehensive hospital. In addition, a septic rat model was induced through cecal ligation and puncture (CLP), after which continuous glucose infusion was promptly initiated via a central venous catheter post-surgery to evaluate the potential implications of AH on SAE. Next, septic rats were assigned to four groups based on target BGLs: high glucose group (HG, ≥ 300 mg/dL), moderate glucose group (MG, 200–300 mg/dL), normal glucose group (NG,

Abstract Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight

Abstract Background Biorefinery using microorganisms to produce biofuels and value-added biochemicals derived from renewable biomass offers a promising alternative to meet our sustainable energy and environmental goals. The ethanologenic strain Zymomonas mobilis is considered as an excellent chassis for constructing microbial cell factories for diverse biochemicals due to its outstanding industrial characteristics in ethanol production, high specific productivity, and Generally Recognized as Safe (GRAS) status. Nonetheless, the restricted substrate range constrains its application. Results The truncated ice nucleation protein InaK from Pseudomonas syringae was used as an autotransporter passenger, and α-amylase was fused to the C- terminal of InaK to equip the ethanol-producing bacterium with the capability to ferment renewable biomass. Western blot and flow cytometry analysis confirmed that the amylase was situated on the outer membrane. Whole-cell activity assays demonstrated that the amylase maintained its activity on the cell surface. The recombinant Z. mobilis facilitated the hydrolysis of starch into oligosaccharides and enabled the streamlining of simultaneous saccharification and fermentation (SSF) processes. In a 5% starch medium under SSF, recombinant strains containing P eno reached a maximum titer of 13.61 ± 0.12 g/L within 48 h. This represents an increase of 111.0% compared to the control strain's titer of titer of 6.45 ± 0.25 g/L. Conclusions By fusing the truncated ice nucleation protein InaK with α-amylase, we achieved efficient expression and surface display of the enzyme on Z. mobilis. This fusion protein exhibited remarkable enzymatic activity. Its presence enabled a cost-effective bioproduction process using starch as the sole carbon source, and it significantly reduced the required cycle time for SSF. This study not only provides an excellent Z. mobilis chassis for sustainable bioproduction from starch but also highlights the potential of Z. mobilis to function as an effective cellular factory for producing high-value products from renewable biomass.

Abstract Exploring the spatial pattern and its influencing mechanism of cultural heritage is of great significance for the systematic protection, inheritance and utilization of cultural heritage. In this study, the national-level cultural heritage of China as the research object, and the spatial patterns of the cultural heritage (CH), tangible cultural heritage (TCH) and intangible cultural heritage (ICH) are analyzed are summarized using the multiple geospatial analysis method, and their spatial distribution differences. Then, the optimal parameter geodetector model was further used to analyze the influencing and interaction effect of natural environment (NE) factors, socioeconomic and cultural environment (SCE) factors on the spatial distribution of CH, TCH and ICH, and the interaction mechanism was deeply discussed. The results show that high-density region of CH are mainly located in the southeastern Heihe-Tengchong Line of China, while low-density region are mostly located in the northwestern Heihe-Tengchong Line. In terms of local spatial differences, the spatial distribution of material cultural heritage is different in different river basins, different terrains and different climates. The spatial distribution of ICH mainly shows significant differences in terrain and climate, and does not show significant differences in river basins. In terms of influencing factors, sociocultural environment, education level, historical settlement environment, road traffic, climate, economy, population and terrain factors all have a significant impact on the spatial distribution of CH and TCH. Sociocultural environment, education level, historical settlement environment, road traffic, climate, economy and population have a significant impact on the spatial distribution of ICH, while topographic factors and water system factors have no significant impact on the spatial distribution of ICH. Compared with ICH, TCH is more likely to be directly affected by topographic conditions (altitude, relief of terrain) and hydrological conditions (production and living water sources and flood risk) during its formation stage. At the same time, topographic and hydrological conditions can also indirectly affect the spatial distribution of TCH by directly affecting human agricultural activities, economic activities and cultural activities.

Abstract Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT.

Abstract Background Vitamin D deficiency has been linked to poor muscle function, cartilage degeneration, and the development of knee osteoarthritis. However, the impact of serum 25-hydroxyvitamin D [25(OH)D] level on quadriceps muscle strength remains inconclusive, largely due to variations in study designs, differences in study populations, and the influence of confounding factors such as co-supplementation with other vitamins. The existing literature presents mixed findings, highlighting the need for a comprehensive evaluation of the available evidence. Purpose This systematic review and meta-analysis aim to summarise. Study design Systematic review; Level of evidence, 4. Methods Searches were conducted using Medline (Ovid), Embase (Ovid), CINAHL (EBSCOhost), and SPORTDiscus (EBSCOhost), which aimed to summarise recent (published after 2000 and before March 1st, 2024) studies reporting the effects of serum 25(OH)D levels on quadriceps strength. Appraisal tool for Cross-Sectional Studies (AXIS) for cross-sectional studies and Quality in Prognosis Studies (QUIPS) for longitudinal studies. Results from the AXIS and QUIPS tools were used for GRADE quality assessment. The review was carried out using PRIMSA guidelines and registered in PROSPERO (ID: CRD42022313240). Results Four hundred studies were screened and 28 studies with 5752 participants were included. 28 published studies (24 cross-sectional and 4 longitudinal) were identified. Key results supported the significant positive correlation between serum 25(OH)D levels and isokinetic quadriceps strength at 180°/s in elderly and athletic populations with a correlation coefficient of 0.245 (95%CI: 0.078–0.398, p = 0.004). However, no significant correlation was found with isometric quadriceps strength or isokinetic strength at 60°/s (r = 0.190, p = 0.085). There was only a weak negative correlation with MVC. Conclusion This review found a statistically significant positive correlation between serum 25(OH)D levels and isokinetic quadriceps strength. This has important clinical implications, especially in the elderly cohort, with higher 25(OH)D levels being associated with a reduced incidence of falls and fragility fractures.

ObjectivesIn the application of sandwich composite materials in ship structures, to ensure the structural strength characteristics, bolt connections are usually used between the sandwich composite structure and steel main hull. However, due to local stress concentration around the holes and the boundary effects at the connection locations, the bolt connection position is often becomes the most critical area of the structure, necessitating strength and fatigue assessments. MethodsFor a full-scale steel-sandwich composite panel structure, the strength characteristics of the plate frame under a 0.1 MPa uniform load are studied using experimental and finite element methods. The accuracy of the finite element method is then verified by comparing its results with those from the experimental method. Subsequently, based on the finite element method, fatigue tests for two equivalent bolted joints are designed through structural stress equivalence, and the fatigue life of the steel-sandwich composite structure is evaluated and verified. ResultsIt is determined that the fatigue life of the panel structure under the design load meets the design requirement of 5 million cycles.ConclusionsRegarding the fatigue problem of large bolted connections, equivalent joints can be designed for fatigue testing, and load equivalence can be achieved through structural stress equivalence.

The male reproductive system has been the subject of considerable attention in recent years due to the adverse effects of Di (2-ethylhexyl) phthalate (DEHP). Although previous research has suggested that DEHP exposure hinders the early meiotic progression of male germ cells, the underlying mechanisms are still not well understood. The transcriptomic changes in testicular cells of postnatal male rodents following DEHP exposure were meticulously analyzed using 10X Genomics single-cell RNA sequencing in this study. For downstream analysis, we acquired 42,000 cells and generated 3172,754,990 reads. DEHP exposure at concentrations of 40 μg/kg/day (DEHP40) and 80 μg/kg/day (DEHP80) substantially decreased the proportion of pachytene and diplotene spermatocytes, indicating a shared inhibitory effect on early meiosis, as demonstrated by our findings. In addition, DEHP exposure disrupted the cellular communication between Sertoli cells and germ cells, which had a significant impact on the p38-MAPK signaling pathway. The expression of key ligand genes Tgfb1 and Tgfb3 in Sertoli cells was significantly reduced. DEHP exposure resulted in a substantial decrease in the expression of the Trp53 gene, which in turn down-regulated three critical downstream genes (Stmn1, Tubb5, and Ccnb1) that are implicated in spindle organization from a mechanistic perspective. This study offers the first comprehensive evidence that DEHP inhibits early meiotic progression in male germ cells through the Trp53-mediated p38-MAPK pathway, providing crucial insights into the molecular mechanisms underlying DEHP-induced male reproductive toxicity. Our results emphasize the enduring negative effects of DEHP exposure on male fertility, which have substantial ramifications for the comprehension and mitigation of the influence of environmental estrogens on reproductive health.

Laser powder bed fusion (LPBF) has been one of the most widely used additive manufacturing (AM) technologies. However, the LPBF-built AlSi10Mg alloy is still restricted by the mechanical performance. In this work, a hybrid laser regulation method combining in-situ laser remelting (LSR) and ex-situ laser shock-based SiC implantation (LSI-SiC) was proposed. The experiments demonstrated that the compressive residual stress with the value of 72 MPa was obtained with weaken surface flatness after hybrid laser regulation. Nanoscale grains were presented with obvious dislocation tangle. The high tensile strength (492 MPa) was achieved while maintaining good ductility (4.5 %) attributed to various strengthening effects. The numerical results showed that the dislocation and atomic stress were more sensitive for the size and shape of nanoscale SiC. This work provides a novel guidance for simultaneously enhancing the strength and ductility of AlSi10Mg alloy via effectively combining in-situ and ex-situ laser regulation.

ABSTRACT Mountains with complex terrain and steep environmental gradients are biodiversity hotspots such as the eastern Tibetan Plateau (TP). However, it is generally assumed that mountain terrain plays a secondary role in plant species assembly on a millennial time‐scale compared to climate change. Here, we investigate plant richness and community changes during the last 18,000 years at two sites: Lake Naleng and Lake Ximen on the eastern TP with similar elevation and climatic conditions but contrasting terrain. We applied plant DNA metabarcoding to lake sediments leveraging a new regional reference database for taxa identification. Furthermore, we developed a simplified species dispersal model named SMARC. This was used to simulate species migration along river valleys in response to past climate change at the taxonomic resolution of the sedimentary ancient DNA (sedaDNA) approach. Statistical analyses, including ordination‐based ecological trajectory analysis, yielded a significant match between sedaDNA and simulated results at single taxon and community levels including certain site‐specific differences. Steep terrain downstream of Lake Naleng enhances connectivity to glacial lowland refugia during postglacial warming. In contrast, gentle terrain over long distances implies weak connectivity to the lowland and thus resulted in a strong migration lag at Lake Ximen. Likewise, terrain differences among our sites defined the different connectivity to alpine refugia during late‐Holocene cooling. Our consistent proxy‐ and model‐based results, for the first time, indicate that dispersal related migration lags in complex mountain terrain lead to uneven vegetation trajectories at sites with similar climatic conditions mainly because of differences in connectivity to refugia. Ultimately our results indicate that connectivity to refugia is a first‐order factor for species migration in addition to elevation‐related climatic conditions shaping the postglacial vegetation trajectory in mountainous terrain. This has hitherto largely been ignored when forecasting mountain vegetation responses to climate change and related risk assessment.

Groundwater seepage can easily cause large deformation and fracture instability of the surrounding rock in deep roadways, and the coupling support of “yield-bolt-grouting” can effectively control the occurrence of such accidents. This paper takes the specific engineering geological conditions of deep water-enriched roadway as the research background, revealing the coupling control mechanism of yield-bolt-grouting. The mechanical characteristics of the yielding tube were determined using lab analysis, and an investigation was conducted for the support control mechanism of high-strength yielding bolts. The control mechanism of grouting reinforcement is summarized, and a comprehensive coupling control technology system of “yield-bolt-grouting” is proposed based on the rheological large deformation characteristics of the surrounding rock of deep water-enriched roadway, with high-strength yielding grouting anchor rods and high-strength yielding grouting anchor cables as the core. The on-site monitoring results indicate that this technology effectively controls the deformation of the surrounding rock. The research results provide new ideas and technical approaches for controlling the surrounding rock of deep water-enriched roadways.

ObjectiveWhile prepregnancy overweight or obesity is known to negatively impact maternal health, its effect on twin infants is not well understood. Therefore, we conducted a nationwide, multicenter retrospective study to investigate the association between maternal prepregnancy weight and health outcomes in twins.Study designThis study collected data from 22 healthcare units across 12 regions in China between January 2018 and December 2020. To control for confounding factors, multiple logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlapping weighting models (OW) were applied to explore the effects of prepregnancy BMI on Apgar scores and other outcomes.ResultsAfter screening, a total of 4,724 women with twin pregnancies and 9,448 newborns were included in the study. Compared to normal prepregnancy weight, prepregnancy overweight/obesity significantly increased the risk of gestational hypertension and gestational diabetes in mothers [adjusted OR (95% CI): 1.85 (1.55–2.21) and 1.49 (1.27–1.74), respectively]. It also increased the incidence of twins with a 1-min Apgar score ≤7, whether they were larger or smaller [1.60 (1.20–2.13) and 1.45 (1.09–1.92), respectively]. Sensitivity analyses using PSM [1.60 (1.20–2.13) and 1.55 (1.07–2.25)], IPTW [1.67 (1.31–2.12) and 1.48 (1.17–1.87)], and OW [1.65 (1.08–2.57) and 1.47 (0.97–2.25)] confirmed the stability of these results. However, it did not affect the likelihood of a 5-min Apgar score ≤7 [adjusted OR (95% CI): 0.82 (0.24–2.17) and 1.40 (0.70–2.73)]. In contrast, prepregnancy underweight was associated with a reduced incidence of twins with a 1-min Apgar score ≤7 [adjusted OR (95% CI): 0.56 (0.32–0.92) and 0.58 (0.34–0.94)], but had no effect on the 5-min Apgar score ≤7 [adjusted OR (95% CI): 0.82 (0.24–2.17) and 0.22 (0.01–1.08)]. Prepregnancy BMI did not significantly affect twin birth weight discordance, NICU admission, preterm birth, or low birth weight.ConclusionMaternal overweight/obesity before pregnancy increases the risk of hypertensive disorders and gestational diabetes in twin pregnancies and significantly raises the likelihood of twins having a low 1-min Apgar score. However, no significant impact on 5-min Apgar scores was observed. These findings highlight the importance of managing weight before pregnancy and ensuring readiness for neonatal resuscitation during delivery.

BackgroundGastroparesis following complete mesocolic excision (CME) can precipitate a cascade of severe complications, which may significantly hinder postoperative recovery and diminish the patient’s quality of life. In the present study, four advanced machine learning algorithms—Extreme Gradient Boosting (XGBoost), Random Forest (RF), Support Vector Machine (SVM), and k-nearest neighbor (KNN)—were employed to develop predictive models. The clinical data of critically ill patients transferred to the intensive care unit (ICU) post-CME were meticulously analyzed to identify key risk factors associated with the development of gastroparesis.MethodsWe gathered 34 feature variables from a cohort of 1,097 colon cancer patients, including 87 individuals who developed gastroparesis post-surgery, across multiple hospitals, and applied a range of machine learning algorithms to construct the predictive model. To assess the model’s generalization performance, we employed 10-fold cross-validation, while the receiver operating characteristic (ROC) curve was utilized to evaluate its discriminative capacity. Additionally, calibration curves, decision curve analysis (DCA), and external validation were integrated to provide a comprehensive evaluation of the model’s clinical applicability and utility.ResultsAmong the four predictive models, the XGBoost algorithm demonstrated superior performance. As indicated by the ROC curve, XGBoost achieved an area under the curve (AUC) of 0.939 in the training set and 0.876 in the validation set, reflecting exceptional predictive accuracy. Notably, in the k-fold cross-validation, the XGBoost model exhibited robust consistency across all folds, underscoring its stability. The calibration curve further revealed a favorable concordance between the predicted probabilities and the actual outcomes of the XGBoost model. Additionally, the DCA highlighted that patients receiving intervention under the XGBoost model experienced significantly greater clinical benefit.ConclusionThe onset of postoperative gastroparesis in colon cancer patients remains an elusive challenge to entirely prevent. However, the prediction model developed in this study offers valuable assistance to clinicians in identifying key high-risk factors for gastroparesis, thereby enhancing the quality of life and survival outcomes for these patients.

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by cognitive decline, primarily affecting memory and executive function. This review highlights recent advancements in single-cell sequencing and spatial transcriptomics, which provide detailed insights into the cellular heterogeneity and neuroimmune mechanisms of AD. The review addresses the need for understanding complex cellular interactions to identify novel therapeutic targets and biomarkers. Single-cell sequencing has revolutionized our understanding by mapping gene expression at the individual cell level, revealing distinct microglial and astrocytic states that contribute to neuroinflammation and neurodegeneration. These technologies have uncovered disease-associated microglial subpopulations and gene expression changes linked to AD risk genes, essential for developing targeted therapies. In conclusion, the integration of single-cell and spatial transcriptomics with other omics data is crucial for a comprehensive understanding of AD, paving the way for personalized medicine. Continued interdisciplinary collaboration will be vital in translating these findings into effective treatments, improving patient outcomes.

This study presents a comparative analysis of two advanced AI models, ChatGPT and ERNIE, in the context of water depth inversion. Utilizing satellite spectral data and in-situ bathymetric measurements collected from Rushikonda Beach, India, we processed and analyzed the data to generate high-resolution bathymetric maps. Both models demonstrated significant accuracy, with ChatGPT slightly outperforming ERNIE in terms of mean absolute error. The study highlights the advantages of AI models, such as efficient data processing and the ability to integrate multi-modal inputs, while also discussing challenges related to data quality, interpretability, and computational demands. The findings suggest that while both models are highly effective for water depth inversion, ongoing improvements in data handling and model transparency are essential for their broader application in environmental monitoring. This research contributes to the understanding of AI capabilities in geospatial analysis and sets the stage for future enhancements in the field.

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. Here, we found that maternal obesity disrupted the genomic methylation of oocytes using a high-fat diet (HFD) induced mouse model, at least a part of which was transmitted to the F2 oocytes and livers via females. We further examined the metabolome of serum and found that the serum concentration of melatonin was reduced. Exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. These suggest that melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in premature infants with no specific treatments available. We aimed to identify the molecular mechanisms underlying NEC and investigate the therapeutic effects of Bacteroides fragilis on NEC. Clinical samples of infant feces, bile acid-targeted metabolomics, pathological staining, bioinformatics analysis, NEC rat model, and co-immunoprecipitation were used to explore the pathogenesis of NEC. Taxonomic characterization of the bile salt hydrolase (bsh) gene, enzyme activity assays, 16S rRNA sequencing, and organoids were used to explore the therapeutic effects of B. fragilis on NEC-related intestinal damage. Clinical samples, NEC rat models, and in vitro experiments revealed that total bile acid increased in the blood but decreased in feces. Moreover, the levels of FXR and other bile acid metabolism-related genes were abnormal, resulting in disordered bile acid metabolism in NEC. Taurochenodeoxycholic acid accelerated NEC pathogenesis and taurodeoxycholate alleviated NEC. B. fragilis displayed bsh genes and enzyme activity and alleviated intestinal damage by restoring gut microbiota dysbiosis and bile acid metabolism abnormalities by inhibiting the FXR-NLRP3 signaling pathway. Our results provide valuable insights into the therapeutic role of B. fragilis in NEC. Administering B. fragilis may substantially alleviate intestinal damage in NEC.

Abstract Chemotherapy, particularly with oxaliplatin, is a key treatment for advanced gastric cancer (GC), and exosomes derived from human bone marrow mesenchymal stem cells (hBM-MSCs) play a vital role in the tumor microenvironment. The study aims to elucidate the previously unexplored role of exosomes derived from hBM-MSCs in GC tumorigenesis, especially under the influence of chemotherapy. We conducted an experimental study, utilizing miRNA sequencing and biological experiments, to analyze the tumorigenicity of exosomal miR-424-3p secreted by hBM-MSCs and its target gene RHOXF2 in GC cell lines. The results were confirmed through experimentation using a xenograft mouse model. This study demonstrated the role of hBM-MSCs in the GC microenvironment, focusing on their epithelial-mesenchymal transition (EMT) facilitation through exosomes, which led to enhanced tumorigenicity in GC cells. Intriguingly, this pro-tumor effect was abrogated when hBM-MSCs were treated with oxaliplatin. Exosomal miRNA sequencing revealed that oxaliplatin can upregulate the levels of miR-424-3p in exosomes secreted by hBM-MSCs, thereby inhibiting the EMT process in GC cells. Furthermore, miR-424-3p was identified to target and downregulate RHOXF2 expression, impeding the malignant behavior of GC cells both in vitro and in the mouse model. These findings uncover a potential hidden mechanism of oxaliplatin's anti-tumor action and propose the delivery of miR-424-3p via exosomes as a promising avenue for anti-tumor therapy.

Abstract Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME.

Abstract Dietary micronutrients are integral to the development and progression of constipation; however, the specific relationship between dietary copper intake and constipation has not been thoroughly investigated. This study aims to examine the correlation between dietary copper intake and constipation among U.S. adults, thereby offering novel insights and recommendations for the clinical management and prevention of constipation. Bowel health data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2005 and 2010 were analyzed. Subjects’ dietary information was collected through questionnaire records. Multivariate logistic regression analysis, subgroup analysis, and curve fitting analysis were used to assess the correlation between dietary copper intake and chronic constipation. After adjusting for all possible confounders, each unit increase in dietary copper intake (converted to natural logarithms) was associated with a 20% reduction in the prevalence of constipation (OR = 0.80; 95% CI 0.65–0.98; P = 0.037). The interaction P-values for all subgroups were greater than 0.05, indicating that the findings were stable and consistent across subgroups. The present study showed a significant negative association between dietary copper intake and chronic constipation in adults. This finding raises clinical and healthcare professionals’ awareness of the impact of dietary trace elements on intestinal health and has important implications for the development of personalized meal plans and rational supplementation of trace copper in patients with constipation.

Abstract Background Chitinase-3 like-protein-1 (CHI3L1) is a member of the mammalian chitinase-like proteins and elevated serum CHI3L1 level has been proved to be associated with poor prognosis in hepatocellular carcinoma (HCC). This study aimed to investigate the relationship between serum CHI3L1 levels and body composition parameters in patients with HCC after liver transplantation (LT). Methods This retrospective study enrolled 200 patients after LT for HCC. Blood samples were collected and serum concentrations of CHI3L1 were measured by enzyme-linked immunosorbent assay. Computer tomography (CT) were used to estimate skeletal muscle and adipose tissue mass. Spearman’s rank correlation test was performed to assess associations between serum CHI3L1 levels and these body composition parameters. A Cox proportional-hazards regression model was performed to identify independent prognostic factors. Overall survival (OS) and recurrence-free survival (RFS) curves were constructed using the Kaplan-Meier method and compared by the log-rank test. Results Total 71 patients (35.5%) were diagnosed with myosteatosis according to skeletal muscle radiation attenuation (SMRA). The 5-year OS rates were 66.9% in non-myosteatosis group, significantly higher than 49.5% in myosteatosis group (p = 0.025), while the RFS of myosteatosis group (5-year RFS: 52.6%) or non-myosteatosis group (5-year RFS: 42.0%) shown no significant difference (p = 0.068). The serum CHI3L1 level were significantly negative correlated with SMRA (r = -0.3, p

Abstract Erectile dysfunction (ED) is the most prevalent consequences in men with diabetes mellitus (DM). Recent studies demonstrates that neutrophil extracellular traps (NETs) play important roles in DM and its complications. Nevertheless, whether NETs are involved in ED remains unknown. This work intended to explore the role and mechanisms of NETs in ED in the context of DM. Here, we observed that NET generation and pyroptosis were promoted in DM rats with ED compared with controls. Mechanistically, NETs facilitated NLRP3 inflammasome activation and subsequently triggered pyroptosis under high glucose stress, ultimately leading to ED. Intriguingly, DNase I (a NET degrading agent) alleviated ED and corpus cavernosum injury in DM rats. Overall, NETs might induce ED in DM by promoting NLRP3-mediated pyroptosis in the corpus cavernosum.

Abstract Background Polycystic ovarian syndrome (PCOS) accounts for about 75% of anovulatory infertility. The cause of PCOS is not clear. CircRNAs acting as miRNA sponges mediate the post-transcriptional regulation of multiple genes. CYP19A1 is a limiting enzyme in the ovarian steroidogenesis pathway. However, the mechanism of circRNAs regulating granulosa cell (GC) estradiol secretion in PCOS remains to be elucidated. Methods Bioinformatics was used to predict the potential target miRNAs of circ_0043532 and target genes of miR-1270. Target miRNAs and mRNA expression were verified by qRT-PCR in GCs from 45 women with PCOS and 65 non-PCOS. Western blot, ELISA and dual-luciferase reporter assays were applied to confirm the substrate of miR-1270. Results Circ_0043532 and CYP19A1 were significant up-regulation in GCs from patients with PCOS. The predicted target miRNAs of circ_0053432, miR-1270, miR-576-5p, miR-421 and miR-142-5p, were notably decreased in GCs from patients with PCOS. Mechanistic experiments showed that circ_0043532 specifically binds to miR-1270. MiR-1270 was negatively regulated by circ_0043532. Concomitantly, miR-1270 inhibited CYP19A1 expression and estradiol production, which could be reversed by circ_0043532 over-expression. Conclusion We identified that circ_0043532/miR-1270/CYP19A1 axis contributes to the aberrant steroidogenesis of GCs from patients with PCOS. This study broadens the spectrum of pathogenic factors of PCOS, and circ_0043532 might be a potential therapeutic target for PCOS.

Objective To report the antibody specific identification process of a pregnant woman who had no history of blood transfusion but presented high-frequency anti-Jra antibodies. Methods Antibody screening and identification were performed by saline and indirect Coomb’s technique (microcolumn gel card, PEG). ABO, Rh and other blood group antigens were identified by saline. Further antibody identification tests were performed by the reaction between cells treated with various enzymes and patient plasma. Jra antigen was identified by human anti-Jra antibody. JR blood type genotyping was performed by MALDI-TOF mass spectrometry detection system. Antibody titer in serum was tested. Results The patient′s blood type was O with RhD(+ ) and CcDEe. The plasma reacted negatively with antibody screening and identification cells by saline, but positively by indirect globulin test. The self-control was negative. The patient′s Jra antigen was negative in serological tests and mass spectrometry blood type genotyping. Mass spectrometry revealed a homozygous nonsense mutation (c.376C>T) in exon 4. The anti-Jra antibody titer was 1∶2. Conclusion The patient developed high-frequency anti-Jra antibodies during pregnancy.

AIM: To assess the clinical efficacy and safety of combining panretinal photocoagulation (PRP) with intravitreal conbercept (IVC) injections for patients with high-risk proliferative diabetic retinopathy (HR-PDR) complicated by mild or moderate vitreous hemorrhage (VH), with or without diabetic macular edema (DME). METHODS: Patients diagnosed with VH with/without DME secondary to HR-PDR and received PRP combined with IVC injections were recruited in this retrospective study. Upon establishing the patient's diagnosis, an initial IVC was performed, followed by prompt administration of PRP. In cases who significant bleeding persisted and impeded the laser operation, IVC was sustained before supplementing with PRP. Following the completion of PRP, patients were meticulously monitored for a minimum of six months. Laser therapy and IVC injections were judiciously adjusted based on fundus fluorescein angiography (FFA) results. Therapeutic effect and the incidence of adverse events were observed. RESULTS: Out of 42 patients (74 eyes), 29 were male and 13 were female, with a mean age of 59.17±12.74y (33-84y). The diabetic history was between 1wk and 26y, and the interval between the onset of visual symptoms and diagnosis of HR-PDR was 1wk-1y. The affected eye received 2.59±1.87 (1-10) IVC injections and underwent 5.5±1.02 (4-8) sessions of PRP. Of these, 68 eyes received PRP following 1 IVC injection, 5 eyes after 2 IVC injections, and 1 eye after 3 IVC injections. Complete absorption of VH was observed in all 74 eyes 5-50wk after initial treatment, with resolution of DME in 51 eyes 3-48wk after initial treatment. A newly developed epiretinal membrane was noted in one eye. Visual acuity significantly improved in 25 eyes. No complications such as glaucoma, retinal detachment, or endophthalmitis were reported. CONCLUSION: The study suggests that the combination of PRP with IVC injections is an effective and safe modality for treating diabetic VH in patients with HR-PDR.

Abstract The aim of this study was to develop a real-time risk prediction model for extrauterine growth retardation (EUGR). A total of 2514 very preterm infants were allocated into a training set and an external validation set. The most appropriate independent variables were screened using univariate analysis and Lasso regression with tenfold cross-validation, while the prediction model was designed using binary multivariate logistic regression. A visualization of the risk variables was created using a nomogram, while the calibration plot and receiver operating characteristic (ROC) curves were used to calibrate the prediction model. Clinical efficacy was assessed using the decision curve analysis (DCA) curves. Eight optimal predictors that namely birth weight, small for gestation age (SGA), hypertensive disease complicating pregnancy (HDCP), gestational diabetes mellitus (GDM), multiple births, cumulative duration of fasting, growth velocity and postnatal corticosteroids were introduced into the logistic regression equation to construct the EUGR prediction model. The area under the ROC curve of the training set and the external verification set was 83.1% and 84.6%, respectively. The calibration curve indicate that the model fits well. The DCA curve shows that the risk threshold for clinical application is 0–95% in both set. Introducing Birth weight, SGA, HDCP, GDM, Multiple births, Cumulative duration of fasting, Growth velocity and Postnatal corticosteroids into the nomogram increased its usefulness for predicting EUGR risk in very preterm infants.

Abstract Exploring the spatial coupling relationship and interaction mechanism between green urbanization (GU) and tourism competitiveness (TC) is of great significance for promoting urban sustainable development. However, the lack of research on the interaction mechanism between GU and TC limits the formulation of effective environmental management policy and urban planning. Taking 734 counties in the Yellow River Basin (YRB) as the study area, this paper analyzes the spatial coupling relationship between GU and TC on the basis of comprehensive evaluation of GU and TC. Then, the interactive mechanism between GU and TC is systematically discussed, and the synergistic development strategy of the two is proposed. The results show that the GU level presents a multicore circle structure, with provincial capitals, prefecture-level urban districts and economically developed counties in east-central regions as high-value centers. The TC at county scale presents a multi-center spatial structure. Additionally, there is a significant positive spatial coupling between GU and TC in the YRB. The analysis further reveals that green urbanization level, social progress, population development, infrastructure construction, economic development quality, and eco-environmental protection has a observably influence on TC. Tourism competitiveness, service competitiveness, location competitiveness, resource competitiveness, market competitiveness, environmental influence, and talent competitiveness has a observably influence on GU. TC can promote GU, and the improvement of green urbanization level can support the development of tourism competitiveness. According to the spatial zoning method, 734 counties are divided into 6 categories, and the coordinated development strategy of GU and TC for each type of district is proposed.

BackgroundChen’s Peiyuan Tang (CSPYT) is a compound herbal formula that has shown the potential to enhance ovarian function and reduce autophagy in ovarian granulosa cells, which plays a crucial role in follicular development and maturation. The application of Chinese herbal medicine offers a promising alternative to traditional hormone replacement therapy (HRT).MethodsThis study explores CSPYT’s therapeutic mechanisms in treating POF, focusing on its modulation of autophagy through network pharmacology and transcriptomics-based analysis, predicting potential interactions and pathways. KGN cell line and rat ovarian granulosa cells were used for in vitro experiment. 4-Hydroperoxy cyclophosphamide(4-HC) stimulation was carried out for establishing the POF cell model. Q-PCR, Western Blot, Transmission electron microscopy to detect the results.ResultsAccording to the drug and disease database, the common targets of Chen’s Peiyuan Tang and premature ovarian failure were screened, combined with autophagy gene targets and transcriptome analysis, and finally 8 intersection targets were obtained, namely CDKN1B, MAPK3, PRKCD, CDKN1A, MAPK1, RAF1, BIRC5, CTSB. Enrichment analysis of 8 genes found that they were closely related to the animal autophagy pathway. Construct PPI network diagram. CytoScape 3.9.1 builds CSPYT Drug Target-POF Disease Target-Autophagy Gene Network Diagram. Based on the PPI network diagram and CytoScape 3.9.1 analysis results, it is estimated that MAPK1 and MAPK3 are the key targets of CSPYT in the treatment of POF. The eight final intersection targets were docked with the corresponding active pharmaceutical ingredients. The one that docked most closely with the MAPK family was naringenin. In cell experiment verification, it was confirmed that Chen’s Peiyuan Tang can inhibit the MAPK signaling pathway, significantly reduce the number of autophagosomes, and reduce autophagy damage in ovarian granulosa cells.DiscussionCSPYT can inhibit the MAPK signaling pathway, prevent autophagy overexpression and restore ovarian granulosa cell function, effectively alleviating the disease pressure of POF.

BackgroundComplications and mortality rates following gastrectomy for gastric cancer have improved over recent years; however, complications such as anastomotic leakage (AL) continue to significantly impact both immediate and long-term prognoses. This study aimed to develop a machine learning model to identify preoperative and intraoperative high-risk factors and predict mortality in patients with AL after radical gastrectomy.MethodsFor this investigation, 906 patients diagnosed with gastric cancer were enrolled and evaluated, with a comprehensive set of 36 feature variables collected. We employed three distinct machine learning algorithms—extreme gradient boosting (XGBoost), random forest (RF), and k-nearest neighbor (KNN)—to develop our models. To ensure model robustness, we applied k-fold cross-validation for internal validation of the four models and subsequently validated them using independent datasets.ResultsIn contrast to the other machine learning models employed in this study, the XGBoost algorithm exhibited superior predictive performance in identifying mortality risk factors for patients with AL across one, three, and five-year intervals. The analysis identified several common risk factors affecting mortality rates at these intervals, including advanced age, hypoproteinemia, a history of anemia and hypertension, prolonged operative time, increased intraoperative bleeding, low intraoperative percutaneous arterial oxygen saturation (SPO2) levels, T3 and T4 tumors, tumor lymph node invasion, and tumor peripheral nerve invasion (PNI).ConclusionAmong the three machine learning models examined in this study, the XGBoost algorithm exhibited superior predictive capabilities concerning the prognosis of patients with AL following gastrectomy. Additionally, the use of machine learning models offers valuable assistance to clinicians in identifying crucial prognostic factors, thereby enhancing personalized patient monitoring and management.

BackgroundParkinson’s disease (PD) is an age-related neurodegenerative disease characterized by the death of dopamine neurons in the substantia nigra. A large number of studies have focused on dopamine neurons themselves, but so far, the pathogenesis of PD has not been fully elucidated.ResultsHere, we explored the significance of oligodendrocyte precursor cells (OPCs)/oligodendrocytes in the pathogenesis of PD using a bioinformatic approach. WGCNA analysis suggested that abnormal development of oligodendrocytes may play a key role in early PD. To verify the transcriptional dynamics of OPCs/oligodendrocytes, we performed differential analysis, cell trajectory construction, cell communication analysis and hdWGCNA analysis using single-cell data from PD patients. Interestingly, the results indicated that there was overlap between hub genes and differentially expressed genes (DEGs) in OPCs not in oligodendrocytes, suggesting that OPCs may be more sensitive to PD drivers. Then, we used ROC binary analysis model to identify five potential biomarkers, including AGPAT4, DNM3, PPP1R12B, PPP2R2B, and LINC00486.ConclusionIn conclusion, our work highlights the potential role of OPCs in driving PD.

BackgroundCurrently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators.MethodsWe integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments.ResultsWe found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences.ConclusionThis study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.

This study introduces an innovative water depth estimation method for complex coastal environments, focusing on Yantian Port. By combining Random Forest algorithms with a Coordinate Attention mechanism, we address limitations of traditional bathymetric techniques in turbid waters. Our approach incorporates geographical coordinates, enhancing spatial accuracy and predictive capabilities of conventional models. The Random Forest Lon./Lat. model demonstrated exceptional performance, particularly in shallow water depth estimation, achieving superior accuracy metrics among all evaluated models. It boasted the lowest Root Mean Square Error (RMSE) and highest coefficient of determination (R²), outperforming standard techniques like Stumpf and Log-Linear approaches. These findings highlight the potential of advanced machine learning in revolutionizing bathymetric mapping for intricate coastal zones, opening new possibilities for port management, coastal engineering, and environmental monitoring of coastal ecosystems. We recommend extending this research to diverse coastal regions to validate its broader applicability. Additionally, exploring the integration of additional geospatial features could further refine the model’s accuracy and computational efficiency. This study marks a significant advancement in bathymetric technology, offering improved solutions for accurate water depth estimation in challenging aquatic environments. As we continue to push boundaries in this field, the potential for enhanced coastal management and environmental stewardship grows, paving the way for more sustainable and informed decision-making in coastal zones worldwide.

Introduction A proportion of people develop Long Covid after acute COVID-19, but with most studies concentrated in high-income countries (HICs), the global burden is largely unknown. Our study aims to characterise long-term COVID-19 sequelae in populations globally and compare the prevalence of reported symptoms in HICs and low-income and middle-income countries (LMICs).Methods A prospective, observational study in 17 countries in Africa, Asia, Europe and South America, including adults with confirmed COVID-19 assessed at 2 to

Zearalenone (ZEN) has been shown to cause reproductive damage by inducing oxidative stress. Astaxanthin and L-carnitine are widely used to alleviate oxidative stress and promote sperm maturation. However, it remains uncertain whether they are effective in mitigating spermatogenesis disorders induced by ZEN. This study aimed to investigate the therapeutic efficacy and potential mechanisms of Vigor King (Vig), a compound preparation primarily consisting of astaxanthin and L-carnitine, in alleviating ZEN-induced spermatogenesis disorders. In the experiment, mice received continuous oral gavage of ZEN (80 μg/kg) for 35 days, accompanied by a rescue strategy with Vig (200 mg/kg). The results showed that Vig effectively reduced the negative impact on semen quality and improved the structural and functional abnormalities of the seminiferous epithelium caused by ZEN. Additionally, the accumulation of reactive oxygen species (ROS), DNA double-strand breaks, apoptosis, and autophagy abnormalities were all significantly ameliorated. Intriguingly, the GSK3β-dependent BTRC-NRF2 signaling pathway was found to play an important role in this process. Furthermore, testing of offspring indicated that Vig could extend its protective effects to the next generation, effectively combating the transgenerational toxic effects of ZEN. In summary, our research suggests that Vig supplementation holds considerable promise in alleviating spermatogenesis disorders induced by zearalenone.

Abstract Tumor recurrence is a life‐threatening complication after liver transplantation (LT) for hepatocellular carcinoma (HCC). Precise recurrence risk stratification before transplantation is essential for the management of recipients. Here, we aimed to establish an inflammation‐related prediction model for posttransplant HCC recurrence based on pretransplant peripheral cytokine profiling. Two hundred and ninety‐three patients who underwent LT in two independent medical centers were enrolled, and their pretransplant plasma samples were sent for cytokine profiling. We identified four independent risk factors, including alpha‐fetoprotein, systemic immune‐inflammation index, interleukin 6, and osteocalcin in the training cohort (n = 190) by COX regression analysis. A prediction model named inflammatory fingerprint (IFP) was established based on the above factors. The IFP effectively predicted posttransplant recurrence (area under the receiver operating characteristic curve [AUROC]: 0.792, C‐index: 0.736). The high IFP group recipients had significantly worse 3‐year recurrence‐free survival rates (37.9 vs. 86.9%, p

Abstract A research model combining a disease and syndrome can provide new ideas for the treatment of ischemic stroke. In the field of traditional Chinese medicine, blood stasis and toxin (BST) syndrome is considered an important syndrome seen in patients with ischemic stroke (IS). However, the biological basis of IS-BST syndrome is currently not well understood. Therefore, this study aimed to explore the biological mechanism of IS-BST syndrome. This study is divided into two parts: (1) establishment of an animal model of ischemic stroke disease and an animal model of BST syndrome in ischemic stroke; (2) use of omics methods to identify differentially expressed genes and metabolites in the models. We used middle cerebral artery occlusion (MCAO) surgery to establish the disease model, and utilized carrageenan combined with active dry yeast and MCAO surgery to construct the IS-BST syndrome model. Next, we used transcriptomics and metabolomics methods to explore the differential genes and metabolites in the disease model and IS-BST syndrome model. It is found that the IS-BST syndrome model exhibited more prominent characteristics of IS disease and syndrome features. Both the disease model and the IS-BST syndrome model share some common biological processes, such as thrombus formation, inflammatory response, purine metabolism, sphingolipid metabolism, and so on. Results of the “gene–metabolite” network revealed that the IS-BST syndrome model exhibited more pronounced features of complement-coagulation cascade reactions and amino acid metabolism disorders. Additionally, the “F2 (thrombin)–NMDAR/glutamate” pathway was coupled with the formation process of the blood stasis and toxin syndrome. This study reveals the intricate mechanism of IS-BST syndrome, offering a successful model for investigating the combination of disease and syndrome.