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Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63–69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.

With the fast-paced growth of underground engineering, the performance demands for construction materials are increasing. It is essential to explore the performance optimization of bentonite-based materials from admixture and material property’s view. In this paper, the rheological and filtration properties were selected as the key indices of the bentonite slurry performance. The synergistic effect of bentonite particle size and content, carboxymethyl starch (CMS), and Na2CO3 content on bentonite slurry performance were investigated by conducting the rheology measurement and filtration test. Rheological behaviour, parameters, and filtration loss of the bentonite slurry with different factors were obtained. Range analysis was employed to evaluate the effect degree of each factor on the slurry performance, and an optimal bentonite-based slurry ratio was presented. Results showed that bentonite slurry exhibited shear-thinning characteristic as the bentonite content and CMS content increased, and bentonite particle size decreased. Excessive addition of Na2CO3 weakened the shear-thinning characteristic. The rheological parameters of the bentonite slurry were positively correlated with the bentonite and CMS contents and negatively correlated with the bentonite particle size. An addition of 0.5 %–1.5 % Na2CO3 resulted in the largest rheological parameter. The bentonite content had the greatest impact on the rheological parameters and filtration loss, followed by the particle size. The influences of the Na2CO3 and CMS contents were relatively weak, but the effect of the CMS content on filtration loss was stronger than that of the Na2CO3 content. An optimal ratio of bentonite-based slurry was presented for engineering reference: the bentonite particle size range of 10–23 μm, bentonite content range of 10 %–15 %, Na2CO3 content range of 0.5 %–0.8 %, and CMS content range of 0.1 %–0.8 %.

The incompletely eliminated Treponema pallidum (T. pallidum) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.

Background Chondrocyte viability, apoptosis, and migration are closely related to cartilage injury in osteoarthritis (OA) joints. Exosomes are identified as potential therapeutic agents for OA.Objective This study aimed to investigate the role of exosomes derived from osteocytes in OA, particularly focusing on their effects on cartilage repair and molecular mechanisms.Methods An injury cell model was established by treating chondrocytes with IL-1β. Cartilage repair was evaluated using cell counting kit-8, flow cytometry, scratch test, and Western Blot. Molecular mechanisms were analyzed using quantitative real-time PCR, bioinformatic analysis, and Western Blot. An OA mouse model was established to explore the role of exosomal DLX2 in vivo.Results Osteocyte-released exosomes promoted cell viability and migration, and inhibited apoptosis and extracellular matrix (ECM) deposition. Moreover, exosomes upregulated DLX2 expression, and knockdown of DLX2 activated the Wnt pathway. Additionally, exosomes attenuated OA in mice by transmitting DLX2.Conclusion Osteocyte-derived exosomal DLX2 alleviated IL-1β-induced cartilage repair and inactivated the Wnt pathway, thereby alleviating OA progression. The findings suggested that osteocyte-derived exosomes may hold promise as a treatment for OA.

Investigating the functional traits of Spartina alterniflora can provide insights towards understanding its invasion mechanism, and developing a method leaves can improve its management in coastal wetlands. Here, we examined the relationship between 11 leaf functional traits of S. alterniflora and hyperspectral data and investigated the feature bands through importance score analysis. Using original spectral and first-order differential conversion data of feature bands, we established four prediction models: random forest (RF), support vector machine (SVM), eXtreme Gradient Boosting (XGBoost), and back propagation neural network (BPNN). The study results showed that: (1) the SVM model based on Random Forest Importance Score is well-suited for S. alterniflora leaf functional trait inversion; (2) the importance score of leaf functional traits differed, and first-order differential spectral data produced more bands with high scores compared with the original hyperspectral reflectance data; (3) first-order differential data modelling effects were slightly better than those of the original spectral data. However, the first-order differential treatment did not show a significant improvement in the validation accuracy compared with the original data, and the accuracy of some traits decreased. Our study provides a new methodological approach for improving the monitoring and management of S. alterniflora in coastal wetlands.

Tuberculosis (TB) remains one of the deadliest chronic infectious diseases globally. Early diagnosis not only prevents the spread of TB but also ensures effective treatment. However, the absence of non-sputum-based diagnostic tests often leads to delayed TB diagnoses. Inflammation is a hallmark of TB, we aimed to identify biomarkers associated with TB based on immune profiling. We collected 222 plasma samples from healthy controls (HCs), disease controls (non-TB pneumonia; PN), patients with TB (TB), and cured TB cases (RxTB). A high-throughput protein detection technology, multiplex proximity extension assays (PEA), was applied to measure the levels of 92 immune proteins. Based on differential analysis and the correlation with TB severity, we selected 9 biomarkers (CXCL9, PDL1, CDCP1, CCL28, CCL23, CCL19, MMP1, IFNγ and TRANCE) and explored their diagnostic capabilities through 7 machine learning methods. We identified combination of these 9 biomarkers that distinguish TB cases from controls with an area under the receiver operating characteristic curve (AUROC) of 0.89–0.99, with a sensitivity of 82–93% at a specificity of 88–92%. Moreover, the model excels in distinguishing severe TB cases, achieving AUROC exceeding 0.95, sensitivities and specificities exceeding 93.3%. In summary, utilizing targeted proteomics and machine learning, we identified a 9 plasma proteins signature that demonstrates significant potential for accurate TB diagnosis and clinical outcome prediction.

Objective Smoking has been suggested as a modifiable and cardiovascular risk factor for chronic kidney disease (CKD). Although long-term smoking has been associated with CKD, the potential relationship between its metabolite hydroxycotinine and CKD has not been clarified.Methods A total of 8,544 participants aged 20 years and above from the National Health and Nutrition Examination Survey (NHANES) 2017 - March 2020 were enrolled in our study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/(min*1.73 m2). Serum hydroxycotinine was measured by an isotope-dilution high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometric (ID HPLC-APCI MS/MS) method with a lower limit of detections (LLOD) at 0.015 ng/mL. The non-linear relationship was explored with restricted cubic splines (RCS). Pearson’s correlation coefficient and a multivariate logistic regression model were used for correlation analysis.Results Serum hydroxycotinine and eGFR were negatively correlated in both non-CKD group (r= −0.05, p

ABSTRACTThe gut microbiota constitutes a vast ecological system within the human body, forming a mutually interdependent entity with the host. In recent years, advancements in molecular biology technologies have provided a clearer understanding of the role of the gut microbiota. They not only influence the local immune status and metabolic functions of the host’s intestinal tract but also impact the functional transformation of hematopoietic stem cells (HSCs) through the gut-blood axis. In this review, we will discuss the role of the gut microbiota in influencing hematopoiesis. We analyze the interactions between HSCs and other cellular components, with a particular emphasis on the direct functional regulation of HSCs by the gut microbiota and their indirect influence through cellular components in the bone marrow microenvironment. Additionally, we propose potential control targets for signaling pathways triggered by the gut microbiota to regulate hematopoietic function, filling crucial knowledge gaps in the development of this research field.

ABSTRACTAiming at the inherent “labeling bias” problem of Hidden Markov Models (HMMs) in the process of low-frequency sampling rate GPS trajectory map matching, this paper proposes a map matching method that combines HMMs and Conditional Random Field Models (CRFs). Various features including vehicle driving direction, direction change between candidate roads, shortest path, and spatial localization accuracy of trajectory points are integrated to optimize the state transfer process in the HMM model. The Viterbi algorithm was then employed to calculate the joint probability values of all candidate paths and the path with maximum probability value was selected as the matching path. The proposed map matching method was validated using publicly available Global Positioning System (GPS) vehicle trajectories from Guangzhou, Dongguan, and field-collected vehicle trajectory data from Ganzhou, China. The results demonstrated that the proposed method achieves high matching accuracy while maintaining efficient matching efficiency. The percentage of correct matching of GPS sampling points remains above 95%, and the average calculation time for each candidate road segment is kept within 50 ms. These advancements can greatly benefit location-based services that rely on map matching technology.

ABSTRACTSynchrotron X-ray imaging has been utilised to detect the dynamic behaviour of molten pools during the metal additive manufacturing (AM) process, where a substantial amount of imaging data is generated. Here, we develop an efficient and robust deep learning model, AM-SegNet, for segmenting and quantifying high-resolution X-ray images and prepare a large-scale database consisting of over 10,000 pixel-labelled images for model training and testing. AM-SegNet incorporates a lightweight convolution block and a customised attention mechanism, capable of performing semantic segmentation with high accuracy (∼96%) and processing speed (< 4 ms per frame). The segmentation results can be used for quantification and multi-modal correlation analysis of critical features (e.g. keyholes and pores). Additionally, the application of AM-SegNet to other advanced manufacturing processes is demonstrated. The proposed method will enable end-users in the manufacturing and imaging domains to accelerate data processing from collection to analytics, and provide insights into the processes’ governing physics.

With the rapid development of various chips towards high performance and integration, the ‘thermal barrier’ difficulty facing electronic devices has become ever increasingly challenging, while at the same time the space size left for thermal management system already becomes much narrower. In view of the intermittent operation or short-time large power consumption of some electronic devices, the thermal management technology based on phase change materials (PCMs) has received more and more attention. Among those cutting edge PCMs, the liquid metal phase change materials (LMPCMs) especially have aroused much interest due to their outstanding merits in thermal conductivity, energy storage density and stability. In this article, the representative works on LMPCMs are comprehensively reviewed. First, the thermophysical parameters of LMPCMs characterized by high thermal conductivity and large density are summarized. Then, some basic research cases on the thermophysical properties of metallic PCMs that are worthy of further investigation are briefly introduced. In view of the serious supercooling problem of the LMPCMs, the factors affecting the supercooling degree of liquid metal (LM), particularly the thermal history effect, based on the nucleation theory, are presented. Strategies for suppressing supercooling using nucleating agents and crystal species as well as external fields are also introduced. In addition, the mathematical models and related numerical algorithms for interpreting the phase change heat transfer mechanisms of LM are illustrated. Finally, the performance advantages of LMPCMs over other PCMs, as well as the technical approaches to further improve various properties of LMPCM heat sinks, are demonstrated by showing typical application cases. Based on the above, the current research status of LMPCMs and promising future research hotspots are prospected.This review is expected to help researchers interested in LMPCMs to quickly grasp the performance, heat transfer evaluation methods, and research status of LMPCMs, and also to provide a guidance for engineers in related fields to conduct further design and practices.

ABSTRACTVaccines utilizing modified messenger RNA (mRNA) technology have shown robust protective efficacy against SARS-CoV-2 in humans. As the virus continues to evolve in both human and non-human hosts, risk remains that the performance of the vaccines can be compromised by new variants with strong immune escape abilities. Here we present preclinical characterizations of a novel bivalent mRNA vaccine RQ3025 for its safety and effectiveness in animal models. The mRNA sequence of the vaccine is designed to incorporate common mutations on the SARS-CoV-2 spike protein that have been discovered along the evolutionary paths of different variants. Broad-spectrum, high-titer neutralizing antibodies against multiple variants were induced in mice (BALB/c and K18-hACE2), hamsters and rats upon injections of RQ3025, demonstrating advantages over the monovalent mRNA vaccines. Effectiveness in protection against several newly emerged variants is also evident in RQ3025-vaccinated rats. Analysis of splenocytes derived cytokines in BALB/c mice suggested that a Th1-biased cellular immune response was induced by RQ3025. Histological analysis of multiple organs in rats following injection of a high dose of RQ3025 showed no evidence of pathological changes. This study proves the safety and effectiveness of RQ3025 as a broad-spectrum vaccine against SARS-CoV-2 variants in animal models and lays the foundation for its potential clinical application in the future.

Background Rituximab (RTX) is considered the first-line treatment for pemphigus vulgaris (PV), which is a B-cell-mediated acquired autoimmune disease. However, no consensus on the optimum dosage has been achieved.Objectives To investigate the efficacy and safety of low-dose RTX (a single infusion of 500 mg) for the treatment of PV, a cohort study was conducted for patients with PV, along with a 12-month follow-up following the administration of RTX.Methods Patients with moderate or severe PV were divided into group A (low-dose RTX combined with corticosteroids) and group B (corticosteroids alone). Data on complete remission (CR) rates, doses of corticosteroids, cumulative doses of corticosteroids at the third, sixth, and twelfth months, pemphigus disease area index and adverse effects (AEs) were collected.Results Forty-four patients with moderate or severe PV were enrolled in this study (19 in group A and 25 in group B). Patients treated with low-dose RTX had higher CR rates, lower doses of corticosteroids at the third, sixth, and twelfth months, lower cumulative doses of corticosteroids at the sixth and twelfth months, and fewer AEs than those who received corticosteroids alone.Conclusions This study indicated that low-dose RTX may be a beneficial and secure therapy option for patients with moderate to severe PV.

AbstractDisruption of p53-MDM2/MDMX interaction by smaller inhibitors is a promising therapeutic intervention gaining tremendous interest. However, no MDM2/MDMX inhibitors have been marketed so far. Drug repurposing is a validated, practical approach to drug discovery. In this regard, we employed structure-based virtual screening in a reservoir of marketed drugs and identified nintedanib as a new MDM2/MDMX dual inhibitor. The computational structure analysis and biochemical experiments uncover that nintedanib binds MDM2/MDMX similarly to RO2443, a dual MDM2/MDMX inhibitor. Furthermore, the mechanistic study reveals that nintedanib disrupts the physical interaction of p53-MDM2/MDMX, enabling the transcriptional activation of p53 and the subsequent cell cycle arrest and growth inhibition in p53+/+ cancer cells. Lastly, structural minimisation of nintedanib yields H3 with the equivalent potency. In summary, this work provides a solid foundation for reshaping nintedanib as a valuable lead compound for the further design of MDM2/MDMX dual inhibitors.

The quality of meat is important to the consumer. Color is a primary indicator of meat quality and is characterized mainly into lightness, redness, and yellowness. Here, we used the genome-wide association study (GWAS) and gene-based association analysis with whole-genome resequencing of 230 fast-growing white-feathered chickens to map genes related to meat lightness and redness to a 6.24 kb QTL region (GGA15: 6298.34-6304.58 kb). This analysis revealed that only the protein phosphatase 1 catalytic subunit gamma (PPP1CC) was associated with meat color (P = 8.65E-08). The causal relationships between PPP1CC expression and meat lightness/redness were further validated through Mendelian randomization analyses (P < 2.9E-12). Inducible skeletal muscle-specific PPP1CC knockout (PPP1CC-SSKO) mice were generated and these mice showed increased lightness and decreased myoglobin content in the limb muscles. In addition, the predominant myofiber shifted from slow-twitch to fast-twitch myofibers. Through transcriptome and targeted metabolome evidence, we found that inhibition of PPP1CC decreased the expression of typical slow-twitch myofiber and myofiber-type specification genes and enhanced the glycolysis pathway. Functional validation through a plasmid reporter assay revealed that a SNP (rs315520807, C > T) located in the intron of PPP1CC could regulate the gene transcription activity. The differences in meat color phenotypes, myoglobin content, frequency of rs315520807 variant, expression of PPP1CC and fast-twitch fiber marker genes were detected between fast-growing white-feathered chickens and local chickens. In this study, PPP1CC was identified as the causative gene for meat color, and the novel target gene and variant that can aid in the innovation of meat improvement technology were detected.

The traditional water supply pipeline leak detection and location method has problems of false alarms, low positioning accuracy, and low stability. This paper focuses on the pipeline leak detection and location experimental platform to investigate water supply pipeline leaks, followed by simulation and experimental validation. This study integrates the mass flow balance method and pressure change inflection points to determine pipeline leaks and introduces an improved negative pressure wave method for locating leakage points. The results demonstrate that the system accurately detects pipeline leaks. The average positioning error of the improved negative pressure wave method for the leakage point is 4.76%, which has good stability and high positioning accuracy.

Enterococcus faecalis (E. faecalis) is one of the dominant bacteria in infected root canals, and it is tolerant to commonly used root canal disinfectants. Ag+ has a certain antibacterial effect on E. faecalis, but the instability and potential toxicity of Ag+ limit its application. Metal azolate framework-7 (MAF-7) is a typical metal–organic framework that has been used for drug delivery due to its high encapsulation efficiency, tunable release profile, and low cytotoxicity. In this study, we used a simple method for the synthesis of Ag+/MAF-7 nanocomposites. After characterization via several techniques, the antibacterial activity of this nanocomposite against E. faecalis was investigated. Ag+ was found to be uniformly bound to MAF-7, and the resulting Ag+/MAF-7 nanocomposite showed significant antibacterial activity against E. faecalis. This study demonstrates the potential application of nanocomposite antibacterial materials in treating infected root canals.

Purpose: This article attempts to find a unique mechanism in the relationship between entrepreneurial bricolage and new ventures growth by testing the mediating role of market ambidexterity, and the moderating effect of entrepreneurial networks. Design/methodology/approach: This article establishes a research model by considering entrepreneurial bricolage as the independent variable, market ambidexterity as mediators, entrepreneurial networks as a moderate variable, and new ventures growth performance as the dependent variable. The survey data collected from 372 Chinese new ventures were subjected to the hierarchical linear regression method for testing the proposed hypotheses. Findings/results: The results of this study indicate that entrepreneurial bricolage has a positive effect on new ventures growth. However, entrepreneurial networks negatively moderate the positive relationship between the two; In addition, both the balanced of market ambidexterity and combined of market ambidexterity partially mediate the relationship between entrepreneurial bricolage and new ventures growth. Finally, entrepreneurial networks have different moderating effects on the relationship between market ambidexterity and new ventures. Practical implications: The study highlights the importance of entrepreneurial bricolage and market ambidexterity strategies for sustainable growth in resource-constrained startups, advising them to focus on leveraging internal resources while selectively building entrepreneurial networks to avoid resource dispersion. This approach helps startups enhance resilience and drive long-term development in a dynamic competitive environment. Originality/value: Drawing from ambidexterity and social network capability, this paper extends the existing research on the relationship between entrepreneurial bricolage and organizational performance from market perspective, confirming the mediating role of market ambidexterity.

ABSTRACT: Bovine viral diarrhea virus (BVDV) can cause acute and persistent infections in cattle, resulting in significant economic losses to the livestock industry each year. Targeted antiviral therapy is an effective strategy. This study was based on network pharmacology, molecular docking techniques and in vitro studies to investigate quercetin’s mechanism in treating bovine viral diarrhea/mucosal disease (BVD-MD). The network topology analysis was carried out using Cytoscape 3.9.0 software to construct the network of “Chinese medicine ingredients-target-diseases”. Protein interactions were explored and analyzed using the String system (PPI). GO and KEGG pathway analysis of the intersected targets was performed using Bioconductor software. The molecular docking and molecular dynamics simulation methods were used to reveal the degree of binding of quercetin to key target genes. Western blot and indirect immunofluorescence were used to characterize the antiviral effects of quercetin. This study utilized network pharmacological analysis, identifying 22 targets associated with BVD-MD. The results of the KEGG pathway showed that quercetin was closely related to Ras and MAPK signaling pathways of BVD-MD. Molecular docking results showed that SRC, NS5B, NOX4 and XDH were the key targets of quercetin in the treatment of BVD-MD. Through network pharmacology, molecular docking and in vitro experiments, quercetin was demonstrated to combat bovine viral diarrhea mucosal disease through key targets of SRC, MAPK1, GSK3B, NS5B and E2. Molecular dynamics analysis showed that quercetin exhibited complex stability with NS5B. This study provides a theoretical and experimental basis for quercetin treatment of BVD-MD and later drug development.

Accurately estimating vehicle emissions is crucial for effective air quality management. As key data for emission inventory construction, emission factors (EFs) are influenced by vehicle usage characteristics and experience deterioration. Current deterioration models often employ single-factor approaches based on vehicle age or accumulated mileage, which fail to capture the effects of varying usage intensities within the same mileage or age intervals. This study addressed this limitation by developing a novel emission deterioration model that incorporates multi-dimensional usage characteristics and that utilizes a large-scale inspection and maintenance (I/M) dataset for light-duty gasoline vehicles (LDGVs). The modeling results reveal distinct deterioration patterns for different pollutants and highlight the synergistic effects of the usage duration and intensity: natural aging significantly impacts HC and NOx emissions, while CO emissions are more strongly affected by intensive use. Specifically, China V LDGVs that were driven 4 × 104 km/yr exhibited HC, CO, and NOx deterioration rates per mile that were approximately 4.1 % lower, 10.3 % higher, and 1.1 % higher, respectively, than those of vehicles driven 2 × 104 km/yr as the mileage increased from 5 × 104 km to 10 × 104 km. By leveraging timely emission data and explicitly accounting for usage intensity, this study corrected biases in local emission estimates by 5–85 % with respect to estimates from commonly used models. This framework enables the development of more effective control strategies and refinements to policy evaluations in megacities with I/M programs.

Chronic otitis media with effusion (COME) is a common cause of hearing loss in children and adults. Laryngopharyngeal reflux (LPR) is often overlooked in the clinical management of COME complicated by LPR. This study aimed to investigate the presence and concentration of trypsin and pepsin in the middle ear effusion (MEE), as well as the recurrence rate of otitis media with effusion (OME) in COME patients with trypsin-/pepsin-positive MEE after acid-suppressive treatment (AST). In this study, trypsin and pepsin were found in the MEE of COME patients. Follow-up results showed that the recurrence rate of OME within 1 year was significantly lower in the AST group than in the non-AST group. Taken together, patients with COME can be offered pepsin detection of MEE, and if the pepsin test is positive, acid-suppressing drugs such as proton pump inhibitors could be recommended to prevent the recurrence of OME.

BackgroundCollision tumors are defined as two or more distinctly bordered, mutually invasive tumors in the same anatomical region. Characterized by low incidence and lack of specificity, they often pose a significant challenge to disease diagnosis. Among these, collision tumors in the sella region are incredibly rare.Case descriptionOn 13 June 2023, the Department of Neurosurgery at Drum Tower Hospital admitted a patient with a pituitary adenoma in the sella region complicated by spindle cell sarcoma. After reviewing the literature, no related cases were reported. A patient presenting with complex clinical symptoms and preoperative imaging showing occupancy in the sella region is considered to have a recurrence of pituitary adenoma. After thorough preoperative evaluation and discussion, a trans-sphenoidal approach (with the aid of an endoscope) was performed to resect the pituitary lesions. Combined with postoperative pathological tissue and imaging, the patient was diagnosed with a pituitary adenoma (postoperative recurrence) in the sella region complicated by spindle cell sarcoma. The patient made a fair recovery and was discharged on the 8th postoperative day.ConclusionThis case report aims to elucidate and discuss the diagnosis and screening of rare collision tumors in the sella region to reduce the misdiagnosis rate and provide accurate treatment.

BackgroundAlcoholic hepatitis (AH) is characterized by intense systemic and liver inflammation, posing significant risks of health complications and mortality. While inflammation is a crucial defense mechanism against injury and infection, its timely resolution is essential to prevent tissue damage and restore tissue homeostasis. The resolution of inflammation is primarily governed by specialized pro-resolving mediators (SPMs), lipid metabolites derived from w-6 and w-3 poly-unsaturated fatty acids (PUFAs). Currently, the balance between pro-inflammatory lipid mediators (PLMs) and SPMs in the w-6 and w-3 PUFA metabolic pathways and the impact of alcohol abstinence on profiles of PLMs and SPMs in AH patients are not well studied.MethodsIn this study, we used LC-MS/MS and ELISA to quantify levels of lipid mediators (LMs) and their precursors in the plasma samples from 58 AH patients, 29 heavy drinkers without overt liver diseases (HDCs), and 35 healthy controls (HCs). Subsequently, we assessed correlations of altered LMs with clinical parameters and inflammatory mediators. Furthermore, we conducted a longitudinal study to analyze the effects of alcohol abstinence on LMs over 6- and 12-month follow-ups.ResultsAH patients exhibited significantly higher plasma levels of w-6 PLMs (PGD2 and LTB4) and SPM RvE1 compared to HDCs or HCs. Conversely, the SPM LXA4 was significantly downregulated in AH patients. Some of these altered LMs were found to correlate with AH disease severity and various inflammatory cytokines. Particularly, the LTB4/LXA4 ratio was substantially elevated in AH patients relative to HDCs and HCs. This altered ratio displayed a positive correlation with the MELD score. Importantly, the majority of dysregulated LMs, particularly PLMs, were normalized following alcohol abstinence.

IntroductionApolipoprotein E (APOE) epsilon 4 is regarded as the most significant genetic contributor linked to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Daily life elements might also influence cognitive abilities to some extent. This research aimed to investigate whether carrying APOE ε4 alters the effects of lifestyle on cognitive ability.MethodsThe research included 1871 senior community members with APOE gene data, all participating in clinical, neuropsychological, and daily living factor assessments. Based on their APOE ε4 status, they were categorized into two groups: the APOE ε4 group (n = 362) and the non-APOE ε4 group (n = 1,509). Subsequently, a multivariate logistic regression analysis was employed to investigate the link between cognitive deficits and APOE ε4, along with lifestyle patterns.ResultsOur research revealed a reduced incidence of MCI (OR = 0.745, 95% CI: 0.587–0.945, p = 0.015) and dementia (OR = 0.422, 95% CI: 0.259–0.688, p = 0.001) in the non-APOE ε4 carriers. Furthermore, the general linear regression analysis revealed a notable interplay between APOE ε4 and sleep disturbances, potentially impacting cognitive deterioration together (F = 6.817, p = 0.001).ConclusionsThe research indicates that possessing APOE ε4 alters the impact of everyday life factors on cognitive decline. In addition, there is a significant interaction between APOE ε4 and sleep disorders, which may jointly lead to the appearance of cognitive impairment.

Abstract The diversity of secondary metabolites is an important means for plants to cope with the complex and ever‐changing terrestrial environment. Plant biosynthetic gene clusters (BGCs) are crucial for the biosynthesis of secondary metabolites. The domestication and evolution of BGCs and how they affect plant secondary metabolites biosynthesis and environmental adaptation are still not fully understood. Buckwheat exhibits strong resistance and abundant secondary metabolites, especially flavonoids, allowing it to thrive in harsh environments. A non‐canonical BGC named UFGT3 cluster is identified, which comprises a phosphorylase kinase (PAK), two transcription factors (MADS1/2), and a glycosyltransferase (UFGT3), forming a complete molecular regulatory module involved in flavonoid biosynthesis. This cluster is selected during Tartary buckwheat domestication and is widely present in species of the Fagopyrum genus. In wild relatives of cultivated buckwheat, a gene encoding anthocyanin glycosyltransferase (AGT), which glycosylates pelargonidin into pelargonidin‐3‐O‐glucoside, is found inserted into this cluster. The pelargonidin‐3‐O‐glucoside can help plants resist UV stress, endowing wild relatives with stronger high‐altitude adaptability. This study provides a new research paradigm for the evolutionary dynamics of plant BGCs, and offers new perspectives for exploring the mechanism of plant ecological adaptability driven by environmental stress through the synthesis of secondary metabolites.

ObjectiveGut health is critical to the health of the host. This study was conducted to investigate the effects of Chitooligosaccharides (COS) on intestinal morphology, intestinal barrier, intestinal immunity and cecum microbiota of blue foxes.MethodsSeventy-two 125-day-old blue foxes were randomly divided into basal diet (BD) group, 200 ppm COS1 (1.5 kDa) group and 200 ppm COS2 (3 kDa) group for 8 weeks.ResultsWe elucidated that dietary COS1 supplementation promoted the development of intestinal villus morphology in blue foxes. Importantly, COS1 increased the number of goblet cells in duodenum, jejunum and ileum by 27.71%, 23.67%, 14.97% and S-IgA secretion in duodenum, jejunum and ileum by 71.59% and 38.56%, and up-regulate the expression of Occludin and ZO-1 by 50.18% and 148.62%, respectively. Moreover, COS1 promoted the pro-inflammatory and anti-inflammatory balance of small intestinal mucosa, and increased the diversity of cecum microbiota of blue foxes, especially Lactobacillus_agilis and Lactobacillus_murinus, and up-regulated the signaling pathways related to polysaccharide decomposition and utilization.ConclusionHere, we present dietary COS1 (1.5 kDa) can promote intestinal villus development, enhance intestinal barrier function, regulate intestinal immune balance and cecum microbiota homeostasis.

This study explores the connection between environmental, social, and governance (ESG) performance, financing constraints, and corporate investment efficiency. The hypotheses in this study are formulated based on the principles of stakeholder and agency theories. We used secondary data from Chinese A-share listed companies from 2010 to 2021 to conduct an empirical analysis using the Ordinary Least Squares (OLS) and Fixed Effect (FE) estimators. The results indicate that good ESG performance can enhance corporate investment efficiency. Compared to over-investment, ESG performance has a more pronounced effect on mitigating under-investment. Using a mediating analysis model, we also find that ESG performance exerts an inhibitory influence on both under- and over-investments by mitigating corporate financing constraints. Heterogeneity analysis indicates that the enhancing effect of ESG performance on corporate investment efficiency is more significant in non-state-owned corporations, low-pollution corporations, and corporations with a higher proportion of institutional investors. This study provides insights for listed companies to improve ESG performance to enhance capital allocation efficiency and promote sustainable development.

Abstract 2D polymers have emerged as a highly promising category of nanomaterials, owing to their exceptional properties. However, the understanding of their fracture behavior and failure mechanisms remains still limited, posing challenges to their durability in practical applications. This work presents an in‐depth study of the fracture kinetics of a 2D polyimine film, utilizing in situ tensile testing within a transmission electron microscope (TEM). Employing meticulously optimized transferring and patterning techniques, an elastic strain of ≈6.5% is achieved, corresponding to an elastic modulus of (8.6 ± 2.5) GPa of polycrystalline 2D polyimine thin films. In step‐by‐step fractures, multiple cracking events uncover the initiation and development of side crack near the main crack tip which toughens the 2D film. Simultaneously captured strain evolution through digital image correlation (DIC) analysis and observation on the crack edge confirm the occurrence of transgranular fracture patterns apart from intergranular fracture. A preferred cleavage orientation in transgranular fracture is attributed to the difference in directional flexibility along distinct orientations, which is substantiated by density functional‐based tight binding (DFTB) calculations. These findings construct a comprehensive understanding of intrinsic mechanical properties and fracture behavior of an imine‐linked polymer and provide insights and implications for the rational design of 2D polymers.

Resumo Fundamento A hipertrofia cardíaca patológica (HC) sustentada é um fator de risco independente para aumento da incidência e mortalidade de eventos cardiovasculares. Objetivos Esta pesquisa foi projetada para desvendar o papel do RNA não codificante longo (LncRNA) CCAT2 na progressão da HC. Métodos Procedimentos de constrição aórtica transversal (TAC) foram conduzidos para construir um modelo de HC in vivo induzido por sobrecarga de pressão. O tratamento com angiotensina II (Ang II) foi utilizado para induzir células hipertróficas de cardiomiócitos de rato H9c2. Resultados Os resultados in vivo mostraram que o silenciamento de CCAT2 reduziu a área de superfície dos cardiomiócitos, aliviou a fibrose cardíaca e diminuiu os níveis de β-MHC, ANP e BNP em modelos de camundongos HC. Os resultados in vitro revelaram que o knockdown de CCAT2 reduziu a área de superfície celular e atenuou os níveis de β-MHC, ANP e BNP em células hipertróficas H9c2. Além disso, o silenciamento de CCAT2 diminuiu os níveis de β-catenina ativa, GSK-3β fosforilada e genes alvo Wnt (c-Myc, ciclinaD1 e c-Jun) em camundongos HC e células H9c2 hipertróficas. É importante ressaltar que o tratamento com o ativador da via Wnt / β-catenina LiCl reverteu a supressão do knockdown de CCAT2 na área de superfície celular H9c2 e nos níveis de MHC, ANP e BNP. Conclusões Coletivamente, o silenciamento do CCAT2 desempenha um papel protetor contra a HC através da inativação da sinalização Wnt/β-catenina, o que sugere que o CCAT2 pode se tornar um alvo terapêutico promissor para o HC.

Pyroptosis is a form of inflammatory programmed cell death, and is activated by pathogen infections or endogenous danger signals. The canonical pyroptosis process is characterized by the inflammasome (typically NLRP3)-mediated activation of caspase-1, which in turn cleaves and activates IL-1β and IL-18, as well as gasdermin D, which is a pore-forming executor protein, leading to cell membrane rupture, and the release of proinflammatory cytokines and damage-associated molecular pattern molecules. Pyroptosis is considered a part of the innate immune response. A certain level of pyroptosis can help eliminate pathogenic microorganisms, but excessive pyroptosis can lead to persistent inflammatory responses, and cause tissue damage. In recent years, pyroptosis has emerged as a crucial contributor to the development of chronic inflammatory respiratory diseases, such as asthma. The present study reviews the involvement of pyroptosis in the development of asthma, in terms of its role in different inflammatory phenotypes of the disease, and its influence on various immune and non-immune cells in the airway. In addition, the potential therapeutic value of targeting pyroptosis for the treatment of specific phenotypes of asthma is discussed.

ObjectiveRobust evidence has demonstrated that inflammation plays an important role in the occurrence and development of abdominal aortic aneurysms (AAA). The serum uric acid (UA)/high-density lipoprotein cholesterol (HDL-C) ratio (UHR) has recently been recognized as a new biomarker for evaluating inflammatory and anti-inflammatory interactions. However, whether UHR is associated with AAA remains unclear. This study aimed to explore the association between UHR and presence of AAA.MethodsWe prospectively performed a hospital-based and community-based AAA screening program using ultrasonography in 9,064 individuals at Guangdong Provincial People’s Hospital and two communities in China. Logistic regression analysis was used to explore the association between UHR and presence of AAA. In addition, the restricted cubic spline (RCS) regression method was used to visually investigate the dose-response relationship between UHR and the presence of AAA. Propensity score matching (PSM) analysis was conducted to adjust for baseline variations and diminish selection bias, and subgroup analysis was performed to investigate the consistency of the conclusions.ResultsThe prevalence of AAA was 2.45% (222/9,064) in the present study. The optimal cut-off value of UHR was 17.0%, which was selected according to the receiver operator characteristic curve. The prevalence of AAA was 3.96% in the high-UHR group (UHR ≥ 17%) and 1.54% in the low-UHR group (UHR

Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a cellular target for central nervous system (CNS) disorders, including those affecting the retina. Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that can enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate microglia replacement as an approach for retinal diseases, we first employed a protocol to efficiently generate human-induced pluripotent stem cell (hiPSC)-derived microglia in quantities sufficient for in vivo transplantation. These cells demonstrated expression of microglia-enriched genes and showed typical microglial functions such as LPS-induced responses and phagocytosis. We then performed xenotransplantation of these hiPSC-derived microglia into the subretinal space of adult mice whose endogenous retinal microglia have been pharmacologically depleted. Long-term analysis post-transplantation demonstrated that transplanted hiPSC-derived microglia successfully integrated into the neuroretina as ramified cells, occupying positions previously filled by the endogenous microglia and expressed microglia homeostatic markers such as P2ry12 and Tmem119. Furthermore, these cells were found juxtaposed alongside residual endogenous murine microglia for up to 8 months in the retina, indicating their ability to establish a stable homeostatic state in vivo. Following retinal pigment epithelial cell injury, transplanted microglia demonstrated responses typical of endogenous microglia, including migration, proliferation, and phagocytosis. Our findings indicate the feasibility of microglial transplantation and integration in the retina and suggest that modulating microglia through replacement may be a therapeutic strategy for treating neurodegenerative retinal diseases.

BackgroundA standard treatment recommendation for third-line and subsequent treatments for advanced HER2-positive breast cancer is still missing, especially for low HER2 expression. Nevertheless, there is evidence that these patients might benefits from antibody-drug conjugates (ADCs) treatment. Therefore, this study aimed to evaluate the clinical efficacy, safety, and factors affecting efficacy of Disitamab Vedotin (RC48) for treating HER2-positive and HER2-low metastatic breast cancer (MBC) in the real-world setting.MethodsA retrospective study at five clinical sites was conducted in China, enrolling MBC patients treated with RC48 from July 01, 2021 and May 31, 2023. Patient demographics, treatment patterns, and adverse events (AEs) were recorded and analyzed.ResultsA total of 154 patients were included: 104 (67.53%) patients with HER2-positive and 50 (32.47%) patients with HER2-low MBC. The median progression-free survival (mPFS) was 5.06 months. The objective response rate (ORR) and disease control rate (DCR) were 36.36% and 68.83%, respectively. HER2-positive patients exhibited a mPFS of 5.93 and an ORR of 41.35%. In contrast, patients with low-HER2 had a mPFS of 4.28 months and an ORR of 26.00%. The most common AEs included neutropenia (54.55%), increased AST (53.25%), leukopenia (51.95%), and fatigue (43.51%), mostly graded mild to moderate (grade 1-2).ConclusionsThis extensive study in China demonstrated that RC48 has excellent therapeutic potential for both HER2-positive and HER2-low MBC with a favorable safety profile. The study also suggests that combination therapy significantly boosts efficacy beyond monotherapy, indicating a promising avenue for future ADC development.

A penetrating brain injury is a rare type of neurosurgical trauma associated with extremely high mortality and disability rates. Penetrating skull base injuries caused by arrows seldom occur because injuries caused by such weapons are more likely to be accidental. However, the number of self-inflicted injuries is increasing, and these injuries have varying patterns and high mortality rates. We report a case of a transoral penetrating craniocerebral injury caused by an arrow in a suicidal patient. Preoperative imaging is crucial for detecting and planning the surgical approach. Surgery is an effective treatment for this type of injury. Additionally, we reviewed previous case reports on this type of injury to provide recommendations for its clinical detection and treatment.

IntroductionAs rural-to-urban migration accelerates, rural areas are experiencing a significant increase in empty-nesters among the older adults. Influenced by traditional concepts of filial piety, older adults in rural areas heavily rely on the family-based old care model, creating a complex interplay between supply and demand for older adults’ care. This study investigates the relationship between intergenerational support and older adults’ care expectations in rural areas. We construct measures of financial and care expectations of older adults’ care to reflect older adults’ intentions and choices.MethodsThis study uses data from the 2018 China Health and Retirement Longitudinal Study and rural case studies to employ a binomial logit regression model, moderation effect analysis, and in-depth interviews.ResultsOur research reveals that the level of financial expectations for older adults’ care is inversely related to the extent of financial support from the parental generation but positively related to the level of financial support from the offspring. However, the older adults’ care expectations do not appear to be influenced by intergenerational support. Furthermore, population characteristics of the parental generation, such as educational attainment, age, and marital status, moderate the relationship between intergenerational support and older adults’ care expectations. Educational attainment negatively moderates the impact of parental financial support on financial expectations, age positively moderates offspring’s financial support on financial expectations. However, age negatively moderates offspring’s financial support on care expectations, while marital status positively moderates offspring’s financial support on care expectations.DiscussionThese findings help to elucidate the older adults’ care expectations of rural residents during the process of urbanization and social transformation, offering family-centered solutions such as ‘promoting cohabitation or proximity of children to their parents, developing diverse older adults’ care models based on different family situations, and ensuring the provision of basic older adults’ care services’ to address the current challenges of rural older adults’ care in China.

BackgroundAlthough the number of studies on treatment-resistant schizophrenia (TRS) has been increasing, the global research hotspots and future research trends have not yet been established.ObjectiveThis study identify the hotspots of TRS research and predict future research trends using a bibliometric analysis.MethodsThe Web of Science Core Collection was searched using the keyword “TRS”, econometric and co-occurrence analyses were conducted using CiteSpace and VOSviewer software, and the results were visualised. PRISMA reporting guidelines were used for this study.ResultsIn total, 912 publications were included in the analysis. The number of publications on TRS has shown an increasing trend over the past 20 years. The United States and University of London were the countries and institutions with the highest total number of publications, respectively. Schizophrenia Research was the journal with the highest number of articles. American Journal of Psychiatry was the most cited journal. Based on the results of this analysis, cognitive impairment, clozapine-resistant schizophrenia, early-onset schizophrenia, and early recognition of TRS will be hotspots for future research in this field.ConclusionThere has been an upward trend in the number of publications on TRS each year. However, issues such as how to use antipsychotics more efficiently to treat TRS and how to predict the emergence of TRS as early as possible are still in urgent need of research and are current challenges for clinicians. The results of this study not only predict and analyse future research hotspots but also help researchers identify appropriate research directions and partners.

IntroductionPanicle number (PN) is one of the three key yield components in rice, maintaining stable tiller and PN is a crucial characteristic of an ideal plant architecture. Understanding the molecular mechanisms underlying PN is essential for breeders aiming to improve rice yield.MethodsTo dissect the genetic architecture of panicle number, a genome-wide association study (GWAS) was conducted in 411 japonica rice varieties. GWAS analysis was carried out with the mixed linear model using 743,678 high-quality SNPs.ResultsOver two experimental years, we detected a total of seven quantitative trait loci (QTLs), located on chromosomes 1, 4, 6, 8, 11, and 12; notably, qPN1.1 and qPN8 were detected consistently in both years. By combining haplotype and expression analyses, OsCKX11 was identified as the candidate gene for qPN8, while LOC_Os01g07870 and LOC_Os01g07950 were identified as candidate genes for qPN1.1. Significant differences were observed among the haplotypes of these candidate genes. Additionally, qRT-PCR results showed that LOC_Os01g07870 expression levels were significantly lower in accessions with high panicle numbers compared to those with low panicle numbers.DiscussionTo understand the natural biological function of these candidate genes, further research involving overexpression or silencing in rice is needed. Despite these challenges, our results will lay the foundation for further study of panicle development and provide valuable genetic resources for developing high-panicle-number rice cultivars using genetic engineering and molecular breeding.

As the gradual emergence of alternating current (AC) electrified rail transit system in urban areas, buried gas pipeline adjacent to the system will be seriously corroded by induced alternating stray current. These buried gas pipelines are at serious risk of electrochemical corrosion, which leads to safety and environmental threaten. In order to study the distribution of alternating stray current corrosion on pipeline surface on a larger spatial scale, this paper conducted numerical simulation and experimental validation of alternating stray current corrosion of buried gas pipeline. In the numerical simulation model, coupling between different physical fields are realized through the relationship between current density of pipe-to-soil interface, electrolyte, and electrodes. Proposed numerical method based on coupled multi-physics in this paper are in good agreement with experimental results under different influencing factors. A novel evaluation index was proposed to assess the corrosion risk within different zones on the pipeline surface. Results show that corrosion distribution is greatly influenced by spatial interaction between buried pipeline and rail transit system including crossing angle and parallel distance. Besides, alternating stray current corrosion on buried gas pipeline are proved to be both affected by dynamic characteristics due to AC fluctuation and operation mode of locomotive.

Introduction and Objectives: Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells. Materials and Methods: TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model. Results: Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model. Conclusions: PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

Recent investigations have underscored the epigenetic modulation of the immune response; however, the interplay between RNA N6-methyladenosine (m6A) modification and immunomodulation in head and neck squamous cell carcinoma (HNSC) remains relatively unexplored. To bridge this knowledge gap, we undertook an extensive examination of the potential contributions of m6A modification and immunomodulation in HNSC. We amalgamated and deduplicated 27 m6A -related genes (m6AGs) and 1342 immune regulation-related genes (IMRGs), resulting in a comprehensive dataset encompassing 1358 genes. This dataset was scrutinized for m6A modification and immunomodulatory patterns within HNSC specimens. Employing Cox regression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) technique, we developed a prognostic risk model for m6A regulator-mediated methylation modification and immunomodulation-related differentially expressed genes (m6A&IMRDEGs). Our differential expression analysis delineated 29 m6A&IMRDEGs, and Weighted Gene Co-expression Network Analysis (WGCNA) elucidated two module genes (IL11 and MMP13) subjected to correlation analysis. The prognostic prediction models revealed that the clinical predictive efficacy peaked for 1-year forecasts, followed sequentially by 3-year and 5-year predictions. The risk scores derived from the model adeptly categorized HNSC patients into high- and low-risk cohorts, with the high-risk group exhibiting a more unfavorable prognosis. Protein-Protein Interaction (PPI) analysis identified 7 hub genes implicated in m6A and immune regulation, namely BPIFB1, BPIFB2, GP2, MUC5B, MUC7, PIP, and SCGB3A1. Furthermore, we noted marked disparities in the expression profiles of 18 immune cell types between the high- and low-risk groups. Our results substantiate that the clustering subpopulations and risk models associated with m6A and immune regulatory genes portend a poor prognosis in HNSC. The risk score emerges as a potent prognostic biomarker and predictive metric for HNSC patients. A thorough assessment of m6A and immune regulatory genes in HNSC will augment our comprehension of the tumor immune microenvironment and facilitate the advancement of HNSC therapeutics.

To obtain the ignition performance of an integrated inclined combustor, we perform an experimental study on the ignition performance of an inclined combustor under various ignition positions, inlet flow rates, and fuel air ratios (FARs). The experimental results reveal the following. 1) During ignition at I1, the inclined combustor presents the best ignition performance. 2) The forward propagation process of flame along the swirler's inclined direction easily realizes flame propagation, whereas the backward flame propagation process in the swirler's inclined direction is difficult to achieve; forward and backward flame propagations exhibit evident differences. 3) The diffusion propagation of swirl flames at the ignition head is the main means swirl flames are generated at the nonignition head. 4) During the ignition process, the combustion intensity increases with the increase in FAR and decreases with the increase in inlet flow rate. 5) The successful ignition time decreases with the increase in inlet flow rate and FAR.

Evaluating the spatiotemporal variations and driving mechanisms of carrying capacity (CC) is critical for optimizing grassland resource utilization and promoting sustainable development in grassland animal husbandry. This study focuses on Xinjiang, an arid and semi-arid region significantly impacted by environmental changes and human activities. To capture the dynamics of grassland CC, we employed Theil-Sen trend analysis and the Mann-Kendall test to assess spatiotemporal trends. The innovative use of the Geodetector method allowed for a detailed quantification of the influence of various environmental and human-related factors on grassland CC. Additionally, we incorporated livestock data to evaluate the overgrazing conditions of the grassland ecosystem. Our findings demonstrate that: (1) Grassland CC has shown a pronounced overall upward trajectory over the last twenty years, with notable inter-annual fluctuations and significant spatial variations, particularly between the northern and southern regions. (2) The spatial distribution of grassland CC is primarily influenced by precipitation patterns and population density, with key determining factors varying across different types of grasslands. Except for alpine steppe and alpine desert, the spatial distribution of grassland CC was primarily influenced by two-factor interactions, surpassing the impacts of single-factor effects. (3) The overgrazing rate has generally declined, peaking in 2014 and showing the mildest condition in 2017. In comparison, the overgrazing situation in Northern Xinjiang is relatively more favorable, whereas the southern and eastern regions necessitates more immediate and comprehensive ecological restoration and management measures. In summary, this study provides important scientific evidence for prioritizing grassland protection and planning for the sustainable animal husbandry development in arid and semi-arid regions.

Aberrant expression of cyclin-dependent kinase 5 (Cdk5) has been reported in pituitary adenomas. However, the role of Cdk5 in the tumorigenesis remains unclear. We show that prenatal p25-activated Cdk5 phosphorylates minichromosome maintenance protein 2 (Mcm2), enhancing minichromosome maintenance (MCM) family proteins and driving intermediate lobe-located melanotrope-originated pituitary tumorigenesis. In a mouse model with CaMKII promoter-driven transgenic induction of p25, we observed intermediate lobe-originated pituitary adenoma producing non-functional proopiomelanocortin (POMC)-derived peptides under persistent p25 overexpression. Single-cell RNA sequencing revealed Mcm2 may play an important role during tumor progression. Subsequently, Mcm2 was identified as a potential phosphorylated substrate of Cdk5, mediating the tumorous proliferation of melanotrope cells. Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis.

Summary: Background: Dementia among younger people is rapidly emerging as a global health concern; however, comprehensive research on its shifting burden trends remains insufficient. Methods: Data on the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) associated with dementia occurring in individuals

ObjectiveTo establish an evaluation index system for the effectiveness of plague prevention and control in demonstration areas to strengthen the plague prevention and control system. MethodsAfter constructing a primary index system to evaluate the effectiveness of plague prevention and control through literature study and expert interview, we conducted three rounds of online Delphi consultation among 20 authoritative experts and scholars engaged in plague prevention, control, and research from 5 provincial-level administrative divisions from June to August 2023. The response rate of the questionnaire was used to represent the expert activity coefficient. The analytical hierarchy method was used to calculate the weights of indicators at three levels. The coefficient of expert authority (Cr) was used to reflect the expert authority, and the coefficient of variation (CV) and Kendall's coefficient of concordance (Kendall′s W) were used to reflect the coordination of expert consultation. SPSS 25.0 and yaahp 10.1 software were used for statistical analysis. ResultsThe activity coefficients of the three rounds of expert consultation were all 100%, indicating a high degree of expert activity. The Cr values of the three rounds were all greater than 0.7, indicating a high degree of expert authority. In the third round, the coefficient of variation (CV) was < 0.25, and the Kendall's W of the indicators increased compared to those of the first and second rounds, approaching 0.4 (P < 0.01). The final index system consisted of 3 first-level indicators (pre-event preparedness, in-event handling ability, and post-event recovery ability, with weights of 33.33%, 33.34%, and 33.33%, respectively), 10 second-level indicators (among which, summary analysis ability and damage repair ability had the highest weights of 16.67%, followed by monitoring and early warning ability with 15.68%), and 58 third-level indicators (among which, network direct reporting rate and professional responsible for plague data had the highest weights of 4.76%, followed by plague monitoring database and early warning platform with 3.62%, 3.10% , respectively). ConclusionThe established index system has certain scientific validity and reliability to comprehensively and accurately evaluate the effectiveness of plague prevention and control in demonstration areas, and is conducive to building a more complete prevention and control system, and provides a reference for other regions to carry out plague prevention and control work.

Abstract Zika virus (ZIKV) infection may lead to severe neurological consequences, including seizures, and early infancy death. However, the involved mechanisms are still largely unknown. TRPC channels play an important role in regulating nervous system excitability and are implicated in seizure development. We investigated whether TRPCs might be involved in the pathogenesis of ZIKV infection. We found that ZIKV infection increases TRPC4 expression in host cells via the interaction between the ZIKV-NS3 protein and CaMKII, enhancing TRPC4-mediated calcium influx. Pharmacological inhibition of CaMKII decreased both pCREB and TRPC4 protein levels, whereas the suppression of either TRPC4 or CaMKII improved the survival rate of ZIKV-infected cells and reduced viral protein production, likely by impeding the replication phase of the viral life cycle. TRPC4 or CaMKII inhibitors also reduced seizures and increased the survival of ZIKV-infected neonatal mice and blocked the spread of ZIKV in brain organoids derived from human-induced pluripotent stem cells. These findings suggest that targeting CaMKII or TRPC4 may offer a promising approach for developing novel anti-ZIKV therapies, capable of preventing ZIKV-associated seizures and death.

Objective To study the changes in erythrocyte osmotic fragility(EOF) in patients with hypercythemia, polycythemia and anemia under a high altitude environment. Methods A total of 174 outpatients, inpatients and people undergoing physical examination in Tibet Autonomous Region People′s Hospital in October 2020 were enrolled and divided into four groups according to hemoglobin levels: the polycythemia group(n=42), the physiologic increase group(n=48), the anemia group(n=29) and the healthy control group(n=55). They were compared with 67 anemia patients and 67 healthy people in the laboratory of Peking Union Medical College Hospital in the same period as the plain control group. The classic EOF test method was used to compare the results of each group′s EOF. The concentrations of NaCl solution for starting hemolysis (STH) and NaCl solution for complete hemolysis (CTH) were included, and the data were statistically analyzed by SPSS software. Results There was a significant difference in CTH between Zang and Han healthy people (P

Abstract Convenient and effective biomarkers are essential for the early diagnosis and treatment of Alzheimer’s disease (AD). In the cross-sectional study, 103 patients with AD, 82 patients with aMCI and 508 normal controls (NC) were enrolled. The single‐molecule array (Simoa) technique was used to assess the levels of plasma proteins, including NfL, T-tau, P-tau-181, Aβ40, Aβ42. Montreal Cognitive Assessment (MoCA) was used to assess the overall cognitive function of all subjects. Moreover, Amyloid PET and structural head MRI were also performed in a subset of the population. In the follow-up, the previous 508 normal older adults were followed up for two years, then COX regression analysis was used to investigate the association between baseline plasma proteins and future cognitive outcomes. NfL, T-tau, P-tau-181, Aβ40, Aβ42 and Aβ42/40 were altered in AD dementia, and NfL, Aβ42 and Aβ42/40 significantly outperformed all plasma proteins in differentiating AD dementia from NC, while NfL and Aβ42/40 could effectively distinguish between aMCI and NC. However, only plasma NfL was associated with future cognitive decline, and it was negatively correlated with MoCA (r = − 0.298, p