Search

Abstract Understanding the molecular circuitries that govern early embryogenesis is important, yet our knowledge of these in human preimplantation development remains limited. Small non-coding RNAs (sncRNAs) can regulate gene expression and thus impact blastocyst formation, however, the expression of specific biotypes and their dynamics during preimplantation development remains unknown. Here we identify the abundance of and kinetics of piRNA, rRNA, snoRNA, tRNA, and miRNA from embryonic day (E)3-7 and isolate specific miRNAs and snoRNAs of particular importance in blastocyst formation and pluripotency. These sncRNAs correspond to specific genomic hotspots: an enrichment of the chromosome 19 miRNA cluster (C19MC) in the trophectoderm (TE), and the chromosome 14 miRNA cluster (C14MC) and MEG8-related snoRNAs in the inner cell mass (ICM), which may serve as ‘master regulators’ of potency and lineage. Additionally, we observe a developmental transition with 21 isomiRs and in tRNA fragment (tRF) codon usage and identify two novel miRNAs. Our analysis provides a comprehensive measure of sncRNA biotypes and their corresponding dynamics throughout human preimplantation development, providing an extensive resource. Better understanding the sncRNA regulatory programmes in human embryogenesis will inform strategies to improve embryo development and outcomes of assisted reproductive technologies. We anticipate broad usage of our data as a resource for studies aimed at understanding embryogenesis, optimising stem cell-based models, assisted reproductive technology, and stem cell biology.

Abstract Limited data on the correlation between the perineal body (PB) and stress urinary incontinence (SUI) are available. The objectives of this study were to quantify the PB using shear wave elastography (SWE) technology with a high-frequency linear array probe to evaluate the relationship between the properties of PB and stress urinary incontinence (SUI). This study included 64 women with SUI and 70 female control participants. The length, height, perimeter, and area of PB in all participants were calculated using transperineal ultrasound, and the elasticity of PB was assessed by SWE at rest and during the maximal Valsalva maneuver, respectively. In addition, the comparison of PB parameters between the patients with SUI and the healthy participants was conducted. The transperineal ultrasound and SWE examination was performed in 134 participants, and the elastic modulus values were significantly increased from participants at rest to those during the maximal Valsalva maneuver in all participants (E max : 35.59 versus 53.13 kPa, P

Abstract Background Bacterial antimicrobial resistance (AMR) is a global threat to both humans and livestock. Despite this, there is limited global consensus on data-informed, priority areas for intervention in both sectors. We compare current livestock AMR data collection efforts with other variables pertinent to human and livestock AMR to identify critical data gaps and mutual priorities. Methods We globally synthesized livestock AMR data from open-source surveillance reports and point prevalence surveys stratified for six pathogens (Escherichia coli, Staphylococcus aureus, non-typhoidal Salmonella, Campylobacter spp., Enterococcus faecalis, Enterococcus faecium) and eleven antimicrobial classes important in human and veterinary use, published between 2000 and 2020. We also included all livestock species represented in the data: cattle, chickens, pigs, sheep, turkeys, ducks, horses, buffaloes, and goats. We compared this data with intended priorities calculated from: disability-adjusted life years (DALYs), livestock antimicrobial usage (AMU), livestock biomass, and a global correlation exercise between livestock and human proportion of resistant isolates. Results Resistance to fluoroquinolones and macrolides in Staphylococcus aureus were identified as priorities in many countries but, less than 10% of these reported livestock AMR data. Resistance data for Escherichia coli specific to cattle, chickens, and pigs, which we prioritized, were also well collected. AMR data collection on non-typhoidal Salmonella and other livestock species were often not prioritized. Of 232 categories prioritized by at least one country, data were only collected for 48% (n = 112). Conclusions The lack of livestock AMR data globally for broad resistance in Staphylococcus aureus could underplay their zoonotic threat. Countries can bolster livestock AMR data collection, reporting, and intervention setting for Staphylococcus aureus as done for Escherichia coli. This framework can provide guidance on areas to strengthen AMR surveillance and decision-making for humans and livestock, and if done routinely, can adapt to resistance trends and priorities.

Abstract Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.

Abstract. Background:. Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants. Methods:. A total of 3053 healthy Han Chinese adults (1922 women) aged 18–79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere–Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance. Results:. All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction

The gut has been a focal point in the research of digestive system disorders. The internal microbiota generates metabolites that function as signaling molecules and substrates, interacting with the intestinal wall and influencing host physiology and pathology. Besides, the gut microbiota and metabolites owe highly diverse types and quantities, posing challenges for quantitative analysis, and monitoring frequent interactions between digestive tract metabolites and the intestinal wall remains a challenge. However, research targeting gut microbiota metabolites has elucidated their relevance to digestive diseases. By modulating metabolites such as short-chain fatty acids, bile acids, and lipopolysaccharides, it is possible to intervene in the progression of diseases such as inflammatory bowel disease and non-alcoholic fatty liver disease. Currently, research on gut microbiota is advancing, and more work is required to explore the interactions between host, microbes and underlying mechanisms. In this review, we have revisited the generation of gut microbiota-related metabolites, their impact on diseases, and modes of interaction, emphasizing the significant role of metabolites in digestive system disorders. It is believed that the linkage between gut microbiota and diseases in current research can be established through metabolites, providing a framework and foundation for research in the field of metabolomics and fundamental mechanisms.

The accurate understanding of rockburst mechanism poses a global challenge in the field of rock mechanics. Particularly for strain rockburst, achieving self-initiated static-dynamic state transition is a crucial step in the formation of catastrophic events. However, the state transition behavior and its impact on rockburst have not received sufficient attention, and are still poorly understood. Therefore, this study specifically focuses on the state transition behavior, aiming to investigate its abrupt transition process and formation mechanism, and triggering effects on rockburst. To facilitate the study, a novel burst rock-surrounding rock combined laboratory test model is proposed and its effectiveness is validated through experiment verification. Subsequently, corresponding numerical models are established using the three-dimensional (3D) discrete element method (DEM), enabling successful simulation of static brittle failure and rockbursts of varying intensities under quasi-static displacement loading conditions. Moreover, through secondary development, comprehensive recording of the mechanical and energy information pertaining to the combined specimen system and its subsystems is achieved. As a result of numerical investigation studies, the elastic rebound dynamic behavior of the surrounding rock was discovered and identified as the key factor triggering rockburst and controlling its intensity. The impact loading on the burst rock, induced by elastic rebound, directly initiates the dynamic processes of rockburst, serving as the direct cause. Additionally, the transient work and energy convergence towards the burst rock resulting from elastic rebound are recognized as the inherent cause of rockburst. Moreover, it has been observed that a larger extent of surrounding rock leads to a stronger elastic rebound, thereby directly contributing to a more intense rockburst. The findings can provide novel theoretical insights for the exploring of rockburst mechanism and the development of monitoring and prevention techniques.

Abstract Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA‐seq analysis, it is found high expression of the splicing factor polypyrimidine region‐ binding protein 3 (PTBP3) in GBC. Multi‐omics analysis revealed that PTBP3 promoted exon skipping of interleukin‐18 (IL‐18), resulting in the expression of ΔIL‐18, an isoform specifically expressed in tumors. That ΔIL‐18 promotes GBC immune escape by down‐regulating FBXO38 transcription levels in CD8+T cells to reduce PD‐1 ubiquitin‐mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL‐18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL‐18 production displayed anti‐tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL‐18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL‐18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL‐18 pre‐mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.

Plant growth and development are characterized by systematic and continuous processes, each involving intricate metabolic coordination mechanisms. Mathematical models are essential tools for investigating plant growth and development, metabolic regulation networks, and growth patterns across different stages. These models offer insights into secondary metabolism patterns in plants and the roles of metabolites. The proliferation of data related to plant genomics, transcriptomics, proteomics, and metabolomics in the last decade has underscored the growing importance of mathematical modeling in this field. This review aims to elucidate the principles and types of metabolic models employed in studying plant secondary metabolism, their strengths, and limitations. Furthermore, the application of mathematical models in various plant systems biology subfields will be discussed. Lastly, the review will outline how mathematical models can be harnessed to address research questions in this context.

Thymallus sp. is a native fish species distributed in the Irtysh River Basin in China. Unfortunately, environmental damage and overfishing have led to a significant decline in Arctic grayling resources, pushing them towards endangerment. However, there is a lack of comprehensive genetic information regarding the wild populations of Thymallus sp., which poses challenges for the development of effective conservation strategies for their genetic resources. In response, this study collected 180 samples from six major tributaries within the Irtysh River Basin. It conducted a thorough investigation of Thymallus sp.'s morphological and genetic variations using morphometric measurements and microsatellite markers. The results showed that the morphological differences among the six populations were relatively minor, and none of the morphological traits reached the subspecies level or higher. Genetic analysis showed that all six populations of Thymallus sp. possessed high genetic diversity, with genetic variations among populations accounting for only 6.30 % of the total variation, suggesting that the current status of the germplasm resources was relatively good. However, due to overfishing, which had led to a decline in the number of effective breeding groups, some inbreeding has occurred within populations. Moreover, the construction of dams has hindered gene exchange, leading to a certain tendency towards genetic differentiation within the populations. This was evidenced by the clustering of Burqin and Haba into one genetic group, while Kuirt, Kayit, Kalaerzis, and Crane were classified into another genetic group. This study offers an important reference for the management and conservation of Thymallus sp. populations in the Irtysh River Basin.

Objective Patients with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular and cerebrovascular events (CCEs). Furthermore, CCE was a significant factor contributing to mortality in patients with SLE. However, no clinical model exists that can predict which patients are at high risk. The purpose of this study was to develop a practical model for predicting the risk of CCE in people with SLE.Methods This study was based on the Chinese SLE Treatment and Research Group cohort. A total of 2399 patients, who had a follow-up period of over 3 years and were diagnosed with SLE for less than 1 year at the start of the study, were included. Cox proportional hazards regression and least absolute shrinkage and selection operator regression were used to establish the model. Internal validation was performed, and the predictive power of the model was evaluated.Results During the follow-up period, 93 patients had CCEs. The prediction model included nine variables: male gender, smoking, hypertension, age of SLE onset >40, cutaneous involvement, arthritis, anti-β2GP1 antibody positivity, high-dose glucocorticoids and hydroxychloroquine usage. The model’s C index was 0.801. Patients with a prognostic index over 0.544 were classified into the high-risk group.Conclusion We have developed a predictive model that uses clinical indicators to assess the probability of CCE in patients diagnosed with SLE. This model has the ability to precisely predict the risk of CCE in patients with SLE. We recommended using this model in the routine assessment of patients with SLE.

Non-alcoholic fatty liver disease (NAFLD) and its more advanced form, non-alcoholic steatohepatitis (NASH), have become global health challenges with significant morbidity and mortality rates. NAFLD encompasses several liver diseases, ranging from simple steatosis to more severe inflammatory and fibrotic forms. Ultimately, this can lead to liver cirrhosis and hepatocellular carcinoma. The intricate role of hepatic macrophages, particularly Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), in the pathogenesis of NAFLD and NASH, has received increasing attention. Hepatic macrophages can interact with hepatocytes, hepatic stellate cells, and endothelial cells, playing a crucial role in maintaining homeostasis. Paradoxically, they also participate in the pathogenesis of some liver diseases. This review highlights the fundamental role of hepatic macrophages in the pathogenesis of NAFLD and NASH, emphasizing their plasticity and contribution to inflammation and fibrosis, and hopes to provide ideas for subsequent experimental research and clinical treatment.

Diabetic wounds are a severe complication of diabetes, characterized by persistent, non-healing ulcers due to disrupted wound-healing mechanisms in a hyperglycemic environment. Key factors in the pathogenesis of these chronic wounds include unresolved inflammation and antioxidant defense imbalances. The cystine/glutamate antiporter SLC7A11 (xCT) is crucial for cystine import, glutathione production, and antioxidant protection, positioning it as a vital regulator of diabetic wound healing. Recent studies underscore the role of SLC7A11 in modulating immune responses and oxidative stress in diabetic wounds. Moreover, SLC7A11 influences critical processes such as insulin secretion and the mTOR signaling pathway, both of which are implicated in delayed wound healing. This review explores the mechanisms regulating SLC7A11 and its impact on immune response, antioxidant defenses, insulin secretion, and mTOR pathways in diabetic wounds. Additionally, we highlight the current advancements in targeting SLC7A11 for treating related diseases and conceptualize its potential applications and value in diabetic wound treatment strategies, along with the challenges encountered in this context.

At present, wireless power transfer (WPT) systems with constant current (CC) or constant voltage (CV) characteristics are typically achieved using a single transmitter and single pickup (STSP) configuration, which cannot transfer power to multiple battery loads simultaneously. In this paper, the LCC-LCC/S reconfigurable topology is proposed to realize the CC-to-CV transition for multiple battery loads. An LCC topology is designed on the primary side to achieve a constant current (0.362A) flowing through the transmitting coil to enable independent operation of power pickups. A reconfigurable LCC/S topology is designed on the secondary side to achieve the CC-to-CV transition of the battery loads. The received power from the pickups remains unaffected when pickups are moved in or out or are in different operating modes (CC or CV). The circuit can maintain zero phase angle (ZPA) operation, which greatly enhances the overall power density of the system. Additionally, detailed design process for the compensation parameters on both the primary and secondary sides are provided. Theoretical analysis proves that good system stability and robustness can be obtained in the case of variable quantity of pickups and quality factors of coils. The experimental prototype was built, with the CC value for the battery load designed at 0.7A and the CV value designed at 8 V. Experimental results demonstrate the smooth CC-to-CV transition of the proposed WPT system (with 3 pickups) at a power output of 15.4 W, and the system’s maximum efficiency can reach 75.5 %.

Impaired wound healing is one of the main clinical complications of type 2 diabetes (T2D) and a major cause of lower limb amputation. Diabetic wounds exhibit a sustained inflammatory state, and reducing inflammation is crucial to diabetic wounds management. Macrophages are key regulators in wound healing, and their dysfunction would cause exacerbated inflammation and poor healing in diabetic wounds. Gene regulation caused by histone modifications can affect macrophage phenotype and function during diabetic wound healing. Recent studies have revealed that targeting histone-modifying enzymes in a local, macrophage-specific manner can reduce inflammatory responses and improve diabetic wound healing. This article will review the significance of macrophage phenotype and function in wound healing, as well as illustrate how histone modifications affect macrophage polarization in diabetic wounds. Targeting macrophage phenotype with histone-modifying enzymes may provide novel therapeutic strategies for the treatment of diabetic wound healing.

Abstract Background To investigate the role of antiphospholipid antibodies (aPLs) in the disease severity and prognosis of SLE-related thrombocytopenia (SLE-TP). Methods This multicenter prospective study was conducted based on data from the CSTAR registry. TP was defined as a platelet count

Abstract The Holocene temperature conundrum, the discrepancy between proxy-based Holocene global cooling and simulated global annual warming trends, remains controversial. Meanwhile, reconstructions and simulations show inconsistent spatial patterns of terrestrial temperature changes. Here we report Holocene alkenone records to address spatial patterns over mid-latitude Eurasia. In contrast with long-term cooling trends in warm season temperatures in northeastern China, records from southwestern Siberia are characterized by colder conditions before ~6,000 years ago, thus long-term warming trends. Together with existing records from surrounding regions, we infer that colder airmass might have prevailed in the interior of mid-latitude Eurasian continent during the early to mid-Holocene, perhaps associated with atmospheric response to remnant ice sheets. Our results challenge the proposed seasonality bias in proxies and modeled spatial patterns in study region, highlighting that spatial patterns of Holocene temperature changes should be re-considered in record integrations and model simulations, with important implications for terrestrial hydroclimate changes.

Considerable efforts have been devoted to treating gastric ulcers. Attempts in this field tend to develop drug delivery systems with prolonged gastric retention time. Herein, we develop novel Chinese herb pollen-derived micromotors as active oral drug delivery system for treating gastric ulcer. Such Chinese herb pollen-derived micromotors are simply produced by asymmetrically sputtering Mg layer onto one side of pollen grains. When exposed to gastric juice, the Mg layer can react with the hydrogen ions, resulting in intensive generation of hydrogen bubbles to propel the micromotors. Benefiting from the autonomous motion and unique spiny structure, our micromotors can move actively in the stomach and adhere to the surrounding tissues. Besides, their special architecture endows the micromotors with salient capacity of drug loading and releasing. Based on these features, we have demonstrated that our Chinese herb pollen-derived micromotors could effective deliver berberine hydrochloride and show desirable curative effect on the gastric ulcer model of mice. Therefore, these Chinese herb pollen-derived micromotors are anticipated to serve as promising oral drug delivery carriers for clinical applications.

Diabetic wounds are more complex than normal chronic wounds because of factors such as hypoxia, reduced local angiogenesis, and prolonged inflammation phase. Fibrous proteins, including collagen, fibrin, laminin, fibronectin, elastin etc., possess excellent inherent properties that make them highly advantageous in the area of wound healing. Accumulating evidence suggests that they contribute to the healing process of diabetic wounds by facilitating the repair and remodel of extracellular matrix, stimulating the development of vascular and granulation tissue, and so on. However, there is currently a lack of a comprehensive review of the application of these proteins in diabetes wounds. An overview of fibrous protein characteristics and the alterations linked to diabetic wounds is given in this article’s initial section. Next is a summary of the advanced applications of fibrous proteins in the last five years, including acellular dermal matrix, hydrogel, foam, scaffold, and electrospun nanofibrous membrane. These dressings have the ability to actively promote healing in addition to just covering wounds compared to traditional wound dressings like gauze or bandage. Research on fibrous proteins and their role in diabetic wound healing may result in novel therapeutic modalities that lower the incidence of diabetic wounds and thereby enhance the health of diabetic patients.

Abstract Background The meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll‐like receptor (TLR) ligands as compared to CFA. Methods A comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein‐3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme‐linked immunosorbent assay quantified antigen‐specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes. Results TLR ligands demonstrated efficacy in inducing PV‐like symptoms in wild‐type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self‐antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study. Conclusions The systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis. Key points/highlights Immunization with desmoglein 3 and Toll‐like receptor (TLR) ligands effectively induces pemphigus symptoms in wild‐type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL‐10‐producing neutrophils, whereas TLR ligands downregulated CCL17 and IL‐10, leading to more effective immune responses.

Background: Homer protein homolog 3 (HOMER3), a factor implicated in both physiological and pathological processes, has been studied extensively to determine the relationship between its expression level and the prognosis of various malignancies. However, the significance and clinicopathological role of HOMER3 in colorectal adenocarcinoma remain unclear. Methods: In this study, bioinformatics techniques were used to find the correlation between high HOMER3 expression levels and clinicopathological features of colorectal adenocarcinoma (COAD) patients. Results: Cellular experiments confirmed the differential expression of HOMER3 in tumor cells compared to normal cells. HOMER3 overexpression was significantly associated with COAD staging and carcinoembryonic antigen (CEA) levels. Patients with high HOMER3 expression levels have a poor prognosis. HOMER3 expression levels can be distinguished more accurately between tumor and non-tumor tissues (AUC = 0.634). The HOMER3 gene variation rate in COAD tissue was 0.7 %. Moreover, 16 of the 22 DNA methylation sites in HOMER3 were associated with COAD prognosis. Our findings confirmed that HOMER3 was positively correlated with immune cell infiltration and immune checkpoints (PD-1, CTLA-4, LMTK3, and LAG3) in COAD, Specifically, we will clearly state that while there is statistical significance, the actual strength of the correlations is weak. During KEGG enrichment analysis, HOMER3 was enriched along with DLG4 and SHANK1 in glutamatergic synapses. Additionally, upstream microRNAs that could bind to HOMER3 were predicted. These findings suggest that HOMER3 might be involved in COAD development and immune regulation. Conclusions: HOMER3 acts as a potential biomarker that can facilitate innovative developments in the diagnosis and prognostic assessment of COAD.

Geopolymer concrete (GPC) is a relatively new, innovative and sustainable green civil engineering material, which has many advantages similar to ordinary Portland Cement (OPC). Through the investigations and analyses of published literature, this review paper summarizes the state-of-the-art research progress with respect to the carbonization performances of GPC from the following aspects. First of all, the advantages, carbonization mechanism, and carbonization identification methods of GPC are introduced. Second, the carbonization properties between GPC and OPC are compared, as well as the influences of different factors on the carbonization performance of GPC are analyzed, such as admixtures, additives, environment, etc. Finally, a series of models to evaluate the degree of carbonization are listed, and the future prospect of GPC carbonization research is also put forward. Based on the literature summaries, existing researchers still have great controversy about the research results on the anti-carbonization properties of geopolymer gelling materials, mainly because of the diversity of raw materials in the geopolymer system, resulting in large differences in the hydration products and microstructure of various geopolymer pulps, so there are differences in their anti-carbon performance. It is significant that the influential factors will be of great importance to determine the carbonization performances of GPC, which can also be extended to the anti-carbonization properties of GPC, such as the filling effect of nanoparticles, changing the proportion of silicon and aluminum substances, and improving the mechanical properties and durability of GPC. In addition, more types of numerical models for the carbonization of GPC should be established, considering more impact factors, to ensure the applicability and accuracy, and the integration of the models needs be more strengthened to serve for the complex engineering practices. Overall, the carbonization model establishment will contribute to analyzing the durability of GPC and provide some clues for prolonging its life.

Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.

Metagenomic next-generation sequencing (mNGS) has revolutionized the detection of pathogens, particularly in immunocompromised individuals such as pediatric patients undergoing intensive chemotherapy and hematopoietic stem cell transplantation. This study aims to explore the impact of neutrophil count on the diagnostic efficacy of mNGS in diagnosing infections in pediatric patients with febrile diseases. We conducted a retrospective analysis of pediatric patients with febrile diseases in the hematology/oncology department from January 2019 to September 2022. The study included 387 patients with 516 febrile episodes. Analyzing data from 516 pediatric cases, our study found that 70.7 % had febrile neutropenia (FN) and 29.3 % had febrile without neutropenia (FWN). mNGS demonstrated a high positive detection rate of 84.9 %, compared to 29.7 % for conventional microbiological tests (CMT). While the positive detection rates of mNGS were similar in both FN and FWN groups, bacterial pathogens were more frequently detected in FN patients. Furthermore, the rate of identifying a “probable” microbial etiology was lower in the FN group (46.8 %) compared to the FWN group (65.6 %, p＜0.001). When analyzing the types of organisms and specimens, the “probable” identification rates were particularly lower for viruses and fungi detected by mNGS, as well as in blood and nasopharyngeal swab samples. These findings underscore the significant influence of neutrophil counts on mNGS results in pediatric febrile patients and highlight the necessity for tailored diagnostic approaches in this population.

Abstract Soil fungi are a key constituent of global biodiversity and play a pivotal role in agroecosystems. How arable farming affects soil fungal biogeography and whether it has a disproportional impact on rare taxa is poorly understood. Here, we used the high-resolution PacBio Sequel targeting the entire ITS region to investigate the distribution of soil fungi in 217 sites across a 3000 km gradient in Europe. We found a consistently lower diversity of fungi in arable lands than grasslands, with geographic locations significantly impacting fungal community structures. Prevalent fungal groups became even more abundant, whereas rare groups became fewer or absent in arable lands, suggesting a biotic homogenization due to arable farming. The rare fungal groups were narrowly distributed and more common in grasslands. Our findings suggest that rare soil fungi are disproportionally affected by arable farming, and sustainable farming practices should protect rare taxa and the ecosystem services they support.

Abstract Primordial germ cells (PGCs) are the embryonic precursors of sperm and eggs. They transmit genetic and epigenetic information across generations. Given the prominent role of germline defects in diseases such as infertility, detailed understanding of human PGC (hPGC) development has important implications in reproductive medicine and studying human evolution. Yet, hPGC specification remains an elusive process. Here, we report the induction of hPGC-like cells (hPGCLCs) in a bioengineered human pluripotent stem cell (hPSC) culture that mimics peri-implantation human development. In this culture, amniotic ectoderm-like cells (AMLCs), derived from hPSCs, induce hPGCLC specification from hPSCs through paracrine signaling downstream of ISL1. Our data further show functional roles of NODAL, WNT, and BMP signaling in hPGCLC induction. hPGCLCs are successfully derived from eight non-obstructive azoospermia (NOA) participant-derived hPSC lines using this biomimetic platform, demonstrating its promise for screening applications.

Abstract Maternal and paternal age at birth is increasing globally. Maternal age may affect perinatal outcomes, but the effect of paternal age and its joint effect with maternal age are not well established. This prospective, multicenter, cohort analysis used data from the University Hospital Advanced Age Pregnant Cohort Study in China from 2016 to 2021, to investigate the separate association of paternal age and joint association of paternal and maternal age with adverse perinatal outcomes. Of 16,114 singleton deliveries, mean paternal and maternal age (± SD) was 38.0 ± 5.3 years and 36.0 ± 4.1 years. In unadjusted analyses, older paternal age was associated with increased risks of gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy, preeclampsia, placenta accreta spectrum disorders, placenta previa, cesarean delivery (CD), and postpartum hemorrhage, preterm birth (PTB), large-for-gestational-age, macrosomia, and congenital anomaly, except for small-for-gestational-age. In multivariable analyses, the associations turned to null for most outcomes, and attenuated but still significant for GDM, CD, PTB, and macrosomia. As compare to paternal age of

Abstract Antimicrobial resistance (AMR) in food animals is a growing threat to animal health and potentially to human health. In resource-limited settings, allocating resources to address AMR can be guided with maps. Here, we mapped AMR prevalence in 7 antimicrobials in Escherichia coli and nontyphoidal Salmonella species across low- and middle-income countries (LIMCs), using 1088 point-prevalence surveys in combination with a geospatial model. Hotspots of AMR were predicted in China, India, Brazil, Chile, and part of central Asia and southeastern Africa. The highest resistance prevalence was for tetracycline (59% for E. coli and 54% for nontyphoidal Salmonella, average across LMICs) and lowest for cefotaxime (33% and 19%). We also identified the antimicrobial with the highest probability of resistance exceeding critical levels (50%) in the future (1.7–12.4 years) for each 10 × 10 km pixel on the map. In Africa and South America, 78% locations were associated with penicillins or tetracyclines crossing 50% resistance in the future. In contrast, in Asia, 77% locations were associated with penicillins or sulphonamides. Our maps highlight diverging geographic trends of AMR prevalence across antimicrobial classes, and can be used to target AMR surveillance in AMR hotspots for priority antimicrobial classes.

In Europe, systematic national surveillance of antimicrobial resistance (AMR) in food-producing animals has been conducted for decades; however, geographic distribution within countries remains unknown. To determine distribution within Europe, we combined 33,802 country-level AMR prevalence estimates with 2,849 local AMR prevalence estimates from 209 point prevalence surveys across 31 countries. We produced geospatial models of AMR prevalence in Escherichia coli, nontyphoidal Salmonella, and Campylobacter for cattle, pigs, and poultry. We summarized AMR trends by using the proportion of tested antimicrobial compounds with resistance >50% and generated predictive maps at 10 × 10 km resolution that disaggregated AMR prevalence. For E. coli, predicted prevalence rates were highest in southern Romania and southern/eastern Italy; for Salmonella, southern Hungary and central Poland; and for Campylobacter, throughout Spain. Our findings suggest that AMR distribution is heterogeneous within countries and that surveillance data from below the country level could help with prioritizing resources to reduce AMR.

Inflammatory bowel disease (IBD) is a systemic disorder affecting intestinal tract and other organs outside the gut, known as extraintestinal manifestations (EIMs). These EIMs are complex and diverse, and early treatment may reduce teratogenic rates and improve quality of life. However, our understanding of EIMs in IBD is currently limited by a lack of mechanistic insight. Fortunately, advances in our understanding of intestinal microecology are allowing us to uncover the underlying mechanisms of EIMs. The gut microbiota can drive aberrant immune activation and intestinal inflammation. Intriguingly, chronic inflammation can also shape the microbiome in reverse and aggravate dysbiosis. Recent research has revealed that microbiome-derived signal molecules play a crucial role in catalyzing enterocolitis and altering mucosal barrier function. Furthermore, gut microbiota-associated antigens can translocate from the intestine to extraintestinal sites, leading to systemic inflammatory responses. The microbiome is showing its potential in treating IBD and EIMs, and microbial engineering approaches, such as probiotic engineering and engineered fecal microbiota transplantation, are exhibiting great promise for IBD therapeutics.

Abstract FIGLA and NOBOX are important oocyte-specific transcription factors. Both figla-/- and nobox-/- mutants showed all-male phenotype in zebrafish due to increased dominance of the male-promoting pathway. The early diversion towards males in these mutants has precluded analysis of their roles in folliculogenesis. In this study, we attenuated the male-promoting pathway by deleting dmrt1, a key male-promoting gene, in figla-/- and nobox-/- fish, which allows a sufficient display of defects in folliculogenesis. Germ cells in figla-/-;dmrt1-/- double mutant remained in cysts without forming follicles. In contrast, follicles could form well but exhibited deficient growth in nobox-/-;dmrt1-/- double mutants. Follicles in nobox-/-;dmrt1-/- ovary could progress to previtellogenic (PV) stage but failed to enter vitellogenic growth. Such arrest at PV stage suggested a possible deficiency in estrogen signaling. This was supported by lines of evidence in nobox-/-;dmrt1-/-, including reduced expression of ovarian aromatase (cyp19a1a) and level of serum estradiol (E2), regressed genital papilla (female secondary sex characteristics), and more importantly the resumption of vitellogenic growth by E2 treatment. Expression analysis suggested Nobox might regulate cyp19a1a by controlling Gdf9 and/or Bmp15. Our discoveries indicate that Figla is essential for ovarian differentiation and follicle formation whereas Nobox is important for driving subsequent follicle development.

The 1500 mm-wide AZ31 magnesium alloy plate is an important material for the molding of large shell components.In the industrial rolling process, the wider the plate, the more uneven the temperature and stress distribution are in the width direction during the industrial rolling process, which results in poor mechanical properties and an uneven microstructure. In this paper, the mechanical properties and microstructure evolution along the width direction during a single-pass rolling process (6–3 mm) of this plate were qualitatively and quantitatively investigated. Additionally, a cellular automaton (CA) model was used to reproduce the grain distribution along the width direction. The result shows that there is a significant difference in the elongation of different parts of the plates along the wide direction, and the elongation of the center part is significantly higher than the edge, which is related to the uneven microstructure distribution. The average grain size from the edge to the center shows a tendency of increase and then decrease, and the degree of grain refinement has increased. The number of twins increased in the edge part, showing a typical mixed grain state with poor unevenness. Further CA shows that the average grain size and percentage of dynamic recrystallization increase and then decrease from the center to the edge. The parts 0–250 mm and 625–700 mm from the edge are fine-grained (average grain size less than 1 μm) and account for about 46 % of the plate. These parts are preferred for the subsequent further processing of rolled plates.

A quick, easy, cheap, effective, rugged and safe pre-treatment method (QuEChERS) was established to evaluate the risk of tetracycline residues in the muscle of Channa argus. The Box-Behnken design (BBD) response surface optimization method was used to optimize the extraction and purification conditions. The samples were extracted with 10 mL acetonitrile (containing 1% formic acid) and 2 mL 0.1 mol/L Na2EDTA-Mcllvaine buffer solution, and the extracts were purified by 150 mg primary secondary amine（PSA）and 200 mg C18, and detected with Ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The result showed that the calibration curve was linear in the range of 0.50~100 ng/mL, with high correlation coefficients (r≥0.999). The limits of detection (LOD) and quantification (LOQ) were 0.25～0.75 μg/kg and 0.84～2.00 μg/kg, respectively. The average recoveries of tetracycline, oxytetracycline, chlortetracycline and doxycycline at three different spiked levels in the muscle of Channa argus were 89.5%～118%, with relative standard deviations (RSDs) of 1.11%～8.88%. This method is simple, sensitive and accurate, and can be used for the rapid quantitative determination of tetracyclines in Channa argus.

Traditional Chinese medicine (TCM) has a long history and particular advantages in the diagnosis and treatment of diabetic foot gangrene (DFG). Patients with DFG are mainly divided into two subtypes, tendon lesion with edema (GT) and ischemic lesion without edema (GI), which are suitable for different medical strategies. Metabolomics has special significance in unravelling the complexities of multifactorial and multisystemic disorders. This study acquired the serum metabolomic profiles of two traditional Chinese medicine subtypes of DFG to explore potential molecular evidence for subtype characterization, which may contribute to the personalized treatment of DFG. A total of 70 participants were recruited, including 20 with DM and 50 with DFG (20 with GI and 30 with GT). Conventional gas chromatography-mass spectrometry (GC-MS) followed by orthogonal partial least-squares discriminant analysis (OPLS-DA) were used as untargeted metabolomics approaches to explore the serum metabolomic profiles. Kyoto encyclopedia of genes and genomes (KEGG) and MetaboAnalyst were used to identify the related metabolic pathways. Compared with DM patients, the levels of 14 metabolites were altered in the DFG group, which were also belonged to the differential metabolites of GI (13) and GT (7) subtypes, respectively. Among these, urea, α-D-mannose, cadaverine, glutamine, L-asparagine, D-gluconic acid, and indole could be regarded as specific potential metabolic markers for GI, as well as L-leucine for GT. In the GI subtype, D-gluconic acid and L-asparagine are positively correlated with activated partial thromboplastin time (APTT) and fibrinogen (FIB). In the GT subtype, L-leucine is positively correlated with the inflammatory marker C-reactive protein (CRP). Arginine and proline metabolism, glycine, serine and threonine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis are the most important metabolic pathways associated with GI. The main metabolic pathways related to GT include pyrimidine metabolism, glutathione metabolism, biosynthesis of valine, leucine, and isoleucine, as well as valine, serine, and isoleucine with metabolites. The results of this study indicate that patients with different DFG subtypes have distinct metabolic profiles, which reflect the pathological characteristics of each subtype respectively. These findings will help us explore therapeutic targets for DFG and develop precise treatment strategies.

Summary: Clarifying the accumulation and decomposition of soil organic carbon (SOC) is crucial for comprehending carbon cycling in terrestrial ecosystems. SOC enrichment and decomposition lead to the fractionation of stable carbon isotopes, a complex process influenced by various factors, including microbes. However, this fractionation process during early soil formation and the role of microorganisms remain poorly explored. This study investigated the relative composition of stable carbon isotopes (δ13C) of recently formed biological soil crusts (BSCs) on stabilized sand dunes in the Tengger Desert, Northern China. A notable increase in δ13C was observed during early BSC development, likely driven by cyanobacteria’s direct fixation of CO2. Yet, δ13C values of BSCs gradually declined, approaching those of soils under native vegetation, probably linked to microbial succession within the BSCs. This finding highlights the potential microbial influence on early soil carbon turnover and underscores the effectiveness of isotope tracers for studying this process.

This short communication reflects upon the challenges and recommendations of multiple COVID-19 modelling and data analytic groups that provided quantitative evidence to support health policy discussions in Switzerland and Germany during the SARS-CoV-2 pandemic.Capacity strengthening outside infectious disease emergencies will be required to enable an environment for a timely, efficient, and data-driven response to support decisions during any future infectious disease emergency.This will require 1) a critical mass of trained experts who continuously advance state-of-the-art methodological tools, 2) the establishment of structural liaisons amongst scientists and decision-makers, and 3) the foundation and management of data-sharing frameworks.

Objective To develop and conduct an initial validation of the Damage Index for IgG4-related disease (IgG4-RD DI).Methods A draft of index items for assessing organ damages in patients with IgG4-RD was generated by experts from the Chinese IgG4-RD Consortium (CIC). The preliminary DI was refined using the Delphi method, and a final version was generated by consensus. 40 IgG4-RD cases representing four types of clinical scenarios were then selected, each with two time points of assessment for at least 3 years of follow-up. 48 rheumatologists from 35 hospitals nationwide were invited to evaluate organ damage using the CIC IgG4-RD DI. The intraclass correlation coefficient (ICC) and the Kendall-W coefficient of concordance (KW) were used to assess the inter-rater reliability. The criterion validity of IgG4-RD DI was tested by calculating the sensitivity and specificity of raters.Results IgG4-RD DI is a cumulative index consisting of 14 domains of organ systems, including a total of 39 items. The IgG4-RD DI was capable of distinguishing stable and increased damage across the active disease subgroup and stable disease subgroup. In terms of scores at baseline and later observations by all raters, overall consistency in scores at baseline and later observations by all raters was satisfactory. ICC at the two time points was 0.69 and 0.70, and the KW was 0.74 and 0.73, respectively. In subgroup analysis, ICC and KW in all subgroups were over 0.55 and 0.61, respectively. The analysis of criterion validity showed a good performance with a sensitivity of 0.86 (95% CI 0.82 to 0.88), a specificity of 0.79 (95% CI 0.76 to 0.82) and an area under the curve of 0.88 (95% CI 0.85 to 0.91).Conclusion The IgG4-RD DI is a useful approach to analyse disease outcomes, and it has good operability and credibility. It is anticipated that the DI will become a useful tool for therapeutic trials and studies of prognosis in patients with IgG4-RD.

Complexities of the intestine have brought enormous controversy and discussions to the research on the digestive diseases. The neglected gas environment is crucial in shaping the dynamic intestinal microenvironment. Many gases are involved in the biological activities within the intestinal anaerobic environment, including oxygen, hydrogen, carbon monoxide, ammonia, methane, hydrogen sulfide, carbon dioxide, and nitrogen. These gases participate in the regulation of systemic inflammation and metabolism via different pathways, thereby alleviating or promoting the development of intestinal disease. Meanwhile, the constitution and changes of gases reflect the intestinal environment, which could be utilized to monitor the variation in local metabolism and imply the progress of digestive disorders. However, individual gas has intrinsic functions in maintaining a healthy intestinal microenvironment or causing digestive diseases, and the underlying mechanisms are still unclear. Therefore, exploring the profile of gases in the digestive tract and their extraordinary impact on the intestinal microenvironment will be of great value in understanding the interplay between intestinal health and diseases. By reviewing the research progress of gases in the digestive tract, we anticipate that a better understanding of the roles of gases would promote the research and application transformation in this field as well as the diagnostics and treatment of clinical diseases.

ABSTRACTThe tensile and shear mechanical properties of laver were investigated in order to reduce the tensile and shear forces, tensile and shear energies consumption during the harvesting and processing. Loading rate, harvest time and origin were selected as the effect factors for laver tensile and shear tests, while mathematical models of the variation of tensile and shear mechanical properties with three factors were also developed. The following results were obtained: tensile force, shear force, tensile energy and shear energy of laver are affected by loading rate, harvest time and origin. Tensile force, shear force and shear energy were generally inversely proportional to the loading rate, while tensile energy was generally positively proportional to the loading rate. The minimum values are 0.0557 N, 0.1650 N, 0.7267 N.mm and 0.7393 N.mm, respectively. Tensile force, shear force and tensile energy all increased with increasing harvest time, while shear energy decreased with increasing harvest time. The maximum values are 0.1581 N, 0.4437 N, 1.5367 N.mm and 1.5177 N.mm, respectively. Both tensile and shear forces (0.0857 N, 0.2549 N) were greatest in Dalian for the first harvest of laver. However, the first harvest of Qingdao laver has the lowest tensile and shear energy. The microstructure after stretching and shearing changed significantly with normally shaped cells deformed and ruptured. The changes in microstructure were consistent with the macro-mechanical properties, verifying the reliability of the test data.

Influenza A virus (IAV) infection often leads to influenza-associated fatalities, frequently compounded by subsequent bacterial infections, particularly Gram-negative bacterial co-infections. Lipopolysaccharide (LPS), a primary virulence factor in Gram-negative bacteria, plays a crucial role in influenza–bacterial co-infections. However, the precise pathogenic mechanisms underlying the synergistic effects of viral–bacterial co-infections remain elusive, posing significant challenges for disease management. In our study, we administered a combination of IAV and LPS to mice and examined associated parameters, including the lung function, lung index, wet/dry ratio, serum inflammatory cytokines, Nedd4L expression in lung tissue, and mRNA levels of inflammatory cytokines. Co-infection with IAV and LPS exacerbated lung tissue inflammation and amplified M1 macrophage expression in lung tissue. Additionally, we stimulated macrophages with IAV and LPS in vitro, assessing the inflammatory cytokine content in the cell supernatant and cytokine mRNA expression within the cells. This combined stimulation intensified the inflammatory response in macrophages and upregulated Nedd4L protein and mRNA expression. Subsequently, we used siRNA to knockdown Nedd4L in macrophages, revealing that suppression of Nedd4L expression alleviated the inflammatory response triggered by concurrent IAV and LPS stimulation. Collectively, these results highlight the pivotal role of Nedd4L in mediating the exacerbated inflammatory responses observed in IAV and LPS co-infections.

Abstract Background Prostate cancer (PC) is the most common neoplasm and is the second leading cause of cancer-related deaths in men worldwide. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. YAP is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal YAP expression in PC remains to be characterized. Methods Western blot was used to measure the protein expression of ATXN3 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; transwell invasion assay was used to measure the invasion ability of PC. The xeno-graft tumor model was used for in vivo study. Protein stability assay was used to detect YAP protein degradation. Immuno-precipitation assay was used to detect the interaction domain between YAP and ATXN3. The ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. Results In the present study, we identified ATXN3, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of YAP in PC. ATXN3 was shown to interact with, deubiquitylate, and stabilize YAP in a deubiquitylation activity-dependent manner. Depletion of ATXN3 decreased the YAP protein level and the expression of YAP/TEAD target genes in PC, including CTGF, ANKRD1 and CYR61. Further mechanistic study revealed that the Josephin domain of ATXN3 interacted with the WW domain of YAP. ATXN3 stabilized YAP protein via inhibiting K48-specific poly-ubiquitination process on YAP protein. In addition, ATXN3 depletion significantly decreased PC cell proliferation, invasion and stem-like properties. The effects induced by ATXN3 depletion could be rescued by further YAP overexpression. Conclusions In general, our findings establish a previously undocumented catalytic role for ATXN3 as a deubiquitinating enzyme of YAP and provides a possible target for the therapy of PC. Video Abstract

Abstract The regulation of neural stem cell (NSC) proliferation and differentiation during brain development is a precisely controlled process, with the production of different neuronal subtypes governed by strict timelines. Glutamate is predominantly used as a neurotransmitter by the subtypes of neurons in the various layers of the cerebral cortex. The expression pattern of BCAT1, a gene involved in glutamate metabolism, in the different layers of neurons has yet to be fully understood. Using single-cell data, we have identified seven different states of NSCs and found that state 4 is closely associated with the development of projection neurons. By inferring the developmental trajectory of different neuronal subtypes from NSC subsets of this state, we discovered that BCAT1 is involved in the regulation of NSC proliferation and differentiation and is specifically highly expressed in layer II/III and IV neurons. Suppression of BCAT1 through shRNA resulted in a reduction in NSC proliferation and an abnormal development of layer II/III and IV neurons. These findings provide new insights into the role of BCAT1 in the regulation of NSC behavior and neuronal development.

Abstract A widely used approach for protein conjugation is through the lysine residues reacting with NHS- or other active esters. However, it is a challenge to precisely control the degree of labeling (DoL) due to the instability of active ester and variability of reaction efficiencies. Here, we provide a protocol for better control of aDoL using existing Copper-free Click Chemistry reagents. It is a two-step reaction with one purification in between. Briefly, proteins of interest were first activated with azide-NHS. After removing unreacted azide-NHS, the protein-N3 is then reacted with a limited amount of complementary click tag. Our studies have shown the click tag will fully react with the protein-N3 after 24 h’ incubation, and therefore does not require additional purification steps. As such, the aDoL is equal to the input molar ratio of the click tag and the protein. Furthermore, this approach offers a much simpler and more economical way to perform parallel microscale labeling. Once a protein is pre-activated with N3-NHS, any fluorophore or molecule with the complementary click tag can be attached to the protein by mixing the two ingredients. Quantities of the protein used in the click reaction can be at any desired amount. In one example, we labeled an antibody in parallel with 9 different fluorophores using a total of 0.5 mg of antibody. In another example, we labeled Ab with targeted aDoL value from 2 to 8. In a stability comparison study, we have found the conjugated fluorophore using the suggested click protocol stayed attached to the protein longer than with standard NHS-fluorophore labeling.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex etiology. The main neuropathological feature is the accumulation of amyloid-beta (Aβ), and the dysregulation of the cholinergic system is well associated with its mechanism of occurrence, for which no effective treatment is yet available. Daily oral administration remains the mainstay of treatment with AD, and how to improve the efficacy, prolong adsorption and medication compliance is still the focus of the current solution. We proposed a microcapsule based on microfluidic electrospray to form an intestinal epithelial lining for AD treatment, reducing the frequency of administration. Microfluidic electrospray technology was recruited to overcome the limitations associated with the variability in the microencapsulation production process and to produce functional microcapsules with finely adapted chemical composition, capsule thickness and encapsulant volume ratio. These microcapsules could slowly release drugs after adhering to the intestine, and their effectiveness and safety were further evaluated using cell culture studies and animal model studies. The results from the in vivo and in vitro experiments showed a significant reduction in administration frequency (i.e., from daily medication to once every five days), superior therapeutic efficacy and sufficient safety of these microcapsules in cell culture and APP/PS1 mice. These features make the microcapsules an excellent drug delivery system and represent great potential for clinical applications in AD.

Based on the research background of Shandong Lilou Coal Mine, this paper used methods such as on-site investigation, engineering comparison, and on-site monitoring to research on the high-energy events that have occurred in Lilou Coal Mine since 2020, and drew the following conclusions: ①Systematically analyzed the relationship between four influencing factors and high-energy microseismic events including the distribution of abutment pressure, working face “square”, crossing faults, and mining speed, and searched the causes of large energy events. The mining influence range of No.1302 (top) working face is about 30 m behind the face to 170 m in front, and the advanced stress peak is about 70 m in front. The lateral microseismic events are mainly distributed along the gob-side entry, and the whole is offset to the side of the goaf. The distribution of microseismic events at No.1303 working face in the advancing direction of the working face ranges from 15 m behind the face to 200 m in front of the face, and the advanced stress peak is about 80 m in front of the face. The microseismic event at the No.1303 working face is bimodal in the lateral distribution pattern, shifting to the belt grooves. Affected by the wide coal pillar, the stress concentration on the belt grooves is higher than that on the track tunnel. The frequency and energy of microseismic events gradually increased before the “square” of the work face, and stabilized after the “square”. Before crossing the fault, the microseismic events gradually increased, decreased sharply during the crossing, and gradually stabilized after crossing the fault. The peak position of the event was about 40 m in front of the “square” or before the fault. When the mining speed of 1302 (top) working face is 50 m/month and the 1303 working face is 60 m/month, the frequency and energy are the largest. ②By analyzing the inducing factors and locations of large-energy events, large-energy events can be divided into three categories: “energy accumulation type” high-energy events, “fault activation type” high-energy events, and “island structure type” high-energy events, and put forward specific prevention and control measures for different types. The research in this article will provide reference for surrounding mines with similar geological factors and mining technical conditions.

Abstract Background Avascular necrosis is a common organ damage in SLE patients, which can influence patients’ life quality. Conflicting results exist in risk factors of AVN in SLE patients. The aim of this study was to illustrate risk factors predicting the occurrence of avascular necrosis (AVN), also known as osteonecrosis, in systemic lupus erythematosus (SLE) patients in Chinese SLE Treatment and Research Group (CSTAR), a multi-center cohort of Chinese SLE patients. Methods SLE patients in CSTAR without existing AVN at registration were included. At least two follow-ups and an observation period of no less than 2 years for AVN event were required. Univariate and multivariate Cox regression analyses were used to evaluate risk factors for AVN in SLE patients. Coefficient B was transformed to risk score for the development of a risk stratification model. Results One hundred six (2.59%) of 4091 SLE patients were diagnosed AVN during follow-ups of no less than 2 years. Multi-variate Cox regression analysis suggested that SLE onset age ≤ 30 (HR 1.616, p 0.023), arthritis (HR 1.642, p 0.018), existing organ damage (SDI ≥ 1) at registration (HR 2.610, p

Abstract BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer‐associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane‐coated liposomes is proposed for specific drug precise target to CAFs‐rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti‐fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs‐targeting liposomal delivery system in pancreatic cancer.

ObjectiveSystemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis. The challenge of early diagnosis, along with the lack of effective treatments for fibrosis, contribute to poor therapeutic outcomes and high mortality of SSc. Therefore, there is an urgent need to identify suitable biomarkers for early diagnosis of SSc.MethodsThree skin gene expression datasets of SSc patients and healthy controls were downloaded from Gene Expression Omnibus (GEO) database (GSE130955, GSE58095, and GSE181549). GSE130955 (48 early diffuse cutaneous SSc and 33 controls) were utilized to screen differentially expressed genes (DEGs) between SSc and normal skin samples. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine recursive feature elimination (SVM-RFE) were performed to identify diagnostic genes and construct a diagnostic prediction model. The results were further validated in GSE58095 (61 SSc and 36 controls) and GSE181549 (113 SSc and 44 controls) datasets. Receiver operating characteristic (ROC) curves were applied for assessing the level of diagnostic ability. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to verify the diagnostic genes in skin tissues of out cohort (10 SSc and 5 controls). Immune infiltration analysis were performed using CIBERSORT algorithm.ResultsA total of 200 DEGs were identified between SSc and normal skin samples. Functional enrichment analysis revealed that these DEGs may be involved in the pathogenesis of SSc, such as extracellular matrix remodeling, cell-cell interactions, and metabolism. Subsequently, two critical genes (ENHO and NOX4) were identified by LASSO and SVM-RFE. ENHO was found down-regulated while NOX4 was up-regulated in skin of SSc patients and their expression levels were validated by above three datasets and our cohort. Notably, these differential expressions were more pronounced in patients with diffuse cutaneous SSc than in those with limited cutaneous SSc. Next, we developed a novel diagnostic model for SSc using ENHO and NOX4, which demonstrated strong predictive power in above three cohorts and in our own cohort. Furthermore, immune infiltration analysis revealed dysregulated levels of various immune cell subtypes within early SSc skin specimens, and a negative correlation was observed between the levels of ENHO and Macrophages M1 and M2, while a positive correlation was observed between the levels of NOX4 and Macrophages M1 and M2.ConclusionThis study identified ENHO and NOX4 as novel biomarkers that can be serve as a diagnostic prediction model for early detection of SSc and play a potential role in the pathogenesis of the disease.

ObjectiveSystemic sclerosis (SSc) is a chronic systemic disease characterized by immune dysregulation and fibrosis for which there is no effective treatment. Animal models are crucial for advancing SSc research. Tree shrews are genetically, anatomically, and immunologically closer to humans than rodents. Thus, the tree shrew model provides a unique opportunity for translational research in SSc.MethodsIn this study, a SSc tree shrew model was constructed by subcutaneous injection of different doses of bleomycin (BLM) for 21 days. We assessed the degree of inflammation and fibrosis in the skin and internal organs, and antibodies in serum. Furthermore, RNA sequencing and a series of bioinformatics analyses were performed to analyze the transcriptome changes, hub genes and immune infiltration in the skin tissues of BLM induced SSc tree shrew models. Multiple sequence alignment was utilized to analyze the conservation of selected target genes across multiple species.ResultsSubcutaneous injection of BLM successfully induced a SSc model in tree shrew. This model exhibited inflammation and fibrosis in skin and lung, and some developed esophageal fibrosis and secrum autoantibodies including antinuclear antibodies and anti-scleroderma-70 antibody. Using RNA sequencing, we compiled skin transcriptome profiles in SSc tree shrew models. 90 differentially expressed genes (DEGs) were identified, which were mainly enriched in the PPAR signaling pathway, tyrosine metabolic pathway, p53 signaling pathway, ECM receptor interaction and glutathione metabolism, all of which are closely associated with SSc. Immune infiltration analysis identified 20 different types of immune cells infiltrating the skin of the BLM-induced SSc tree shrew models and correlations between those immune cells. By constructing a protein-protein interaction (PPI) network, we identified 10 hub genes that were significantly highly expressed in the skin of the SSc models compared to controls. Furthermore, these genes were confirmed to be highly conserved in tree shrews, humans and mice.ConclusionThis study for the first time comfirmed that tree shrew model of SSc can be used as a novel and promising experimental animal model to study the pathogenesis and translational research in SSc.