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Abstract Timely and effective interventions after tracheal mucosal injury are lack in clinical practices, which elevate the risks of airway infection, tracheal cartilage deterioration, and even asphyxiated death. Herein, we proposed a biomaterial-based strategy for the repair of injured tracheal mucosal based on a copper hydrogen phosphate nanosheets (CuHP NSs) functionalized commercial hydrogel (polyethylene glycol disuccinimidyl succinate-human serum albumin, PH). Such CuHP/PH hydrogel achieved favorable injectability, stable gelation, and excellent adhesiveness within the tracheal lumen. Moreover, CuHP NSs within the CuHP/PH hydrogel effectively stimulate the proliferation and migration of endothelial/epithelial cells, enhancing angiogenesis and demonstrating excellent tissue regenerative potential. Additionally, it exhibited significant inhibitory effects on both bacteria and bacterial biofilms. More importantly, when injected injured site of tracheal mucosa under fiberoptic bronchoscopy guidance, our results demonstrated CuHP/PH hydrogel adhered tightly to the tracheal mucosa. The therapeutic effects of the CuHP/PH hydrogel were further confirmed, which significantly improved survival rates, vascular and mucosal regeneration, reduced occurrences of intraluminal infections, tracheal stenosis, and cartilage damage complications. This research presents an initial proposition outlining a strategy employing biomaterials to mitigate tracheal mucosal injury, offering novel perspectives on the treatment of mucosal injuries and other tracheal diseases.

Background: Long-term physical inactivity probably leads to a co-existence of osteoporosis and sarcopenia which result in a high risk of falls, fractures, disability and even mortality. However, universally applicable and feasible approaches are lacking in the concurrent treatment of osteoporosis and sarcopenia. In this study, we evaluated the effect of strontium zinc silicate bioceramic (SZS) extract on osteoporosis and sarcopenia and explored its underlying mechanisms. Methods: Hindlimb osteoporosis and sarcopenia were established in a tail-suspended rat model. The bones were conducted μCT scanning, histological examination, and gene expression analysis, and the muscles were conducted histological examination and gene expression analysis. In vitro, the effect of SZS extract on osteoblasts was determined by alizarin red S staining, immunofluorescence and qPCR. Similarly, the effect of SZS extract on myoblasts was determined by immunofluorescence and qPCR.. At last, the role of Piezo1 and the change of intracellular calcium ion (Ca2+) were explored through blockading the Piezo1 by GsMTx4 in MC3T3-E1 and C2C12 cells, respectively. Results: We found that SZS extract could concurrently and efficiently prevent bone structure deterioration, muscle atrophy and fibrosis in hind limbs of the tail-suspended rats. The in vivo study also showed that SZS extract could upregulate the mRNA expression of Piezo1, thereby maintaining the homeostasis of bones and muscles. In vitro study demonstrated that SZS extract could promote the proliferation and differentiation of MC3T3-E1 and C2C12 cells by increasing the intracellular Ca2+ in a Piezo1-dependent manner. Conclusion: This study demonstrated that SZS extract could increase Piezo1-mediated intracellular Ca2+, and facilitate osteogenic differentiation of osteoblast and myogenic differentiation of myoblasts, contributing to alleviation of osteoporosis and sarcopenia in a tail-suspended rat model. The translational potential of this article: The current study might provide a universally applicable and efficient strategy to treat musculoskeletal disorders based on bioactive ceramics. The verification of the role of Piezo1-modulated intracellular Ca2+ during osteogenesis and myogenesis provided a possible therapeutic target against mechanical related diseases.

Abstract Silicate bioceramics have demonstrated great potential in hydrogel dressings for wound healing due to their special origins of promoting endothelial cell angiogenesis and inhibiting apoptosis of cardiomyocyte. However, there are still some deficiencies, such as insufficient biological activity, instability of silicate ion release, and lower wet adhesion on wounds with tissue exudate, limiting their further clinical applications. Herein, inspired by mussels, a multifunctional double-network hydrogel (FS/PAM-Gel-PDA) wound dressing composited gelatin with silicate ceramic powder with satisfactory wet adhesion, stable release of bioactive ions, hemostasis, and the ability of promoting vascular regeneration was engineered through specifically grafting dopamine to gelatin and introducing ferrous silicate ceramic powder into the hydrogel. The comprehensive experimental results substantiate that the FS/PAM-Gel-PDA has wet-adhesion strength of up to 21.78 kPa, and remains stably adherent to porcine myocardial tissues intuitively after bending, twisting, soaking in water, and stretching. The test results of ion release behavior in vitro show that the oxidation and agglomeration of ferrous silicate ceramic powder can be effectively inhibited by using dopamine to form an antioxidant layer on the surface of ceramic powder, and thus, the stable release of Fe2+ and SiO4 4− effective ions can be realized. The animal experiment exhibits that FS/PAM-Gel-PDA can achieve rapid hemostasis in the lethal liver defect model. Meanwhile, the FS/PAM-Gel-PDA reveals the remarkable ability to promote wound healing in a full-thickness skin injury model, which can obviously accelerate skin re-epithelialization. To sum up, the FS/PAM-Gel-PDA has excellent wet adhesion and stable release of active ions to accelerate angiogenesis, which shows great potential in promoting wound healing. Graphical Abstract

Abstract Inspired by the scar‐free wound healing in infants, an anti‐scar strategy is proposed by accelerating wound healing using silicate bioactive materials. Bioglass/alginate composite hydrogels are applied, which significantly inhibit scar formation in rabbit ear scar models. The underlining mechanisms include stimulation of Integrin Subunit Alpha 2 expression in dermal fibroblasts to accelerate wound healing, and induction of apoptosis of hypertrophic scar fibroblasts by directly stimulating the N‐Acylsphingosine Amidohydrolase 2 expression in hypertrophic scar fibroblasts, and indirectly upregulating the secretion of Cathepsin K in dermal fibroblasts. Considering specific functions of the bioactive silicate materials, two scar treatment regimes are tested. For severe scars, a regenerative intervention is applied by surgical removal of the scar followed by the treatment with bioactive hydrogels to reduce the formation of scars by activating dermal fibroblasts. For mild scars, the bioactive dressing is applied on the formed scar and reduces scar by inducing scar fibroblasts apoptosis.

Marine protected areas (MPAs) across various countries have contributed to safeguarding coastal and marine environments. Despite these efforts, marine non-native species (NNS) continue to threaten biodiversity and ecosystems, even within MPAs. Currently, there is a lack of comprehensive studies on the inventories, distribution patterns, and effect factors of NNS within MPAs. Here we show a database containing over 15,000 occurrence records of 2714 marine NNS across 16,401 national or regional MPAs worldwide. To identify the primary mechanisms driving the occurrence of NNS, we utilize model selection with proxies representing colonization pressure, environmental variables, and MPA characteristics. Among the environmental predictors analyzed, sea surface temperature emerged as the sole factor strongly associated with NNS richness. Higher sea surface temperatures are linked to increased NNS richness, aligning with global marine biodiversity trends. Furthermore, human activities help species overcome geographical barriers and migration constraints. Consequently, this influences the distribution patterns of marine introduced species and associated environmental factors. As global climate change continues to alter sea temperatures, it is crucial to protect marine regions that are increasingly vulnerable to intense human activities and biological invasions.

In light of the clinical challenges posed by bacterial infection and vascular damage in chronic diabetic wounds, this study presents a novel bioactive copper vanadate-based hydrogel (CVH) with multiple functions including the sustained release of copper and vanadium ions, photocatalytic activity under visible (VIS) light, and photothermal ability under near-infrared (NIR) light. In vitro experiments demonstrated that CVH effectively repairs high glucose-impaired human umbilical vein endothelial cells (HUVECs) and exhibits potent antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Furthermore, the dual biological functions are augmented by the NIR-light-induced mild photothermal effect, demonstrating a synergistic effect. The infected diabetic wound model further substantiates the therapeutic efficacy of the CVH dressing in eliminating bacteria and promoting angiogenesis under VIS/NIR light irradiation. Collectively, the CVH dressing demonstrates significant potential as a therapeutic intervention for managing chronic diabetic wounds.

Abstract Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients’ prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co‐activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR‐3191‐5p. As a result, ADGRB1 prevents MDM2‐mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti‐tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.

Background The development and progression of colorectal cancer (CRC) are influenced by the gut environment, much of which is modulated by microbial-derived metabolites. Although some research has been conducted on the gut microbiota, there have been limited empirical investigations on the role of the microbial-derived metabolites in CRC.Methods In this study, we used LC-MS and 16S rRNA sequencing to identify gut microbiome-associated fecal metabolites in patients with CRC and healthy controls. Moreover, we examined the effects of Faecalibacterium prausnitzii and tyrosol on CRC by establishing orthotopic and subcutaneous tumor mouse models. Additionally, we conducted in vitro experiments to investigate the mechanism through which tyrosol inhibits tumor cell growth.Results Our study revealed changes in the gut microbiome and metabolome that are linked to CRC. We observed that Faecalibacterium prausnitzii, a bacterium known for its multiple anti-CRC properties, is significantly more abundant in the intestines of healthy individuals than in those of individuals with CRC. In mouse tumor models, our study illustrated that Faecalibacterium prausnitzii has the ability to inhibit tumor growth by reducing inflammatory responses and enhancing tumor immunity. Additionally, research investigating the relationship between CRC-associated features and microbe–metabolite interactions revealed a correlation between Faecalibacterium prausnitzii and tyrosol, both of which are less abundant in the intestines of tumor patients. Tyrosol demonstrated antitumor activity in vivo and specifically targeted CRC cells without affecting intestinal epithelial cells in cell experiments. Moreover, tyrosol treatment effectively reduced the levels of reactive oxygen species (ROS) and inflammatory cytokines in MC38 cells. Western blot analysis further revealed that tyrosol inhibited the activation of the NF-κB and HIF-1 signaling pathways.Conclusions This study investigated the relationship between CRC development and changes in the gut microbiota and microbial-derived metabolites. Specifically, the intestinal metabolite tyrosol exhibits antitumor effects by inhibiting HIF-1α/NF-κB signaling pathway activation, leading to a reduction in the levels of ROS and inflammatory factors. These findings indicate that manipulating the gut microbiota and its metabolites could be a promising approach for preventing and treating CRC and could provide insights for the development of anticancer drugs.

Abstract With the increased use of data-driven approaches and machine learning-based methods in material science, the importance of reliable uncertainty quantification (UQ) of the predicted variables for informed decision-making cannot be overstated. UQ in material property prediction poses unique challenges, including multi-scale and multi-physics nature of materials, intricate interactions between numerous factors, limited availability of large curated datasets, etc. In this work, we introduce a physics-informed Bayesian Neural Networks (BNNs) approach for UQ, which integrates knowledge from governing laws in materials to guide the models toward physically consistent predictions. To evaluate the approach, we present case studies for predicting the creep rupture life of steel alloys. Experimental validation with three datasets of creep tests demonstrates that this method produces point predictions and uncertainty estimations that are competitive or exceed the performance of conventional UQ methods such as Gaussian Process Regression. Additionally, we evaluate the suitability of employing UQ in an active learning scenario and report competitive performance. The most promising framework for creep life prediction is BNNs based on Markov Chain Monte Carlo approximation of the posterior distribution of network parameters, as it provided more reliable results in comparison to BNNs based on variational inference approximation or related NNs with probabilistic outputs.

In order to study the evolution of fracture permeability under shear action, a Weierstrass random fractal function was used in Comsol to generate a single fracture, and the relative displacements of two fracture surfaces were adjusted to simulate shear action. Changes of fracture width under different shear displacements and the defined range of nonlinear effects under different flow rates were analyzed, the factors affecting fracture permeability in shear process were determined by using scatter plot and function curve fitting, and the quantitative relationship was given. The results show that the probability density distribution of the gap width meets the standard Gaussian distribution without shearing, but with the shearing process, the Gaussian distribution of the gap width is destroyed and only reflects parts of the characteristics of the standard Gaussian distribution. When the shear occurs, the permeability first has a decreasing process, and then fluctuate within a certain range. The smaller aperture is unfavorable to the water flow through near the contact area. When Re>9.6, the fluid begins to develop from linear to nonlinear. The influence of fracture aperture on fluid seepage characteristics during shear deformation of single fracture of rock is simulated, which provides some reference for analyzing the geothermal change caused by fracture deformation in geological bodies.

Abstract Background Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear. Methods RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events. Results RBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the C2H2-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced β-catenin signaling, which promoted CCA progression. Conclusions Our results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/β-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

Abstract Background Ulcerative colitisis (UC) classified as a form of inflammatory bowel diseases (IBD) characterized by chronic, nonspecific, and recurrent symptoms with a poor prognosis. Common clinical manifestations of UC include diarrhea, fecal bleeding, and abdominal pain. Even though anti-inflammatory drugs can help alleviate symptoms of IBD, their long-term use is limited due to potential side effects. Therefore, alternative approaches for the treatment and prevention of inflammation in UC are crucial. Methods This study investigated the synergistic mechanism of Lactobacillus plantarum SC-5 (SC-5) and tyrosol (TY) combination (TS) in murine colitis, specifically exploring their regulatory activity on the dextran sulfate sodium (DSS)-induced inflammatory pathways (NF-κB and MAPK) and key molecular targets (tight junction protein). The effectiveness of 1 week of treatment with SC-5, TY, or TS was evaluated in a DSS-induced colitis mice model by assessing colitis morbidity and colonic mucosal injury (n = 9). To validate these findings, fecal microbiota transplantation (FMT) was performed by inoculating DSS-treated mice with the microbiota of TS-administered mice (n = 9). Results The results demonstrated that all three treatments effectively reduced colitis morbidity and protected against DSS-induced UC. The combination treatment, TS, exhibited inhibitory effects on the DSS-induced activation of mitogen-activated protein kinase (MAPK) and negatively regulated NF-κB. Furthermore, TS maintained the integrity of the tight junction (TJ) structure by regulating the expression of zona-occludin-1 (ZO-1), Occludin, and Claudin-3 (p

This study aimed to develop an “environment-psychological” safety assessment model for urban villages. The objective was to create a comprehensive safety evaluation and identify key influencing factors. To start, establish a spatial environmental safety assessment system for urban villages, drawing on the six principles of Crime Prevention Through Environmental Design (CPTED) theory. Use Analytic Hierarchy Process and Bayesian network analysis for determining weights and scores. The research findings reveal that: 1) The safety of the spatial environment in urban villages is directly induced by factors such as “natural surveillance” and “image maintenance” while being indirectly impacted by factors like “territoriality” and “access control.” Notably, the effects of activity support and target hardening on spatial environmental safety are found to be insubstantial. 2) Z urban village in Xuzhou city has a level IV spatial environmental safety rating. Factors include line-of-sight transparency, environmental hygiene, and road layout. The proposed optimization measures include improving space layout, enhancing surveillance levels, and maintaining a favorable environment for crime prevention. This study aids decision-makers in establishing priority sequences for spatial planning during urban village renewal. The “Environment-Psychology” model enhances the explanatory power of environmental factors on psychological elements and can aid in spatial optimization strategies.

Abstract About one third of vascular plants develop glandular trichomes, which produce defensive compounds that repel herbivores and act as a natural biofactory for important pharmaceuticals such as artemisinin and cannabinoids. However, only a few regulators of glandular structures have been characterized so far. Here we have identified two closely-related MYB-like genes that redundantly inhibit the formation of glandular cells in tomatoes, and they are named as GLAND CELL REPRESSOR (GCR) 1 and 2. The GCR genes highly express in the apical cells of tomato trichomes, with expression gradually diminishing as the cells transition into glands. The spatiotemporal expression of GCR genes is coordinated by a two-step inhibition process mediated by SlTOE1B and GCRs. Furthermore, we demonstrate that the GCR genes act by suppressing Leafless (LFS), a gene that promotes gland formation. Intriguingly, homologous GCR genes from tobacco and petunia also inhibit gland formation, suggesting that the GCR-mediated repression mechanism likely represents a conserved regulatory pathway for glands across different plant species.

Unsupervised learning algorithms can effectively solve sample imbalance. To address battery consistency anomalies in new energy vehicles, we adopt a variety of unsupervised learning algorithms to evaluate and predict the battery consistency of three vehicles using charging fragment data from actual operating conditions. We extract battery-related features, such as the mean of maximum difference, standard deviation, and entropy of batteries and then apply principal component analysis to reduce the dimensionality and record the amount of preserved information. We then build models through a collection of unsupervised learning algorithms for the anomaly detection of cell consistency faults. We also determine whether unsupervised and supervised learning algorithms can address the battery consistency problem and document the parameter tuning process. In addition, we compare the prediction effectiveness of charging and discharging features modeled individually and in combination, determine the choice of charging and discharging features to be modeled in combination, and visualize the multidimensional data for fault detection. Experimental results show that the unsupervised learning algorithm is effective in visualizing and predicting vehicle core conformance faults, and can accurately predict faults in real time. The “distance+boxplot” algorithm shows the best performance with a prediction accuracy of 80%, a recall rate of 100%, and an F1 of 0.89. The proposed approach can be applied to monitor battery consistency faults in real time and reduce the possibility of disasters arising from consistency faults.

Microplastics (MPs), emerging as significant pollutants, have been consistently detected in aquatic environments, with the Yangtze River experiencing a particularly severe level of microplastic pollution, exceeding all other watersheds in China. Polypropylene (PP), the plastic most abundantly found in the middle and lower reaches of the Yangtze River Basin, has less comprehensive research results into its toxic effects. Consequently, the present investigation employed zebrafish as a model organism to delve into the toxicological impacts of polypropylene microplastics (PP-MPs) with a diameter of 5 μm across varying concentrations (300 mg/L and 600 mg/L). Using histopathological, microbiota profiling, and transcriptomic approaches, we systematically evaluated the impact of PP-MPs exposure on the intestine and liver of zebrafish. Histopathological analysis revealed that exposure to PP-MPs resulted in thinner intestinal walls, damaged intestinal mucosa, and hepatic cellular damage. Intestinal microbiota profiling demonstrated that, the richness, uniformity, diversity, and homogeneity of gut microbes significantly increased after the PP-MPs exposure at high concentration. These alterations were accompanied by shifts in the relative abundance of microbiota associated with intestinal pathologies, suggesting a profound impact on the intestinal microbial community structure. Concurrently, hepatic transcriptome analysis and RT-qPCR indicated that the downregulation of pathways and genes associated with cell proliferation regulation and DNA damage repair mechanisms contributed to hepatic cellular damage, ultimately exerting adverse effects on the liver. Correlation analysis between the intestinal microbiota and liver transcriptome profiles further highlighted significant associations between intestinal microbiota and the downregulated hepatic pathways. Collectively, these results provide novel insights into the subacute toxicological mechanisms of PP-MPs in aquatic organisms and highlight the need for further research on the ecological and health risks associated with PP-MPs pollution.

Abstract Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an “ion cocktail therapy” is proposed to simultaneously reverse cardiac structural and electrical remodeling post‐MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post‐MI by ameliorating infarct size, promoting angiogenesis in both peri‐infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination.

Regenerating skin nerves in deep burn wounds poses a significant clinical challenge. In this study, we designed an electrospun wound dressing called CuCS/Cur, which incorporates copper-doped calcium silicate (CuCS) and curcumin (Cur). The unique wound dressing releases a bioactive Cu2+-Cur chelate that plays a crucial role in addressing this challenge. By rebuilding the “factory” (hair follicle) responsible for producing nerve cells, CuCS/Cur induces a high expression of nerve-related factors within the hair follicle cells and promotes an abundant source of nerves for burn wounds. Moreover, the Cu2+-Cur chelate activates the differentiation of nerve cells into a mature nerve cell network, thereby efficiently promoting the reconstruction of the neural network in burn wounds. Additionally, the Cu2+-Cur chelate significantly stimulates angiogenesis in the burn area, ensuring ample nutrients for burn wound repair, hair follicle regeneration, and nerve regeneration. This study confirms the crucial role of chelation synergy between bioactive ions and flavonoids in promoting the regeneration of neuralized skin through wound dressings, providing valuable insights for the development of new biomaterials aimed at enhancing neural repair.

In the era of urbanization, the imperative to safeguard ecological security and navigate toward sustainable development is paramount. The emergence of remote sensing technologies has unveiled a nuanced approach to understanding and refining regional ecological networks, which are crucial for achieving these objectives. However, in constructing regional ecological networks, the spatial integration of ecological supply and demand frequently goes unaddressed. The balance of supply and demand for ecosystem services is a complex challenge. In addition, there is an absence of comprehensive effectiveness assessment for regional ecological networks constructed based on element evaluation. To address these challenges, this study focuses on the highly urbanized Xuzhou metropolitan area (XMA) in eastern China, utilizing remote sensing data to develop an ecological network focused on balancing ecological supply and demand. The study adeptly applies complex network theory to model the ecological network, analyzing its structure and function to propose thorough and specific optimization strategies. The results indicate that the ecological network in the XMA encompasses 20 ecological supply sources, 21 demand sources, and various corridors and nodes, displaying a “dense in the center, sparse on the periphery” spider-web-like distribution. After postoptimization, the network integrates further stepping stones and corridors, evolving into a denser and more intricate structure. The study emphasizes the significance of constructing regional ecological networks based on ecological supply and demand, aiding the balance of ecosystem services in urbanized areas. It highlights the transformative potential of complex network models in ecological network optimization, facilitating effective ecosystem management and spatial planning.

AbstractBackground The epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce. The study aimed to prospectively assess the interactions and joint effects of birthweight and genetic risk levels on gastrointestinal cancer incidence in adulthood.Methods A total of 254,997 participants were included in the UK Biobank study. We used multivariate restricted cubic splines and Cox regression models to estimate the hazard ratios (HRs) and 95% confidential intervals (CI) for the association between birthweight and gastrointestinal cancer risk, then constructed a polygenic risk score (PRS) to assess its interaction and joint effect with birthweight on the development of gastrointestinal cancer.Results We documented 2512 incident cases during a median follow-up of 8.88 years. Compare with participants reporting a normal birthweight (2.5–4.5 kg), multivariable-adjusted HR of gastrointestinal cancer incidence for participants with high birthweight (≥4.5 kg) was 1.17 (95%CI: 1.01–1.36). Such association was remarkably observed in pancreatic cancer, with an HR of 1.82 (95%CI: 1.26–2.64). No statistically significant association was observed between low birth weight and gastrointestinal cancers. Participants with high birthweight and high PRS had the highest risk of gastrointestinal cancer (HR: 2.95, 95%CI: 2.19–3.96).Conclusion Our findings highlight that high birthweight is associated with a higher incidence of gastrointestinal cancer, especially for pancreatic cancer. Benefits would be obtained from birthweight control, particularly for individuals with a high genetic risk.KEY MESSAGESThe epidemiologic studies investigating the association of birthweight and genetic factors with gastrointestinal cancer remain scarce.This cohort study of 254,997 adults in the United Kingdom found an association of high birthweight with the incidence of gastrointestinal cancer, especially for pancreatic cancer, and also found that participants with high birthweight and high polygenic risk score had the highest risk of gastrointestinal cancer.Our data suggests a possible effect of in utero or early life exposures on adulthood gastrointestinal cancer, especially for those with a high genetic risk.

The aim of the present work is to evaluate the effect of ultrafast heating on the microstructure and mechanical properties of hot forming steel. The initial microstructure utilized in this study was a cold-rolled microstructure, and the test steel was heated to full austenitization at a rate of 200 °C/s, followed by water quenching. It was observed that the ultrafast heating process significantly refines both the prior austenite grains and martensite laths while inheriting high-density dislocations from the initial cold-rolled microstructure. Consequently, the coupling mechanism between dislocation strengthening and grain refinement strengthening remarkably enhanced both the yield strength and ultimate tensile strength of the test steel. Eventually, the yield strength of the hot forming steel reached 1524 MPa, along with an ultimate tensile strength of 2221 MPa and uniform elongation of 5.2%.

Summary: Tumors are intricate and heterogeneous systems characterized by mosaic cancer cell populations with diverse expression profiles. Leveraging single-cell technologies, we employed the Scissor algorithm to delineate an epithelial subpopulation associated with the aggressive phenotype in esophageal squamous cell carcinoma (ESCC). This identified subpopulation exhibited elevated expression of genes involved in critical pathways, such as epithelial-mesenchymal transition and PI3K-Akt. Key signature genes within this subpopulation, namely CAV1, COL3A1, COL6A1, POSTN, and TAGLN, demonstrated significant upregulation concomitant with both tumorigenesis and tumor progression across independent single-cell datasets. Furthermore, we selected 1,450 expression quantitative trait loci of the top 62 signature genes of this cell subpopulation to investigate their potential in predicting ESCC risk. The results showed that the POSTN loci were predominantly associated with ESCC susceptibility. Through functional annotation and replication analyses, we identified that the rs1028728 in the POSTN promoter was significantly associated with increased ESCC risk in 7,049 ESCC cases and 8,063 controls (odds ratio = 1.29, 95% confidence interval: 1.18–1.42, p = 4.03 × 10−8). Subsequent biochemical experiments showed that the rs1028728[T] allele enhanced POSTN expression by affecting the binding of PRRX1 in the POSTN promoter. In summary, our meticulous single-cell analysis delineates an invasive epithelial subpopulation in ESCC, with POSTN emerging as an important marker for the aggressive phenotype. These findings offer more insights into potential strategies for the prevention and intervention of ESCC, enriching our understanding of this complex cancer landscape.

Abstract Background Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. Methods Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. Results SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery. Conclusion Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.

Abstract The prognosis of lung metastatic osteosarcoma (OS) remains disappointing. siRNA-based gene silencing of VEGFR2 is a promising treatment strategy for lung metastatic OS, but there is a lack of safe and efficient delivery systems to encapsulate siRNAs for in vivo administration. This study presented a synthetic biological strategy that remolds the host liver with synthesized genetic circuits for efficient in vivo VEGFR2 siRNA delivery. After being taken-up by hepatocytes, the genetic circuit (in the form of a DNA plasmid) reprogrammed the liver to drive the autonomous intrahepatic assembly and encapsulation of VEGFR2 siRNAs into secretory small extracellular vesicles (sEVs), thus allowing for the transport of self-assembled VEGFR2 siRNAs towards the lung. The results showed that our strategy was superior to the positive medicine (Apatinib) for OS lung metastasis in terms of therapeutic efficacy and toxic adverse effects and may provide a feasible and viable therapeutic solution for lung metastatic OS.

Mitochondria play a key role in the cerebral ischemia-reperfusion injury. Although the extracellular signal-regulated kinase 1/2 inhibitor PD98059 (PD) is a selective and reversible flavonoid that can protect the mitochondria in a rat model of cardiac arrest/cardiopulmonary resuscitation, its role requires further confirmation. In this study, we investigated whether PD could maintain mitochondrial homeostasis and decrease reactive oxygen species (ROS) production in neuroblastoma (SH-SY5Y) cells exposed to oxygen–glucose deprivation/reperfusion (OGD/R). PD improved the mitochondrial morphology and function, reversed the increase in ROS production and cell apoptosis, and reduced total-superoxide dismutase and Mn-superoxide dismutase activities induced by OGD/R. PD decreases ROS production and improves mitochondrial morphology and function, protecting SH-SY5Y cells against OGD/R-induced injury.

Rapid urbanization is universally acknowledged to degrade ecosystem services, posing significant threats to human well-being. However, the effects of urban shrinkage, a global phenomenon and a counterpart to urbanization, on ecosystem services (ESs) remain unclear. This study focuses on China’s Rust Belt during the period from 2000 to 2020, constructing a comprehensive analytical framework based on long-term remote sensing data to reveal the temporal and spatial patterns of ESs and their associations with cities experiencing varying degrees of shrinkage. It employs a random forest (RF) model and a Shapley additive explanation (SHAP) model to measure and visualize the significance and thresholds of socioeconomic factors influencing changes in ESs. Our findings highlight the following: (1) Since 2010, the three provinces of Northeast China (TPNC) have begun to shrink comprehensively, with the degree of shrinkage intensifying over time. Resource-based cities have all experienced contraction. (2) Regional urban shrinkage has been found to enhance the overall provision capacity of ESs, with the most significant improvements in cities undergoing continuous shrinkage. (3) The impact of the same socioeconomic drivers varies across cities with different levels of shrinkage; increasing green-space ratios and investing more in public welfare have been identified as effective measures to enhance ESs. (4) Threshold analysis indicates that the stability of the tertiary sector’s proportion is critically important for enhancing ESs in cities undergoing intermittent shrinkage. An increase of 10% to 15% in this sector can allow continuously shrinking cities to balance urban development with ecological improvements. This research highlights the positive aspects of urban shrinkage, demonstrating its ability to enhance the provision capacity of ESs. It offers new insights into the protection and management of regional ecosystems and the urban transformation of the three eastern provinces.

Incorporating green and low-carbon building targets into the rural planning management system requires scientific and quantitative methods for assessing carbon emissions from rural land use. At present, the research in this field mainly focuses on urban areas, but there are fewer theoretical and practical studies on the assessment of carbon emissions from rural land use. This paper proposes a new carbon emission assessment method based on land use modes, and the model can not only assess carbon emissions but also directly reflect the carbon emission intensity of different land use spaces in rural areas and guide the carbon emission control of construction land in village planning. In this paper, we take suburban rural areas in Hunan Province as an example and establish a land use carbon emission assessment model with 13 indicators in five dimensions: total carbon emission, carbon emission efficiency, carbon emission intensity per unit of land use, carbon emission structure of land use, and carbon emission intensity of buildings, based on the bottom-up field research data. We practised our method in Jinlong Town, Hunan Province, and gave examples of model applications. It was found that the carbon emission calculation method based on the carbon emission intensity of land use can be used to calculate the current status of carbon emissions in different villages in Jinlong Town. At the same time, the carbon emission assessment results can be used as a scientific basis for carbon emission control in detailed village planning in Jinlong Town. In general, the carbon emission assessment model can complete the assessment of land carbon emissions in rural areas and provide a low-carbon land use management tool for the government.

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr2+ and SiO32− ions within 28 days. The biological activity of the bioactive ions released from the hydrogels was verified on HUVECs, SMCs, C2C12 and Raw 264.7 cells in vitro, and the therapeutic effect of the hydrogel was confirmed using C57BL/6 mouse model of femoral artery ligation in vivo. The results showed that the composite hydrogel stimulated angiogenesis, developed new collateral capillaries, and re-established the blood supply. In addition, the bioactive hydrogel directly promoted the expression of muscle-regulating factors (MyoG and MyoD) to protect skeletal muscle from necrosis, inhibited M1 polarization, and promoted M2 polarization of macrophages to reduce inflammation, thereby protecting skeletal muscle cells and indirectly promoting vascularization. Our results indicate that these bioceramic/alginate composite bioactive hydrogels are effective biomaterials for treating hindlimb ischemia and suggest that biomaterial-based approaches may have remarkable potential in treating ischemic diseases.

Aortic aneurysm and dissection (AAD) are leading causes of death in the elderly. Recent studies have demonstrated that silicate ions can manipulate multiple cells, especially vascular-related cells. We demonstrated in this study that silicate ions as soluble form of bioactive ceramics effectively alleviated aortic aneurysm and dissection in both Ang II and β-BAPN induced AAD models. Different from the single targeting therapeutic drug approaches, the bioactive ceramic derived approach attributes to the effect of bioactive silicate ions on the inhibition of the AAD progression through regulating the local vascular microenvironment of aorta systematically in a multi-functional way. The in vitro experiments revealed that silicate ions did not only alleviate senescence and inflammation of the mouse aortic endothelial cells, enhance M2 polarization of mouse bone marrow-derived macrophages, and reduce apoptosis of mouse aortic smooth muscle cells, but also regulate their interactions. The in vivo studies further confirm that silicate ions could effectively alleviate senescence, inflammation, and cell apoptosis of aortas, accomplished with reduced aortic dilation, collagen deposition, and elastin laminae degradation. This bioactive ceramic derived therapy provides a potential new treatment strategy in attenuating AAD progression.

Abstract Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation. By microRNA (miRNA) array, a Kaposi’s sarcoma-associated herpes virus (KSHV)-encoded miRNA, kshv-miR-K12-1-5p, was detected in patients with DCM. The KSHV DNA load and kshv-miR-K12-1-5p level in plasma from 696 patients with DCM were measured and these patients were followed-up. Increased KSHV seropositivity and quantitative titers were found in the patients with DCM compared with the non-DCM group (22.0% versus 9.1%, p

A nanocomposite microneedle (ZCQ/MN) patch containing copper/zinc dual-doped mesoporous silica nanoparticles loaded with quercetin (ZCQ) was developed as a combination therapy for androgenic alopecia (AGA). The degradable microneedle gradually dissolves after penetration into the skin and releases the ZCQ nanoparticles. ZCQ nanoparticles release quercetin (Qu), copper (Cu2+) and zinc ions (Zn2+) subcutaneously to synergistically promote hair follicle regeneration. The mechanism of promoting hair follicle regeneration mainly includes the regulation of the main pathophysiological phenomena of AGA such as inhibition of dihydrotestosterone, inhibition of inflammation, promotion of angiogenesis and activation of hair follicle stem cells by the combination of Cu2+ and Zn2+ ions and Qu. This study demonstrates that the systematic intervention targeting different pathophysiological links of AGA by the combination of organic drug and bioactive metal ions is an effective treatment strategy for hair loss, which provides a theoretical basis for development of biomaterial based anti-hair loss therapy.

IntroductionOsteoporosis, one of the most common non-communicable human diseases worldwide, is one of the most prevalent disease of the adult skeleton. Glucocorticoid-induced osteoporosis(GIOP) is the foremost form of secondary osteoporosis, extensively researched due to its prevalence.Probiotics constitute a primary bioactive component within numerous foods, offering promise as a potential biological intervention for preventing and treating osteoporosis. This study aimed to evaluate the beneficial effects of the probiotic Lactobacillus plantarum on bone health and its underlying mechanisms in a rat model of glucocorticoid dexamethasone-induced osteoporosis, using the osteoporosis treatment drug alendronate as a reference.MethodsWe examined the bone microstructure (Micro-CT and HE staining) and analyzed the gut microbiome and serum metabolome in rats.Results and discussionThe results revealed that L. plantarum treatment significantly restored parameters of bone microstructure, with elevated bone density, increased number and thickness of trabeculae, and decreased Tb.Sp. Gut microbiota sequencing results showed that probiotic treatment increased gut microbial diversity and the ratio of Firmicutes to Bacteroidota decreased. Beneficial bacteria abundance was significantly increased (Lachnospiraceae_NK4A136_group, Ruminococcus, UCG_005, Romboutsia, and Christensenellaceae_R_7_group), and harmful bacteria abundance was significantly decreased (Desulfovibrionaceae). According to the results of serum metabolomics, significant changes in serum metabolites occurred in different groups. These differential metabolites were predominantly enriched within the pathways of Pentose and Glucuronate Interconversions, as well as Propanoate Metabolism. Furthermore, treatment of L. plantarum significantly increased serum levels of Pyrazine and gamma-Glutamylcysteine, which were associated with inhibition of osteoclast formation and promoting osteoblast formation. Lactobacillus plantarum can protect rats from DEX-induced GIOP by mediating the “gut microbial-bone axis” promoting the production of beneficial bacteria and metabolites. Therefore L. plantarum is a potential candidate for the treatment of GIOP.

Population genomic data could provide valuable information for conservation efforts; however, limited studies have been conducted to investigate the genetic status of threatened pheasants. Reeves's Pheasant (Syrmaticus reevesii) is facing population decline, attributed to increases in habitat loss. There is a knowledge gap in understanding the genomic status and genetic basis underlying the local adaptation of this threatened bird. Here, we used population genomic data to assess population structure, genetic diversity, inbreeding patterns, and genetic divergence. Furthermore, we identified candidate genes linked with adaptation across the current distribution of Reeves's Pheasant. The present study assembled the first de novo genome sequence of Reeves's Pheasant and annotated 19,458 genes. We also sequenced 30 individuals from three populations (Dabie Mountain, Shennongjia, Qinling Mountain) and found that there was clear population structure among those populations. By comparing with other threatened species, we found that Reeves's Pheasants have low genetic diversity. Runs of homozygosity suggest that the Shennongjia population has experienced serious inbreeding. The demographic history results indicated that three populations experienced several declines during the glacial period. Local adaptative analysis among the populations identified 241 candidate genes under directional selection. They are involved in a large variety of processes, including the immune response and pigmentation. Our results suggest that the three populations should be considered as three different conservation units. The current study provides genetic evidence for conserving the threatened Reeves's Pheasant and provides genomic resources for global biodiversity management.

Abstract Purpose The purpose of this study was to test the hypothesis that brain white matter hyperintensities (WMH) are more common in patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) and identify clinical risk factors associated with WMH. Experimental design This multiple‐center, prospective cohort study was conducted from March 2017 to July 2020. Two groups of patients with non‐small cell lung cancer (NSCLC) who received or did not receive EGFR‐TKI were included and followed up for more than 24 months. The progression of WMH was defined as an increase of ≥1 point on the Fazekas visual rating scale between the baseline and at the 2‐year follow‐up. A modified Poisson regression model was performed to evaluate risk factors on increased WMH load. Results Among 286 patients with NSCLC, 194 (68%) patients with NSCLC who received EGFR‐TKI and 92 (32%) patients with NSCLC without EGFR‐TKI treatment were analyzed. Modified Poisson regression analysis showed that EGFR‐TKI treatment was independently associated with the WMH progression (EGFR‐TKI: aRR 2.72, 95% confidence interval [CI] 1.46–5.06, p = .002). Interleukin (IL)‐2, IL‐4, and IL‐10 were associated with increased WMH in the adjusted model (IL‐2: aRR 1.55 [95% CI 1.06–2.25], p = .023; IL‐4: aRR 1.66 [95% CI 1.13–2.43], p = .010; IL‐10: aRR 1.48 [95% CI 1.06–2.06], p = .020). Conclusion Patients with NSCLC who received EGFR‐TKI may be at higher risk of developing WMH or worsening of WMH burden. The impact of increased WMH lesions in these patients is to be further assessed. IL‐2, IL‐4, and IL‐10 may be used as potential biomarkers to monitor the risk of increased WMH burden

Abstract The intricate nature of the tendon–bone interface poses significant challenges for current surgical methods aimed at repairing tendon–bone interface injuries. Despite notable progress in surgical techniques, these methods continue to grapple with hurdles such as complications and suboptimal healing effects. In this study, we prepared a three‐dimensional‐printed composite scaffold by incorporating bioactive ceramic zinc silicate (Zn2SiO4) into sodium alginate (SA) hydrogel. The physicochemical properties and mechanical strength of the SA hydrogel scaffold composited with Zn2SiO4 (ZnSi/SA) were investigated in vitro. Impressively, the 0.5‐ZnSi/SA scaffold exhibited a sustained release of Zn and Si ions, while exhibiting mechanical properties compatible with tendon–bone interface repair. Moreover, cell viability, cell migration, and osteogenic differentiation assay results showed that 0.5‐ZnSi/SA scaffold facilitated the viability, mobility, and osteogenic differentiation of bone marrow stromal cells. In parallel, assessments of cell viability, cell migration, and tendon differentiation indicated that 0.5‐ZnSi/SA scaffold promoted the viability, migration, and tenogenic differentiation of tendon stem/progenitor cells. Moreover, cell viability, cell migration, and tube formation assay results demonstrated that 0.5‐ZnSi/SA scaffold enhanced the viability, migration rate, and angiogenic performance of human umbilical vein endothelial cells. Collectively, our findings suggest a promising therapeutic avenue employing ZnSi/SA scaffold for tendon–bone interface healing.

BackgroundThe COVID-19 pandemic has inevitably affected the distribution of medical resources, and epidemic lockdowns have had a significant impact on the nursing and treatment of patients with other acute diseases, including intracerebral hemorrhage (ICH). ObjectiveThis study aimed to investigate how the COVID-19 pandemic affected the manifestations and outcomes of patients with ICH. MethodsPatients with acute ICH before (December 1, 2018-November 30, 2019) and during (December 1, 2019-November 30, 2020) the COVID-19 pandemic at 31 centers in China from the Chinese Cerebral Hemorrhage: Mechanism and Intervention (CHEERY) study were entered into the analysis. Demographic information and clinical manifestations and outcomes were collected and compared between the 2 groups. ResultsFrom December 1, 2018, to November 30, 2020, a total of 3460 patients with ICH from the CHEERY study were enrolled and eventually analyzed. The results showed that during the COVID-19 pandemic, patients with ICH were more likely to be older (P

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

Abstract Extracellular vesicles have shown good potential in disease treatments including ischemic injury such as myocardial infarction. However, the efficient production of highly active extracellular vesicles is one of the critical limitations for their clinical applications. Here, we demonstrate a biomaterial-based approach to prepare high amounts of extracellular vesicles with high bioactivity from endothelial progenitor cells (EPCs) by stimulation with silicate ions derived from bioactive silicate ceramics. We further show that hydrogel microspheres containing engineered extracellular vesicles are highly effective in the treatment of myocardial infarction in male mice by significantly enhancing angiogenesis. This therapeutic effect is attributed to significantly enhanced revascularization by the high content of miR-126a-3p and angiogenic factors such as VEGF and SDF-1, CXCR4 and eNOS in engineered extracellular vesicles, which not only activate endothelial cells but also recruit EPCs from the circulatory system.

Regeneration of severe bone defects remains an enormous challenge in clinic. Developing regenerative scaffolds to directionally guide bone growth is a potential strategy to overcome this hurdle. Conch, an interesting creature widely spreading in ocean, has tough spiral shell that can continuously grow along the spiral direction. Herein, inspired by the physiological features of conches, a conch-like (CL) scaffold based on β-TCP bioceramic material was successfully prepared for guiding directional bone growth via digital light processing (DLP)-based 3D printing. Benefiting from the spiral structure, the CL scaffolds significantly improved cell adhesion, proliferation and osteogenic differentiation in vitro compared to the conventional 3D scaffolds. Particularly, the spiral structure in the scaffolds could efficiently induce cells to migrate from the bottom to the top of the scaffolds, which was like “cells climbing stairs”. Furthermore, the capability of guiding directional bone growth for the CL scaffolds was demonstrated by a special half-embedded femoral defects model in rabbits. The new bone tissue could consecutively grow into the protruded part of the scaffolds along the spiral cavities. This work provides a promising strategy to construct biomimetic biomaterials for guiding directional bone tissue growth, which offers a new treatment concept for severe bone defects, and even limb regeneration.

Abstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Methods Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant. Results We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10−4), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32–2.02, P = 7.67×10−6). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2. Conclusions These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention. Graphical Abstract

This study describes a novel species of Diploderma (Squamata, Agamidae) from the lower valley of the Dadu River of the Sichuan Province of Western China based on its distinct morphological features and molecular evidence. D. daduense sp. nov. can be distinguished from its congeners by its tympanum concealed; head mainly green-yellow, supplemented by black; skin folds under the nuchal and dorsal crest obviously present in adult males only, its vertebral crest discontinuous between nuchal and dorsal sections with a distinct gap; transverse gular fold present but not obvious in some individuals; gular spot absent in both sexes; dorsolateral stripes green-yellow anteriorly, cyan in the center and blurry off-white posteriorly in adult males, the upper edge of dorsolateral stripes strongly jagged in adult males; no radial stripes around the eyes; inner-lip coloration smoky-white, and the coloration of the tongue and oral cavity as a light-flesh color in life; bright green-yellow transverse stripes on dorsal body in males; black patches are evenly distributed along the vertebral line between the dorsolateral stripes from the neck to the base of the tail in males; beech-brown or gray-brown line along the vertebral line with heart-shaped or diamond-shaped black patches on the dorsal body in females; and supratemporals fewer than four on at least one side. The phylogenetic tree based on mitochondrial ND2 sequences indicates that D. daduense sp. nov. forms an independent clade with strong support 1/100 in ML bootstrap/Bayesian posterior probability and is the sister group to D. splendidum. At the inter-species level, the p-distance is at least 6.95%, further confirming that an independent species had been identified. Our work raises the number of species within the genus Diploderma to 47.

With the development of urbanization, the accurate prediction of effluent quality has become increasingly critical for the real-time control of wastewater treatment processes. The conventional method for measuring effluent biochemical oxygen demand (BOD) suffers from significant time delays and high equipment costs, making it less feasible for timely effluent quality assessment. To tackle this problem, we propose a novel approach called En-WBF (ensemble learning based on weighted BoostForest) to predict effluent BOD in a soft-sensing manner. Specifically, we sampled several independent subsets from the original training set by weighted bootstrap aggregation to train a series of gradient BoostTrees as the base models. Then, the predicted effluent BOD was derived by weighting the base models to produce the final prediction. Experiments on real datasets demonstrated that on the UCI dataset, the proposed En-WBF approach achieved a series of improvements, including by 28.4% in the MAE, 40.9% in the MAPE, 29.8% in the MSE, 18.2% in the RMSE, and 2.3% in the R2. On the Fangzhuang dataset, the proposed En-WBF approach achieved a series of improvements, including by 8.8% in the MAE, 9.0% in the MAPE, 12.8% in the MSE, 6.6% in the RMSE, and 1.5% in the R2. This paper contributes a cost-effective and timely solution for wastewater treatment management in real practice with a more accurate effluent BOD prediction, validating the research in the application of ensemble learning methods for environmental monitoring and management.

Collision tumour of the thyroid is a rare entity for which surgical resection is the primary treatment. We present here a case of a collision thyroid tumour of oncocytic and papillary carcinoma with lung metastases occurring in a 62-year-old woman who initially presented with a rapidly enlarging cervical mass and dyspnoea. The patient had extensive venous tumour thrombosis in the internal jugular and subclavian veins. The patient received six cycles of combined chemotherapy with nedaplatin and paclitaxel which significantly reduced the size of the metastases in the lungs. Following discharge from the hospital, the patient was treated with oral anlotinib and at 14 months follow up she had not experienced any serious side effects and the metastases in her lung and thyroid surgery areas were well controlled.

ImportanceEarly neurological deterioration (END) is a critical complication in acute ischemic stroke (AIS) patients receiving intravenous thrombolysis (IVT), with a need for reliable prediction tools to guide clinical interventions.ObjectiveThis study aimed to develop and validate a rating scale, utilizing clinical variables and multisystem laboratory evaluation, to predict END after IVT.Design, setting, and participantsThe Clinical Trial of Revascularization Treatment for Acute Ischemic Stroke (TRAIS) cohort enrolled consecutive AIS patients from 14 stroke centers in China (Jan 2018 to Jun 2022).OutcomesEND defined as NIHSS score increase >4 points or death within 24 h of stroke onset.Results1,213 patients (751 in the derivation cohort, 462 in the validation cohort) were included. The CNS-LAND score, a 9-point scale comprising seven variables (CK-MB, NIHSS score, systolic blood pressure, LDH, ALT, neutrophil, and D-dimer), demonstrated excellent differentiation of END (derivation cohort C statistic: 0.862; 95% CI: 0.796–0.928) and successful external validation (validation cohort C statistic: 0.851; 95% CI: 0.814–0.882). Risk stratification showed END risks of 2.1% vs. 29.5% (derivation cohort) and 2.6% vs. 31.2% (validation cohort) for scores 0–3 and 4–9, respectively.ConclusionCNS-LAND score is a reliable predictor of END risk in AIS patients receiving IVT.

The Chinese section of the Irtysh River Basin and the Ulungur River Basin, two major river basins of the Altay region, are located at the northwest of Xinjiang Uygur Autonomous Region of China. As an international river, the Chinese section has seven state-level protected fish and seven local-level protected species as well. Many more commercial species have been introduced from eastern China and other countries, accompanied by some low-value and small-sized fish in recent decades. The non-native fish species have already threatened these protected fish. This study investigated the distribution of non-native fish species in the Chinese section of the Irtysh River Basin and the Ulungur River Basin. The basic data for the biodiversity conservation and the information of the non-native fish in these two river basins were gathered.There are a lot of studies on native fish in the Chinese section of the Irtysh River Basin and Urungur River Basin in China, but there is a lack of studies on non-native fish. Thirteen non-native fish belonging to four orders, nine families and 12 genera were collected in this study. The study includes one dataset. The dataset presents taxonomy, distribution, water body and location for each of the non-native fish collected from the Chinese section of the Irtysh River Basin and the Ulungur River Basin. Our study has found that the proportion of native species has declined, while the number of non-native species has increased from 2013 to 2022. The information we provided could help to develop an international strategy for the protection of aquatic biodiversity.

At present, portrait painting robots generally have the problems of low portrait quality, single artistic style, long rendering time and high computational complexity. Aiming at these problems, a simple facial line painting generation method based on knowledge distillation was proposed. First of all, using the large model as the teacher network, through the idea of knowledge distillation, this paper proposed a distillation loss to guide the training process of the light-weight student network, so that the light-weight model could achieve a better generation effect. Secondly, style loss was introduced to improve the continuity of generated lines. The experimental results show that this method can generate simple and beautiful face line drawings, and the robot can complete the drawing in 2 min. Compared with the teacher model, the amount of calculation is reduced by about 65.3%, and the amount of parameters is reduced by about 97.1%. This proposed method which is significantly better than the benchmark student model.

Abstract Background Many endangered species exist in small, genetically depauperate, or inbred populations, hence promoting genetic differentiation and reducing long-term population viability. Forest Musk Deer (Moschus berezovskii) has been subject to illegal hunting for hundreds of years due to the medical and commercial values of musk, resulting in a significant decline in population size. However, it is still unclear to what extent the genetic exchange and inbreeding levels are between geographically isolated populations. By using whole-genome data, we reconstructed the demographic history, evaluated genetic diversity, and characterized the population genetic structure of Forest Musk Deer from one wild population in Sichuan Province and two captive populations from two ex-situ centers in Shaanxi Province. Results SNP calling by GATK resulted in a total of 44,008,662 SNPs. Principal component analysis (PCA), phylogenetic tree (NJ tree), ancestral component analysis (ADMIXTURE) and the ABBA-BABA test separated Sichuan and Shaanxi Forest Musk Deer as two genetic clusters, but no obvious genetic differentiation was observed between the two captive populations. The average pairwise FST value between the populations in Sichuan and Shaanxi ranged from 0.05–0.07, suggesting a low to moderate genetic differentiation. The mean heterozygous SNPs rate was 0.14% (0.11%—0.15%) for Forest Musk Deer at the genomic scale, and varied significantly among three populations (Chi-square = 1.22, p

Summary: Metabolism plays a crucial role in B cell differentiation and function. GSDMA3 is related to mitochondrial metabolism and is involved in immune responses. Here, we used Gsdma3 KO mice to examine the effect of GSDMA3 on B cells. The results demonstrated that GSDMA3 deficiency reprogrammed B cell metabolism, evidenced by upregulating PI3K-Akt-mTOR signaling, along with elevated ROS reproduction and reduced maximal oxygen consumption rate in mitochondria. Moreover, the BCR signaling in the KO B cells was impaired. The reduced BCR signaling was associated with decreased BCR clustering, caused by inhibited activation of WASP. However, GSDMA3 deficiency had no effects on B cell development and functions in humoral immunity, which might be associated with the compensation of upregulated GSDMA2 expression and the fine balance between PI3K signaling and BCR signals interaction. Our observations reveal a previously unknown influence of GSDMA3 on B cells under physiological and immunized states.

BackgroundCancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility.MethodsA cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases.ResultsMeta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (PASSET< 5×10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (Padj

In order to investigate the effect of protein structure changes on the texture of scallop adductor muscles under ultra-high pressure, the protein structure, hardness, elasticity, cohesion, and chewing properties of untreated scallops maintained at 200 MPa for 60 s, 120 s, and 180 s were measured and compared. At the same time, sensory indicators were evaluated to verify the effect of ultra-high pressure treatment on the quality of scallop adductor muscles. The results indicated that the mass fraction of the α-helix was decreased by 13.70% and the mass fraction of β–folding was 2.72 times higher in the adductor muscle of scallops compared to the fresh adducts without ultra-high pressure treatment, maintained for 180 s at an ultra-high pressure of 200 MPa. At the same time, the value of I850/I830 of protein tyrosine residues was 1.094, which weakened the water retention ability of the protein, the elasticity of the scallop adduct was reduced from the original 7.16 N to 6.17 N, the cohesion was reduced by 3.76%, and the hardness was increased by 17.45%. This improved the cooking quality of scallops, which was consistent with the sensory evaluation results. Therefore, under ultra-high pressure treatment, changes in the protein structure of the adductor muscle of scallops had a certain impact on their texture, which was able to provide support for in-depth research on the mechanism of ultra-high pressure action.