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Abstract High myopia (HM) is a leading cause of blindness worldwide with currently no effective interventions available. A major hurdle lies in its often isolated perception as a purely ocular morbidity, disregarding potential systemic implications. Recent evidence suggests the existence of a gut-eye axis; however, the role of gut microbiota in the pathogenesis of HM remains largely unexplored. Herein, we provide a potential crosstalk among HM’s gut dysbiosis, microbial metabolites, and scleral remodeling. Utilizing 16S rRNA gene sequencing, we observed an altered gut microbiota profile in HM patients with a significant reduction in probiotic abundance compared with healthy controls. Subsequent targeted metabolic profiling revealed a notable decrease in plasma levels of the gut microbiota-derived metabolite indole-3-acetic acid (3-IAA) among HM patients, which is closely associated with the reduced probiotics, both negatively correlated with HM severity. Genetic analyses determined that gut microbiota are causally associated with myopia risk. Importantly, when mice subjected to HM modeling receive fecal microbiota transplantation from healthy donors, there is an increase in 3-IAA plasma levels and simultaneous retardation of HM progression along with better maintenance of collagen type I alpha 1 (COL1A1) expression in the sclera. Furthermore, 3-IAA gavage achieves similar effects. Mechanistic investigations confirm the transcriptional activation of COL1A1 by 3-IAA via promoting the enrichment of SP1 to its promoter. Together, our findings provide novel insights into the gut microbiota-eye axis in the pathogenesis of HM and propose new strategies for HM intervention by remodeling the gut microbiota and indole supplementation.

Abstract Background There is increasing evidence that gut fungi dysbiosis plays a crucial role in the development and progression of colorectal cancer (CRC). It has been reported that gut fungi exacerbate the severity of CRC by regulating tumor immunity. Our previous studies have shown that the opportunistic pathogenic fungal pathogen, Candida tropicalis (C. tropicalis) promotes CRC progression by enhancing the immunosuppressive function of MDSCs and activating the NLRP3 inflammasome of MDSCs. However, the relationship between IL-1β produced by NLRP3 inflammasome activation and the immunosuppressive function of MDSCs enhanced by C. tropicalis in CRC remains unclear. Methods The TCGA database was used to analyze the relationship between IL-1β and genes related to immunosuppressive function of MDSCs in human CRC. The expression of IL-1β in human CRC tissues was detected by immunofluorescence staining. The proteomic analysis was performed on the culture supernatant of C. tropicalis-stimulated MDSCs. The experiments of supplementing and blocking IL-1β as well as inhibiting the NLRP3 inflammasome activation were conducted. A mouse colon cancer xenograft model was established by using MC38 colon cancer cell line. Results Analysis of CRC clinical samples showed that the high expression of IL-1β was closely related to the immunosuppressive function of tumor-infiltrated MDSCs. The results of in vitro experiments revealed that IL-1β was the most secreted cytokine of MDSCs stimulated by C. tropicalis. In vitro supplementation of IL-1β further enhanced the immunosuppressive function of C. tropicalis-stimulated MDSCs and NLRP3-IL-1β axis mediated the immunosuppressive function of MDSCs enhanced by C. tropicalis. Finally, blockade of IL-1β secreted by MDSCs augmented antitumor immunity and mitigated C. tropicalis-associated colon cancer. Conclusions C. tropicalis promotes excessive secretion of IL-1β from MDSCs via the NLRP3 inflammasome. IL-1β further enhances the immunosuppressive function of MDSCs to inhibit antitumor immunity, thus promoting the progression of CRC. Therefore, targeting IL-1β secreted by MDSCs may be a potential immunotherapeutic strategy for the treatment of CRC.

Abstract Background It has been proposed that anti-angiogenesis therapy could induce tumor "vascular normalization" and further enhance the efficacy of chemotherapy, radiotherapy, target therapy, and immunotherapy for nearly twenty years. However, the detailed molecular mechanism of this phenomenon is still obscure. Method Overexpression and knockout of CCL28 in human lung adenocarcinoma cell line A549 and murine lung adenocarcinoma cell line LLC, respectively, were utilized to establish mouse models. Single-cell sequencing was performed to analyze the proportion of different cell clusters and metabolic changes in the tumor microenvironment (TME). Immunofluorescence and multiplex immunohistochemistry were conducted in murine tumor tissues and clinical biopsy samples to assess the percentage of pericytes coverage. Primary pericytes were isolated from lung adenocarcinoma tumor tissues using magnetic-activated cell sorting (MACS). These pericytes were then treated with recombinant human CCL28 protein, followed by transwell migration assays and RNA sequencing analysis. Changes in the secretome and metabolome were examined, and verification of retinoic acid metabolism alterations in pericytes was conducted using quantitative real-time PCR, western blotting, and LC–MS technology. Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) was employed to validate the transcriptional regulatory ability and affinity of RXRα to specific sites at the ANGPT1 promoter. Results Our study showed that after undergoing anti-angiogenesis treatment, the tumor exhibited a state of ischemia and hypoxia, leading to an upregulation in the expression of CCL28 in hypoxic lung adenocarcinoma cells by the hypoxia-sensitive transcription factor CEBPB. Increased CCL28 could promote tumor vascular normalization through recruiting and metabolic reprogramming pericytes in the tumor microenvironment. Mechanistically, CCL28 modified the retinoic acid (RA) metabolism and increased ANGPT1 expression via RXRα in pericytes, thereby enhancing the stability of endothelial cells. Conclusion We reported the details of the molecular mechanisms of "vascular normalization" after anti-angiogenesis therapy for the first time. Our work might provide a prospective molecular marker for guiding the clinical arrangement of combination therapy between anti-angiogenesis treatment and other therapies.

Abstract Background Programmed cell death (PCD) has recently been implicated in modulating the removal of neutrophils recruited in acute myocardial infarction (AMI). Nonetheless, the clinical significance and biological mechanism of neutrophil-related PCD remain unexplored. Methods We employed an integrative machine learning-based computational framework to generate a predictive neutrophil-derived PCD signature (NPCDS) within five independent microarray cohorts from the peripheral blood of AMI patients. Non-negative matrix factorization was leveraged to develop an NPCDS-based AMI subtype. To elucidate the biological mechanism underlying NPCDS, we implemented single-cell transcriptomics on Cd45+ cells isolated from the murine heart of experimental AMI. We finally conducted a Mendelian randomization (MR) study and molecular docking to investigate the therapeutic value of NPCDS on AMI. Results We reported the robust and superior performance of NPCDS in AMI prediction, which contributed to an optimal combination of random forest and stepwise regression fitted on nine neutrophil-related PCD genes (MDM2, PTK2B, MYH9, IVNS1ABP, MAPK14, GNS, MYD88, TLR2, CFLAR). Two divergent NPCDS-based subtypes of AMI were revealed, in which subtype 1 was characterized as inflammation-activated with more vibrant neutrophil activities, whereas subtype 2 demonstrated the opposite. Mechanically, we unveiled the expression dynamics of NPCDS to regulate neutrophil transformation from a pro-inflammatory phase to an anti-inflammatory phase in AMI. We uncovered a significant causal association between genetic predisposition towards MDM2 expression and the risk of AMI. We also found that lidoflazine, isotetrandrine, and cepharanthine could stably target MDM2. Conclusion Altogether, NPCDS offers significant implications for prediction, stratification, and therapeutic management for AMI.

Abstract Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas. Graphical Abstract

Abstract Background Genome‐wide association studies (GWAS) have identified more than a thousand loci for blood pressure (BP). Functional genes in these loci are cell‐type specific. The aim of this study was to elucidate potentially functional genes associated with BP in the aorta through the utilization of RNA modification‐associated single‐nucleotide polymorphisms (RNAm‐SNPs). Methods Utilizing large‐scale genetic data of 757,601 individuals from the UK Biobank and International Consortium of Blood Pressure consortium, we identified associations between RNAm‐SNPs and BP. The association between RNAm‐SNPs, gene expression, and BP were examined. Results A total of 355 RNAm‐SNPs related to m6A, m1A, m5C, m7G, and A‐to‐I modification were associated with BP. The related genes were enriched in the pancreatic secretion pathway and renin secretion pathway. The BP GWAS signals were significantly enriched with m6A‐SNPs, highlighting the potential functional relevance of m6A in physiological processes influencing BP. Notably, m6A‐SNPs in CYP11B1, PDE3B, HDAC7, ACE, SLC4A7, PDE1A, FRK, MTHFR, NPPA, CACNA1D, and HDAC9 were identified. Differential methylation and differential expression of the BP genes in FTO‐overexpression and METTL14‐knockdown vascular smooth muscle cells were detected. RNAm‐SNPs were associated with ascending and descending aorta diameter and the genes showed differential methylation between aortic dissection (AD) cases and controls. In scRNA‐seq study, we identified ARID5A, HLA‐DPB1, HLA‐DRA, IRF1, LINC01091, MCL1, MLF1, MLXIPL, NAA16, NADK, RERG, SRM, and USP53 as differential expression genes for AD in aortic cells. Conclusion The present study identified RNAm‐SNPs in BP loci and elucidated the associations between the RNAm‐SNPs, gene expression, and BP. The identified BP‐associated genes in aortic cells were associated with AD.

The objectives of this research were to analyze anthocyanins in blue honeysuckle (Lonicera caerulea L.), bilberry (Vaccinium vitis-idaea L), and cranberry (Vaccinium macrocarpon Ait.), using HPLC-ESI-QTOF-MS2, Fourteen, fifteen, and eight anthocyanins were identified in blue honeysuckle, bilberry, and cranberry, respectively. Cyanidin-3-glucoside (C3G) and peonidin-3-glucoside were detected in all three types of berries, with blue honeysuckle showing the highest C3G content at 5686.28 mg/100 g DW. Total phenolic content (TPC) and total flavonoid content (TFC), along with ABTS, DPPH, and FRAP assays, were measured. Blue honeysuckle exhibited the highest levels of TPC and TFC. The SOD, POD, and CAT activities in blue honeysuckle were 1761.17 U/g, 45,525.65 U/g, and 1043.24 U/g, respectively, which were significantly superior to those in bilberry and cranberry. The antioxidant mechanisms of these enzymes were investigated by molecular docking, C3G showed a higher affinity for POD, confirming the effectiveness of C3G as an antioxidant.

Accurate measurement of socio-economic loss and the impact of disasters is crucial for effective risk assessment and management. This study introduces a Disaster Severity Index (DSI) and a Disaster Impact Index (DII), along with a composite severity matrix, to evaluate comprehensive disaster losses. By utilizing seven loss indicators across six types of natural disasters and socioeconomic indicators, we thoroughly assessed Shanghai’s historical disaster losses from 1978 to 2020. Our analysis reveals that Shanghai’s most severe annual disaster losses occurred in 1991 and 2005; however, the overall impact on the local socio-economy has been declining. According to the DSI, Chongming (0.88), Songjiang (0.64), and Qingpu (0.51) Districts exhibit the highest severity. In terms of the DII, Songjiang (0.87), Chongming (0.71), and Qingpu (0.64) Districts are most affected. The comprehensive disaster severity grading indicates that Chongming and Songjiang Districts experience the most severe impacts, while Huangpu and Xuhui Districts are less affected. The spatial distribution of disaster losses is concentrated in suburban areas, with less impact in the central city. Our methodology provides a framework for analyzing and comparing historical disaster losses in terms of time (inter-annual), space (administrative divisions), and types of disasters. It can also be used for statistical analysis and regular monitoring of disaster losses. This study not only elucidates the spatiotemporal distribution of historical disaster losses in Shanghai but also validates the efficacy of our comprehensive index models.

Abstract Background Caspase Recruitment Domain-containing protein 9 (CARD9) expressed in myeloid cells has been demonstrated to play an antifungal immunity role in protecting against disseminated candidiasis. Hereditary CARD9 ablation leads to fatal disseminated candidiasis. However, the myeloid cell types and molecular mechanisms implicated in CARD9 protecting against disseminated candidiasis remain wholly elusive. Methods The role of CARD9 ablation in exacerbating disseminated candidiasis was determined in vivo and in vitro. The molecular mechanism by which CARD9 ablation promotes acute kidney injury in disseminated candidiasis was identified by RNA-sequencing analysis. The expression of mitochondrial proteins and ferroptosis-associated proteins were measured by Quantitative real-time PCR and western blot. Results CARD9 ablation resulted in a reduced proportion of myeloid-derived suppressor cells (MDSCs) and a substantially lower expression of solute carrier family 7 member 11 (SLC7A11) in the kidneys, which increased susceptibility to acute kidney injury and renal ferroptosis during disseminated Candida tropicalis (C. tropicalis) infection. Moreover, CARD9-deficient MDSCs were susceptible to ferroptosis upon stimulation with C. tropicalis, which was attributed to augmented mitochondrial oxidative phosphorylation (OXPHOS) caused by reduced SLC7A11 expression. Mechanistically, C-type lectin receptors (CLRs)-mediated recognition of C. tropicalis promoted the expression of SLC7A11 which was transcriptionally manipulated by the Syk-PKCδ-CARD9-FosB signaling axis in MDSCs. FosB enhanced SLC7A11 transcription by binding to the promoter of SLC7A11 in MDSCs stimulated with C. tropicalis. Mitochondrial OXPHOS, which was negatively regulated by SLC7A11, was responsible for inducing ferroptosis of MDSCs upon C. tropicalis stimulation. Finally, pharmacological inhibition of mitochondrial OXPHOS or ferroptosis significantly increased the number of MDSCs in the kidneys to augment host antifungal immunity, thereby attenuating ferroptosis and acute kidney injury exacerbated by CARD9 ablation during disseminated candidiasis. Conclusions Collectively, our findings show that CARD9 ablation enhances mitochondria-mediated ferroptosis in MDSCs, which negatively regulates antifungal immunity. We also identify mitochondria-mediated ferroptosis in MDSCs as a new molecular mechanism of CARD9 ablation-exacerbated acute kidney injury during disseminated candidiasis, thus targeting mitochondria-mediated ferroptosis is a novel therapeutic strategy for acute kidney injury in disseminated candidiasis.

Abstract We report a rare regime of Earth's magnetosphere interaction with sub‐Alfvénic solar wind in which the windsock‐like magnetosphere transforms into one with Alfvén wings. In the magnetic cloud of a Coronal Mass Ejection (CME) on 24 April 2023, NASA's Magnetospheric Multiscale mission distinguishes the following features: (a) unshocked and accelerated low‐beta CME plasma coming directly against Earth's dayside magnetosphere; (b) dynamical wing filaments representing new channels of magnetic connection between the magnetosphere and foot points of the Sun's erupted flux rope; (c) cold CME ions observed with energized counter‐streaming electrons, evidence of CME plasma captured due to by reconnection between magnetic‐cloud and Alfvén‐wing field lines. The reported measurements advance our knowledge of CME interaction with planetary magnetospheres, and open new opportunities to understand how sub‐Alfvénic plasma flows impact astrophysical bodies such as Mercury, moons of Jupiter, and exoplanets close to their host stars.

Abstract This study investigates the escape of Mercury's sodium‐group ions (Na+‐group, including ions with m/q from 21 to 30 amu/e) and their dependence on true anomaly angle (TAA), that is, Mercury's orbital phase around the Sun, using measurements from MESSENGER. The measurements are categorized into solar wind, magnetosheath, and magnetosphere, and further divided into four TAA intervals. Na+‐group ions form escape plumes in the solar wind and magnetosheath, with higher fluxes along the solar wind's motional electric field. The total escape rates vary from 0.2 to 1 × 1025 atoms/s with the magnetosheath being the main escaping region. These rates exhibit a TAA dependence, peaking near the perihelion and similar during Mercury's remaining orbit. Despite Mercury's tenuous exosphere, Na+‐group ions escape rate is comparable to other inner planets. This can be attributed to several processes, including that Na+‐group ions may include several ion species, efficient photoionization frequency for elements within Na‐group, etc.

Abstract is missing (Short communication)

Abstract Using a two‐way coupled magnetohydrodynamics with embedded kinetic physics model, we perform a substorm event simulation to study electron velocity distribution functions (VDFs) evolution associated with Bursty Bulk Flows (BBFs). The substorm was observed by Magnetospheric Multiscale satellite on 16 May 2017. The simulated BBF macroscopic characteristics and electron VDFs agree well with observations. The VDFs from the BBF tail to its dipolarization front (DF) during its earthward propagation are revealed and they show clear energization and heating. The electron pitch angle distributions (PADs) at the DF are also tracked, which show interesting energy dependent features. Lower energy electrons develop a “two‐hump” PAD while the higher energy ones show persist “pancake” distribution. Our study reveals for the first time the evolution of electron VDFs as a BBF moves earthward using a two‐way coupled global and kinetic model, and provides valuable contextual understanding for the interpretation of satellite observations.

Abstract Wet age‐related macular degeneration (AMD) is a common cause of vision loss in the elderly. It is characterised by choroidal neovascularisation (CNV), caused by overexpression of vascular endothelial growth factor (VEGF), resulting in abnormal vessel proliferation. Current clinical management predominantly relies on anti‐VEGF agents, which require frequent and costly injections. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising strategy for permanently suppressing angiogenesis by targeting the VEGF‐related pathway. Increased research suggests that disrupting this pathway holds potential for preventing CNV progression. This review provides an overview of the aetiology, classification and pathophysiology of wet AMD, followed by a concise summary of current gene editing research using the CRISPR/Cas system via viral vector delivery strategies to target ocular pro‐angiogenic factors, including Hif‐1α, VEGF and VEGFR. The importance of timely targeting of VEGFA is emphasised and the challenges associated with gene editing therapies are also highlighted.

Abstract Mars lacks a global magnetic field, and instead possesses small-scale crustal magnetic fields, making its magnetic environment fundamentally different from intrinsic magnetospheres like those of Earth or Saturn. Here we report the discovery of magnetospheric ion drift patterns, typical of intrinsic magnetospheres, at Mars using measurements from Mars Atmosphere and Volatile EvolutioN mission. Specifically, we observe wedge-like dispersion structures of hydrogen ions exhibiting butterfly-shaped distributions (pitch angle peaks at 22.5°−45° and 135°−157.5°) within the Martian crustal fields, a feature previously observed only in planetary-scale intrinsic magnetospheres. These dispersed structures are the results of drift motions that fundamentally resemble those observed in intrinsic magnetospheres. Our findings indicate that the Martian magnetosphere embodies an intermediate case where both the unmagnetized and magnetized ion behaviors could be observed because of the wide range of strengths and spatial scales of the crustal magnetic fields around Mars.

Arteriovenous malformations (AVMs) are serious congenital vascular anomalies in which the arteries connect directly with veins without capillaries. This condition will continue to worsen without proper intervention and cause ulcers, repeated hemorrhages, and even cardiac insufficiency. Primary treatment options for AVMs include surgery and interventional treatment; however, they are associated with high risk and recurrence rates. Recent studies revealed that excessive activation of the Ras/MAPK pathway can induce the formation and development of peripheral AVM, whereas MEK inhibitors can effectively control nidus progression, making them a potential novel treatment for AVM. This review provides an up-to-date overview of correlated laboratory and clinical research to provide information for further research and clinical practice.

Arteriovenous malformations (AVMs) are aggressive congenital high-flow vascular anomalies, in which the feeding artery and draining vein are connected through fistulas without normal capillary networks. In severe cases, the condition may cause swelling, ulceration, bleeding, and even heart failure. Various treatment options are available for AVMs, including laser, surgical resection, embolization, and targeted drug therapy. With the development of endovascular treatment technology, absolute ethanol embolization of AVMs has become one of the first-line therapies owing to its sustained efficacy and low recurrence rate. However, administration of this therapy is challenging and may lead to serious complications if inappropriately managed. In this article, we reviewed and summarized previous clinical articles, literature reviews, and clinical trial data to comprehensively describe clinical manifestations of AVMs, the mechanism of ethanol embolotherapy, key points in treatment and management of complications, and issues that need to be addressed. We expect to provide a reliable information reference source for clinical physicians and researchers.

Background: Recent studies have demonstrated that the migrasome, a newly functional extracellular vesicle, is potentially significant in the occurrence, progression, and diagnosis of cardiovascular diseases. Nonetheless, its diagnostic significance and biological mechanism in acute myocardial infarction (AMI) have yet to be fully explored. Methods: To remedy this gap, we employed an integrative machine learning (ML) framework composed of 113 ML combinations within five independent AMI cohorts to establish a predictive migrasome-related signature (MS). To further elucidate the biological mechanism underlying MS, we implemented single-cell RNA sequencing (scRNA-seq) of cardiac Cd45+ cells from AMI-induced mice. Ultimately, we conducted mendelian randomization (MR) and molecular docking to unveil the therapeutic effectiveness of MS. Results: MS demonstrated robust predictive performance and superior generalization, driven by the optimal combination of Stepglm and Lasso, on the expression of nine migrasome genes (BMP1, ITGB1, NDST1, TSPAN1, TSPAN18, TSPAN2, TSPAN4, TSPAN7, TSPAN9, and WNT8A). Notably, ITGB1 was found to be predominantly expressed in cardiac macrophages in AMI-induced mice, mechanically regulating macrophage transformation between anti-inflammatory and pro-inflammatory. Furthermore, we showed a positive causality between genetic predisposition towards ITGB1 expression and AMI risk, positioning it as a causative gene. Finally, we showed that ginsenoside Rh1, which interacts closely with ITGB1, could represent a novel therapeutic approach for repressing ITGB1. Conclusions: Our MS has implications in forecasting and curving AMI to inform future diagnostic and therapeutic strategies for AMI.

Objective: To understand the prevalence of home-related anxiety among adolescent athletes during the novel coronavirus pandemic and to ascertain the factors influencing this anxiety. Methods: We employed cluster sampling to select 1150 adolescent athletes (aged 8–18 years) from six sports training schools in Yantai City, Shandong Province. Mental health status was assessed and recorded. Chi-square tests and multivariable logistic regression were used to analyze the factors contributing to athletes’ anxiety. Results: The survey revealed a COVID-19 infection rate of 38.23% (437 individuals) with an anxiety score of 40.98 ± 8.20 and an anxiety detection rate of 11.29% (129 individuals) during the COVID-19 epidemic. Female athletes exhibited a higher anxiety rate of 14.40% compared to 8.40% in male athletes. Multivariate analysis identified female gender as a risk factor for anxiety (OR = 1.64), while participation in aquatics emerged as a protective factor (OR = 0.24, 95% CI: 1.08–2.48). Professional training duration exceeding three years increased anxiety risk (OR = 3.05, 95% CI: 1.67–5.58), as did not seeking help during difficulties (OR = 2.59, 95% CI: 1.33–5.01). Interestingly, parental care was linked to increased anxiety risk (OR = 2.44, 95% CI 1.34–4.44), while care from friends was protective (OR = 0.60, 95% CI: 0.36–1.01), which was possibly due to the pressure associated with parental expectations. Conclusions: Adolescent athletes, particularly females and those with extended training durations, exhibit a heightened susceptibility to anxiety. This study also highlights that athletes who proactively seek assistance during challenging situations tend to experience lower anxiety levels. Additionally, a lack of COVID-19 infection and the involvement of concerned parents contribute to reduced anxiety among these young athletes.

This study aims to analyze the load-bearing characteristics of non-pneumatic tires with composite spokes using experimental and finite element simulation methods and to establish a mechanical analysis model based on the Timoshenko beam theory. Subsequently, experiments were conducted on carbon fiber-reinforced plastics and rubbers to establish the corresponding constitutive model. A finite element model of the non-pneumatic tires with composite spokes was also developed. The main structural and material parameters were selected, and their correlation with the vertical stiffness of the non-pneumatic tires with composite spokes was studied using response surface methodology. The stiffness characteristics of the composite spokes were simplified, and a load-bearing characteristic analysis model was established. The results indicated that among the parameters of the reinforcement plate structure and rubber, the constitutive parameter C10 of the rubber in the spokes had the greatest impact, with a comprehensive influence value of 319.83 N/mm. Under a load of 5000 N, the load-bearing characteristic analysis model results were consistent with those of the finite element simulation, with a maximum relative error of 7.49%. The proposed load-bearing characteristic analysis model can assist in the rapid design and performance prediction of non-pneumatic tires with composite spokes.

With the development of Chinese society, there is an increasing demand for emissions reduction and the stable operation of the power grid. Regional comprehensive energy supply systems have entered the public’s view owing to their advantages of reducing capacity, unified dispatch, improving efficiency, and reducing energy consumption. This paper focuses on a system under construction in Chongqing, which adopts a combined gas tri-supply (combined cooling, heat, and power, CCHP) and dynamic ice storage cooling system as the research object. By establishing a mathematical model for the simulation research, this study examines the start–stop priority sequence of the gas tri-supply subsystem and the heat pump subsystem under the ice storage priority strategy in winter and summer and proposes corresponding optimization solutions. By comparing the annual operating energy consumption of the system, we conclude that the gas tri-supply composite system has good economic efficiency and peak-shaving capability, indicating that regional gas tri-supply composite systems have great application potential in the future. The proposed optimized operation strategy and simulated energy consumption calculation provide theoretical guidance for the construction and operation of both this project and similar projects.

The pollen receptor-like protein kinase (PRK) family, an LRR receptor-like protein kinase, not only plays a role in pollen development and fertilization, but also plays a role in stress response. Based on the analysis of transcriptome data that generated in our previous study, we found that AhPRK4 was an aluminum-responsive gene. To explore the role of AhPRK4 in response to aluminum stress, we analyzed the expression of AhPRK4 by qRT-PCR in ‘ZH2’ (Al-sensitive) and ‘99-1507’ (Al-tolerant), clarified the protein structure and genetic relationship of AhPRK4 by sequence analysis, phylogenetic tree construction and other genetic analysis, constructed the recombinant plasmid by homologous recombination, obtained the intracellular domain recombinant protein of AhPRK4 by prokaryotic expression technology and determined the activity of the recombinant protein by incubation with phosphorylated antibodys. The results were as follows: (1) The transcription level of AhPRK4 was up-regulated after different aluminum treatments time and different aluminum concentrations, indicating that AhPRK4 was an aluminum inducible gene. (2) The AhPRK4 protein had 673 amino acids with transmembrane domain, signal peptide and phosphorylation active sites, belonging to the LRR-III protein kinase family. (3) The GST-AhPRK4-CD recombinant protein was induced in vitro and verified by Western Blot. And the recombinant protein had phosphorylated on both serine/threonine and tyrosine residues, but had no significant auto-phosphorylation activity. In conclusion, AhPRK4 is an aluminum responsive gene, which participates in the regulation of short-term aluminum stress and is phosphorylated in vitro.

Wheat stripe rust poses a marked threat to global wheat production. Accurate and effective disease severity assessments are crucial for disease resistance breeding and timely management of field diseases. In this study, we propose a practical solution using mobile-based deep learning and model-assisted labeling. StripeRust-Pocket, a user-friendly mobile application developed based on deep learning models, accurately quantifies disease severity in wheat stripe rust leaf images, even under complex backgrounds. Additionally, StripeRust-Pocket facilitates image acquisition, result storage, organization, and sharing. The underlying model employed by StripeRust-Pocket, called StripeRustNet, is a balanced lightweight 2-stage model. The first stage utilizes MobileNetV2-DeepLabV3+ for leaf segmentation, followed by ResNet50-DeepLabV3+ in the second stage for lesion segmentation. Disease severity is estimated by calculating the ratio of the lesion pixel area to the leaf pixel area. StripeRustNet achieves 98.65% mean intersection over union (MIoU) for leaf segmentation and 86.08% MIoU for lesion segmentation. Validation using an additional 100 field images demonstrated a mean correlation of over 0.964 with 3 expert visual scores. To address the challenges in manual labeling, we introduce a 2-stage labeling pipeline that combines model-assisted labeling, manual correction, and spatial complementarity. We apply this pipeline to our self-collected dataset, reducing the annotation time from 20 min to 3 min per image. Our method provides an efficient and practical solution for wheat stripe rust severity assessments, empowering wheat breeders and pathologists to implement timely disease management. It also demonstrates how to address the “last mile” challenge of applying computer vision technology to plant phenomics.

Background: Diabetes is common yet challenging chronic disease, that affects a wide range of people around the world. Complex cellular environments around diabetic wounds tend to damage the function of effector cells, including vascular endothelial cells (VECs), fibroblasts and epithelial cells. This study aims to analyze the differences between diabetic wounds and normal skin as well as whether adipose-derived stem cell (ADSC) exosome could promote healing of diabetic wound. Methods: Human diabetic wounds and normal skin were collected and stained with HE, Masson, CD31 and 8-hydroxy-2 deoxyguanosine immunohistochemical staining. RNA-seq data were collected for further bioinformatics analysis. ADSC exosomes were isolated and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. The effect of ADSC exosomes on diabetic wound healing was assessed on full thickness wounds in mice. To further verify the regulative impact of ADSCs exosomes in high glucose treated fibroblasts, we isolated fibroblasts from normal skin tissue and measured the cell viability, apoptosis rate, proliferation and migration of fibroblasts. In addition, collagen formation and fibrosis-related molecules were also detected. To further disclose the mechanism of ADSC exosomes on the function of high glucose treated fibroblasts, we detected the expression of apoptosis related molecules including BCL2, Bax, and cleaved caspase-3. Results: Histological observation indicated that perilesional skin tissues from diabetic patients showed structural disorder, less collagen disposition and increased injury compared with normal skin. Bioinformatics analysis showed that the levels of inflammatory and collagen synthesis related molecules, as well as oxidative stress and apoptosis related molecules, were significantly changed. Furthermore, we found that ADSC exosomes could not only speed up diabetic wound healing, but could also improve healing quality. ADSC exosomes restored high glucose induced damage to cell viability, migration and proliferation activity, as well as fibrosis-related molecules such as SMA, collagen 1 and collagen 3. In addition, we verified that ADSC exosomes downregulated high glucose induced increased apoptosis rate in fibroblast and the protein expression of Bax as well as cleaved caspases 3. Conclusions: This study indicated that ADSC exosomes alleviated high glucose induced damage to fibroblasts and accelerate diabetic wound healing by inhibiting Bax/caspase 3.

Abstract. Background:. Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV). Methods:. We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development. Results:. We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs. 75.0% [30/40], P = 0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes (P = 1.656e–9). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron. Conclusion:. Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.

Dispersion control is a critical aspect in nano-optical systems. Moreover, chromatic aberration significantly impacts image quality. Despite metasurfaces being a novel approach to tackle chromatic aberration in diffractive lenses, numerous challenges hinder their practical implementation due to the complexity of 3D fabrication techniques and high manufacturing costs. In contrast, ultra-thin graphene oxide lenses are simpler and less expensive to manufacture. The optical performance of graphene oxide lenses, such as high focusing efficiency, large depth of field, wide bandwidth, and zooming capability, depends on the design of the positional arrangement of reduced graphene oxide regions. In this study, we utilized the self-constructed datasets to train machine learning models based on the structure of the graphene oxide lens and combined it with intelligent optimization algorithms. This approach facilitated the design of the graphene oxide achromatic lens in multi-wavelengths with high-performance. Experimental results substantiate that the designed ultra-thin graphene oxide lens, with a thickness of ~200 nm, effectively controls dispersion across multiple incident wavelengths (450, 550, and 650 nm) and achieves super resolution with consistent intensity at the focal point. Our graphene oxide lens holds the potential for integration into micro-optical systems that demand dispersion control, providing broad applications in optical imaging, optical communication, the biomedical field, and beyond.

BackgroundSeveral observational studies have reported the correlation between gut microbiota and the risk of erectile dysfunction (ED). However, the causal association between them remained unestablished owing to intrinsic limitations, confounding factors, and reverse causality. Therefore, the two-sample Mendelian randomization (MR) study was performed to determine the causal effect of gut microbiota on the risk of ED.MethodsThe MR analysis utilized the publicly available genome-wide association study (GWAS) summary-level data to explore the causal associations between gut microbiota and ED. The gut microbiota data were extracted from the MiBioGen study (N = 18,340), and the ED data were extracted from the IEU Open GWAS (6,175 ED cases and 217,630 controls). The single nucleotide polymorphisms (SNPs) served as instrumental variables (IVs) by two thresholds of P-values, the first P-value setting as

Abstract Background Age‐related macular degeneration (AMD), particularly wet AMD characterised by choroidal neovascularization (CNV), is a leading cause of vision loss in the elderly. The hypoxia‐inducible factor‐1α (HIF‐1α)/vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) pathway contributes to CNV pathogenesis. Previous gene editing research indicated that disrupting these genes in retinal pigment epithelial cells could have a preventive effect on CNV progression. However, no studies have yet been conducted using gene editing to disrupt VEGF signalling after CNV induction for therapeutic validation, which is critical to the clinical application of wet AMD gene editing therapies. Method Here, we employed the single‐adeno‐associated virus‐mediated Nme2Cas9 to disrupt key molecules in VEGF signalling, Hif1α, Vegfa and Vegfr2 after inducing CNV and estimated their therapeutic effects. Results We found that Nme2Cas9 made efficient editing in target genes up to 71.8% post 11 days in vivo. And only Nme2Cas9‐Vegfa treatment during the early stage of CNV development reduced the CNV lesion area by 49.5%, compared to the negative control, while Nme2Cas9‐Hif1α or Nme2Cas9‐Vegfr2 treatment did not show therapeutic effect. Besides, no off‐target effects were observed in Nme2Cas9‐mediated gene editing in vivo. Conclusions This study provides proof‐of‐concept possibility of employing Nme2Cas9 for potential anti‐angiogenesis therapy in wet AMD.

The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development. However, its function in retina regeneration remains elusive. Here we report that Sox11b, a zebrafish Sox11 homolog, regulates the migration and fate determination of Müller glia-derived progenitors (MGPCs) in an adult zebrafish model of mechanical retinal injury. Following a stab injury, the expression of Sox11b was induced in proliferating MGPCs in the retina. Sox11b knockdown did not affect MGPC formation at 4 days post-injury, although the nuclear morphology and subsequent radial migration of MGPCs were altered. At 7 days post-injury, Sox11b knockdown resulted in an increased proportion of MGPCs in the inner retina and a decreased proportion of MGPCs in the outer nuclear layer, compared with controls. Furthermore, Sox11b knockdown led to reduced photoreceptor regeneration, while it increased the numbers of newborn amacrines and retinal ganglion cells. Finally, quantitative polymerase chain reaction analysis revealed that Sox11b regulated the expression of Notch signaling components in the retina, and Notch inhibition partially recapitulated the Sox11b knockdown phenotype, indicating that Notch signaling functions downstream of Sox11b. Our findings imply that Sox11b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish, which may have critical implications for future explorations of retinal repair in mammals.

Abstract Background Accumulating evidence implicates that gut fungi are associated with the pathogenesis of colorectal cancer (CRC). Our previous study has revealed that Candida tropicalis (C. tropicalis) promotes colorectal tumorigenesis by enhancing immunosuppressive function of myeloid-derived suppressor cells (MDSCs) and increasing accumulation of MDSCs, but the underlying mechanisms remain unestablished. Methods Bone marrow–derived MDSCs were stimulated with C. tropicalis. RNA-sequencing analysis was performed to screen the differentially expressed genes. Quantitative real-time PCR and western blot were used to measure the expression of related proteins. Co-culture assay of MDSCs and CD8+ T cells was used to determine the immunosuppressive ability of MDSCs. Metabolomic analysis was conducted to detect metabolic reprogramming of MDSCs. Aerobic glycolysis of MDSCs was assessed by extracellular acidification rate (ECAR), glucose consumption and lactate production. A CAC mouse model was induced by AOM and DSS to determine the therapeutic action of TEPP-46. IHC and immunofluorescence were performed to examine the expression of PKM2, PKM2 (p-Y105) and iNOS in human CRC-infiltrated MDSCs. Results C. tropicalis facilitates immunosuppressive function of MDSCs by increasing the expression of iNOS, COX2 and NOX2, production of nitric oxide (NO) and reactive oxygen species (ROS). Mechanistically, C. tropicalis facilitates the immunosuppressive function of MDSCs through the C-type lectin receptors Dectin-3 and Syk. C. tropicalis-enhanced immunosuppressive function of MDSCs is further dependent on aerobic glycolysis. On the one hand, NO produced by MDSCs enhanced aerobic glycolysis in a positive feedback manner. On the other hand, C. tropicalis promotes p-Syk binding to PKM2, which results in PKM2 Tyr105 phosphorylation and PKM2 nuclear translocation in MDSCs. Nuclear PKM2 interacts with HIF-1α and subsequently upregulates the expression of HIF-1α target genes encoding glycolytic enzymes, GLUT1, HK2, PKM2, LDHA and PDK1, which are required for the C. tropicalis-induced aerobic glycolysis of MDSCs. Blockade of PKM2 nuclear translocation attenuates C. tropicalis-mediated colorectal tumorigenesis. The high expression of PKM2, PKM2 (p-Y105) and iNOS in CRC-infiltrated MDSCs correlates with the development of human CRC. Conclusion C. tropicalis enhances immunosuppressive function of MDSCs via Syk-PKM2-HIF-1α-glycolysis signaling axis, which drives CRC. Therefore, we identify the Syk-PKM2-HIF-1α-glycolysis signaling axis as a potential therapeutic target for CRC.

Abstract Patients with teratozoospermia exhibit low phosducin-like protein (Pdcl2) expression. As a member of the phosducin family, chaperonin-related Pdcl2, a germline-specific gene, may be involved in germ cell protein folding. Given that PDCL2 is highly conserved in evolution, it may be indispensable for mammalian spermiogenesis; however, the function of PDCL2 in higher mammalian species remains unknown. To determine the role of PDCL2 in male fertility, we generated Pdcl2 knockout mice using CRISPR/Cas9. Our results revealed that Pdcl2 heterozygous (Pdcl2 +/− ) male mice were normal, but male Pdcl2-null (Pdcl2 −/− ) mice were infertile. Accordingly, Pdcl2 −/− male mice exhibited lower testis weight, epididymis weight, and sperm number than Pdcl2 +/+ mice. Moreover, Pdcl2 −/− mice displayed malformed and immotile sperm. Apoptotic cells were significantly enhanced in Pdcl2 −/− testes and epididymis when compared with those in wild-type mice. Mechanistically, PDCL2 can interact with the CCT complex, and dysfunction in this complex might lead to infertility in Pdcl2 −/− male mice. Collectively, these findings confirm that Pdcl2 knockout leads to male infertility in mice and that PDCL2 may function as a chaperone to promote protein folding during spermiogenesis.

The 2019 novel coronavirus disease (COVID-19) has lasted for over 3 years and has seriously affected the regular life trajectory of human beings. The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) has caused non-negligible harm to people’s respiratory systems and multiple organs. Although the pathogenesis of COVID-19 has been fully elucidated, there is still a lack of effective and specific treatment for COVID-19. Mesenchymal stem cells (MSCs) or MSC-derived extracellular vesicles (MSC-EVs) by far have become the most promising candidates in preclinical studies and clinical trials, and MSC-related therapies have shown their potential to treat severe COVID-19. The multidirectional differentiation potential and immunomodulatory function of MSCs have allowed the cells to exert multiple cellular and molecular actions on different immune cells and organs. It is critical to understand the therapeutic roles of MSCs before entering the clinics for COVID-19 and other diseases. This review summarizes the recent progress of particular mechanisms underlying the immunomodulatory and tissue regenerative effects of MSCs toward COVID-19. We focused on discussing the functional roles of MSC-mediated effects on immune cell responses, cell survival, and organ regeneration. Besides, the novel discoveries and recent findings of MSC clinical application in patients with COVID-19 were highlighted. This will provide an overview of the current research on the rapid development of MSC-based therapies not only for COVID-19 but also for other immune-mediated/immune-dysregulating diseases.

Most stars generate winds and move through the interstellar medium that surrounds them. This movement creates a cocoon formed by the deflection of these winds that envelops and protects the stars. We call these “cocoons” astrospheres. The Sun has its own cocoon, the heliosphere. The heliosphere is an immense shield that protects the Solar System from harsh, galactic radiation. The radiation that enters the heliosphere affects life on Earth as well as human space exploration. Galactic cosmic rays are the dominant source of radiation and principal hazard affecting space missions within our Solar System. Current global heliosphere models do not successfully predict the radiation environment at all locations or under different solar conditions. To understand the heliosphere’s shielding properties, we need to understand its structure and large-scale dynamics. A fortunate confluence of missions has provided the scientific community with a treasury of heliospheric data. However, fundamental features remain unknown. The vision of the Solar wind with Hydrogen Ion charge Exchange and Large-Scale Dynamics (SHIELD) DRIVE Science Center is to understand the nature and structure of the heliosphere. Through four integrated research thrusts leading to the global model, SHIELD will: 1) determine the global nature of the heliosphere; 2) determine how pickup ions evolve from “cradle to grave” and affect heliospheric processes; 3) establish how the heliosphere interacts with and influences the Local Interstellar Medium (LISM); and 4) establish how cosmic rays are filtered by and transported through the heliosphere. The key deliverable is a comprehensive, self-consistent, global model of the heliosphere that explains data from all relevant in situ and remote observations and predicts the radiation environment. SHIELD will develop a “digital twin” of the heliosphere capable of: (a) predicting how changing solar and LISM conditions affect life on Earth, (b) understanding the radiation environment to support long-duration space travel, and (c) contributing toward finding life elsewhere in the Galaxy. SHIELD also will train the next-generation of heliophysicists, a diverse community fluent in team science and skilled working in highly transdisciplinary collaborative environments.

Background: Sepsis is a fatal disease with a high rate of morbidity and mortality, during which acute lung injury is the earliest and most serious complication. Injury of pulmonary microvascular endothelial cells (PMVECs) induced by excessive inflammation plays an important role in sepsis acute lung injury. This study is meant to explore the protective effect and mechanism of ADSCs exosomes on excessive inflammation PMVECs injury. Results: We successfully isolated ADSCs exosomes, the characteristic of which were confirmed. ADSCs exosomes reduced excessive inflammatory response induced ROS accumulation and cell injury in PMVECs. Besides, ADSCs exosomes inhibited excessive inflammatory response induced ferroptosis while upregulated expression of GPX4 in PMVECs. And further GPX4 inhibition experiments revealed that ADSCs exosomes alleviated inflammatory response induced ferroptosis via upregulating GPX4. Meanwhile, ADSCs exosomes could increase the expression and nucleus translocation of Nrf2, while decrease the expression of Keap1. miRNA analysis and further inhibition experiments verified that specific delivery of miR-125b-5p by ADSCs exosomes inhibited Keap1 and alleviated ferroptosis. In CLP induced sepsis model, ADSCs exosomes could relieve the lung tissue injury and reduced the death rate. Besides, ADSCs exosomes alleviated oxidative stress injury and ferroptosis of lung tissue, while remarkably increase expression of Nrf2 and GPX4. Conclusion: Collectively, we illustrated a novel potentially therapeutic mechanism that miR-125b-5p in ADSCs exosomes could alleviate the inflammation induced PMVECs ferroptosis in sepsis induced acute lung injury via regulating Keap1/Nrf2/GPX4 expression, hence improve the acute lung injury in sepsis.

IntroductionTea is one of the most widely consumed beverages around the world. Larvae of the moth, Ectropis obliqua Prout (Geometridae, Lepidoptera), are one of the most destructive insect pests of tea in China. E. obliqua is a polyphagus insect that is of increasing concern due to the development of populations resistant to certain chemical insecticides. Microbial biological control agents offer an environmentally friendly and effective means for insect control that can be compatible with “green” and organic farming practices.MethodsTo identify novel E. obliqua biological control agents, soil and inset cadaver samples were collected from tea growing regions in the Fujian province, China. Isolates were analyzed morphologically and via molecular characterization to identity them at the species level. Laboratory and greenhouse insect bioassays were used to determine the effectiveness of the isolates for E. obliqua control.ResultsEleven isolates corresponding to ten different species of Metarhizium were identified according to morphological and molecular analyses from soil and/or insect cadavers found on tea plants and/or in the surrounding soil sampled from eight different regions within the Fujian province, China. Four species of Metarhizium including M. clavatum, M. indigoticum, M. pemphigi, and M. phasmatodeae were documented for the first time in China, and the other species were identified as M. anisopliae, M. brunneum, M. lepidiotae, M. majus, M. pinghaense, and M. robertsii. Insect bioassays of the eleven isolates of Metarhizium revealed significant variation in the efficacy of each isolate to infect and kill E. obliqua. Metarhizium pingshaense (MaFZ-13) showed the highest virulence reaching a host target mortality rate of 93% in laboratory bioassays. The median lethal concentration (LC50) and median lethal time (LT50) values of M. pingshaense MaFZ-13 were 9.6 × 104 conidia/mL and 4.8 days, respectively. Greenhouse experiments and a time-dose-mortality (TDM) models were used to further evaluate and confirm the fungal pathogenic potential of M. pingshaense MaFZ-13 against E. obliqua larvae.DiscussionIsolation of indigenous microbial biological control agents targeting specific pests is an effective approach for collecting resources that can be exploited for pest control with lowered obstacles to approval and commercialization. Our data show the presence of four different previously unreported Metarhizium species in China. Bioassays of the eleven different Metarhizium strains isolated revealed that each could infect and kill E. obliqua to different degrees with the newly isolated M. pingshaense MaFZ-13 strain representing a particularly highly virulent isolate potentially applicable for the control of E. obliqua larvae.

P2X receptors, including seven subtypes, i.e., P2X1-7, are the ligand-gated ion channels activated by the extracellular ATP playing the critical roles in inflammation and immune response. Even though the immune functions of P2X receptors have been characterized extensively in mammals, their functions in fish remain largely unknown. In this study, four P2X receptor homologues were characterized in spotted sea bass (Lateolabrax maculatus), which were named LmP2X2, LmP2X4, LmP2X5, and LmP2X7. Their tissue distributions and expression patterns were then investigated by real-time quantitative PCR (qPCR). Furthermore, their functions in regulating the expressions of inflammation-associated genes and possible signaling pathway were examined by qPCR and luciferase assay. The results showed that they share similar topological structures, conserved genomic organization, and gene synteny with their counterparts in other species previously investigated. And the four P2X receptors were expressed constitutively in the tested tissues. In addition, the expression of each of the four receptor genes was significantly induced by stimulation of Edwardsiella tarda and/or pathogen-associated molecular patterns (PAMPs) in vivo. Also, in primary head kidney leukocytes of spotted sea bass, LmP2X2 and LmP2X5 were induced by using PAMPs and/or ATP. Notably, the expressions of CCL2, IL-8, and TNF-α recognized as the pro-inflammatory cytokines, and of the four apoptosis-related genes, i.e., caspase3, caspase6, caspase7, and P53, were differentially upregulated in the HEK 293T cells with over-expressed LmP2X2 and/or LmP2X7 following ATP stimulation. Also, the over-expression of LmP2X4 can upregulate the expressions of IL-8, caspase6, caspase7, and P53, and LmP2X5 upregulates of IL-8, TNF-α, caspase7, and P53. Then in the present study it was demonstrated that the activation of any one of the four receptors significantly upregulated the activity of NF-κB promoter, suggesting that the activated LmP2Xs may regulate the expressions of pro-inflammatory cytokines via the NF-κB pathway. Taken together, the four P2X receptors were identified firstly from fish species in Perciformes, and they participate in innate immune response of spotted sea bass possibly by regulating the expressions of the inflammation-related genes. Our study provides the new evidences for the P2X receptors’ involvement in fish immunity.

The charge exchange between the interstellar medium and the solar wind plasma is crucial for determining the structures of the heliosphere. Since both the neutral-ion and neutral–neutral collision mean free paths are either comparable to or larger than the size of the heliosphere, the neutral phase space distribution can deviate far away from the Maxwellian distribution. A kinetic description for the neutrals is crucial for accurately modeling the heliosphere. It is computationally challenging to run three-dimensional time-dependent kinetic simulations due to the large number of macroparticles. In this paper, we present the new highly efficient Solar Wind with Hydrogen Ion Exchange and Large-scale Dynamics-2 model with a kinetic model of neutrals and a magnetohydrodynamic model for the ions and electrons. To improve the simulation efficiency, we implement adaptive mesh refinement and particle splitting and merging algorithms for the neutral particles to reduce the particle number that is required for an accurate simulation. We present several tests to verify and demonstrate the capabilities of the model.

The characterization of natural fungal diversity impacts our understanding of ecological and evolutionary processes and can lead to novel bioproduct discovery. Russula and Lactarius, both in the order Russulales, represent two large genera of ectomycorrhizal fungi that include edible as well as toxic varieties. Based on morphological and phylogenetic analyses, including nucleotide sequences of the internal transcribed spacer (ITS), the 28S large subunit of ribosomal RNA (LSU), the second largest subunit of RNA polymerase II (RPB2), the ribosomal mitochondrial small subunit (mtSSU), and the translation elongation factor 1-α (TEF1-α) gene sequences, we here describe and illustrate two new species of Russula and one new species of Lactarius from southern China. These three new species are: R. junzifengensis (R. subsect. Virescentinae), R. zonatus (R. subsect. Crassotunicatae), and L. jianyangensis (L. subsect. Zonarii).

The coronal heating problem has been a major challenge in solar physics, and a tremendous amount of effort has been made over the past several decades to solve it. In this paper, we aim at answering how the physical processes behind the Alfvén wave turbulent heating adopted in the Alfvén Wave Solar atmosphere Model (AWSoM) unfold in individual plasma loops in an active region (AR). We perform comprehensive investigations in a statistical manner on the wave dissipation and reflection, temperature distribution, heating scaling laws, and energy balance along the loops, providing in-depth insights into the energy allocation in the lower solar atmosphere. We demonstrate that our 3D global model with a physics-based phenomenological formulation for the Alfvén wave turbulent heating yields a heating rate exponentially decreasing from loop footpoints to top, which had been empirically assumed in the past literature. A detailed differential emission measure (DEM) analysis of the AR is also performed, and the simulation compares favorably with DEM curves obtained from Hinode/Extreme-ultraviolet Imaging Spectrometer observations. This is the first work to examine the detailed AR energetics of our AWSoM model with high numerical resolution and further demonstrates the capabilities of low-frequency Alfvén wave turbulent heating in producing realistic plasma properties and energetics in an AR.

Little is known concerning terpenoids produced by members of the fungal order Ophiostomales, with the member Harringtonia lauricola having the unique lifestyle of being a beetle symbiont but potentially devastating tree pathogen. Nine known terpenoids, including six labdane diterpenoids (1–6) and three hopane triterpenes (7–9), were isolated from H. lauricola ethyl acetate (EtOAc) extracts for the first time. All compounds were tested for various in vitro bioactivities. Six compounds, 2, 4, 5, 6, 7, and 9, are described functionally. Compounds 2, 4, 5, and 9 expressed potent antiproliferative activity against the MCF-7, HepG2 and A549 cancer cell lines, with half-maximal inhibitory concentrations (IC50s) ~12.54–26.06 μM. Antimicrobial activity bioassays revealed that compounds 4, 5, and 9 exhibited substantial effects against Gram-negative bacteria (Escherichia coli and Ralstonia solanacearum) with minimum inhibitory concentration (MIC) values between 3.13 and 12.50 μg/mL. Little activity was seen towards Gram-positive bacteria for any of the compounds, whereas compounds 2, 4, 7, and 9 expressed antifungal activities (Fusarium oxysporum) with MIC values ranging from 6.25 to 25.00 μg/mL. Compounds 4, 5, and 9 also displayed free radical scavenging abilities towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide (O2−), with IC50 values of compounds 2, 4, and 6 ~3.45–14.04 μg/mL and 22.87–53.31 μg/mL towards DPPH and O2−, respectively. These data provide an insight into the biopharmaceutical potential of terpenoids from this group of fungal insect symbionts and plant pathogens.

The insect pathogenic fungus, Ascosphaera apis, is the causative agent of honeybee chalk brood disease. Amylases are secreted by many plant pathogenic fungi to access host nutrients through the metabolism of starch, and the identification of new amylases can have important biotechnological applications. Production of amylase by A. apis in submerged culture was optimized using the response surface method (RSM). Media composition was modeled using Box–Behnken design (BBD) at three levels of three variables, and the model was experimentally validated to predict amylase activity (R2 = 0.9528). Amylase activity was highest (45.28 ± 1.16 U/mL, mean ± SE) in media composed of 46 g/L maltose and1.51 g/L CaCl2 at a pH of 6.6, where total activity was ~11-fold greater as compared to standard basal media. The enzyme was purified to homogeneity with a 2.5% yield and 14-fold purification. The purified enzyme had a molecular weight of 75 kDa and was thermostable and active in a broad pH range (> 80% activity at a pH range of 7–10), with optimal activity at 55 °C and pH = 7.5. Kinetic analyses revealed a Km of 6.22 mmol/L and a Vmax of 4.21 μmol/mL·min using soluble starch as the substrate. Activity was significantly stimulated by Fe2+ and completely inhibited by Cu2+, Mn2+, and Ba2+ (10 mM). Ethanol and chloroform (10% v/v) also caused significant levels of inhibition. The purified amylase essentially exhibited activity only on hydrolyzed soluble starch, producing mainly glucose and maltose, indicating that it is an endo-amylase (α-amylase). Amylase activity peaked at 99.38 U/mL fermented in a 3.7 L-bioreactor (2.15-fold greater than what was observed in flask cultures). These data provide a strategy for optimizing the production of enzymes from fungi and provide insight into the α-amylase of A. apis.

Abstract Background Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Results Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Conclusions Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis.

In fish, the immune system plays a crucial role in defending against pathogen-induced infections. The interleukin 17 (IL-17) family, which is a well-studied class of cytokines, serves as a key component of the immune response against external pathogens. In this research, four IL-17 ligands (IL-17A/F1, IL-17B, IL-17C and IL-17D) and one receptor (IL-17RB) genes were identified from spotted sea bass (Lateolabrax maculatus). Alignment analysis showed that the C-terminal region of IL-17 ligands in spotted sea bass was highly conserved. The expression of the IL-17 ligand and receptor genes differed in unstimulated tissues. To investigate the impact of various factors on the immune response of spotted sea bass, we assessed the effect of lipopolysaccharide (LPS), polyinosinic–polycytidylic acid [poly (I:C)] and Edwardsiella tarda treatment on the IL-17 ligands and receptor responses. Our results reveal that the expression of the IL-17 ligand and receptor transcripts is modulated by LPS, poly (I:C) and E. tarda, indicating their significant role in the immune system.

Collisionless magnetic reconnection typically requires kinetic treatment that is, in general, computationally expensive compared to fluid-based models. In this study, we use the magnetohydrodynamics with an adaptively embedded particle-in-cell (MHD-AEPIC) model to study the interaction of two magnetic flux ropes. This innovative model embeds one or more adaptive PIC regions into a global MHD simulation domain such that the kinetic treatment is only applied in regions where the kinetic physics is prominent. We compare the simulation results among three cases: (1) MHD with adaptively embedded PIC regions, (2) MHD with statically (or fixed) embedded PIC regions, and (3) a full PIC simulation. The comparison yields good agreement when analyzing their reconnection rates and magnetic island separations as well as the ion pressure tensor elements and ion agyrotropy. In order to reach good agreement among the three cases, large adaptive PIC regions are needed within the MHD domain, which indicates that the magnetic island coalescence problem is highly kinetic in nature, where the coupling between the macro-scale MHD and micro-scale kinetic physics is important.

Aim: Quxie capsule (QX), a compound of 21 kinds of Traditional Chinese Medicine (TCM) herbs, has been used to treat patients with metastatic colorectal cancer (mCRC) and could suppress the growth of colon cancer. However, the mechanisms of QX inhibiting colorectal cancer remain unclear. In current study, we attempted to determine the anti-colorectal cancer (CRC) effects of QX and the mechanisms of QX in alleviating colorectal cancer. Methods: A colitis-associated colon cancer (CAC) model was established by intraperitoneally injecting mice with AOM followed by 3 cycles of 2% DSS in water. During establishment of CAC model, we orally gavaged mice with QX. Hematoxylin and eosin (H&E) and immunohistochemistry were performed to assess lesion of the colonic tumors. The expression of pro-inflammatory cytokines in colonic tumors was measured by qPCR. The proportion of immune cells in colonic tumors was analyzed by flow cytometry. Internal transcribed spacer (ITS) sequencing and 16S rRNA gene sequencing were performed to detect intestinal microbiota. The expression of glycolytic related enzymes, lactate production, and extracellular acidification rate (ECAR) were used to assess the level of aerobic glycolysis. Results: QX markedly inhibited intestinal tumorigenesis by decreasing the expression of pro-inflammatory cytokines and the proportion of myeloid-derived suppressor cells (MDSCs), and increasing the proportion of CD8 + T cells in colon tumors. Fecal microbiota sequencing revealed that QX increased the relative abundances of intestinal symbiotic probiotics, such as, Lactobacillus , Bifidobacterium and Faecalibacterium genera. What’s more, opportunistic pathogens, Bacteroides genera and Aspergillus - Aspergillus fumigatus , exhibited remarkably reduced abundances in mice treated with QX compared with untreated CAC mice. Further experiments showed that QX significantly reduced glycolysis of colon tumor and suppressed A. fumigatus -induced glycolytic metabolism of colon cancer cells. Conclusions: QX alleviates the development of CRC at least in part through modulating intestinal microbiota and reducing A. fumigatus -induced aerobic glycolysis of colon cancer cells.

In this study, we analyzed the clay mineralogy and geochemistry of surface and drill core samples from the northeastern Beibu Gulf in order to unravel the sediment provenance of, and factors controlling, the sedimentary environment. The main clay mineral assemblage in the surface sediment samples included kaolinite (27–72%), smectite (4–51%), illite (7–20%), and chlorite (8–17%). The study area comprises three major clay distribution zones (from the northeastern coastal area to central Beibu Gulf basin), i.e., the kaolinite-dominated, kaolinite–smectite, and smectite-dominated zones. The zoning of the clay mineralogy and major and trace elements indicated the mixing of coarse terrigenous sediments with distal fine sediments. Early Holocene sea level rise was documented in core B15-1, which had three sedimentary units (divided into Units 1–3 from top to bottom), as revealed by the changes in the dominant clay minerals and geochemical/oxide ratios (SiO2/Al2O3, Rb/Sr, Sr/Ba, and Ti/Ca) in Unit 2. Unit 1 and Unit 3 were likely deposited in the continental and marine environments, respectively. The low sedimentation rate and hydrodynamic disturbance may have influenced the deposition process more than climatic fluctuations.

The water immersion of Pterocarpus wood produces strong blue fluorescence, which comes from the extract. The fluorescence contained in the extract is of interest for the identification of Pterocarpus wood. We conducted an investigation into the extraction solution of Pterocarpus wood and analyzed the mechanism of fluorescence in this species. Possible species of the fluorescent molecules are discussed based on the mixture. Liquid chromatography mass spectrometry (LC-MS) is used for an analysis of the extract, the obtained substances that may be fluorescent in Pterocarpus wood. In addition, the change in the fluorescence intensity with changes in the pH and concentration in the extract is also studied. The results show that the fluorescent molecule is quenched by aggregation (Aggregation-Caused Quenching; ACQ) and is unstable in over-acidic and over-alkaline conditions (especially acidic).

Marbling characteristics are important traits for the genetic improvement of pork quality. Accurate marbling segmentation is the prerequisite for the quantification of these traits. However, the marbling targets are small and thin with dissimilar sizes and shapes and scattered in pork, complicating the segmentation task. Here, we proposed a deep learning-based pipeline, a shallow context encoder network (Marbling-Net) with the usage of patch-based training strategy and image up-sampling to accurately segment marbling regions from images of pork longissimus dorsi (LD) collected by smartphones. A total of 173 images of pork LD were acquired from different pigs and released as a pixel-wise annotation marbling dataset, the pork marbling dataset 2023 (PMD2023). The proposed pipeline achieved an IoU of 76.8%, a precision of 87.8%, a recall of 86.0%, and an F1-score of 86.9% on PMD2023, outperforming the state-of-art counterparts. The marbling ratios in 100 images of pork LD are highly correlated with marbling scores and intramuscular fat content measured by the spectrometer method (R2 = 0.884 and 0.733, respectively), demonstrating the reliability of our method. The trained model could be deployed in mobile platforms to accurately quantify pork marbling characteristics, benefiting the pork quality breeding and meat industry.

Abstract Background Exploring etiological clues to adolescent depression, especially in female adolescents, might be helpful to improve the social environment of female adolescents. The aim at this study is to explore psycho-social factors of female adolescents with high depressive symptomatology and gender differences in depressive symptoms among Chinese adolescents. Method We examined 4100 adolescents from Wuhan city and Jianli county via a cross-sectional study. Depressive symptomatology was screened through the Chinese version of Center for Epidemiology Studies Depression Scale. Multivariate logistic regression was performed to explore the factors related to high depressive symptomatology in female and male adolescents, respectively. Results The prevalence of high depressive symptomatology in female and male were 38.9 and 30.2% respectively. The psycho-social factors of high depressive symptomatology in female adolescents were age (Adjusted odds ratio [aOR] = 1.201, 95% confidence interval [CI], 1.076 ~ 1.341), single parent family (aOR = 2.004, 95%CI, 1.448 ~ 2.772) and fathers’ education level (compared to primary school and below, [Junior middle school, aOR = 0.641, 95%CI, 0.439 ~ 0.934; Senior middle school, aOR = 0.603, 95%CI, 0.410 ~ 0.888; College degree and above, aOR = 0.639, 95%CI, 0.437 ~ 0.936]). Conclusion Fathers’ education level was associated with high depressive symptomatology in female adolescents. Female adolescents whose father with primary school education or below deserves more attention. Further epidemiologic researches need to be conducted to explore the different risk factors between female and male adolescents in China.