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Abstract Background and Aim Visceral fat (VF) was proved to be a more precise predictor of atherosclerotic cardiovascular disease (ASCVD) risk in individuals with type 2 diabetes mellitus (T2DM) than body mass index (BMI) itself. Even when the BMI was normal, visceral fat area (VFA) ≥ 90 cm² could raise the ten-year risk of developing ASCVD. Therefore, it was worth evaluating the association of influencing factors with high VF in non-obese T2DM individuals. Methods This study enrolled 1,409 T2DM participants with T2DM, of whom 538 had a normal BMI. Based on VFA, these subjects were divided into two groups: VF (+) (VFA ≥ 90cm2) (n = 110) and VF (-) (VFA

Abstract Proteinopathies in neurology typically refer to pathological changes in proteins associated with neurological diseases, such as the aggregation of amyloid β and Tau in Alzheimer’s disease, α-synuclein in Parkinson’s disease and multiple system atrophy, and TAR DNA-binding protein 43 in amyotrophic lateral sclerosis and frontotemporal dementia. Interestingly, these proteins are also commonly found in peripheral tissues, raising important questions about their roles in neurological disorders. Multiple studies have shown that peripherally derived pathological proteins not only travel to the brain through various routes, aggravating brain pathology, but also contribute significantly to peripheral dysfunction, highlighting their crucial impact on neurological diseases. Investigating how these peripherally derived proteins influence the progression of neurological disorders could open new horizons for achieving early diagnosis and treatment. This review summarizes the distribution, transportation pathways, and pathogenic mechanisms of several neurodegenerative disease-related pathological proteins in the periphery, proposing that targeting these peripheral pathological proteins could be a promising strategy for preventing and managing neurological diseases.

Abstract Anxiety disorder, a prevalent mental health issue, is one of the leading causes of disability worldwide. Damage to the blood–brain barrier (BBB) is implicated in anxiety, but its regulatory mechanisms remain unclear. Herein, we show that adrenomedullin 2 (ADM2), a novel angiogenic growth factor, alleviates autistic and anxiety-like behaviors in mice. Based on transcriptome analysis and biochemical analyses, we found that ADM2 facilitates the expression of insulin-like growth factor 2 (IGF-II), which then triggers the activation of the AKT-GSK3β-mTOR signaling pathway via the IGF-II receptor (IGF-IIR), rather than the IGF-I receptor (IGF-IR). Furthermore, as evidenced by increased Evans blue staining and decreased VE-cadherin levels, the BBB exhibited dysfunction in ADM2 knockout mice with anxiety-like behaviors. In in vitro studies, ADM2 administration promoted the expression of VE-cadherin and decreased IGF-II leakage through the endothelial barrier in a BBB model. Taken together, ADM2 may alleviate anxiety-like behavior and social deficits by enhancing BBB integrity and increasing IGF-II levels in the brain. These findings highlight the potential of ADM2 as a therapeutic target for anxiety and related mental disorders.

Abstract Background The prevalence of type 2 diabetes (T2D) and asthma is rising, yet evidence regarding the relationship between T2D and asthma, particularly in the context of genetic predispositions, remains limited. Methods This study utilized data from the UK Biobank longitudinal cohort, involving 388,775 participants. A polygenic risk score (PRS) for asthma was derived from genome-wide association studies summary. Cox regression models were used to assess the association between T2D and asthma, incorporating the asthma PRS. Results Over a median follow-up of 13.62 years, 10,211 asthma cases were documented. After adjusting for age, sex, current smoking status, and other confounding variables, T2D was significantly associated with an increased risk of developing asthma (Hazard Ratios [HR] 1.16, 95% confidence interval [CI] 1.06–1.26). This association remained significant after further adjustments for genetic susceptibility to asthma. Furthermore, T2D increased the risk of developing asthma across both high and low genetic risk groups. Conclusions T2D is associated with an increased risk of developing asthma, irrespective of genetic susceptibility. These findings underscore the importance of incorporating glucose regulation strategies into asthma prevention efforts.

Abstract In recent years, the development of immunosuppression has become common, and probiotics are a vital immunomodulatory strategy. This study evaluated the alleviating effect of Lactiplantibacillus plantarum (L. plantarum) YY‐112 on cyclophosphamide‐induced immune imbalance and resolved the possible mechanism of action. L. plantarum YY‐112 at 109 CFU/mL lowered loss of body weight and alleviated splenic injury, intestinal injury, and inflammation, according to the hematoxylin and eosin staining. Biochemical results showed that 109 CFU/mL L. plantarum YY‐112 increased interleukin‐10 and immunoglobulin M levels and decreased interferon‐γ levels. Additionally, the immunoregulatory effect at the molecular levels of L. plantarum YY‐112 was analyzed by transcriptome sequencing. L. plantarum YY‐112 significantly upregulated Cr2 and downregulated C5aR1 to regulate the complement system; downregulated S100a8, S100a9, and Mmp9 to inhibit neutrophil aggregation; upregulated Cd19, Cd72, Cd3e, Cd28, Cd80, Cd8a, and histocompatibility‐2‐related genes to regulate B‐ and T‐cell activation; and upregulated Xiap, Malt1, Ikbkb, Mapk11, Mef2c, Mapk12, Ras, and Myc to activate immune signaling pathways. Furthermore, L. plantarum YY‐112 improved intestinal microbial structure and reduced enrichment of Lachnospiraceae_NK4A136_group, norank_f_Lachnospiraceae, Desulfovibrio, Colidextribacter, and Helicobacter. In conclusion, these findings offer valuable insights into the potential mechanisms through which L. plantarum YY‐112 regulates immune imbalance.

Abstract In the context of a highly dynamic environment, there has been a notable focus on the development of innovative knowledge assets. The objective of this paper is to investigate whether there is a relationship between CEO power and innovative knowledge assets, and to examine the joint moderating effect of firm size and firm age on that relationship. This can help to achieve the United Nations Sustainable Development Goals (SDGs) like 8: promote sustained, inclusive and sustainable economic growth and 9: promote inclusive and sustainable industrialization and foster innovation. This paper empirically tested the hypotheses based on a sample of manufacturing firms listed on the Shanghai and Shenzhen Stock Exchanges from 2009 to 2019. The fixed effect model was employed to examine the relationship between CEO power and innovative knowledge assets, as well as the joint moderating effect of firm size and firm age. The research results showed that there is a significant positive relationship between CEO power and innovative knowledge assets. Moreover, the significant positive relationship between CEO power and innovative knowledge assets is stronger in larger and older firms. This paper contributes to the existing literature on CEO power and firm innovation, and also offering valuable insights for firms seeking to develop innovative knowledge assets.

Abstract Objective This retrospective cohort study aims to evaluate and compare different postoperative pain management strategies for esophageal squamous cell carcinoma (ESCC), in order to provide scientific evidence for clinical practice and decision-making. Methods A total of 274 ESCC patients who underwent surgery at the Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University were included in the study. Of these, 127 received conventional nursing decisions for postoperative pain management, and 147 received the “5 + nursing” postoperative pain management strategy. The main observation indicators of both groups included postoperative pain score, analgesic dosage, postoperative analgesic side effects, and length of hospital stays. Results The “5 + nursing” postoperative pain management group showed significantly lower postoperative pain score and significantly shorter length of hospital stays than the conventional nursing group. There was no significant difference in postoperative analgesic side effects between the two groups. Multiple logistic regression analysis showed that the postoperative pain score is an independent risk factor for predicting postoperative arrhythmias in ESCC patients. When the daily average dose of opioids used postoperatively was between 37.5 and 50 mg, the patient’s postoperative pain score dropped the fastest. Conclusion The “5 + nursing” pain management strategy can effectively reduce the degree of postoperative pain and shorten the length of hospital stays, improving patient’s quality of life. Our research emphasizes the importance of opioids in postoperative pain management, as well as the need for individualized perioperative pain management strategies.

Objective: Mume fructus is commonly used in traditional Chinese medicine to treat nocturnal asthma symptoms. However, the molecular mechanisms underlying its effects on nocturnal asthma have not yet been established. This study evaluated the therapeutic mechanisms of Mume fructus in treating nocturnal asthma. Materials and Methods: Network pharmacology was used to investigate the chemical composition, critical targets, and potential mechanisms of action of Mume fructus in treating nocturnal asthma. “Mume fructus” and “nocturnal asthma” were used as keywords to search the relevant databases. The 16HBE and RAW264.7 cells were treated with various concentrations of Mume fructus and lipopolysaccharides (LPSs). Data provided included analyses of cell viability detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, cell proliferation and apoptosis detected by 5-ethynyl-2’-deoxyuridine and Hoechst 33342, messenger ribonucleic acid (mRNA) levels obtained by real-time polymerase chain reaction, and protein expression detected by Western blotting. Additionally, immunofluorescence was used to detect nuclear translocation. Results: Network pharmacology analyses were mainly enriched in nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathway, and interleukin (IL)-6. Mume fructus and LPS had no effect on viability, proliferation, and apoptosis in 16HBE and RAW264.7 cells under certain concentration conditions. Mume fructus counteracted LPS-stimulated mRNA and protein expression of IL-6. In addition, Mume fructus treatment prevented the LPS-induced phosphorylation of NF-κB and MAPK pathways, as well as the nuclear translocation of NF-κB p-p65 in the 16HBE and RAW264.7 cells. Conclusions: Mume fructus can treat nocturnal asthma by regulating the NF-κB and MAPK pathways and counteracting IL-6 expression. These findings provide a scientific basis for the use of Mume fructus in the treatment of nocturnal asthma.

Abstract A strategy was proposed to predict accurately the dielectric permittivity and dielectric strength based on the Onsager local field theory. The molecular dynamic simulation was utilised to analyse the dipole moment fluctuation in polyimide (PI) to reflect the polarisation response of applied electric field. The simulation results revealed that the optical dielectric permittivity and static dielectric permittivity were 2.62 and 3.34, showing that the electronic displacement polarisation of the PI acted as a major contributor. The deviation between simulated and measured values of the frequency‐dependent relative dielectric permittivity was no more than 5%, which exhibited high accuracy. As the polarisation response of the polar groups in the PI was at infrared frequencies, the conductive loss may be the dominant role in 102–106 Hz at room temperature. Moreover, the effect of Joule heat on the structure, dielectric permittivity and Young modulus was considered to accurately predict the dielectric strength of the PI (359 kV/mm), which was in agreement with experimental values in the literature. These results establish a clear correlation between structural characteristics and dielectric properties of the PI, which would be the theoretical insights into the design and synthesis of the PI with tailored dielectric properties.

Abstract Abdominal aortic aneurysm is a potentially fatal vascular inflammatory disease characterized by infiltration of various inflammatory cells.The GABA-A receptor is expressed in many inflammatory cells such as macrophages and T cells and has anti-inflammatory and antioxidant effects. Therefore, the GABA-A receptor may become a potential therapeutic target for abdominal aortic aneurysms. The purpose of this study was to investigate the effect of regulating the activity of the GABA-A receptor on the formation of experimental abdominal aortic aneurysm in rats. In this study, the abdominal aortic aneurysm model of rats was established by aorta intracavitary perfusion of elastase combined with aorta extracavitary infiltration of calcium chloride. GABA-A receptor agonist (topiramate) and antagonist (bicuculline) were used to treating the abdominal aortic aneurysm model rats, which were divided into sham operation group, model group, topiramate group, and bicuculline group(n = 10). Histopathology, immunohistochemistry, fluorescence quantitative PCR, Western blotting, ELISA and Gelatine zymogram were used to study. Regulation of GABA-A receptor activity can interfere with the development and severity of abdominal aortic aneurysms in rats. The GABA-A receptor agonist topiramate reduces the infiltration of inflammatory cells, particularly T cells, into the abdominal aortic wall, while also modulating the balance of Th1/Th2 cytokines in peripheral blood, leading to a significant reduction in inflammatory responses. Additionally, topiramate decreases the secretion of matrix metalloproteinases MMP2 and MMP9, thereby inhibiting extracellular matrix degradation and slowing the progression of aneurysms. In contrast, the GABA-A receptor antagonist bicuculline exacerbates inflammation and promotes aneurysm development. At the molecular level, the mechanisms of action of the GABA-A receptor agonist topiramate and the antagonist bicuculline may involve inhibition or activation of the p38 MAPK signaling pathway. Regulation of GABA-A receptor activity can effectively intervene in the occurrence and development of abdominal aortic aneurysms in rats.

Abstract Background The phenomenon of growth in drug consumption within the framework of national volume-based procurement (VBP) policy raises speculations about demand release and policy inducing. This study aims to explore the reasons and mechanisms of drug consumption increases following VBP policy from two perspectives. Methods We collected data from the China Drug Supply Information Platform, National Bureau of Statistics and the Joint Procurement Office. Twenty cardiovascular international non-proprietary names (INNs) in the first three VBP batches and 28 observation regions were included, constructing 418 valid INN-region combinations as the unit for analysis. The average monthly consumption volume of VBP cardiovascular drug was assigned as the explained variable. The generalized difference-in-difference method was conducted using the price reduction level and the size of policy assessment task as the policy intensity indicator. Moderating effect model was employed to examine the role of resident’s income level. Results Increased cardiovascular drug consumption was observed in 285 (68.18%) INN-region combinations after policy implementation. Under VBP policy, the price reduction level was significantly correlated with drug consumption in total (β = 0.144, p 0.05). The size of policy assessment task was positively associated with drug consumption in total (β = 0.052, p

Gln, one of the most abundant amino acids (AA) in the body, performs a diverse range of fundamental physiological functions. However, information about the role of dietary Gln on AA levels, transporters, protein synthesis, and underlying mechanisms in vivo is scarce. The present study aimed to explore the effects of low-crude protein diet inclusion with differential doses of L-Gln on intestinal AA levels, transporters, protein synthesis, and potential mechanisms in weaned piglets. A total of 128 healthy weaned piglets (Landrace × Yorkshire) were randomly allocated into four treatments with four replicates. Pigs in the four groups were fed a low-crude protein diet containing 0%, 1%, 2%, or 3% L-Gln for 28 d. L-Gln administration markedly (linear, P

Objective: To investigate the physicochemical properties and functional changes of the polysaccharides prepared from Sargassum fusiforme by different combinations of enzymes. Methods: Six enzyme combinations of cellulase-alcalase (C-A), pectinase-alcalase (P-A), viscozyme-alcalase (V-A), cellulase-neutrase (C-N), pectinase-neutrase (P-N), and viscozyme-neutrase (V-N) were used to assist the extraction of polysaccharides from Sargassum fusiforme. The physicochemical properties, structural composition, and antioxidant activity in vitro and in vivo of Sargassum fusiforme polysaccharides prepared by six combined enzymes were analyzed. Results: The contents of total sugar, uronic acid and sulfate in the polysaccharides prepared by the six combined enzymes changed greatly, and the monosaccharide composition and chemical structure were similar. The total sugar content and polysaccharide yield of the C-N group were the highest. The reducing power of Fe2+ and DPPH radical scavenging capacity of polysaccharides were the highest in the V-N group, amounting to 0.103±0.003 (Abs) and 0.540±0.022 (mg/mL) (IC50), respectively, and in the P-N group, the hydroxyl radical scavenging capacity of polysaccharides was the highest at 1.341±0.265 (mg/mL) (IC50). The polysaccharides prepared by different combined enzymes had different protective effects on AAPH-induced oxidative stress. Among them, compared with the NO group, the polysaccharides in the P-A, C-A, V-A and P-N groups had a stronger ability to reduce reactive oxygen species. The polysaccharides in the P-A, P-N and V-N groups had significant lipid peroxidation inhibition. Compared with the induction group, the polysaccharides in the C-N and V-N groups significantly increased CAT enzyme activity (P

Abstract Plant‐wide processes are usually characterized by large scale, multiple operating units and complicated interactions. Effective monitoring for such processes is imperative and challenging. Traditional data‐driven methods have some limitations due to the neglect of internal relationships between operating units. This paper proposes a plant‐wide monitoring and diagnostic framework based on the multi‐variate statistical analysis and causal graphical inference. Initially, the optimized process decomposition is performed by combining the mechanistic knowledge and historical data from the perspective of improving the monitoring performance. Taking into account the fact that shared variables among the different subsystems lead to the information interaction rather than being independent as in the existing methods, the multi‐variate causal model based on probability density estimation is established to identify the quantitative association of the process variables in a single subsystem. The complete model is structured by the link of shared variables. Finally, system anomalies are detected by changes in the probability density of the observed variables; the root cause is pinpointed by the causal inference. Experiments with the Tenessee Eastman (TE) process and Panamax bulk carriers demonstrate the applicability of the proposed methodology.

Abstract Asian cultivated rice (Oryza sativa L.) is the most important cultivated species in the AA genome species of the genus Oryza. basmati is a special and famous subgroup in Asian cultivated rice, and temperate japonica is one of the most important cultivated subgroup, too. However, hybrid sterility hinders the introgression of favorable traits and the utilization of hybrid vigour between the two subgroups. The genetic basis of intraspecific hybrid sterility between temperate japonica and basmati remained elusive. In this study, a novel hybrid sterility locus S67 was identified, which caused hybrid male sterility in hybrids between the temperate japonica rice variety Dianjingyou 1 (DJY1) and the basmati rice variety Dom-sufid. Initial mapping with BC1F1, BC4F1, BC4F2 populations and DNA markers located S67 between RM5362 and K1-40.6 on the long arm of chromosome 1. Genetic analysis confirmed that S67 caused a transmission advantage for the temperate japonica rice S67-te allele in the hybrid offsprings. This result not only fills the gap in the research on hybrid sterility between basmati and temperate japonica, but also lays a good foundation for the systematic study of the genetic nature of hybrid sterility between basmati and other subgroups, as well as the full exploration and utilization of this subgroup through the creation of wide or specific compatibility lines to overcome hybrid sterility. In addition, this result can also help us broaden our understanding of genetic differentiation within Asian cultivated rice and hybrid sterility between inter-subgroups.

Abstract Improved treatment options are urgently needed for neurological injuries resulting from trauma or iatrogenic events causing long-term disabilities that severely impact patients’ quality of life. In vitro and animal studies have provided promising proof-of-concept examples of regenerative therapies using mesenchymal stromal cells (MSC) for a wide range of pathological conditions. Over the previous decade, various MSC-based therapies have been investigated in clinical trials to treat traumatic neurological injuries. However, while the safety and feasibility of MSC treatments has been established, the patient outcomes in these studies have not demonstrated significant success in the translation of MSC regenerative therapy for the treatment of human brain and spinal cord injuries. Herein, we have reviewed the literature and ongoing registered trials on the application of MSC for the treatment of traumatic brain injury, traumatic spinal cord injury, and peripheral nerve injury. We have focused on the shortcomings and technological hurdles that must be overcome to further advance clinical research to phase 3 trials, and we discuss recent advancements that represent potential solutions to these obstacles to progress.

Abstract Background The association of lipoprotein-associated phospholipase A2 (Lp-PLA2) with various cardiovascular events has been well-established. However, the exploration of its potential involvement in Chronic obstructive pulmonary disease (COPD) is currently limited. Therefore, our study aims to examine the relationship between Lp-PLA2 and pulmonary conditions, including emphysema, obstructive ventilatory dysfunction as well as small airway dysfunction, to provide further evidence of a possible association with COPD development. Methods Using data from the Southwest Hospital Health Management Center, spanning January 2013 to July 2024, we analyze relationship of serum Lp-PLA2 levels with diffuse pulmonary emphysema and pulmonary functions. In univariate analysis, group differences were assessed with t-tests for numerical variables and Chi-square tests for categorical data. Variables found to be statistically significant (two-sided P

Abstract Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.

Dielectric capacitors with high power density and fast charge-discharge speed play an essential role in the development of pulsed power systems. The increased demands for miniaturization and practicality of pulsed power equipment also necessitate the development of dielectric materials that possess high energy density while maintaining ultrahigh efficiency (η). In particular, ultrahigh efficiency signifies minimal energy loss, which is essential for practical applications but challenging to effectively mitigate. Here, we demonstrate a strategy of incorporating heterovalent elements into Ba(Zr0·1Ti0.9)O3, which contributes to achieving relaxor ferroelectric ceramics and reducing lattice strain, thereby improving the comprehensive energy storage performance. Finally, optimal energy storage performance is attained in 0.85Ba(Zr0·1Ti0.9)O3-0.15Bi(Zn2/3Ta1/3)O3 (BZT-0.15BiZnTa), with an ultrahigh η of 97.37% at 440 kV/cm (an advanced level in the lead-free ceramics) and an excellent recoverable energy storage density (Wrec) of 3.74 J/cm3. Notably, the BZT-0.15BiZnTa ceramics also exhibit exceptional temperature stability, maintaining fluctuations in Wrec within ∼10% and η consistently exceeding 90% across the wide temperature range of −55 °C to160 °C, and under a high electric field of 250 kV/cm. All these features demonstrate that the relaxor and lattice strain engineering strategies have been successful in achieving high-performance lead-free ceramics, paving the way for designing high-efficiency dielectric capacitors with a wide temperature range.

Abstract As vehicular technology advances, intelligent vehicles generate numerous computation‐intensive tasks, challenging the computational resources of both the vehicles and the Internet of Vehicles (IoV). Traditional IoV struggles with fixed network structures and limited scalability, unable to meet the growing computational demands and next‐generation mobile communication technologies. In congested areas, near‐end Mobile Edge Computing (MEC) resources are often overtaxed, while far‐end MEC servers are underused, resulting in poor service quality. A novel network framework utilizing sixth‐generation mobile communication (6G) and digital twin technologies, combined with task migration, promises to alleviate these inefficiencies. To address these challenges, a task migration and re‐offloading model based on task attribute classification is introduced, employing a hybrid deep reinforcement learning (DRL) algorithm—Dueling Double Q Network DDPG (QDPG). This algorithm merges the strengths of the Deep Deterministic Policy Gradient (DDPG) and the Dueling Double Deep Q‐Network (D3QN), effectively handling continuous and discrete action domains to optimize task migration and re‐offloading in IoV. The inclusion of the Mini Batch K‐Means algorithm enhances learning efficiency and optimization in the DRL algorithm. Experimental results show that QDPG significantly boosts task efficiency and computational performance, providing a robust solution for resource allocation in IoV.

Abstract Background Chickens play a crucial role as the primary global source of eggs and poultry, and the quality of rooster semen significantly impacts poultry reproductive efficiency. Therefore, it is imperative to comprehend the regulatory mechanisms underlying sperm development. Results In this study, we established transcriptome profiles of lncRNAs, miRNAs, and mRNAs in 3 testis tissues and 3 epididymis tissues from “Jing Hong No.1” roosters at 24, 35, and 64 weeks of age. Using the data, we conducted whole transcriptome analysis and constructed a ceRNA network. We detected 10 differentially expressed mRNAs (DEmRNAs), 33 differentially expressed lncRNAs (DElncRNAs), and 10 differentially expressed miRNAs (DEmiRNAs) in the testis, as well as 149 DEmRNAs, 12 DElncRNAs, and 10 DEmiRNAs in the epididymis. These genes were found to be involved in cell differentiation and development, as well as various signaling pathways such as GnRH, MAPK, TGF-β, mTOR, VEGF, and calcium ion pathways. Subsequently, we constructed two competing endogenous RNA (ceRNA) networks comprising DEmRNAs, DElncRNAs, and DEmiRNAs. Furthermore, we identified four crucial lncRNA-mRNA-miRNA interactions that govern specific biological processes in the chicken reproductive system: MSTRG.2423.1-gga-miR-1563-PPP3CA and MSTRG.10064.2-gga-miR-32-5p-GPR12 regulating sperm motility in the testis; MSTRG.152556.1-gga-miR-9-3p-GREM1/THYN1 governing immunomodulation in the epididymis; and MSTRG.124708.1-gga-miR-375-NDUFB9/YBX1 controlling epididymal sperm maturation and motility. Conclusions Whole transcriptome sequencing of chicken testis and epididymis screened several key genes and ceRNA regulatory networks, which may be involved in the regulation of epididymal immunity, spermatogenesis and sperm viability through the pathways of MAPK, TGF-β, mTOR, and calcium ion. These findings contribute to our comprehensive understanding of the intricate molecular processes underlying rooster spermatogenesis, maturation and motility.

Abstract Abnormal growth of blood vessels (choroidal neovascularization) can lead to age-related macular degeneration (AMD) and eventually cause vision loss due to detachment of the retinal pigmented epithelium. This indicates that choroidal neovascularization is important for the treatment of AMD. The circadian clock in the mammalian retina is responsible for controlling various functions of the retina, enabling it to adjust to changes in light and darkness. Recent studies have revealed a potential connection between the circadian clock and eye diseases, although a cause-and-effect relationship has not been definitively established. C57BL/6J male mice (aged 6 weeks) were randomly divided into two groups (Control group: 9:00–21:00 light period (300 lx); Jet lag group: 8-hour phase advance once every 4 days). A laser-induced CNV model was created after 2 weeks of feeding in a controlled or jet-lagged environment. Then, full transcriptome sequencing was performed. The pathways regulated by differentially expressed mRNAs were identified by GO analysis and GSEA. Further protein networks were constructed with the STRING database and Cytoscape software. WGCNA was used to further explore the co-expression modules of these differential genes and the correlation between these differential genes and phenotypes. ceRNA networks were constructed with miRanda and TargetScan. The pathways associated with the overlapping differentially expressed mRNAs in the ceRNA network were identified, and the hub genes were validated by qPCR. A total of 661 important DEGs, 31 differentially expressed miRNAs, 106 differentially expressed lncRNAs and 87 differentially expressed circRNAs were identified. GO and GSEA showed that the upregulated DEGs were mainly involved in reproductive structure development and reproductive system development. The STRING database and Cytoscape were used to determine the protein interaction relationships of these DEGs. WGCNA divided the expression of these genes into several modules and screened the hub genes of each module separately. Furthermore, a ceRNA network was constructed. GO analysis and GSEA showed that these target DEmRNAs mainly function in wound healing, cell spreading, epiboly involved in wound healing, epiboly, and morphogenesis of an epithelial sheet. Finally, ten key genes were identified, and their expression patterns were confirmed by real-time qPCR. In this study, we investigated the regulatory mechanism of ceRNAs in choroidal neovascularization according to different light-dark cycles in the eyeball.

Abstract BamA is the central component of the essential β-barrel assembly machine (BAM), a conserved multi-subunit complex that dynamically inserts and folds β-barrel proteins into the outer membrane of Gram-negative bacteria. Despite recent advances in our mechanistic and structural understanding of BamA, there are few potent and selective tool molecules that can bind to and modulate BamA activity. Here, we explored in vitro selection methods and different BamA/BAM protein formulations to discover peptide macrocycles that kill Escherichia coli by targeting extreme conformational states of BamA. Our studies show that Peptide Targeting BamA-1 (PTB1) targets an extracellular divalent cation-dependent binding site and locks BamA into a closed lateral gate conformation. By contrast, PTB2 targets a luminal binding site and traps BamA into an open lateral gate conformation. Our results will inform future antibiotic discovery efforts targeting BamA and provide a template to prospectively discover modulators of other dynamic integral membrane proteins.

Abstract In neuroinflammation, distinguishing microglia from macrophages and identifying microglial-specific biomarkers in peripheral blood pose significant challenges. This study comprehensively profiled the extracellular vesicles (EVs) of microglia and macrophages, respectively, revealing co-expressed EVs with UCHL1 and CX3CR1 as EVs derived specifically from microglia in human blood. After extensive validation, using optimized nano flow cytometry, we evaluated plasma CX3CR1+/UCHL1+ EVs across clinical cohorts [multiple sclerosis (MS), HTLV-1 associated myelopathy (HAM), Alzheimer’s disease (AD), and Parkinson’s disease (PD)], along with established neurodegenerative markers (NMDAR2A and NFL). The findings discovered a notable rise in CX3CR1+/UCHL1+ EVs in MS, particularly heightened in HAM, in contrast to controls. Conversely, AD and PD exhibited unaltered or diminished levels of microglial EVs. An integrated model of CX3CR1+/UCHL1+, NMDAR2A+, and NFL+ EVs demonstrated promising diagnostic potential for distinguishing MS from controls and HAM. As to the disease duration, CX3CR1+/UCHL1+ EVs increased in the initial five years of MS, stabilizing thereafter, whereas NMDAR2A+ and NFL+ EVs remained stable initially but increased significantly in the subsequent five years, suggesting their correlation with disease duration. This study uncovers unique blood microglial EVs with potential as biomarkers for MS diagnosis, differentiation from HAM, and correlation with disease duration.

Abstract Background Despite significant progress in the prognosis of pediatric T-cell acute lymphoblastic leukemia (T-ALL) in recent decades, a notable portion of children still confronts challenges such as treatment resistance and recurrence, leading to limited options and a poor prognosis. LIM domain-binding protein 1 (LDB1) has been confirmed to exert a crucial role in various physiological and pathological processes. In our research, we aim to elucidate the underlying function and mechanisms of LDB1 within the background of T-ALL. Methods Employing short hairpin RNA (shRNA) techniques, we delineated the functional impact of LDB1 in T-ALL cell lines. Through the application of RNA-Seq, CUT&Tag, and immunoprecipitation assays, we scrutinized master transcription factors cooperating with LDB1 and identified downstream targets under LDB1 regulation. Results LDB1 emerges as a critical transcription factor co-activator in cell lines derived from T-ALL. It primarily collaborates with master transcription factors (ERG, ETV6, IRF1) to cooperatively regulate the transcription of downstream target genes. Both in vitro and in vivo experiments affirm the essential fuction of LDB1 in the proliferation and survival of cell lines derived from T-ALL, with MYB identified as a significant downstream target of LDB1. Conclusions To sum up, our research establishes the pivotal fuction of LDB1 in the tumorigenesis and progression of T-ALL cell lines. Mechanistic insights reveal that LDB1 cooperates with ERG, ETV6, and IRF1 to modulate the expression of downstream effector genes. Furthermore, LDB1 controls MYB through remote enhancer modulation, providing valuable mechanistic insights into its involvement in the progression of T-ALL.

Abstract. Background:. While some studies have reported the impact of COVID-19 vaccines on immune recovery and human immunodeficiency virus (HIV) reservoirs in persons living with HIV (PLWH), their findings remain inconsistent. Furthermore, limited data exist on the safety of multiple COVID-19 vaccines among PLWH. This study aimed to investigate the safety of heterological COVID-19 vaccine administration in PLWH receiving antiretroviral treatment (ART) and its effects on HIV reservoirs and immune recovery. Such an investigation can help provide a basis for vaccinations against COVID-19 in PLWH. Methods:. In this cross-sectional study, PLWH receiving ART were recruited from the outpatient clinic of the Department of Infectious Diseases at the Fifth Medical Center of the Chinese PLA General Hospital from September 1, 2021 to December 31, 2021. Fifty-three PLWH receiving ART were vaccinated against COVID-19, with 35 receiving an inactivated vaccine (IN group) and 18 receiving a recombinant protein (CHO cells) vaccine (CHO group) as the third dose. We assessed the changes in liver and kidney functions, blood lipids, and other laboratory parameters at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose. We also monitored CD4+ and CD8+ T cell counts using flow cytometry at 0, 1, 2, 4, 7, 8, 10, and 13 months after the first vaccination dose, as well as levels of cell-associated HIV DNA (CA HIV DNA) and cell-associated HIV RNA (CA HIV RNA) in peripheral blood using the corresponding quantitative detection kits at 0, 2, and 8 months after the first vaccination dose. Results:. No severe adverse events related to either type of COVID-19 vaccine were observed in HIV patients, irrespective of their CD4+ T cell levels. Both the IN and CHO groups showed significant increases in CD4+ T cell counts during follow-up, CD4+ T cells increased from 438 ± 45 cells/μL to 557 ± 48 cells/μL in the CHO group, while in the IN group, it increased from 448 ± 34 cells/μL to 572 ± 39 cells/μL (both P < 0.001). CA HIV DNA initially decreased and then increased in both groups. CA HIV RNA levels showed significantly decreased in both group after three doses of vaccination (P < 0.01 in CHO group and P < 0.001 in IN group). CD8+ T cells increased from 608 ± 77 cells/μL to 812 ± 116 cells/μL in the CHO group (P < 0.01), while in the IN group, it increased from 702 ± 71 cells/μL to 852 ± 68 cells/μL(P < 0.001) from baseline to the 13 month of following up. Conclusion:. Our data suggest that the SARS-CoV-2 booster vaccine is safe for PLWH on ART, although it may affect HIV reservoirs and CD8+ T cell counts.

Abstract Background The excavation and utilization of endophytic fungi from medicinal plants is highly important for the development of new drugs. The endophytic fungus Aspergillus tamarii TPD11, which was isolated and obtained by the authors in the previous stage, can produce a variety of polyphyllins with important potential applications in hemostasis, inflammation and antitumor activities; however, the genomic information of TPD11 is still unknown. Results In this study, we sequenced and assembled the whole genome of the endophytic fungus A. tamarii TPD11, resolved the genome evolutionary relationships of 24 Aspergillus strains, and phylogenetic analysis of the genomes of 16 strains revealed the evolutionary differences between Aspergillus and Penicillium and the mechanisms of genome expansion and contraction. CAZy annotation analysis revealed that TPD11 obtains nutrients mainly by ingesting starch from the host plant. TPD11 has a biosynthesis-related gene cluster for the synthesis of squalestatin S1, and the silencing of this biosynthesis-related gene cluster might increase the content of polyphyllin. Annotation of 11 UDP-glycosyltransferase genes helps to further reveal the biosynthetic pathway of polyphyllin. In addition, secondary metabolism gene cluster and CAZy analyses confirmed the potential probiotic, insecticidal and antimicrobial activities of TPD11 on host plants. Conclusions This study reveals the intrinsic mechanism by which endophytic fungi increase the content of polyphyllin, which provides a basis for the synthetic synthesis of the natural product polyphyllin.

Abstract Background Recurrent depressive disorder (RDD) is mainly manifested as a low mood, negative and pessimistic mood, and often presents suicidal tendencies when severe. This study reports on a patient with RDD who experienced rat poison poisoning occurring tongue biting. The patient’s psychiatric symptoms improved after receiving emergency management and subsequent combined medical care. Case presentation The patient was a 51-year-old female with RDD complicated with rat poison poisoning. Tongue bite occurred on the third day of hospitalization. She received emergency treatment. Depression, anxiety and suicide risk assessment, safety management and caregiver-health education were conducted on the day of admission and before discharge. At the follow-up after discharge, the risk of suicide was reduced. Conclusions Suicide in patients with RDD is characterized by repetition and complexity. The occurrence of clinical cases involving tongue bite after gastric lavage is rare. Suicide assessment and emergency management play an auxiliary role in the treatment of patients with recurrent depressive disorder.

Abstract Background This study aimed to quantitatively evaluate the left ventricular global and regional myocardial work of patients in Fabry disease (FD) by echocardiographic pressure–strain loop (PSL) analysis. Results The study included 48 patients with FD and 48 healthy controls matched for age and sex. According to the presence/absence of left ventricular hypertrophy (LVH), the patients with FD were divided into an LVH + group and an LVH– group. Left ventricular blood pressure was estimated noninvasively according to echocardiographic valvular events and systolic pressure in the brachial artery. Left ventricular myocardial work parameters were acquired by echocardiographic pressure–strain loop analysis. The FD groups had a significantly lower global longitudinal strain (GLS), global work index, global work efficiency (GWE), global constructive work and higher global waste work than the control group (P

Abstract Spatial transcriptomics technologies have been widely applied to decode cellular distribution by resolving gene expression profiles in tissue. However, sequencing techniques still limit the ability to create a fine-resolved spatial cell-type map. To this end, we develop a novel deep-learning-based approach, STASCAN, to predict the spatial cellular distribution of captured or uncharted areas where only histology images are available by cell feature learning integrating gene expression profiles and histology images. STASCAN is successfully applied across diverse datasets from different spatial transcriptomics technologies and displays significant advantages in deciphering higher-resolution cellular distribution and resolving enhanced organizational structures.

Abstract Background On March 16th 2024, the first case of Human infection with avian influenza H10N3 since the end of the global COVID-19 Pandemic was reported in Kunming, China. To enhance comprehension of the source of infection and risk factors of the H10N3 virus infection, this case report summarizes the clinical features, epidemiological investigation, and laboratory test results. Provides recommendations for the prevention and control of Human infection with avian influenza H10N3. Case presentation A 51-year-old male with a history of COVID-19 infection and a smoking habit of 30 years, worked in livestock breeding and was exposed to sick and dead poultry before falling ill with fever and chills on 28th February 2024. A week later, he was diagnosed with severe pneumonia, influenza, and respiratory failure by the Third People's Hospital of Kunming(KM-TPH). He was discharged on 17th April and none of his 6 close contacts showed any symptoms of illness. Environmental samples taken from the epidemic spot revealed that peacock feces tested positive for avian influenza sub-type H9 and waterfowl specimens showed positive results for avian influenza sub-type H5. Gene sequencing conducted on positive specimens from the patient's respiratory tract by the Chinese Centre for Disease Control and Prevention (CCDC) showed a high degree of similarity (98.6–99.5%) with the strain responsible for the second global case of human infected with H10N3 (reported from Zhejiang, China 2022). Conclusions According to the available epidemiological information, there is limited evidence to suggest that H10N3 viruses are excessively lethal. However, adaptive site mutations have been observed in the H10N3 isoform of mammals. While it is unlikely that the H10N3 virus will spread among humans, the possibility of additional cases cannot be entirely ruled out. Symptoms of human infection with H10N3 avian influenza are similar to those of common respiratory infections, which may result in them being overlooked during initial clinical consultations. Therefore, it is essential to improve surveillance of the H10 sub-type of avian influenza and to increase the awareness of hospital-related workers of cases of pneumonia of unknown origin.

Abstract This study aimed to explore potential radiomics biomarkers in predicting the efficiency of chemo-immunotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients were prospectively assigned to receive chemo-immunotherapy, and were divided into a primary cohort (n = 138) and an internal validation cohort (n = 58). Additionally, a separative dataset was used as an external validation cohort (n = 60). Radiomics signatures were extracted and selected from the primary tumor sites from chest CT images. A multivariate logistic regression analysis was conducted to identify the independent clinical predictors. Subsequently, a radiomics nomogram model for predicting the efficiency of chemo-immunotherapy was conducted by integrating the selected radiomics signatures and the independent clinical predictors. The receiver operating characteristic (ROC) curves demonstrated that the radiomics model, the clinical model, and the radiomics nomogram model achieved areas under the curve (AUCs) of 0.85 (95% confidence interval [CI] 0.78–0.92), 0.76 (95% CI 0.68–0.84), and 0.89 (95% CI 0.84–0.94), respectively, in the primary cohort. In the internal validation cohort, the corresponding AUCs were 0.93 (95% CI 0.86–1.00), 0.79 (95% CI 0.68–0.91), and 0.96 (95% CI 0.90–1.00) respectively. Moreover, in the external validation cohort, the AUCs were 0.84 (95% CI 0.72–0.96), 0.75 (95% CI 0.62–0.87), and 0.86 (95% CI 0.75–0.96), respectively. In conclusion, the radiomics nomogram provides a convenient model for predicting the effect of chemo-immunotherapy in advanced NSCLC patients.

Abstract Type 2 diabetes mellitus (T2DM) is globally recognized as a significant health concern, with diabetic foot (DF) identified as a severe long-term complication that can lead to tissue death or amputation. The discovery of the impact of mycobiota, a diverse group of multicellular eukaryotes in the gut microbiome, on the onset of endocrine disorders holds great significance. Therefore, this research aimed to examine variations in fungal mycobiome and identify potential biomarkers for T2DM and T2DM-DF. Fecal and blood samples were collected from 33 individuals with T2DM, 32 individuals with T2DM-DF, and 32 healthy individuals without any health conditions (HC). Blood samples were used for laboratory parameters analysis, while total DNA was extracted from fecal samples and sequenced using Illumina 18s rRNA. Bioinformatics tools were employed to analyze fungal abundance and diversity, revealing differentially expressed fungal species and signature fungi that distinguished between T2DM, T2DM-DF, and HC groups. Firstly, significant alterations in some laboratory parameters were observed among the three groups, which also differed between T2DM and T2DM-DF. The diversity of gut fungi in T2DM and T2DM-DF significantly differed from that of the HC group; however, more pronounced changes were observed in T2DM-DF. Additionally, two significantly altered phyla, Ascomycota and Basidiomycota, were identified with higher Ascomycota abundance but lower Basidiomycota abundance in both the T2DM and T2DM-DF compared to the HC group. Furthermore, the top 15 fungi showing significant changes at the species level included a notable decrease in Rhodotorula_mucilaginosa abundance in patients with T2DM compared to HC and a substantial increase in unclassified_g_Candida abundance specifically seen only among patients with T2DM-DF, but not among those diagnosed with T2DM or HC. Thirdly, KEGG was employed to analyze enzyme expression across the three groups, revealing a more pronounced alteration in gut fungal function within T2DM-DF compared to T2DM. Subsequently, to accurately identify signature fungi in each group, a random forest was utilized to rank the top 15 significant fungi. Notably, 11 fungi were identified as potential biomarkers for distinguishing T2DM or T2DM-DF from HC, while eight fungi could discriminate between T2DM and T2DM-DF. Furthermore, receiver operating characteristic curve (ROC) analysis demonstrated enhanced accuracy of predicted outcomes. These findings suggest that changes in fungal mycobiome are closely associated with the progression and complications of T2DM and DF, offering promising prospects for diagnosis and treatment.

Abstract Microplastics (MPs), a brand-new class of worldwide environmental pollutant, have received a lot of attention. MPs are consumed by both humans and animals through water, food chain and other ways, which may cause potential health risks. However, the effects of MPs on embryonic development, especially placental function, and its related mechanisms still need to be further studied. We investigated the impact on fetal development and placental physiological function of pregnant mice by consecutive gavages of MPs at 0, 25, 50, 100 mg/kg body weight during gestational days (GDs 0–14). The results showed that continuous exposure to high concentrations of MP significantly reduced daily weight gain and impaired reproductive performance of pregnant mice. In addition, MPs could significantly induce oxidative stress and placental dysfunction in pregnant mice. On the other hand, MPs exposure significantly decreased placental barrier function and induced placental inflammation. Specifically, MPs treatment significantly reduced the expression of tight junction proteins in placentas, accompanied by inflammatory cell infiltration and increased mRNA levels of pro-inflammatory cytokines and chemokines in placentas. Finally, we found that MPs induced placental apoptosis and endoplasmic reticulum (ER) stress through the GRP78/IRE1α/JNK axis, leading to placental dysfunction and decreased reproductive performance in pregnant mice. We revealed for the first time that the effects of MPs on placental dysfunction in pregnant animals. Blocking the targets of MPs mediated ER stress will provide potential therapeutic ideas for the toxic effects of MPs on maternal pregnancy.

Abstract MgO nanoparticles have good As-adsorption capacity in treating As-contaminated wastewater but suffer from high production cost. In this study, instead of using pre-formed MgO nanoparticles, we found that in-situ formed Mg(OH)2 from MgCl2 and NaOH reaction exhibited super high arsenate (As(V)) removal efficiency. Only 1.5 mmol/L of in-situ formed Mg(OH)2 could remove more than 95% As(V) within 10 min to make the As contaminated water (10 mg-As(V)/L) meet the municipal wastewater treatment standard, whereas MgO nanoparticles failed. The Mg-As sludge has an amorphous crystal structure while no Mg(OH)2 phase could be observed. As(V) existed uniformly within the sludge which was confirmed by elemental mapping. A precipitation-adsorption-coagulation mechanism might exist, which could relieve the restriction of limited surface area of solid MgO adsorbents. This study not only reveals an applicable method for efficient removal of trace level As(V) from water but also implies the huge potential of in-situ formed adsorbents in water treatment.

Abstract. Background:. Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. Methods:. We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n = 125), a validation cohort (n = 82), and a control cohort (n = 80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. Results:. A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. Conclusion:. These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Abstract In the healing process of myocardial infarction, cardiac fibroblasts are activated to produce collagen, leading to adverse remodeling and heart failure. Our previous study showed that ASPP1 promotes cardiomyocyte apoptosis by enhancing the nuclear trafficking of p53. We thus explored the influence of ASPP1 on myocardial fibrosis and the underlying mechanisms. Here, we observed that ASPP1 was increased after 4 weeks of MI. Both global and myofibroblast knockout of ASPP1 in mice mitigated cardiac dysfunction and fibrosis after MI. Strikingly, ASPP1 produced the opposite influence on p53 level and cell fate in cardiac fibroblasts and cardiomyocytes. Knockdown of ASPP1 increased p53 levels and inhibited the activity of cardiac fibroblasts. ASPP1 accumulated in the cytoplasm of fibroblasts while the level of p53 was reduced following TGF-β1 stimulation; however, inhibition of ASPP1 increased the p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 is directly bound to deubiquitinase OTUB1, thereby promoting the ubiquitination and degradation of p53, attenuating myofibroblast activity and cardiac fibrosis, and improving heart function after MI.

Generally, referring to the stability of perovskite, the most studied perovskite material has been MA-free mixed-cation perovskite. The precise role of MA in the light-thermal-humid stability of perovskite solar cells still lacks of a systematically understanding. In this work, the evolution of crystallographic structures, intermediate phase, ultrafast dynamics, and thermal decomposition behavior of MA-mixed perovskite FA1-xMAxPbI3 (x=0–100%) are investigated. The influence of MA on the stability of devices under heat, light, and humidity exposure are revealed. In the investigated compositional space (x=0–100%), device efficiencies vary from 19.5% to 22.8%, and the light, thermal, and humidity exposure stability of the related devices are obviously improved for FA1-xMAxPbI3 (x=20%–30%). Incorporation 20%–30% of MA cations lowers nucleation barrier and causes a significant volume shrinkage, which enhances the interaction between FA and I, thus improving crystallization and stability of the FA1-xMAxPbI3. Thermal behavior analysis reveals that the decomposition temperature of FA0.8MA0.2PbI3 reaches 247 ​°C (FAPbI3, 233 ​°C) and trace amounts of MA cations enhance the thermal stability of the perovskite. Remarkably, we observe lattice shrinkage using spherical aberration corrected transmission electron microscope (AC-TEM). This work implies that stabilizing perovskites will be realized by incorporating trace amounts of MA, which improve the crystallization and carrier transport, leading to improved stability and performances.

ABSTRACT Background Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder. Although individuals with variants in the SMC1A gene are less commonly seen in CdLS, they exhibit a high incidence of epilepsy and atypical phenotypic variability. Methods The clinical data of a patient with non‐classic CdLS and epilepsy caused by an SMC1A variant were summarized. A literature review was conducted to analyze the genotype–phenotype correlations and epilepsy characteristics in related cases. Results A 5‐year‐6‐month‐old female patient presented with facial features, double outlet right ventricle (DORV), and recurrent epilepsy. Whole exome sequencing (WES) identified a de novo heterozygous frameshift mutation, c.2890_2893del (p.Ser964Valfs*26), in the SMC1A gene. A review of the literature identified several characteristics of non‐classic CdLS with epilepsy caused by SMC1A variants: the majority of cases were non‐classic (81.5%), predominantly female (68.2%), with a median onset age of 11.5 months. Common features included severe/profound developmental delay (52.6%), hypotonia (18.2%), cardiovascular anomalies (36.4%), and intrauterine growth retardation (IUGR) (22.7%). Among the non‐classic cases, seizure clusters occurred in 22.7%, status epilepticus in 18.2%, and drug‐resistant epilepsy in 33.3%. Genotypes in non‐classic cases included missense mutations (40.9%), frameshift mutations (31.8%), splice site variants (9.1%), nonsense mutations (9.1%), deletions (4.5%), and truncations (4.5%). Conclusion Our study expanded the phenotypic data and mutational spectrum of non‐classic CdLS with epilepsy caused by SMC1A variants. Compared to individuals with the classic form of CdLS, the non‐classic cases appeared more frequently in females and were associated with a higher prevalence of severe/profound developmental delay and cardiovascular anomalies. In contrast, IUGR was significantly less common in non‐classic individuals. Regarding epilepsy characteristics, some individuals including seizure clusters, status epilepticus, drug resistance, and hypotonia, no significant differences were observed between classic and non‐classic cases. The predominant genotypes in non‐classic cases were missense and frameshift mutations.

Abstract Developing single fluorescent probe for simultaneously visualizing mitophagy flux and oxidative stress with super‐resolution is highly demanded yet quite challenging. Herein, a ratiometric HClO probe AHOH is designed and synthesized which is capable of simultaneously staining lysosomes and mitochondria with red and green colour, respectively. AHOH could be selectivity oxidized by HClO, leading to a large emission blue shift (90 nm) and an over 1300‐fold enhancement of the emission ratio of Fl547nm/Fl637nm. We apply AHOH in super‐resolution microscopy and clearly visualize the dynamics of mitochondria–lysosomes interactions and the oxidative stress states upon different stimuli. Mitochondria dysfunction triggered by different drugs and genetic defect lead to elevated oxidative stress and higher levels of mitophagy. Moreover, AHOH could serve as a reliable tool for evaluating the efficacy of drugs regulating mitochondria dysfunction. This work provides a powerful dual‐colour super‐resolution imaging agent for real‐time monitoring the dynamics of organelle interactions and oxidative stress.

Chemically induced neurotoxicity is a critical aspect of chemical safety assessment. Traditional and costly experimental methods call for the development of high-throughput virtual screening. However, the small datasets of neurotoxicity have limited the application of advanced deep learning techniques. The current study developed a hybrid deep learning architecture, NeuTox 2.0, through multimodal feature fusion for enhanced prediction accuracy and generalization ability. We incorporated transfer learning based on self-supervised learning, graph neural networks, and molecular fingerprints/descriptors. Four datasets were used to profile neurotoxicity; these were related to blood–brain barrier permeability, neuronal cytotoxicity, microelectrode array–based neural activity, and mammalian neurotoxicity. Comprehensive performance evaluations demonstrated that NeuTox 2.0 has relatively higher predictive capability across all statistical metrics. Specifically, NeuTox 2.0 exhibits remarkable performance in three of the four datasets. In the BBB dataset, although it does not outperform the PaDEL descriptor model, its performance closely approximates that of the top single-modal model. The ablation experiments indicated that NeuTox 2.0 can learn the deeper structural differences of molecules from various feature extractions and capture complex interactions and mapping relationships between various modalities, thereby improving performance for neurotoxicity prediction. Evaluations of anti-noise ability indicated that NeuTox 2.0 has excellent noise resistance relative to traditional machine learning. We applied the NeuTox 2.0 model to predict the neurotoxicity of 315,790 compounds in the REACH database. The results showed that 701 compounds exhibited potential neurotoxicity in the four neurotoxicity-related predictions. In conclusion, NeuTox 2.0 can be used as an efficient tool for early neurotoxicity screening of environmental chemicals.

Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA-Dachshund homolog 1 (lncDach1) can bind to dystrophin, which drove us to investigate if lncDach1 can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of lncDach1 (lncDach1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak INa was reduced in the hearts of lncDach1-TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from lncDach1 cardiomyocyte conditional knockout (lncDach1-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDach1-TG mice in vivo and ex vivo. The conservative fragment of lncDach1 inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of Dystrophin transcription by dCas9-SAM system in lncDach1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, lncDach1 was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of lncDach1 is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to lncDach1 and decreases its stability. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.

ObjectiveTo explore the differential gene expression in peripheral blood immune cells of individuals with type 2 diabetes mellitus (DM), comparing those with and without non-proliferative diabetic retinopathy (NPDR).MethodsFrom a pool of 126 potential participants, 60 were selected for detailed analysis. This group included 12 healthy donors (HDs), 22 individuals with DM, and 26 with NPDR. We analyzed peripheral blood mononuclear cells (PBMCs) using RNA sequencing and quantitative PCR (qPCR) to pinpoint differentially expressed genes (DEGs). Western blot and flow cytometry were also employed to evaluate the protein expression of specific genes.ResultsIn patients with NPDR compared to those with DM alone, MerTK—a gene implicated in inherited retinal dystrophies due to its mutations—was notably downregulated in PBMCs. Through flow cytometry, we assessed the protein levels and cellular distribution of MerTK, finding a predominant expression in monocytes and myeloid-derived suppressor cells (MDSCs), with a marked reduction in CD4+ and CD8+ T cells, as well as in natural killer T (NKT) cells. Patients with DM demonstrated a significant deviation in the PBMCs composition, particularly in B cells, CD4+ T cells, and NK cells, when compared to HDs. ConclusionsThe study indicates that MerTK expression in T cells within PBMCs could act as a viable blood biomarker for NPDR risk in patients with DM. Furthermore, the regulation of T cells by MerTK might represent a critical pathway through which DM evolves into NPDR.

Abstract Background Hippocampal disruptions represent potential neuropathological biomarkers in depressed adolescents with cognitive dysfunctions. Given heterogeneous outcomes of whole-hippocampus analyses, we investigated subregional abnormalities in depressed adolescents and their associations with symptom severity and cognitive dysfunctions. Methods MethodsSeventy-nine first-episode depressive patients (ag = 15.54 ± 1.83) and 71 healthy controls (age = 16.18 ± 2.85) were included. All participants underwent T1 and T2 imaging, completed depressive severity assessments, and performed cognitive assessments on memory, emotional recognition, cognitive control, and attention. Freesurfer was used to segment each hippocampus into 12 subfields. Multivariable analyses of variance were performed to identify overall and disease severity-related abnormalities in patients. LASSO regression was also conducted to explore the associations between hippocampal subfields and patients’ cognitive abilities. Results Depressed adolescents showed decreases in dentate gyrus, CA1, CA2/3, CA4, fimbria, tail, and molecular layer. Analyses of overall symptom severity, duration, self-harm behavior, and suicidality suggested that severity-related decreases mainly manifested in CA regions and involved surrounding subfields with disease severity increases. LASSO regression indicated that hippocampal subfield abnormalities had the strongest associations with memory impairments, with CA regions and dentate gyrus showing the highest weights. Conclusions Hippocampal abnormalities are widespread in depressed adolescents and such abnormalities may spread from CA regions to surrounding areas as the disease progresses. Abnormalities in CA regions and dentate gyrus among these subfields primarily link with memory impairments in patients. These results demonstrate that hippocampal subsections may serve as useful biomarkers of depression progression in adolescents, offering new directions for early clinical intervention.

Objective To characterize the epidemiological characteristics of malignancy in Chinese patients with rheumatoid arthritis (RA) versus American patients and investigate their associated factors. Methods Data were collected from a real-world Chinese RA population and American patients with RA from the National Health and Nutritional Examination Survey. The prevalence and subtypes of malignancy and their potential associated factors were investigated in both populations. Results A total of 2,073 Chinese and 2,928 American patients with RA were included. There was a lower prevalence of malignancy in Chinese than in their American counterparts before (5.7% vs. 17.1%) and after matching (6.2% vs. 12.6%, both P < 0.001). Gender discrepancies in malignancy prevalence were observed, with a male predilection for RA with malignancy in China (8.2% vs. 5.5%), while it was the opposite in American patients (10.1% vs. 13.5%, both P < 0.05). The top type of malignancy among male patients with RA was lung cancer in Chinese (2.29%), but non-melanoma skin cancer (3.43%) in American; while among female patients was breast cancer both in Chinese (1.72%) and American (3.43%). Multivariate logistic regression analyses showed that older age (odds ratio (OR) = 1.050) and positive anti-cyclic citrullinated peptide antibody (OR = 2.752) were independently associated with malignancy in Chinese patients with RA, while female (OR = 1.395), older age (OR = 1.033), active smoking (OR = 1.580) and cardiovascular diseases (OR = 1.523) in American patients. Conclusion The prevalence, subtypes and risk factors of malignancy were substantially different in Chinese patients with RA and their American counterparts, which implied the importance of individualized malignancy screening strategies for patients with RA.

IntroductionDespite the established influence of gut bacteria, the role of the gut virome in modulating colorectal cancer (CRC) patient chemotherapy response remains poorly understood. In this study, we investigated the impact of antiviral (AV) drug-induced gut virome dysbiosis on the efficacy of 5-FU in CRC treatment.MethodsUsing a subcutaneous CRC mouse model, we assessed tumor growth and immune responses following AV treatment, fecal microbiota transplantation (FMT), and 5-FU administration.ResultsAV therapy reduced the abundance of gut DNA and RNA viruses, leading to accelerated tumor growth, shortened survival, and diminished chemotherapy efficacy. FMT restored the gut virome, improving tumor suppression and extending the survival of 5-FU-treated mice. Metagenomic sequencing revealed significant changes in virome composition, AV treatment expanded Kahnovirus, Petivirales, and Enterogokushovirus, whereas FMT enriched Peduovirus STYP1, Mahlunavirus rarus, and Jouyvirus ev207. AV treatment reduced the number of dendritic cells and CD8+ T cells in peripheral blood and tumor tissues, impairing antitumor immunity, FMT reversed these deficiencies. To further investigate the underlying mechanisms, we examined the TLR3-IRF3-IFN-β pathway, essential for recognizing viral RNA and triggering immune responses. AV treatment downregulated this pathway, impairing immune cell recruitment and reducing chemotherapy efficacy, while activation of TLR3 with Poly(I:C) restored pathway function and enhanced the effectiveness of 5-FU.DiscussionThese findings suggest the importance of maintaining gut virome integrity or activating TLR3 as adjunct strategies to enhance chemotherapy outcomes in CRC patients.

Insulin resistance, a key factor in the development of type 2 diabetes mellitus (T2DM), is defined as a defect in insulin-mediated control of glucose metabolism in tissues such as liver, fat and muscle. Insulin resistance is a driving force behind various metabolic diseases, such as T2DM, hyperlipidemia, hypertension, coronary heart disease and fatty liver. Therefore, improving insulin sensitivity can be considered as an effective strategy for the prevention and treatment of these complex metabolic diseases. Cell-based models are extensively employed for the study of pathological mechanisms and drug screening, particularly in relation to insulin resistance in T2DM. Currently, numerous methods are available for the establishment of in vitro insulin resistance models, a comprehensive review of these models is required and can serve as an excellent introduction or understanding for researchers undertaking studies in this filed. This review examines and discusses the primary methods for establishing and evaluating insulin resistance cell models. Furthermore, it highlights key issues and suggestions on cell selection, establishment, evaluation and drug screening of insulin resistance, thereby providing valuable references for the future research efforts.

The gut mycobiome significantly affects host health and immunity. However, most studies have focused on symbiotic bacteria in the gut microbiome, whereas less attention has been given to symbiotic fungi. Although fungi constitute only 0.01%–0.1% of the gut microbiome, their larger size and unique immunoregulatory functions make them significant. Factors like diet, antimicrobials use, and age can disrupt the fungal community, leading to dysbiosis. Fungal-bacterial-host immune interactions are critical in maintaining gut homeostasis, with fungi playing a role in mediating immune responses such as Th17 cell activation. This review highlights methods for studying gut fungi, the composition and influencing factors of the gut mycobiome, and its potential in therapeutic interventions for intestinal and hepatic diseases. We aim to provide new insights into the underexplored role of gut fungi in human health.