Search

Abstract Didymocarpus heucherifolius Hand.-Mazz. is plant of the genus Didymocarpus wall. (Gesneriaceae). Species in this genus have long been used in folk medicine to treat various illnesses, including wounds, kidney stones, inflammations, asthma, influenza, etc. However, there are few studies on chemical components. Crude plant extracts are a complex mixture of several biologically active specialized metabolites. Therefore, a rapid and accurate identification and quantification are critical in phytochemical analysis. An efficient approach based on molecular networking strategy coupled with ultra high-performance liquid chromatography coupled with Q-Exactive Orbitrap tandem mass spectrometry (UHPLC Q-Exactive Orbitrap MS) was used to analyze the chemical components systematically. The chemical was identified using retention time, accurate molecular weight, parent peaks, fragment peaks, fragmentation characteristics, comparative analysis with the literature, reference standards, and standard databases, including mzVault. A total of 108 compounds (32 phenylpropanoids, 14 phenolic acid, 6 fatty acids, 14 organic acid, 9 flavonoid, 15 amino acids, and 28 other components) were identified in the leaves and roots of D. heucherifolius in which 84 and 84 compounds were found in the leaves and roots, respectively. The results showed that 68 components were different in plant roots and leaves, and these compounds were mainly represented in organic acids. Moreover, 50 identical chemical compounds were identified in plant roots and leaves, and these compounds were mainly phenylpropanoid compounds. The UHPLC Q-Exactive Orbitrap MS method was used for the first time to accurately, quickly, and systematically identify the compounds of the roots and leaves of Didymocarpus heucherifolius Hand.-Mazz., thereby providing a theoretical basis for its quality control, in-depth research, and further development.

Introduction Trabecular bone score (TBS) is gaining attention as a novel approach for evaluating bone quality, as it provides insights into skeletal microarchitecture. We aimed to investigate the possible relationship between serum cotinine and TBS in the US population. Methods This cross-sectional study utilized data from the 2005–2008 National Health and Nutrition Examination Survey (NHANES). A total of 6961 adults aged ≥20 years with complete data on TBS and serum cotinine were included. Serum cotinine levels were measured using isotope-dilution high-performance liquid chromatography coupled with tandem mass spectrometry. TBS was derived from lumbar spine DXA images using the Med-Imap SA TBS Calculator. Weighted multivariable linear regression analyses were conducted, adjusting for age, sex, race, BMI, poverty income ratio (PIR), total spine bone mineral density (TSBMD), smoking status, C-reactive protein (CRP), total protein, blood urea nitrogen, serum creatinine, serum uric acid, serum calcium, alkaline phosphatase, and serum phosphorus. Subgroup analyses were stratified by sex, race, BMI, and PIR. Results A total of 6961 individuals were included in the analysis, with a mean (± SE) age of 45.20 ± 0.39 years, comprising 49.21% males and 50.79% females. The serum level of cotinine was negatively associated with TBS in the fully adjusted model. Specifically, for each unit increase in the log2-cotinine score, there was a corresponding 0.01 unit decrease in TBS (β= -0.01; 95% CI: -0.02 – -0.01, p=0.002). Participants in the highest tertile of serum cotinine had a significantly lower TBS compared to those in the lowest tertile (β= -0.01; 95% CI: -0.02 – -0.01, p=0.002). Subgroup analysis revealed a significant negative association between serum cotinine and TBS in females (β= -0.021; 95% CI: -0.03 – -0.01), but not in males. No significant associations were found when stratified by race, BMI, and PIR. Conclusions Serum cotinine was negatively associated with TBS in US adults. Further large-scale prospective studies are still needed to explore the associative relationship of cotinine in TBS.

Abstract Low temperature is one of the environmental factors that restrict the growth and geographical distribution of Brassica. To investigate the effects of exogenous calcium and calcium inhibitor on the ability of winter turnip rapeseed (Brassica rapa L.) to withstand low temperatures (4℃), we used a strong cold-resistant variety Longyou 7 (L7) and a weak cold-resistant variety Longyou 99 (L99) as the materials. The seedlings were treated with CaCl2 (20 mmol·L-1) and calcium inhibitor LaCl3 (10 mmol·L-1) at 0 h (CK), 6 h, 12 h, 24 h and 48 h after 4℃ treatments. Physiological characteristics, Ca2+ flux and Ca2+ concentration in roots after treatments were analyzed. Results illustrated that under 4℃ treatment, activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) increased by both CK and exogenous CaCl2 treatments. Contents of soluble protein (SP) and proline (Pro) increased, while contents of malondialdehyde (MDA) decreased, resulting in reduced membrane lipid peroxidation. But enzyme activity decreased and MDA content increased following treatment with exogenous LaCl3. The rate of Ca2+ flow showed a higher uptake in L7 roots compared with L99. L99 showed Ca2+ efflux with a rate of 30.21 pmol‧cm-2‧s-1, whereas L7 showed short efflux then returned to influx. Calcium ion content in roots decreased in both cultivars after CaCl2 treatment. Results of RNA-seq revealed that genes were differentially expressed in response to low temperatures, hormones, photosystem II, chloroplasts, DNA replication, ribosomal RNA processing, and translation. This study found significant expression genes related to cellular signal transduction (MAPK signaling pathway) and material metabolism (nitrogen metabolism, glycerol ester metabolism).It was also analyzed by WGCNA that two modules had the strongest correlation with physiological indicators. Eight candidate genes were identified among MAPK signaling pathway and the two modules.

Abstract Background Worldwide, ulcerative colitis (UC) is becoming increasingly fast growing. Ginsenoside Rh2 has been reported to alleviate UC. However, the latent biological mechanism of Rh2 in the treatment of UC remains uncertain. In this study, the goal was to determine the therapeutic effect of Rh2 on dextran sulfate sodium (DSS)-induced UC. Methods A DSS-induced UC mouse model was established and divided into 7 groups for Rh2 gavage and/or miR-125a-5p lentivirus injection (n = 10 per group). Colonic specimens were collected for phenotypic and pathological analysis. miR-125a-5p and specific protein 1 (SP1) expression, inflammation-related factors IL-6 and IL-10, and apoptosis were detected in mice. Human normal colon epithelial cell line NCM460 was treated with H2O2 and ferric chloride hexahydrate to construct an in vitro cell model of colitis and induce ferroptosis. Independent sample t-test was used to compare cell proliferation, cell entry, apoptosis, and oxidative stress between the two groups. One way analysis of variance combined with the least significant difference t test was used for comparison between groups. Multiple time points were compared by repeated measurement analysis of variance. Results DSS-induced UC mice had significantly decreased body weight, increased disease activity index, decreased colon length, and decreased miR-125a-5p expression (all P

BackgroundMuscle mass plays a pivotal role in health maintenance, yet its connection to biological aging remains underexplored. This study investigates the association between appendicular skeletal muscle mass index (ASMI) and phenotypic age(PhenoAge), while examining the mediating role of systemic inflammation.MethodsThe analysis included 7,440 participants from the NHANES 2011–2018. Phenotypic Age Acceleration (PhenoAgeAccel) was calculated as the residuals from regressing PhenoAge on chronological age. Multivariable linear regression analyses were performed to assess the association between ASMI and PhenoAgeAccel. Mediation analysis was conducted to quantify the extent to which systemic inflammation contributes to this association.ResultsOur analysis revealed that higher ASMI is linked to slower biological aging, as evidenced by lower PhenoAgeAccel (β = −0.48, 95% CI: −0.66 to −0.29, p = 0.0001). Systemic inflammation partially mediated this effect, with a mediation proportion of 35.1%. The association varied notably across demographic and health-related subgroups, being particularly significant in females, individuals with obesity, and those with lower physical activity.ConclusionThese findings highlight the critical importance of muscle mass in slowing biological aging, with systemic inflammation emerging as a key biological mediator. The public health implications are substantial, suggesting that targeted interventions—such as resistance training, anti-inflammatory diets, and personalized medical approaches—could play a pivotal role in decelerating biological aging and improving long-term health outcomes.

ObjectiveExplore the application effects of “Internet +” continuous emotional management training in depression patients and analyze the feasibility of innovative rehabilitation training methods.MethodsConveniently selected 100 discharged patients meeting the diagnostic criteria for depression from the Second Affiliated Hospital of Xinxiang Medical University between August 2022 and January 2023 as study subjects. They were divided into an intervention group and a control group according to their discharge time, with 50 patients in each group. The control group received routine monthly telephone follow-ups and “Internet +” health popularization. The intervention group received “Internet +” continuous emotional management training in addition to the control group’s protocol. Before and after the intervention, the Hamilton Depression Rating Scale (HAMD), the Chinese version of the Cognitive Emotion Regulation Questionnaire (CERQ-C), and the Social Adaptation Function Evaluation Scale (SAFE) were used to compare the differences in depression relief, cognitive emotion regulation levels, and social functions between the two groups.ResultsTwo patients in the control group and three patients in the intervention group were lost to follow-up during the intervention, Ultimately, 48 patients in the control group and 47 patients in the intervention group completed the study. Before the intervention, there were no statistically significant differences between the two groups in HAMD scores, CERQ-C subscale scores, and SAFE scores (P < 0.05). After the intervention, the intervention group had significantly lower HAMD and SAFE scores compared to the control group (P < 0.05). In the CERQ-C questionnaire, the intervention group scored lower in self-blame, rumination, catastrophizing, and blaming others but higher in acceptance, positive refocusing, refocusing on planning, positive reappraisal, and putting into perspective compared to the control group, with statistically significant differences (P < 0.05).Conclusion“Internet +” continuity emotion management training can reduce the severity of depression in post-discharge patients and enhance their emotional management and social adaptability. This approach is feasible in clinical practice.

With the prevalence of sequentially-emerged sublineages including BA.1, BA.2 and BA.5, SARS-CoV-2 Omicron infection has transformed into a regional epidemic disease. As a sublineage of BA.5, the BA.5.2.48 outbroke and evolved into multi-subvariants in China without clearly established virological characteristics. Here, we evaluated the virological characteristics of two isolates of the prevalent BA.5.2.48 subvariant, DY.2 and DY.1.1 (a subvariant of DY.1). Compared to the normal BA.5 spike, the double-mutated DY.1.1 spike demonstrates efficient cleavage, reduced fusogenicity and higher hACE2 binding affinity. BA.5.2.48 demonstrated enhanced airborne transmission capacity than BA.2 in hamsters. The pathogenicity of BA.5.2.48 is greater than BA.2, as revealed in Omicron-lethal H11-K18-hACE2 rodents. In both naïve and convalescent hamsters, DY.1.1 shows stronger fitness than DY.2 in hamster turbinates. Thus regional outbreaking of BA.5.2.48 promotes the multidirectional evolution of its subvariants, gaining either enhanced pathogenicity or a fitness in upper airways which is associated with higher transmission.

The liver is the largest solid organ in the body and is primarily composed of hepatocytes (HCs), endothelial cells (ECs), Kupffer cells (KCs), and hepatic stellate cells (HSCs), which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Gdf2 (also known as Bmp9) and Bmp10 in different liver cell types and demonstrated that HSCs were the major source of GDF2 and BMP10 in the liver. Using transgenic ALK1 (receptor for GDF2 and BMP10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and GDF2 and BMP10 secreted by HSCs promote the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after Gdf2 and Bmp10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2, and Rspo3, to regulate HC iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Gdf2/Bmp10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of GDF2 and BMP10, highlighting the important role of intercellular interaction in organ development and homeostasis.

Background: This study investigates the molecular mechanisms behind firmicutes-mediated macrophage (Mψ) polarization and glycolytic metabolic reprogramming through HIF-1α in response to intrinsic mucosal barrier injury induced by high-altitude hypoxia. Methods: Establishing a hypoxia mouse model of high altitude, we utilized single-cell transcriptome sequencing to identify key cell types involved in regulating intestinal mucosal barrier damage caused by high-altitude hypoxia. Through proteomic analysis of colonic tissue Mψ and metabolomic analysis of Mψ metabolites, we determined crucial proteins and metabolic pathways influencing intestinal mucosal barrier damage induced by high-altitude hypoxia. Mechanistic validation was conducted using RAW264.7 Mψ in vitro by assessing cell viability with CCK-8 assay following treatment with different metabolites. The hypoxia mouse model was further validated in vivo by transplanting gut microbiota of Firmicutes. Histological examinations through H&E staining assessed colonic cell morphology and structure, while the FITC-dextran assay evaluated intestinal tissue permeability. Hypoxia probe signal intensity in mouse colonic tissue was assessed via metronidazole staining. Various experimental techniques, including flow cytometry, immunofluorescence, ELISA, Western blot, and RT-qPCR, were employed to study the impact of HIF-1α/glycolysis pathway and different gut microbiota metabolites on Mψ polarization. Results: Bioinformatics analysis revealed that single-cell transcriptomics identified Mψ as a key cell type, with their polarization pattern playing a crucial role in the intestinal mucosal barrier damage induced by high-altitude hypoxia. Proteomics combined with metabolomics analysis indicated that HIF-1α and the glycolytic pathway are pivotal proteins and signaling pathways in the intestinal mucosal barrier damage caused by high-altitude hypoxia. In vitro cell experiments demonstrated that activation of the glycolytic pathway by HIF-1α led to a significant upregulation of mRNA levels of IL-1β, IL-6, and TNFα while downregulating mRNA levels of IL-10 and TGFβ, thereby promoting M1 Mψ activation and inhibiting M2 Mψ polarization. Further mechanistic validation experiments revealed that the metabolite butyric acid from Firmicutes bacteria significantly downregulated the protein expression of HIF-1α, GCK, PFK, PKM, and LDH, thus inhibiting the HIF-1α/glycolytic pathway that suppresses M1 Mψ and activates M2 Mψ, consequently alleviating the hypoxic symptoms in RAW264.7 cells. Subsequent animal experiments confirmed that Firmicutes bacteria inhibited the HIF-1α/glycolytic pathway to modulate Mψ polarization, thereby mitigating intestinal mucosal barrier damage in high-altitude hypoxic mice. Conclusion: The study reveals that firmicutes, through the inhibition of the HIF-1α/glycolysis pathway, mitigate Mψ polarization, thereby alleviating intrinsic mucosal barrier injury in high-altitude hypoxia.

Objectives To compare the level of knowledge of depression, recognition ability and attitudes towards depression among urban and rural residents in Beijing.Design A cross-sectional study.Setting Six districts in Beijing, China, 2021.Participants A total of 6463 participants aged 18 years and above who had lived for more than 6 months over the last year in Beijing were selected in this study.Outcome The awareness and recognition of depression and the views of residents towards people with depression.Results A total of 2554 urban and 2043 rural residents completed the survey. Urban residents of Beijing exhibited a higher average total score on the Depression Knowledge Questionnaire [(20.4±3.3) vs (18.7±3.5), p

In this paper, we studied the properties of generalized John domains in metric space. We prove that a domain $ D $ is a $ \varphi $-John domain if, and only if, $ D\backslash P $ is a $ \varphi' $-John domain, where $ P $ is a subset of $ D $ containing finitely many points of $ D $. Meanwhile, we also showed that the union of $ \varphi $-John domains is a $ \varphi'' $-John domain in metric space.

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Abstract Diffuse large B cell lymphoma (DLBCL) is an aggressive blood cancer known for its rapid progression and high incidence. The growing use of immunohistochemistry (IHC) has significantly contributed to the detailed cell characterization, thereby playing a crucial role in guiding treatment strategies for DLBCL. In this study, we developed an AI-based image analysis approach for assessing PD-L1 expression in DLBCL patients. PD-L1 expression represents as a major biomarker for screening patients who can benefit from targeted immunotherapy interventions. In particular, we performed large-scale cell annotations in IHC slides, encompassing over 5101 tissue regions and 146,439 live cells. Extensive experiments in primary and validation cohorts demonstrated the defined quantitative rule helped overcome the difficulty of identifying specific cell types. In assessing data obtained from fine needle biopsies, experiments revealed that there was a higher level of agreement in the quantitative results between Artificial Intelligence (AI) algorithms and pathologists, as well as among pathologists themselves, in comparison to the data obtained from surgical specimens. We highlight that the AI-enabled analytics enhance the objectivity and interpretability of PD-L1 quantification to improve the targeted immunotherapy development in DLBCL patients.

In recent years, the periodic outbreak of green tides in the coastal areas of China, caused by the combined effects of environmental changes and human activities, has been attracting extensive attention due to the serious negative impacts on the coastal marine ecosystem. In the study, the samples of Ulva linza, a green tide species, were cultivated under two light intensities (LL: 80 μmol photons m-2 s-1; HL: 300 μmol photons m-2 s-1) and three stocking densities (LD: 0.2 g L-1; MD:1 g L-1; HD:2 g L-1) to explore the photosynthetic physiological responses and nutrients absorption capacity. The results showed that high light and low density significantly increased the growth rate of U. linza. Under the HLLD, the maximum growth rate of U. linza was 43.13% day-1 and the energy captured per unit reaction center for electron transfer (ET0/RC) was the highest. The higher density significantly decreased the maximum relative electron transfer rate (rETRmax) of U. linza, especially among groups subjected to high-light condition. Under HL condition, HD also significantly decreased light utilization efficiency (α) in U. linza. The contents of chlorophyll a, b and carotenoids of U. linza were significantly lower in HLLD group compared to other treatment groups. The P uptake of U. linza was prominently inhibited by higher density, and the maximum P uptake and minimum P uptake was 17.94 μM g-1 FW day-1 in LLLD group and 2.74 μM g-1 FW day-1 in LLHD group, respectively. Lower density improved N uptake of U. linza, but high light had no effect on it. These results suggest that high light and lower density synergistically promote the growth of U. linza, which is likely due to enhanced photosynthetic efficiency and nutrient uptake. And the inhibitory effects of higher densities on growth, particularly under high-light conditions, may be due to increased competition for light and nutrients. In the late stage of the green tides outbreak, an increase in accumulation density could help to suppress the sustained outbreak of the green tides, particularly in high-light condition.

Abstract Unlike bulky and rigid traditional power systems, 1D fiber batteries possess appealing features such as flexibility and adaptability, which are promising for use in wearable electronic devices. However, the performance and energy density fiber batteries are limited by the contradiction between ionic transfer and robust structure of fiber electrodes. Herein, these problems are addressed via polymer engineering to regulate the microenvironment in electrodes, realizing high‐linear‐capacity thick fiber electrodes with excellent cycling performance. The porosity of the electrodes is regulated using polymer crosslink networks designed with various components, and lithium‐ion transfer is optimized through ether‐abundant polymer chains. Furthermore, reinforced covalent bonding with carbon nanotube networks is established based on the modified functional groups of polymer networks. The multiscale optimizations of the porous structure, ionic transportation, and covalent bonding network enhance the lithium‐ion dynamics property and structural stability. Therefore, ultrahigh linear‐capacity fiber electrodes (17.8 mAh m−1) can be fabricated on a large scale and exhibit excellent stability (92.8% after 800 cycles), demonstrating obvious superiority among the reported fiber electrodes. Moreover, this study highlights the high effectiveness of polymer regulation in fiber electrodes and offers new avenues for designing next‐generation wearable energy‐storage systems.

ABSTRACT: Riemerella anatipestifer, belonging to Weeksellaceae family Riemerella, is a bacterium that can infect ducks, geese, and turkeys, causing diseases known as duck infectious serositis, new duck disease, and duck septicemia. We collected diseased materials from ducks on a duck farm in China and then isolated and purified a strain of serotype 1 R. anatipestifer named SX-1. Animal experiments showed that SX-1 is a highly virulent strain with an LD50 value of 101 CFU/mL. The complete genome sequence was obtained. The complete genome sequence of R. anatipestifer SX-1 was 2,112,539 bp; 847 genes were involved in catalytic activity, and 445 genes were related to the cell membrane. The total length of the repetitive sequences was 8746 bp. Four CRISPR loci were predicted in R. anatipestifer strain SX-1, and 4 genomic islands were predicted. Concentration and ultra-high-speed centrifugation were used to extract the outer membrane vesicles of R. anatipestifer SX-1. The OMVs were extracted successfully. Particle size analysis revealed the size and abundance of particles: 147.4 nm, 94.9%; 293.6 nm, 1.1%; 327.2 nm, 1.1%; 397.2 nm, 0.3%; and 371.8 nm, 1.1%. The average size was 173.5 nm. Label-free proteomic technology was used to identify proteins in the outer membrane vesicles. ATCC 11845 served as the reference genome sequence, and 148 proteins were identified using proteomic analysis, which were classified into 5 categories based on their sources. Among them, 24 originated from cytoplasmic proteins, 4 from extracellular secreted proteins, 27 from outer membrane proteins, 10 from periplasmic proteins, and 83 from unknown sources. This study conducted a proteomic analysis of OMVs to provide a theoretical basis for the development of R. anatipestifer OMVs vaccines and adjuvants and lays the foundation for further research on the relationship between the pathogenicity of R. anatipestifer and OMVs.

In recent years, golden tides caused by floating Sargassum have induced severe ecological disasters globally. Eutrophication is a significant factor contributing to the massive spread of Sargassum golden tides. Furthermore, the thalli of Sargassum that float on the ocean surface are subjected to more ultraviolet radiation (UVR). The coupled impact of eutrophication and UVR on the photosynthetic physiology of golden tide species remains unclear. In this study, the thalli of Sargassum horneri, known to cause golden tide, were cultured and acclimated to three distinct nitrogen (N) conditions (natural seawater, NSW; NH4+-N enrichment; and NO3–N enrichment) for 6 days. Subsequently, the thalli were exposed to two different radiation treatments (photosynthetically active radiation (150 W m-2), PAR, 400–700 nm; PAR (150 W m-2) + UVR (28 W m-2), 280–700 nm) for 120 min, to investigate the photosynthetic effects of UVR and N on this alga. The findings demonstrated that exposure to UVR impeded the photosynthetic capacity of S. horneri, as evidenced by a decrease in the maximum photochemical quantum yield (Fv/Fm), photosynthetic efficiency (α) and chlorophyll content. Under diverse N-enrichment conditions, the alga tended to adopt various strategies to mitigate the adverse effects of UVR. NH4+-enrichment dissipated excess UVR energy through a greater increase in non-photochemical quenching (NPQ). While NO3–enrichment protected alga by enhancing N assimilation (higher nitrate reductase activity (NRA) and soluble protein content), and maintained a stable energy captured per unit reaction center for electron transfer (ET0/RC) and a higher net photosynthetic rate. Although different N enrichments could not completely offset the damage caused by UV radiation, they secured the photoprotective ability of S. horneri in several ways.

Abstract Parkinson’s disease (PD) is characterized by the formation of Lewy body in dopaminergic neurons in the substantia nigra pars compacta (SNpc). Alpha-synuclein (α-syn) is a major component of Lewy body. Autophagy eliminates damaged organelles and abnormal aggregated proteins. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays roles in protecting dopaminergic neurons against neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). However, the relationship between Trx-1 and α-syn in PD is still unknown. In the present study, the movement disorder and dopaminergic neurotoxicity in MPTP-treated mice were improved by Trx-1 overexpression and were aggravated by Trx-1 knockdown in the SNpc in mice. The expression of α-syn was increased in the SNpc of MPTP-treated mice, which was inhibited by Trx-1 overexpression and was exacerbated in Trx-1 knockdown mice. Autophagosomes was increased under electron microscope after MPTP treatment, which were recovered in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown in the SNpc in mice. The expressions of phosphatase and tensin homolog deleted on chromosome ten (PTEN)-induced putative kinase 1 (PINK1), Parkin, LC3 II and p62 were increased by MPTP, which were blocked in Trx-1 overexpressing mice and were further increased in Trx-1 knockdown mice. Cathepsin D was decreased by MPTP, which was restored in Trx-1 overexpressing mice and was further decreased in Trx-1 knockdown mice. The mRFP-GFP-LC3 green fluorescent dots were increased by 1-methyl-4-phenylpyridinium (MPP+) and further increased in Trx-1 siRNA transfected PC12 cells, while mRFP-GFP-LC3 red fluorescent dots were increased in Trx-1 overexpressing cells. These results indicate that Trx-1 may eliminate α-syn in PD mice through potentiating autophagy-lysosome pathway.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a five-year survival rate of approximately 10%. Genetic mutations are pivotal drivers in PDAC pathogenesis, but recent investigations also revealed the involvement of non-genetic alterations in the disease development. In this study, we undertook a multi-omics approach, encompassing ATAC-seq, RNA-seq, ChIP-seq, and Hi-C methodologies, to dissect gene expression alterations arising from changes in chromosome accessibility and chromatin three-dimensional interactions in PDAC. Results Our findings indicate that chromosomal structural alterations can lead to abnormal expressions on key genes during PDAC development. Notably, overexpression of oncogenes FGFR2, FOXA2, CYP2R1, and CPOX can be attributed to the augmentation of promoter accessibility, coupled with long-range interactions with distal elements. Additionally, our findings indicate that chromosomal structural alterations caused by genomic instability can lead to abnormal expressions in PDACs. As an example, by analyzing chromosomal changes, we identified a putative oncogenic gene, LPAR1, which shows upregulated expression in both PDAC cell lines and clinical samples. The overexpression is correlated with alterations in LPAR1-associated 3D genome structure and chromatin state. We further demonstrated that high LPAR1 activity is required for enhanced PDAC cell migration in vitro. Conclusions Collectively, our findings reveal that the chromosomal conformational alterations, in addition to the well-known genetic mutations, are critical for PDAC tumorigenesis.

Abstract Background Electrical storm (ES) is a clinical emergency characterized by multiple malignant ventricular arrhythmias or ICD discharges within 24 h, requiring early rational management. Case presentation We report a 55-year-old man who underwent aortic valve replacement experienced recurrent ventricular tachycardia/ventricular fibrillation. A temporary permanent pacemaker with the EnSite system was implanted, and significant inhibition of the electrical storm, attributed to the atrial overdrive pacing, ensued. Conclusions In emergency regarding an electrical storm, the bedside temporary permanent pacemaker implantation with the EnSite system is concluded to be feasible and safe.

Special environmental microorganisms are considered to be of great industrial application value because of their special genotypes, physiological functions and metabolites. The research and development of special environmental microorganisms will certainly bring about some innovations in biotechnology processes and change the face of bioengineering. The Special Environmental Microbial Database (DSEMR) is a comprehensive database that provides information on special environmental microbial resources and correlates them with synthetic biological parts. DSEMR aggregates information on specific environmental microbial genomes, physiological properties, culture media, biological parts, and metabolic pathways, and provides online tool analysis data, including 5268 strains from 620 genera, 31 media, and 42,126 biological parts. In short, DSEMR will become an important resource for the study of microorganisms in special environments and actively promote the development of synthetic biology.

Objective·To investigate the effect of F-box only protein 38 (FBXO38) on the ocular melanoma proliferation and the potential regulatory pathway.Methods·Human skin cutaneous melanoma A375 and human uveal melanoma OMM2.3 cell lines with FBXO38 knockdown and overexpression were constructed by FBXO38 short hairpin RNA (shRNA) and FBXO38 overexpression plasmids respectively. Knockdown and overexpression efficiency of FBXO38 at transcription and protein levels were verified by using quantitative real-time PCR (qRT-PCR) and Western blotting. The effects of FBXO38 on melanoma cell proliferation were detected through clonal formation assay, BrdU immunofluorescence staining and CCK8 cell proliferation assay. By using The Cancer Genome Atlas (TCGA) database, differentially expressed genes were analyzed in the high and low expression groups of FBXO38. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was performed to reveal the signaling pathways associated with FBXO38. CCK8 cell proliferation assay was used to detect the inhibition rates of the signaling pathway inhibitors on cells with different FBXO38 expression levels. qRT-PCR and Western blotting were used to detect whether the signaling pathway was activated after knocking down FBXO38.Results·qRT-PCR and Western blotting verified that mRNA and protein expression levels of FBXO38 in FBXO38 knockdown A375 and OMM2.3 cell lines decreased compared with the control group, while the expression levels of FBXO38 in the overexpression cell lines increased compared with wild type group (P

Background: Transposable elements (TEs) and noncoding sequences are major components of the genome, yet their functional contributions to long noncoding RNAs (lncRNAs) are not well understood. Although many lncRNAs originating from TEs (TE-lncRNAs) have been identified across various organisms, their characteristics and regulatory roles, particularly in insects, remain largely unexplored. This study integrated multi-omics data to investigate TE-lncRNAs in D. melanogaster, focusing on the influence of transposons across different omics levels. Results: We identified 16,118 transposons overlapping with lncRNA sequences that constitute 2119 TE-lncRNAs (40.4% of all lncRNAs) using 256 public RNA-seq samples and 15 lncRNA-seq samples of Drosophila S2 cells treated with heavy metals. Of these, 67.2% of TE-lncRNAs contain more than one TE. The LTR/Gypsy family was the most common transposon insertion. Transposons preferred to insert into promoters, transcription starting sites, and intronic regions, especially in chromosome ends. Compared with lncRNAs, TE-lncRNAs showed longer lengths, a lower conservation, and lower levels but a higher specificity of expression. Multi-omics data analysis revealed positive correlations between transposon insertions and chromatin openness at the pre-transcriptional level. Notably, a total of 516 TE-lncRNAs provided transcriptional factor binding sites through transposon insertions. The regulatory network of a key transcription factor was rewired by transposons, potentially recruiting other transcription factors to exert regulatory functions under heavy metal stress. Additionally, 99 TE-lncRNAs were associated with m6A methylation modification sites, and 115 TE-lncRNAs potentially provided candidate small open reading frames through transposon insertions. Conclusions: Our data analysis demonstrated that TEs contribute to the regulation of lncRNAs. TEs not only promote the transcriptional regulation of lncRNAs, but also facilitate their post-transcriptional and epigenetic regulation.

Parkinson’s disease (PD) is a common neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra and the aggregation of alpha-synuclein (α-syn). The central nervous system (CNS) has previously been considered as an immune-privileged area. However, studies have shown that the immune responses are involved in PD. The major histocompatibility complex (MHC) presents antigens from antigen-presenting cells (APCs) to T lymphocytes, immune responses will be induced. MHCs are expressed in microglia, astrocytes, and dopaminergic neurons. Single nucleotide polymorphisms in MHC are related to the risk of PD. The aggregated α-syn triggers the expression of MHCs by activating glia cells. CD4+ and CD8+ T lymphocytes responses and microglia activation are detected in brains of PD patients. In addiction immune responses further increase blood-brain barrier (BBB) permeability and T cell infiltration in PD. Thus, MHCs are involved in PD through participating in immune and inflammatory responses.

Porcine circovirus disease (PCV) causes substantial economic losses in the pig industry, primarily from porcine circovirus type 2 (PCV2) and porcine circovirus type 3 (PCV3). Novel vaccines are necessary to prevent and control PCV infections. PCV coat proteins are crucial for eliciting immunogenic proteins that induce the production of antibodies and immune responses. A vaccine platform utilizing Semliki Forest virus RNA replicons expressing vesicular stomatitis virus glycoprotein (VSV-G), was recently developed. This platform generates virus-like vesicles (VLVs) containing VSV-G exclusively, excluding other viral structural proteins. In our study, we developed a novel virus-like vesicle vaccine by constructing recombinant virus-like vesicles (rVLVs) that also express EGFP. These rVLVs were created using the RNA replicon of Venezuelan equine encephalomyelitis (VEEV) and New Jersey serotype VSV-G. The rVLVs underwent characterization and safety evaluation in vitro. Subsequently, rVLVs expressing PCV2d-Cap and PCV3-Cap proteins were constructed. Immunization of C57 mice with these rVLVs led to a significant increase in anti-porcine circovirus type 2 and type 3 capsid protein antibodies in mouse serum. Additionally, a cellular immune response was induced, as evidenced by high production of IFN-γ and IL-4 cytokines. Overall, this study demonstrates the feasibility of developing a novel porcine circovirus disease vaccine based on rVLVs.

ABSTRACTObservational evidence suggests that human milk oligosaccharides (HMOs) promote the growth of commensal bacteria in early life and adulthood. However, the mechanisms by which HMOs benefit health through modulation of gut microbial homeostasis remain largely unknown. 2′-fucosyllactose (2′-FL) is the most abundant oligosaccharide in human milk and contributes to the essential health benefits associated with human milk consumption. Here, we investigated how 2′-FL prevents colitis in adulthood through its effects on the gut microbial community. We found that the gut microbiota from adult mice that consumed 2′-FL exhibited an increase in abundance of several health-associated genera, including Bifidobacterium and Lactobacillus. The 2′-FL-modulated gut microbial community exerted preventive effects on colitis in adult mice. By using Bifidobacterium infantis as a 2′-FL-consuming bacterial model, exploratory metabolomics revealed novel 2′-FL-enriched secretory metabolites by Bifidobacterium infantis, including pantothenol. Importantly, pantothenate significantly protected the intestinal barrier against oxidative stress and mitigated colitis in adult mice. Furthermore, microbial metabolic pathway analysis identified 26 dysregulated metabolic pathways in fecal microbiota from patients with ulcerative colitis, which were significantly regulated by 2′-FL treatment in adult mice, indicating that 2′-FL has the potential to rectify dysregulated microbial metabolism in colitis. These findings support the contribution of the 2′-FL-shaped gut microbial community and bacterial metabolite production to the protection of intestinal integrity and prevention of intestinal inflammation in adulthood.IMPORTANCEAt present, neither basic research nor clinical studies have revealed the exact biological functions or mechanisms of action of individual oligosaccharides during development or in adulthood. Thus, it remains largely unknown whether human milk oligosaccharides could serve as effective therapeutics for gastrointestinal-related diseases. Results from the present study uncover 2′-FL-driven alterations in bacterial metabolism and identify novel B. infantis-secreted metabolites following the consumption of 2′-FL, including pantothenol. This work further demonstrates a previously unrecognized role of pantothenate in significantly protecting the intestinal barrier against oxidative stress and mitigating colitis in adult mice. Remarkably, 2′-FL-enhanced bacterial metabolic pathways are found to be dysregulated in the fecal microbiota of ulcerative colitis patients. These novel metabolic pathways underlying the bioactivities of 2′-FL may lay a foundation for applying individual oligosaccharides for prophylactic intervention for diseases associated with impaired intestinal homeostasis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent and severe side effect of first-line chemotherapeutic agents. The association between circular RNAs (circRNAs) and CIPN remains unclear. In this study, CIPN models were constructed with Taxol, while 134 differentially expressed circRNAs, 353 differentially expressed long non-coding RNAs, and 86 differentially expressed messenger RNAs (mRNAs) were identified utilizing RNA sequencing. CircRNA-targeted microRNAs (miRNAs) were predicted using miRanda, and miRNA-targeted mRNAs were predicted using TargetScan and miRDB. The intersection of sequencing and mRNA prediction results was selected to establish the circRNA–miRNA–mRNA networks, which include 15 circRNAs, 18 miRNAs, and 11 mRNAs. Functional enrichment pathway analyses and immune infiltration analyses revealed that differentially expressed mRNAs were enriched in the immune system, especially in T cells, monocytes, and macrophages. Cdh1, Satb2, Fas, P2ry2, and Zfhx2 were further identified as hub genes and validated by RT-qPCR, correlating with macrophages, plasmacytoid dendritic cells, and central memory CD4 T cells in CIPN. Additionally, we predicted the associated diseases, 36 potential transcription factors (TFs), and 30 putative drugs for hub genes using the DisGeNET, TRRUST, and DGIdb databases, respectively. Our results indicated the crucial role of circRNAs, and the immune microenvironment played in CIPN, providing novel insights for further research.

Abstract Aim To determine the potential profile classes of anxiety reported by ischaemic stroke survivors in rural China, and to explore the characteristics of patients having different types of post‐stroke anxiety. Design A cross‐sectional survey. Methods A cross‐sectional survey was conducted by using convenience sampling to collect data from 661 ischaemic stroke survivors in rural Anyang city, Henan Province, China, from July 2021 to September 2021. The parameters included in the study were the socio‐demographic characteristics, self‐rating anxiety scale (SAS), self‐rating depression scale (SDS) and the Barthel index of daily activity ability. Potential profile analysis was done to recognize subgroups of post‐stroke anxiety. The Chi‐square test was performed to explore the characteristics of individuals with different types of post‐stroke anxiety. Results The model fitting indices of stroke survivors supported three classes of anxiety models which were as follows: (a) Class 1, low‐level, stable group (65.3%, N = 431); (b) Class 2, moderate‐level, unstable group (17.9%, N = 118) and (c) Class 3, high‐level, stable group (16.9%, N = 112). The risk factors associated with post‐stroke anxiety were female patients, lower levels of education, living alone, lower monthly household income, other chronic diseases, impaired daily activity ability and depression. Conclusions This study identified three different subgroups of post‐ischaemic stroke anxiety and their characteristics in patients in rural China. Impact This study has significance in providing evidence for the development of targeted intervention measures to reduce negative emotions in different subgroups of post‐stroke anxiety patients. Patient or Public Contribution In this study, the researchers arranged the time of questionnaire collection with the village committee in advance, gathered the patients to the village committee for face‐to‐face questionnaire survey and collected the household data of the patients with mobility difficulties.

Wheat dwarf virus (WDV, genus Mastrevirus, family Geminiviridae) is one of the causal agents of wheat viral disease, which severely impacts wheat production in most wheat-growing regions in the world. Currently, there is little information about natural resistance against WDV in common wheat germplasms. CRISPR/Cas9 technology is being utilized to manufacture transgenic plants resistant to different diseases. In the present study, we used the CRISPR/Cas9 system targeting overlapping regions of coat protein (CP) and movement protein (MP) (referred to as CP/MP) or large intergenic region (LIR) in the wheat variety ‘Fielder’ to develop resistance against WDV. WDV-inoculated T1 progenies expressing Cas9 and sgRNA for CP/MP and LIR showed complete resistance against WDV and no accumulation of viral DNA compared with control plants. Mutation analysis revealed that the CP/MP and LIR targeting sites have small indels in the corresponding Cas9-positive plants. Additionally, virus inhibition and indel mutations occurred in T2 homozygous lines. Together, our work gives efficient results of the engineering of CRISPR/Cas9-mediated WDV resistance in common wheat plants, and the specific sgRNAs identified in this study can be extended to utilize the CRISPR/Cas9 system to confer resistance to WDV in other cereal crops such as barley, oats, and rye.

Qingqiao Kangdu granule (QQKDG), a traditional Chinese medicine (TCM), has been used clinically to treat various viral diseases, including flu, mumps, and viral hepatitis, owing to its abundant bioactivities. Nevertheless, the chemical components of QQKDG have not been sufficiently elucidated; consequently, the development of standards for quality evaluation and complete understanding of the pharmacological mechanisms of action are hindered. Therefore, a systematic approach must be developed to efficiently discover novel compounds and advance pharmacological research. In this regard, this study proposed an integrated strategy for the comprehensive characterization of the chemical components in QQKDG by UHPLC-Q-Exactive-MS coupled with feature-based molecular networking (FBMN) to improve annotation accuracy and achieve visualization. First, the chromatographic and mass spectrum conditions were optimized to obtain good separation and abundant signal response. Subsequently, an in-house library was established by searching for relevant literature to improve annotation confidence. Finally, the raw data acquired under optimized conditions were uploaded to the FBMN to achieve component visualization by connecting precursor ions of the same color, in which compounds have similar structural features. Thus, a total of 231 compounds, including 89 flavonoids, 36 phenolic acids, 26 phenylethanoid glycosides, 23 coumarins, 17 chlorogenic acid derivatives, 14 terpenoids, 10 alkaloids, 10 lignans and 6 other compounds, were characterized, and numerous novel compounds with new structures were explored. Thus, this study provides a strategy for comprehensive characterization, which can also be applied to other TCMs.

The aim was to determine the response of a bloom-forming Microcystis aeruginosa to climatic changes. Cultures of M. aeruginosa FACHB 905 were grown at two temperatures (25°C, 30°C) and exposed to high photosynthetically active radiation (PAR: 400–700 nm) alone or combined with UVR (PAR + UVR: 295–700 nm) for specified times. It was found that increased temperature enhanced M. aeruginosa sensitivity to both PAR and PAR + UVR as shown by reduced PSII quantum yields (Fv/Fm) in comparison with that at growth temperature (25°C), the presence of UVR significantly exacerbated the photoinhibition. M. aeruginosa cells grown at high temperature exhibited lower PSII repair rate (Krec) and sustained nonphotochemical quenching (NPQs) induction during the radiation exposure, particularly for PAR + UVR. Although high temperature alone or worked with UVR induced higher SOD and CAT activity and promoted the removal rate of PsbA, it seemed not enough to prevent the damage effect from them showing by the increased value of photoinactivation rate constant (Kpi). In addition, the energetic cost of microcystin synthesis at high temperature probably led to reduced materials and energy available for PsbA turnover, thus may partly account for the lower Krec and the declination of photosynthetic activity in cells following PAR and PAR + UVR exposure. Our findings suggest that increased temperature modulates the sensitivity of M. aeruginosa to UVR by affecting the PSII repair and defense capacity, thus influencing competitiveness and abundance in the future water environment.

ABSTRACTSeveral probiotic-derived factors have been identified as effectors of probiotics for exerting beneficial effects on the host. However, there is a paucity of studies to elucidate mechanisms of their functions. p40, a secretory protein, is originally isolated from a probiotic bacterium, Lactobacillus rhamnosus GG. Thus, this study aimed to apply structure-functional analysis to define the functional peptide of p40 that modulates the epigenetic program in intestinal epithelial cells for sustained prevention of colitis. In silico analysis revealed that p40 is composed of a signal peptide (1–28 residues) followed by a coiled-coil domain with uncharacterized function on the N-terminus, a linker region, and a β-sheet domain with high homology to CHAP on the C-terminus. Based on the p40 three-dimensional structure model, two recombinant p40 peptides were generated, p40N120 (28–120 residues) and p40N180 (28–180 residues) that contain first two and first three coiled coils, respectively. Compared to full-length p40 (p40F) and p40N180, p40N120 showed similar or higher effects on up-regulating expression of Setd1b (encoding a methyltransferase), promoting mono- and trimethylation of histone 3 on lysine 4 (H3K4me1/3), and enhancing Tgfb gene expression and protein production that leads to SMAD2 phosphorylation in human colonoids and a mouse colonic epithelial cell line. Furthermore, supplementation with p40F and p40N120 in early life increased H3K4me1, Tgfb expression and differentiation of regulatory T cells (Tregs) in the colon, and mitigated disruption of epithelial barrier and inflammation induced by DSS in adult mice. This study reveals the structural feature of p40 and identifies a functional peptide of p40 that could maintain intestinal homeostasis.

Only few glufosinate-tolerant genes, such as phosphinothricin acetyltransferase (PAT) and bialaphos resistance (bar) identified from Streptomyces, are currently available for developing genetically modified rice in agricultural application. Following the rapid development of genome editing technology, generation of novel glufosinate-tolerant gene resources through artificial evolution of endogenous genes is more promising and highly desirable in rice molecular breeding program. In this study, the endogenous Glutamine synthetase1 (OsGS1) was artificially evolved by base-editing-mediated gene evolution (BEMGE) in rice cells to create novel alleles conferring glufosinate tolerance in rice germplasms. Two novel glufosinate-tolerant OsGS1 alleles (OsGS1-AVPS and OsGS1-+AF) and one reported tolerant allele (OsGS1-SGTA) were successfully identified from approximately 4200 independent hygromycin-tolerant calli. Germination assays and spray tests revealed that these three OsGS1 alleles confer glufosinate tolerance in rice. Furthermore, OsGS1-AVPS and OsGS1-SGTA were quickly deployed into the elite rice cultivar Nangeng 46 through precise base editing. Overall, our results demonstrate the feasibility of developing glufosinate-tolerant rice by editing an endogenous rice gene in molecular breeding programs.

Abstract Diabetic cardiomyopathy (DCM) is a serious cardiovascular complication and the leading cause of death in diabetic patients. Patients typically do not experience any symptoms and have normal systolic and diastolic cardiac functions in the early stages of DCM. Because the majority of cardiac tissue has already been destroyed by the time DCM is detected, research must be conducted on biomarkers for early DCM, early diagnosis of DCM patients, and early symptomatic management to minimize mortality rates among DCM patients. Most of the existing implemented clinical markers are not very specific for DCM, especially in the early stages of DCM. Recent studies have shown that a number of new novel markers, such as galactin-3 (Gal-3), adiponectin (APN), and irisin, have significant changes in the clinical course of the various stages of DCM, suggesting that we may have a positive effect on the identification of DCM. As a summary of the current state of knowledge regarding DCM biomarkers, this review aims to inspire new ideas for identifying clinical markers and related pathophysiologic mechanisms that could be used in the early diagnosis and treatment of DCM.

Plasmonic hot spots located between metallic dimer nanostructures have been utilized comprehensively to achieve efficient light emission. However, different from the enhancement occurred in the plasmonic hot spot, the investigation of light emission off the hot spot on submicron scale remains challenge. In this work, we have constructed a plasmonic nanowire dimer (NWD) system to brighten the light emission of the surface defects of silicon off the hot spot on the submicron scale. The NWD can trap light through plasmonic gap, then, the excited emitter on the submicron scale can radiate light efficiently by coupling with the dipole gap plasmonic mode. Furthermore, the coupling of dipole plasmonic mode with the emitters can be tuned by changing the gap size, and then photoluminescence emission was drastically enhanced up to 126 folds. Theoretical simulations reveal the photoluminescence enhancement arises from the combination of the NWD’s high radiation efficiency, Purcell enhancement, efficient redirection of the emitted photoluminescence and the excitation enhancement. In this study, the photoluminescence signal can be effectively enhanced by placing nano-antenna patch on the detected low-quantum-efficiency emitters, which may open up a pathway toward controlling plasmonic gap mode enhanced light emission off the hot spot on submicron scale.

The tumor suppressor protein P53 can regulate the cell cycle, thereby preventing cell abnormalities. In this paper, we study the dynamic characteristics of the P53 network under the influence of time delay and noise, including stability and bifurcation. In order to study the influence of several factors on the concentration of P53, bifurcation analysis on several important parameters is conducted; the results show that the important parameters could induce P53 oscillations within an appropriate range. Then we study the stability of the system and the existing conditions of Hopf bifurcation by using Hopf bifurcation theory with time delays as the bifurcation parameter. It is found that time delay plays a key role in inducing Hopf bifurcation and regulating the period and amplitude of system oscillation. Meanwhile, the combination of time delays can not only promote the oscillation of the system but it also provides good robustness. Changing the parameter values appropriately can change the bifurcation critical point and even the stable state of the system. In addition, due to the low copy number of the molecules and the environmental fluctuations, the influence of noise on the system is also considered. Through numerical simulation, it is found that noise not only promotes system oscillation but it also induces system state switching. The above results may help us to further understand the regulation mechanism of the P53-Mdm2-Wip1 network in the cell cycle.

Oxidative stress due to excessive reactive oxygen species (ROS) production in the skin microenvironment is one of the main mechanisms in psoriasis pathogenesis. A nano drug delivery system based on ROS-responsive release can enhance drug release at the target site. In this study, a ROS-sensitive material methoxypolyethylene glycol-thioether-thiol (mPEG-SS) was synthesized using mPEG as the parent structure with sulfide structural modification. An mPEG-SS-calcipotriol (mPEG-SS-CPT, PSC) nano-micelle percutaneous delivery system was prepared by encapsulating CPT. A small animal imaging system was used to study PSC’s the ROS-sensitive drug release process. It is shown that endogenous ROS mainly affects PSC and releases drugs. Finally, the therapeutic effect of PSC on psoriasis was explored by animal experiments. Ultimately, it ameliorates imiquimod-induced psoriasis-like inflammation. Overall, PSC is an effective ROS-sensitive transdermal drug delivery system that is expected to provide a new strategy for treating psoriasis.

Quercetin is one of the most common flavonoids. More and more studies have found that quercetin has great potential utilization value in cardiovascular diseases (CVD), such as antioxidant, antiplatelet aggregation, antibacterial, cholesterol lowering, endothelial cell protection, etc. However, the medicinal value of quercetin is mostly limited to animal models and preclinical studies. Due to the complexity of the human body and functional structure compared to animals, more research is needed to explore whether quercetin has the same mechanism of action and pharmacological value as animal experiments. In order to systematically understand the clinical application value of quercetin, this article reviews the research progress of quercetin in CVD, including preclinical and clinical studies. We will focus on the relationship between quercetin and common CVD, such as atherosclerosis, myocardial infarction, ischemia reperfusion injury, heart failure, hypertension and arrhythmia, etc. By elaborating on the pathophysiological mechanism and clinical application research progress of quercetin's protective effect on CVD, data support is provided for the transformation of quercetin from laboratory to clinical application.

With the development of safety science, the concept of safety capacity (SC) has been proposed. SC has been applied in many fields. Concurrently, there has been an active and robust development of research pertaining to it. However, SC research mainly focuses on practical engineering problems, and SC research is only regarded as the establishment of a quantitative model for system safety. Hence, the theoretical study of SC is ignored. Indeed, the integrated theoretical system and connotation of SC are lacking. In this study, an attempt is made to enrich the theoretical connotation of SC. The following aspects of theoretical exploration are included: (a) The theoretical connotation of SC is redefined so that the lack of theory with respect to SC can be made up. Moreover, research directions of SC are indicated as dimension mining (DM) and dimensionality reduction (DR). (b) The application value of safety similarity theory in the DM of SC is expounded according to the principle of analogism. Core principles of DM are proposed and explained. (c) Common methods of DR are summarized, and the one-sided cognition of DR for the current SC research is corrected. A case study of an explosion accident caused by a boiler water shortage is employed for further discussion. For the investigation of the explosion accident using fault tree analysis (FTA), DR of SC is utilized to provide a more comprehensive explanation. Therefore, the proposed SC is proven to be practical for the analysis of system safety. The results obtained from this study have important implications for research and practice of SC.

Alfalfa (Medicago sativa L.) is an important forage legume and soil salinization seriously affects its growth and yield. In a previous study, we identified a salt-tolerant variety ‘Gongnong NO.1’ and a salt-sensitive variety ‘Sibeide’. To unravel the molecular mechanism involved in salt stress, we conducted transcriptomic analysis on these two cultivars grown under 0 and 250 mM NaCl treatments for 0, 12, and 24 h. Totals of 336, and 548 differentially expressed genes (DEGs) in response to NaCl were, respectively, identified in the ‘Gongnong NO.1’ and ‘Sibeide’ varieties. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathway enrichment analysis showed that the DEGs were classified in carbohydrate metabolism, energy production, transcription factor, and stress-associated pathway. Expression of MsHPCA1, encoding a putative H2O2 receptor, was responsive to both NaCl and H2O2 treatment. MsHPCA1 was localized in cell membrane and overexpression of MsHPCA1 in alfalfa increased salt tolerance and H2O2 content. This study will provide new gene resources for the improvement in salt tolerance in alfalfa and legume crops, which has important theoretical significance and potential application value.

Introduction Incidences of stroke are on the rise and approximately 80 million stroke survivors worldwide live with disabilities. Supportive care needs of stroke survivors are not adequately defined, and the assessment tools to help care service providers identify these needs are unclear. The overall aim of this scoping review will be to map the supportive care needs of stroke survivors against the Supportive Care Needs Framework.Methods and analysis This scoping review will be conducted following Arksey and O’Malley’s methodological framework and Joanna Briggs Institute (JBI) updated methodological guidance for scoping review. This review will mainly use Arksey and O’Malley’s methodological framework as the basic framework. The review will also follow JBI’s updated methodological guidance for scoping reviews to optimise the review. For the search strategy, the three-step method recommended by the JBI will be used in the study. The review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews. Six English databases, including PubMed, CINAHL, Web of Science, Embase, Cochrane Library and PsycInfo, and four Chinese databases, including CNKI, Wanfang, VIP and China Biomedical Literature Database will be systematically searched from inception to the present. Studies published in English and Chinese will be included.Ethics and dissemination Ethical approval is not required as this scoping review does not involve human participants. The findings shall be disseminated at scientific conferences and published in a peer-reviewed journal.

Mouse zygotes undergo multiple rounds of cell division, resulting in the formation of preimplantation blastocysts comprising three lineages: trophectoderm (TE), epiblast (EPI), and primitive endoderm (PrE). Cell fate determination plays a crucial role in establishing a healthy pregnancy. The initial separation of lineages gives rise to TE and inner cell mass (ICM), from which trophoblast stem cells (TSC) and embryonic stem cells (ESC) can be derived in vitro. Studying lineage differentiation is greatly facilitated by the clear functional distinction between TSC and ESC. However, transitioning between these two types of cells naturally poses challenges. In this study, we demonstrate that inhibiting LATS kinase promotes the conversion of ICM to TE and also effectively reprograms ESC into stable, self-renewing TS-like cells (TSLC). Compared to TSC, TSLC exhibits similar molecular properties, including the high expression of marker genes such as Cdx2, Eomes, and Tfap2c, as well as hypomethylation of their promoters. Importantly, TSLC not only displays the ability to differentiate into mature trophoblast cells in vitro but also participates in placenta formation in vivo. These findings highlight the efficient reprogramming of ESCs into TSLCs using a small molecular inducer, which provides a new reference for understanding the regulatory network between ESCs and TSCs.

Abstract Background Heart disease is a major cause of mortality in developed countries. The associated pathology is mainly characterized by the loss of cardiomyocytes that contributes to heart failure (HF). This study aims to investigate the mechanism of euchromatic histone lysine methyltransferase 2 (EHMT2, also term G9a) in HF in rats. Methods Differentially expressed mRNAs in HF were screened using GEO database. Sera from subjects with or without HF were collected, and PCR was performed to detect the G9a expression. G9a was downregulated in cardiomyocytes exposed to oxygen–glucose deprivation (OGD), followed by CCK8, flow cytometry, colorimetric method, and western blot assays. Established HF rats were delivered with lentiviral vectors carrying sh-G9a, and TTC staining, HE staining, TUNEL, ELISA, and western blot were performed. The regulation of G9a on the downstream target BDNF was investigated by RT-qPCR, Western blot, and ChIP-qPCR. Finally, rescue experiments were carried out to substantiate the effect of G9a on cardiomyocyte apoptosis and injury via the BDNF/TrkB axis. Results G9a was overexpressed, whereas BDNF was downregulated in HF. Knockdown of G9a inhibited apoptosis and injury in OGD-treated cardiomyocytes and attenuated the extent of HF and myocardial injury in rats. Silencing of G9a promoted BDNF transcription by repressing H3K9me2 modification of the BDNF promoter. Further depletion of BDNF partially reversed the effect of sh-G9a in alleviating cardiomyocyte apoptosis and injury by inhibiting the TrkB signaling pathway. Conclusion G9a inhibits BDNF expression through H3K9me2 modification, thereby impairing the TrkB signaling pathway and exacerbating the development of HF.

In this paper, the kinetics of p53 in two cell lines with different degrees of sensitivity to chemotherapeutic drugs is studied. There is much research that has explored the p53 oscillation, but there are few comparisons between cells that are sensitive to drug treatment and those that are not. Here, the kinetics of the p53 system between etoposide-sensitive and etoposide-resistant cell lines in response to different drug doses and different protein synthesis time delays are studied and compared. First, the results showed that time delay is an important condition for p53 oscillation by producing Hopf bifurcation in both the etoposide-sensitive and etoposide-resistant cells. If the protein synthesis time delays are zero, the system cannot oscillate even the dose of the drug increases. Second, the time delay required for producing sustained oscillation in sensitive cells is shorter than the drug-resistant cells. In addition, the p53-Wip1 negative feedback loop in drug-resistant cells is relatively highly strengthened than the drug-sensitive cells. To sum up, p53 oscillation is controlled by time delay, drug dose, and the coupled negative feedback network including p53-mdm2 and p53-wip1. Moreover, in the two different types of cells, the control mechanisms are similar, but there are also differences.

Abstract Background Increasing interest in the hazardous properties of zinc oxide nanoparticles (ZnO NPs), commonly used as ultraviolet filters in sunscreen, has driven efforts to study the percutaneous application of ZnO NPs to diseased skin; however, in-depth studies of toxic effects on melanocytes under conditions of epidermal barrier dysfunction remain lacking. Methods Epidermal barrier dysfunction model mice were continuously exposed to a ZnO NP-containing suspension for 14 and 49 consecutive days in vivo. Melanoma-like change and molecular mechanisms were also verified in human epidermal melanocytes treated with 5.0 µg/ml ZnO NPs for 72 h in vitro. Results ZnO NP application for 14 and 49 consecutive days induced melanoma-like skin lesions, supported by pigmented appearance, markedly increased number of melanocytes in the epidermis and dermis, increased cells with irregular nuclei in the epidermis, recruited dendritic cells in the dermis and dysregulated expression of melanoma-associated gene Fkbp51, Trim63 and Tsp 1. ZnO NPs increased oxidative injury, inhibited apoptosis, and increased nuclear factor kappa B (NF-κB) p65 and Bcl-2 expression in melanocytes of skin with epidermal barrier dysfunction after continuously treated for 14 and 49 days. Exposure to 5.0 µg/ml ZnO NPs for 72 h increased cell viability, decreased apoptosis, and increased Fkbp51 expression in melanocytes, consistent with histological observations in vivo. The oxidative stress–mediated mechanism underlying the induction of anti-apoptotic effects was verified using the reactive oxygen species scavenger N-acetylcysteine. Conclusions The entry of ZnO NPs into the stratum basale of skin with epidermal barrier dysfunction resulted in melanoma-like skin lesions and an anti-apoptotic effect induced by oxidative stress, activating the NF-κB pathway in melanocytes. Graphical Abstract

IntroductionNon-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of triglycerides within the liver. However, whether the circulating levels of triglycerides and cholesterol transported in triglyceride-rich lipoproteins (remnant cholesterol, remnant-C) are related to the occurrence of NAFLD has not yet been studied. This study aims to assess the association of triglycerides and remnant-C with NAFLD in a Chinese cohort of middle aged and elderly individuals.MethodsAll subjects in the current study are from the 13,876 individuals who recruited in the Shandong cohort of the REACTION study. We included 6,634 participants who had more than one visit during the study period with an average follow-up time of 43.34 months. The association between lipid concentrations and incident NAFLD were evaluated by unadjusted and adjusted Cox proportional hazard models. The potential confounders were adjusted in the models including age, sex, hip circumference (HC), body mass index (BMI), systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), diabetes status and cardiovascular disease (CVD) status.ResultsIn multivariable-adjusted Cox proportional hazard model analyses, triglycerides (hazard ratio[HR], 95% confidence interval [CI]:1.080,1.047-1.113;p1.69 mmol/L, HDL-C

IntroductionNewly weaned animals are susceptible to a wide range of microbial infections taking a high risk of developing post-weaning diarrhea. Trained immunity is the capacity of the innate immune system to produce a stronger and non-specific response against a secondary infection after the inflammatory response caused by previous stimulus has returned to normal state. The objective of this study was to evaluate if the heat-inactivated Escherichia coli (IEC) as an immunostimulant on suckling pups elicits a protective effect on the intestine of post-weaning rats challenged with Salmonella Typhimurium (S.Typhimurium). We adapted a newborn rat model for this purpose.MethodsSixty newborn pups were randomly separated into two groups: IEC group (n =30) orally administrated IEC during suckling, while the CON group received orally the same dose of saline. Both of the two group challenged with various doses of S.Typhimurium after experiencing a 4-week resting period. Twelve of individuals were selected to detect the survival rate, and ten of the rest were necropsied 48 hours post-challenge.Results and DiscussionThe results showed that oral administration of IEC during suckling alleviated the injury in ileal morphology induced by post-weaning S.Typhimurium infection via increasing the levels of two tight junction proteins [zonula occluden-1 (ZO-1) and Occludin-1] and several secreted proteins (Lysozyme, Mucin-2, and SIgA) in the intestinal mucosa. Furthermore, the pre-stimulation with IEC significantly increased cytokines tumor necrosis factor-alpha (TNF- α) and interleukin-1 beta (IL-1 β) expressions in an enhanced secondary reaction way after experiencing a 4-week resting period. This implicated the possible involvement of trained immunity. The 16S rDNA sequence results showed that pre-stimulation with IEC decreased the abundance of Clostridia, Prevotella, Christensenellaceae_R-7_group and Parabacteroides after intestinal infection of S.Typhimurium. Our results confirmed that the previous oral administration of IEC had a protective effect on S.Typhimurium-induced intestinal injury in weaned rats by inducing a robust immune response. The present study suggested a new strategy for preventing intestinal infection of newborn animals.