Potent and specific antibiotic combination therapy against Clostridioides difficile.

Keratinicyclins and keratinimicins are recently discovered glycopeptide antibiotics. Keratinimicins show broad-spectrum activity against Gram-positive bacteria, while keratinicyclins form a new chemotype by virtue of an unusual oxazolidinone moiety and exhibit specific antibiosis against Clostridioides difficile. Here we report the mechanism of action of keratinicyclin B (KCB). We find that steric constraints preclude KCB from binding peptidoglycan termini. Instead, KCB inhibits C. difficile growth by binding wall teichoic acids (WTAs) and interfering with cell wall remodeling. A computational model, guided by biochemical studies, provides an image of the interaction of KCB with C. difficile WTAs and shows that the same H-bonding framework used by glycopeptide antibiotics to bind peptidoglycan termini is used by KCB for interacting with WTAs. Analysis of KCB in combination with vancomycin (VAN) shows highly synergistic and specific antimicrobial activity, and that nanomolar combinations of the two drugs are sufficient for complete growth inhibition of C. difficile, while leaving common commensal strains unaffected.

The MdMYB44-MdTPR1 repressive complex inhibits MdCCD4 and MdCYP97A3 expression through histone deacetylation to regulate carotenoid biosynthesis in apple.

Carotenoids are photosynthetic pigments and antioxidants that contribute to different plant colors. However, the involvement of TOPLESS (TPL/TPR)-mediated histone deacetylation in the modulation of carotenoid biosynthesis through ethylene-responsive element-binding factor-associated amphiphilic repression (EAR)-containing transcription factors (TFs) in apple (Malus domestica Borkh.) is poorly understood. MdMYB44 is a transcriptional repressor that contains an EAR repression motif. In the present study, we used functional analyses and molecular assays to elucidate the molecular mechanisms through which MdMYB44-MdTPR1-mediated histone deacetylation influences carotenoid biosynthesis in apples. We identified two carotenoid biosynthetic genes, MdCCD4 and MdCYP97A3, that were confirmed to be involved in MdMYB44-mediated carotenoid biosynthesis. MdMYB44 enhanced ß-branch carotenoid biosynthesis by repressing MdCCD4 expression, whereas MdMYB44 suppressed lutein level by repressing MdCYP97A3 expression. Moreover, MdMYB44 partially influences carotenoid biosynthesis by interacting with the co-repressor TPR1 through the EAR motif to inhibit MdCCD4 and MdCYP97A3 expression via histone deacetylation. Our findings indicate that the MdTPR1-MdMYB44 repressive cascade regulates carotenoid biosynthesis, providing profound insights into the molecular basis of histone deacetylation-mediated carotenoid biosynthesis in plants. These results also provide evidence that the EAR-harboring TF/TPL repressive complex plays a universal role in histone deacetylation-mediated inhibition of gene expression in various plants.

Abscisic acid activates transcription factor module MdABI5-MdMYBS1 during carotenoid-derived apple fruit coloration.

Carotenoids are major pigments contributing to fruit coloration. We previously reported that the apple (Malus domestica Borkh.) mutant fruits of "Beni Shogun" and "Yanfu 3" show a marked difference in fruit coloration. However, the regulatory mechanism underlying this phenomenon remains unclear. In this study, we determined that carotenoid is the main factor influencing fruit flesh color. We identified an R1-type MYB transcription factor (TF), MdMYBS1, which was found to be highly associated with carotenoids and abscisic acid (ABA) contents of apple fruits. Overexpression of MdMYBS1 promoted, and silencing of MdMYBS1 repressed, ß-branch carotenoids synthesis and ABA accumulation. MdMYBS1 regulates carotenoid biosynthesis by directly activating the major carotenoid biosynthetic genes encoding phytoene synthase (MdPSY2-1) and lycopene ß-cyclase (MdLCYb). 9-cis-epoxycarotenoid dioxygenase 1 (MdNCED1) contributes to ABA biosynthesis, and MdMYBS1 enhances endogenous ABA accumulation by activating the MdNCED1 promoter. In addition, the basic leucine zipper domain TF ABSCISIC ACID-INSENSITIVE5 (MdABI5) was identified as an upstream activator of MdMYBS1, which promotes carotenoid and ABA accumulation. Furthermore, ABA promotes carotenoid biosynthesis and enhances MdMYBS1 and MdABI5 promoter activities. Our findings demonstrate that the MdABI5-MdMYBS1 cascade activated by ABA regulates carotenoid-derived fruit coloration and ABA accumulation in apple, providing avenues in breeding and planting for improvement of fruit coloration and quality.

TSHR signaling promotes hippocampal dependent memory formation through modulating Wnt5a/ß-catenin mediated neurogenesis.

Subclinical hyperthyroidism is defined biochemically as a low or undetectable thyroid-stimulating hormone (TSH) with normal thyroid hormone levels. Low TSHR signaling is considered to associate with cognitive impairment. However, the underlying molecular mechanism by which TSHR signaling modulates memory is poorly understood. In this study, we found that Tshr-deficient in the hippocampal neurons impairs the learning and memory abilities of mice, accompanying by a decline in the number of newborn neurons. Notably, Tshr ablation in the hippocampus decreases the expression of Wnt5a, thereby inactivating the ß-catenin signaling pathway to reduce the neurogenesis. Conversely, activating of the Wnt/ß-catenin pathway by the agonist SKL2001 results in an increase in hippocampal neurogenesis, resulting in the amelioration in the deficits of memory caused by Tshr deletion. Understanding how TSHR signaling in the hippocampus regulates memory provides insights into subclinical hyperthyroidism affecting cognitive function and will suggest ways to rationally design interventions for neurocognitive disorders.

Childhood maltreatment and risk of endocrine diseases: an exploration of mediating pathways using sequential mediation analysis.

BACKGROUND: Adverse childhood experiences (ACEs), including childhood maltreatment, have been linked with increased risk of diabetes and obesity during adulthood. A comprehensive assessment on the associations between childhood maltreatment and all major endocrine diseases, as well as the relative importance of different proposed mechanistic pathways on these associations, is currently lacking. METHODS: Based on the UK Biobank, we constructed a cohort including 151,659 participants with self-reported data on childhood maltreatment who were 30 years of age or older on/after January 1, 1985. All participants were followed from the index date (i.e., January 1, 1985, or their 30th birthday, whichever came later) until the first diagnosis of any or specific (12 individual diagnoses and 9 subtypes) endocrine diseases, death, or the end of follow-up (December 31, 2019), whichever occurred first. We used Cox models to examine the association of childhood maltreatment, treated as continuous (i.e., the cumulative number of experienced childhood maltreatment), ordinal (i.e., 0, 1 and ≥ 2), or binary (< 2 and ≥ 2) variable, with any and specific endocrine diseases, adjusted for multiple covariates. We further examined the risk of having multiple endocrine diseases using Linear or Logistic Regression models. Then, sequential mediation analyses were performed to assess the contribution of four possible mechanisms (i.e., suboptimal socioeconomic status (SES), psychological adversities, unfavorable lifestyle, and biological alterations) on the observed associations. RESULTS: During an average follow-up of 30.8 years, 20,885 participants received a diagnosis of endocrine diseases. We observed an association between the cumulative number of experienced childhood maltreatment and increased risk of being diagnosed with any endocrine disease (adjusted hazard ratio (HR) = 1.10, 95% confidence interval 1.09-1.12). The HR was 1.26 (1.22-1.30) when comparing individuals ≥ 2 with those with < 2 experienced childhood maltreatment. We further noted the most pronounced associations for type 2 diabetes (1.40 (1.33-1.48)) and hypothalamic-pituitary-adrenal (HPA)-axis-related endocrine diseases (1.38 (1.17-1.62)), and the association was stronger for having multiple endocrine diseases, compared to having one (odds ratio (95% CI) = 1.24 (1.19-1.30), 1.35 (1.27-1.44), and 1.52 (1.52-1.53) for 1, 2, and ≥ 3, respectively). Sequential mediation analyses showed that the association between childhood maltreatment and endocrine diseases was consistently and most distinctly mediated by psychological adversities (15.38 ~ 44.97%), while unfavorable lifestyle (10.86 ~ 25.32%) was additionally noted for type 2 diabetes whereas suboptimal SES (14.42 ~ 39.33%) for HPA-axis-related endocrine diseases. CONCLUSIONS: Our study demonstrates that adverse psychological sequel of childhood maltreatment constitutes the main pathway to multiple endocrine diseases, particularly type 2 diabetes and HPA-axis-related endocrine diseases. Therefore, increased access to evidence-based mental health services may also be pivotal in reducing the risk of endocrine diseases among childhood maltreatment-exposed individuals.

Cognitive enhancing effect of rTMS combined with tDCS in patients with major depressive disorder: a double-blind, randomized, sham-controlled study.

BACKGROUND: Cognitive dysfunction is one of the common symptoms in patients with major depressive disorder (MDD). Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been studied separately in the treatment of cognitive dysfunction in MDD patients. We aimed to investigate the effectiveness and safety of rTMS combined with tDCS as a new therapy to improve neurocognitive impairment in MDD patients. METHODS: In this brief 2-week, double-blind, randomized, and sham-controlled trial, a total of 550 patients were screened, and 240 MDD inpatients were randomized into four groups (active rTMS + active tDCS, active rTMS + sham tDCS, sham rTMS + active tDCS, sham rTMS + sham tDCS). Finally, 203 patients completed the study and received 10 treatment sessions over a 2-week period. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was performed to assess patients' cognitive function at baseline and week 2. Also, we applied the 24-item Hamilton Depression Rating Scale (HDRS-24) to assess patients' depressive symptoms at baseline and week 2. RESULTS: After 10 sessions of treatment, the rTMS combined with the tDCS group showed more significant improvements in the RBANS total score, immediate memory, and visuospatial/constructional index score (all p < 0.05). Moreover, post hoc tests revealed a significant increase in the RBANS total score and Visuospatial/Constructional in the combined treatment group compared to the other three groups but in the immediate memory, the combined treatment group only showed a better improvement than the sham group. The results also showed the RBANS total score increased significantly higher in the active rTMS group compared with the sham group. However, rTMS or tDCS alone was not superior to the sham group in terms of other cognitive performance. In addition, the rTMS combined with the tDCS group showed a greater reduction in HDRS-24 total score and a better depression response rate than the other three groups. CONCLUSIONS: rTMS combined with tDCS treatment is more effective than any single intervention in treating cognitive dysfunction and depressive symptoms in MDD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052122).

The causal relationship between autoimmune thyroid disorders and telomere length: A Mendelian randomization and colocalization study.

This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (ß = -1.93 × 10-2 ; p = 4.54 × 10-5 ). There was no causal relationship between autoimmune hypothyroidism and TL (ß = -3.99 × 10-3 ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10-4 ) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10-3 ). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.

Selective Detection of Dynamics-Complete Set of Correlations via Quantum Channels.

Correlations of fluctuations are essential to understanding many-body systems and key information for advancing quantum technologies. To fully describe the dynamics of a physical system, all time-ordered correlations (TOCs), i.e., the dynamics-complete set of correlations are needed. The current measurement techniques can only access a limited set of TOCs, and there has been no systematic and feasible solution for extracting the dynamic-complete set of correlations hitherto. Here we propose a platform-universal protocol to selectively detect arbitrary types of TOCs via quantum channels. In our method, the quantum channels are synthesized with various controls, and engineer the evolution of a sensor-target system along a specific path that corresponds to a desired correlation. Using nuclear magnetic resonance, we experimentally demonstrate this protocol by detecting a specific type of fourth-order TOC that has never been accessed previously. We also show that the knowledge of the TOCs can be used to significantly improve the precision of quantum optimal control. Our method provides a new toolbox for characterizing the quantum many-body states and quantum noise, and hence for advancing the fields of quantum sensing and quantum computing.

Homotherapy for heteropathy: therapeutic effect of Butein in NLRP3-driven diseases.

BACKGROUND: Aberrant inflammatory responses drive the initiation and progression of various diseases, and hyperactivation of NLRP3 inflammasome is a key pathogenetic mechanism. Pharmacological inhibitors of NLRP3 represent a potential therapy for treating these diseases but are not yet clinically available. The natural product butein has excellent anti-inflammatory activity, but its potential mechanisms remain to be investigated. In this study, we aimed to evaluate the ability of butein to block NLRP3 inflammasome activation and the ameliorative effects of butein on NLRP3-driven diseases. METHODS: Lipopolysaccharide (LPS)-primed bone-marrow-derived macrophages were pretreated with butein and various inflammasome stimuli. Intracellular potassium levels, ASC oligomerization and reactive oxygen species production were also detected to evaluate the regulatory mechanisms of butein. Moreover, mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis were used to test whether butein has protective effects on these NLRP3-driven diseases. RESULTS: Butein blocks NLRP3 inflammasome activation in mouse macrophages by inhibiting ASC oligomerization, suppressing reactive oxygen species production, and upregulating the expression of the antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2). Importantly, in vivo experiments demonstrated that butein administration has a significant protective effect on the mouse models of LPS-induced peritonitis, dextran sodium sulfate-induced colitis, and high-fat diet-induced non-alcoholic steatohepatitis. CONCLUSION: Our study illustrates the connotation of homotherapy for heteropathy, i.e., the application of butein to broaden therapeutic approaches and treat multiple inflammatory diseases driven by NLRP3.

Enhancing Nutrition Support for Esophageal Cancer Patients: Understanding Factors Influencing Feeding Tube Utilization.

Objective: We sought to identify factors that can predict esophageal cancer (EC) patients at high risk of requiring feeding tube insertion. Methods: A retrospective cohort review was conducted, including all patients diagnosed with EC at our cancer center from 2013 to 2018. Multivariate logistic regression was performed comparing the group that required a reactive feeding tube insertion to those who did not require any feeding tube insertion to identify risk factors. Results: A total of 350 patients were included in the study, and 132/350 (38%) patients received a feeding tube. 50 out of 132 (38%) patients had feeding tube inserted reactively. Severe dysphagia (OR 19.9, p < 0.001) at diagnosis and decision to undergo chemotherapy (OR 2.8, p = 0.008) appeared to be predictors for reactive feeding tube insertion. The reactive insertion group had a 7% higher rate of complications relating to feeding tube. Conclusion: Severe dysphagia at diagnosis and undergoing chemotherapy were identified as risk factors for requiring a feeding tube. Ultimately, the aim is to create a predictive tool that utilizes these risks factors to accurate identify high-risk patients who may benefit from prophylactic feeding tube insertion.

Sulfur Migration Enhanced Proton-Coupled Electron Transfer for Efficient CO2 Desorption with Core-Shelled C@Mn3O4.

Transforming hazardous species into active sites by ingenious material design was a promising and positive strategy to improve catalytic reactions in industrial applications. To synergistically address the issue of sluggish CO2 desorption kinetics and SO2-poisoning solvent of amine scrubbing, we propose a novel method for preparing a high-performance core-shell C@Mn3O4 catalyst for heterogeneous sulfur migration and in situ reconstruction to active -SO3H groups, and thus inducing an enhanced proton-coupled electron transfer (PCET) effect for CO2 desorption. As anticipated, the rate of CO2 desorption increases significantly, by 255%, when SO2 is introduced. On a bench scale, dynamic CO2 capture experiments reveal that the catalytic regeneration heat duty of SO2-poisoned solvent experiences a 32% reduction compared to the blank case, while the durability of the catalyst is confirmed. Thus, the enhanced PCET of C@Mn3O4, facilitated by sulfur migration and simultaneous transformation, effectively improves the SO2 resistance and regeneration efficiency of amine solvents, providing a novel route for pursuing cost-effective CO2 capture with an amine solvent.

Effects of Bifidobacterium breve 207-1 on regulating lifestyle behaviors and mental wellness in healthy adults based on the microbiome-gut-brain axis: a randomized, double-blind, placebo-controlled trial.

PURPOSE: Our study aimed to explore the efficacy of Bifidobacterium breve 207-1 on specific neurotransmitters and hormones and the ability to regulate lifestyle behaviors in healthy adults. METHODS: In total, 120 healthy adults with high mental stress, overweight, insomnia, and constipation were randomly assigned to receive low-dose B. breve 207-1 (LD, n = 40), high-dose B. breve 207-1 (HD, n = 40), or placebo (n = 40) for 28 days. Fecal and blood samples were collected and questionnaires were answered before and after the trial. Neurotransmitters and serum hormones were detected using enzyme-linked immunosorbent assay. The gut microbiota composition was assessed using 16 S rRNA sequencing. Short-chain fatty acids (SCFAs) concentrations were determined via gas chromatography-mass spectrometry (GC-MS). RESULTS: The primary outcome of our study was changes in mental wellness, including neurotransmitters, the hypothalamic-pituitary-adrena (HPA) axis hormones, and the psychological scales. The results showed that γ-aminobutyric acid (GABA) increased significantly and the HPA axis hormones were suppressed overall in the probiotic groups while 5-hydroxytryptamine (5-HT) did not change significantly. However, there was no significant change in mood scale scores. The secondary outcome focused on the ability of 207-1 to regulate the body and lifestyle of healthy adults (e.g., sleep, diet, exercise, etc.). The PSQI scores in the probiotics groups significantly decreased, indicating improved sleep quality. Meanwhile, the probiotic groups had a slight increase in exercise consumption while dietary intake stabilized. By physical examination, the participants showed weight loss although no statistically significant difference was observed between the groups. Then, validated by gut microbiota, changes in the gut microbiota were observed under the effective intervention of 207-1 while short-chain fatty acids (SCFAs) increased in the LD group, particularly acetic and propionic acids. There was a slight decrease in alpha-diversity in the HD group. CONCLUSION: Bifidobacterium breve 207-1 entered the organism and affected neurotransmitter and the HPA axis hormone levels via the microbiome-gut-brain axis. Meanwhile, 207-1 supplementation improved daily lifestyle behaviors in healthy adults, which may in turn lead to changes in their bodies (e.g. weight and lipid metabolism). However, this study did not find significant mood-modulating efficacy. The mechanism of the overall study is unclear, but we hypothesize that SCFAs may be the key pathway, and more experiments are needed for validation in the future. TRIAL REGISTRATION: This trial was retrospectively registered in the Chinese Clinical Trial Registry under the accession number ChiCTR2300069453 on March 16, 2023.

exoRBase 2.0: an atlas of mRNA, lncRNA and circRNA in extracellular vesicles from human biofluids.

Extracellular vesicles (EVs) are small membranous vesicles that contain an abundant cargo of different RNA species with specialized functions and clinical implications. Here, we introduce an updated online database (http://www.exoRBase.org), exoRBase 2.0, which is a repository of EV long RNAs (termed exLRs) derived from RNA-seq data analyses of diverse human body fluids. In exoRBase 2.0, the number of exLRs has increased to 19 643 messenger RNAs (mRNAs), 15 645 long non-coding RNAs (lncRNAs) and 79 084 circular RNAs (circRNAs) obtained from ∼1000 human blood, urine, cerebrospinal fluid (CSF) and bile samples. Importantly, exoRBase 2.0 not only integrates and compares exLR expression profiles but also visualizes the pathway-level functional changes and the heterogeneity of origins of circulating EVs in the context of different physiological and pathological conditions. Our database provides an attractive platform for the identification of novel exLR signatures from human biofluids that will aid in the discovery of new circulating biomarkers to improve disease diagnosis and therapy.

Negative life events and suicidality among adolescents in Western China: the mediating effect of depressive symptoms and the moderating effect of self-esteem.

OBJECTIVE: To investigate the mediating role of depressive symptoms in the relationship between negative life events (NLEs) and suicidality, as well as to test the moderating effect of self-esteem in the mediation model. METHODS: A total of 3,003 adolescents from Han, Tibetan, and Yi ethnic groups living in Western China were included in this study. Utilizing the structural equation model, a mediation model and a moderated mediation model were constructed. RESULTS: The presence of NLEs was positively associated with suicidality (ß = 0.17, p < 0.001). Depressive symptoms partially mediated the relationship between NLEs and suicidality (indirect effect ß = 0.19, p < 0.001). Self-esteem moderated both the antecedent and subsequent segments of the mediating paths of "NLEs → depressive symptoms → suicidality" and the direct relationship between NLEs and suicidality. Among adolescents with a low level of self-esteem, the mediating effect coefficient of depressive symptoms was higher at 0.18 (95% confidence interval (CI): 0.14-0.23), in contrast to adolescents with a high level of self-esteem, where the mediating effect coefficient of depressive symptoms was 0.04 (95% CI: 0.02-0.07). CONCLUSION: NLEs are directly associated with an increased risk of suicidality and indirectly related to suicidality by increasing the risk of depressive symptoms among adolescents. Self-esteem can moderate the mediating effect of depressive symptoms and the relationship between NLEs and suicidality. The intervention strategy for preventing suicidality among adolescents who have experienced NLEs should focus on reducing depressive symptoms and improving self-esteem.

Exploring the molecular mechanisms by which per- and polyfluoroalkyl substances induce polycystic ovary syndrome through in silico toxicogenomic data mining.

The pathogeny of polycystic ovary syndrome (PCOS) is intricate, with endocrine disruptors (EDCs) being acknowledged as significant environmental factors. Research has shown a link between exposure to per- and polyfluoroalkyl substances (PFAS) and the development and progression of PCOS, although the precise mechanism is not fully understood. This study utilized toxicogenomics and comparative toxicogenomics databases to analyze data and investigate how PFAS mixtures may contribute to the development of PCOS. The results indicated that 74 genes are associated with both PFAS exposure and PCOS progression. Enrichment analysis suggested that cell cycle regulation and steroid hormone synthesis may be crucial pathways through which PFAS mixtures participate in the development of PCOS, involving important genes such as CCNB1 and SRD5A1. Furthermore, the study identified transcription factors (TFs) and miRNAs that may be involved in the onset and progression of PCOS, constructing regulatory networks encompassing TFs-mRNA interactions and miRNA-mRNA relationships to elucidate their regulatory roles in gene expression. By utilizing data mining techniques based on toxicogenomic databases, this study provides relatively comprehensive insights into the association between exposure factors and diseases compared to traditional toxicology studies. These findings offer new perspectives for further in vivo or in vitro investigations and contribute to understanding the pathogenesis of PCOS, thereby providing valuable references for identifying clinical treatment targets.

Toxicological impacts of microplastics on virulence, reproduction and physiological process of entomopathogenic nematodes.

Microplastics have emerged as significant and concerning pollutants within soil ecosystems. Among the soil biota, entomopathogenic nematodes (EPNs) are lethal parasites of arthropods, and are considered among the most effective biological agents against pests. Infective juveniles (IJs) of EPNs, as they navigate the soil matrix scavenging for arthropod hosts to infect, they could potentially encounter microplastics. Howver, the impact of microplastics on EPNs has not been fully elucidated yet. We addressed this gap by subjecting Steinernema feltiae EPNs to polystyrene microplastics (PS-MPs) with various sizes, concentrations, and exposure durations. After confirming PS-MP ingestion by S. feltiae using fluorescent dyes, we found that the PS-MPs reduced the survival, reproduction, and pathogenicity of the tested EPNs, with effects intensifying for smaller PS-MPs (0.1-1 µm) at higher concentrations (105 µg/L). Furthermore, exposure to PS-MPs triggered oxidative stress in S. feltiae, leading to increased reactive oxygen species levels, compromised mitochondrial membrane potential, and increased antioxidative enzyme activity. Furthermore, transcriptome analyses revealed PS-MP-induced suppression of mitochondrial function and oxidative phosphorylation pathways. In conclusion, we show that ingestion of PS-MPs by EPNs can compromise their fitness, due to multple toxicity effects. Our results bear far-reaching consequences, as the presence of microplastics in soil ecosystems could undermine the ecological role of EPNs in regulating pest populations.

Exosomal encapsulation of miR-3198 promotes proliferation and migration of trophoblasts in preeclampsia.

PURPOSE: Preeclampsia (PE) is a vascular remodeling disorder cloesly linked to trophoblast dysfunction, involving defects in their proliferation, migration, and apoptosis. Maternal exosomal microRNAs (miRNAs) have been reported to play pivotal roles in the development of PE. However, the mechanism underlying the role of maternal exosomes in trophoblast dysfunction regarding the development of PE is poorly understood. METHODS: Plasma exosomes from maternal peripheral blood were collected from pregnant women with PE and from those with normal pregnancy. Bioinformatics analysis was used to identify significantly differentially expressed miRNAs under these two conditions. The expression of the miR-3198 gene in plasma exosomes was detected using quantitative real-time polymerase chain reaction. Dual luciferase reporter assay was used to confirm binding of miR-3198 and 3'UTR region of WNT3. Cell proliferation was examined using the Cell Count Kit-8 and EdU assays, and flow cytometry was performed to detect apoptosis and cell cycle. Changes in cell migration were examined using transwell and scratch assays. RESULTS: Patients with PE showed decreased expression of plasma-derived exosomal miR-3198. The proliferation and migration abilities of HTR-8/SVneo and primary human trophoblast cells were both improved when cocultured with miR-3198-rich exosomes. Exposure to miR-3198-enriched exosomes facilitated cell cycle progression but reduced apoptosis in HTR-8/SVneo cells. Notably, overexpression of miR-3198 partially prevented the inhibitory effects of WNT3 on proliferation and migration in HTR-8/SVneo cells. CONCLUSION: Exosomal miR-3198 in the maternal peripheral blood may regulate the biological functions of trophoblasts by targeting WNT3 and influence the development of diseases of placental origin.

Inhibition of canine parvovirus 2 (CPV-2) replication by TAT-scFv through targeting of the viral structural protein VP2 of CPV-2.

Canine parvovirus (CPV) causes severe infectious disease with a high mortality rate in dogs. CPV is still a major health issue of dogs in the clinic. Therefore, there is an urgent need to develop effective drugs to treat the disease. In this study, we fused the transactivating transcriptional activator peptide (TAT) with scFv. TAT-scFv was identified by Western blot. CCK8 kit was used to detect the toxicity of TAT-scFv to cells. The binding activity of TAT-scFv to CPV-2-VP2 was detected by DAS ELISA. The cell uptake rate of TAT-scFv was assessed by IFA. After infection with CPV-2, F81 cells were incubated by TAT-scFv. The replication of virus was measured to determine the neutralization effect of TAT-scFv on intracellular and extracellular viruses. Protein docking was used to predict the amino acid (AA) sites of VP2 binding to TAT-scFv. TAT-scFv was expressed in Escherichia coli and purified. The DAS ELISA showed that TAT-scFv could bind with CPV-2-VP2. We demonstrated that TAT-scFv entered cells in a dose-dependent and time-dependent manner and effectively inhibited the replication of CPV-2. Using protein docking, we determined the interaction pattern and found that the N-terminal region (AA 41-49) and the C-terminal region (AA 558) of VP2 interacted with the TAT-scFv. Taken together, these results suggest that, TAT-scFv may be a potential antiviral drug for inhibiting CPV-2 replication and controlling disease caused by CPV-2.

Internet addiction and depressive and anxious symptoms among Chinese rural left-behind adolescents: Mediating roles of resilience and friendship quality.

BACKGROUND: Rural left-behind adolescents are more vulnerable to Internet addiction and depressive and anxious symptoms due to the lack of family support and parental supervision. This study was the first to investigate the longitudinal relationships between Internet addiction and depressive and anxious symptoms and to examine the mediating roles of resilience and friendship quality in rural left-behind adolescents. METHODS: Included in this study, which was from a longitudinal study conducted five times over 2 years, were 1001 rural left-behind adolescents. The internationally used scales for depressive and anxious symptoms, Internet addiction, resilience and friendship quality were administered. A structural equation model was used for analysis. RESULTS: The prevalence of Internet addiction, depressive and anxious symptoms among rural left-behind adolescents were 17.7%, 35.8% and 27.6%, respectively. Internet addiction predicted the later depressive and anxious symptoms (ß = 0.200, 95% confidence interval [CI]: 0.116-0.274 and ß = 0.263, 95% CI: 0.188-0.330). Resilience acted as an independent mediator in the relationships between Internet addiction and depressive and anxious symptoms (ß = 0.037 and 0.034, P < 0.01). Resilience and friendship quality played a chain-mediating role on the longitudinal relationships between Internet addiction and depressive and anxious symptoms (ß = 0.011 and 0.010, P < 0.001). The mediating effects accounted for 24.0% and 16.7% of the total effects, respectively. CONCLUSION: Resilience and friendship quality play an independent or chain-mediating role in longitudinal relationships between Internet addiction and depressive and anxious symptoms. The findings inform targeted intervention strategies to improve the mental health of left-behind adolescents.

Porcine Epidemic Diarrhea Virus Infection Disrupts the Nasal Endothelial Barrier To Favor Viral Dissemination.

Crossing the endothelium from the entry site and spreading in the bloodstream are crucial but obscure steps in the pathogenesis of many emerging viruses. Previous studies confirmed that porcine epidemic diarrhea virus (PEDV) caused intestinal infection by intranasal inoculation. However, the role of the nasal endothelial barrier in PEDV translocation remains unclear. Here, we demonstrated that PEDV infection causes nasal endothelial dysfunction to favor viral dissemination. Intranasal inoculation with PEDV compromised the integrity of endothelial cells (ECs) in nasal microvessels. The matrix metalloproteinase 7 (MMP-7) released from the PEDV-infected nasal epithelial cells (NECs) contributed to the destruction of endothelial integrity by degrading the tight junctions, rather than direct PEDV infection. Moreover, the proinflammatory cytokines released from PEDV-infected NECs activated ECs to upregulate ICAM-1 expression, which favored peripheral blood mononuclear cells (PBMCs) migration. PEDV could further exploit migrated cells to favor viral dissemination. Together, our results reveal the mechanism by which PEDV manipulates the endothelial dysfunction to favor viral dissemination and provide novel insights into how coronavirus interacts with the endothelium. IMPORTANCE The endothelial barrier is the last but vital defense against systemic viral transmission. Porcine epidemic diarrhea virus (PEDV) can cause severe atrophic enteritis and acute viremia. However, the mechanisms by which the virus crosses the endothelial barrier and causes viremia are poorly understood. In this study, we revealed the mechanisms of endothelial dysfunction in PEDV infection. The viral infection activates NECs and causes the upregulation of MMP-7 and proinflammatory cytokines. Using NECs, ECs, and PBMCs as in vitro models, we determined that the released MMP-7 contributed to the destruction of endothelial barrier, and the released proinflammatory cytokines activated ECs to facilitate PBMCs migration. Moreover, the virus further exploited the migrated cells to promote viral dissemination. Thus, our results provide new insights into the mechanisms underlying endothelial dysfunction induced by coronavirus infection.