Brainstem Dbh+ neurons control allergen-induced airway hyperreactivity.

Exaggerated airway constriction triggered by repeated exposure to allergen, also called hyperreactivity, is a hallmark of asthma. Whereas vagal sensory neurons are known to function in allergen-induced hyperreactivity1-3, the identity of downstream nodes remains poorly understood. Here we mapped a full allergen circuit from the lung to the brainstem and back to the lung. Repeated exposure of mice to inhaled allergen activated the nuclei of solitary tract (nTS) neurons in a mast cell-, interleukin-4 (IL-4)- and vagal nerve-dependent manner. Single-nucleus RNA sequencing, followed by RNAscope assay at baseline and allergen challenges, showed that a Dbh+ nTS population is preferentially activated. Ablation or chemogenetic inactivation of Dbh+ nTS neurons blunted hyperreactivity whereas chemogenetic activation promoted it. Viral tracing indicated that Dbh+ nTS neurons project to the nucleus ambiguus (NA) and that NA neurons are necessary and sufficient to relay allergen signals to postganglionic neurons that directly drive airway constriction. Delivery of noradrenaline antagonists to the NA blunted hyperreactivity, suggesting noradrenaline as the transmitter between Dbh+ nTS and NA. Together, these findings provide molecular, anatomical and functional definitions of key nodes of a canonical allergen response circuit. This knowledge informs how neural modulation could be used to control allergen-induced airway hyperreactivity.

In vivo efficacy of phage cocktails against carbapenem resistance Acinetobacter baumannii in the rat pneumonia model.

Acinetobacter baumannii, an opportunistic pathogen, poses a significant threat in intensive care units, leading to severe nosocomial infections. The rise of multi-drug-resistant strains, particularly carbapenem-resistant A. baumannii, has created formidable challenges for effective treatment. Given the prolonged development cycle and high costs associated with antibiotics, phages have garnered clinical attention as an alternative for combating infections caused by drug-resistant bacteria. However, the utilization of phage therapy encounters notable challenges, including the narrow host spectrum, where each phage targets a limited subset of bacteria, increasing the risk of phage resistance development. Additionally, uncertainties in immune system dynamics during treatment hinder tailoring symptomatic interventions based on patient-specific states. In this study, we isolated two A. baumannii phages from wastewater and conducted a comprehensive assessment of their potential applications. This evaluation included sequencing analysis, genome classification, pH and temperature stability assessments, and in vitro bacterial inhibition assays. Further investigations involved analyzing histological and cytokine alterations in rats undergoing phage cocktail treatment for pneumonia. The therapeutic efficacy of the phages was validated, and transcriptomic studies of rat lung tissue during phage treatment revealed crucial changes in the immune system. The findings from our study underscore the potential of phages for future development as a treatment strategy and offer compelling evidence regarding immune system dynamics throughout the treatment process.IMPORTANCEDue to the growing problem of multi-drug-resistant bacteria, the use of phages is being considered as an alternative to antibiotics, and the genetic safety and application stability of phages determine the potential of phage application. The absence of drug resistance genes and virulence genes in the phage genome can ensure the safety of phage application, and the fact that phage can remain active in a wide range of temperatures and pH is also necessary for application. In addition, the effect evaluation of preclinical studies is especially important for clinical application. By simulating the immune response situation during the treatment process through mammalian models, the changes in animal immunity can be observed, and the effect of phage therapy can be further evaluated. Our study provides compelling evidence that phages hold promise for further development as therapeutic agents for Acinetobacter baumannii infections.

TP53 disruptive mutation predicts platinum-based chemotherapy and PD-1/PD-L1 blockade response in urothelial carcinoma.

TP53 mutation is one of the most common genetic alterations in urothelial carcinoma (UrCa), and heterogeneity of TP53 mutants leads to heterogeneous clinical outcomes. This study aimed to investigate the clinical relevance of specific TP53 mutations in UrCa. In this study, a total of eight cohorts were enrolled, along with matched clinical annotation. TP53 mutations were classified as disruptive and nondisruptive according to the degree of disturbance of p53 protein function and structure. We evaluated the clinical significance of TP53 mutations in our local datasets and publicly available datasets. The co-occurring events of TP53 mutations in UrCa, along with their therapeutic indications, functional effects, and the tumor immune microenvironment, were also investigated. TP53 mutations were identified in 49.7% of the UrCa patients. Within this group, 25.1% of patients carried TP53Disruptive mutations, a genetic alteration correlated with a significantly poorer overall survival (OS) when compared to individuals with TP53Nondisruptive mutations and those with wild-type TP53. Significantly, patients with TP53Disruptive mutations exhibit an increased probability of responding favorably to PD-1/PD-L1 blockade and chemoimmunotherapy. Meanwhile, there was no noteworthy distinction in OS among patients with varying TP53 mutation status who underwent chemotherapy. Samples with TP53Disruptive mutations showed an enriched APOBEC- and POLE-related mutational signature, as well as an elevated tumor mutation burden. The sensitivity to immunotherapy in tumors carrying TP53Disruptive mutation may be attributed to the inflamed tumor microenvironment characterized by increased CD8+T cell infiltration and interferon-gamma signaling activation. In conclusion, UrCa patients with TP53Disruptive mutations have shown reduced survival rates, yet they may respond well to PD-1/PD-L1 blockade therapy and chemoimmunotherapy. By distinguishing specific TP53 mutations, we can improve risk stratification and offer personalized genomics-guided therapy to UrCa patients. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Small RNAs contribute to citrus Huanglongbing tolerance by manipulating methyl salicylate signaling and exogenous methyl salicylate primes citrus groves from emerging infection.

Citrus production is severely threatened by the devastating Huanglongbing (HLB) disease globally. By studying and analyzing the defensive behaviors of an HLB-tolerant citrus cultivar 'Shatangju', we discovered that citrus can sense Candidatus Liberibacter asiaticus (CLas) infection and induce immune responses against HLB, which can be further strengthened by both endogenously produced and exogenously applied methyl salicylate (MeSA). This immune circuit is turned on by an miR2977-SAMT (encoding a citrus Salicylate [SA] O-methyltransferase) cascade, by which CLas infection leads to more in planta MeSA production and aerial emission. We provided both transgenic and multi-year trail evidences that MeSA is an effective community immune signal. Ambient MeSA accumulation and foliage application can effectively induce defense gene expression and significantly boost citrus performance. We also found that miRNAs are battle fields between citrus and CLas, and about 30% of the differential gene expression upon CLas infection are regulated by miRNAs. Furthermore, CLas hijacks host key processes by manipulating key citrus miRNAs, and citrus employs miRNAs that coordinately regulate defense-related genes. Based on our results, we proposed that miRNAs and associated components are key targets for engineering or breeding resistant citrus varieties. We anticipate that MeSA-based management, either induced expression or external application, would be a promising tool for HLB control.

Integration of CD4+ T cells and molecular subtype predicts benefit from PD-L1 blockade in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4+ T cells, there is an emerging need to integrate CD4+ T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune-molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4+ Thigh, which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4+ Tlow, characterized by the highest level of fibroblast growth factor receptor 3 (FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4+ Thigh, which could benefit from a combination of ICB and chemotherapy; and basal CD4+ Tlow, characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor-ß (TGF-ß) inhibition. This immune-molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.

Integrative score based on CDK6, PD-L1 and TMB predicts response to platinum-based chemotherapy and PD-1/PD-L1 blockade in muscle-invasive bladder cancer.

BACKGROUND: Cyclin-dependent kinase 6 (CDK6) was proved to be an important regulator in the progression of cell cycle and has been a promising therapeutic target in cancer treatment. However, the clinical significance of CDK6 in muscle-invasive bladder cancer (MIBC) remains obscure. Herein, we attempt to explore the clinical relevance of CDK6 and assess the feasibility of the integrative model to predict immune checkpoint blockade (ICB) response. METHODS: This study enrolled 933 patients with muscle-invasive bladder cancer (MIBC) from Zhongshan Hospital (ZSHS), The Cancer Genome Atlas (TCGA), Chemo, IMvigor210 and UC-GENOME cohorts. Kaplan-Meier survival and Cox regression analyses were performed to assess clinical outcomes based on CDK6 expression. RESULTS: High CDK6 expression conferred poor prognosis and superior response to platinum-based chemotherapy but inferior response to ICB in MIBC. Furthermore, the integrative model named response score based on CDK6, PD-L1 and TMB could better predict the response to ICB and chemotherapy. Patients with higher response scores were characterised by inflamed immune microenvironment and genomic instability. CONCLUSIONS: CDK6 expression was correlated with prognosis and therapy response in MIBC. Integration of CDK6, PD-L1 and TMB could better identify patients who were most likely to benefit from ICB and chemotherapy.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Integrative analysis of single-cell and bulk RNA sequencing unveils a machine learning-based pan-cancer major histocompatibility complex-related signature for predicting immunotherapy efficacy.

Major histocompatibility complex (MHC) could serve as a potential biomarker for tumor immunotherapy, however, it is not yet known whether MHC could distinguish potential beneficiaries. Single-cell RNA sequencing datasets derived from patients with immunotherapy were collected to elucidate the association between MHC and immunotherapy response. A novel MHCsig was developed and validated using large-scale pan-cancer data, including The Cancer Genome Atlas and immunotherapy cohorts. The therapeutic value of MHCsig was further explored using 17 CRISPR/Cas9 datasets. MHC-related genes were associated with drug resistance and MHCsig was significantly and positively associated with immunotherapy response and total mutational burden. Remarkably, MHCsig significantly enriched 6% top-ranked genes, which were potential therapeutic targets. Moreover, we generated Hub-MHCsig, which was associated with survival and disease-special survival of pan-cancer, especially low-grade glioma. This result was also confirmed in cell lines and in our own clinical cohort. Later low-grade glioma-related Hub-MHCsig was established and the regulatory network was constructed. We provided conclusive clinical evidence regarding the association between MHCsig and immunotherapy response. We developed MHCsig, which could effectively predict the benefits of immunotherapy for multiple tumors. Further exploration of MHCsig revealed some potential therapeutic targets and regulatory networks.

Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer.

BACKGROUND: Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC. METHODS: This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC. RESULTS: Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy. CONCLUSIONS: We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.

Cascaded Nanozyme Based pH-Responsive Oxygenation for Targeted Eradication of Resistant Helicobacter Pylori.

Nanozymes, as substitutes for natural enzymes, are constructed as cascade catalysis systems for biomedical applications due to their inherent catalytic properties, high stability, tunable physicochemical properties, and environmental responsiveness. Herein, a multifunctional nanozyme is reported to initiate cascade enzymatic reactions specific in acidic environments for resistant Helicobacter pylori (H. pylori) targeting eradication. The cobalt-coated Prussian blue analog based FPB-Co-Ch NPs displays oxidase-, superoxide dismutase-, peroxidase-, and catalase- mimicking activities that trigger • O 2 - ${\mathrm{O}}_2^ - {\bm{\ }}$ and H2O2 to supply O2, thereby killing H. pylori in the stomach. To this end, chitosan is modified on the surface to exert bacterial targeted adhesion and improve the biocompatibility of the composite. In the intestinal environment, the cascade enzymatic activities are significantly inhibited, ensuring the biosafety of the treatment. In vitro, sensitive and resistant strains of H. pylori are cultured and the antibacterial activity is evaluated. In vivo, murine infection models are developed and its success is confirmed by gastric mucosal reculturing, Gram staining, H&E staining, and Giemsa staining. Additionally, the antibacterial capacity, anti-inflammation, repair effects, and biosafety of FPB-Co-Ch NPs are comprehensively investigated. This strategy renders a drug-free approach that specifically targets and kills H. pylori, restoring the damaged gastric mucosa while relieving inflammation.

Hemicyanine-Based Highly Water-Soluble Probe for Extracellular Nitroreductase.

Nitroreductase (NTR) has long been a target of interest for its important role involved in the nitro compounds metabolism. Various probes have been reported for NTR analysis, but rarely able to distinguish the extracellular NTR from intracellular ones. Herein we reported a new NTR sensor, HCyS-NO2, which was a hemicyanine molecule with one nitro and two sulfo groups attached. The nitro group acted as the reporting group to respond NTR reduction. Direct linkage of nitro group into the hemicyanine π conjugate system facilitated the intramolecular electron transfer (IET) process and thus quenched the fluorescence of hemicyanine core. Upon reduction with NTR, the nitro group was rapidly converted into the hydroxylamino and then the amino group, eliminating IET process and thus restoring the fluorescence. The sulfo groups installed significantly increased the hydrophilicity of the molecule, and introduced negative charges at physiological pH, preventing the diffusion into bacteria. Both gram-negative and gram-positive bacteria were able to turn on the fluorescence of HCyS-NO2, without detectable diffusion into cells, providing a useful tool to probe the extracellular reduction process.

Transcriptional convergence after repeated duplication of an amino acid transporter gene leads to the independent emergence of the black husk/pericarp trait in barley and rice.

The repeated emergence of the same trait (convergent evolution) in distinct species is an interesting phenomenon and manifests visibly the power of natural selection. The underlying genetic mechanisms have important implications to understand how the genome evolves under environmental challenges. In cereal crops, both rice and barley can develop black-coloured husk/pericarp due to melanin accumulation. However, it is unclear if this trait shares a common origin. Here, we fine-mapped the barley HvBlp gene controlling the black husk/pericarp trait and confirmed its function by gene silencing. The result was further supported by a yellow husk/pericarp mutant with deletion of the HvBlp gene, derived from gamma ray radiation of the wild-type W1. HvBlp encodes a putative tyrosine transporter homologous to the black husk gene OsBh4 in rice. Surprisingly, synteny and phylogenetic analyses showed that HvBlp and OsBh4 belonged to different lineages resulted from dispersed and tandem duplications, respectively, suggesting that the black husk/pericarp trait has emerged independently. The dispersed duplication (dated at 21.23 MYA) yielding HvBlp occurred exclusively in the common ancestor of Triticeae. HvBlp and OsBh4 displayed converged transcription in husk/pericarp tissues, contributing to the black husk/pericarp trait. Further transcriptome and metabolome data identified critical candidate genes and metabolites related to melanin production in barley. Taken together, our study described a compelling case of convergent evolution resulted from transcriptional convergence after repeated gene duplication, providing valuable genetic insights into phenotypic evolution. The identification of the black husk/pericarp genes in barley also has great potential in breeding for stress-resilient varieties with higher nutritional values.

Extracellular vesicle-encapsulated miR-25-3p promotes epithelial-mesenchymal transition and migration of endometrial epithelial cells by inducing macrophage polarization.

The pathogenesis of adenomyosis is closely related to the epithelial-mesenchymal transition and macrophages. MicroRNAs have been extensively investigated in relation to the epithelial-mesenchymal transition in a range of malignancies. However, there is a paucity of research on extracellular vesicles derived from the eutopic endometrium of adenomyosis and their encapsulated microRNAs. In this study, we investigated the role of microRNA-25-3p derived from extracellular vesicles in inducing macrophage polarization and promoting the epithelial-mesenchymal transition in endometrial epithelial cells of patients with adenomyosis and controls. We obtained eutopic endometrial samples and isolated extracellular vesicles from the culture supernatant of primary endometrial cells. Real-time quantitative PCR analysis demonstrated that microRNA-25-3p was highly expressed in extracellular vesicles, as well as in macrophages stimulated by extracellular vesicles from eutopic endometrium of adenomyosis; and macrophages transfected with microRNA-25-3p exhibited elevated levels of M2 markers, while displaying reduced levels of M1 markers. After co-culture with the above polarized macrophages, endometrial epithelial cells expressed higher levels of N-cadherin and Vimentin, and lower protein levels of E-cadherin and Cytokeratin 7. It was revealed that microRNA-25-3p encapsulated in extracellular vesicles from eutopic endometrial cells could induce macrophage polarization toward M2, and the polarized macrophages promote epithelial-mesenchymal transition in epithelial cells. However, in vitro experiments revealed no significant disparity in the migratory capacity of endometrial epithelial cells between the adenomyosis group and the control group. Furthermore, it was observed that microRNA-25-3p-stimulated polarized macrophages also facilitated the epithelial-mesenchymal transition and migration of endometrial epithelial cells within the control group. Thus, the significance of microRNA-25-3p-induced polarized macrophages in promoting the development of adenomyosis is unclear, and macrophage infiltration alone may be adequate for this process. We emphasize the specificity of the local eutopic endometrial microenvironment and postulate its potential significance in the pathogenesis of adenomyosis.

Effects of fecal microbial transplantation on police performance and transportation stress in Kunming police dogs.

Fecal microbiota transplantation (FMT) has been shown to improve gut dysbiosis in dogs; however, it has not completely been understood in police dogs. This study aimed to investigate the effects of FMT on performance and gut microflora in Kunming police dogs. Twenty Wolf Cyan dogs were randomly assigned to receive physiological saline or fecal suspension at low, medium, or high doses through oral gavage for 14 days. Growth performance, police performance, serum biochemical profiling, and gut microflora were determined 2-week post-FMT. Dogs after FMT treatment were also subjected to an hour road transportation and then were evaluated for serum stress indicators. Overall, FMT enhanced the growth performance and alleviated diarrhea rate in Kunming dogs with the greatest effects occurring in the low dose FMT (KML) group. The improvement of FMT on police performance was also determined. These above alterations were accompanied by changed serum biochemical parameters as indicated by elevated total protein and albumin and reduced total cholesterol and glycerol. Furthermore, the serum stress indicators after road transportation in dog post-FMT significantly decreased. Increased bacterial diversity and modified bacterial composition were found in the feces of dogs receiving FMT. The fecal samples from FMT dogs were characterized by higher abundances of the genera Lactobacillus, Prevotella, and Fusobacterium and lower concentrations of Cetobacterium, Allobaculum, Bifidobacterium, and Streptococcus. The present study supports a potential benefit of FMT on police performance in Kunming dogs. KEY POINTS: • FMT improves the growth performance and reduces diarrhea rates in Kunming police dogs. • FMT alleviates the serum stress profiles after road transportation in Kunming police dogs. • FMT modifies the gut microbiota composition of Kunming police dogs.

A novel Saclayvirus Acinetobacter baumannii phage genomic analysis and effectiveness in preventing pneumonia.

Acinetobacter baumannii, which is resistant to multiple drugs, is an opportunistic pathogen responsible for severe nosocomial infections. With no antibiotics available, phages have obtained clinical attention. However, since immunocompromised patients are often susceptible to infection, the appropriate timing of administration is particularly important. During this research, we obtained a lytic phage vB_AbaM_P1 that specifically targets A. baumannii. We then assessed its potential as a prophylactic treatment for lung infections caused by clinical strains. The virus experiences a period of inactivity lasting 30 min and produces approximately 788 particles during an outbreak. Transmission electron microscopy shows that vB_AbaM_P1 was similar to the Saclayvirus. Based on the analysis of high-throughput sequencing and bioinformatics, vB_AbaM_P1 consists of 107537 bases with a G + C content of 37.68%. It contains a total of 177 open reading frames and 14 tRNAs. No antibiotic genes were detected. In vivo experiments, using a cyclophosphamide-induced neutrophil deficiency model, tested the protective effect of phage on neutrophil-deficient rats by prophylactic application of phage. The use of phages resulted in a decrease in rat mortality caused by A. baumannii and a reduction in the bacterial burden in the lungs. Histologic examination of lung tissue revealed a decrease in the presence of immune cells. The presence of phage vB_AbaM_P1 had a notable impact on preventing A. baumannii infection, as evidenced by the decrease in oxidative stress in lung tissue and cytokine levels in serum. Our research offers more robust evidence for the early utilization of bacteriophages to mitigate A. baumannii infection. KEY POINTS: •A novel Saclayvirus phage infecting A. baumannii was isolated from sewage. •The whole genome was determined, analyzed, and compared to other phages. •Assaying the effect of phage in preventing infection in neutrophil-deficient models.

Maternal and neonatal outcomes of intrahepatic cholestasis of pregnancy after in vitro fertilization.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic disease of pregnancy. Little is known about how it specifically affects pregnancies resulting from in vitro fertilization (IVF). Our aim is to evaluate the impact of IVF on the perinatal outcomes of ICP. METHODS: A retrospective study of 242 patients with intrahepatic cholestasis of pregnancy, comprising 36 conceived through IVF and 206 spontaneous conceptions (SC), enrolled between 2019 and 2021 was carried out. Data were analyzed from the medical archives of the Huazhong University of Science and Technology, Tongji Hospital. RESULTS: Numerical values of transaminases (ALT, alanine aminotransferase; AST, aspartate aminotransferase) and serum total bile acid (TBA) are significantly lower in the IVF group than that in the spontaneous conceived group (p < 0.05). The incidence of gestational diabetes mellitus (GDM) was higher in the IVF group than in SC group (30.6% vs. 16%, p = 0.037). The cesarean section (CS) rates are higher in the IVF group (97.2% vs. 85.4%, p = 0.023). On the other hand, the prevalence of premature rupture of membranes (PROM) was higher in the SC group (10.7%) while none was reported in the IVF-ICP group. Other maternal comorbidities and neonatal outcomes were similar between the two groups. CONCLUSION: ICP patients who underwent IVF are more likely to suffer from GDM. Therefore, monitoring and management of blood glucose should be strengthened during pregnancy. Fortunately, IVF does not seem to worsen the progression or outlook of ICP, so sticking to standard management practices is recommended.

Association between ambient fine particular matter components and subsequent cognitive impairment in community-dwelling older people: a prospective cohort study from eastern China.

BACKGROUND: Fine particular matter (PM2.5) has been associated with dementia, but limited information is available regarding the association between PM2.5 components and dementia. AIMS: We aimed to identify the major components of PM2.5 that affect cognitive function to further investigate its mechanism of action, and develop a prevention strategy for dementia. METHODS: In this study, we included 7804 participants aged ≥ 60 years recruited from seven counties in Zhejiang province, eastern China. The participants completed the baseline survey between 2014 and 2015, and were followed up until the end of 2020. We adopted single-component robust Poisson regression models for analyses, and estimated relative risks and 95% confidence intervals describing associations between the chemical constituents of PM2.5 exposure and incident cognitive impairment in those who were free from cognitive impairment at baseline. RESULTS: Significantly positive associations were observed between sulfate, nitrate, ammonium, and organic matter in PM2.5 and incident cognitive impairment across different exposure periods; the relative risks of 10-year exposure before enrollment ranged from 1.01 to 1.02. However, we did not find a significant association between black carbon and cognitive impairment. The point estimates of the relative risk values did not change substantially after performing the sensitivity analyses. CONCLUSIONS: Our findings strengthen the idea that long-term exposure to PM2.5 mass and its chemical components is associated with an elevated risk of incident cognitive impairment among older adults.

Real-Time Direction Judgment System for Dual-Frequency Laser Interferometer.

Current real-time direction judgment systems are inaccurate and insensitive, as well as limited by the sampling rate of analog-to-digital converters. To address this problem, we propose a dynamic real-time direction judgment system based on an integral dual-frequency laser interferometer and field-programmable gate array technology. The optoelectronic signals resulting from the introduction of a phase subdivision method based on the amplitude resolution of the laser interferometer when measuring displacement are analyzed. The proposed system integrates the optoelectronic signals to increase the accuracy of its direction judgments and ensures these direction judgments are made in real time by dynamically controlling the integration time. Several experiments were conducted to verify the performance of the proposed system. The results show that, compared with current real-time direction judgment systems, the proposed system makes accurate judgements during low-speed motions and can update directions within 0.125 cycles of the phase difference change at different speeds. Moreover, a sweep frequency experiment confirmed the system's ability to effectively judge dynamic directions. The proposed system is capable of accurate and real-time directional judgment during low-speed movements of a table in motion.

STAT3 Increases CVB3 Replication and Acute Pancreatitis and Myocarditis Pathology via Impeding Nuclear Translocation of STAT1 and Interferon-Stimulated Gene Expression.

Acute pancreatitis (AP) is an inflammatory disease initiated by the death of exocrine acinar cells, but its pathogenesis remains unclear. Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates immunity and the inflammatory response. The protective role of STAT3 is reported in Coxsackievirus B3 (CVB3)-induced cardiac fibrosis, yet the exact role of STAT3 in modulating viral-induced STAT1 activation and type I interferon (IFN)-stimulated gene (ISG) transcription in the pancreas remains unclarified. In this study, we tested whether STAT3 regulated viral-induced STAT1 translocation. We found that CVB3, particularly capsid VP1 protein, markedly upregulated the phosphorylation and nuclear import of STAT3 (p-STAT3) while it significantly impeded the nuclear translocation of p-STAT1 in the pancreases and hearts of mice on day 3 postinfection (p.i.). Immunoblotting and an immunofluorescent assay demonstrated the increased expression and nuclear translocation of p-STAT3 but a blunted p-STAT1 nuclear translocation in CVB3-infected acinar 266-6 cells. STAT3 shRNA knockdown or STAT3 inhibitors reduced viral replication via the rescue of STAT1 nuclear translocation and increasing the ISRE activity and ISG transcription in vitro. The knockdown of STAT1 blocked the antiviral effect of the STAT3 inhibitor. STAT3 inhibits STAT1 activation by virally inducing a potent inhibitor of IFN signaling, the suppressor of cytokine signaling-3 ((SOCS)-3). Sustained pSTAT1 and the elevated expression of ISGs were induced in SOCS3 knockdown cells. The in vivo administration of HJC0152, a pharmaceutical STAT3 inhibitor, mitigated the viral-induced AP and myocarditis pathology via increasing the IFNß as well as ISG expression on day 3 p.i. and reducing the viral load in multi-organs. These findings define STAT3 as a negative regulator of the type I IFN response via impeding the nuclear STAT1 translocation that otherwise triggers ISG induction in infected pancreases and hearts. Our findings identify STAT3 as an antagonizing factor of the IFN-STAT1 signaling pathway and provide a potential therapeutic target for viral-induced AP and myocarditis.

Phenotypic Characteristics, Antimicrobial Susceptibility and Virulence Genotype Features of Trueperella pyogenes Associated with Endometritis of Dairy Cows.

Trueperella pyogenes can cause various infections in the organs and tissues of different livestock (including pigs, cows, goats, and sheep), including mastitis, endometritis, pneumonia, or abscesses. Moreover, diseases induced by T. pyogenes cause significant economic losses in animal husbandry. In recent large-scale investigations, T. pyogenes has been identified as one of the main pathogens causing endometritis in lactating cows. However, the main treatment for the above-mentioned diseases is still currently antibiotic therapy. Understanding the impact of endometritis associated with T. pyogenes on the fertility of cows can help optimize antibiotic treatment for uterine diseases, thereby strategically concentrating the use of antimicrobials on the most severe cases. Therefore, it is particularly important to continuously monitor the prevalence of T. pyogenes and test its drug resistance. This study compared the uterine microbiota of healthy cows and endometritis cows in different cattle farms, investigated the prevalence of T. pyogenes, evaluated the genetic characteristics and population structure of isolated strains, and determined the virulence genes and drug resistance characteristics of T. pyogenes. An amount of 186 dairy cows were involved in this study and 23 T. pyogenes strains were isolated and identified from the uterine lavage fluid of dairy cows with or without endometritis.