Targeting inflammation for the treatment of endometritis in bovines.

The uterine endometrial surface of bovines is in constant exposureconstantly exposed with to a multitude ofmany microbial populations that changes throughout the post-partum phase in terms of complexity and dynamics. These microbes contribute to the host pathology, leading to severe economic losses along withnd reproductive capabilities. The basic primary interface that occurs between the internal tissues of the body of the hostbetween the host body's internal tissues and the microbes is the endometrial surface of the uterus. As a result of the infinite pathogenic population, there is always a danger for the opportunistic organisms to attack. Therefore, it is paramount that any interactions, especially microbial microbes with the endometrial surface, are regulated by the host cells. However, the inflammatory response as the defense mechanism contributes a pivotal roleis pivotal in host immunity and pathology. The inflammatory cascade and pathways are important essential to eliminate this clinical problem. In this review, we will discuss and explain how the inflammation and the various components of the immune system play their role in host pathology and therapeutic strategies, taking into account the interface between the host and the microbes on the surface of the endometrium. This review is also instrumental in further explanation of inflammatory uterine disease by discussing the response of inflammation to external insult.

Ceftiofur in swine manure contributes to reducing pathogens and antibiotic resistance genes during composting.

Aerobic composting is a common way for the disposal of feces produced in animal husbandry, and can reduce the release of antibiotic resistance genes (ARGs) from feces into the environment. In this study, we collected samples from two distinct treatments of swine manure compost with and without ceftiofur (CEF), and identified the ARGs, mobile genetic elements (MGEs), and bacterial community by metagenomic sequencing. The impacts of CEF on the bacterial community composition and fate of ARGs and MGEs were investigated. With increasing composting temperature and pH, the concentration of CEF in the manure decreased rapidly, with a degradation half-life of 1.12 d and a 100% removal rate after 10 d of aerobic composting. Metagenomics demonstrated that CEF in the manure might inhibit the growth of Firmicutes and Proteobacteria, thereby reducing some ARGs and MGEs hosted by these two bacteria, which was further confirmed by the variations of ARGs and MGEs. A further redundancy analysis suggested that pH and temperature are key environmental factors affecting ARG removal during composting, and intI1 and bacterial communities also have significant influence on ARG abundance. These results are of great significance for promoting the removal of some ARGs from animal manure by controlling some key environmental factors and the type of antibiotics used in animals.

Immune Checkpoint Inhibitor Plus Chemotherapy as First-Line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer: A Systematic Review and Meta-Analysis.

Background: Immune checkpoint inhibitor (ICI) plus chemotherapy is effective in advanced gastric or gastroesophageal junction (G/GEJ) cancer. This study aims to evaluate the clinical effect of first-line immunotherapy in combination with chemotherapy for advanced G/GEJ cancer. Methods: PubMed, Web of Science, Embase and Cochrane databases were systematically searched from the inception of the databases to December 2021. Randomized trials comparing ICI plus chemotherapy with chemotherapy in first-line treatment for advanced G/GEJ cancer were included. The outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Analyses were performed in Stata 14.0 software. The study protocol was registered with PROSPERO, number CRD42022300907. Results: Five trials were included for analysis, involving 2, 814 patients. ICI plus chemotherapy can significantly improve OS (hazards ratio [HR], 0.86; 95% CI 0.78-0.94; P = .002), PFS (HR, 0.79; 95% CI 0.63-0.99; P ＜ .001) and ORR (relative ratio [RR], 1.20; 95% CI 1.11-1.30; P < .001). In safety analyses, there were no significant differences in incidence of all AEs, treatment-related adverse event (TRAE), TRAE of grade 3 or higher, serious TRAE and TRAE leading to death between two arms (P > .05). Conclusions: ICI plus chemotherapy is more effective first-line treatment for advanced G/GEJ cancer in contrast to chemotherapy regrading to improving OS, PFS and ORR, without increasing TRAE risk. This study will redefine the role of ICI in combination with chemotherapy in the first-line setting for G/GEJ cancer, and provide reference for clinical treatment.

Unraveling the Atomistic Mechanisms Underlying Effective Reverse Osmosis Filtration by Graphene Oxide Membranes.

The graphene oxide (GO) membrane displays promising potential in efficiently filtering ions from water. However, the precise mechanism behind its effectiveness remains elusive, particularly due to the lack of direct experimental evidence at the atomic scale. To shed light on this matter, state-of-the-art techniques are employed such as integrated differential phase contrast-scanning transmission electron microscopy and electron energy loss spectroscopy, combined with reverse osmosis (RO) filtration experiments using GO membranes. The atomic-scale observations after the RO experiments directly reveal the binding of various ions including Na+, K+, Ca2+, and Fe3+ to the defects, edges, and functional groups of GO. The remarkable ion-sieving capabilities of GO membranes are confirmed, which can be attributed to a synergistic interplay of size exclusion, electrostatic interactions, cation-π, and other non-covalent interactions. Moreover, GO membranes modified by external pressure and cation also demonstrated further enhanced filtration performance for filtration. This study significantly contributes by uncovering the atomic-scale mechanism responsible for ion sieving in GO membranes. These findings not only enhance the fundamental understanding but also hold substantial potential for the advancement of GO membranes in reverse osmosis (RO) filtration.

Bacterial Efflux Pump Inhibitors Reduce Antibiotic Resistance.

Bacterial resistance is a growing problem worldwide, and the number of deaths due to drug resistance is increasing every year. We must pay great attention to bacterial resistance. Otherwise, we may go back to the pre-antibiotic era and have no drugs on which to rely. Bacterial resistance is the result of several causes, with efflux mechanisms widely recognised as a significant factor in the development of resistance to a variety of chemotherapeutic and antimicrobial medications. Efflux pump inhibitors, small molecules capable of restoring the effectiveness of existing antibiotics, are considered potential solutions to antibiotic resistance and have been an active area of research in recent years. This article provides a review of the efflux mechanisms of common clinical pathogenic bacteria and their efflux pump inhibitors and describes the effects of efflux pump inhibitors on biofilm formation, bacterial virulence, the formation of bacterial persister cells, the transfer of drug resistance among bacteria, and mismatch repair. Numerous efforts have been made in the past 20 years to find novel efflux pump inhibitors which are known to increase the effectiveness of medicines against multidrug-resistant strains. Therefore, the application of efflux pump inhibitors has excellent potential to address and reduce bacterial resistance.

Deciphering the causal association and co-disease mechanisms between psoriasis and breast cancer.

Background: Prior research has indicated a link between psoriasis and the susceptibility to breast cancer (BC); however, a definitive causal relationship remains elusive. This study sought to elucidate the causal connection and shared underlying mechanisms between psoriasis and BC through bidirectional Mendelian randomization (MR) and bioinformatic approaches. Methods: We employed a bidirectional MR approach to examine the potential causal connection between psoriasis and BC. Genetic data pertaining to psoriasis and BC were sourced from extensive published genome-wide association studies. The inverse -variance weighted or wald ratio served as the primary method for estimating causal effects. Sensitivity analysis of the MR results was applied with multiple methods. Leveraged datasets from the Gene Expression Omnibus and the Cancer Genome Atlas repositories to identify common differentially expressed genes, shedding light on the shared mechanisms underlying these two conditions. Results: The MR analysis revealed that when considering psoriasis as an exposure factor, the incidences of BC (OR=1.027) and estrogen receptor negative (ER-) BC (OR=1.054) were higher than in the general population. When using Her2+ BC as an exposure factor, the risk of psoriasis was 0.822 times higher (OR=0.822) than in the general population. Sensitivity analysis indicated that the results were robust. Transcriptome analysis showed that CXCL13 and CCL20 were activated in both BC and psoriasis. Both diseases were also linked to neutrophil chemotaxis, the IL-17 pathway, and the chemokine pathway. Conclusion: The results suggest that psoriasis may increase the risk of BC, especially ER- BC, while reverse MR suggests a decreased risk of psoriasis in Her2+ BC. Transcriptome analysis revealed a shared mechanism between psoriasis and BC.

A physiologically based pharmacokinetic/pharmacodynamic model to determine dosage regimens and withdrawal intervals of aditoprim against Streptococcus suis.

Introduction: Streptococcus suis (S. suis) is a zoonotic pathogen threatening public health. Aditoprim (ADP), a novel veterinary medicine, exhibits an antibacterial effect against S. suis. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was used to determine the dosage regimens of ADP against S. suis and withdrawal intervals. Methods: The PBPK model of ADP injection can predict drug concentrations in plasma, liver, kidney, muscle, and fat. A semi-mechanistic pharmacodynamic (PD) model, including susceptible subpopulation and resistant subpopulation, is successfully developed by a nonlinear mixed-effect model to evaluate antibacterial effects. An integrated PBPK/PD model is conducted to predict the time-course of bacterial count change and resistance development under different ADP dosages. Results: ADP injection, administrated at 20 mg/kg with 12 intervals for 3 consecutive days, can exert an excellent antibacterial effect while avoiding resistance emergence. The withdrawal interval at the recommended dosage regimen is determined as 18 days to ensure food safety. Discussion: This study suggests that the PBPK/PD model can be applied as an effective tool for the antibacterial effect and safety evaluation of novel veterinary drugs.

SLC38A3 Promotes the Proliferation and Migration of Tumor Cells and Predicts Poor Prognosis in Colorectal Cancer.

Previous studies have revealed that abnormal expressions of membrane transporters were associated with colorectal cancer (CRC). We herein performed a comprehensive bioinformatics analysis to identify the key transporter protein-related genes involved in CRC and potential mechanisms. Differentially expressed transporter protein-related genes (DE-TPRGs) were identified from CRC and normal samples using The Cancer Genome Atlas database. SLC38A3 expression was validated by immunohistochemistry and RT-qPCR, and the potential mechanism was explored. A total of 63 DE-TPRGs (29 up-regulated and 34 down-regulated) were screened. Inside, ABCC2, ABCG2, SLC4A4, SLC9A3, SLC15A1, and SLC38A3 were identified as hub genes. SLC38A3 is indeed upregulated in colorectal cancer patients. Furthermore, we found that knockdown of SLC38A3 inhibited the proliferation and migration of HCT116 cells, and Hsp70 ATPase activator could rescue it. Overall, SLC38A3 is a novel potential biomarker involved in CRC progression and promotes the proliferation and migration of tumor cells by positively regulating the function of Hsp70.

Metagenomic analysis reveals impact of acyl homoserine endolipid-like signaling molecules on the aqueous sediment resistome under florfenicol stress.

Quorum sensing potentially helps microorganisms adapt to antibiotic stress encountered in the environment. This experiment investigated the effect of acyl homoserine endolipid-like signaling molecules on microbial antibiotic resistance gene structures in aqueous sediments under florfenicol stress. Additional acyl homoserine endolipid-like signaling molecules (AHLs) alter the structure of multidrug resistance genes in florfenicol-stressed sediments, particularly the multidrug resistance efflux pump gene family. Prophages and integrative and conjugative elements (ICEs) determined the resistance genes structure, and pathways related to mobile genetic elements (MGEs) transfer may play an essential role in this process. The practical application of AHLs to regulate quorum sensing systems may alter bacterial stress responses to environmental florfenicol residues, thereby reducing the development of antibiotic resistance in the environment.

Co-selection mechanism for bacterial resistance to major chemical pollutants in the environment.

Bacterial resistance is an emerging global public health problem, posing a significant threat to animal and human health. Chemical pollutants present in the environment exert selective pressure on bacteria, which acquire resistance through co-resistance, cross-resistance, co-regulation, and biofilm resistance. Resistance genes are horizontally transmitted in the environment through four mechanisms including conjugation transfer, bacterial transformation, bacteriophage transduction, and membrane vesicle transport, and even enter human bodies through the food chain, endangering human health. Although the co-selection effects of bacterial resistance to chemical pollutants has attracted widespread attention, the co-screening mechanism and co-transmission mechanisms remain unclear. Therefore, this article summarises the current research status of the co-selection effects and mechanism of environmental pollutants resistance, emphasising the necessity of studying the co-selection mechanism of bacteria against major chemical pollutants, and lays a solid theoretical foundation for conducting risk assessment of bacterial resistance.

Biodegradation strategies of veterinary medicines in the environment: Enzymatic degradation.

One Health closely integrates healthy farming, human medicine, and environmental ecology. Due to the ecotoxicity and risk of transmission of drug resistance, veterinary medicines (VMs) are regarded as emerging environmental pollutants. To reduce or mitigate the environmental risk of VMs, developing friendly, safe, and effective removal technologies is an important means of environmental remediation for VMs. Many previous studies have proved that biodegradation has significant advantages in removing VMs, and biodegradation based on enzyme catalysis presents higher operability and specificity. This review focused on biodegradation strategies of environmental pollutants and reviewed the enzymatic degradation of VMs including antimicrobial drugs, insecticides, and disinfectants. We reviewed the sources and catalytic mechanisms of peroxidase, laccase, and organophosphorus hydrolases, and summarized the latest research status of immobilization methods and bioengineering techniques in improving the performance of degrading enzymes. The mechanism of enzymatic degradation for VMs was elucidated in the current research. Suggestions and prospects for researching and developing enzymatic degradation of VMs were also put forward. This review will offer new ideas for the biodegradation of VMs and have a guide significance for the risk mitigation and detoxification of VMs in the environment.

Distribution and genetic characterization of fluoroquinolone resistance gene qnr among Salmonella strains from chicken in China.

The prevalence and dissemination of the plasmid-mediated fluoroquinolone (FQ) resistance gene qnr in Salmonella are considered serious public health concerns worldwide. So far, no comprehensive large-scale studies have focused on the prevalence and genetic characteristics of the qnr gene in Salmonella isolated from chickens. Herein, this study aimed to investigate the prevalence, antimicrobial resistance (AMR) patterns, and molecular characteristics of chicken-originated qnr-positive Salmonella strains from chicken farms, slaughterhouses, and markets in 12 provinces of China in 2020-2021. The overall prevalence of the qnr gene was 21.13% (56/265), with the highest prevalence in markets (36.11%, 26/72), followed in farms (17.95%, 21/117), and slaughterhouses (10.53%, 9/76). Only the qnrS and qnrB genes were detected, and the prevalence rate of the qnrS gene (19.25%, 51/265) was higher than that of the qnrB gene (1.89%, 5/265). Whole genome sequencing identified 37 distinct AMR genes and 15 plasmid replicons, and the most frequent mutation in quinolone resistance determining regions was parC (T57S; 91.49%, 43/47). Meanwhile, four different qnrS and two qnrB genetic environments were discovered among 47 qnr-positive Salmonella strains. In total, 21.28% (10/47) of the strains were capable of conjugative transfer, and all were qnrS1-positive strains, with the majority of transferable plasmids being IncHI2 types (n = 4). Overall, the prevalence of qnr-positive Salmonella strains from chickens in China and their carriage of multiple resistance and virulence genes and transferable plasmids is a major concern, which calls for continuous surveillance of qnr-positive Salmonella and the development of measures to control its prevalence and transmission.IMPORTANCESalmonella is a common foodborne pathogen responsible for 155,000 deaths annually worldwide. Fluoroquinolones (FQs) are used as first-line drugs for the treatment of Salmonella infections in several countries and regions. However, the emergence and increasing prevalence of the FQ-resistant gene qnr in Salmonella isolated from chickens have been widely reported. Gaining insight into the genetic mechanisms of AMR genes in chicken could lead to the development of preventive measures to control and reduce the risk of drug resistance. In this study, we identified qnr-positive Salmonellae isolated from chickens in different regions of China and their AMR patterns and genome-wide characteristics, providing a theoretical basis for further control of their prevalence and transmission.

Basic concepts, recent advances, and future perspectives in the diagnosis of bovine mastitis.

Mastitis is one of the most widespread infectious diseases that adversely affects the profitability of the dairy industry worldwide. Accurate diagnosis and identification of pathogens early to cull infected animals and minimize the spread of infection in herds is critical for improving treatment effects and dairy farm welfare. The major pathogens causing mastitis and pathogenesis are assessed first. The most recent and advanced strategies for detecting mastitis, including genomics and proteomics approaches, are then evaluated . Finally, the advantages and disadvantages of each technique, potential research directions, and future perspectives are reported. This review provides a theoretical basis to help veterinarians select the most sensitive, specific, and cost-effective approach for detecting bovine mastitis early.

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.