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Domestic dogs (Canis lupus familiaris) serve as valuable translational models for human cancer research due to their biological similarities. Canine mammary tumors (CMTs), frequently diagnosed in female dogs, share various characteristics with human breast cancers. This study investigates the PIK3CA (H1047R) mutation in CMTs using droplet digital PCR (ddPCR) and explores the potential of liquid biopsy for non-invasive detection. We analyzed 80 formalin-fixed, paraffin-embedded (FFPE) CMT tissue samples and compared ddPCR results with next-generation sequencing (NGS) data, achieving high concordance. Plasma and serum samples were also assessed for mutation concordance with tissue results. Our findings indicate a higher frequency of the PIK3CA (H1047R) mutations in benign and grade I malignant CMTs compared to more aggressive malignancies. The ddPCR assay demonstrated high sensitivity and specificity, with plasma testing showing 78.6% sensitivity and 87.5% specificity, and serum testing showing 66.7% sensitivity and 90.0% specificity. These results highlight the viability of liquid biopsy as a minimally invasive method for monitoring PIK3CA mutations in canine patients. The study suggests that liquid biopsy techniques hold significant promise for improving the early detection and monitoring of canine cancers, warranting further research to refine these methods and explore their applications in canine cancer diagnostics and treatment., (© 2024. The Author(s).)

Bovine tuberculosis is one of the most important common infectious diseases between humans and livestock. Cow's milk can be investigated as one of the transmission reservoirs of the disease. Our study was conducted to investigate the presence of Mycobacterium bovis (M. bovis) DNA in cow's milk from different regions of Lorestan province using Touch-down PCR (TD-PCR) method. So, 100 milk samples from industrial and traditional cattle farms were collected and evaluated according to the animal breed, the average age of the animal and the region where the animal was kept. Seven (26.9%) out of the 26 cow's milk samples contaminated with Mycobacterium spp., were diagnosed as M. bovis positive. The cattle with an average age of more than 5 years were most infected with Mycobacterium. Also, the crossbred cattle with an average age of 3 to 5 years, which were kept and raised in tropical areas, showed the highest rate of M. bovis infection. Based on our knowledge, this is the first study regarding the presence of Mycobacterium in cow's milk in Iran., (© 2024. The Author(s).)

Type II toxin-antitoxin systems such as mazEF3, vapBC3, and relJK play a role in antibiotic resistance and tolerance. Among the different known TA systems, mazEF3, vapBC3, and relJK, which are type II systems, have specific roles in drug resistance. Therefore, the aim of this study was to investigate the mutations in these genes in sensitive and resistant isolates of Mycobacterium tuberculosis. Thirty-two rifampin-resistant and 121 rifampin-sensitive M. tuberculosis isolates were collected from various regions of Iran. Lineage typing was performed using the ASO-PCR method. Mutations in the rpoB gene were analyzed in all isolates by MAS-PCR. Furthermore, mutations in the mazEF3, relJK, and vapBC3 genes of the type II toxin system were assessed through PCR sequencing. These sequences were analyzed using COBALT and SnapGene 2017, and submitted to the GenBank database. Among the 153 M. tuberculosis samples, lineages 4, 3 and 2 were the most common. Lineage 2 had the highest rate of rifampin resistance. Mutations in rpoB531 were the most frequent in resistant isolates. Examination of the toxin-antitoxin system showed that rifampin-resistant isolates belonging to lineage 3 had mutations in either the toxin or antitoxin parts of all three TA systems. A mutation in nucleotide 195 (codon 65) of mazF3 leading to an amino acid change from threonine to isoleucine was detected in all rifampin-resistant isolates. M. tuberculosis isolates belonging to lineage 2 exhibited the highest rifampin resistance in our study. Identifying the mutation in mazF3 in all rifampin-resistant isolates can highlight the significance of this mutation in the development of drug resistance in M. tuberculosis. Expanding the sample size in future studies can help develop a new method for identifying resistant isolates., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Shafipour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Enteral nutrition (EN) is essential for management of hepatic lipidosis (HL) in cats., Objectives: To determine if time to start of EN and other clinicopathologic variables are associated with outcome in cats with HL., Animals: Forty-eight cats with HL., Methods: Retrospective study. Information retrieved from medical records and client communications included clinicopathologic findings, time to start of EN, initial % of resting energy requirements provided, type of feeding tube, duration of hospitalization, and 3-month survival. Variables were compared between surviving and nonsurviving cats and between cats fed ≤12 hours and >12 hours after hospital admission. Multivariable statistical testing was performed to further investigate variables of interest., Results: Seventeen of 25 (68%) cats fed ≤12 hours and 13 of 23 (57%) of cats fed >12 hours after hospital admission survived (P = .55). Only increasing age (odds ratio [OR], 1.313; 95% confidence interval [CI], 1.032-1.671; P = .03) and the presence of ascites (OR, 6.415; 95% CI, 1.354-30.395; P = .02) were associated with death in multivariable analysis. Hospitalization duration (median, interquartile range [IQR]) was shorter in cats fed >12 hours (2.8 days; IQR, 2.1-3.8 days) as compared with cats fed ≤12 hours (4.8 days; IQR, 3.6-6.2 days) after hospital admission (P < .001)., Conclusions and Clinical Importance: An initial stabilization period before EN introduction does not decrease survival or increase duration of hospitalization in cats with HL., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Introduction: The lung is a moderately radio-sensitive organ. When cells are damaged due to accidental radiation exposure or treatment, they release molecules that lead to the recruitment of immune cells, accumulating inflammatory cytokines at the site of damage. Apigenin (Api) is a natural flavonoid known for its anti-inflammatory properties. In this study, we investigated the radioprotective properties of Api in the lung., Methods: Thirty-six Wistar rats were randomly assigned to nine groups: control, radiation (Rad), CMC+Rad, Api10+Rad, and Api20+Rad. Api was administered with an intraperitoneal injection for 7 days, after which the rats were irradiated with 6 Gy whole-body X-ray. At 6 and 72 hours post-irradiation, the rats were euthanized, and their lung tissue was extracted., Results: Radiation led to increased alveolar wall thickness and the infiltration of macrophages and lymphocytes. Furthermore, the expression levels of inflammatory factors such as a nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-ĸB), Glycogen synthase kinase-3 beta (GSK-3β), transforming growth factor-beta1 (TGF-β1), and epigenetic factors including DNA methyltransferase 3a (DNMT3a) and Histone deacetylase 2 (HDAC2) were elevated in the lung tissue following radiation. Meanwhile, the expression level of IκB-α decreased. However, administration of Api (at both 10&20 mg/kg) reversed the adverse effects of radiation., Conclusion: Api administration mitigated radiation-induced lung damage by reversing inflammatory and epigenetic changes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Inappropriate antibiotic use is a key driver of antibiotic resistance and one that can be mitigated through stewardship. A better understanding of current prescribing practices is needed to develop successful stewardship efforts. This study aims to identify factors that are associated with human cases of enteric illness receiving an antibiotic prescription. Cases of laboratory-confirmed enteric illness reported to the FoodNet Canada surveillance system between 2015 and 2019 were the subjects of this study. Laboratory data were combined with self-reported data collected from an enhanced case questionnaire that included demographic data, illness duration and symptoms, and antibiotic prescribing. The data were used to build univariable logistic regression models and a multivariable logistic regression model to explore what factors were associated with a case receiving an antibiotic prescription. The final multivariable model identified several factors as being significantly associated with cases being prescribed an antibiotic. Some of the identified associations indicate that current antibiotic prescribing practices include a substantial level of inappropriate use. This study provides evidence that antibiotic stewardship initiatives targeting infectious diarrhoea are needed to optimize antibiotic use and combat the rise of antibiotic resistance.

The incidence of human infection by zoonotic avian influenza viruses, especially H5N1 and H7N9 viruses, has increased. Current zoonotic H7N9 avian influenza viruses (identified since 2013) emerged during reassortment of viruses belonging to different subtypes. Despite analyses of their genetic background, we do not know why current H7N9 viruses are zoonotic. Therefore, there is a need to identify the factor(s) responsible for the extended host tropism that enables these viruses to infect humans as well as birds. To identify H7N9-specific amino acids that confer zoonotic properties on H7N9 viruses, we performed multiple alignment of the hemagglutinin (HA) amino acid sequences of A/Shanghai/1/2013 (H7N9) and A/duck/Zhejiang/12/2011(H7N3) (a putative, non- or less zoonotic HA donor to the zoonotic H7N9 virus). We also analyze the function of an H7N9 HA-specific amino acid with respect to HA acid stability, and evaluated the effect of acid stability on viral infectivity and virulence in a mouse model. HA2-116D, preserved in current zoonotic H7N9 viruses, was crucial for loss of HA acid stability. The acid-labile HA protein in H7 viruses played an important role in infection of human airway epithelial cells; HA2-116D contributed to infection and replication of H7 viruses. Finally, HA2-116D served as a H7 virulence factor in mice. These results suggest that acid-labile HA harboring HA2-116D confers zoonotic characteristics on H7N9 virus and that future novel zoonotic avian viruses could emerge from non-zoonotic H7 viruses via acquisition of mutations that remove HA acid stability., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Daidoji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Between 2013 and 2018, the novel A/Anhui/1/2013 (AH/13)-lineage H7N9 virus caused at least five waves of outbreaks in humans, totaling 1,567 confirmed human cases in China. Surveillance data indicated a disproportionate distribution of poultry infected with this AH/13-lineage virus, and laboratory experiments demonstrated that this virus can efficiently spread among chickens but not among Pekin ducks. The underlying mechanism of this selective transmission remains unclear. In this study, we demonstrated the absence of Neu5Gc expression in chickens across all respiratory and gastrointestinal tissues. However, Neu5Gc expression varied among different duck species and even within the tissues of the same species. The AH/13-lineage viruses exclusively bind to acetylneuraminic acid (Neu5Ac), in contrast to wild waterbird H7 viruses that bind both Neu5Ac and N-glycolylneuraminic acid (Neu5Gc). The level of Neu5Gc expression influences H7 virus replication and facilitates adaptive mutations in these viruses. In summary, our findings highlight the critical role of Neu5Gc in affecting the host range and interspecies transmission dynamics of H7 viruses among avian species.IMPORTANCEMigratory waterfowl, gulls, and shorebirds are natural reservoirs for influenza A viruses (IAVs) that can occasionally spill over to domestic poultry, and ultimately humans. This study showed wild-type H7 IAVs from waterbirds initially bind to glycan receptors terminated with N-acetylneuraminic acid (Neu5Ac) or N-glycolylneuraminic acid (Neu5Gc). However, after enzootic transmission in chickens, the viruses exclusively bind to Neu5Ac. The absence of Neu5Gc expression in gallinaceous poultry, particularly chickens, exerts selective pressure, shaping IAV populations, and promoting the acquisition of adaptive amino acid substitutions in the hemagglutinin protein. This results in the loss of Neu5Gc binding and an increase in virus transmissibility in gallinaceous poultry, particularly chickens. Consequently, the transmission capability of these poultry-adapted H7 IAVs in wild water birds decreases. Timely intervention, such as stamping out, may help reduce virus adaptation to domestic chicken populations and lower the risk of enzootic outbreaks, including those caused by IAVs exhibiting high pathogenicity., Competing Interests: The authors declare no conflict of interest.

Background: Sepsis is a main contributor to calf mortality, but diagnosis is difficult., Objectives: Develop and validate a predictive model for bacteremia in critically ill calves (CIC)., Animals: A total of 334 CIC, sampled for blood culture., Methods: Cross-sectional study. Multivariable logistic regression and classification tree analysis on clinical, ultrasonographic, and laboratory variables were performed on a dataset including all animals. Model validation was done on 30% of the dataset. Similar statistics (except validation) were performed on a subset of the database (n = 143), in which presumed contaminants were excluded., Results: The best performing model to predict bacteremia, taking all detected bacteria into account, included tachypnea, tachycardia, acidemia, hypoglycemia, venous hypoxemia, and hypoproteinemia. Sensitivity and specificity of this model were 70.6% and 98.0%, respectively, but decreased to 61.5% and 91.7% during model validation. The best-performing model, excluding presumed contaminants, included abnormal temperature, heart rate, absence of enteritis, hypocalcemia, and hyperlactatemia as risk factors for bacteremia. Sensitivity and specificity of this model were 71.4% and 93.9%, respectively. Both classification trees performed less well in comparison to logistic regression. The classification tree excluding presumed contaminants, featured hypoglycemia, absence of diarrhea, and hyperlactatemia as risk factors for bacteremia. Sensitivity and specificity were 39.4% and 92.7%, respectively., Conclusions and Clinical Importance: Hypoglycemia, hyperlactatemia, and hypoproteinemia seem relevant in assessing bacteremia in CIC. The performance of these models based on basic clinical and blood variables remains insufficient to predict bacteremia., (© 2024 The Author(s). Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Effective targeting and delivery of large amounts of medications into the cancer cells enhance their therapeutic efficacy through saturation of cellular defensive mechanisms, which is the most privilege of nano drug delivery systems (NDDS) compared to traditional approaches. Herein, we designed dual-pH/redox responsive DTX-loaded poly (β-amino ester) (PBAS) micelles decorated with a chimeric peptide and TA1 aptamer. In vitro and in vivo results demonstrated that the designed nanoplatform possessed an undetectable nature in the blood circulation, but after exposure to the tumor microenvironment (TME) of 4T1 breast cancer, it suddenly changed into dual targeting nanoparticles (NPs) (containing two ligands, SRL-2 and TA1 aptamer). The dual targeting NPs destruction in the high GSH and low pH conditions of the cancer cells led to amplified DTX release (around 70% at 24 h). The IC50 value of DTX-loaded MMP-9 sensitive heptapeptide/TA1 aptamer-modified poly (β-amino ester) (MST@PBAS) micelles and free DTX after 48 h of exposure was determined to be 1.5 µg/ml and 7.5 µg/ml, respectively. The nano-formulated DTX exhibited cytotoxicity that was 5-fold stronger than free DTX (Pvalue˂0.001). Cell cycle assay test results showed that following exposure to MST@PBAS micelles, a considerable rise in the sub G1 population (48%) suggested that apoptosis by cell cycle arrest had occurred. DTX-loaded MST@PBAS micelles revealed significantly higher (Pvalue ˂ 0.001) levels of early apoptosis (59.8%) than free DTX (44.7%). Interestingly, in vitro uptake studies showed a significantly higher TME accumulation of dual targeted NPs (6-fold) compared to single targeted NPs (Pvalue < 0.001) which further confirmed by in vivo biodistribution and fluorescent TUNEL assay experiments. NPs treated groups demonstrated notable tumor growth inhibition in 4T1 tumor bearing Balb/c mice by only 1/10th of the DTX therapeutic dose (TD) as a drug model. In conclusion, cleverly designed nanostructures here demonstrated improved anticancer effects by enhancing tumor targeting, delivering chemotherapeutic agents more accurately, promoting drug release, reducing the therapeutic dosage, and lowering side effects of anticancer drugs., (© 2024. The Author(s).)

Background: The main characteristic of asthma is chronic inflammation. We examined cellular senescence by histology and molecular assay in the lungs of a rat model of asthma. This model comprises sensitization by several intraperitoneal injections of ovalbumin with aluminium hydroxide, followed by aerosol challenges every other day., Results: Data showed that asthma induction caused histological changes including, hyperemia, interstitial pneumonia, fibrinogen clots, and accumulation of inflammatory cells in the pleura. There is an elevation of IL-1β and NF-kB proteins in the asthmatic group (P < 0.001) compared to the control group. The expression of ß-galactosidase increased (P < 0.01), while the expression of Klotho and Sox2 genes was decreased in the lung tissue of the asthmatic group (P < 0.01)., Conclusion: Taken together, these findings suggest that asthmatic conditions accelerated the cellular senescence in the lung tissue., (© 2024. The Author(s).)

Objective: Acute intranasal (IN) instillation of lupus-prone NZBWF1 mice with crystalline silica (cSiO 2 ) triggers robust lung inflammation that drives autoimmunity. Prior studies in other preclinical models show that soluble epoxide hydrolase (sEH) inhibition upregulates pro-resolving lipid metabolites that are protective against pulmonary inflammation. Herein, we assessed in NZBWF1 mice how acute IN cSiO 2 exposure with or without the selective sEH inhibitor TPPU influences lipidomic, transcriptomic, proteomic, and histopathological biomarkers of inflammation, fibrosis, and autoimmunity., Methods: Female 6-week-old NZBWF1 mice were fed control or TPPU-supplemented diets for 2 weeks then IN instilled with 2.5 mg cSiO 2 or saline vehicle. Cohorts were terminated at 7 or 28 days post-cSiO 2 instillation (PI) and lungs analyzed for prostaglandins, cytokines/chemokines, gene expression, differential cell counts, histopathology, and autoantibodies., Results: cSiO 2 -treatment induced prostaglandins, cytokines/chemokine, proinflammatory gene expression, CD206 + monocytes, Ly6B.2 + neutrophils, CD3 + T cells, CD45R + B cells, centriacinar inflammation, collagen deposition, ectopic lymphoid structure neogenesis, and autoantibodies. While TPPU effectively inhibited sEH as reflected by skewed lipidomic profile in lung and decreased cSiO 2 -induced monocytes, neutrophils, and lymphocytes in lung lavage fluid, it did not significantly impact other biomarkers., Discussion: cSiO 2 evoked robust pulmonary inflammation and fibrosis in NZBWF1 mice that was evident at 7 days PI and progressed to ELS development and autoimmunity by 28 days PI. sEH inhibition by TPPU modestly suppressed cSiO 2 -induced cellularity changes and pulmonary fibrosis. However, TPPU did not affect ELS formation or autoantibody responses, suggesting sEH minimally impacts cSiO 2 -triggered lung inflammation, fibrosis, and early autoimmunity in our model.

Feline cancer is increasingly recognized as a major cause of mortality, yet data on tumor prevalence and behavior in cats, particularly in non-Western regions, remain limited. This study analyzed a decade of feline tumor data in Korea from 2012 to 2022, focusing on age, breed, and anatomical location as predictors of malignancy. Data were collected from 683 cats, with regression analysis applied to determine significant associations. Older cats exhibited a markedly higher risk of malignancy, particularly in mast cell and mammary tumors. Tumors in the mammary gland and alimentary tract had malignancy rates exceeding 90%, underscoring the need for early detection in these regions. Interestingly, squamous cell carcinoma was rare in the skin, in stark contrast to Western studies, likely reflecting differences in environmental exposure. While breed was not a statistically significant predictor, certain breeds, including Persians and Russian Blues, showed a higher frequency of malignancy. These findings highlight the importance of regional tumor research in cats and the need for larger, multicenter datasets that incorporate environmental, genetic, and lifestyle factors. Understanding these influences will help refine veterinary care and improve cancer treatment outcomes in feline populations.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly infectious agent that poses a significant economic threat to the global swine industry. Efficient viral entry relies on interactions with cellular receptors, with CD163-a cysteine-rich scavenger receptor found on porcine alveolar macrophages (PAMs)-playing a critical role. Extensive evidence supports CD163's essential function in PRRSV infection. This review synthesizes current knowledge about CD163's role, examining its structure-function relationship and identifying specific regions crucial for viral entry. We evaluate the established role of CD163 in PRRSV pathogenesis and highlight areas requiring further investigation, along with the potential for targeted therapeutic interventions. Understanding the molecular determinants of CD163's function is vital for developing effective strategies to control PRRSV infection and mitigate its economic impact on swine production. Further research into the PRRSV-CD163 interactions will be crucial for creating novel antiviral strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-POU domain-containing octamer-binding protein (NONO) is a multi-functional nuclear protein which belongs to the Drosophila behavior/human splicing (DBHS) protein family. NONO is known to regulate multiple important biological processes including host antiviral immune response. However, whether NONO can inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication is less well understood. In this study, we demonstrated that swine NONO (sNONO) inhibited PRRSV replication, via increasing expression of IFN-β, whereas NONO knockdown or knockout in PAM-KNU cells was more susceptible to PRRSV infection. As an IRF3 positive regulation factor, NONO promoted IFN-β expression by enhancing activation of IRF3. During PRRSV infection, NONO further up-regulated IRF3-mediated IFN-β expression by interacting with PRRSV N protein. Mechanistically, NONO functioned as a scaffold protein to detect PRRSV N protein and formed N-NONO-IRF3 complex in the nucleus. Interestingly, it was found that the NONO protein reversed the inhibitory effect of PRRSV N protein on type I IFN signaling pathway. Taken together, our study provides a novel mechanism for NONO to increase the IRF3-mediated IFN-β activation by interacting with the viral N protein to inhibit PRRSV infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jiang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To compare the antibacterial activities of different types of honey against common bacterial isolates cultured from wounds of dogs and cats., Methods: 4 types of honey were used including a medical-grade manuka honey, a non-medical-grade manuka honey, a locally sourced non-medical-grade honey (non-MGH), and a commercially sourced non-MGH. Bacterial isolates were obtained from clinical wound cultures of dogs and cats including Staphylococcus pseudintermedius, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa. The macro-broth dilution method was used to analyze the MIC and minimum bactericidal concentration. The percentage of growth inhibition was assessed for different types of honey at different concentrations using a generalized linear regression model., Results: Medical-grade honey exhibited the lowest minimum bactericidal concentration against S pseudintermedius, E faecalis, and P aeruginosa, alongside the lowest MIC at 90% with statistically significant higher bacterial growth inhibition in medium and low concentrations. Non-medical-grade manuka honey had a similar bactericidal activity against S pseudintermedius and P aeruginosa compared to locally and commercially sourced non-MGH., Conclusions: In this in vitro study, MGH exhibited superior antibacterial activity against all bacterial isolates compared to other types of honey., Clinical Relevance: Medical-grade honey displayed the greatest antibacterial activity against common wound pathogens and could be considered over other types of honey for wound management in cats and dogs. Locally and commercially sourced non-MGH appears to have a comparative efficacy against certain bacteria compared to non-medical-grade manuka honey and is more cost effective. Further in vivo studies are needed to confirm these findings.

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15 Ink4b , p21 Cip1 , p27 Kip1 , and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy.

Sepsis remains a huge unmet medical need for which no approved drugs, besides antibiotics, are on the market. Despite the clinical impact of sepsis, its molecular mechanism remains inadequately understood. Recent insights have shown that profound hepatic transcriptional reprogramming, leading to fatal metabolic abnormalities, might open a new avenue to treat sepsis. Translation of experimental results from rodents to larger animal models of higher relevance for human physiology, such as pigs, is critical and needs exploration. We performed a comparative analysis of the transcriptome profiles in murine and porcine livers using the following sepsis models: cecal ligation and puncture (CLP) in mice and fecal instillation (FI) in pigs, both of which induce polymicrobial septic peritonitis, and lipopolysaccharide (LPS)-induced endotoxemia in pigs, inducing sterile inflammation. Using bulk RNA sequencing, Metascape pathway analysis, and HOMER transcription factor motif analysis, we were able to identify key genes and pathways affected in septic livers. Conserved upregulated pathways in murine CLP and porcine LPS and FI generally comprise typical inflammatory pathways, except for ER stress, which was only found in the murine CLP model. Conserved pathways downregulated in sepsis comprise almost exclusively metabolic pathways such as monocarboxylic acid, steroid, biological oxidation, and small-molecule catabolism. Even though the upregulated inflammatory pathways were equally induced in the two porcine models, the porcine FI model more closely resembles the metabolic dysfunction observed in the CLP liver compared to the porcine LPS model. This comprehensive comparison focusing on the hepatic responses in mouse CLP versus LPS or FI in pigs shows that the two porcine sepsis models generally resemble quite well the mouse CLP model, with a typical inflammatory signature amongst the upregulated genes and metabolic dysfunction amongst the downregulated genes. The hepatic ER stress observed in the murine model could not be replicated in the porcine models. When studying metabolic dysfunction in the liver upon sepsis, the porcine FI model more closely resembles the mouse CLP model compared to the porcine LPS model.

Alzheimer's Disease (AD) is the primary neurodegenerative disorder in the elderly, lacking a definitive treatment. The gut microbiota influences the gut-brain axis by aiding in hypothalamic-pituitary-adrenal (HPA) axis development and neuromodulator production. Research links AD and gut microbiota, suggesting gut microbiota regulation could be a therapeutic approach for AD. This study explores Akkermansia muciniphila's impact on preventing AD. This research investigates the effect of A. muciniphila consumption (1 × 10 9 CFU) on tau protein-induced AD rats compared to a control group. Rats were divided into four groups: sham, sham + Akk, AD (tau-induced rats), and AD + Akk (tau-induced rats treated with A. muciniphila). A. muciniphila gavage lasted five weeks. Rats underwent qRT-PCR analysis to assess mRNA expression of pro-inflammatory factors (TNF-α, IL-6, IL-1β, IFN-γ) in the hippocampus. Behavioral tests included Morris Water Maze (MWM), Passive Avoidance Memory Test (Shuttle box), Elevated Plus Maze (EPM), and marble burying. After five weeks of A. muciniphila treatment, anxiety-like behavior significantly decreased. The AD group receiving A. muciniphila showed improved spatial and recognition memory compared to the AD group. Pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6, IFN-γ) decreased. A. muciniphila effectively reduces cognitive impairments and anxiety-related behavior, showing promise as an AD therapeutic by influencing the gut-brain axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Endocrine diagnostics currently depend on the ability to measure low and high concentrations of diagnostic hormones using immunoassays. This often is challenging in species other than humans, dogs, cats, and horses due to lack of validated assays and reference intervals. There are strategies to approach endocrine testing in zoo, wildlife, and zoologic companion animals but caution is needed in interpreting results. Newer techniques such as liquid chromatography-tandem mass spectrometry (LC-MS/MS) may be more useful for all species, although technical hurdles remain for this method too., Competing Interests: Disclosure Drs D. Agnew and B.K. Petroff are employed by Michigan State University Veterinary Diagnostic Laboratory, which performs endocrine testing in animals., (Copyright © 2024 Elsevier Inc. All rights reserved.)

West Nile virus (WNV) is an emerging arbovirus transmitted by mosquitoes. Although it is considered the most widespread mosquito-borne arbovirus in Iran, vectors of this zoonotic pathogen remain unknown in many regions. This study aimed to assess the presence of WNV in mosquitoes collected in the western city of Hamedan in 2022. Adult mosquitoes were captured using light traps, and mosquito larvae were collected by dipping technique from 45 diverse habitats, including urban, suburban, and rural sites. Specimens were identified and pooled into 69 batches based on their species for viral RNA extraction and Real-Time PCR. In total, 3243 mosquitoes (2209 larvae and 1034 adults) were captured and identified as Culiseta longiareolata, Culex hortensis, Anopheles maculipennis s.l., Culex theileri, Culex pipiens, Anopheles claviger, and Anopheles superpictus s.l. in decreasing order. Molecular screening revealed seven WNV-positive pools of Culiseta longiareolata and Culex hortensis in rural (n = 5) and urban areas (n = 2). Detection of WNV RNA indicates active circulation in mosquitoes and risk of transmission to humans and animals in Hamadan. These findings identify putative vectors in Hamadan, though vectors likely vary regionally in Iran. Further surveillance is needed to elucidate local WNV epidemiology and transmission dynamics fully. Nonetheless, this study provides important baseline evidence of WNV activity to guide prevention strategies in this area., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alireza Sazmand is editorial board member of Acta Tropica. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study was carried out to evaluate and compare the protective potential of two well-known antioxidants of herbal origin in a mouse model of acute DIC-induced nephro- and hepatotoxicity. The tested antioxidants included lemongrass essential oil (LO) and its predominant bioactive constituent citral (CIT). A third herbal product, silymarin (SILY), was used as a reference hepato-renal protective agent. DIC administration led to elevated serum urea and creatinine levels, and prompted oxidative stress along with histopathological changes in the kidney tissue. In parallel, DIC administration increased serum liver enzyme activity, decreased total protein, albumin, and globulin levels, and caused oxidative stress with associated histopathological changes in the liver tissue. Pre-treatment with LO or CIT mitigated DIC-induced alterations in all serum biochemical markers of kidney and liver health (except albumin). High-dose LO, like SILY, within kidney and liver tissues, counteracted DIC-induced oxidative stress and histomorphological alterations. By contrast, CIT failed to mitigate DIC-induced oxidative stress in the kidneys and provided only partial control of DIC-induced oxidative stress in the liver, resulting in less efficient preservation of kidney function and liver structural integrity than LO. Besides confirming the efficacy of SILY at protecting kidneys and liver against the toxicity of DIC in a rodent species different from the one tested so far (rat), this study demonstrated the preventive properties of LO and, to a lesser extent, of CIT against DIC-induced hepato-renal toxicity in mice, supporting their developmental potential as therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study examined the effects of fumonisins (FBs) and aflatoxin B1 (AFB1), alone or in combination, on the productivity and health of laying hens, as well as the transfer of aflatoxins (AFs) to chicken food products. The efficacy and safety of mycotoxin detoxifiers (bentonite and fumonisin esterase) to mitigate these effects were also assessed. Laying hens (400) were divided into 20 groups and fed a control, moderate (54.6 µg/kg feed) or high (546 µg/kg feed) AFB1 or FBs (7.9 mg/kg feed) added diets, either alone or in combination, with the mycotoxin detoxifiers added in selected diets. Productivity was evaluated by feed intake, egg weight, egg production, and feed conversion ratio whereas health was assessed by organ weights, blood biochemistry, and mortality. Aflatoxins residues in plasma, liver, muscle, and eggs were determined using UHPLC-MS/MS methods. A diet with AFB1 at a concentration of 546 µg/kg feed decreased egg production and various AFB1-contaminated diets increased serum uric acid levels and weights of liver, spleen, heart, and gizzard. Interactions between AFB1 and FBs significantly impacted spleen, heart, and gizzard weights as well as AFB1 residues in eggs. Maximum AFB1 residues of 0.64 µg/kg and aflatoxin M1 (below limits of quantification) were observed in liver, plasma, and eggs of layers fed diets with AFB1. The mycotoxin detoxifiers reduced effects of AFB1 and FBs on egg production, organ weights, blood biochemistry, and AFB1 residues in tissues. This study highlights the importance of mycotoxin detoxifiers as a mitigation strategy against mycotoxins in poultry production., (© 2024. The Author(s).)

This study aimed to investigate the clinical and molecular characteristics of Giardia duodenalis ( G. duodenalis ) infection and identify potential risk factors in children and teenagers with malignancies in Shiraz, southwestern Iran. A total of 200 fresh fecal samples were collected from children and adolescents suffering from 32 different cancer types at Amir, Nemazee, and Saadi hospitals affiliated with Shiraz University of Medical Sciences between October 2021 and May 2022. Direct microscopy using saline and iodine wet mount was conducted, and all fecal samples were rechecked by SSU -PCR. Subsequently, a specific fragment of the tpi gene was amplified on all samples for prevalence, sequencing, and assemblage identification. Our study found a 4% (8/200) prevalence of G. duodenalis using microscopy and PCR. The molecular findings were consistent with the microscopic results. All eight positive samples with SSU-rRNA gene were also detected as positive with tpi gene and were correctly sequenced. Among the examined cancer patients, two assemblages were identified: A [sub-assemblage AI (2/8, 25%) and sub-assemblage AII (3/8, 37.5%)] and B [sub-assemblage BIV (3/8, 37.5%)]. Notably, patients were more vulnerable to G. duodenalis infection after receiving at least 8 treatment episodes ( p < 0.05) and displaying gastrointestinal symptoms ( p > 0.05). The demographic characteristics of cancer patients with G. duodenalis infection and the statistical conclusions were separately detailed. The small sample size and low prevalence rate in this study hindered precise epidemiological conclusions. Nonetheless, the results suggest that G. duodenalis infection among cancer patients in Shiraz city originates from humans, without any specific animal groups (C-H) involved.

This cross-sectional herd-level study aimed to determine the occurrence of and risk factors for pathogens associated with neonatal calf diarrhea and bovine respiratory disease on Ontario dairy farms. From April to August 2022, a convenience sample of 100 dairy farms were visited once. A questionnaire covering farm biosecurity, calving and colostrum management, preweaning nutrition, and housing was administered on-farm. At each farm visit, approximately 5 calves between 2 and 35 d old were randomly selected for fecal sampling. Furthermore, approximately 5 calves between 21 to 122 d old were randomly selected for nasopharyngeal sampling. In total, 363 fecal samples (from 83 dairy farms) and 390 nasopharyngeal swab samples (from 80 dairy farms) were collected. Fecal samples were analyzed individually using a multiplex PCR to identify bacterial and parasitic enteric pathogens. Nasopharyngeal swabs were analyzed as one pooled sample per farm using bacterial culture and real-time PCR. The most common enteric pathogens detected at herd-level were Cryptosporidium parvum (67.4%) and Escherichia coli K99+ (13.2%). The most common respiratory pathogens detected at herd-level were Pasteurella multocida (62.5%), bovine coronavirus (42.5%), and Mycoplasma bovis (21.2%). Multivariable logistic models were built to explore associations between the most common pathogens and herd-level predictors selected from the questionnaire. Herd positivity for C. parvum was positively associated with having more than 61 preweaned calves per year and feeding mainly whole milk to calves. The presence of M. bovis was positively associated with herds that combined manual and automatic milk-feeding systems, and the presence of bovine coronavirus was positively associated with having more than 98 preweaned calves during the year. Univariable Poisson regression models were built to explore the association between the most common pathogens and preweaning calf mortality. Herds that were positive for C. parvum, M. bovis, or bovine coronavirus had a greater risk of preweaning calf mortality. These results provide insights for future research on pathogens associated with NCD and BRD and offer guidance for veterinarians and dairy farmers in implementing disease control measures in dairy calf herds., (© 2025, The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

The rapid geographic spread of chronic wasting disease (CWD) in white-tailed deer (WTD; Odocoileus virginianus ) increases the need for the development and validation of new detection tests. Real-time quaking-induced conversion (RT-QuIC) has emerged as a sensitive tool for CWD prion detection, but federal approval in the United States has been challenged by practical constraints on validation and uncertainty surrounding RT-QuIC robustness between laboratories. To evaluate the effect of inter-laboratory variation on CWD prion detection using RT-QuIC, we conducted a multi-institution comparison on a shared anonymized sample set. We hypothesized that RT-QuIC can accurately and reliably detect the prions that cause CWD in postmortem samples from medial retropharyngeal lymph node (RPLN) tissue despite variation in laboratory protocols. Laboratories from 6 U.S. states (Michigan, Minnesota, Missouri, New York, Pennsylvania, Wisconsin) were enlisted to compare the use of RT-QuIC in determining CWD prion status (positive or negative) among 50 anonymized RPLNs of known prion status. Our sample set included animals of 3 codon 96 WTD genotypes known to affect CWD progression and detection (G96G, G96S, S96S). All 6 laboratories successfully identified the true disease status consistently for all 3 tested codon 96 genotypes. Our results indicate that RT-QuIC is a suitable test for the detection of CWD prions in RPLN tissues in several genotypes of WTD., Competing Interests: Declaration of conflicting interestsMarc D. Schwabenlander and Peter A. Larsen are co-founders and stock owners, and Gage R. Rowden is a stock owner, of Priogen, a diagnostic company specializing in the ultra-sensitive detection of pathogenic proteins associated with prion and protein-misfolding diseases. The University of Minnesota licensed patent applications to Priogen. None of the other authors declared a competing interest.

For a sustainable ecology, slaughterhouse sludge must be managed effectively in preview of the parasitic or coliforms' spill over to the community. In order to determine the effectiveness of a customized biological decomposer solution in lowering the parasitic eggs and coliform bacteria, three composting units (Unit 1, Unit 2, and Unit 3) were treated with its different amounts. Over a period of 60 days, pH, temperature, humidity, number of the parasitic eggs per gram (EPG) of faecal material, viability of eggs, and coliform counts were evaluated. By the fifth day of the composting process, pH had significantly (P < 0.05) increased across all the treatments and then decreased gradually. Also on the 5th day, all three units entered the thermophilic range (> 45 °C), which persisted for 20 days for Unit 3 and 15 days for Units 1 and 2. Humidity levels initially increased significantly (P < 0.05) in all three units (Unit 3 = 71%, Unit 2 = 64%, and Unit 1 = 55%) but then gradually decreased. On day 5, no decrease in EPG in Unit 1 was detected; however, a non-significant (P > 0.05) 12.5% decline in EPG in Unit 2 and Unit 3 was recorded. After that, a significant (P < 0.05) reduction in EPG was observed in all the three treatments until day 25. By day 5, decreased egg viability was significantly (P < 0.05) recorded in Unit 3 (21.43%); in Unit 1 and Unit 2, the decrease was 6.25% and 14.29%, respectively. Additionally, all units showed a significant (P < 0.05) decrease in total coliforms, meeting minimum allowable limit in Unit 2 and 3 on day 10 and on day 15 in Unit 1. The most substantial reduction in faecal coliforms was observed in Unit 3 (from 2.6 log₁₀ to 1.3 log₁₀), followed by Unit 2 (from 2.6 log₁₀ to 1.5 log₁₀), and then Unit 1 (from 2.6 log₁₀ to 1.6 log₁₀). The results of this study support recommendation of advanced composting techniques to eradicate or reduce the abundance of pathogens (parasites and coliforms). Hence, we endorse the value of careful composting procedures in environment-friendly abattoir waste management and agricultural practices through creating pathogen-free, eco-friendly fertilizers to promote both agricultural and environmental sustainability., (© 2024. The Author(s).)

CRISPR/Cas9 system has been successfully implemented in animals and plants is a second-generation genome editing tool. We are able to optimize a Cas9 system to edited Ntab06050 and Ntab0857410 genes in HD and K326 tobacco cultivars respectively. The gene Ntab06050 is related to lignin synthesis while the gene Ntab0857410 belongs to pectin synthesis by utilizing Agrobacterium-mediated leaf disc method. We have constructed total eight different constructs for the lignin related gene family CCoAMT, out of which three constructs have been selected from Ntab0184090, two constructs from Ntab0392460 while one construct from each Ntab0540120, Ntab0857410 and Ntab0135940 gene. To study the Cas9 system in pectin related genes, total five constructs have been utilized under Cas9 system and multiple target sites were selected by identifying PAM sequences. Out of which three constructs were targeted from NtabGAE1and NtabGAE6 homologous while two were targeted from NtabGAUT4 homologous. Where as, UDP-D-glucuronate 4-epimerase gene family is a Golgi localized, might have a role in the interconvertion of UDP-D-GlcA and UDP-D-GalA in pectin synthesis. We have succeeded in the mutation of pectin related NtabGAUT4 and lignin related NtabCCoAMT genes with 6.2% and 9.4% mutation frequency., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The anti-inflammatory/immunomodulatory effects of Teucrium montanum L. (TM), a plant distributed in the Mediterranean region, have been insufficiently examined. The effects of the TM ethanol extract were tested in a rat collagen-induced arthritis (CIA) model of rheumatoid arthritis. LC-MS was used for the phytochemical analysis of the TM extract. Dark Agouti rats were immunized with bovine type II collagen (CII) in incomplete Freund's adjuvant for CIA, and treated with 100 or 200 mg/kg of TM extract daily via oral administration. Clinical and histopathological evaluations and a flow cytometric analysis of the phenotypic and functional characteristics of splenocytes and draining lymph node cells were performed. The cytokines in the paw tissue culture supernatants and anti-CII antibodies in serum were determined by ELISA. The TM extract, with the dominant components verbascoside and luteolin 7- O -rutinoside, reduced the arthritic score and ankle joint inflammation in CIA rats, promoted the antioxidant profile in serum, and lowered pro-inflammatory TNF-α, IL-6 and IL-1β production. It suppressed the activation status of CD11b+ cells by lowering CD86, MHCII and TLR-4 expression, and promoted the Th17/T regulatory cell (Tregs) balance towards Tregs. A lower frequency of B cells was accompanied by a lower level of anti-CII antibodies in treated rats. These findings imply the favorable effect of TM extract on the clinical presentation of CIA, suggesting its anti-inflammatory/immunomodulatory action and potential therapeutic effect.

Chronic osteomyelitis presents significant treatment challenges, necessitating an efficient system for infection elimination and bone repair. This study developed a natural hydrogel scaffold using silk fibroin (SF) and chitosan thiourea (CST), incorporating vancomycin (VC) and quercetin (QC) loaded PLGA nanoparticles (NPs) for dual-purpose treatment. SF/CST hydrogel scaffolds exhibited homogeneous porosity and smaller interconnected pore size than pure SF and pure CST hydrogel scaffolds. Optimal PLGA/QC NPs measured 206 nm in size, displayed spherical morphology, had uniform distribution, and achieved 87 % QC loading. The release study showed sustained long-term release of VC and QC from the hydrogel scaffolds for over 20 days. Biocompatibility tests indicated that hydrogel scaffolds promoted osteoblast adhesion without cytotoxicity, with QC-containing scaffolds enhancing osteoblast growth. Antibacterial tests confirmed retained VC activity against methicillin-resistant Staphylococcus aureus (MRSA) in SF/CST. An experimental study assessed the efficacy of the hydrogel scaffolds in a MRSA-infected rat osteomyelitis model. Radiographic scores demonstrated a significant reduction for SF/CST-VC-PLGA/QC NPs compared to control, indicating reduced osteomyelitis effects. Macroscopic evaluations showed notable reductions in gross pathological effects for VC-containing groups. Histopathological assessments revealed significantly lower osteomyelitis scores and higher healing scores in the SF/CST-VC-PLGA/QC NPs, with reduced inflammatory cell infiltration and more organized connective tissue formation. In conclusion, SF/CST-VC-PLGA/QC NPs is an effective dual drug delivery system for osteomyelitis treatment, demonstrating significant antibacterial activity, enhanced bone regeneration, and reduced infection rate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is the most common cardiomyopathy in cats. The diagnosis can be difficult, requiring advanced echocardiographic skills. Additionally, circulating biomarkers (N-terminal pro-B type natriuretic peptide and cardiac troponin I) have several limitations when used for HCM screening. In previous work, we identified interleukin 18 (IL-18), insulin-like growth factor binding protein 2 (IGFBP-2), brain-type glycogen phosphorylase B (PYGB), and WNT Family Member 5 A (WNT5A) as myocardial genes that show significant differential expression between cats with HCM and healthy cats. The products of these genes are released into the circulation, and we hypothesized that IL-18, IGFBP-2, PYGB, and WNT5A serum RNA and protein concentrations differ between healthy cats, cats with subclinical HCM, and those with HCM and congestive heart failure (HCM + CHF). Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) and enzyme-linked immunosorbent assay (ELISA) were applied to evaluate gene and protein expression, respectively, in the serum of eight healthy controls, eight cats with subclinical HCM, and six cats with HCM + CHF. Serum IGFBP-2 RNA concentrations were significantly different among groups and were highest in cats with subclinical HCM. Compared to healthy controls, serum IL-18 and WNT5A gene expression were significantly higher in cats with HCM + CHF, and WNT5A was higher in cats with subclinical HCM. No differences were observed for PYGB. These results indicate that further investigation via large scale clinical studies for IGFBP-2, WNT5A, and IL-18 may be valuable in diagnosing and staging feline HCM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2024. Published by Elsevier Ltd. All rights reserved.)

Purpose: To describe the clinical and histopathologic features of pediatric eyelid cutaneous horns., Design: Retrospective observational case series and review of literature., Subjects: Five pediatric patients with eyelid cutaneous horns Methods: Five cases with eyelid cutaneous horns were retrospectively identified using departmental databases. Patients' records were analyzed for demographic data, clinical appearance, histologic findings, and clinical course. An excisional biopsy of the lesion was performed in 3 patients. The remaining 2 patients were managed conservatively., Main Outcome Measures: Clinical outcome and histopathologic evaluation with emphasis on excluding malignancy., Results: All 5 cutaneous horn lesions resolved surgically or conservatively. The average age at presentation was 6.6 years (range 5-11 years). Clinically, 4 lesions were preceded by a hordeolum or chalazion and all excised lesions had benign features on histologic examination. Mitotic figures or atypia were not observed. None of the patients developed recurrence during the follow-up period ranging from 1 to 96 months. Five previous reports of five cases were found on review of the literature. Our case series doubles this number to support the benign nature of these lesions in children., Conclusions: Pediatric eyelid cutaneous horns are closely related to eyelid margin inflammatory disease and appear to follow a benign course. This contrasts with the adult population where cutaneous horns are frequently associated with neoplasia., (Copyright © 2024. Published by Elsevier Inc.)

The cytokine tumor necrosis factor (TNF) plays important roles in limiting infection but is also linked to sepsis. The mechanisms underlying these paradoxical roles are unclear. Here, we show that TNF limits the antimicrobial activity of Paneth cells (PCs), causing bacterial translocation from the gut to various organs. This TNF-induced lethality does not occur in mice with a PC-specific deletion in the TNF receptor, P55. In PCs, TNF stimulates the IFN pathway and ablates the steady-state unfolded protein response (UPR), effects not observed in mice lacking P55 or IFNAR1. TNF triggers the transcriptional downregulation of IRE1 key genes Ern1 and Ern2, which are key mediators of the UPR. This UPR deficiency causes a significant reduction in antimicrobial peptide production and PC antimicrobial activity, causing bacterial translocation to organs and subsequent polymicrobial sepsis, organ failure, and death. This study highlights the roles of PCs in bacterial control and therapeutic targets for sepsis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)