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The occurrence of esophagitis and ingluvitis caused by Salmonella Typhimurium in passerines seized from illegal wildlife trafficking is described. This illegal activity causes stress and leads to lowered immunity in the birds. Additionally, inadequate hygiene conditions predispose the birds to diseases such as salmonellosis. Few studies report the occurrence of Salmonella-induced lesions in the esophagus and crop of passerines; therefore, this study aimed to describe the disease in birds of the genus Sporophila, as well as to investigate the presence of the bacterium in the environment and determine the antimicrobial resistance profile of the isolated bacteria. Three birds of the genus Sporophila were necropsied. In the esophagus and crop, yellowish plaques corresponding to necrosis with bacterial aggregates were observed. Salmonella spp. was isolated from these lesions, with genus confirmation via MALDI-TOF mass spectrometry. Environmental samples were collected from the enclosures and cages where the animals were quarantined, and the same bacterium was isolated. In two birds, the serotype S. Typhimurium was identified. Antibiograms performed on the strains from the birds and the environment revealed resistance to antibiotics in the classes of penicillins, sulfonamides, aminoglycosides, monobactams, tetracyclines, and first and third-generation cephalosporins. To the authors’ knowledge, this is the first report of this agent causing death in Sporophila due to esophagitis and ingluvitis. It is also the first report of salmonellosis in three species of passerines in Brazil. The study underscores the importance of understanding the pathogens circulating in wild animals, especially within the context of One Health. Full article

Background/Objectives: Defensins are important components of the innate plant immune system, exhibiting antimicrobial activity against phytopathogens, as well as against fungi pathogenic to humans. Along with antifungal activity, plant defensins are also capable of influencing various immune processes, but not much is known about these effects. In this study, we investigated the immunomodulatory effects of the tobacco defensin NaD1, which possesses a pronounced antifungal activity. Methods and Results: We showed that NaD1 could penetrate the Caco-2 polarized monolayer. Using a multiplex assay with a panel of 48 cytokines, chemokines and growth factors, we demonstrated that NaD1 at a concentration of 2 μM had immunomodulatory effects on human dendritic cells and blood monocytes, mainly inhibiting the production of various immune factors. Using the sandwich ELISA method, we demonstrated that NaD1 at the same concentration had a pronounced immunomodulatory effect on unstimulated THP-1-derived macrophages and those stimulated by bacterial LPS or fungal zymosan. NaD1 had a dual effect and induced the production of both pro-inflammatory cytokine IL-1β as well as anti-inflammatory IL-10 on resting and pro-inflammatory THP-1-derived macrophages. We also found that the immunomodulatory effects of the tobacco defensin NaD1 and the pea defensin Psd1 differed from each other, indicating nonuniformity in the modes of action of plant defensins. Conclusions: Thus, our data demonstrated that the tobacco defensin NaD1 exhibits different immunomodulatory effects on various immune cells. We hypothesized that influence on human immune system along with antifungal activity, could determine the effectiveness of this peptide under infection in vivo. Full article

Long COVID or Post-Acute Sequelae of SARS-CoV-2 infection (PASC) is a condition characterized by numerous lingering symptoms that persist for weeks to months following the viral illness. While treatment for PASC is still evolving, several therapeutic approaches beyond traditional antiviral therapies are being investigated, such as immune-modulating agents, anti-inflammatory drugs, and various supportive interventions focusing at alleviating symptoms and enhancing recovery. We aimed to summarize the breadth of available evidence, identify knowledge gaps, and highlight promising non-antiviral therapies for Long COVID/PASC. We followed the framework of a scoping methodology by mapping existing evidence from a range of studies, including randomized clinical trials, observational research, and case series. Treatments evaluated include metformin, low-dose naltrexone (LDN), dexamethasone, statins, omega-3 fatty acids, L-arginine, and emerging therapies like intravenous immunoglobulin (IVIg) and therapeutic apheresis. Early findings suggest that metformin has the strongest clinical evidence, particularly from large phase 3 trials, while LDN and dexamethasone show potential based on observational studies. However, many treatments lack robust, large-scale trials. This review emphasizes the need for further research to confirm the efficacy of these treatments and guide clinical practice for Long COVID management. Full article

Background: Bacterial infections are a major challenge in food processing and public health, and there is an urgent need to develop novel antimicrobial agents. Objectives: The purpose of this study is to investigate the potential mechanism and key components of Pinctada martensii antimicrobial proteins (Pm-Aps) to provide a theoretical basis for the development of novel antimicrobial agents. Methods: The researchers used Vibrio parahaemolyticus (VP) to stimulate Pinctada martensii, extracted the antimicrobial proteins, and analyzed their antimicrobial activities, potential mechanisms of action, and key components using proteomics. Results: The results showed that the antimicrobial activity of Pm-Aps, with broad-spectrum antimicrobial effects, was significantly enhanced after VP stimulation. This was associated with the upregulation of LAAO, CHDH, TLR2, ATG16L1, BAK, CLCA4, and CASP8 and the downregulation of MCM3, MCM5, DTYMK, PLK1, FBXO6, LPCAT3, GST, LAMTOR5, CYP17A, CTSA, and RRM1. It is hypothesized that these proteins may inhibit bacterial growth and multiplication by activating immune-related signaling pathways, inhibiting DNA replication and repair, and inducing apoptosis and autophagy. Furthermore, it was found that LAAO may be a key component of the antimicrobial action of Pm-Aps, killing bacteria by catalyzing the oxidation of amino acids to produce hydrogen peroxide (H₂O₂). Conclusions: These results strongly suggest that Pm-Aps is an effective antimicrobial protein, and it is expected that new LAAO can be obtained from Pm-Aps. Full article

Cutaneous leishmaniasis (CL), caused by Leishmania braziliensis, is closely associated with a severe form of the disease, indicated by a positive Leishmania skin test (LST) that assesses and reflects the presence of immune T cells specific to Leishmania antigens. In this study, we compare the clinical, immunologic, and histopathologic features between Leishmania skin test-positive (LST+) and Leishmania skin test-negative (LST-) in CL. Compared to LST+ patients, LST- patients had larger lesions and had been sicker for longer, presented with more instances of therapeutic failure with meglumine antimonate, (MA) and the healing times were higher than LST+. While granulomas were less frequent and the parasite load was higher in LST-, there were more CD8+ T cells and an enhanced production of Granzyme B in the supernatants of biopsies from LST- subjects. This study shows that in LST-, an impairment in Th1 immune response is associated with a high parasite burden, and the pathology is mediated by CD8+ T cells and the enhanced production of Granzyme B. The abnormalities in the immunologic response in LST- patients lead to a more severe disease with a high rate of failure to therapy. Full article

To evaluate the impact of different roughages on the intestinal microbiota of yak calves, we fed them oat hay in substitution of alfalfa hay, in addition to milk replacer and starter powder. Twenty-one 45-day-old male yak calves were selected and randomly assigned to three groups: the milk replacer + starter + alfalfa hay group (AH), the milk replacer + starter + oat hay group (OH), and the milk replacer + starter + mixed hay group (AO), in which the alfalfa hay and oat hay were administered in a 1:1 ratio. All calves in the three groups were fed the same milk replacer and an equivalent amount of dry matter. The formal experiment commenced after a 21-day pre-test period and lasted for 120 days. Following the experiment, the contents of the jejunum and colon were collected to investigate the intestinal microbiota and metabolites using 16S rRNA sequencing and LC-MS metabolomics. The result showed that the AO group had greater final body weights overall than the AH group and OH group (p < 0.05). The AH group and OH group had considerably greater feed-to-gain ratios than the AO group (p < 0.05). At the phylum level, the OH group exhibited an increased relative abundance of Bacteroidota and Spirochaetota in the jejunum (p < 0.05). The relative abundance of Actinobacteriota in the colon was increased in the AO group (p < 0.05). At the genus level, the AO group exhibited a decreased abundance of Clostridium sensu_stricto_1 (p < 0.05), and the OH group showed an increased abundance UCG-005 and Alistipes in the jejunum. There were many differential metabolites in the OH group and AO group compared to the AH group, and the different metabolites of the OH group were associated with the metabolic pathways of the nervous system, sensory system, amino acid metabolism, and lipid metabolism in the jejunum and with lipid metabolism, amino acid metabolism, and the nervous system in the colon. In the AO group, these metabolites were associated with the digestive system and the translation and metabolism of cofactors in the jejunum and with the metabolism of cofactors and vitamins in the colon. In summary, it is feasible to replace alfalfa hay with oat hay based on milk replacer and starter. The combination of the two forages enhanced nutrient absorption, improved immune function, maintained the internal homeostasis of yak calves, and was more beneficial to their growth and development. Full article

Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell–ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting. Full article

The SNP variation in sockeye salmon across the Asian part of its range was studied in 23 samples from 16 lake–river systems of the West Pacific Coast to improve understanding of genetic adaptation in response to spawning watersheds conditions. Identification of candidate SNPs and environmental factors that can contribute to local adaptations in sockeye salmon populations was carried out using redundancy analysis (RDA), a powerful tool for landscape genetics proven to be effective in genotype–environment association studies. Climatic and hydrographic indices (7 indices in total), reflecting abiotic conditions in freshwater habitats of sockeye salmon and characterizing the temperature regime in the river basin, its variability during the year, the amount of precipitation, as well as the height of the maximum tide in the estuary, were used as predictor factors. Among the 45 analyzed SNPs, several loci (ALDOB-135, HGFA, and RAG3-93) correlated with predictors gradients along the northwest Pacific coast were identified. The putative candidate loci localized in genes involved in the immune and inflammatory responses, as well as genes encoding temperature-sensitive enzymes and some hormones regulating ion homeostasis in fish during the anadromous migration and smoltification, were potentially associated with environmental conditions in natal rivers. The findings could have implications for aquaculture, conservation, and resource management in the context of global climate change. Full article

Highly pathogenic H5N1 (HP H5N1) influenza A virus (IAV) has been detected annually in North American ducks since its introduction during 2021, but it is unknown if this virus will follow the same seasonal and geographic patterns that have been observed with low-pathogenicity (LP) IAV in this reservoir. We monitored blue-winged teal in the Mississippi flyway prior to the detection of HP H5N1 and during two post-introduction migration cycles from spring 2022 to spring 2024, testing birds for infection and antibodies to IAV nucleoprotein (NP), hemagglutinin subtype H5, and neuraminidase subtype N1. Antigens representing clade 2.3.4.4b HP H5 and LP North American H5 were used for hemagglutination inhibition (HI) and virus neutralization (VN) tests for H5 antibodies. Virologic results were consistent with historic seasonal and geographic patterns reported for LP IAV with peak infections occurring in pre-migration staging areas in Minnesota during fall 2022. However, the high prevalence of the H5 subtype was exceptional compared to historic prevalence estimates at this same site and for the Mississippi flyway. HP H5N1 was detected on wintering areas in Louisiana and Texas during the fall of that same year and this was followed by an increase in estimated antibody prevalence to NP, H5, and N1 with no HP H5N1 detections during the wintering or spring migration periods of 2022/2023. HP H5N1 was not detected in Minnesota during fall 2023 but was detected from a single bird in Louisiana. However, a similar increase in antibody prevalence was observed during the winter and spring period of 2023 and 2024. Over the two migration cycles, there was a temporal shift in observed prevalence and relative titers against the H5 antigens with a higher proportion of ducks testing positive to the 2.3.4.4b H5 antigen and higher relative titer to that antigen compared to the representative LP North American H5 antigen. The seasonal and geographic patterns observed appear to be driven by population immunity during the migration cycle. Results support an initial high infection rate of HP H5N1 in blue-winged teal in the Mississippi flyway followed by a high prevalence of antibodies to NP, H5, and N1. Although prevalence was much reduced in the second migration cycle following introduction, it is not known if this pattern will persist in the longer term or affect historic patterns of subtype diversity in this reservoir. Full article

Purpose: Colorectal cancer (CRC) is a common malignancy with a low survival rate as well as a low response rate to immunotherapy. This study aims to develop a risk model based on tertiary lymphoid structure (TLS)-associated gene signatures to enhance predictions of prognosis and immunotherapy response. Methods: TLS-associated gene data were obtained from TCGA-CRC and GEO cohorts. A comprehensive analysis using univariate Cox regression identified TLS-associated genes with significant prognostic implications. Subsequently, multiple algorithms were employed to select the most influential genes, and a stepwise Cox regression model was constructed. The model’s predictive performance was validated using independent datasets (GSE39582, GSE17536, and GSE38832). To further investigate the immune microenvironment, immune cell infiltration in high-risk (HRG) and low-risk (LRG) groups was assessed using the CIBERSORT and ssGSEA algorithms. Additionally, we evaluated the model’s potential to predict immune checkpoint blockade therapy response using data from The Cancer Imaging Archive, the TIDE algorithm, and external immunotherapy cohorts (GSE35640, GSE78200, and PRJEB23709). Immunohistochemistry (IHC) was employed to characterize TLS presence and CCL2 gene expression. Results: A three-gene (CCL2, PDCD1, and ICOS) TLS-associated model was identified as strongly associated with prognosis and demonstrated predictive power for CRC patient outcomes and immunotherapy efficacy. Notably, patients in the low-risk group (LRG) had a higher overall survival rate as well as a higher re-response rate to immunotherapy compared to the high-risk group (HRG). Finally, IHC results confirmed significantly elevated CCL2 expression in the TLS regions. Conclusions: The multi-algorithm-integrated model demonstrated robust performance in predicting patient prognosis and immunotherapy response, offering a novel perspective for assessing immunotherapy efficacy. CCL2 may function as a TLS modulator and holds potential as a therapeutic target in CRC. Full article

The diet of Apis mellifera L. is a crucial factor for managing its colonies particularly during dearth periods. Numerous diets have been developed; however, their global implementation faces challenges due to diverse climatic conditions and some other factors. To address this issue, three previously evaluated diets (selected from seven) were tested to assess their effects on A. mellifera using key health biomarkers (immune function, stress response) and performance metrics (foraging activity, honey quality, and social interactions). The experiment was conducted using 12 colonies, including three replications, in The Islamia University of Bahawalpur, Pakistan, from June to September 2023. The results revealed that all the tested parameters were significantly affected by diets. Highest phenol-oxidase activity was recorded in T1 (28.7 U/mg). Heat shock protein (HSP) bands showed that T1 had the fewest (Hsp70), while T0 had more bands (Hsp40, Hsp60, and Hsp70), indicating stress differences. In foraging activity, average number of outgoing bees were highest in T1 (81.8) and lowest in T0 (31.2) and similar trend was followed for returning bees, i.e., T1 (81.8) and T0 (31.2). For pollen-carrying bees, the highest bees were counted in T1 (34.9), and the lowest in T0 (4.10). Honey quality was also significantly affected by diets, pH was highest in T1 (3.85), while moisture was highest in T0 (19.44%). Diastase activity, ash content, and electrical conductivity were best in T1 (13.74 units/g, 0.17%, 0.94 mS/cm, respectively). Mineral content was highest in T1 (406.54 mg/kg), and fructose content also peaked in T1 (396.21 mg/kg). Antioxidant contents, total phenolic content, flavonoid content, and ORAC value were highest in T1 (60.50 mg GAE/100 g, 44.41 mg QE/100 g, 10,237.30 µmol TE/g), while T0 consistently showed the lowest values across all parameters. In social interaction experiments, trophallaxis events were most frequent in T1 (7.38), and T1 also exhibited the longest trophallaxis time (5.51 s). The number of bees per trophallaxis event and antennation frequency followed a similar trend, with the highest recorded in T1 (5.16 bees/event, 10.1 antennation frequency) and the lowest in T0 (2.94 bees/event, 4.18 antennation frequency). Therefore, diet-1 (Watermelon juice 20 mL + Fenugreek powder 2 g + Chickpea flour 20 g + Lupin flour 20 g + Mung bean flour 20 g + Yeast 10 g + Powdered sugar 40 g + vegetable oil 10 mL) is recommended as a suitable substitute for managing A. mellifera colonies during dearth periods. Full article

Background/Objectives: The hepatitis A virus (HAV) cellular receptor 1 (HAVCR1) is a type I integral membrane glycoprotein discovered in monkeys and humans as a HAV receptor. HAVCR1 contains an N-terminal immunoglobulin-like variable domain (IgV) followed by a mucin-like domain (Muc), a transmembrane domain, and a cytoplasmic tail with a canonical tyrosine kinase phosphorylation site. The IgV binds phosphatidylserine on apoptotic cells, extracellular vesicles, and enveloped viruses. Insertions/deletions at position 156 (156ins/del) of the Muc were associated in humans with susceptibility to atopic, autoimmune, and infectious diseases. However, the molecular basis for the differential function of the HAVCR1 variants is not understood. Methods: We used mutagenesis, apoptotic cell binding, and signal transduction analyses to study the role of the 156ins/del in the function of HAVCR1. Results: We found that the HAVCR1 variant without insertions at position 156 (156delPMTTTV, or short-HAVCR1) bound more apoptotic cells than that containing a six amino acid insertion (156insPMTTTV, or long-HAVCR1). Furthermore, short-HAVCR1 induced stronger cell signaling and phagocytosis than long-HAVCR1. Conclusions: Our data indicated that the 156ins/del determine how the IgV is presented at the cell surface and modulate HAVCR1 binding, signaling, and phagocytosis, suggesting that variant-specific targeting could be used as therapeutic interventions to treat immune and infectious diseases. Full article

Soil collembolans have been regarded as the effective bioindicator of environmental changes. However, the physiological mechanisms through which collembolans respond to agricultural activities are largely unknown. Given the plasticity and sensitivity to environmental changes, even subtle responses can be quantified via transcriptomics. Therefore, the relevant in situ soil ecosystem and numerically dominant collembolan species Entomobrya proxima Folsom was selected to explore the dynamic responses to fertilizer type and concentration using transcriptome sequencing over three periods (6 h, 24 h and 10 d). The results showed that exposure duration caused significant alterations in gene expression profiles. At day 10 after exposure, gene expression patterns differed remarkably between the two fertilizer types and the control. Relative to organic fertilizer, the number of DEGs was increased by 114.31% under inorganic fertilizer, which declined with increasing inorganic fertilizer concentrations. Functional enrichment analysis was indicative of enhanced fatty acid and carbohydrate metabolism and reduced disease occurrence by organic fertilizer; however, an inhibited lipid synthesis process promoted susceptibility to infection, triggered oxidative stress, etc. by inorganic fertilizer. Overall, fertilizer addition changed the transcriptional pattern of the collembolan, potentially causing shifts in pathways related to metabolism, immunity, etc. In comparison to inorganic fertilizer, organic fertilizer impacted less on the gene expression patterns, implying that organic fertilizer application may be more beneficial to soil animal health. Full article

Gene therapies hold significant promise for treating previously incurable diseases. A number of gene therapies have already been approved for clinical use. Currently, gene therapies are mostly limited to the use of adeno-associated viruses and the herpes virus. Viral vectors, particularly those derived from human viruses, play a critical role in this therapeutic approach due to their ability to efficiently deliver genetic material to target cells. Despite their advantages, such as stable gene expression and efficient transduction, viral vectors face numerous limitations that hinder their broad application. These limitations include small cloning capacities, immune and inflammatory responses, and risks of insertional mutagenesis. This review explores the current landscape of viral vectors used in gene therapy, discussing the different types of DNA- and RNA-based viral vectors, their characteristics, limitations, and current medical and potential clinical applications. The review also highlights strategies to overcome existing challenges, including optimizing vector design, improving safety profiles, and enhancing transgene expression both using molecular techniques and nanotechnologies, as well as by approved drug formulations. Full article

The objective of this study was to investigate the differences in the energy metabolites, immunity, antioxidant capacity, and rumen microbiota of ewes with different numbers of fetuses. Thirty healthy ewes were selected and divided into single- (SL, n = 10), twin- (TL, n = 10), and triplet-fetal (PL, n = 10) ewes according to the number of fetuses. Sampling was carried out on days 21 (Q21) and 7 (Q7) before lambing. The results show no differences (p > 0.05) in the DMI and BW of ewes with different numbers of fetuses, and the body condition score (BCS) of PL ewes was lower (p < 0.05) than that of SL ewes. The concentrations of β-hydroxybutyric acid (BHBA), non-esterified fatty acids (NEFA), interleukin-2 (IL-2), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) in the PL ewes were higher (p < 0.05), while the glucose (Glu), triglyceride (TG), total cholesterol (TC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) values were lower (p < 0.05) than those of the SL ewes. ANOSIM analysis showed that the rumen bacterial structure of the SL, TL, and PL ewes was different on days Q21 and Q7. The relative abundance of Firmicutes and Bacteroidota in the rumen was affected (p < 0.05) by the number of fetuses: the relative abundance of Firmicutes (Ruminococcus, Butyrivibrio, Christensenellaceae_R-7_group, Lachnospiraceae_AC2044_group, Lachnospiraceae_XPB1014_group, and Anaeroplasma) was higher (p < 0.05), while that of Bacteroidota (Prevotella, Prevotellaceae_UCG-003, and Prevotellaceae_UCG-001) was lower (p < 0.05) in the SL ewes than in the PL ewes. In summary, the rumen microbial structure and energy metabolites of ewes in late gestation with different numbers of fetuses were different. Triplet-fetal ewes were characterized by lower BCS and antioxidant capacity and were prone to the triggering of inflammatory responses. Full article