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Background: Recent advancements in advanced non‐small‐cell lung cancer (NSCLC) treatment have significantly improved primary therapy outcomes owing to the emergence of various molecular targeted therapies and immune checkpoint inhibitors (ICIs). However, for Kirsten rat sarcoma viral antigen (KRAS) mutations, molecular targeted drugs, such as sotorasib, are not applicable as first‐line treatments, and the optimal primary treatment remains unclear. Therefore, we aimed to investigate the efficacy of ICI combination therapy as first‐line treatment for KRAS‐mutant NSCLC. Methods: We conducted a systematic search for phase 3 randomized controlled trials (RCTs) that presented data on KRAS mutation status in advanced NSCLC. The primary endpoints were progression‐free survival (PFS) and overall survival (OS). A random‐effects network meta‐analysis was conducted to perform direct and indirect comparisons among treatment groups. Results: Six RCTs were eligible for inclusion. In the network meta‐analysis for KRAS‐mutant NSCLC, Chemo + bevacizumab (Bev) + ICI was associated with improved PFS (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.22–0.64), followed by Chemo + ICI + ICI (HR 0.66, 95% CI 0.47–0.93) and Chemo + ICI (HR 0.67, 95% CI 0.49–0.91). The most beneficial effect on OS was observed with Chemo + Bev + ICI (HR 0.50, 95% CI 0.34–0.73), followed by Chemo + ICI + ICI (HR 0.64, 95% CI 0.48–0.87) and Chemo + ICI (HR 0.72, 95% CI 0.56–0.92). Regarding OS in wild‐type KRAS, ICI + ICI (HR 0.73, 95% CI 0.50–1.07) produced the most favorable effects, followed by Chemo + ICI (HR 0.79, 95% CI 0.63–0.99). Conclusion: The efficacy of Chemo + Bev + ICI is potentially high for improving PFS and OS in KRAS‐mutant NSCLC. In advanced NSCLC, the presence or absence of KRAS mutations may need to be considered when administering first‐line treatment. [ABSTRACT FROM AUTHOR]

Background: It is doubtful that any of the treatments proposed for feline leukaemia virus (FeLV) infection are effective, despite the entity being described 60 years ago. Methods: Eighteen pet cats with progressive FeLV infections were recruited in Australia. One or more antiviral drugs were trialled in 16 cats, while two FeLV‐infected cats were not handleable and served as untreated controls. Six cats were administered RetroMAD1™ only (0.5 mg/kg orally twice daily), a commercially available recombinant chimeric protein with proposed antiretroviral activity. Three cats were administered the integrase inhibitor raltegravir only (10–15 mg/kg orally twice daily), a drug used as a component of highly effective antiretroviral therapy for human immunodeficiency virus (HIV‐1) infection. Three cats were administered RetroMAD1™ and raltegravir concurrently, and four cats were administered raltegravir and the reverse transcriptase inhibitor zidovudine (AZT, 5 mg/kg orally twice daily) concurrently. FeLV RNA and p27 antigen loads were measured at two timepoints (T1‐2 months and T3‐5 months) during therapy and compared to baseline (pretreatment) levels, to assess the response to therapy using linear modelling. The median survival time (MST) of the cats from commencement of FeLV treatment to death was also determined and compared between treatments. Results: The MST for the 16 FeLV‐positive cats which received antiviral therapy was 634 days, while the MST from FeLV diagnosis to death for the two untreated control cats was 780 days. In cats treated with RetroMAD1™, FeLV viral load decreased from T0 to T1‐2 months (median viral load reduced from 1339 × 106 to 705 × 106 copies/mL plasma; P = 0.012), but MST was reduced compared to cats not given RetroMAD1™ (426 days vs 1006 days; P = 0.049). Cats treated with raltegravir and AZT had no significant changes in FeLV viral load over time, but p27 antigen load was decreased from T0 to T3‐5 months in cats treated with raltegravir (median p27 antigen level reduced from 50.2% to 42.7%; P = 0.005). All other results were not significantly affected by the treatment provided. Importantly, statistically significant and substantial associations were found between age at FeLV diagnosis and survival time (P = 0.046, R2 = 18.6) and between FeLV viral load at T0 and survival time (P = 0.004, R2 = 44.4). Younger cats, and cats with higher levels of pretreatment FeLV RNA, had reduced survival times. Cats treated with RetroMAD1™ were typically younger (median age 2.0 vs 8.0 years), likely explaining the observed reduction in MST. A significant association was found between FeLV viral load and p27 antigen load at T0 (P = 0.015, R2 = 32.9). Conclusions: Results from this small case series do not provide convincing support for the use of RetroMAD1™, raltegravir or AZT, alone or in combination, for the treatment of cats progressively infected with FeLV. The changes observed were biologically insignificant. Age and FeLV viral load at diagnosis are useful prognostic markers, and p27 antigen concentration can be used to predict viral load. Larger field trials should be performed examining antiretroviral therapy in FeLV‐positive cats with progressive infections, preferably using three or more drugs from at least two classes, as is standard with human antiretroviral therapy. Future studies would be easier in countries with a higher prevalence of FeLV infections than Australia. [ABSTRACT FROM AUTHOR]

Summary The human genome harbors hundreds of thousands of integrations of ancient retroviruses, amassed over millions of years of evolution. To reduce further amplification in the genome, the host prevents transcription of these now endogenous retroviruses (ERVs) through epigenetic repression and, with evolutionary time, ERVs are incapacitated by accumulating mutations and deletions. However, several members of recently endogenized ERV groups still retain the capacity to produce viral RNA, retroviral proteins, and higher order structures, including virions. The retention of viral characteristics, combined with the reversible nature of epigenetic repression, particularly as seen in cancer, allow for immunologically unanticipated ERV expression, perceived by the adaptive immune system as a genuine retroviral infection, to which it has to respond. Accordingly, antibodies reactive with ERV antigens have been detected in diverse disorders and, occasionally, in healthy individuals. Although they are part of self, the retroviral legacy of ERV antigens, and association with and, possibly, causation of disease states may set them apart from typical self‐antigens. Consequently, the pathogenic or, indeed, host‐protective capacity of antibodies targeting ERV antigens is likely to be context‐dependent. Here, we review the immunogenicity of typical ERV proteins, with emphasis on the antibody response and its potential disease implications. [ABSTRACT FROM AUTHOR]

Endogenous retroviruses (ERVs) are the remnants of retroviral germline infections and are highly abundant in the genomes of vertebrates. At one time considered to be nothing more than inert 'junk' within genomes, ERVs have been tolerated within host genomes over vast timescales, and their study continues to reveal complex co-evolutionary histories within their respective host species. For example, multiple instances have been characterized of ERVs having been 'borrowed' for normal physiology, from single copies to ones involved in various regulatory networks such as innate immunity and during early development. Within the cell, the accessibility of ERVs is normally tightly controlled by epigenetic mechanisms such as DNA methylation or histone modifications. However, these silencing mechanisms of ERVs are reversible, and epigenetic alterations to the chromatin landscape can thus lead to their aberrant expression, as is observed in abnormal cellular environments such as in tumors. In this review, we focus on ERV transcriptional control and draw parallels and distinctions concerning the loss of regulation in disease, as well as their precise regulation in early development. [ABSTRACT FROM AUTHOR]

Ovine pulmonary adenocarcinoma (OPA) is an infectious, neoplastic lung disease of sheep that causes significant animal welfare and economic issues throughout the world. Understanding OPA pathogenesis is key to developing tools to control its impact. Central to this need is the availability of model systems that can monitor and track events after Jaagsiekte sheep retrovirus (JSRV) infection. Here, we report the development of an experimentally induced OPA model intended for this purpose. Using three different viral dose groups (low, intermediate and high), localised OPA tumour development was induced by bronchoscopic JSRV instillation into the segmental bronchus of the right cardiac lung lobe. Pre-clinical OPA diagnosis and tumour progression were monitored by monthly computed tomography (CT) imaging and trans-thoracic ultrasound scanning. Post mortem examination and immunohistochemistry confirmed OPA development in 89% of the JSRV-instilled animals. All three viral doses produced a range of OPA lesion types, including microscopic disease and gross tumours; however, larger lesions were more frequently identified in the low and intermediate viral groups. Overall, 31% of JSRV-infected sheep developed localised advanced lesions. Of the sheep that developed localised advanced lesions, tumour volume doubling times (calculated using thoracic CT 3D reconstructions) were 14.8 ± 2.1 days. The ability of ultrasound to track tumour development was compared against CT; the results indicated a strong significant association between paired CT and ultrasound measurements at each time point (R2 = 0.799, p < 0.0001). We believe that the range of OPA lesion types induced by this model replicates aspects of naturally occurring disease and will improve OPA research by providing novel insights into JSRV infectivity and OPA disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Endogenous retroviruses (ERVs), which originated from exogenous retroviral infections of germline cells millions of years ago and were inherited by subsequent generations as per Mendelian inheritance patterns, predominantly comprise non-protein-coding sequences due to the accumulation of mutations, insertions, deletions, and truncations. Nevertheless, recent studies have revealed that ERVs play a crucial role in diverse biological processes by encoding various proteins. Methods: In this study, we successfully identified an ERV envelope (env) gene in a mink species. A phylogenetic tree of mink ERV-V env and reference sequences was constructed using Bayesian methods and maximum-likelihood inference. Results: Phylogenetic analyses indicated a significant degree of sequence conservation and positive selection within the env-surface open reading frame. Additionally, qRT-PCR revealed diverse patterns of mink ERV-V env expression in various tissues. The expression of mink ERV-V env gene in testicular tissue strongly correlated with the seasonal reproductive cycles of minks. Discussion: Our study suggests that the ERV-V env gene in mink may have been repurposed for host functions. [ABSTRACT FROM AUTHOR]

Background: Pulmonary embolism (PE) and deep venous thrombosis (DVT) are the two most important manifestations of venous thromboembolism (VTE). DVT remains a significant condition since associated morbidity is significant and has elevated healthcare-related costs. Methods: A retrospective cohort study was conducted among DVT patients admitted to Tikur Anbessa Specialized Hospital, Zewditu Memorial Hospital and St. Paul's Hospital Millennium Medical College on follow-up from July 1, 2017, to July 01, 2020. Data on sociodemographic characteristics, types of DVT, laboratory findings, medications, risk factors of DVT, complications and outcomes of DVT were collected. The data were analyzed using SPSS version 25. Multivariate logistic regression analysis was conducted to determine predictors of DVT recurrence and major bleeding. A P value < 0.05 was considered to identify significant predictors. Results: The mean age of the participants was 45.2 years, with SD of 15.36. The major causes of DVT included immobilization (29.9%), previous surgery (27.5%) and cancer (21.1%). The DVT recurrence rate was 22.5%. Nine (2.2%) of the participants died, and 19.9% developed complications. Bilateral DVT (Adjusted odds ratio (AOR) = 2.8, 95% Confidence interval (CI) = 1.14, 6.66), obesity (AOR = 3.3, 95% CI = 1.15, 9.59), hypertension (AOR = 6.5, 95% CI = 2.90, 14.70) and retroviral infection (AOR = 6.3, 95% CI = 2.34, 16.94) were predictors of recurrent DVT. Nineteen (4.7%) patients had major bleeding, and patients with bilateral DVT, active cancer and terminal age had an increased risk of major bleeding. Conclusions: The overall DVT recurrence rate was alarmingly high and further complicated by PE, post thrombotic syndrome and chronic vein insufficiency, resulting in a 2.2% death rate. Major bleeding after DVT and PE remained high. Close monitoring should be performed for patients with advanced age, active cancer, bilateral DVT, retroviral infection, obesity and hypertension to prevent the recurrence of DVT and major bleeding. [ABSTRACT FROM AUTHOR]

This study aimed to investigate how the presence of co-morbid conditions influenced antimicrobial usage as presumptive prophylaxis for suspected bacteremia in dogs and cats undergoing dental treatments at primary care veterinary clinics in the United States. In 2020, data was collected from 1076 veterinary clinics across 44 US states. A total of 681,541 general anesthesia dental procedures were conducted on 592,472 dogs and 89,069 cats. This revealed that systemic antimicrobials were administered in 8.8% of dog procedures and 7.8% of cat procedures in the absence of concurrent periodontal disease or extractions. Cefpodoxime, clindamycin, and amoxicillin-clavulanate were the most frequently used antimicrobials in dogs, while cefovecin, amoxicillin-clavulanate, and clindamycin topped the list for cats. Dogs with cardiovascular, hepato-renal, and endocrine co-morbidities, as well as those undergoing concurrent removal of cutaneous or subcutaneous neoplasia, displayed higher antimicrobial use. Similarly, cats with endocrine or hepato-renal disease, retroviral infection (i.e., feline leukemia virus (FeLV), feline immunodeficiency virus (FIV)), and concurrent removal of cutaneous or subcutaneous neoplasia exhibited increased antimicrobial use. Dogs with hepato-renal abnormalities had longer treatment durations compared to those without (10.1 vs. 9.6 days). Conversely, cats with concurrent removal of cutaneous or subcutaneous neoplasia had shorter durations of treatment as compared to those that did not have this procedure performed (8.4 vs 9.2 days). The findings of this study underscore the necessity for further research and collaboration within the veterinary community to develop evidence-based guidelines, promoting responsible antimicrobial use, and advancing the field of veterinary dentistry for enhanced patient outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: The self-controlled case series (SCCS) is often used to monitor vaccine safety. The evaluation of intussusception after the rotavirus vaccine is complicated because the baseline rate varies with age. Time-varying baseline risk adjustments with data from unexposed cohorts are utilised. Self-controlled risk interval (SCRI), with a shorter observation period, can also mitigate the problem by studying a control period close to the risk period. OBJECTIVE: An Indian rotavirus vaccine has previously been studied using SCCS. The risk of intussusception in the high-risk windows (21 days after vaccination) was comparable to the background risk. The aim was to re-analyse data of an existing SCCS study using alternate statistical methods to examine vaccine safety. METHODS: We examined the mean age of intussusception in the vaccinated and the unvaccinated. We performed an SCRI analysis of the surveillance data from the SCCS study, limiting the observation period to 180 days. We analysed the time-to-intussusception from the last vaccination. Finally, we performed an SCCS analysis, excluding unvaccinated cases from the analysis. RESULTS: We found that the mean age of intussusception was significantly lower in the vaccinated (205 days) compared to the unvaccinated (223 days) (p-value 0.0026). The Incident Risk Ratio (IRR) on SCRI analysis was 1.62 (95% CI 1.07-2.44). There were significantly more intussusceptions in the first 30 days after vaccination compared to the next 30-day window. (92 vs 63 p-value = 0.009). We found that excluding unvaccinated infants from the SCCS analysis demonstrated significantly increased risk for the risk period 1–21 days after the 3rd dose (IRR 2.47, 95% CI 1.70-3.59). The risks of intussusception were missed in traditional SCCS analysis using unvaccinated infants as controls. CONCLUSION: Traditional risk adjustments using data from unexposed cohorts in SCCS may not be appropriate for investigating the risk of intussusception where vaccination lowers the mean age of intussusception. [ABSTRACT FROM AUTHOR]

The mechanisms driving metabolic reprogramming during B cell activation are unclear, particularly roles for enzymatic pathways involved in lipid remodeling. We found that murine B cell activation with lipopolysaccharide (LPS) led to a 1.6-fold increase in total lipids that included higher levels of phosphatidylethanolamine (PE) and plasmenyl PE. Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase involved in the synthesis of both PE and plasmenyl PE, and SELENOI expression was also upregulated during activation. Selenoi knockout (KO) B cells exhibited decreased levels of plasmenyl PE, which plays an important antioxidant role. Lipid peroxidation was measured and found to increase ∼2-fold in KO vs. wild-type (WT) B cells. Cell death was not impacted by KO in LPS-treated B cells and proliferation was only slightly reduced, but differentiation into CD138 + Blimp-1+ plasma B cells was decreased ∼2-fold. This led to examination of B cell receptors important for differentiation that recognize the ligand B cell activating factor, and levels of TACI (transmembrane activator, calcium-modulator, and cytophilin ligand interactor) (CD267) were significantly decreased on KO B cells compared with WT control cells. Vaccination with ovalbumin/adjuvant led to decreased ovalbumin-specific immunoglobulin M (IgM) levels in sera of KO mice compared with WT mice. Real-time polymerase chain reaction analyses revealed a decreased switch from surface to secreted IgM in spleens of KO mice induced by vaccination or LP-BM5 retrovirus infection. Overall, these findings detail the lipidomic response of B cells to LPS activation and reveal the importance of upregulated SELENOI for promoting differentiation into IgM-secreting plasma B cells. [ABSTRACT FROM AUTHOR]

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)—a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocyte (CTL) motility is an important feature of effective CTL responses and is impaired when CTLs become exhausted, e.g. during chronic retroviral infections. A prominent T cell exhaustion marker is programmed cell death protein 1 (PD-1) and antibodies against the interaction of PD-1 and PDligand 1 (PD-L1) are known to improve CTL functions. However, antibody blockade affects all PD-1/PD-L1-expressing cell types, thus, the observed effects cannot be attributed selectively to CTLs. To overcome this problem, we performed CRISPR/ Cas9 based knockout of the PD-1 coding gene PDCD1 in naïve Friend Retrovirus (FV)-specific CTLs. We transferred 1,000 of these cells into mice where they proliferated upon FV-infection. Using intravital two-photon microscopy we visualized CTL motility in the bone marrow and evaluated cytotoxic molecule expression by flow cytometry. Knockout of PDCD1 improved the CTL motility at 14 days post infection and enhanced the expression of cytotoxicity markers. Our data show the potential of genetic tuning of naive antiviral CTLs and might be relevant for future designs of improved T cell-mediated therapies. [ABSTRACT FROM AUTHOR]

Despite mounting attention in recent years, health threats posed by antimicrobial resistance are not new. Antimicrobial resistance has dogged infectious disease treatment processes since the first modern antimicrobials were discovered. [ABSTRACT FROM AUTHOR]

Introduction: Macrophages are an important component of innate immunity and involved in the immune regulation of multiple diseases. The functional diversity and plasticity make macrophages to exhibit different polarization phenotypes after different stimuli. During tumor progression, the M2-like polarized tumor-associated macrophages (TAMs) promote tumor progression by assisting immune escape, facilitating tumor cell metastasis, and switching tumor angiogenesis. Our previous studies demonstrated that functional remodeling of TAMs through engineered-modifying or gene-editing provides the potential immunotherapy for tumor. However, lack of proliferation capacity and maintained immune memory of infused macrophages restricts the application of macrophage-based therapeutic strategies in the repressive tumor immune microenvironment (TIME). Although J2 retrovirus infection enabled immortalization of bone marrow-derived macrophages (iBMDMs) and facilitated the mechanisms exploration and application, little is known about the phenotypic and functional differences among multi kinds of macrophages. Methods: HE staining was used to detect the biosafety of iBMDMs, and real-time quantitative PCR, immunofluorescence staining, and ELISA were used to detect the polarization response and expression of chemokines in iBMDMs. Flow cytometry, scratch assay, real-time quantitative PCR, and crystal violet staining were used to analyze its phagocytic function, as well as its impact on tumor cell migration, proliferation, and apoptosis. Not only that, the inhibitory effect of iBMDMs on tumor growth was detected through subcutaneous tumor loading, while the tumor tissue was paraffin sectioned and flow cytometry was used to detect its impact on the tumor microenvironment. Results: In this study, we demonstrated iBMDMs exhibited the features of rapid proliferation and long-term survival. We also compared iBMDMs with RAW264.7 cell line and mouse primary BMDMs with in vitro and in vivo experiments, indicating that the iBMDMs could undergo the same polarization response as normal macrophages with no obvious cellular morphology changes after polarization. What's more, iBMDMs owned stronger phagocytosis and proapoptosis functions on tumor cells. In addition, M1-polarized iBMDMs could maintain the anti-tumor phenotypes and domesticated the recruited macrophages of receptor mice, which further improved the TIME and repressed tumor growth. Discussion: iBMDMs can serve as a good object for the function and mechanism study of macrophages and the optional source of macrophage immunotherapy. [ABSTRACT FROM AUTHOR]

TREX1 acts in the initial prevention of an autoimmune response, but it may contribute to the permissiveness of retrovirus infections. This study investigated the association between the levels of TREX1 gene expression with the polymorphisms TREX1 rs3135941 (T/C) and TREX1 rs3135945 (G/A), and the presence of antinuclear antibodies (ANA) in antiretroviral therapy (ART)-naïve individuals and after 1 year of treatment. Blood samples from 119 individuals with HIV-1 were subjected to genotyping of polymorphisms and quantification of TREX1 gene expression and HIV-1 viral load by qPCR. The concentration of IFN-α and the number of CD4+/CD8+ T lymphocytes were determined by ELISA and flow cytometry, respectively; ANA was investigated by immunofluorescence. A control group of 167 seronegative individuals was used for the comparison of genotypic frequencies. The frequency of the polymorphisms were not associated with HIV infection or with variations in the expression of TREX1 and IFN-α (p > 0.05). ART-naïve individuals exhibited higher TREX1 expression and lower IFN-α expression. After 1 year of ART, TREX1 levels were reduced, while IFN-α and CD4+ T lymphocytes were elevated (p < 0.05). Some individuals on ART presented ANA. These results suggest that ART-mediated restoration of immune competence is associated with a reduction in TREX1 expression, which may induce the development of ANA, regardless of the polymorphism investigated. [ABSTRACT FROM AUTHOR]

Endogenous retroviruses (ERVs) have long been thought as 'junk DNA' or 'fossil records' of ancestral retrovirus invasions. ERVs can be transcriptionally active and critical for human development and health. ERVs are involved in pathological processes such as virus infection, immune response, and aging. Various emerging strategies target human ERVs (HERVs) for the treatment of cancers and aging-associated diseases. Endogenous retroviruses (ERVs) are evolutionary remnants of retroviral infections in which the viral genome became embedded as a dormant regulatory element within the host germline. When ERVs become activated, they comprehensively rewire genomic regulatory networks of the host and facilitate critical developmental events, such as preimplantation development and placentation, in a manner specific to species, developmental stage, and tissues. However, accumulating evidence suggests that aberrant ERV transcription compromises genome stability and has been implicated in cellular senescence and various pathogenic processes, underscoring the significance of host genomic surveillance mechanisms. Here, we revisit the prominent functions of ERVs in early development and highlight their emerging roles in mammalian post-implantation development and organogenesis. We also discuss their implications for aging and pathological processes such as microbial infection, immune response. Furthermore, we discuss recent advances in stem-cell-based models, single-cell omics, and genome editing technologies, which serve as beacons illuminating the versatile nature of ERVs in mammalian development and health. [ABSTRACT FROM AUTHOR]

Host antiviral proteins inhibit primate lentiviruses and other retroviruses by targeting many features of the viral life cycle. The lentiviral capsid protein and the assembled viral core are known to be inhibited through multiple, directly acting antiviral proteins. Several phenotypes, including those known as Lv1 through Lv5, have been described as cell type-specific blocks to infection against some but not all primate lentiviruses. Here we review important features of known capsid-targeting blocks to infection together with several blocks to infection for which the genes responsible for the inhibition still remain to be identified. We outline the features of these blocks as well as how current methodologies are now well suited to find these antiviral genes and solve these long-standing mysteries in the HIV and retrovirology fields. [ABSTRACT FROM AUTHOR]

Endogenous retroviruses (ERVs) are remnants of ancestral viral infections. Feline leukemia virus (FeLV) is an exogenous and endogenous retrovirus in domestic cats. It is classified into several subgroups (A, B, C, D, E, and T) based on viral receptor interference properties or receptor usage. ERV-derived molecules benefit animals, conferring resistance to infectious diseases. However, the soluble protein encoded by the defective envelope (env) gene of endogenous FeLV (enFeLV) functions as a co-factor in FeLV subgroup T infections. Therefore, whether the gene emerged to facilitate viral infection is unclear. Based on the properties of ERV-derived molecules, we hypothesized that the defective env genes possess antiviral activity that would be advantageous to the host because FeLV subgroup B (FeLV-B), a recombinant virus derived from enFeLV env, is restricted to viral transmission among domestic cats. When soluble truncated Env proteins from enFeLV were tested for their inhibitory effects against enFeLV and FeLV-B, they inhibited viral infection. Notably, this antiviral machinery was extended to infection with the Gibbon ape leukemia virus, Koala retrovirus A, and Hervey pteropid gammaretrovirus. Although these viruses used feline phosphate transporter 1 (fePit1) and phosphate transporter 2 as receptors, the inhibitory mechanism involved competitive receptor binding in a fePit1-dependent manner. The shift in receptor usage might have occurred to avoid the inhibitory effect. Overall, these findings highlight the possible emergence of soluble truncated Env proteins from enFeLV as a restriction factor against retroviral infection and will help in developing host immunity and antiviral defense by controlling retroviral spread. IMPORTANCE Retroviruses are unique in using reverse transcriptase to convert RNA genomes into DNA, infecting germ cells, and transmitting to offspring. Numerous ancient retroviral sequences are known as endogenous retroviruses (ERVs). The soluble Env protein derived from ERVs functions as a co-factor that assists in FeLV-T infection. However, herein, we show that the soluble Env protein exhibits antiviral activity and provides resistance to mammalian retrovirus infection through competitive receptor binding. In particular, this finding may explain why FeLV-B transmission is not observed among domestic cats. ERV-derived molecules can benefit animals in an evolutionary arms race, highlighting the double-edged-sword nature of ERVs. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study is to evaluate the demographic and clinical characteristics and vaccination status of patients under 5 years with rotavirus antigen-positive acute gastroenteritis (RVGE). Methods: Patients diagnosed with RVGE, who were admitted between December 1, 2017, and November 30, 2018, were included in the study. The demographic and laboratory characteristics and the vaccination status of the children were retrospectively evaluated. Results: Of the 194 patients included in the study, 115 (59.3%) were male and 79 (40.7%) were female. Children who breastfed for less than 6 months had a longer length of hospital stay (LOS) than those who breastfed for 6 months or more (p=0.001). LOS for unvaccinated children was longer than for vaccinated children (p=0.003). Children with blood group A had longer LOS than children with other blood groups. Children with significant stool leukocyte presence had longer LOS than those without stool leukocytes (p=0.013). The complication that significantly increased the LOS was hypokalemia (p=0.042). Discussion and Conclusion: Vaccination has a protective effect that reduces morbidity in children under 5 years with RVGE. Our study found that both breastfeeding and the rotavirus vaccine significantly reduced the length of hospital stay. [ABSTRACT FROM AUTHOR]

The article focuses on evaluating chronic pain and its impact on functional capacity in individuals with HTLV-1. Topics include the prevalence and characteristics of chronic pain in these patients, the relationship between chronic pain and functional impairment, and the influence of sociodemographic and clinical factors on pain severity and functional outcomes.

An introduction is presented in which the editor discusses articles within the issue on topics including the role of human leukocyte antigen (HLA)-1 and CD4 downregulation functions of the pathogenic accessory HIV-1 Nef protein in the differences in prevalence of viruses, role of human immunodeficiency virus (HIV)-1 entry phenotypes in pathogenesis, and barriers to HIV-1 cure.

Five to ten percent of mammalian genomes is occupied by multiple clades of endogenous retroviruses (ERVs), that may count thousands of members. New ERV clades arise by retroviral infection of the germline followed by expansion by reinfection and/or retrotransposition. ERV mobilization is a source of deleterious variation, driving the emergence of ERV silencing mechanisms, leaving "DNA fossils". Here we show that the ERVK[2-1-LTR] clade is still active in the bovine and a source of disease-causing alleles. We develop a method to measure the rate of ERVK[2-1-LTR] mobilization, finding an average of 1 per ~150 sperm cells, with >10-fold difference between animals. We perform a genome-wide association study and identify eight loci affecting ERVK[2-1-LTR] mobilization. We provide evidence that polymorphic ERVK[2-1-LTR] elements in four of these loci cause the association. We generate a catalogue of full length ERVK[2-1-LTR] elements, and show that it comprises 15% of C-type autonomous elements, and 85% of D-type non-autonomous elements lacking functional genes. We show that >25% of the variance of mobilization rate is determined by the number of C-type elements, yet that de novo insertions are dominated by D-type elements. We propose that D-type elements act as parasite-of-parasite gene drives that may contribute to the observed demise of ERV elements. Endogenous retroviruses constitute 5–10% of mammalian genome space. This study characterize the bovine ERVK[2-1- LTR] clade showing that its activity varies between individuals as a function of the number of inherited autonomous elements, yet that most de novo insertions are non-autonomous elements lacking functional genes. [ABSTRACT FROM AUTHOR]

The interest in endogenous retroviruses (ERVs) has been fueled by their impact on the evolution of the host genome. In this study, we used multiple pipelines to conduct a de novo exploration and annotation of ERVs in 13 species of the Caprinae subfamily. Through analyses of sequence identity, structural organization, and phylogeny, we defined 28 ERV groups within Caprinae, including 19 gamma retrovirus groups and 9 beta retrovirus groups. Notably, we identified four recent and potentially active groups prevalent in the Caprinae genomes. Additionally, our investigation revealed that most long noncoding genes (lncRNA) and protein-coding genes (PC) contain ERV-derived sequences. Specifically, we observed that ERV-derived sequences were present in approximately 75% of protein-coding genes and 81% of lncRNA genes in sheep. Similarly, in goats, ERV-derived sequences were found in approximately 74% of protein-coding genes and 75% of lncRNA genes. Our findings lead to the conclusion that the majority of ERVs in the Caprinae genomes can be categorized as fossils, representing remnants of past retroviral infections that have become permanently integrated into the genomes. Nevertheless, the identification of the Cap_ERV_20, Cap_ERV_21, Cap_ERV_24, and Cap_ERV_25 groups indicates the presence of relatively recent and potentially active ERVs in these genomes. These particular groups may contribute to the ongoing evolution of the Caprinae genome. The identification of putatively active ERVs in the Caprinae genomes raises the possibility of harnessing them for future genetic marker development. [ABSTRACT FROM AUTHOR]

Key messages: Passive immunoprophylaxis with broadly neutralizing monoclonal antibodies (bNAbs) could be a game changer in the prevention of human immunodeficiency virus (HIV) acquisition.The prevailing view is that available resources should be focused on identifying a fixed combination of at least three bNAbs for universal use in therapeutic and preventive protocols, regardless of target populations or routes of transmission.HIV transmission through breastfeeding is unique: it involves free viral particles and cell‐associated virus from breast milk and, in the case of acute/recent maternal infection, a viral population with restricted Env diversity.HIV transmission through breastfeeding in high incidence/prevalence areas could potentially be eliminated by subcutaneous administration to all newborns of one or two long‐acting bNAbs with extended breadth, high potency, and effector properties (ADCC, phagocytosis) against circulating HIV strains. [ABSTRACT FROM AUTHOR]

Background: Low serum concentrations of 25-hydroxyvitamin D correlate with higher susceptibility to acute respiratory tract infections (ARTIs). The case study presented here aims at sheding light on the correlation between vitamin D levels, the vitamin D supplement dose, and the incidence of ARTIs. Case Report: A 23-year-old female patient with a vitamin D insufficiency was able to successfully increase her vitamin D levels from 45.60 nmol/l to 85.91 nmol/l (reference ranges 75-200 nmol/l) through the use of supplements. However, it was surprising to observe a decrease in vitamin D levels even though the patient continued taking supplements. Further examination indicated that the patient was experiencing common symptoms of an acute respiratory tract infection (ARTI). This case highlights the intricate connection between ARTIs and vitamin D intake. Conclusion: This case study clearly demonstrates the intricate connection between vitamin D levels, supplement treatment, and ARTIs. The observed decrease in vitamin D levels during the course of supplementation, while the patient was suffering from an ARTI, suggests that respiratory infections may affect vitamin D metabolism. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are the remnants of ancient retroviral infections integrated into the human genome. Although most HERVs are silenced or rendered inactive by various regulatory mechanisms, they retain the potential to influence the nearby genes. We analyzed the regulatory map of 91 HERV-Ks on neighboring genes in human breast cancer and investigated the impact of HERV-Ks on the tumor microenvironment (TME) and prognosis of breast cancer. Nine RNA-seq datasets were obtained from GEO and NCBI SRA. Differentially expressed genes and HERV-Ks were analyzed using DESeq2. Validation of high-risk prognostic candidate genes using TCGA data. These included Overall survival (multivariate Cox regression model), immune infiltration analysis (TIMER), tumor mutation burden (maftools), and drug sensitivity analysis (GSCA). A total of 88 candidate genes related to breast cancer prognosis were screened, of which CD48, SLAMF7, SLAMF1, IGLL1, IGHA1, and LRRC8A were key genes. Functionally, these six key genes were significantly enriched in some immune function-related pathways, which may be associated with poor prognosis for breast cancer (p = 0.00016), and the expression levels of these genes were significantly correlated with the sensitivity of breast cancer treatment-related drugs. Mechanistically, they may influence breast cancer development by modulating the infiltration of various immune cells into the TME. We further experimentally validated these genes to confirm the results obtained from bioinformatics analysis. This study represents the first report on the regulatory potential of HERV-K in the neighboring breast cancer genome. We identified three key HERV-Ks and five neighboring genes that hold promise as novel targets for future interventions and treatments for breast cancer. [ABSTRACT FROM AUTHOR]

The subgroup J avian leukosis virus (ALV-J), a retrovirus, uses its gp85 protein to bind to the receptor, the chicken sodium hydrogen exchanger isoform 1 (chNHE1), facilitating viral invasion. ALV-J is the main epidemic subgroup and shows noteworthy mutations within the receptor-binding domain (RBD) region of gp85, especially in ALV-J layer strains in China. However, the implications of these mutations on viral replication and transmission remain elusive. In this study, the ALV-J layer strain JL08CH3-1 exhibited a more robust replication ability than the prototype strain HPRS103, which is related to variations in the gp85 protein. Notably, the gp85 of JL08CH3-1 demonstrated a heightened binding capacity to chNHE1 compared to HPRS103-gp85 binding. Furthermore, we showed that the specific N123I mutation within gp85 contributed to the enhanced binding capacity of the gp85 protein to chNHE1. Structural analysis indicated that the N123I mutation primarily enhanced the stability of gp85, expanded the interaction interface, and increased the number of hydrogen bonds at the interaction interface to increase the binding capacity between gp85 and chNHE1. We found that the N123I mutation not only improved the viral replication ability of ALV-J but also promoted viral shedding in vivo. These comprehensive data underscore the notion that the N123I mutation increases receptor binding and intensifies viral replication. Author summary: Attachment is a critical initial step in retroviral infections. The RBD of gp85 in ALV-J is critical for binding to the cell membrane receptor, chNHE1. This investigation establishes a strong link between the heightened replication ability of the layer strain JL08CH3-1 and the enhanced binding capacity exhibited by gp85 toward chNHE1 compared to the prototype strain HPRS103. We found for the first time that the N123I mutation within the RBD region of gp85 increased the binding capacity between gp85 and chNHE1 and enhanced the replication ability of ALV-J. Our results provide important information on the implications of mutations within the RBD region of gp85 and highlight the importance of monitoring variations in the RBD region of ALV-J to prevent future outbreaks. [ABSTRACT FROM AUTHOR]

A recent increase in the number of high-quality genome sequences and assemblies facilitates systematic screening of vertebrate DNA, better reflecting endogenous retrovirus (ERV) variability across wildlife and providing a means for evaluating historic and contemporary retrovirus transmission. In contrast to commonly studied laboratory and domestic animals, recent studies of wildlife ERVs and exogenous retroviruses (XRVs) offer insights into historic and contemporary retrovirus activities in hosts undergoing natural selection. Wildlife host populations under natural selection provide insights into ERV variation that segregates at various frequencies in host populations and highlight limitations of ERV detection relying on reference genome assemblies derived from one or a few individuals alone. Phylogenetic differences between ERVs and contemporary XRVs suggest that XRVs are prone to extinction over evolutionary timescales, while the ERV record persists, or that many retroviruses remain to be discovered. Large-scale phylogenomic screening for coopted ERV functions suggest that the frequency of coopted genes is underestimated. Endogenous retroviruses (ERVs) are inherited genomic remains of past germline retroviral infections. Research on human ERVs has focused on medical implications of their dysregulation on various diseases. However, recent studies incorporating wildlife are yielding remarkable perspectives on long-term retrovirus–host interactions. These initial forays into broader taxonomic analysis, including sequencing of multiple individuals per species, show the incredible plasticity and variation of ERVs within and among wildlife species. This demonstrates that stochastic processes govern much of the vertebrate genome. In this review, we elaborate on discoveries pertaining to wildlife ERV origins and evolution, genome colonization, and consequences for host biology. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are the result of retroviral infections acquired millions of years ago; nowadays, they compose around 8% of human DNA. Multiple mechanisms have been employed for endogenous retroviral deactivation, rendering replication and retrotransposition defective, while some of them have been co-opted to serve host evolutionary advantages. A pleiad of mechanisms retains the delicate balance of HERV expression in modern humans. Thus, epigenetic modifications, such as DNA and histone methylation, acetylation, deamination, chromatin remodeling, and even post-transcriptional control are recruited. In this review, we aim to summarize the main HERV silencing pathways, revisit paradigms of human disease with a HERV component, and emphasize the human immunodeficiency virus (HIV) and HERV interactions during HIV infection. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are the germline embedded proviral fragments of ancient retroviral infections that make up roughly 8% of the human genome. Our understanding of HERVs in physiology primarily surrounds their non-coding functions, while their protein coding capacity remains virtually uncharacterized. Therefore, we applied the bioinformatic pipeline "hervQuant" to high-resolution ribosomal profiling of healthy tissues to provide a comprehensive overview of translationally active HERVs. We find that HERVs account for 0.1–0.4% of all translation in distinct tissue-specific profiles. Collectively, our study further supports claims that HERVs are actively translated throughout healthy tissues to provide sequences of retroviral origin to the human proteome. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are cytotoxic innate immune cells, able to recognize and eliminate virus-infected as well as cancer cells. Metabolic reprogramming is crucial for their activity as they have enhanced energy and nutritional demands for their functions during an infection. Fatty acids (FAs) represent an important source of cellular energy and are essential for proliferation of immune cells. However, the precise role of FAs for NK cells activity in retrovirus infection was unknown. Here we show that activated NK cells increase the expression of the FA uptake receptor CD36 and subsequently the uptake of FAs upon acute virus infection. We found an enhanced flexibility of NK cells to utilize FAs as source of energy compare to naïve NK cells. NK cells that were able to generate energy from FAs showed an augmented target cell killing and increased expression of cytotoxic parameters. However, NK cells that were unable to generate energy from FAs exhibited a severely decreased migratory capacity. Our results demonstrate that NK cells require FAs in order to fight acute virus infection. Susceptibility to severe virus infections as it is shown for people with malnutrition may be augmented by defects in the FA processing machinery, which might be a target to therapeutically boost NK cell functions in the future. [ABSTRACT FROM AUTHOR]

Despite the absence of a confirmed exogenously replicating retrovirus in Canis lupus familiaris (C. familiaris), past retroviral infections are evident in the genomes of living animals via the presence of endogenous retroviruses (ERVs). Although gammaretrovirus-like transcripts and enzyme activities were previously reported to be present in canine leukemias and lymphomas, those findings were not further explored. Initial analysis of the C. familiaris reference genome revealed a minor subset of one ERV lineage, classified as CfERV-Fc1(a), or Fc1(a) here, with features characteristic of recent integration, including the presence of ORFs and identical or nearly identical LTRs. Our previous analysis of whole genome sequence data belonging to extant Canidae revealed a burst of past infections in Canis ancestors resulting in numerous young, polymorphic, and highly intact loci now segregating in dogs. Here, we demonstrate the expression of full-length Fc1(a) proviruses in tissues collected from healthy animals and from animals with cancer. We observed significantly higher expression in samples of dogs with various cancer diagnoses when compared to samples from healthy dogs. Genotyping of insertionally polymorphic Fc1(a) loci identified candidate expressed proviruses and delineated distributions over sample groups. Collectively, the data show that Fc1(a) proviruses retain biological activity in the domestic dog and provides a means to examine potential genetic links with disease states in this species. Author summary: The domestic dog is an important biomedical model of human genetics and disease. Until now, the dog has been largely excluded from research focusing on retrovirus biology and retrovirus-host coevolution in the context of the canine as a host. Our work reveals that numerous recently integrated endogenous retroviruses are variably present in the genomes of domestic dogs including ones that are transcriptionally active or are present within or near genes, and that transcriptional activity is significantly elevated in tumors of various canine cancers. Thus, our work characterizes a previously unexplored resource of genomic impact to the domestic dog as a model of health and disease. The results from this study begin span a significant knowledge gap in our understanding of retrovirus-host dynamics in the dog as a biomedical model of genetics and improve our understanding of the biological activity and prevalence of a zoonotic-relevant and highly intact endogenous retrovirus lineage in the domestic dog. [ABSTRACT FROM AUTHOR]

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in the host genome. Although mutations and silencing mechanisms impair their original role in viral replication, HERVs are believed to play roles in various biological processes. Long interspersed nuclear elements (LINEs) are non-LTR retrotransposons that have a lifecycle resembling that of retroviruses. Although LINE expression is typically silenced in somatic cells, it also contributes to various biological processes. The aberrant expression of HERVs and LINEs is closely associated with the development of cancer and/or immunological diseases, suggesting that they are integrated into various pathways related to the diseases. HERVs/LINEs control gene expression depending on the context as promoter/enhancer elements. Some RNAs and proteins derived from HERVs/LINEs have oncogenic potential, whereas others stimulate innate immunity. Non-retroviral endogenous viral elements (nrEVEs) are a novel type of virus-like element in the genome. nrEVEs may also be involved in host immunity. This article provides a current understanding of how these elements impact cellular physiology in cancer development and innate immunity, and provides perspectives for future studies. [ABSTRACT FROM AUTHOR]

The innate immune system of mammals is formed by a complex web of interacting proteins, which together constitute the first barrier of entry for infectious pathogens. Genes from the E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in the innate immune system by restricting the activity of different retrovirus species. For example, TRIM5 and TRIM22 have both been associated with HIV restriction and are regarded as crucial parts of the antiretroviral machinery of mammals. Our analyses of positive selection corroborate the great significance of these genes for some groups of mammals. However, we also show that many species lack TRIM5 and TRIM22 altogether. By analyzing a large number of mammalian genomes, here we provide the first comprehensive view of the evolution of these genes in eutherians, showcasing that the pattern of accumulation of TRIM genes has been dissimilar across mammalian orders. Our data suggest that these differences are caused by the evolutionary plasticity of the immune system of eutherians, which have adapted to use different strategies to combat retrovirus infections. Altogether, our results provide insights into the dissimilar evolution of a representative family of restriction factors, highlighting an example of adaptive and idiosyncratic evolution in the innate immune system. [ABSTRACT FROM AUTHOR]

Introduction: Human T‐cell lymphotropic virus type 1 (HTLV‐1) is a chronic infection affecting 5–10 million people worldwide. Ten percent develop HTLV‐1‐associated diseases, and 3%–5% develop HTLV‐1‐associated myelopathy (HAM)/tropical spastic paraparesis. Low health‐related quality of life (HRQoL) is a significant concern for those with HTLV‐1, and little is known about how it impacts daily life or what patients need from healthcare services. To address this, we report on patient involvement workshops aimed at identifying research priorities for HTLV‐1 health service provision. Methods: Participants recruited through HTLV‐1 clinics in England attended six 90‐min virtual workshops over 10 months, and two 60‐min consolidation workshops. Content developed iteratively from topic focussed group discussions. All workshops were video‐recorded with consent, transcribed verbatim and thematically analysed. Using consensus voting rounds, participants individually ranked their top six and then collectively their top three research priorities from the themes inferred from the analysis. A final feedback session explored the experiences of participating in the workshops. Findings: Twenty‐seven people with HTLV‐1 engaged with the workshops with up to 22 participants attending each meeting. The majority were diagnosed with HAM (n = 22). The top three research priorities were identified as understanding disease progression, psychosocial wellbeing, and information and knowledge. Participants valued being asked to set research priorities that directly addressed their needs and enjoyed the workshops. They stressed the importance of patient advocates for promoting research that positively impacts everyday life. Conclusion: This is the first of this type of research engagement with people with HTLV‐1 in the United Kingdom. Participants identified several avenues of investigation that could lead to improvements in healthcare services and HRQoL. Participants believed the workshops signified the start of a conversation to progress person‐centred and meaningful research in HTLV‐1. Patient or Public Contribution: People living with HTLV‐1 were involved in the iterative design, conduct, analysis, writing and dissemination of this project through the patient involvement workshops. As a result of this engagement, a patient led advisory group has been set up to assist with the dissemination of the findings. [ABSTRACT FROM AUTHOR]

Objectives: The incidence of waterborne and foodborne infectious diseases (WFIDs) continues to increase annually, attracting significant global attention. This study examined trends in WFID outbreaks in the Republic of Korea over the 5-year period before and during the coronavirus disease 2019 (COVID-19) pandemic and provided foundational data to establish measures for the prevention and control of WFID outbreaks. Methods: We analyzed 2,541 WFID outbreaks from 2017 to 2021 (42,805 cases) that were reported through the Integrated Disease Surveillance System of the Korea Disease Control and Prevention Agency. Outbreaks were defined as the occurrence of gastrointestinal symptoms in =2 individuals within a group with temporal and regional epidemiological associations. The related factors associated with WFID outbreaks during the observation period were statistically analyzed. Results: The total number of WFID outbreaks significantly decreased in 2020 during the COVID-19 pandemic and increased to the pre-pandemic level in 2021. Different patterns were observed for each pathogen. The incidence of Salmonella outbreaks more than doubled, while norovirus outbreaks decreased significantly. Conclusion: WFID outbreaks in the Republic of Korea showed different patterns before and during the COVID-19 pandemic, influenced by infection control measures and changes in dietary consumption patterns. Outbreaks of some diseases increased, but the infection control measures applied during the pandemic resulted in a significant decrease in the overall number of WFID outbreaks. This highlights the importance of strengthening the management strategies for outbreak prevention through hygiene inspections, long-term monitoring, education, and promotion by conducting multidimensional analyses to understand the complex related factors. [ABSTRACT FROM AUTHOR]

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Background: Cancer, as a complex, heterogeneous disease, is currently affecting millions of people worldwide. Even if the most common traditional treatments, namely, chemotherapy (CTx) and radiotherapy (RTx), have been so far effective in some conditions, there is still a dire need for novel, innovative approaches to treat types of cancer. In this context, oncoviruses are responsible for 12% of all malignancies, such as human papillomavirus (HPV), Merkel cell polyomavirus (MCPyV), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), as well as hepatitis B virus (HBV) and hepatitis C virus (HCV), and the poorest in the world also account for 80% of all human cancer cases. Against this background, nanomedicine has developed nano-based drug delivery systems (DDS) to meet the demand for drug delivery vectors, e.g., extracellular vesicles (EVs). This review article aimed to explore the potential of engineered small EVs (sEVs) in suppressing human oncovirus-associated cancers. Methods: Our search was conducted for published research between 2000 and 2022 using several international databases, including Scopus, PubMed, Web of Science, and Google Scholar. We also reviewed additional evidence from relevant published articles. Results: In this line, the findings revealed that EV engineering as a new field is witnessing the development of novel sEV-based structures, and it is expected to be advanced in the future. EVs may be further exploited in specialized applications as therapeutic or diagnostic tools. The techniques of biotechnology have been additionally utilized to create synthetic bilayers based on the physical and chemical properties of parent molecules via a top-down strategy for downsizing complicated, big particles into nano-sized sEVs. Conclusion: As the final point, EV-mediated treatments are less toxic to the body than the most conventional ones, making them a safer and even more effective option. Although many in vitro studies have so far tested the efficacy of sEVs, further research is still needed to develop their potential in animal and clinical trials to reap the therapeutic benefits of this promising platform. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) is principally derived from vagal neural crest cells that migrate caudally along the entire length of the gastrointestinal tract, giving rise to neurons and glial cells in two ganglionated plexuses. Incomplete migration of enteric neural crest-derived cells (ENCDC) leads to Hirschsprung disease, a congenital disorder characterized by the absence of enteric ganglia along variable lengths of the colorectum. Our previous work strongly supported the essential role of the avian ceca, present at the junction of the midgut and hindgut, in hindgut ENS development, since ablation of the cecal buds led to incomplete ENCDC colonization of the hindgut. In situ hybridization shows bone morphogenetic protein-4 (BMP4) is highly expressed in the cecal mesenchyme, leading us to hypothesize that cecal BMP4 is required for hindgut ENS development. To test this, we modulated BMP4 activity using embryonic intestinal organ culture techniques and retroviral infection. We show that overexpression or inhibition of BMP4 in the ceca disrupts hindgut ENS development, with GDNF playing an important regulatory role. Our results suggest that these two important signaling pathways are required for normal ENCDC migration and enteric ganglion formation in the developing hindgut ENS. [ABSTRACT FROM AUTHOR]

Co-infection of avian leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) in poultry flocks induces synergistic replication, which worsens immunosuppression, growth inhibition, and increased mortality. However, the synergistic replication mechanism between ALV-J and REV is still not fully understood. We showed that microRNA-155 (miR-155) targets a dual pathway, PRKCI-MAPK8 and TIMP3-MMP2, which interacts with the U3 region of ALV-J and REV to promote synergistic replication between ALV-J and REV. Initially, we found that the RNA levels of ALV-J and REV increased significantly in ALV-J and REV co-infected cells and tissues compared with mono-infected cells and tissues. Next, miRNAomics showed that ALV-J and REV synergistically increased miR-155 levels. In co-infected cells, miR-155 promoted synergistic replication of ALV-J and REV. All structural proteins of the two viruses activated the expression of miR-155, especially gag proteins, rather than insertional activation. Proteomic study of cells co-infected with ALV-J and REV and transfected with miR-155 indicated that miR-155 directly suppressed PRKCI and TIMP3 and that PRKCI directly prevented MAPK8 expression, while TIMP3 directly interfered MMP2 expression. We also found that MAPK8 and MMP2 co-interacted with ALV-J and REV's U3 to enhance synergistic replication. In conclusion, ALV-J and REV synergistically activate miR-155, facilitating the synergistic replication of ALV-J and REV by PRKCI-MAPK8 and TIMP3- MMP2 dual-pathway interaction with the U3 region of ALV-J and REV. This discovery will assist in explaining how two retroviruses replicate synergistically. [ABSTRACT FROM AUTHOR]

Retroviruses have been proven to cause infections and diseases in a series of mammalian hosts but not in dogs. Then, this letter discussed the dog susceptibility to retrovirus infection, encompassing arguments to understand why dogs may have not been infected by retroviruses thus far. The potential resistance of retrovirus in dogs enables this provocative short communication to discuss this question, looking at some evolutive aspects. The lineage of canids has shown, throughout its evolutionary history, a smaller accumulation of retroviruses in canid genomes, classified as endogenous retroviruses. In this context, the genomes of canids seem to offer obstacles, which have been evolutionarily conserved, in the face of retroviral infection. [ABSTRACT FROM AUTHOR]

Feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) are retroviral infections of cats worldwide whose clinical manifestations range from mild to severe disease. In both cases, infected cats can live a long life with proper care and should be managed to prevent infection of other cats. Dirofilaria immitis, the nematode that causes heartworm disease, can infect cats in any region where dogs are infected. Though cats are more resistant to infection, clinical diseases in the form of heartworm-associated respiratory disease can cause death. Screening for these infectious diseases enables veterinarians to manage their cases and prevent the spread to other cats. We describe the diagnostic accuracy of a point-of-care immunoassay for FIV, FeLV, and heartworm, compared to reference methods commonly available through reference laboratories to the practicing veterinarian. For FIV, we report 100% sensitivity (95% confidence limits (CL): 96.2–100%) and 97.8% specificity (95% CL: 95.4–99.4%). For FeLV, we report 100% sensitivity (95% CL: 97.7–100%) and 99.2% specificity (95% CL: 97.1–99.9%). And for heartworm, we report 90.2% sensitivity (95% CL: 76.9–97.3%) and 100% specificity (95% CL: 98.3–100%). Veterinarians may expect this performance relative to the reference methods they use for confirmatory serological testing. [ABSTRACT FROM AUTHOR]

Introduction: Rotavirus is one of the major infectious agents of childhood acute gastroenteritis (AGE). Definitive diagnosis depends on laboratory test results. Our study aimed to compare the laboratory results, number of emergency admissions, and length of hospital stay of patients with an initial diagnosis of AGE in the pediatric emergency department according to the presence of rotavirus antigen. Methods: 74 patients who tested positive and 91 patients who tested negative for rotavirus antigen in fresh stool specimens admitted to the pediatric emergency service of our hospital between April 1, 2019, and May 1, 2019, were included in our study. Demographic characteristics, laboratory results, and length of hospital stay of both groups of patients were evaluated retrospectively. The Shapiro--Wilk test was used for statistical analysis, whereas the Student t-test and the Mann--Whitney U-test were used for the comparison of quantitative variables, and the Pearson Chi-square test was used for the comparison of qualitative data. A value of p<0.05 was considered statistically significant. Results: Among the patients included in the study, 54.1% of the patients who tested positive for rotavirus antigen were girls and 45.9% were boys, whereas 45.1% of the patients in the control group were girls and 54.9% were boys. The ages of the subjects participating in the study were between 1 and 107 months in the study group and 2-163 months in the control group. Patients' length of stay was 1-47 h in the rotavirus antigen-positive group and 1-34 h in the control group. Evaluation of the number of hospital admissions revealed that recurrent admissions to the emergency department were more common in rotavirus cases, which constituted the study group. Discussion and Conclusion: It was observed that patients diagnosed with AGE who tested positive for the rotavirus antigen in the emergency department were younger, their length of hospital stay was longer, and the number of admissions to the emergency department was higher. Especially in viral gastroenteritis, unnecessary use of antibiotics should be avoided, and breast milk should be supported to prevent dehydration, as well as rotavirus vaccination, which is not yet in the national vaccination calendar, especially in the infant age group. [ABSTRACT FROM AUTHOR]

Rotavirus causes a gastrointestinal tract infection that primarily affects young children. Due to the COVID-19 pandemic, individuals infected with the virus were subjected to quarantine measures, with strong emphases on personal hygiene and social distancing. The present study aimed to evaluate the characteristics of rotaviruses and compare the prevalence of rotavirus infection before and during the COVID-19 pandemic. This nationwide representative study was conducted using data acquired from the National Health Insurance Service between 2010 and 2021. We analyzed the data of patients younger than 12 months old who were diagnosed with rotavirus enteritis between January 2010 and December 2021. During the study period, a total of 34,487 infants younger than 12 months were diagnosed with rotavirus enteritis in South Korea. During the two-year COVID-19 pandemic (2020–2021), the rate of decline was significant (5843 cases in 2010 and 1125 in 2019), and by 2021, the total number of patients was almost negligible, as there are only 18 cases in 2021. A significant increase in the ratio of low birth weight (LBW) infants of inpatient department was observed from 2010 to 2021 (4.86% in 2010; 7.77% in 2019; and 23.08% in 2021), indicating that LBW infants are more vulnerable than infants born with normal weight. Average medical expenses related to rotavirus infections also declined significantly from 3,789,443,998 per year (pre-pandemic) to 808,353,795 per year (pandemic). Overall, personal hygiene and social distancing may play important roles in reducing rotavirus infections. However, further studies are needed to determine whether this decreasing trend persists after quarantine and whether the social life of individuals resumes. [ABSTRACT FROM AUTHOR]

Bone marrow (BM) evaluation is highly important for the diagnosis of numerous hematological alterations in animals, especially cats, given their greater propensity for hematopoietic changes associated with retrovirus infections. This study aims to describe the main aspects of the BM of cats with different hematological conditions, comparing with reference intervals established from animals without hematological alterations and also with a previously established reference interval. To do so, we evaluated full blood and BM samples from 120 cats with no abnormalities on physical examination, negative for FeLV and FIV. Hemograms were performed from automated total cell and platelet and leukocyte differential counts in blood smears. BM samples were placed in Petri dishes; medullary spicules were selected to make up to eight cytological slides stained by the May–Grunwald–Giemsa technique, which were subjected to quantitative and cellular morphology evaluations. The cats were predominantly young, 64.2% female and 35.8% male. The average number of medullary spicules in samples was 13.7%, and density was 44%. In the BM quantitative analysis, prorubricytes and rubriblasts had higher quantities than the recommended one for all cats with or without hematological alterations. In all groups, lymphocytes were decreased, and cats with lymphocytosis were closest to the reference range, showing flame cells and Mott cells. The reference interval for the bone marrow cell count obtained from the samples in this work differs from previously established data, leading to different interpretations of the patient's BM condition, according to the cell population observed and the reference interval used. This divergence strongly emphasizes the need to correlate clinical, epidemiological, hematological, and bone marrow data of each patient for a better understanding of the patient's condition. The popularization of BM assessment is essential so that more reliable reference intervals can be established according to the population served by each pathologist and clinical laboratory. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent data suggest that feline lymphoma may no longer be strongly associated with viruses like feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV), possibly causing a change in the occurrence of specific anatomical subtypes and treatment outcomes. This study aimed to analyze this shift in disease presentation in a country with a low appearance of FIV/FeLV, such as the Netherlands, to investigate if these changes can be solely attributed to the prevalence of these viruses or if other risk factors should be considered. In total, 174 cats with large cell lymphoma (110 treated) during the last 10 years were included and compared to previous data from the Netherlands. This study demonstrates a shift in patient characteristics of cats with malignant lymphoma in the Netherlands, which could not be ascribed to differences in FIV/FeLV occurrence. While treatment response remained consistent, some anatomical subtypes showed longer disease-free periods. Feline lymphoma is currently less commonly associated with retrovirus infections as the feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV). This is thought to have caused a shift in the distribution of anatomical subtypes and eventually have led to poorer treatment outcomes. The aim of this study was to evaluate whether this change was also notable in the Netherlands, a country historically known for its low prevalence of FeLV and FIV, and to determine its consequences on treatment response. A 10-year cohort of 174 cats with large cell lymphoma (110 treated) were included and compared to historical data from previously published reports in the Netherlands. Of the 90 cats screened, only one tested positive for FeLV and three for FIV. The most current cohort had an increased age (median 8.7 years) and fever Siamese cats (6.3%) compared to previous reports, with alimentary (24.5%) and nasopharyngeal lymphoma (22.7%) being the most common subtypes. Sixty-six of the one hundred and ten cats (60%) went into complete remission, (CR) resulting in a median disease-free period (DFP) of 763 days, with nasopharyngeal and mediastinal having the longest DFP. The median overall survival time was 274 days with an estimated 1-year survival of 41.3% and a 2-year survival of 34.6%, respectively. Patient characteristics of cats with malignant lymphoma in the Netherlands have changed over the years, but this cannot be explained by differences in FeLV/FIV prevalence. Although the overall response rate to therapy did not change over time, for some lymphoma subtypes, longer DFPs were observed compared to 30 years ago. [ABSTRACT FROM AUTHOR]

Extracellular vesicles secreted from uveal melanoma (UM) cells are involved in the establishment of the premetastatic niche and display transforming potential for the formation of metastases, preferentially in the liver. In this study, we cultivated human primary UM cells and uveal melanoma-associated fibroblasts in vitro to be transduced by infection with a retrovirus containing the suicide gene—fused yeast cytosine deaminase::uracil phospho-ribosyl transferase (yCD::UPRT). A homogenous population of yCD::UPRT-UM cells with the integrated provirus expressed the gene, and we found it to continuously secrete small extracellular vesicles (sEVs) possessing mRNA of the suicide gene. The yCD::UPRT-UM-sEVs were internalized by tumor cells to the intracellular conversion of the prodrug 5-fluorocytosine (5-FC) to the cytotoxic drug 5-fluorouracil (5-FU). The host range of the yCD::UPRT-UM-sEVs was not limited to UMs only. The yCD::UPRT-UM-sEVs inhibited the growth of the human cutaneous melanoma cell line A375 and uveal melanoma cell line MP38, as well as other primary UMs, to various extents in vitro. The yCD::UPRT-UM-sEVs hold the therapeutic and prophylactic potential to become a therapeutic drug for UM. However, the use of yCD::UPRT-UM-sEVs must first be tested in animal preclinical studies. [ABSTRACT FROM AUTHOR]

Endogenous retroviruses (ERVs) record past retroviral infections, providing molecular archives for interrogating the evolution of retroviruses and retrovirus-host interaction. However, the vast majority of ERVs are not active anymore due to various disruptive mutations, and ongoing retroviral invasion of vertebrate genomes has been rarely documented. Here we analyze genomics data from 2004 vertebrates for mining invading ERVs (ERVi). We find that at least 412 ERVi elements representing 217 viral operational taxonomic units are invading the genomes of 123 vertebrates, 18 of which have been assessed to be threatened species. Our results reveal an unexpected prevalence of ongoing retroviral invasion in vertebrates and expand the diversity of retroviruses recently circulating in the wild. We characterize the pattern and nature of ERVi in the historical and biogeographical context of their hosts, for instance, the generation of model organisms, sympatric speciation, and domestication. We suspect that these ERVi are relevant to conservation of threatened species, zoonoses in the wild, and emerging infectious diseases in humans. Ongoing retroviral invasion into vertebrates has been rarely documented. Here the authors have identified 412 endogenous retroviruses that are invading the genomes of over a hundred vertebrate species. This may be relevant to conservation of threatened species, zoonoses in the wild, and emerging infectious diseases in humans. [ABSTRACT FROM AUTHOR]

Background: There are between 1 and 2 million annual deaths in children due to severe acute malnutrition. It's one of the leading preventable causes of death among kids every year. Severe acute malnutrition is a global problem that has been overlooked by child survival programs despite its criticality. Methods: The research was a descriptive study conducted in a hospital setting. During Department of Paediatric, Dhanalakshmi Srinivasan Medical College, Siruvachur, Perambalur, Tamil Nadu, India, research was carried out at the December 2021 to November, 2022. All hospitalized kids diagnosed with SAM per WHO criteria. Results: 100 children with Severe Acute Malnutrition were hospitalized. Age at onset was, on average, 17.75 months in most cases, infants were seen at 15 months of age. Sixty of the youngsters were younger than two years old. Seven girls and 93 boys made up the total of 100 SAM youngsters hospitalized. Conclusion: Children with SAM who are hospitalized often suffer from multiple co-occurring diseases, the most common of which are acute gastroenteritis and acute respiratory infections. Significant risk factors for mortality were the presence of underlying organic illness, as well as sepsis and retroviral infections. [ABSTRACT FROM AUTHOR]

Introduction: Human endogenous retroviruses (HERVs) are transcriptionally-active remnants of ancient retroviral infections that may play a role in Alzheimer's disease. Methods: We combined two, publicly available RNA-Seq datasets with a third, novel dataset for a total cohort of 103 patients with Alzheimer's disease and 45 healthy controls. We use telescope to perform HERV quantification for these samples and simultaneously perform gene expression analysis. Results: We identify differentially expressed genes and differentially expressed HERVs in Alzheimer's disease patients. Differentially expressed HERVs are scattered throughout the genome; many of them are members of the HERVK superfamily. A number of HERVs are correlated with the expression of dysregulated genes in Alzheimer's and are physically proximal to genes which drive disease pathways. Discussion: Dysregulated expression of ancient retroviral insertions in the human genome are present in Alzheimer's disease and show localization patterns that may explain how these elements drive pathogenic gene expression. [ABSTRACT FROM AUTHOR]