Search Results (770)

Background: Acute kidney injury (AKI) remains a serious complication among individuals with type 2 diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed and often regarded as kidney-protective, yet post-marketing reports have linked them to AKI. Tirzepatide, a newer dual GIP/GLP-1 agonist, shows well-documented metabolic benefits, but its renal safety in real-world use is not well characterized. Methods: We conducted a disproportionality analysis of the U.S. FDA Adverse Event Reporting System (FAERS) from January 2022 to September 2025. Reporting odds ratios (RORs) and proportional reporting ratios (PRRs) were used to compare AKI reporting between tirzepatide and semaglutide. Results: Among 133,872 reports (92,807 tirzepatide; 41,065 semaglutide), AKI was listed in 432 (0.47%) and 440 (1.07%) cases, respectively. The ROR for tirzepatide versus semaglutide was 0.44 (95% CI, 0.38–0.50), suggesting a lower reporting frequency for AKI with tirzepatide. Conclusions: In this real-world pharmacovigilance analysis, semaglutide but not tirzepatide showed a disproportionality signal for AKI. While causality cannot be confirmed, clinicians should ensure hydration and renal monitoring when initiating GLP-1 RAs, particularly semaglutide. Semaglutide showed a higher AKI reporting rate than tirzepatide, though these findings should be interpreted cautiously given reporting bias and potential confounders. Both agents appear safe, with low AKI frequency in practice. Further studies should determine if differences reflect biological or reporting effects. These findings support the need for larger epidemiologic studies to define risk modifiers and optimize clinical safety strategies. Full article

Background: Stomatitis is a common adverse event associated with targeted therapies for hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer, particularly those inhibiting the PI3K/AKT/mTOR pathway. While mTOR-inhibitor-associated stomatitis is well established, less is known about its occurrence with other kinase inhibitors in real-world settings. We performed a pharmacovigilance disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) to evaluate stomatitis reports for alpelisib, capivasertib, everolimus, and palbociclib. Methods: Events were identified using four term sets—Stomatitis, Original Trial Terms (OTT), Comprehensive Trial Terms (CTT), and Stomatitis-Associated Main Terms (SAMT)—which reflect varying definitions and medical terminologies. Disproportionality analyses using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Information Component (IC) were calculated with 95% confidence intervals. Results: All agents showed ROR and PRR >1, indicating higher odds and reporting proportions of stomatitis compared with other drugs. These findings were confirmed by IC analysis. Everolimus demonstrated the strongest association (ROR: 30.72 [29.61–31.88]), followed by alpelisib (ROR: 13.11 [11.79–14.58]) and palbociclib (ROR: 11.73 [11.35–12.11]). Capivasertib had the lowest reporting odds (ROR: 3.14 [1.81–5.43]), though limited by fewer reports. Differences between CTT and SAMT were minimal (~2%). Conclusions: These results support the use of the SAMT as an efficient screening tool. Furthermore, these findings underscore the need for optimized stomatitis detection and continued monitoring, particularly for PI3K and mTOR inhibitors, in both clinical trials and postmarketing surveillance. Full article

The stimulator of interferon genes (STING) serves as a pivotal signaling hub in innate immunity, orchestrating type I interferon (IFN-I) and pro-inflammatory responses upon detection of cytosolic DNA. While the canonical cyclic GMP-AMP synthase (cGAS)-STING axis has been extensively studied in host defense and sterile inflammation, increasing evidence indicates that STING can also be activated through a variety of both pattern recognition receptors (PRRs)-dependent and PRRs-independent mechanisms. In this review, we comprehensively summarize the molecular pathways through which PRRs—including cGAS, interferon gamma inducible protein 16 (IFI16), DEAD-box helicase 41 (DDX41), and DNA-dependent protein kinase (DNA-PK)—engage and regulate STING activation. Beyond PRRs-triggered pathways, we explore emerging evidence of PRRs-independent STING activation, driven by genetic mutations, endoplasmic reticulum (ER) stress, dysregulated intracellular trafficking, and impaired protein degradation. These mechanisms contribute to the pathogenesis of a broad spectrum of inflammatory and autoimmune disorders affecting multiple organ systems, including the digestive, cardiovascular, renal, pulmonary, and nervous systems. We also highlight the current landscape of pharmacological inhibitors targeting cGAS and STING, categorized according to their mechanisms of action and therapeutic potential. The redundancy and complexity of components within the STING signaling network present challenges in effectively suppressing inflammatory overactivation by targeting a single molecule. Nevertheless, the central role of STING offers multiple opportunities for therapeutic intervention, whether by modulating upstream or downstream signaling elements. This review not only provides a systematic framework for understanding the intricacies of STING signaling, but offers insights into the development of next-generation therapeutics aimed at selectively modulating STING activity in disease contexts. Full article

This paper presents a novel method for locally estimating vehicle density on highways based on vehicle-to-vehicle (V2V) communication, a communication mode within intelligent transport systems (ITSs), enabled via IEEE 802.11p and 3GPP C-V2X technologies. Awareness messages (AMs), such as basic safety messages (BSMs, SAE J2735) and cooperative awareness messages (CAMs, ETSI EN 302 637-2), are periodically broadcast by vehicles and can be leveraged to sense the presence of nearby vehicles. Unlike existing approaches that directly combine the number of sensed vehicles with measured packet reception ratio (PRR) of the AM, our method accounts for the deviations in PRR caused by imperfect channel conditions. To address this, we estimate the actual packet reception probability (PRP)–distance curve by exploiting its inherent downward trend along with multiple measured PRR points. From this curve, two metrics are introduced: node awareness probability (NAP) and average awareness ratio (AAR), the latter representing the ratio of sensed vehicles to the total number of vehicles. The real density is then estimated using the number of sensed vehicles and AAR, mitigating the underestimation issues common in V2V-based methods. Simulation results across densities ranging from 0.02 vehs/m to 0.28 vehs/m demonstrate that our method improves estimation accuracy by up to 37% at an actual density of 0.28 vehs/m, compared with methods relying solely on received AMs, without introducing additional communication overhead. Additionally, we demonstrate a practical application where the basic safety message (BSM) transmission rate is dynamically adjusted based on the estimated density, thereby improving traffic management efficiency. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant cause of economic loss in the swine industry, yet its control remains challenging in wean-to-harvest sites. This prospective observational study followed 95 wean-to-harvest sites across six U.S. states for one production cycle. Sites were required to be PRRSV-negative or vaccinated with a modified live virus (MLV) and free of major coronaviruses. Outbreaks were defined as RT-qPCR-positive in unvaccinated sites or detection of ORF5 sequences distinct from the MLV strain. Biosecurity data were collected through a survey, and oral fluids were tested every four weeks. PRRS outbreaks occurred in 14/42 nurseries (33.3%), 8/12 wean-to-finish (66.7%), and 35/41 finishers (82.4%), with lineage 1C.5 most frequently detected. In univariate models, higher odds of outbreaks were associated with transporting pigs of unknown status (OR 9.80, 1.73–55.37), rendering (OR 6.47, 1.62–25.84), and employee cohabitation (OR 6.15, 1.51–25.09). Protective factors included exclusive pumping equipment (OR 0.07, 0.01–0.43) and overnight downtime for multi-site workers (OR 0.15, 0.04–0.56). In multivariable models, finisher sites (OR 17.47, 2.44–125.19) and greater swine site density within one mile (OR 1.62, 1.09–2.41) significantly increased outbreak odds. These results support targeted biosecurity practices, helping farmers and the swine industry reduce PRRS outbreaks. Full article

Ilex verticillata (winterberry) is a valuable ornamental shrub increasingly threatened by leaf blight, a disease that compromises its aesthetic and economic value. While fungal pathogens like Alternaria alternata are known to cause leaf blight in horticultural crops, their role in I. verticillata and the host’s defense mechanisms have not been fully characterized. Our study investigated the pathogen-host interaction by identifying the causal agent and examining the physiological and molecular defense mechanisms of I. verticillata. Through morphological and multi-locus molecular analyses (ITS, TEF1-α, G3PDH, RPB2), A. alternata was confirmed as the primary pathogen, fulfilling Koch’s postulates. Pathogenicity assays revealed distinct disease progression stages, from necrotic lesions to tissue degradation. Transcriptomic profiling uncovered dynamic host responses, with early upregulation of pattern recognition receptors (PRRs) and transcripts encoding antioxidant enzymes (SOD, CAT), followed by downregulation of metabolic pathway genes. Phytohormone analysis highlighted intricate crosstalk, with salicylic acid (SA) peaking during mid-infection and jasmonic acid (JA) rebounding later, reflecting a coordinated defense strategy. Additionally, the oxidative stress marker malondialdehyde (MDA), an indicator of membrane lipid peroxidation, surged early, indicating membrane damage, while sustained induction of antioxidant enzymes suggested adaptive responses. The key finding was distinct phytohormone crosstalk, characterized by a mid-infection SA peak followed by a late JA rebound, alongside an early oxidative burst marked by MDA accumulation and sustained antioxidant enzyme activity. These findings provide a framework for understanding I. verticillata’s defense mechanisms and offer insights for developing targeted disease management strategies, such as resistant cultivar breeding or hormone-mediated interventions. Full article

LoRa is a long-range, low-power wireless communication technology widely used in Internet of Things (IoT) applications. However, its conventional implementation through Long Range Wide Area Network (LoRaWAN) presents operational constraints due to its centralized topology and reliance on gateways. To overcome these limitations, this work designs and validates a gateway-free mesh communication system that operates directly on commercially available commodity microcontrollers, implementing lightweight self-healing mechanisms suitable for resource-constrained devices. The system, based on ESP32 microcontrollers and LoRa modulation, adopts a mesh topology with custom mechanisms including neighbor-based routing, hop-by-hop acknowledgments (ACKs), and controlled retransmissions. Reliability is achieved through hop-by-hop acknowledgments, listen-before-talk (LBT) channel access, and duplicate suppression using alternate link triggering (ALT). A modular prototype was developed and tested under three scenarios such as ideal conditions, intermediate node failure, and extended urban deployment. Results showed robust performance, achieving a Packet Delivery Ratio (PDR), the percentage of successfully delivered DATA packets over those sent, of up to 95% in controlled environments and 75% under urban conditions. In the failure scenario, an average Packet Recovery Ratio (PRR), the proportion of lost packets successfully recovered through retransmissions, of 88.33% was achieved, validating the system’s self-healing capabilities. Each scenario was executed in five independent runs, with values calculated for both traffic directions and averaged. These findings confirm that a compact and fault-tolerant LoRa mesh network, operating without gateways, can be effectively implemented on commodity ESP32-S3 + SX1262 hardware. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes significant economic losses in swine production. In May 2021 and March 2023, we detected PRRSV genes in serum samples from two weaned pigs with respiratory disorders on a farm in Japan. Partial gene sequences of these strains closely resembled those of a PRRS vaccine strain. We subsequently isolated two PRRSV field strains, KU-IG21-1 and KU-IG23-1, from the 2021 and 2023 samples, respectively. The KU-IG21-1 strain exhibited more pronounced cytopathic effects and significantly higher replication efficiency in cultured cells compared to both the vaccine and KU-IG23-1 strains. Despite these phenotypic differences, complete genome sequencing revealed high genetic similarity between the field isolates and the vaccine strain, with only 16 and 24 amino acid differences in the KU-IG21-1 and KU-IG23-1 strains, respectively. These findings suggest that the field strains likely emerged through the accumulation of point mutations in the vaccine strain rather than through homologous recombination. Furthermore, we identified three amino acid substitutions that may contribute to the enhanced replication of the KU-IG21-1 strain. This study underscores the potential impact of point mutations on PRRSV phenotypes and provides new insights into the complex evolutionary dynamics of PRRSV. Full article

Porcine Reproductive and Respiratory Syndrome (PRRS) causes significant economic losses in the swine industry. Circular RNAs (circRNAs), a class of stable non-coding RNAs, are increasingly recognized as regulators in immune responses and host–virus interactions. This study investigated the genome-wide circRNA responses in porcine alveolar macrophages (PAMs), key cell targets of PRRSV, following treatment with a modified live virus (MLV) vaccine or two interferon (IFN) subtypes (IFN-α1, IFN-ω5). Using RNA sequencing, we identified over 1000 differentially expressed circRNAs across treatment groups, revealing both conserved and distinct expression profiles. Gene Ontology and KEGG pathway analyses indicated that circRNA-associated genes are significantly enriched in immune-related processes and pathways, including cytokine signaling and antiviral defense. Notably, IFN-ω5 treatment induced a pronounced circRNA response, aligning with its potent antiviral activity. We further explored the regulatory potential of these circRNAs by predicting miRNA binding sites, revealing complex circRNA-miRNA interaction networks. Additionally, we assessed the coding potential of differentially expressed circRNAs by identifying open reading frames (ORFs), internal ribosome entry sites (IRESs), and N6-methyladenosine (m⁶A) modification sites, suggesting a subset may undergo non-canonical translation. These findings provide a comprehensive landscape of circRNA expression in PAMs under different antiviral conditions, highlighting their potential roles as immune regulators and novel players in interferon-mediated antiviral responses, particularly downstream of IFN-ω5. This work contributes to understanding the non-coding RNA landscape in the PRRSV-swine model and suggests circRNAs as potential targets for future antiviral strategies. Full article

This review investigates genetic strategies aimed at improving robustness in pigs to enhance disease resistance and reduce reliance on antibiotics. Robustness refers to a pig’s ability to stay healthy and productive under stressful or challenging conditions. The review outlines current breeding practices focused on key traits such as maternal ability, growth, immune function, and survival, and highlights that these robustness-related traits show measurable heritability, making them suitable for genetic improvement. Special attention is given to resistance against porcine reproductive and respiratory syndrome (PRRS), a major disease in swine. We also evaluate breed-specific differences, environmental influences, and immune response profiles, emphasizing their impact on breeding outcomes. The development of robust pig lines emerges as a sustainable strategy to reduce antibiotic dependence and enhance herd health. A distinctive contribution of this work is the integration of genetic robustness and resilience strategies with antibiotic stewardship objectives. We link genomic selection, advanced phenotyping, and targeted management interventions within a One Health framework to outline actionable, system-level pathways for reducing antimicrobial inputs. To our knowledge, this combined genetic and public health perspective has not been comprehensively addressed previously. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is recognized by pattern recognition receptors (PRRs), which play a vital role in triggering innate immune responses such as the production of type I and III interferons (IFNs). While modest PRR activation helps to defend against SARS-CoV-2, excessive or sustained activation can cause harmful inflammation and contribute to severe Coronavirus Disease 2019 (COVID-19). Altered expression of Toll-like receptors (TLRs), which are among the most important members of the PRR family members, particularly TLRs 2, 3, 4, 7, 8 and 9, has been strongly linked to COVID-19 severity. Furthermore, retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), collectively known as RLRs (RIG-I-like receptors), act as sensors that detect SARS-CoV-2 RNA. The expression of these receptors, as well as that of different DNA sensors, varies in patients infected with SARS-CoV-2. Changes in PRR expression, particularly that of TLRs, cyclic GMP-AMP synthase (cGAS), and the stimulator of interferon genes (STING), have also been shown to play a role in the development and persistence of long COVID (LC). However, SARS-CoV-2 has evolved strategies to evade PRR recognition and subsequent signaling pathway activation, contributing to the IFN response dysregulation observed in SARS-CoV-2-infected patients. Nevertheless, PRR agonists and antagonists remain promising therapeutic targets for SARS-CoV-2 infection. This review aims to describe the PRRs involved in recognizing SARS-CoV-2, explore their expression during SARS-CoV-2 infection, and examine their role in determining the severity of both COVID-19 and long-term manifestations of the disease. It also describes the strategies developed by SARS-CoV-2 to evade PRR recognition and activation. Moreover, given the considerable interest in modulating PRR activity as a novel immunotherapy approach, this review will provide a description of PRR agonists and antagonists that have been investigated as antiviral strategies against SARS-CoV-2. This review aims to explore the complex interplay between PRRs and SARS-CoV-2 in depth, considering its implications for prognostic biomarkers, targeted therapeutic strategies and the mechanistic understanding of long LC. Additionally, it outlines future perspectives that could help to address knowledge gaps in PRR-mediated responses during SARS-CoV-2 infection. Full article

This article examines how populist radical right parties (PRR) in three contrasting European contexts—Slovenia, France, and Poland—strategically instrumentalize Christianity within their anti-immigration agendas. Rather than using religion as a matter of faith, these parties recast Christianity as a cornerstone of national and European identity, positioning it in opposition to Islam and non-European migration. The study argues that such instrumentalization serves not only to construct a religiously defined national identity, but also to legitimize exclusionary policies. By analyzing selected political speeches, party manifestos, and media discourse, we explore how far-right actors frame Islam as incompatible with European values, reinforcing the division between “Christian Europe” and “foreign non-Christian migrants.” Drawing on recent scholarship on civilizational populism and religious boundary-making, we further assess how processes of globalization and European integration have been interpreted by populist parties to fuel anti-immigrant sentiment. Methodologically, we employ qualitative content analysis to identify recurring themes and rhetorical strategies, with a focus on the intersection of religion, nationalism, and migration. The findings contribute to debates on religious pluralism in contemporary Europe, shedding light on how far-right populism reframes pluralism and challenges secular principles across different political and cultural settings. Full article

The human microbiome plays a central role in modulating the immune system and maintaining immunophysiological homeostasis, contributing to the prevention of immune-mediated diseases. In particular, the gut microbiota is a key ecosystem for immune system maturation, especially in early life. This review aimed to analyze the molecular and cellular mechanisms linking the microbiome to immune and neuronal functions, as well as the impact of dysbiosis and emerging therapeutic strategies targeting the microbiome. The analysis was based on scientific databases, prioritizing studies published since 2000, with special emphasis on the past decade. The microbiome influences immune signaling through microorganism-associated molecular patterns (MAMPs) and pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). Additionally, microbial metabolites—such as short-chain fatty acids (SCFAs), tryptophan derivatives, and secondary bile acids—exert significant immunomodulatory effects. The intestinal epithelial barrier is also described as an active immunological interface contributing to systemic regulation. The literature highlights innovative therapies, including fecal microbiota transplantation (FMT), probiotics, and microbiome editing with CRISPR-Cas technologies. These strategies aim to restore microbial balance and improve immune outcomes. The growing body of evidence positions the microbiome as a valuable clinical and diagnostic target, with significant potential for application in personalized medicine. Full article

The landscape of cancer immunotherapy must shift from personalized neoantigen vaccines toward universal platforms that leverage innate immune activation. This review examines a novel mRNA vaccine strategy that encodes non-tumor-specific antigens, carefully selected pathogen-derived or synthetic sequences designed to transform immunologically “cold” tumors into inflamed therapy-responsive microenvironments. Unlike conventional approaches requiring patient-specific tumor sequencing and 8–12-week manufacturing timelines, this platform utilizes pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to trigger broad innate immune activation through multiple pattern recognition receptors (PRRs). The key therapeutic mechanism is epitope spreading, where vaccine-induced inflammation reveals previously hidden tumor antigens, enabling the immune system to mount responses against cancer-specific targets without prior knowledge of these antigens. Delivered via optimized lipid nanoparticles (LNPs) or alternative polymer-based systems, these vaccines induce epitope spreading, enhance checkpoint inhibitor responsiveness, and establish durable antitumor memory. This approach offers several potential advantages, including immediate treatment availability, a cost reduction of up to 100-fold compared to personalized vaccines, scalability for global deployment, and efficacy across diverse tumor types. However, risks such as cytokine release syndrome (CRS), potential for off-target autoimmunity, and challenges with pre-existing immunity must be addressed. By eliminating barriers of time, cost, and infrastructure, this universal platform could help democratize access to advanced cancer treatment, potentially benefiting the 70% of cancer patients in low- and middle-income countries (LMICs) who currently lack immunotherapy options. Full article

Background: Tirzepatide (Mounjaro or Zepbound), a dual GLP-1/GIP receptor agonist, is approved for type 2 diabetes and weight management. Despite its efficacy, real-world safety data remain limited. This study analyzed post-marketing adverse events (AEs) associated with tirzepatide using the FDA Adverse Event Reporting System (FAERS) to identify emerging safety concerns. Methods: FAERS reports from 2022 to Q1 2025 were analyzed. Disproportionality analyses (proportional reporting ratio [PRR], reporting odds ratio [ROR], empirical Bayes geometric mean [EBGM], and information component [IC]) were performed to detect safety signals. Reports were stratified by year, demographics, and AE type, focusing on cases in which tirzepatide was the primary suspect. Results: Among 65,974 reports, the majority originated from the U.S. (96%), with middle-aged females (40–59 years; 67%) most frequently affected. Incorrect dose administration was the top AE, increasing 8-fold from 1248 (2022) to 9800 (2024), with strong risk signals (ROR 22.15, 95% CI (20.75–23.65), and ROR 23.43, 95% CI (22.82–24.05), respectively, and PRR 16.80, 95% CI (15.74–17.93), and PRR 17.62, 95% CI (17.16–18.09), respectively). Other common AEs included injection-site reactions (e.g., pain [5273 cases in 2024]), gastrointestinal issues (nausea [3602 in 2024]), and off-label use. Class-related AEs (e.g., decreased appetite and blood glucose fluctuations) were also reported. Conclusions: Tirzepatide is associated with significant dosing errors, injection-site reactions, and gastrointestinal AEs in real-world use. The rising trend in reports underscores the need for enhanced provider and patient education, clearer dosing guidelines, and proactive monitoring. Further research is warranted to explore causative factors and optimize risk mitigation strategies. Full article