Search Results (336)

Prognostic uncertainty and missed diagnoses of sepsis remain frequent after cardiopulmonary bypass (CPB) surgery, where systemic inflammatory response (SIRS) arises from surgical trauma, blood activation in the extracorporeal circuit, ischemia/reperfusion injury, and endotoxin release. Among innovative biomarkers, pro-adrenomedullin (pro-ADM), particularly its stable fragment mid-regional pro-adrenomedullin (MR-proADM), has shown promise for detecting endothelial dysfunction and predicting organ failure in sepsis. SeptiCyte^® RAPID (Seattle, WA, USA) also represents a novel diagnostic tool that assesses the host immune response by quantifying PLA2G7 and PLAC8 gene expression in whole blood, offering potential for early differentiation between sepsis and sterile inflammation. We analyzed traditional and innovative biomarkers within 24 h post-CPB in a pilot group of patients admitted to the cardiac Intensive Care Unit of the “Città della Salute e della Scienza” University Hospital (Turin, Italy) between June and November 2023. Data from the following 14 patients were collected: 7 undergoing surgery for infective endocarditis (IE, Group 1) and 7 having standard elective cardiac surgery (Group 2). Procalcitonin (PCT), lactate, and pro-ADM increased in Group 1 but not in Group 2. SeptiCyte^® RAPID showed a moderate, borderline increase in Group 1. The innovative biomarkers had a good performance in patients exhibiting signs of organ dysfunction and in subjects demonstrating at least cardiovascular and/or pulmonary damage and under vasopressor and inotropic support. Although limited by the small sample, our preliminary data suggest no biomarker alterations in patients with standard elective cardiac surgery, unlike in those with IE. Full article

The COVID-19 pandemic exposed the urgent need for innovative tools to strengthen pandemic preparedness and health defense, especially in low- and middle-income countries (LMICs). While vaccination has been the cornerstone of the defense strategy against many infectious agents, there is a critical gap in vaccine equity, ensuring it is accessible to all, especially among the most vulnerable populations. The conventional vaccine delivery platforms, through parenteral administration, face notable limitations, including reliance on trained personnel, sterile conditions, and cold chain logistics. The parenteral vaccines often fail to induce robust mucosal immunity, which is critical for preventing infections at mucosal surfaces, the primary entry point for many pathogens. Bacillus subtilis, a Gram-positive, spore-forming bacterium, has emerged as a promising platform for mucosal vaccine delivery owing to its Generally Recognized as Safe (GRAS) status. Its robust spores are highly resilient to harsh environmental conditions, which may eliminate the need for cold chain storage and further facilitate distribution in LMICs. This review explores the potential of B. subtilis as a next-generation vaccine delivery platform, focusing on its unique characteristics, mechanisms of action, and applications in addressing global health challenges. This review also examines existing research demonstrating the safety, immunogenicity, and efficacy of B. subtilis spore-based vaccines while identifying limitations and future directions for optimization as a scalable and adaptable solution for resilient health defense, particularly in LMICs. Full article

Cardiovascular diseases hinge on a vicious, self-amplifying cycle in which mitochondrial deoxyribonucleic acid (mtDNA) dysfunction undermines cardiac bioenergetics and unleashes sterile inflammation. The heart’s reliance on oxidative phosphorylation (OXPHOS) makes it exquisitely sensitive to mtDNA insults—mutations, oxidative lesions, copy-number shifts, or aberrant methylation—that impair ATP production, elevate reactive oxygen species (ROS), and further damage the mitochondrial genome. Damaged mtDNA fragments then escape into the cytosol, where they aberrantly engage cGAS–STING, TLR9, and NLRP3 pathways, driving cytokine storms, pyroptosis, and tissue injury. We propose that this cycle represents an almost unifying pathogenic mechanism in a spectrum of mtDNA-driven cardiovascular disorders. In this review, we aim to synthesize the pathophysiological roles of mtDNA in this cycle and its implications for cardiovascular diseases. Furthermore, we seek to evaluate preclinical and clinical strategies aimed at interrupting this cycle—bolstering mtDNA repair and copy-number maintenance, reversing pathogenic methylation, and blocking mtDNA-triggered innate immune activation—and discuss critical gaps that must be bridged to translate these approaches into precision mitochondrial genome medicine for cardiovascular disease. Full article

Peripheral artery disease is a common manifestation of atherosclerosis, characterized by insufficient tissue perfusion and chronic ischemia. Arteriogenesis and angiogenesis are essential endogenous mechanisms to restore blood flow and limit ischemic injury. The metalloprotease ADAMTS13, known for cleaving ultra-large von Willebrand factor, has been implicated in thrombotic and inflammatory regulation. However, its role in ischemic vascular remodeling remains unclear. Using a murine hind limb ischemia model, we investigated the effect of ADAMTS13 deficiency on arteriogenesis and angiogenesis by comparing male ADAMTS13^−/− and wild-type control mice. Perfusion recovery, vascular cell proliferation, immune cell infiltration, and thrombotic activity were evaluated using laser Doppler measurements, immunohistochemical analysis of adductor and gastrocnemius muscle tissues, and in vivo microscopy. ADAMTS13 deficiency did not impair perfusion recovery, collateral artery growth, or capillarization. While platelet adhesion was slightly increased in ADAMTS13^−/− mice, no thrombotic occlusions were observed. Inflammatory responses, including macrophage and neutrophil infiltration as well as macrophage polarization, were largely unaffected. Despite previous in vitro evidence indicating an angiogenic role for ADAMTS13, its absence did not compromise angiogenesis in vivo. Our findings suggest that ADAMTS13 does not play a critical role in ischemia-related angiogenesis and arteriogenesis under sterile conditions and may be relevant only in contexts involving acute and sufficiently strong thromboinflammatory stimuli. Full article

Background/Objectives: Inactivation of the dnd gene involved in the development of primordial germ cells (PGCs) leads to the loss of gametes and halts reproductive development. Studies on sterile fish allow for the identification of genes and processes associated with GC differentiation. Methods: Atlantic salmon with GC-ablated testes were produced by temporal silencing of dnd. Gene expression was analyzed in sterile and fertile testes using 44k microarray and qPCR. Results: In sterile testes, transcripts of several GC markers were detected at low levels, suggesting the presence of cells with a GC-related expression profile that failed to initiate spermatogenesis. Expression of 260 genes was undetectable in the gonads of sterile males and females, and 61.5% of these were also inactivated during first maturation of fertile testes. This group was enriched with genes highly expressed in the brain, including those involved in endocrine and paracrine regulation, synaptic transmission, and numerous genes critical for brain development; among them, 45 genes encoding homeobox proteins. Another group of 229 genes showed increased expression in developing testes and included genes involved in neurosecretion and brain development regulation. GC-ablated testes showed increased expression of reproductive regulators such as amh and sdy and numerous immune genes, suggesting a reprogramming of GC-depleted testes. Temporal silencing of dnd indicated common developmental processes in the brains and gonads of Atlantic salmon testis that become inactive in testes at first maturation. These processes may play roles in PGC homing, the creation of a specific environment required for spermatogenesis, or facilitating communication between the gonads. Full article

The yolk sac (YS) plays a pivotal role in avian embryonic development, contributing to both haematopoiesis and immune maturation. This study aimed to evaluate the effects of in ovo administration of a commercial probiotic blend (Slab51^®) on YS cellular dynamics in chicken embryos. At embryonic day (ED) 18, Ross308 broiler eggs were injected with either the probiotic suspension (P) or sterile saline solution (C). YS tissues were sampled at 8, 12, 24 and 36 h post-inoculation for histological and immunohistochemical analysis. Probiotic-treated embryos exhibited a significant reduction in granulocytic foci within the YS, potentially reflecting enhanced peripheral migration of mature granulocytes. Concurrently, a progressive increase in Iba-1+ macrophages was observed in the probiotic group, suggesting accelerated macrophage differentiation. Immunophenotyping revealed a predominance of M1-iNOS+ macrophages across all timepoints, although a significant increase in M2-CD204+ macrophages was detected at 36 h in probiotic-treated embryos, indicating a possible anti-inflammatory shift. Furthermore, a marked increase in CD31+ endothelial cells in the probiotic group supports an associated rise in neo-angiogenesis. These findings suggest that in ovo probiotic administration modulates the YS microenvironment by promoting early macrophage recruitment, macrophage polarization and vascular remodeling. To our knowledge, this is the first report to demonstrate probiotic-induced structural and immunological alterations in the chicken embryo YS. These results provide novel insights into the early immunomodulatory effects of probiotics and highlight the potential of the YS as a key mediator of host–probiotic interaction during embryogenesis. Full article

Ploidy level exerts profound influences on the phenotypic and physiological traits of Crassostrea gigas. Compared to diploids, triploids exhibit desirable characteristics such as sterility, a faster growth rate, and improved meat quality. In contrast, tetraploids often suffer from slow growth, yet the mechanisms underlying these polyploid-associated traits remain unclear. This study aimed to elucidate these mechanisms by comparing differences in growth-related phenotypes and gene expression among diploid, triploid, and tetraploid oysters. We identified 1533 differentially expressed genes (DEGs) between diploids and triploids, 946 DEGs between triploids and tetraploids, and 1326 DEGs between diploids and tetraploids. Through trend analysis, we clustered genes with similar expression changes across ploidy levels and conducted functional enrichment analysis on these gene clusters. The results revealed that genes associated with the innate immune response were significantly up-regulated in tetraploids, whereas genes related to biomineralization and metabolism were markedly up-regulated in triploids. These findings suggest that tetraploid oysters may mount a stronger innate immune response compared to diploids and triploids, while triploids demonstrate superior growth performance. This study provides valuable resources for investigating the functional aspects of genes related to polyploid phenotype differences. Full article

Prostate cancer (PCa) is the most common genitourinary malignancy in men, with a multifactorial etiology influenced by genetic, environmental, and microbial determinants. Although the prostate was traditionally considered sterile, advances in microbiome research have challenged this view, revealing potential links between microbial communities and PCa development, progression, and treatment response. This review synthesizes evidence on the gut, urinary, seminal fluid, and prostatic microbiomes, highlighting their potential contributions to PCa pathogenesis and therapeutic outcomes. Key studies utilizing next-generation sequencing (NGS), whole-genome sequencing (WGS), PCR, and metagenomic analyses have identified specific bacterial and fungal taxa associated with Pca; however, findings remain inconsistent across methodologies and cohorts. Microorganisms such as Propionibacterium acnes and Pseudomonas spp. may modulate inflammation, immune responses, and resistance to androgen-deprivation therapy. Further research is required to determine whether microbial signatures can serve as reliable biomarkers for early detection, prognosis, or novel therapeutic strategies in PCa management. Full article

This study provides the first long-term, cross-border evaluation of Lithuanian potato (Solanum tuberosum L.) cultivars, integrating agronomic performance, tuber quality, and resistance to major pathogens across diverse environments. Field and controlled trials conducted in Lithuania and Ukraine from 2014 to 2024 revealed substantial genetic variability among 14 national cultivars, enabling their classification into five distinct maturity groups. Maincrop cultivars outperformed others in yield and starch accumulation, with ‘VB Meda’, ‘Goda’, and ‘VB Aista’ exhibiting a superior balance of productivity (up to 49 t ha⁻¹), starch content (>19%), and moderate-to-high resistance to Phytophthora infestans. A broader genetic screening of 287 accessions—including varieties, breeding lines, and hybrids—demonstrated wide diversity in phenological development, disease resistance, and reproductive traits. Notably, Ro₁ pathotype resistance was identified in 85 genotypes, predominantly with yellow-skinned tubers, while genotypic sterility in flowering and berry set was associated with both parental lineage and elevated temperatures. Although no complete immunity to P. infestans was detected, several genotypes displayed stable polygenic field resistance, suggesting the presence of horizontally inherited defense mechanisms effective under variable agroclimatic conditions. These results underscore the strategic breeding potential of Lithuanian potato germplasm for developing high-performing cultivars with enhanced resilience to late blight and nematodes and offer valuable insights for climate-adapted potato breeding in Northern and Eastern Europe. Full article

The breast microbiome remains stable throughout a woman’s life. The breast is not a sterile organ, and its microbiota exhibits a distinct composition compared to other body sites. The breast microbiome is a community characterized by an abundance of Proteobacteria and Firmicutes, which represent the result of host microbial adaptation to the fatty acid environment in the tissue. The breast microbiome demonstrates dynamic adaptability during lactation, responding to maternal physiological changes and infant interactions. This microbial plasticity modulates local immune responses, maintains epithelial integrity, and supports tissue homeostasis, thereby influencing both breast health and milk composition. Disruptions in this balance, the dysbiosis, are closely linked to inflammatory breast conditions such as mastitis. Risk factors for breast cancer (BC) include genetic mutations, late menopause, obesity, estrogen metabolism, and alterations in gut microbial diversity. Gut microbiota can increase estrogen bioavailability by deconjugating estrogen-glucuronide moieties. Perturbations of this set of bacterial genes and metabolites, called the estrobolome, increases circulating estrogens and the risk of BC. Fusobacterium nucleatum has recently been associated with BC. It moves from the oral cavity to other body sites hematogenously. This review deals with the characteristics of the breast microbiome, with a focus on F. nucleatum, highlighting its dual role in promoting tumor growth and modulating immune responses. F. nucleatum acts both on the Wnt/β-catenin pathway by positively regulating MYC expression and on apoptosis by inhibiting caspase 8. Furthermore, F. nucleatum binds to TIGIT and CEACAM1, inhibiting T-cell cytotoxic activity and protecting tumor cells from immune cell attack. F. nucleatum also inhibits T-cell function through the recruitment of myeloid suppressor cells (MDSCs). These cells express PD-L1, which further reduces T-cell activation. A deeper understanding of F. nucleatum biology and its interactions with host cells and co-existing symbiotic microbiota could aid in the development of personalized anticancer therapy. Full article

Inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) are chronic immune-mediated inflammatory diseases (IMIDs) that affect the gastrointestinal and hepatobiliary systems. They are characterized by persistent inflammation, potentially progressive fibrosis, and an elevated risk of developing cholangiocarcinoma and colorectal cancer. IBD and PSC share phenotypical, genetic, and immunological features, largely due to the central role of immune cell dysregulation. Despite their increasing global prevalence, the underlying drivers remain poorly understood, and effective treatment options are still lacking. Efforts towards an improved comprehension of their pathogenic mechanisms are therefore pivotal. Emerging evidence highlights the role of canonical ASC-dependent inflammasomes—multiprotein bioactive Interleukin (IL)-1-producing complexes of the innate immune system—and serum amyloid A (SAA) as key structures of gastrointestinal and hepatobiliary inflammation, tissue remodeling, stromal crosstalk, and fibrosis. In this review, we explore immunological connections and analogies between IBD and PSC, highlighting the converging roles of canonical ASC-dependent inflammasomes, the IL-1 superfamily, SAA, and sustained gut microbiota-driven chronic inflammation in disease pathology and their surging potential as therapeutic targets across the gut–liver axis. Full article

Peripheral nerve injuries affect over one million individuals annually worldwide due to various causes such as trauma, metabolic disorders, and autoimmune diseases. While autologous nerve grafting remains the gold standard for treating large-gap nerve injuries, its limitations, including limited tissue availability, donor site morbidity, infection risk, and suboptimal functional recovery, have spurred interest in alternative approaches. Among these, allogeneic nerve grafting has emerged as a promising option, offering structural and functional advantages due to the native architecture of donor nerves. However, immune rejection due to histocompatibility antigens remains a significant challenge. Decellularisation protocols utilising mild detergents have shown the most promise in preserving the extracellular matrix’s structural and regenerative properties while mitigating immunogenicity. The study aimed to adapt and validate a decellularisation protocol for human nerves within our tissue bank, adhering to European and national regulatory guidelines. The protocol, based on the cleanroom-compliant method previously developed by our group, was optimised to reduce tissue handling time and ensure regulatory compliance. Decellularised sural nerves were assessed for extracellular matrix preservation and sterility using European (EU) Pharmacopoeia and European Directorate for the Quality of Medicines & HealthCare (EDQM) guidelines. The results demonstrated the feasibility of producing high-quality acellular nerve allografts (ANAs) that are suitable for peripheral nerve repair, paving the way for cost-effective and widely accessible grafting solutions. Full article

Mammals harbor diverse microbial communities across different body sites, which are crucial to physiological functions and host homeostasis. This study aimed to understand the structure and function of gut and lung microbiota of pregnant Pomona leaf-nosed bats using V3-V4 16S rRNA gene sequencing. Of the 350 bats captured using mist nets in Yunnan, nine pregnant Pomona leaf-nosed bats with similar body sizes were chosen. Gut and lung samples were aseptically collected from each bat following cervical dislocation and placed in sterile cryotubes before microbiota investigation. Microbial taxonomic annotation revealed that the phyla Firmicutes and Actinobacteriota were most abundant in the guts of pregnant bats, whereas Proteobacteria and Bacteroidota were abundant in the lungs. Family-level classification revealed that Bacillaceae, Enterobacteriaceae, and Streptococcaceae were more abundant in the guts, whereas Rhizobiaceae and Burkholderiaceae dominated the lungs. Several opportunistic and potentially pathogenic bacterial genera were present at the two body sites. Bacillus, Cronobacter, and Corynebacterium were abundant in the gut, whereas Bartonella, Burkholderia, and Mycoplasma dominated the lungs. Alpha diversity analysis (using Chao1 and Shannon indices) within sample groups examined read depth and species richness, whereas beta diversity using unweighted and weighted UniFrac distance metrics revealed distinct clustering patterns between the two groups. LEfSe analysis revealed significantly enriched bacterial taxa, indicating distinct microbial clusters within the two body sites. The two Random Forest classifiers (MDA and MDG) evaluated the importance of microbial features in the two groups. Comprehensive functional annotation provided insights into the microbiota roles in metabolic activities, human diseases, signal transduction, etc. This study contributes to our understanding of the microbiota structure and functional potential in pregnant wild bats, which may have implications for host physiology, immunity, and the emergence of diseases. Full article

Background/Objectives: Radiolabeled interleukin-2 (IL2) could allow for imaging activated T-lymphocytes in the tumor microenvironment (TME). The aims of this study were to assess the shelf life of a lyophilized kit containing THP-desIL2 to allow for the labeling of IL2 with ⁶⁸Ga at room temperature and to test the in vitro binding of ⁶⁸Ga-THP-desIL2 on different T-cell populations in order to determine which specific T-cell subset expresses the CD25 subunit of the IL2 receptor (IL2R). Methods: desIL2 was conjugated with THP and lyophilized. ⁶⁸Ga labeling was performed and several quality controls, including HPLC, iTLC and SDS-PAGE, were carried out at different storage times (1, 3 and 6 months) and temperatures (4 °C and −80 °C). Moreover, flow cytometric analysis on different T-cell populations and the in vitro and competitive binding of ⁶⁸Ga-THP-desIL2 were performed. Results: The lyophilized kit of THP-desIL2 was stable up to 6 months at −80 °C, preserving its sterility, integrity and acceptable values of labeling yield (51.80 ± 3.74%), radiochemical purity (>96%) and specific activity (5.59 ± 0.40 MBq/µg). Binding of ⁶⁸Ga-THP-desIL2 on activated lymphocytes was specific and exhibited a low dissociation constant from IL2R on stimulated Tregs (Kd: 10⁻⁹–10⁻¹⁰ mol/L). Conclusions: We assessed the shelf life of a lyophilized kit containing THP-desIL2 for the easy labeling of IL2 with ⁶⁸Ga at room temperature. The kit can be stored at −80 °C up to 6 months, thus facilitating the adoption of ⁶⁸Ga-THP-desIL2 into clinical practice. ⁶⁸Ga-THP-desIL2 showed high affinity and specificity for CD25 on activated T-lymphocytes, particularly Tregs, thus opening new opportunities for imaging immune cells trafficking in the TME. Full article

The term “vaccine” has been broadly and inconsistently applied to a range of products with widely divergent immunological outcomes, leading to the erosion of public trust and confusion among both medical professionals and the public. Historically, and by broad public understanding, a vaccine is expected to prevent infection, transmission, and disease through the induction of sterilizing, or true neutralizing immunity, specifically, the prevention of pathogen entry and replication in vivo. This ideal extends beyond the mere elicitation of neutralizing antibodies demonstrable in vitro. This paper proposes a three-tier classification system designed to differentiate products currently designated as “vaccines,” specifically to address the distinction between those that meet the traditional, highest-expectation definition (Tier 1), therapeutic vaccines that primarily prevent disease (Tier 2), and immunomodulatory therapeutics that primarily reduce disease severity (Tier 3). By detailing the mechanism of action of each product and emphasizing the urgent need for this refined classification, our aim is to restore public confidence in vaccination programs, improve understanding of vaccine-induced immunity among healthcare professionals, and empower informed decision-making by the public. We argue that a clearer understanding of vaccine capabilities will ultimately lead to increased vaccine uptake for those vaccines that do prevent infection, transmission, and disease. Full article