Search Results (589)

Background/Objectives: Fusarium wilt of cotton, caused by Fusarium oxysporum f. sp. vasinfectum (FOV), is a destructive vascular disease that severely impacts cotton production. Among its variants, race 4 (FOV4) is especially aggressive, leading to early season stand losses and yield reductions. While resistant cultivars of Gossypium barbadense (pima cotton) have been developed, the molecular basis of this resistance remains unclear. This study aimed to characterize transcriptomic responses associated with FOV4 resistance in pima cotton. Methods: We conducted an in vitro infection assay using two G. barbadense cultivars with contrasting phenotypes: the highly resistant ‘DP348RF’ and the highly susceptible ‘GB1031’. Root tissues were sampled at multiple stages of infection, and RNA sequencing was performed to identify differentially expressed genes and pathways contributing to resistance. Results: Resistant plants ‘DP348RF’ showed strong induction of genes related to reactive oxygen species (ROS) metabolism, chitinase activity, and lignification compared to the susceptible cultivar. Notably, genes involved in the biosynthesis and reinforcement of the Casparian strip, a critical biochemical barrier limiting pathogen penetration into vascular tissues, were uniquely and significantly upregulated in resistant roots. These transcriptional responses suggest that fortification of cell wall barriers and enhanced antimicrobial defenses contribute to effective restriction of FOV4 colonization. Conclusions: Our findings identify a distinct molecular signature of resistance to FOV4 in pima cotton, with Casparian strip reinforcement emerging as a potential mechanism limiting vascular infection. These insights provide a foundation for breeding strategies aimed at improving Fusarium wilt resistance in cotton. Full article

Placental dysfunction underlies the major obstetric syndromes, including preeclampsia, fetal growth restriction, placenta accreta spectrum, pregnancy loss, and monochorionic twin complications. Recent molecular studies have revealed that dysregulated oxygen sensing, impaired angiogenic signaling, altered immune tolerance, and defective trophoblast fusion represent shared pathogenic pathways that converge across these disorders. Integrating morphological evidence with mechanistic data highlights how villous maldevelopment, shallow trophoblast invasion, and aberrant vascular remodeling translate into clinical disease. Advances in biomarker research have already transformed clinical care: the sFlt-1/PlGF ratio is now established in the prediction and management of preeclampsia, while placental proteins such as PAPP-A and PP13, nucleic acid signatures including cfDNA, cfRNA and miRNAs, and extracellular vesicle cargo show promising potential for early, non-invasive detection of placental pathology. Multi-omics approaches, particularly single-cell and spatial transcriptomics combined with proteomic and metabolomic profiling, are paving the way for composite diagnostic panels that capture the polygenic and multicellular nature of placental disease. This review synthesizes current knowledge of molecular mechanisms, histological correlates, and translational biomarkers, and outlines how precision obstetrics may emerge from bridging mechanistic discoveries with clinical applications. Full article

Background: Calvarial venous malformations (VMs) are rare and genetically understudied. While somatic TEK receptor tyrosine kinase (TEK) mutations drive sporadic VMs, their role in scalp–calvarial VMs is unknown. We report the first pediatric case of a calvarial VM with a pathogenic somatic TEK mutation and its molecular implications. Methods: A 16-year-old female with a symptomatic parietal scalp VM underwent neurosurgical resection. Exome sequencing was performed on both lesional and blood DNA. Single-cell RNA sequencing (scRNA-seq) data from normal brain vasculature were analyzed for TEK expression and pathway enrichment. Results: A novel somatic TEK L914F mutation (chr9:27212760-C-T [GRCh38]), absent in germline DNA and population databases, was identified and predicted to be deleterious (CADD: 24). scRNA-seq data analysis revealed TEK enrichment in endothelial cells, particularly in fetal and arterial subtypes, and implicated angiogenesis and PI3K/Rho signaling as potential downstream phenotypic and molecular consequences. Conclusions: This first pediatric scalp VM with a somatic TEK L914F mutation expands the phenotypes associated with TEK-related vascular anomalies. These findings emphasize the role of somatic TEK mutation in diverse VMs and support genetic testing in sporadic cases. Further studies are needed to define therapeutic targets. Full article

Autoimmune diseases arise from complex interactions of genetic, environmental, and hormonal factors, yet their precise causes remain elusive. Beyond its canonical role in fibrin degradation, the fibrinolytic system is increasingly recognized as both a pathogenic driver and a regulatory modulator in autoimmunity. Key factors—plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1)—not only reflect secondary responses to vascular and immune dysregulation but also actively shape innate and adaptive immunity. They influence macrophage activation, dendritic cell maturation, T cell responses, and cytokine production, thereby bridging coagulation, inflammation, and tissue repair. This review integrates current evidence on the dual pathogenic and regulatory roles of fibrinolytic factors, organizing autoimmune diseases into systemic, organ-specific, and secondary syndromes. We further discuss how the imbalance of fibrinolysis can either promote inflammatory persistence or, conversely, facilitate resolution through fibrin clearance and immune homeostasis. By highlighting this bidirectional influence, the review aims to refine our understanding of fibrinolytic components as both contributors to and regulators of autoimmune disease pathogenesis. Full article

Antiphospholipid syndrome (APS) is the most common acquired form of thrombophilia and is associated with the presence of antiphospholipid antibodies (aPL) in the patient’s serum. Until now, the “double-hit” hypothesis remains the prevailing theory for APS pathogenesis. According to this model, the presence of aPL (first hit) is insufficient to trigger thrombosis. A secondary event, such as an inflammatory trigger or vascular injury (second hit), is required to initiate immunothrombosis, which ultimately leads to thromboembolism. Although immunothrombosis has a critical role in several mechanisms, such as in defense against pathogens, chronic immune system activation by aPL appears to disrupt its protective function. In the last three decades, the role of the complement system has gained increasing recognition in the pathophysiology of APS. aPL are involved in the dysregulation of multiple components, such as platelets, β2-glycoprotein I, and complement factor H, resulting in excessive activation of the complement system. Thus, the complement system is a key driver of thrombosis in APS and stands as a promising target for the development of future therapeutic strategies. In the current review article, we aim to summarize the ongoing research regarding the role of complement system dysregulation in APS-associated thrombosis development, while recognizing potential therapeutic targets. In the era of precision medicine, more data concerning targeted therapeutics in the field of APS are essential. Full article

Fig (Ficus carica) orchards in the Salento peninsula (southeastern Apulia region, Italy) are increasingly affected by decline syndromes whose etiology remains poorly resolved. In this paper, we provide a first characterization of a complex disease outbreak, integrating field surveys, fungal isolation, molecular phylogenetics, and pathogenicity assays. Symptomatic trees displayed chlorosis, defoliation, cankers, vascular discoloration, and wilting, frequently associated with bark beetle galleries. Mycological analyses revealed a diverse assemblage of fungi, dominated by Botryosphaeriaceae (including Neofusicoccum algeriense, and Lasiodiplodia theobromae), the Fusarium solani species complex (notably Neocosmospora perseae), and Ceratocystis ficicola. While C. ficicola was isolated with lower frequency, its recovery from adult beetles—including Cryphalus dilutus—supports a role in insect-mediated dissemination in addition to soilborne infection. Pathogenicity tests demonstrated that N. algeriense and N. perseae, together with C. ficicola, caused severe vascular lesions and wilting, confirming their contribution to fig decline. By contrast, other Fusarioid strains showed no pathogenicity, consistent with their role as latent or stress-associated pathogens. This study provides the first evidence that N. algeriense and N. perseae act as pathogenic agents on fig, highlights their interaction with C. ficicola within a multifactorial decline syndrome, and identifies dual epidemiological pathways involving both soil/root infection and insect-facilitated dissemination via beetles such as C. dilutus. These findings redefine fig decline in the Salento peninsula (southern Italy) as a multifactorial disease rather than a single-pathogen outbreak, with significant implications for diagnosis, epidemiology, and integrated management strategies. Full article

Background/Objectives: This report documents the first confirmed case in Romania of fatal pneumonia and septicemia in a domestic rabbit caused by multidrug-resistant Escherichia coli, highlighting both its pathogenic potential and One Health implications. Case Study: An 8-month-old male German Giant Spotted rabbit raised on a rural farm under poor husbandry conditions developed acute respiratory distress and died within 48 h. Post-mortem examination revealed severe pulmonary congestion, tracheal inflammation, serofibrinous pericarditis, and systemic vascular lesions. Bacteriological analysis confirmed E. coli from lung, trachea, and bone marrow samples. The isolate demonstrated strong Congo red binding, was confirmed by MALDI-TOF mass spectrometry, and showed resistance to beta-lactams, fluoroquinolones, tetracyclines, sulfonamides, macrolides, and phenicols, remaining susceptible only to aminoglycosides. PCR screening identified virulence genes (fimH, papC, iutA, ompA) linked to adhesion, immune evasion, and iron acquisition, with potential for horizontal gene transfer. Conclusions: This first documented case in Romania emphasizes the clinical threat posed by multidrug-resistant E. coli in rabbits and the importance of early diagnosis, improved biosecurity, and responsible antimicrobial use. The zoonotic and environmental risks in backyard farming underscore the urgent need for integrated surveillance. Alternative control strategies, including phage therapy and probiotics, should be explored to reduce reliance on conventional antibiotics. Full article

Diabetic retinopathy (DR) is the most common microvascular complication associated with diabetes mellitus and represents a leading cause of visual impairment worldwide. Inflammation, endothelial dysfunction, angiogenesis, neurodegeneration, and oxidative stress are key pathogenic processes in the development and progression of DR. Numerous microRNAs (miRNAs) show altered expression in DR and modulate critical biological pathways. Pro-inflammatory miRNAs such as miR-155 and miR-21 promote cytokine release and vascular inflammation, while miR-146a acts as a negative regulator of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. MiR-126 and miR-21 regulate endothelial integrity and angiogenesis through pathways involving Vascular Endothelial Growth Factor (VEGF). MiR-200b and miR-126 are downregulated in DR, leading to increased neovascularization via activation of the VEGF/ Mitogen-Activated Protein Kinase (MAPK) cascade. Apoptotic processes are affected by miR-195, which downregulates Sirtuin 1 (SIRT1) and B-cell lymphoma 2 (Bcl-2), promoting retinal cell death, while miR-29b downregulation permits upregulation of the transcription factor SP1, enhancing caspase-mediated apoptosis in Müller cells and endothelial cells. miRNAs collectively modulate an intricate regulatory network that contributes to the underlying mechanisms of diabetic retinopathy development and progression. This narrative review aims to summarize knowledge regarding the mechanisms miRNAs mediating pathogenetic mechanisms of DR. Full article

Studies spanning decades provide important information about the epidemiology and occurrence of a broad range of diseases that affect the central nervous system (CNS) of dogs. This study analyzed records and formalin-fixed paraffin-embedded (FFPE) CNS tissue samples from necropsied dogs with neuropathologic changes between 1962 and 2022. A total of 134,854 animals, including 20,117 dogs, were submitted for necropsy during this time span. Of these dogs, 2646 displayed alterations of the CNS. Degenerative and non-suppurative inflammatory lesions were the most common changes, accounting for 35.6% and 28.6%, respectively. Vascular diseases, neoplasms, congenital malformations, and suppurative inflammation represented 13.8%, 8.6%, 7.2%, and 5.4% of cases, respectively. Morbillivirus canis, the agent of canine distemper, was the most commonly diagnosed. The second most commonly detected virus, varicellovirus suidalpha1, the agent of pseudorabies, occurred almost exclusively between the mid-1970s and 1990s. Other pathogens, including Lyssavirus rabies, canine herpes virus, tick-borne encephalitis virus, apicomplexan parasites, such as Neospora caninum and Toxoplasma gondii, as well as fungal and other parasitic infections, were less frequently diagnosed. Interestingly, 47.6% of cases with non-suppurative inflammation remained etiologically undetermined. This study provides insights into the epidemiology of canine neurotropic infections and shows the value of FFPE material for investigations of past disease outbreaks. Full article

Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematologic malignancies characterized not only by driver mutations such as JAK2V617F, CALR, and MPL but also by a profoundly dysregulated immune microenvironment. Chronic inflammation and immune remodeling sustain malignant hematopoiesis and contribute to disease progression from essential thrombocythemia (ET) and polycythemia vera (PV) to overt myelofibrosis (MF). Pro-inflammatory cytokines and chemokines—including IL-2, IFN-α, IL-23, and TNF-α—drive abnormal T cell polarization, favoring a pathogenic Th17 phenotype. Lymphocyte subset analysis reveals a predominance of exhausted PD-1⁺ T cells, reflecting impaired immune surveillance. Concurrently, alterations in neutrophil apoptosis lead to persistent inflammation and stromal activation. GRO-α (CXCL1) is elevated in ET but reduced in MF, suggesting a subtype-specific role in disease biology. Fibrosis-promoting factors such as TGF-β and IL-13 mediate bone marrow remodeling and megakaryocyte expansion, while VEGF and other angiogenic factors enhance vascular niche alterations, particularly in PV. These immunopathologic features underscore novel therapeutic vulnerabilities. In addition to JAK inhibition, targeted strategies such as CXCR1/2 antagonists, anti-TGF-β agents, and immune checkpoint inhibitors (PD-1/PD-L1 blockade) may offer disease-modifying potential. Understanding the interplay between cytokine signaling and immune cell dysfunction is crucial for developing precision immunotherapies in MPNs. Full article

Vascular smooth muscle cells (VSMCs) are a major cell type in the arterial wall responsible for regulating vascular homeostasis. Under physiological conditions, VSMCs reside in the medial layer of the arteries, express elevated levels of contractile proteins, regulate vascular tone, and provide mechanical strength and elasticity to the blood vessel. In response to obesity, hyperglycemia, and insulin resistance, critical pathogenic hallmarks of Type 2 diabetes (T2D), VSMCs undergo a phenotypic transformation, adopting new phenotypes with increased proliferative (synthetic), inflammatory (macrophage-like), or bone-like (osteogenic) properties. While crucial for normal repair and vascular adaptation, VSMC phenotypic plasticity is a key driver for the development and progression of macrovascular complications associated with T2D. Despite advances in lineage tracing and multi-omics profiling that have uncovered key molecular regulators of VSMC phenotypic switching in vasculopathy, our understanding of the cellular and molecular mechanisms underlying VSMC transformation into diseased phenotypes in T2D remains incomplete. This review will provide a holistic summary of research from the past 15 years, with a focus on the signaling pathways and transcriptional regulators that govern VSMC phenotypic transition in response to obesity, hyperglycemia, and insulin resistance. We examine the integrated molecular mechanisms that orchestrate VSMC fate reprogramming in T2D and highlight the dynamic interplay among diverse signaling and transcriptional networks. Emphasis is placed on how these interconnected pathways collectively influence VSMC behavior and contribute to the pathogenesis of T2D-associated atherosclerosis. Full article

Background: Glaucoma is a progressive optic neuropathy marked by retinal ganglion cells (RGCs), apoptosis, vascular insufficiency, oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. While intraocular pressure (IOP) reduction remains the primary intervention, many patients continue to lose vision despite adequate pressure control. Emerging neuroprotective agents—citicoline, coenzyme Q10 (CoQ10), pyruvate, nicotinamide, pyrroloquinoline quinone (PQQ), homotaurine, berberine, and gamma-aminobutyric acid (GABA)—target complementary pathogenic pathways in experimental and clinical settings. Methods: This literature review synthesizes current evidence on glaucoma neuroprotection, specifically drawing on the most relevant and recent studies identified via PubMed. Results: Citicoline enhances phospholipid synthesis, stabilizes mitochondrial membranes, modulates neurotransmitters, and improves electrophysiological and visual field outcomes. CoQ10 preserves mitochondrial bioenergetics, scavenges reactive oxygen species, and mitigates glutamate-induced excitotoxicity. Pyruvate supports energy metabolism, scavenges reactive oxygen species, and restores metabolic transporter expression. Nicotinamide and its precursor nicotinamide riboside boost NAD⁺ levels, protect against early mitochondrial dysfunction, and enhance photopic negative response amplitudes. PQQ reduces systemic inflammation and enhances mitochondrial metabolites, while homotaurine modulates GABAergic signaling and inhibits β-amyloid aggregation. Berberine attenuates excitotoxicity, inflammation, and apoptosis via the P2X7 and GABA-PKC-α pathways. Preclinical models demonstrate synergy when agents are combined to address multiple targets. Clinical trials of fixed-dose combinations—such as citicoline + CoQ10 ± vitamin B3, citicoline + homotaurine ± vitamin E or PQQ, and nicotinamide + pyruvate—show additive improvements in RGCs’ electrophysiology, visual function, contrast sensitivity, and quality of life without altering IOP. Conclusions: A multi-targeted approach is suitable for glaucoma’s complex neurobiology and may slow progression more effectively than monotherapies. Ongoing randomized controlled trials are essential to establish optimal compound ratios, dosages, long-term safety, and structural outcomes. However, current evidence remains limited by small sample sizes, heterogeneous study designs, and a lack of long-term real-world data. Integrating combination neuroprotection into standard care holds promise for preserving vision and reducing the global burden of irreversible glaucoma-related blindness. Full article

Background/Objectives: Tick-borne diseases (TBDs) are increasingly recognized as causes of both systemic and neurologic illness. While their impact on vascular health is established, their role in cerebrovascular disease remains underexplored. This review aims to synthesize clinical evidence linking TBDs with cerebrovascular events, focusing on mechanisms of injury, pathogen-specific associations, and treatment outcomes. Methods: A narrative review was conducted using Boolean keyword searches across PubMed, Scopus, EMBASE, and Web of Science. Relevant literature on ischemic and hemorrhagic stroke, cerebral vasculitis, and stroke mimics associated with TBDs was examined. The review included case reports, observational studies, and mechanistic research. Pathogen-specific data and disease characteristics were extracted and summarized. Results: Several tick-borne pathogens were associated with cerebrovascular complications. Borrelia burgdorferi was most commonly implicated and typically presented with large-vessel vasculitis. Rickettsia, Ehrlichia, and Anaplasma species caused endothelial injury through immune-mediated inflammation. Powassan virus and Crimean–Congo hemorrhagic fever virus exhibited central nervous system involvement and hemorrhagic potential. Babesia species contributed to vascular injury through thrombocytopenia and embolic complications. Neuroimaging frequently demonstrated multifocal stenoses and vessel wall inflammation. Antimicrobial treatment, particularly with doxycycline or ceftriaxone, was often effective, especially when administered early. Supportive care for stroke symptoms varied by presentation and underlying pathogen. Conclusions: Cerebrovascular disease caused by tick-borne pathogens is an underrecognized but potentially reversible condition. Despite diverse etiologies, most pathogens share a final common pathway of endothelial dysfunction. Early recognition and targeted antimicrobial therapy, combined with supportive stroke care, are essential to improving patient outcomes. Full article

Background: The Karius Test (KT), a microbial cell-free DNA next-generation sequencing assay, is increasingly utilized in challenging infectious syndromes. However, its real-world clinical utility and cost-effectiveness remain uncertain. Methods: We conducted a retrospective review of 88 KT results from adult patients at UC San Diego Health between July 2017 and April 2024. Each case was evaluated for clinical impact using standardized criteria. We analyzed diagnostic yield, turnaround time, number needed to test (NNT), and institutional billing data for reimbursement and cost implications. Results: Of 88 unique tests, forty-nine (55.7%) identified at least one pathogen. Eleven (12.5%) had a positive clinical impact—eight provided the only microbiologic diagnosis, and three were faster than conventional methods. Vascular/graft infections showed the highest yield. Twenty-one tests had a neutral impact; fifty-six showed no clinical benefit. The Median turnaround time was 3 days. The NNT was 6.1 or 2.75 including neutral cases. Cost analysis revealed a substantial financial burden without transparent reimbursement mechanisms in inpatient settings. Conclusion: The KT demonstrates modest clinical utility with noteworthy benefits in select scenarios. Given its high cost and variable impact, we advocate for diagnostic stewardship led by infectious disease specialists to optimize test use and minimize unnecessary expense. Full article

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases. Full article