Search Results (3,505)

Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this reaction has long suggested an underlying genetic contribution, yet its molecular architecture has remained poorly characterized. We hypothesized that alteplase-associated angioedema represents a multigenic susceptibility phenotype, arising from the convergence of rare genetic variants across multiple interacting physiological systems rather than from a single causal variant. To explore this hypothesis, we performed clinical exome sequencing in a cohort of 11 patients who developed angioedema following alteplase administration. Rather than identifying a shared pathogenic variant, we observed distinct yet convergent patterns of genetic vulnerability, allowing patients to be grouped according to dominant, but overlapping, biological axes. These included alterations affecting bradykinin regulation (e.g., ACE, SERPING1, XPNPEP2), endothelial structure and hemostasis (e.g., VWF, COL4A1), neurovascular and calcium signaling (e.g., SCN10A, RYR1), and vascular repair or remodeling pathways (e.g., PSEN2, BRCA2). Notably, many of the identified variants were classified as Variant of Uncertain Significance (VUS) or likely benign significance in isolation. However, when considered within an integrated, pathway-based framework, these variants can be interpreted as capable of contributing cumulatively to system level fragility, a phenomenon best described as “contextual pathogenicity”. Under the acute biochemical and proteolytic stress imposed by thrombolysis, this reduced physiological reserve may allow otherwise compensated vulnerabilities to become clinically manifest. Together, these findings support a model in which severe alteplase-associated angioedema appears as an emergent property of interacting genetic networks, rather than a monogenic disorder. This systems level perspective underscores the limitations of gene centric interpretation for adverse drug reactions and highlights the potential value of pathway informed, multi-genic approaches to risk stratification. Such frameworks may ultimately contribute to safer, more personalized thrombolytic decision, while providing a conceptual foundation for future functional and translational studies. Full article

To address the depletion of shallow coal resources, mining activities have progressed to greater depths, where rock masses contain numerous fractures due to complex geological conditions, making grouting reinforcement essential for ensuring stability. Using digital image correlation, this study investigated the strain evolution characteristics of grouted fractured specimens of three rock types—mudstone, coal–rock, and sandstone—under uniaxial compression. Analysis of the strain evolution process focused on two typical fracture inclinations of 0° and 60°, while examination of the peak strain characteristics covered five inclinations, namely 0°, 15°, 30°, 45°, and 60°. The findings indicate that the mechanical response varies systematically with lithology and fracture inclination. The post-peak curves differ significantly among rock types: coal–rock shows a gentle descent, mudstone exhibits a rapid strength drop but higher residual strength, and sandstone is characterized by “serrated” fluctuations. The failure mode transitions from tensile splitting at a horizontal inclination of 0° to shear failure at inclinations of 15°, 30°, 45°, and 60°. Strain nephograms corresponding to the peak stress point D reveal sharp, band-shaped zones of strain localization. The maximum principal strain exhibits a non-monotonic trend, first increasing and then decreasing with increasing inclination angle. For grouted coal–rock and sandstone, the peak values of 47.47 and 45.00 occur at α = 45°. In contrast, grouted mudstone reaches a maximum value of 26.80 at α = 30°, indicating its lower susceptibility to damage. The study systematically clarifies the strain evolution behavior of grouted fractured rock masses, providing a theoretical basis for evaluating the effectiveness of reinforcement and predicting failure mechanisms. Crucially, the findings highlight mudstone’s role as a high-integrity medium and the particular vulnerability of horizontal fractures, offering direct guidance for the targeted grouting design in stratified rock formations. Full article

The concept of individual cellular intelligence reframes cells as dynamic entities endowed with sensory, reactive, adaptive, and memory-like capabilities, enabling them to navigate lifelong metabolic and extrinsic stressors. A likely vital component of this intelligence system is stress-responsive G protein-coupled receptor (GPCR) networks, interconnected by common signaling adaptors. These stress-regulating networks orchestrate the detection, processing, and experience retention of environmental cues, events, and stressors. These networks, along with other sensory mechanisms such as receptor-mediated signaling and DNA damage detection, allow cells to acknowledge and interpret stressors such as oxidative stress or nutrient scarcity. Reactive responses, including autophagy and apoptosis, mitigate immediate damage, while adaptive strategies, such as metabolic rewiring, receptor expression alteration and epigenetic modifications, enhance long-term survival. Cellular experiences that are effectively translated into ‘memories’, both transient and heritable, likely rely on GPCR-induced epigenetic and mitochondrial adaptations, enabling anticipation of future insults. Dysregulation of these processes and networks can drive pathological states, shaping resilience or susceptibility to chronic diseases like cancer, neurodegeneration, and metabolic disorders. Employing molecular evidence, here, we underscore the presence of an effective cellular intelligence, supported by multi-level sensory GPCR networks. The quality of this intelligence acts as a critical determinant of somatic health and a promising frontier for therapeutic innovation. Future research leveraging single-cell omics and systems biology may unravel the molecular underpinnings of these capabilities, offering new strategies to prevent or reverse stress-induced pathologies. Full article

Steel bridge deck pavements (SBDPs) are susceptible to complex mechanical and service environmental conditions, yet current design methods often struggle to simultaneously capture global bridge system behavior and local pavement responses. To address this issue, this study develops a multi-scale finite element modeling framework that integrates a full-bridge model, a refined girder-segment model, and a detailed pavement submodel. The framework is applied to an extra-long suspension bridge to evaluate the mechanical responses of five typical pavement structural configurations—including double-layer SMA, double-layer Epoxy Asphalt (EA), EA-SMA combinations, and a composite scheme with a thin epoxy resin aggregate overlay. By coupling global deformations from a full-bridge model to the local pavement submodel, the proposed method enables a consistent assessment of both bridge-level effects and pavement-level stress concentrations. The analysis reveals that pavement structures significantly alter the stress and strain distributions within the deck system. The results indicate that while the composite configuration with a thin overlay effectively reduces shear stress at the pavement–deck interface, it results in excessive tensile strain, posing a high risk of fatigue cracking. Conversely, the double-layer EA configuration exhibits the lowest fatigue-related strain, demonstrating superior deformation coordination, while the optimized EA-SMA combination offers a robust balance between fatigue control and interfacial stress distribution. These findings validate the effectiveness of the multi-scale approach for SBDP analysis and highlight that rational structural configuration selection—specifically balancing layer stiffness and thickness—is critical for enhancing the durability and long-term performance of steel bridge deck pavements. Full article

Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in podocyte injury. This study investigated the role of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a podocyte-enriched lipid-modulating enzyme, in radiation- and cisplatin-induced nephrotoxicity. Using a doxycycline-inducible, podocyte-specific SMPDL3B transgenic mouse model, renal injury was assessed following focal kidney irradiation, cisplatin administration, or their combination through functional assays, histopathology, ultrastructural analysis, immunofluorescence, and targeted lipidomics. Combined radiation and cisplatin exposure markedly reduced podocyte SMPDL3B expression, accompanied by podocyte depletion, glomerular basement membrane remodeling, proteinuria, and impaired renal function. These structural and functional abnormalities were associated with the selective accumulation of long-chain ceramide-1-phosphate species. In contrast, podocyte-specific induction of SMPDL3B preserved glomerular architecture, maintained renal function, and prevented pathological ceramide-1-phosphate elevation. Collectively, these findings identify SMPDL3B as a key regulator of podocyte stability and lipid homeostasis during chemoradiation stress. Enhancing SMPDL3B activity may represent a mechanistically grounded strategy to mitigate treatment-induced kidney injury while preserving anticancer efficacy. Full article

Freeze-thaw (F-T) cycles in seasonally frozen regions induce progressive volumetric strains leading to degradation of soils’ mechanical properties and performance of earthen infrastructure. Conventional chemical stabilization techniques often are not adaptive to cyclic thermal stresses and do not address the fundamental phase changes of porous media, underscoring the need for sustainable alternatives. This study explores the potential of extracellular polymeric substances (EPS) produced by the psychrophilic bacterium Polaromonas hydrogenivorans as a bio-mediated soil treatment to enhance freeze-thaw durability. Two EPS formulations were examined—EPS 1 (high ice-binding activity) and EPS 2 (low ice-binding activity)—to evaluate their effectiveness in improving volumetric stability and thawing strength of silty soil subjected to ten F-T cycles. Tests were conducted at four moisture contents (12%, 18%, 24%, and 30%) and three EPS concentrations (3, 10, and 20 g/L). Volumetric strain measurements quantified freezing expansion and thawing contraction, while unconfined compressive strength assessed post-thaw mechanical integrity. The untreated soils exhibited maximum net volumetric strains (γ_Net) of 5.62% and only marginal strength recovery after ten F-T cycles. In contrast, EPS 1 at 20 g/L mitigated volumetric changes across all moisture contents and increased compressive strength to 191.2 kPa. EPS 2 yielded moderate improvements, reducing γ_Net to 0.98% and enhancing strength to 183.9 kPa at 30% moisture. Lower EPS concentrations (3 and 10 g/L) partially mitigated volumetric strain, with performance strongly dependent on moisture content. These results demonstrate that psychrophilic EPS, particularly EPS 1, effectively suppresses ice formation within soil pores and preserves mechanical structure, offering a sustainable, high-performance solution for stabilizing frost-susceptible soils in cold-regions. Full article

Helicobacter pylori (H. pylori) is recognized as one of the most widespread and persistent bacterial infections globally, with a remarkable ability to colonize the human stomach. This pathogen is a major contributor to the development of gastric diseases, including gastric lymphoma and adenocarcinoma. The H. pylori infection triggers a complex pathogenic cascade within the gastric environment, characterized by prolonged inflammation and heightened oxidative stress, which fosters a milieu of immune dysregulation, where both innate and adaptive immune cells become activated inappropriately, thereby leading to epithelial injury and subsequent remodeling of the gastric tissue. As the infection persists, repeated cycles of inflammation and epithelial damage contribute to the development of epigenetic alterations, including changes in DNA methylation, histone modifications, and non-coding RNA expression, all of which render the gastric epithelium more susceptible to further aberrations, including dysplasia and cancer. In this article, we review the latest advances in understanding the molecular mechanisms of H. pylori-induced gastritis and its role in the progression of gastric cancer, offering new perspectives on the complex biology of this infection and its potential therapeutic implications for preventing the development of gastric malignancies. Full article

The skeletal muscle system is particularly susceptible to degenerative and inflammatory processes that threaten mobility, quality of life, and systemic health. Marine plants, including brown, red, and green algae, are valuable yet understudied sources of bioactive compounds with therapeutic potential against skeletal muscle inflammation and degeneration. This narrative review provides the first overview of polyphenols, polysaccharides, carotenoids, and multiminerals derived from marine plants, with a particular focus on their effects on skeletal muscle, bone, and joint tissues. It highlights both the therapeutic potential and the limitations of marine plant-derived bioactive compounds in the musculoskeletal system. The compounds discussed, such as phlorotannins, ulvan, fucoidan, carotenoids, spirulina derivatives, and Aquamin, modulate key signaling pathways, including NF-κB, JAK/STAT3, and the NLRP3 inflammasome. Among these, MAPK emerges as the most consistently affected axis across all compound classes, leading to a reduction in TNF-α, IL-1β, IL-6, and oxidative stress markers. These bioactive compounds have been shown in both in vitro and in vivo models to reduce muscle catabolism, enhance osteoblast differentiation and mineralization, and reduce cartilage inflammation. Despite favorable safety, biocompatibility, and biodegradability profiles, current evidence shows that systemic applications significantly dominate over local delivery, highlighting the untapped potential of localized delivery strategies. Overall, this narrative review underscores the growing importance of marine plant-derived bioactives as promising natural agents for maintaining musculoskeletal integrity and alleviating degenerative disorders. Full article

Achieving high reliability remains the critical challenge for pulsed power supplies (PPS), whose core components are susceptible to severe degradation and catastrophic failure due to long-term operation under electrical, thermal and magnetic stresses, particularly those associated with high voltage and high current. This reliability challenge fundamentally limits the widespread deployment of PPSs in defense and industrial applications. This article provides a comprehensive and systematic review of the reliability challenges and recent technological progress concerning PPSs, focusing on three hierarchical levels: component, system integration, and extreme operating environments. The review investigates the underlying failure mechanisms, degradation characteristics, and structural optimization of key components, such as energy storage capacitors and power switches. Furthermore, it elaborates on advanced system-level techniques, including novel thermal management topologies, jitter control methods for multi-module synchronization, and electromagnetic interference (EMI) source suppression and coupling path optimization. The primary conclusion is that achieving long-term, high-frequency operation depends on multi-physics field modeling and robust, integrated design approaches at all three levels. In summary, this review outlines important research directions for future advancements and offers technical guidance to help speed up the development of next-generation PPS systems characterized by high power density, frequent repetition, and outstanding reliability. Full article

Gastrointestinal nematode (GIN) infections are the most prevalent parasitic diseases in grazing sheep worldwide, causing significant productivity losses, high mortality and, as a result, economic losses and emerging animal welfare concerns. Conventional control strategies, primarily relying on anthelmintic treatments, face limitations due to rising drug resistance and environmental concerns, underscoring the need for sustainable alternatives. Selective breeding for host genetic resistance has emerged as a promising strategy, while recent advances in transcriptomics and integrative omics research are providing deeper insights into the immune pathways and molecular and genetic mechanisms that underpin host–parasite interactions. This review summarizes current evidence on transcriptomic signatures associated with resistance and susceptibility to H. contortus and T. circumcincta GIN infections, highlighting candidate genes, functional genetic markers, key immune pathways, and regulatory networks. Furthermore, we discuss how other omics approaches, including genomics, proteomics, metabolomics, microbiome, and multi-omics integrations, provide perspectives that enhance the understanding of the complexity of the GIN resistance trait. Transcriptomic studies, particularly using RNA-Sequencing technology, have revealed differential gene expression, functional genetic variants, such as SNPs and INDELs, in expressed regions and splice junctions, and regulatory long non-coding RNAs that distinguish resistance from susceptible sheep, highlighting pathways related to Th2 immunity, antigen presentation, tissue repair, and stress signaling. Genomic analyses have identified SNPs, QTL, and candidate genes linked to immune regulation and parasite resistance. Proteomic and metabolomic profiling further elucidates breed- and tissue-specific alterations in protein abundance and metabolic pathways, while microbiome studies demonstrate distinct microbial signatures in resistant sheep, suggesting a role in modulating host immunity. In conclusion, emerging multi-omics approaches and their integration strategies provide a comprehensive framework for understanding the complex host–parasite interactions that govern GIN resistance, offering potential candidate biomarkers for genomic selection and breeding programs aimed at developing sustainable, parasite-resistant sheep populations. Full article

Obesity is a systemic metabolic disorder characterized by chronic low-grade inflammation and insulin resistance, with growing evidence indicating that the brain represents a primary and particularly vulnerable target organ. Beyond peripheral metabolic consequences, obesity induces region-specific structural, functional, and biochemical alterations within the central nervous system, contributing to cognitive impairment, dysregulated energy homeostasis, and increased susceptibility to neurodegenerative diseases. This narrative review examines key neurometabolic and neuroinflammatory mechanisms underlying obesity-related brain vulnerability, including downstream neuroinflammation, impaired insulin signaling, mitochondrial dysfunction, oxidative stress, blood–brain barrier disruption, and impaired brain clearance mechanisms. These processes preferentially affect frontal and limbic networks involved in executive control, reward processing, salience detection, and appetite regulation. Advanced neuroimaging has substantially refined our understanding of these mechanisms. Magnetic resonance spectroscopy provides unique in vivo insight into early neurometabolic alterations that may precede irreversible structural damage and is complemented by diffusion imaging, volumetric MRI, functional MRI, cerebral perfusion imaging, and positron emission tomography. Together, these complementary modalities reveal microstructural, network-level, structural, hemodynamic, and molecular alterations associated with obesity-related brain vulnerability and support the concept that such brain dysfunction is dynamic and potentially modifiable. Integrating neurometabolic and multimodal neuroimaging biomarkers with metabolic and clinical profiling may improve early risk stratification and guide preventive and therapeutic strategies aimed at preserving long-term brain health in obesity. Full article

Betanodavirus infection poses a significant threat to marine fish species in the Mediterranean, affecting both aquaculture and wild populations. Despite increasing evidence of viral circulation in farmed and wild fish, data on natural outbreaks in wild groupers remain limited. This study investigated mortality episodes in wild dusky groupers (Epinephelus marginatus) within two marine protected areas (MPAs): Portofino MPA (Liguria, Italy) and Larvotto MPA (Principality of Monaco) during 2018–2019. Pathological examinations and virological diagnostics confirmed that the causative agents were betanodavirus strains belonging to the RGNNV genotype. Phylogenetic analyses revealed high genetic similarity among viral strains detected at geographically distant sites and across host species, suggesting potential regional connectivity mediated by mobile vectors or environmental transport. Seawater temperature analysis indicated that extreme and prolonged high-water temperatures were prodromal and coincided with observed outbreaks, supporting a role for thermal stress in triggering outbreak onsets. These findings highlight the susceptibility of wild dusky grouper populations to betanodavirus and underscore the interplay between host behavior, environmental conditions, and pathogen dynamics. The study emphasizes the importance of integrated health surveillance strategies within and around MPAs to monitor fish health and environmental parameters, thereby conserving wild fish populations and biodiversity. Full article

Kidney cells are exposed to a wide range of physiological and pathological stresses, including hormonal changes, mechanical forces, hypoxia, hyperglycemia, and inflammation. These insults can trigger adaptive responses, but when they persist, they can lead to organelle stress. Organelles such as mitochondria, the endoplasmic reticulum, and primary cilia sustain cellular metabolism and tissue homeostasis. When organelle stress occurs, it disrupts cellular processes and organelle communication, leading to metabolic dysfunction, inflammation, fibrosis, and progression of kidney disease. Sex and hormonal factors play a significant role in the development of renal disorders. Many glomerular diseases show distinct differences between the sexes. Chronic Kidney Disease is more common in women, while men often experience a faster decline in kidney function, partly due to the influence of androgens. Additionally, the loss of female hormonal protection after menopause highlights the importance of sex as a factor in renal susceptibility. This narrative review synthesizes preclinical evidence on how sexual dimorphism and sex hormones affect organelle stress in mitochondria, the endoplasmic reticulum, and primary cilia, from 33 studies identified through a non-systematic literature search of the PubMed database, to provide an overview of how these mechanisms contribute to sex-specific differences in kidney disease pathophysiology. Full article

Introduction. Sleep is an essential component in the recovery, performance, and injury prevention processes of soccer players. Associated psychological variables, such as the balance between stress and recovery, have been less explored, despite their potential influence on rest and injury vulnerability. This study aims to examine the relationship between sleep quality, quantity, and chronotype and injury risk in soccer players, also incorporating the modulating role of stress and recovery. Method. A PRISMA systematic review was conducted using searches in ScienceDirect, PubMed, Ovid, EBSCO, MDPI, Springer Nature Link, SPORTDiscuss (full text), and Dialnet. Original studies and reviews on sleep and its relationship with sports injuries in soccer players or comparable athletic populations were included. Eighteen studies were selected that addressed sleep indicators (quality, quantity, chronotype), injury incidence, and, to a lesser extent, measures of stress and recovery using instruments such as the RESTQ-Sport or wellness questionnaires. Results. There is evidence of an association between poor sleep quality or quantity and an increased risk of injury or illness. Chronotype is an emerging variable of interest, although still insufficiently researched. Regarding stress and recovery, direct evidence is limited, although studies that address this issue show that an imbalance between these two dimensions negatively impacts sleep quality and increases susceptibility to injury. Conclusions: Sleep and the stress–recovery balance are key and interdependent factors in the risk of injury in soccer players. Future research should consider including these variables to further understand the mechanisms underlying the injury process and optimize prevention and recovery strategies. Full article

Adipose tissue thermogenesis is a promising strategy to counter obesity and metabolic disease, but sustained activation of thermogenic adipocytes elevates oxidative and lipid-peroxidation stress, increasing susceptibility to ferroptotic cell death. Existing models often treat redox buffering, hypoxia signaling and ferroptosis as separate processes, which cannot explain why similar interventions—such as antioxidants, β-adrenergic agonists or iron modulators—alternately enhance thermogenesis or precipitate tissue failure. Here, we propose the Redox–Thermogenesis–Ferroptosis Compass (RTF-Compass) as a framework that maps adipose depots within a space defined by ferroptosis resistance capacity (FRC), ferroptosis signaling intensity (FSI) and HIF-1α-dependent hypoxic tone. Within this space, thermogenic output follows a hormetic, inverted-U trajectory, with a Thermogenic Ferroptosis Window (TFW) bounded by two failure states: a Reductive-Blunted state with excessive antioxidant buffering and weak signaling, and a Cytotoxic state with high ferroptotic pressure and inadequate defense. We use this model to reinterpret genetic, nutritional and pharmacological studies as state-dependent vectors that move depots through FRC–FSI–HIF space and to outline principles for precision redox medicine. Although the TFW is represented as coordinates in FRC–FSI–HIF space, we use ‘Compass’ to denote a coordinate framework in which perturbations act as vectors that orient depots toward thermogenic or cytotoxic outcomes. Finally, we highlight priorities for testing the model in vivo, including defining lipid species that encode ferroptotic tone, resolving spatial heterogeneity within depots and determining how metabolic memory constrains reversibility of pathological states. Full article