Search Results (201)

Toll-like receptor 3 (TLR3) initiates antiviral and inflammatory responses exclusively through the adaptor protein TRIF (TIR-domain-containing adapter-inducing interferon-β). In contrast, MyD88 (myeloid differentiation primary response 88), a central adaptor for most other TLRs, is traditionally considered dispensable for TLR3 signaling. Here, we demonstrate that MyD88 directly contributes to TLR3-mediated NF-κB activation and cytokine production in macrophages. Bone marrow-derived macrophages (BMDMs) from MyD88 deficient mice exhibited significantly attenuated NF-κB activation in response to the TLR3 agonist polyinosinic–polycytidylic acid (poly(I:C)) compared to wild-type cells, as evidenced by the reduced phosphorylation of NF-κB p65 and IκBα, as well as IκBα degradation. Consistently, pro-inflammatory cytokine production, including IL-6, TNF-α, and IFN-β, was attenuated in MyD88-deficient BMDMs in vitro following stimulation by poly(I:C) or poly(A:U), another TLR3 agonist. Blood concentrations of IL-6, TNF-α, and IFN-β were significantly reduced in both TRIF-deficient mice and MyD88-deficient mice challenged by the i.p. injection of poly(I:C). Mechanistic analyses revealed that MyD88 physically associates with activated TLR3 upon poly(I:C) stimulation, and that TLR3 engagement triggered MyD88 oligomerization, which was absent in TLR3 or TRIF deficient macrophages. Our findings highlight a previously unrecognized dual-adaptor mechanism for TLR3, wherein MyD88 recruitment amplifies NF-κB signaling dynamics by bridging TLR3 to the canonical NF-κB activation cascade and robust cytokine induction. This study expands the paradigm of TLR3 signaling by establishing MyD88 as a direct contributor to TLR3-driven innate immune responses, offering new insight into cross-talk between MyD88-dependent and -independent pathways. Full article

Psoriasis is a chronic inflammatory skin disorder affecting approximately 2% of the global population, characterized by abnormal keratinocyte proliferation and dysregulated immune responses. This review examines the emerging role of long non-coding RNAs (lncRNAs) in psoriasis pathogenesis, highlighting their significance as regulatory molecules in disease initiation, progression, and chronicity. LncRNAs demonstrate distinct expression patterns in psoriatic lesions, with upregulated transcripts such as MALAT1, XIST, MIR31HG, and HOTAIR promoting keratinocyte hyperproliferation, inhibiting apoptosis, and amplifying inflammatory cascades through mechanisms including microRNA sponging and transcription factor modulation. These molecules primarily target key signaling pathways including NF-κB, STAT3, and PI3K/AKT. Conversely, downregulated lncRNAs like NEAT1, MEG3, and PRINS normally function as tumor suppressor molecules that maintain epidermal homeostasis through pro-apoptotic and anti-inflammatory mechanisms. Their reduced expression contributes to the pathological hyperproliferative phenotype characteristic of psoriatic skin. Importantly, genetic variants within lncRNA loci have been identified as significant contributors to psoriasis susceptibility and treatment responses across different populations. Single- nucleotide polymorphisms in genes such as TRAF3IP2-AS1, HOTAIR, and CDKN2B-AS1 demonstrate population-specific associations with disease risk and therapeutic outcomes, suggesting their potential utility as pharmacogenomic markers. The complex regulatory networks involving lncRNAs provide new insights into psoriasis pathogenesis and offer promising avenues for personalized treatment strategies. Integration of lncRNA profiling into clinical practice may enhance our understanding of disease heterogeneity and improve therapeutic outcomes for psoriatic patients. Full article

This study investigates how bank mergers and acquisitions (M&As) reshape the monitoring architecture of syndicated loans and, by extension, borrowers’ financing conditions. Using a global panel of 20,299 syndicated loan contracts, originating in 43 countries between 1982 and 2020, we link LPC DealScan data to Securities Data Company M&A records to trace each loan’s lead arrangers before and after consolidation events. Fixed-effects regressions, enriched with borrower- and loan-level controls, reveal three key patterns. First, post-merger loans exhibit significantly more concentrated syndicates: the Herfindahl–Hirschman Index rises by roughly 130 points and lead arrangers retain an additional 0.8–1.1 percentage points of the loan, consistent with heightened monitoring incentives. Second, these effects are amplified when information asymmetry is acute, i.e., for opaque or unrated firms, supporting moral hazard theory predictions that lenders internalize greater risk by holding larger stakes. Third, relational capital tempers the impact of consolidation: borrowers with repeated pre-merger relationships face smaller increases in syndicate concentration, while switchers experience the most significant jumps. Robustness checks using lead arranger market share, alternative spread measures, and lag structures confirm the findings. Overall, the results suggest that bank consolidation strengthens lead arrangers’ incentives to monitor but simultaneously reduces risk-sharing among participant lenders. For borrowers, the net effect is a trade-off between potentially tighter oversight and reduced syndicate diversification, with the balance hinging on transparency and prior ties to the lender. These insights refine our understanding of how structural shifts in the banking sector cascade into corporate credit markets and should inform both antitrust assessments and borrower funding strategies. Full article

MicroRNAs are closely associated with various physiological and pathological processes, making their in situ fluorescence imaging crucial for functional studies and disease diagnosis. Current methods for the in situ fluorescence imaging of microRNA predominantly rely on linear signal amplification, resulting in relatively weak imaging signals. This study introduces a Y-shaped cascade assembly (YCA) method for high-brightness microRNA imaging in cells. Triggered by target microRNA, catalytic hairpin assembly forms double-stranded DNA (H). Through annealing and hybridization, a Y-shaped structure (P) is created. These components assemble into DNA nanofluorescent particles with multiple FAM fluorophores, significantly amplifying fluorescence signals. Optimization experiments revealed that a 1:1 ratio of P to H and an assembly time of 60 min yielded the best results. Under these optimal conditions, the resulting fluorescent nanoparticles exhibited diameters of 664.133 nm, as observed by DLS. In Huh7 liver cancer cells, YCA generated DNA nanoparticles with a fluorescence intensity increase of 117.77%, triggered by target microRNA-21, producing high-intensity fluorescence images and enabling qualitative detection of microRNA-21. The YCA in situ imaging method offers excellent imaging quality and high efficiency, providing a robust and reliable analytical tool for the diagnosis and monitoring of microRNA-related diseases. Full article

Gout is a chronic inflammatory disease characterized by the deposition of monosodium urate (MSU) crystals within joints, leading to recurrent acute flares and long-term tissue damage. While various hypotheses have been proposed to explain the self-limiting nature of acute gout attacks, we posit that aggregated neutrophil extracellular traps (aggNETs) play a central role in this process. This review focuses on the mechanisms underlying MSU crystal-induced formation of neutrophil extracellular traps (NETs) and explores their dual role in the clinical progression of gout. During the initial phase of acute flares, massive NET formation is accompanied by the release of preformed inflammatory mediators, which is a condition that amplifies inflammatory cascades. As neutrophil recruitment reaches a critical threshold, the NETs tend to form high-order aggregates (aggNETs). The latter encapsulate MSU crystals and further pro-inflammatory mediators within their three-dimensional scaffold. High concentrations of neutrophil serine proteases (NSPs) within the aggNETs facilitate the degradation of soluble inflammatory mediators and eventually promote the resolution of inflammation in a kind of negative inflammatory feedback loop. In advanced stages of gout, MSU crystal deposits are often visible via dual-energy computed tomography (DECT), and the formation of palpable tophi is frequently observed. Based on the mechanisms of resolution of inflammation and the clinical course of the disease, building on the traditional static model of “central crystal–peripheral fibrous encapsulation,” we have expanded the NETs component and refined the overall concept, proposing a more dynamic, multilayered, multicentric, and heterogeneous model of tophus maturation. Notably, in patients with late-stage gout, tophi exist in a stable state, referred to as “silent” tophi. However, during clinical tophus removal, the disruption of the structural or functional stability of “silent” tophi often leads to the explosive reactivation of inflammation. Considering these findings, we propose that future therapeutic strategies should focus on the precise modulation of NET dynamics, aiming to maintain immune equilibrium and prevent the recurrence of gout flares. Full article

Cerebral ischemia–reperfusion injury (CIRI) is a complex pathological process that arises when blood flow is restored to the brain after ischemia, often resulting in significant neuronal damage and triggering secondary inflammatory responses. This review explores the immune mechanisms underlying CIRI, focusing on the activation and polarization of resident central nervous system (CNS) cells—particularly microglia and astrocytes—and the infiltration of peripheral immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes. We discuss the central role of microglia in the neuroinflammatory cascade, their polarization between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, and how this process influences neuronal damage and tissue repair. This review highlights the roles of the complement system, inflammasome activation, and blood–brain barrier disruption as key drivers of inflammation and neuronal injury. Additionally, we elaborate on the dynamic interactions between resident and infiltrating immune cells, which amplify inflammation and impede post-ischemic recovery. Finally, we discuss emerging therapeutic strategies targeting immune modulation, including cytokine regulation, microglial reprogramming, and targeted drug delivery systems, which offer promising avenues for improving outcomes in ischemic stroke. Full article

Chronic inflammation underpins the pathogenesis of both rheumatoid arthritis (RA) and neurodegenerative conditions such as Alzheimer’s disease (AD). This narrative review explores the role of C-reactive protein (CRP), particularly its monomeric form (mCRP), as a central molecular link connecting systemic autoimmune inflammation with neuroinflammatory and vascular pathology. In RA, fibroblast-like synoviocytes (FLSs) are activated by CRP through CD32/CD64-mediated signaling, triggering proinflammatory cascades involving NF-κB and p38 MAPK. Recent studies have highlighted that locally synthesized CRP within the synovium may convert to mCRP, amplifying inflammation and tissue damage. Beyond RA, mCRP has been identified within amyloid-beta (Aβ) plaques in AD brains, suggesting a direct role in neurodegenerative pathology. Experimental models also demonstrate that mCRP is upregulated in stroke-affected brain regions and associated with complement activation and blood–brain barrier (BBB) disruption, which is central to AD progression. The convergence of pathways involving IL-6, RAGE (receptor for advanced glycation end-products), and mCRP-mediated complement activation reveals a shared axis of inflammation between RA and AD. This highlights the potential of mCRP not only as a biomarker of chronic inflammation but also as a therapeutic target. Furthermore, evidence from periodontal disease and cardiovascular comorbidities highlights the systemic nature of mCRP-driven inflammation, offering insights into the mechanisms of disease overlap. This review advocates for further mechanistic studies into mCRP signaling, particularly its role at the interface of systemic and neuroinflammation, with the goal of identifying new interventional strategies for patients with RA at elevated risk of neurodegenerative and vascular complications. Full article

As manufacturing and logistics-oriented supply chains continue to expand in scale and complexity, and the coupling between their physical execution layers and information–decision layers deepens, the resulting high interdependence within the system significantly increases overall fragility. Driven by key technological barriers, economies of scale, and the trend toward resource centralization, supply chains have increasingly evolved into centralized structures, with critical functions such as decision-making highly concentrated in a few focal firms. While this configuration may enhance coordination under normal conditions, it also significantly increases dependency on focal nodes. Once a focal node is disrupted, the intense task, information, and risk loads it carries cannot be effectively dispersed across the network, thereby amplifying load spillovers, coordination imbalances, and information delays, and ultimately triggering large-scale cascading failures. To capture this phenomenon, this study develops a coupled network model comprising a Physical Network and an Information and Decision Risk Network. The Physical Network incorporates a tri-load coordination mechanism that distinguishes among theoretical operational load (capacity), actual production load (production output), and actual delivery load (order fulfillment), using a load sensitivity coefficient to describe the asymmetric propagation among them. The Information and Decision Risk Network is further divided into a communication subnetwork, which represents transmission efficiency and delay, and a decision risk subnetwork, which reflects the diffusion of uncertainty and risk contagion caused by information delays. A discrete-event simulation approach is employed to evaluate system resilience under various failure modes and parametric conditions. The results reveal the following: (1) under a centralized structure, poorly allocated redundancy can worsen local imbalances and amplify disruptions; (2) the failure of a focal firm is more likely to cause a full network collapse; and (3) node failures in the Communication System Network have a greater destabilizing effect than those in the Physical Network. Full article

Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc⁻ transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood–brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life. Full article

Cardiovascular and metabolic disorders significantly reduce healthspan and lifespan, with oxidative stress being a major contributing factor. Oxidative stress, marked by elevated reactive oxygen species (ROS), disrupts cellular and systemic functions. One proposed mechanism involves TRPM2 (Transient Receptor Potential Melastatin2)-dependent Ca²⁺ dysregulation. These channels, activated by ROS (via ADP-ribose), not only respond to ROS but also amplify it, creating a self-sustaining cycle. Recent studies suggest that TRPM2 activation triggers a cascade of signals from intracellular organelles, enhancing ROS production and affecting cell physiology and viability. This review examines the role of TRPM2 channels in oxidative stress-associated cardiovascular and metabolic diseases. Oxidative stress induces TRPM2-mediated Ca²⁺ influx, leading to lysosomal damage and the release of Zn²⁺ from lysosomal stores to the mitochondria. In mitochondria, Zn²⁺ facilitates electron leakage from respiratory complexes, reducing membrane potential, increasing ROS production, and accelerating mitochondrial degradation. Excess ROS activates PARP1 in the nucleus, releasing ADP-ribose, a TRPM2 agonist, thus perpetuating the cycle. Lysosomes act as Ca²⁺-sensitive signalling platforms, delivering toxic Zn²⁺ signals to mitochondria. This represents a paradigm shift, proposing that the toxic effects of Ca²⁺ on mitochondria are not direct, but are instead mediated by lysosomes and subsequent Zn²⁺ release. This cycle exhibits a ‘domino’ effect, causing sequential and progressive decline in the function of lysosomes, mitochondria, and the nucleus—hallmarks of ageing and oxidative stress-related cardiovascular and metabolic diseases. These insights could lead to new therapeutic strategies for addressing the widespread issue of cardiovascular and metabolic diseases. Full article

This paper presents the design and implementation of an ultra-wideband (UWB) and flat gain low noise amplifier (LNA) using 0.15 µm GaAs pHEMT technology, specifically tailored for applications that benefit from multi-band capability, such as satellite communication. The designed LNA consists of three stages: Two stages are cascoded using source degeneration with a resistor for low noise and high linearity, and the third cascaded stage is utilized for high gain. The designed UWB LNA exhibits a measured gain of 17.4 ± 1 dB between 312 and GHz and a 3 dB bandwidth of 12.4 GHz (1.6–14 GHz). It achieves a noise figure (NF) of 2.5–4.3 dB and an output P1dB of 15 dBm. The chip size is $3\times 1$${\mathrm{mm}}^2$, and it operates without the need for any external components. When compared to LNAs in the literature, the proposed design stands out for its flat gain in the specified frequency band, making the LNA particularly attractive for volume-limited and power-constrained applications. Full article

Osteoarthritis (OA) is a multifactorial joint disease traditionally characterized by cartilage degradation, while growing evidence underscores the critical role of synovial fibrosis in driving disease progression. The synovium exhibits pathological remodeling in OA, primarily due to the phenotypic transition of fibroblast-like synoviocytes (FLSs) into myofibroblasts. This fibroblast–myofibroblast transition (FMT) results in excessive deposition of extracellular matrix (ECM) and increased tissue stiffness and contractility, collectively contributing to chronic inflammation and fibrotic stiffening of the joint capsule. These fibrotic changes not only impair synovial function but also exacerbate cartilage degeneration, nociceptive sensitization, and joint dysfunction, thereby amplifying OA severity. Focusing on the frequently overlooked role of the FMT of synovial fibroblasts in OA, this review introduces the biological characteristics of FLSs and myofibroblasts and systematically examines the key molecular pathways implicated in OA-related FMT, including TGF-β, Wnt/β-catenin, YAP/TAZ, and inflammatory signaling cascades. It also discusses emerging therapeutic strategies targeting synovial fibrosis and FMT and considers their implications for the clinical management of OA. By highlighting recent advances and unresolved challenges, this review provides critical insights into the fibroblast–myofibroblast axis as a central contributor to OA progression and a promising therapeutic target for modifying disease trajectory. Full article

Foodborne pathogens represent a class of pathogenic microorganisms capable of causing food poisoning or serving as foodborne vectors, constituting a major source of food safety concerns. With increasing demands for rapid diagnostics, conventional culture-based methods and PCR assays face limitations due to prolonged turnaround times and specialized facility requirements. While CRISPR-based detection has emerged as a promising rapid diagnostic platform, its inherent inability to detect low-abundance targets necessitates coupling with isothermal amplification, thereby increasing operational complexity. In this study, we preliminarily developed a novel amplification-free Cascade-CRISPR detection system utilizing a hairpin DNA amplifier. This method achieves detection sensitivity as low as 10 fM (82 parasites/μL) for DNA targets within 30 min without requiring pre-amplification, with background signal suppression achieved through optimized NaCl concentration. Validation using artificially contaminated food samples demonstrated the platform’s robust performance for both Toxoplasma gondii (T. gondii) and Listeria monocytogenes (L. monocytogenes) detection, confirming broad applicability. In summary, this study preliminarily establishes an amplification-free Cascade-CRISPR detection platform that achieves high sensitivity and rapid turnaround, demonstrating strong potential for on-site screening of foodborne pathogens. Full article

Automated surface defect detection in steel manufacturing is pivotal for ensuring product quality, yet it remains an open challenge owing to the extreme heterogeneity of defect morphologies—ranging from hairline cracks and microscopic pores to elongated scratches and shallow dents. Existing approaches, whether classical vision pipelines or recent deep-learning paradigms, struggle to simultaneously satisfy the stringent demands of industrial scenarios: high accuracy on sub-millimeter flaws, insensitivity to texture-rich backgrounds, and real-time throughput on resource-constrained hardware. Although contemporary detectors have narrowed the gap, they still exhibit pronounced sensitivity–robustness trade-offs, particularly in the presence of scale-varying defects and cluttered surfaces. To address these limitations, we introduce MBY (MBDNet-Attention-YOLO), a lightweight yet powerful framework that synergistically couples the MBDNet backbone with the YOLO detection head. Specifically, the backbone embeds three novel components: (1) HGStem, a hierarchical stem block that enriches low-level representations while suppressing redundant activations; (2) Dynamic Align Fusion (DAF), an adaptive cross-scale fusion mechanism that dynamically re-weights feature contributions according to defect saliency; and (3) C2f-DWR, a depth-wise residual variant that progressively expands receptive fields without incurring prohibitive computational costs. Building upon this enriched feature hierarchy, the neck employs our proposed MultiSEAM module—a cascaded squeeze-and-excitation attention mechanism operating at multiple granularities—to harmonize fine-grained and semantic cues, thereby amplifying weak defect signals against complex textures. Finally, we integrate the Inner-SIoU loss, which refines the geometric alignment between predicted and ground-truth boxes by jointly optimizing center distance, aspect ratio consistency, and IoU overlap, leading to faster convergence and tighter localization. Extensive experiments on two publicly available steel-defect benchmarks—NEU-DET and PVEL-AD—demonstrate the superiority of MBY. Without bells and whistles, our model achieves 85.8% mAP@0.5 on NEU-DET and 75.9% mAP@0.5 on PVEL-AD, surpassing the best-reported results by significant margins while maintaining real-time inference on an NVIDIA Jetson Xavier. Ablation studies corroborate the complementary roles of each component, underscoring MBY’s robustness across defect scales and surface conditions. These results suggest that MBY strikes an appealing balance between accuracy, efficiency, and deployability, offering a pragmatic solution for next-generation industrial quality-control systems. Full article

Microglia, the brain’s resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood–brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders. Full article