This study aimed to use a propensity score matching (PSM) design to examine the association between artificial intelligence (AI)-driven conversational agents (CAs) and physician-patient interaction quality during outpatient consultations. We used the Chinese version of the Consultation and Relational Empathy Measure to survey the patients' perceived quality of physician-patient interactions during outpatient consultations, involving 419 adult residents who received outpatient services from China's tertiary public hospitals. Propensity score matching was first conducted to organize the sampled population into the treated and control groups based on the demographic and visit covariates, and the average treatment effect on the treated (ATT) was further calculated to estimate the causal association between the AI-driven CAs and physician-patient interaction quality. Overall, the PSM results showed a positive causal association of the AI-driven CAs with the physician-patient interaction quality. Specifically, the ATT estimate results showed that the treated residents gave significantly higher scores than the control residents in the total perceived physician-patient interaction quality score (ATT=2.987, Z=2.92, P=0.003) and its 8 items at the 5% confidence level. The sensitivity analysis results further showed that when the γ increased to greater than 2, the ATT estimate results remained significant (P<0.001), indicating the ATT estimate results were not sensitive to the hidden bias. Our findings will help to confirm the association between the AI-driven CAs and physician-patient interaction quality, and also offer valuable guidance for policy makers and hospital managers in promoting the adoption of the AI-driven CAs to continuously improve the physician-patient interaction quality during outpatient consultations.
Flow diverters (FDs) have revolutionized intracranial aneurysm management, but current permanent metallic devices remain constrained by their bulk and surface properties, which induce chronic inflammation, thrombotic risk, and impaired vessel-wall integration. In this review we address these material-driven design challenges, examining how bioactive bioabsorbable biomaterials can overcome current limitations by balancing scaffold resorption with aneurysm occlusion. Moving beyond the clinical focus of existing literature, we establish a rational design roadmap bridging the gap between bulk material properties and FD architecture. We analyze how synchronized degradation kinetics and neointimal encapsulation govern device functionality, identifying this biological isolation as a necessary safety requirement to ensure resorption occurs only after the scaffold is shielded from the active flow. We analyze the mechanical-biological trade-offs of current platforms, whereby bioabsorbable polymers offer superior flexibility but limited radial support, whereas bioabsorbable metals provide higher mechanical integrity but require precision control over degradation. Hybrid strategies, combining transient and permanent components, emerge as effective solutions to balance mechanical reliability with controlled resorption. Across material classes, sustained flow diversion and vascular healing are primarily dictated by the interplay of scaffold architecture, material composition, and time-dependent surface evolution. Our analysis highlights that converging bulk material selection with advanced interfacial engineering enables the rational design of bioabsorbable FDs that maintain temporary mechanical integrity, while ensuring predictable aneurysm occlusion. These design principles establish a scientific framework for next-generation bioactive neurovascular implants, emphasizing a materials-driven approach to optimize safety and translational potential.
Lung cancer remains a leading cause of cancer-related mortality worldwide, and the clinical translation of chimeric antigen receptor (CAR)-based immunotherapy into solid tumors continues to be constrained by antigen heterogeneity, an immunosuppressive microenvironment, and stromal barriers that impede immune cell trafficking and curtail efficacy. Here, we present a comprehensive bibliometric analysis of CAR-based immunotherapy for lung cancer, drawing on publications indexed in the Web of Science Core Collection and Scopus between 2016 and 2025. Bibliometric and network analyses elucidate global research trajectories, collaboration patterns, and emergent therapeutic themes, while clinical trial data from ClinicalTrials.gov further appraise translational progress. This landscape has expanded rapidly, with growing emphasis on CAR engineering, microenvironment modulation, precision targeting, and combinatorial strategies. Clinical evidence, though drawn from a still-limited number of trials, indicates generally tolerable toxicity in most reported cases; nevertheless, severe and occasionally fatal adverse events have been documented, underscoring the need for continued vigilance in safety evaluation. Antitumor efficacy remains modest, reflecting persistent challenges in target selection, tumor accessibility, cellular persistence, and functional maintenance. Emerging strategies, including multi-target CAR architectures, rational drug combinations, and biomarker-guided patient stratification, may offer avenues for overcoming these limitations. This study furnishes a data-driven pharmacological atlas of CAR-based immunotherapy in lung cancer, illuminating key therapeutic targets, evolving treatment paradigms, and prospective opportunities for clinical translation.
We investigate the dynamics of an actively driven semiflexible polymer confined by a soft harmonic potential. Our study is inspired by in-vitro motility assays where cytoskeletal filaments are propelled by motor proteins under controlled confinement. Using coarse-grained simulations that couple polymer elasticity with stochastic motor attachment, detachment, and force generation, we obtain distinct dynamical regimes ranging from fully confined to freely escaping states, separated by a region of intermittent coexistence. The transitions between these regimes are governed by the combined effects of activity, filament stiffness, confinement strength, and motor processivity. Moderate confinement stabilizes compact spiral conformations through a balance between active forcing and bending elasticity. Stronger activity promotes escape. The motion of the center-of-mass of the polymer exhibits diffusive-ballistic-localized crossovers and oscillations characteristic of trapped chiral active Brownian particles. Our results establish a minimal physical framework for understanding how activity and geometric confinement interact to regulate the transport and morphology of active filaments.
The tomato plant is considered one of the most important crops in the world, yet it is vulnerable to various diseases that affect crop quality and agricultural productivity. These challenges have driven the need for an efficient and intelligent plant disease detection system. With the development of computer vision and artificial intelligence, this proposed methodology based on deep learning for tomato leaf diseases has been presented. Two public datasets: Taiwan DS with nine classes and Tomato Leaf Diseases Detection Computer Vision Dataset (TLDDCV DS) with seven classes have been used to test this system. This system begins with plant image processing, which includes gamma correction and bilateral filtering, to enhance image quality and clarity while preserving key disease features. Then, a genetic metaheuristic algorithm was used to automatically select the most significant hyperparameters, further optimizing both processing time and accuracy. After that, the tomato leaf disease detection applies the You Only Look Once version 11 Nano (YOLOv11n) model. The YOLOv11n backbone is edited through a Data-efficient Image Transformer (DeiT) to improve the system's capacity for learning global contextual information and long-range dependencies. Experimental results demonstrate that the proposed system outperforms existing methods. It achieved an average mAP@50 of 97.8%, mAP@50-95 of 93.4%, precision of 97.3%, recall of 93.8%, and F1-score of 95.5% on the Taiwan dataset. Additionally, it achieved an average mAP@50 of 87%, mAP@50-95 of 48%, precision of 83.9%, recall of 70.3%, and F1-score of 76.4% on the TLDDCV dataset. These results demonstrate the generalizability and effectiveness of the proposed system in real-world agricultural situations.
Vaccine-related communication can be harnessed to curb infection; yet, in practice, it often undermines vaccine uptake and sustains transmission even when effective vaccines are available. Our goal is to understand how vaccine information dynamics may shape infection spread within a coupled information-infection modeling framework. We present a coupled information-infection modeling framework that links a standard SVIRS infection-spread model with an integrate-and-fire-inspired information-dissemination model. Vaccine-positive and vaccine-critical active groups disseminate competing information that shapes non-active/hesitant individuals' vaccine attitudes through direct peer influence, threshold-based acceptance, and persistence of engagement, while infection prevalence can feed back by amplifying caution. The evolving vaccine attitudes modulate vaccination uptake, and the model tracks the joint evolution of information dynamics and epidemic trajectories. Our analysis shows that, under the assumed coupling, information dynamics can shift the system among qualitatively distinct infection outcomes. In particular, reducing resistance to vaccine-positive information and sustaining vaccine-positive engagement can move the system toward lower-endemic regimes more reliably than changes focused only on weakening vaccine-critical engagement, for the parameter ranges considered here. These findings highlight the potential importance of information dynamics in epidemic modeling and suggest that sustained vaccine-positive engagement can be an important qualitative mechanism for reducing long-term infection burden.
Background and objective Neurocardiac interaction is bidirectional, with neurological disorders influencing cardiac electrophysiology through the autonomic nervous system (ANS) pathways. Patients may present with central nervous system (CNS) manifestations, autonomic symptoms, or both. Despite the absence of overt cardiac symptoms, subtle autonomic disturbances may precede clinically detectable cardiovascular dysfunction. This study aimed to evaluate cardiac electrophysiology using heart rate variability (HRV) and electrocardiography (ECG) data from neurologically symptomatic but cardiac-asymptomatic individuals; to assess correlations between ECG parameters and HRV indices; and to determine the utility of HRV for early detection of neurocardiac risk in this population. Methods Artifact-free five-minute ECG recordings were analyzed using LabChart Version 8 (ADInstruments, Bella Vista, Australia) to derive HRV and ECG parameters. HRV assessment included both time-domain and frequency-domain measures, while ECG analysis comprised heart rate, PR interval, QRS duration, QT interval, and corrected QT interval (QTc). Demographic and clinical information were retrieved from departmental records for a total of 314 subjects. Following data quality assessment and exclusion of recordings with artifacts or incomplete data, HRV and ECG analyses were conducted on 278 subjects. Statistical analyses were performed using Jamovi macOS Pro (Version 2.6.45) and Statistics Kingdom, a freely accessible online statistical platform. Depending on the distribution and nature of the data, analyses included Spearman rank correlation, Welch's t-test, and one-sample and two-sample t-tests. Results ECG findings demonstrated largely preserved cardiac conduction and repolarization parameters across the cohort, although inter-individual variability in repolarization amplitude was observed. In contrast, HRV analysis revealed subtle autonomic dysregulation, including among subjects presenting predominantly with autonomic symptoms, suggesting impaired parasympathetic modulation despite normal ECG findings. Several HRV indices differed significantly from normative reference values, indicating altered autonomic regulation. Conclusions HRV is a sensitive, noninvasive tool for detecting early autonomic dysfunction in neurologically symptomatic adults, irrespective of the underlying neurogenic presentation. While conventional ECG parameters remain largely preserved in cardiac-asymptomatic individuals, HRV can identify subclinical neurocardiac alterations that may not be evident on routine electrocardiographic assessment. These findings support the integration of HRV into neurological evaluation protocols to facilitate early neurocardiac risk stratification and preventive cardiovascular care.
miR-210-3p is a well-established hypoxia-induced microRNA that is commonly upregulated in a wide range of solid tumors, traditionally linked to mitochondrial repression and hypoxia-inducible factor (HIF) signaling. However, its functional role in cancer remains complex and highly context dependent. Here we perform a comprehensive pan-cancer transcriptomic analysis together with functional assays, revealing that miR-210-3p not only mediates classical hypoxic responses but also amplifies mitotic gene expression through activation of FOXM1. Mechanistically, this effect is shown to be dependent on HIF1α but not on HIF2α and, importantly, it has not been recapitulated by hypoxia alone. Notably, activation of the mitotic program is observed in breast cancer cells but not in head and neck squamous carcinoma models, highlighting a strong degree of context dependency across tumor types. In breast cancer cells, miR-210-3p overexpression enhances FOXM1 phosphorylation, upregulates kinetochore regulators, and induces mitotic defects, correlating with poor prognosis in aggressive tumors. Together, these findings position miR-210-3p as a molecular integrator linking pseudohypoxia to mitotic dysregulation, contributing to tumor aggressiveness by sustaining HIF activity and promoting mitotic stress. This dual functionality reconciles its paradoxical effects on proliferation and highlights its potential as a therapeutic target in cancers characterized by pseudohypoxia and mitotic abnormalities.
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Osteoarthritis (OA) arises from chondrocyte senescence driven by intertwined oxidative stress and abnormal m6A methylation, with few treatments targeting both pathological pathways. Lycopene, an antioxidant, is limited by poor bioavailability, whereas Wilms tumor 1-associating protein (WTAP), a core m6A methyltransferase, has no specific inhibitors. Herein, we fabricated cartilage-targeted HPcLW nanoparticles (∼250 nm) via electrostatic self-assembly of human serum albumin (HSA) and poly-L-lysine (PLL) with collagen II-binding peptide, co-loaded with lycopene and WTAP siRNA. The targeting modification extended joint fluorescence retention to 10 days after intra-articular injection with good serum stability and biosafety. In aged mice and medial meniscus (DMM)-induced OA mouse models, intra-articular HPcLW attenuated cartilage degeneration, restored COL2 expression, and suppressed MMP13 levels. Mechanistically, WTAP siRNA suppressed m6A modification to downregulate PAI-1 expression, while lycopene scavenged ROS and protected siRNA integrity, cooperatively disrupting the WTAP/PAI-1 axis and alleviating mitochondrial dysfunction. By integrating antioxidant and epigenetic strategies, HPcLW counteracts the senescence loop, establishing the WTAP/PAI-1 axis as a therapeutic target and highlighting co-delivery nanomedicine for age-related joint diseases.
Converting waste activated sludge (WAS) into medium-chain fatty acids (MCFAs) via chain elongation (CE) offers a promising route for sludge valorization. In two-stage sludge CE systems, primary fermentation is typically optimized to maximize the short-chain fatty acid (SCFA) pool for downstream MCFA production; however, whether retained refractory dissolved and undissolved organic matter (rDOM and rUOM) also contributes to CE remains unclear. Here, we evaluated the roles of rDOM and rUOM in ethanol-driven CE using sludge alkaline fermentation liquid (SAFL) and thermal-alkaline pretreatment fermentation liquid (STAPFL) as feedstocks. Although SAFL contained fewer SCFAs after primary fermentation than STAPFL (3.25 vs. 3.60 g COD/L), it yielded 44% more MCFAs during CE (11.56 vs. 8.03 g COD/L). Integrated physicochemical and molecular analyses indicated that this advantage arose from greater retention of refractory organics during primary alkaline fermentation and their continued mobilization during downstream CE. Filtration experiments and COD-based estimation indicated a much greater total apparent COD contribution from retained rUOM and rDOM in SAFL than in STAPFL (2.16 vs. 0.15 g COD/L). FT-ICR-MS and metagenomic analyses further suggested compositional transformation of retained refractory organics and stronger functional potential for coordinated hydrolysis, acidogenesis, and CE in SAFL, which together supported continued precursor supply and higher MCFA production. These results indicate that downstream MCFA production in real sludge fermentation liquids depends not only on the initial soluble SCFA pool, but also on the continued mobilization of retained refractory carbon during CE. This study advances understanding of retained refractory carbon utilization during ethanol-driven CE in two-stage sludge fermentation for MCFA production.
Asthma is a heterogeneous chronic airway disease arising from a complex interplay of genetic susceptibility and environmental exposures. Key pathobiological features include dysregulated immune responses (particularly type 2 inflammation), structural airway remodeling, and mucus hypersecretion. Recent advances have illuminated mechanisms from epithelial "alarmin" cytokine release (TSLP, IL-33, IL-25) to downstream cellular networks involving Th2/Th17 lymphocytes, group 2 innate lymphoid cells (ILC2s), eosinophils, and mast cells. These pathways converge on bronchial hyperresponsiveness and airflow obstruction. Traditional therapy with inhaled corticosteroids and bronchodilators has improved asthma control, yet many patients, especially those with non-type 2-driven endotypes such as neutrophilic or obesity-related asthma, remain suboptimally controlled. This limitation has driven the development of precision medicine approaches that target specific cytokines and signaling cascades, including IgE, IL-5, IL-4/13, and TSLP, as well as intracellular signaling processes such as JAK-STAT. Parallel innovations in biomarkers such as FeNO, blood eosinophils, periostin, and multi-omics-based signatures facilitate patient stratification and prediction of treatment response. This comprehensive review synthesizes current knowledge from genetic and epigenetic foundations of asthma, through immunologic and neurogenic mechanisms, to translational advances in therapeutics from laboratory to clinic. We highlight the importance of endotyping and "treatable traits" such as eosinophilia, mucus plugging, or small-airway dysfunction in guiding individualized therapy. The emerging paradigm aims not only for symptom control but also for disease modification and remission, leveraging biomarkers and multidisciplinary approaches to achieve long-term asthma control in a broad patient population.
Severe bacterial sepsis caused by Klebsiella pneumoniae (KP) is characterized by dysregulated inflammation, multiorgan injury, and high mortality, yet the key molecular drivers of this process remain incompletely understood. This study aimed to elucidate how the Z-DNA binding protein 1 (ZBP1) regulates inflammatory injury during KP-induced sepsis and to identify potential therapeutic targets with translational relevance. To investigate the role of macrophage ZBP1 in sepsis, we combined transcriptomic datasets from human sepsis cohorts and murine sepsis and KP-infection models with single-cell RNA sequencing of infected tissues. We further established both global and myeloid-specific Zbp1 knockout (Zbp1 fl/fl Lyz2-Cre +/- ) mice, as well as myeloid-specific Lgmn (encoded Legumain) knockout (Lgmn fl/fl Lyz2-Cre +/- , Lgmn CKO ) mice, to delineate the macrophage-dependent mechanisms of immune regulation. In addition, macrophage-targeted adeno-associated virus 9 (AAV9) vectors driven by the F4/80 promoter were used to overexpress Lgmn in vivo. Flow cytometry, immunofluorescence, and survival analyses were performed to evaluate systemic inflammation, organ injury, and sepsis severity. The effect of recombinant LGMN supplementation on macrophage activation and barrier restoration was also assessed. ZBP1 activation was driven by both type I interferon (IFN-I) signaling and mitochondrial damage. Mechanistically, ZBP1 directly interacted with signal transducer and activator of transcription 3 (STAT3), suppressed its phosphorylation and nuclear translocation, and consequently inhibited transcription of Lgmn, a gene associated with anti-inflammatory macrophage polarization and tissue repair. Genetic and myeloid-specific deletion of Zbp1 resulted in reduced proinflammatory cytokine production and improved survival in both KP- and cecal ligation and puncture (CLP)-induced sepsis models. In contrast, Lgmn CKO aggravated systemic inflammation, organ injury, and barrier dysfunction, whereas macrophage-targeted AAV9-mediated Lgmn overexpression or recombinant LGMN supplementation alleviated macrophage inflammation, restored epithelial function, and improved survival. These findings reveal a previously unrecognized ZBP1-STAT3-LGMN signaling axis that contributes to immune and inflammatory dysregulation in KP-induced sepsis and suggest that targeting ZBP1 or restoring LGMN activity may represent a promising therapeutic strategy for severe bacterial infections.
The European Union (EU) Registration, Evaluation, Authorisation and Restriction of Chemicals Regulation (EC No. 1907/2006) (REACH) includes the principle of testing only when scientifically necessary, integrating mechanisms for data sharing, read-across, and adaptations to minimise vertebrate animal testing. REACH already provides a framework to promote non-animal testing (Annex XI). Nevertheless, the challenge lies in translating its flexibility into consistent practice. New in vivo (vertebrates) studies are still requested to meet information requirements in cases where these tests may add limited or no regulatory or scientific value. In this paper, an initiative of the Animal-Free Safety Assessment (AFSA) Collaboration to define specific scientific and procedural criteria to identify when animal testing is difficult, impossible, or meaningless (DIM), and how non-animal methods can effectively address such cases. Objective DIM criteria were defined and applied to screen REACH registration dossiers for potential DIM testing cases. More specifically, the AFSA DIM initiative identifies concrete scenarios where animal testing adds no value and demonstrates how existing non-animal approaches can address information needs in those situations. Based on these cases, the following recommendations were: i) further refine the DIM criteria and considerations to be suitable for other REACH endpoints, prioritising human health; ii) evaluate adaptations for avoiding DIM testing for human health endpoints; iii) address more specifically the use of exposure-driven assessment under Next-Generation Risk Assessment (NGRA) considerations (major use of exposure-driven assessment).
Congenital microcephaly and lissencephaly spectrum disorders are characterized by disrupted neuronal proliferation and migration, often driven by underlying genetic variants. Here, we identified and characterized of a novel gene (Tetratricopeptide Repeat Domain 14, TTC14) and its homozygous missense variant (c.89 A > G; p.His30Arg (p.H30R)) in a female proband presenting with microcephaly, epileptic spasms, global developmental delay, and neuroimaging features of simplified gyral pattern, focal pachygyria, and corpus callosum thinning. Trio-based whole exome sequencing revealed this variant to be rare and autosomal recessively inherited from both asymptomatic parents. Structural modeling demonstrated that H30 lies at the start of an α-helical region and is evolutionarily conserved. The p.His30Arg substitution caused significant steric clashes and disrupted local folding. Interaction network analysis and molecular dynamics simulations confirmed structural destabilization, increased conformational flexibility, and loss of stability in the mutant protein. While mRNA and protein levels remained unaltered, the TTC14-p.His30Arg protein mislocalized from the nucleus to the cytosol and formed aggregates. Functionally, proband fibroblasts exhibited increased cell death and altered cell cycle progression. TTC14 interacts with RNA splicing and mRNA processing proteins, and gene ontology analysis implicated it in RNA binding and spliceosomal complex assembly in key brain regions including the cerebral cortex, hippocampus, and white matter. These findings collectively suggest that TTC14 plays a crucial role in RNA metabolism during neurodevelopment, and that the p.His30Arg variant impairs its function, possibly leading to a neurodevelopmental disorder within the lissencephaly spectrum. This study identifies TTC14 as a likely pathogenic candidate gene in cortical malformation syndromes.
Cervical cancer aggressiveness and therapeutic resistance are driven by metabolic reprogramming and redox imbalance. Within this context, NAD(P)H: quinone oxidoreductase 1 (NQO1), a critical regulator of cellular redox homeostasis and energy metabolism, is highly expressed in several types of cancer and is associated with poor prognosis; however, its role in cervical cancer remains unclear. This study demonstrates that NQO1 is significantly upregulated in cervical cancer, promoting proliferation, metastasis, and epithelial-mesenchymal transition (EMT). Mechanistically, NQO1 suppresses AMP-activated protein kinase (AMPK) phosphorylation to reduce reactive oxygen species (ROS), while stabilizing HIF1α by preventing its proteasomal degradation. Consequently, stabilized HIF1α upregulates sine oculis homeobox 1 (SIX1) to enhance glycolytic enzyme transcription, driving aerobic glycolysis. Functional rescue experiments demonstrated that knockdown of NQO1, HIF1α, or SIX1 significantly inhibited glycolytic flux, tumor growth, and metastasis in vivo. Thus, the NQO1/HIF1α-SIX1 axis orchestrates metabolic reprogramming and EMT to promote cervical cancer progression and is a promising therapeutic target.
Monoclonal gammopathy of undetermined significance (MGUS), monoclonal B-cell lymphocytosis (MBL), and clonal hematopoiesis (CH) of indeterminate potential represent highly prevalent, age-associated precursor states characterized by detectable serological, cellular, or genetic alterations in otherwise asymptomatic individuals. The advent of high-sensitivity technologies, including mass spectrometry, multiparametric flow cytometry, and next-generation sequencing, has revealed that these conditions are far more widespread than previously appreciated, yet only a minority of affected individuals progress to overt malignancies such as multiple myeloma, chronic lymphocytic leukemia, or myeloid neoplasms. Across these entities, a unifying paradigm is emerging in which malignant transformation is governed not simply by the presence of driver lesions, but by dynamic clonal evolution shaped by intrinsic fitness, temporal acquisition of alterations, and selective pressures imposed by the aging microenvironment. In CH, mutation-specific growth kinetics and inflammation-driven selection define both hematologic and systemic risks. In MBL, antigenic stimulation, immune dysfunction, and genetic complexity modulate progression to CLL. In MGUS, disease evolution reflects a gradual co-evolution between plasma cell clones and a progressively permissive niche. Aging-associated inflammation and tissue remodeling act as common denominators, fostering a competitive landscape that selectively advantages aberrant clones while suppressing normal hematopoiesis. In turn, these clones actively remodel their microenvironment, establishing feed-forward loops that sustain clonal expansion and malignant potential. Integrating insights across CH, MBL, and MGUS highlights shared biological principles and supports a shift toward "precision prevention" strategies aimed at intercepting high-risk trajectories while minimizing unnecessary surveillance in low-risk individuals.
Negative biases in emotional processing are central to cognitive models of Major Depressive Disorder (MDD), yet it remains unclear whether negatively biased valence attribution covaries with depressive symptoms or represents a more stable vulnerability. In this longitudinal study, we examined emotional valence ratings during a subliminal affective priming task in n = 232 MDD patients and n = 496 healthy controls (HC's) across multiple follow-up assessments, yielding 1395 observations. Multilevel models tested effects of depressive symptom severity, diagnostic group (MDD vs. HC), affective prime (happy, sad, neutral), and their interactions. To separate within-person fluctuations from between-person differences, depressive symptom severity was decomposed (Mundlak within-between specification). Exploratory analyses examined whether long-term symptom trajectory clusters were associated with emotional bias. Greater depressive symptom severity was associated with more negative valence ratings. Within-between analyses indicated that this association was primarily driven by within-person symptom fluctuations, indicating more negative ratings when symptom severity exceeded individual average. In contrast, diagnostic group, prime condition, and symptom severity × prime interactions did not significantly predict valence ratings, and no group differences emerged between HC's and remitted MDD patients. Exploratory trajectory analyses suggested that patients with recurrent symptom patterns may show more negative valence ratings, although cluster stability was limited and findings should be interpreted cautiously. Overall, the results suggest that negative valence attribution in MDD is more closely linked to current depressive symptom severity than to diagnostic status alone. Longitudinal approaches separating within- and between-person processes may help clarify when negative biases emerge and persist during depression progression.
Musculoskeletal disorders (MSDs) are a leading cause of chronic pain and disability worldwide, yet available pharmacological treatments remain largely ineffective or palliative. Increasing evidence indicates that chronic inflammation in MSDs reflects not only excessive pro-inflammatory signaling but also impaired endogenous anti-inflammatory and pro-resolving mechanisms. In this context, cytokines IL-34 through IL-41 have recently emerged as important regulators of immune activation, tissue remodeling, and tissue regeneration. This review provides a mechanistically informed analysis of the roles of IL-34-IL-41 in the pathogenesis of major MSDs, including inflammatory arthritis, osteoarthritis, osteoporosis, intervertebral disc degeneration, and sarcopenia. A functional dichotomy within this cytokine spectrum is highlighted: IL-34, IL-36, IL-39, and IL-40 act as pro-inflammatory or inflammation-amplifying mediators that promote macrophage activation, osteoclastogenesis, and autoimmune responses, whereas IL-35, IL-37, IL-38, and IL-41 exert anti-inflammatory and pro-resolving effects by suppressing Th1/Th17-driven immunity and fostering regulatory immune phenotypes. Notably, IL-41 also integrates immune modulation with metabolic regulation and muscle repair. We discuss emerging translational strategies targeting this cytokine group and address key unresolved questions related to cytokine redundancy, disease heterogeneity, patient stratification, and safety. Collectively, the available evidence highlights the growing mechanistic and translational relevance of cytokines IL-34 through IL-41 in MSDs.
Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant precursor to multiple myeloma (MM). While development of end-organ damage in MM largely reflects increasing clonal burden, emerging evidence indicates that qualitative properties of the monoclonal immunoglobulins in MGUS can be directly pathogenic, leading to serious organ injury independent of disease burden. This has led to the recognition of a broader spectrum of disorders collectively termed monoclonal gammopathy of clinical significance (MGCS). MGCS can be further subclassified based on the organ system involved; for example, monoclonal gammopathy of renal significance specifically refers to monoclonal immunoglobulin-driven renal injury. Along these lines, we propose monoclonal gammopathy of thrombotic significance (MGTS) as encompassing thrombotic disorders in which there is definitive, mechanistically supported evidence that a monoclonal (M)-protein associated with a clonal plasma or B-cell disorder directly contributes to thrombosis. Based on current evidence, monoclonal protein-induced immune thrombocytopenia and thrombosis is the only disorder that meets our criteria for MGTS. Other thrombotic disorders, such as thrombotic microangiopathy and antiphospholipid syndrome, may occur in the setting of a monoclonal protein and have biologically plausible M-protein-mediated mechanisms; however, direct evidence implicating the M-protein in thrombosis is currently lacking. Accordingly, we provisionally classify these disorders as thrombotic syndromes associated with M-proteins, pending causal validation. We also highlight thrombotic disease associations with multifactorial pathogenesis that should not be classified as MGTS. Broader recognition of MGTS is essential to advance consensus definitions, establish diagnostic criteria, and develop evidence-based management strategies for this clinically important group of disorders.