BACKGROUND:Neuroimmunomodulation examines nervous-immune interactions via hormonal and inflammatory pathways. This study investigated whether the anxiety-sleep disturbance symptom cluster in colorectal cancer (CRC) patients undergoing chemotherapy is associated with neuroendocrine dysregulation, cellular immune alterations, and quality of life (QoL), and tested whether cortisol and interleukin-6 (IL-6) act as biological mediators. METHODS:In this prospective baseline observational study, 268 CRC patients scheduled to initiate systemic chemotherapy were assessed within 24 hours before their first chemotherapy cycle. Anxiety (HADS-A), sleep quality (PSQI), and QoL (EORTC QLQ-C30) were assessed. Serum cortisol, IL-6, and TNF-α were quantified by ELISA. Lymphocyte subsets (CD3+, CD4+, CD8+, NK cells) and regulatory T cells (Tregs) were analyzed by flow cytometry. Patients with HADS-A ≥8 and PSQI >5 formed the Symptom Cluster group (n=118), while the remaining patients constituted the Non-cluster comparator group (n=150). Mediation analysis using bootstrapping tested cortisol and IL-6 as intermediaries. RESULTS:The Symptom Cluster group showed significantly elevated cortisol, IL-6, and TNF-α (all P<0.001), higher Treg proportion (8.4% vs. 4.6%, P<0.001), and lower CD3+, CD4+, and NK cell counts (all P<0.001). Global QoL was reduced (36.4 vs. 69.5, P<0.001). Cross-sectional mediation models indicated that the association between symptom-cluster status and CD4+ T-cell count was statistically mediated by cortisol (indirect effect, -117.45; 95% bootstrap CI, -168.22 to -75.40), and the association with global QoL was statistically mediated by IL-6 (indirect effect, -13.85; 95% bootstrap CI, -18.50 to -9.80), accounting for 37.9% and 41.8% of the total effects, respectively. CONCLUSION:The anxiety-sleep disturbance symptom cluster in CRC chemotherapy patients is associated with neuroendocrine-inflammatory dysregulation, effector immune suppression, Treg expansion, and impaired QoL. Exploratory mediation findings suggest that cortisol and IL-6 may be involved in statistical indirect associations between this pre-chemotherapy anxiety-sleep disturbance phenotype and immune/QoL outcomes; longitudinal studies are needed to determine temporal and causal relationships.
INTRODUCTION:Patients with inflammatory rheumatic diseases exhibit reduced physical activity (PA), contributing to increased cardiovascular risk and functional decline. While PA is recommended in both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), variables associated with PA remain poorly understood. Therefore, this study explored shared and disease-specific associations with PA in RA and SLE. METHODS:In this cross-sectional study, patients with RA (n = 200) and 94 SLE (n = 94), fulfilling ACR classification criteria, were recruited from the rheumatological outpatient clinic of the University Hospital Leipzig. Sociodemographic data were obtained from electronic records. Patient-reported outcome measures assessed comorbidities, PA and health-related quality of life. PA was quantified using the International Physical Activity Questionnaire Long Form. Associations were examined using multivariable logistic regression models. RESULTS:Patients with RA showed lower physical performance (p < 0.001) but higher PA levels than SLE (p < 0.001). In RA, fibromyalgia remained the only statistically significant variable and was associated with lower PA (OR = 0.001, 95 % CI <0.001-0.289; p = 0.017). In SLE, no independent predictors were identified; fibromyalgia (OR = 0.374, p = 0.209) and depressive symptoms (OR = 0.341, p = 0.063) showed non-significant trends. Self-reported PA and objective walking performance were moderately associated in both groups (RA: R² = 0.19; SLE: R² = 0.12). CONCLUSION:Associations with PA differ between RA and SLE. In RA, fibromyalgia is associated with lower PA, whereas in SLE, PA reflects a multifactorial interplay of functional and psychological factors, supporting disease-specific approaches to PA promotion.
BACKGROUND AND AIMS:The effects of adjuvant hyperthermia on glioblastoma-associated astrocytes remain poorly characterized. This study aimed to investigate the role of the purinergic P2X7 receptor, an ATP-gated ion channel, in mediating heat-induced astrocyte activation and its impact on tumor progression. METHODS:Primary mouse astrocytes were subjected to heat stress (mild hyperthermia at 42°C). P2X7 signaling was examined using a specific antagonist (A-740003), siRNA-mediated knockdown, and live-cell calcium imaging. Astrocyte activation was evaluated by assessing Glial Fibrillary Acidic Protein (GFAP) expression and pro-inflammatory markers. The pro-tumorigenic potential of astrocyte-conditioned medium was tested on U87 glioblastoma cells. An orthotopic mouse model was used to validate the effects of local hyperthermia, with or without P2X7 inhibition. RESULTS:Mild hyperthermia upregulated P2X7 expression in astrocytes and induced a substantial calcium influx, leading to activation of the Calcineurin-NFAT pathway. This process promoted a reactive astrocyte phenotype and a pro-tumorigenic secretory profile, enhancing U87 cell proliferation, migration, and invasion. In vivo, mild hyperthermia was associated with increased tumor progression, which was attenuated by pharmacological inhibition of P2X7. CONCLUSION:Heat stress facilitates glioblastoma progression by activating astrocytes through the P2X7-mediated calcium-calcineurin-NFAT signaling pathway. These findings highlight P2X7 as a potential therapeutic target for optimizing hyperthermia-based strategies in glioblastoma treatment.
Introduction: Depression is a common mental disease. Carboxypeptidase E (CPE) may be a therapeutic target for depression. This study aimed to investigate whether CPE regulates NOD-like receptor protein 3 (NLRP3) inflammasome signaling and affects pyroptosis, thereby improving cellular damage and depression-like behaviors in depressed mice. Methods: A mouse model of depression-like behavior was established with chronic unpredictable mild stress (CUMS) and treated with Lv-oe-CPE, an NLRP3 inflammasome activator (nigericin), or an NLRP3 inflammasome inhibitor (MCC950). Anxiety- and depression-like behaviors were assessed through open field test, forced swim test, tail suspension test, and sucrose preference test. Cellular damage in the hippocampal CA1 region was evaluated with H&E and Nissl staining. CPE, gasdermin D-N (GSDMD-N), NLRP3, cleaved caspase 1, apoptosis-associated spot-like protein (ASC), oxidative stress, interleukin (IL)-1β, and IL-18 levels, and GSDMD-N-positive cells were assessed with Western blot, kits, and immunohistochemistry. Results: CPE was downregulated in the hippocampal CA1 region of CUMS mice, and its reexpression attenuate depression-like behaviors. CPE overexpression suppressed NLRP3, cleaved caspase 1, ASC, IL-1β, and IL-18 levels in the hippocampal CA1 region. NLRP3 inflammasome inactivation alleviated CA1 cellular damage to inhibit depressive-like behaviors, whereas its activation reversed the improving effect of CPE. CPE inactivated NLRP3 inflammasomes, thereby attenuating cell pyroptosis in the hippocampal CA1 region. Conclusions: CPE is downregulated in the hippocampal CA1 region of the mouse model of depression-like behavior. CPE overexpression can inhibit NLRP3 inflammasome activation and then reduce pyroptosis, hence repairing cellular damage in the hippocampal CA1 region and eventually suppressing depressive-like behaviors.
Background: The thymus is the primary lymphoid organ responsible for the generation of a self-tolerant and immunocompetent T-cell repertoire. Its function is not autonomous but is finely tuned by a complex neuroendocrine network, integrating signals from the central nervous system and the endocrine system to modulate thymopoiesis. While the roles of classical hormones and neurotransmitters in regulating thymic epithelial cell (TEC) function and T-cell development are increasingly recognized, the mechanistic pathways by which these signals are integrated within the thymic microenvironment still have much to be understood. Summary: A key, yet underexplored, component of the thymic microenvironment is the extracellular matrix (ECM). It is very clear today that ECM is not a passive scaffold but a dynamic structure that presents critical signals for thymocyte migration, proliferation, and selection. This review synthesizes current evidence to propose a novel paradigm: the thymic ECM acts as a key mediator of neuroendocrine control. We explore how specific ECM molecules, such as laminins, collagens, and fibronectin, expressed by TECs and other microenvironmental cells, can be modulated by neuroendocrine ligands. Key Messages: Theses ECM modulations directly impact the presentation of key receptors, such as integrins, thereby influencing the critical crosstalk between a given thymic niche and developing lymphocytes. By delineating the ECM-mediated mechanisms, this review aimed to provide a more holistic understanding of how neuroendocrine factors govern thymic physiology, with implications for aging, stress-related immunosenescence, and therapeutic strategies aimed at thymic regeneration.
Background: Aging is associated with enumerative and functional changes of peripheral innate immune cells, notably myeloid cells (ex., monocytes/macrophages and neutrophils). Peripheral myeloid cells routinely infiltrate the brain, particularly at the brain borders, influencing cognition, mood, and stress responses. Summary: Here, we review how the dysfunctional crosstalk between circulating myeloid cells and brain cells may contribute to the development of late-life depression and Alzheimer’s disease during aging. The aged cerebral microglia (i.e., resident macrophages) exhibit dystrophic morphology and impaired phagocytosis while peripheral myeloid cells expand in number but display functional deficits, including impaired phagocytosis and pro-inflammatory biased response. The peripheral myeloid changes collectively contribute to systemic chronic inflammation and tissue dysfunction. Epigenetic changes and metabolic disruptions, such as altered glucose utilization, exacerbate pro-inflammatory states. Key messages: The cumulative impact of these alterations undermines neuroprotection and facilitates age-related neuropsychiatric conditions, including neurodegenerative diseases and late-life depression. The identification of pro-aging circulating factors and cells could pave the way for new therapeutic strategies aimed at mitigating cognitive decline and improving mood. Targeting myeloid cell metabolism or inflammatory signaling pathways emerges as a promising strategy to mitigate aging-associated neuropsychiatric syndromes.
To enhance the durability of recycled coarse aggregate concrete (RCAC) under early dry-wet cycles, this study investigates the effects of incorporating copper-plated steel fibers (CPSFs) at volume fractions of 0%, 0.5%, 1.0%, and 1.5%. We systematically evaluated the Cl- erosion resistance, splitting tensile strength, mass-change rate, pore structure, phase composition, and microstructural evolution of RCAC subjected to 21 NaCl dry-wet cycles. Results show that CPSF effectively inhibits microcrack propagation and improves the interfacial transition zone within the concrete matrix. At a fiber content of 1.5%, the mass of the specimen increased by 1.23% after 21 erosion cycles, and the splitting tensile strength reached 2.86 MPa, which is 80% higher than that of the fiber-free control group. Comprehensive evaluation using the entropy weight method confirms that RCAC with 1.5% CPSF exhibits the best durability performance. This study demonstrates that an appropriate dosage of CPSF significantly mitigates the detrimental effects of early dry-wet cycles on RCAC performance.
Interpersonal physiological synchrony (IPS)-the temporal alignment of autonomic physiological signals-is emerging as a prominent feature of social interaction. IPS can predict complex social phenomena such as relationship quality or social bonding. Yet, the origins of IPS remain poorly understood. Here, we investigated whether and how IPS can emerge spontaneously through mere visual contact. Thirty-eight dyads of familiar participants were asked to face each other without speaking or making coverbal gestures. IPS was measured using four autonomic signals-heart rate, skin conductance, respiration rate, and pupil diameter-and quantified as the Pearson correlation between dyad members' signals. We found that visual contact was sufficient to synchronize all physiological signals in real dyads, compared with chance-level synchrony in surrogate dyads. Notably, heart rate and pupil diameter IPS were particularly vision-dependent, showing significant reductions when visual contact was prevented. Furthermore, examining the link between IPS and spontaneous social cues revealed that heart rate IPS co-occurred with synchronized body movements, whereas pupil diameter IPS co-occurred with synchronized smiling. These findings show that IPS can emerge spontaneously through mere visual contact and is linked to the exchange of social cues. They position IPS as a robust, self-organizing phenomenon that occurs naturally in social interactions.
Chondrichthyans are among the most ancient vertebrates, and their morphology has enabled adaptation to diverse marine environments. In sharks, the head is the functional center for feeding, respiration, and sensory perception, reflecting a balance between phylogenetic constraints and ecological demands. Striking specializations, such as the cephalofoil of hammerhead sharks or the elongated rostrum of sawsharks, illustrate remarkable adaptations. Most studies on head shape have focused on single species or restricted clades, whereas broader analyses have focused on parts of the skull. We analyzed the ventral head morphology of 453 shark species (Selachii), focusing on the relative position of the rostrum, mouth, and nostrils (in a subset of 395 species), using standardized illustrations and landmark-based geometric morphometrics. Shape variation was related to ecological and anatomical factors. The morphological space reveals a phylogenetic signal, with reconstructed ancestral shapes close to the overall mean configuration, indicating strong morphological conservatism. Evolutionary model fitting supports Brownian motion dynamics with limited divergence from ancestral forms. Correlations with habitat and body size are weak, whereas stronger associations are observed with the number of olfactory lamellae. Our results provide a large-scale comparative framework of ventral head morphology in sharks, highlighting its evolutionary stability and predominant phylogenetic control.
Rhythm is a fundamental organizing principle in biological systems, shaping physiological regulation, affect, and social interaction across species. In caregiving, rhythmic passive movement, such as carrying and rocking, has long been recognized as a soothing strategy in mammals, reducing crying, heart rate, and arousal while promoting sleep. Anecdotal and behavioral evidence in humans also suggest that some forms of rhythmic motion, such as sliding or tossing infants, can elicit overt enjoyment. Yet, no study has directly investigated the effects of passive rhythmic movement beyond the mammalian lineage or in species lacking maternal carrying, nor assessed its potential to evoke pleasurable states. Here, we examined the effects of rhythmic passive movement in domestic chicks (Gallus gallus), a precocial bird that walks immediately after hatching and is never carried by the mother. Chicks were exposed to rocking (horizontal, vertical) and carrying-like motion at different frequencies. Slow rhythmic movements reduced contact calls, replicating the soothing effects known in mammals, while faster movements increased brood calls, indicating a transition from distress reduction to positive arousal. These results demonstrate that rhythmic passive motion modulates affective states in birds, revealing both calming and pleasurable dimensions and suggesting deeply conserved mechanisms for rhythm-based affect regulation across vertebrates.
When a sound occurs (i.e., its acoustic onset) is not the same as when we perceive that sound to occur. The latter location is known as the "P-center" in both music and language perception, and can be a few to over a hundred milliseconds after a sound's acoustic onset. While P-center perception in music has received scrutiny, it remains unclear how P-centers emerge when multiple instruments play together, particularly when they are not perfectly synchronized. Here, we investigate the effect of different degrees of instrument asynchrony on the P-center of their combined sound. In two experiments, participants aligned a click probe to pairs of instruments used in popular music with varying asynchronies (0-±80 ms). Results show that increasing asynchrony shifts the P-center of the compound sound later in time. Moreover, fast-attack instruments (e.g., kick drum) exert a strong pull on the P-center; fast-slow pairs largely retained a single P-center anchored to the fast-attack sound. By contrast, pairs of fast-attack sounds with ≥40 ms asynchronies between their individual P-centers provided evidence of perceptual segregation of the sound into two events. The findings show how inter-instrument asynchronies and attack characteristics jointly structure the perceived timing and unity of compound musical sounds.
Driving is evolving from a transportation task into a rich, multisensory experience in automated vehicles. This study developed and evaluated three multisensory solutions combining music with synchronized vibrotactile stimulation for autonomous driving contexts: safe (city driving), engagement (highway cruising), and entertainment (highway entry). Eighteen healthy adult drivers experienced three context-solution pairs presented in music only (M) and music with vibration (MV) modalities with simulated autonomous driving scenarios. Participants' responses were measured using self-assessment manikin (SAM) ratings and electroencephalography (EEG). A significant main effect of modality showed that MV led to greater pleasure than M (EEG: p < 0.05; SAM: p < 0.05), with arousal showing a similar pattern (EEG: p < 0.05; SAM: p = 0.099). Behavioral data showed different emotional profiles across the three context-solution pairs (p < 0.001 for pleasure, arousal, and dominance), whereas the EEG contrast, which subtracted the video-only condition, showed no significant pair effect. These findings demonstrate that vibrotactile enhancement provides consistent emotional benefits across diverse driving contexts. Because each musical solution was paired with a unique driving scenario, these differences cannot be attributed solely to the music intervention. Future optimization of music and vibrotactile parameters may further enhance the autonomous driving experience.
The brain's ability to associate information from different sensory modalities, known as cross-modal integration, is crucial for forming a coherent perception of objects and events. When such associations follow systematic and predictable patterns, they are referred to as cross-modal correspondences. Humans, for example, tend to associate large objects with low-pitched sounds and small objects with high-pitched sounds, a phenomenon known as pitch-size cross-modal correspondence. This phenomenon has been documented in several vertebrate species, yet direct experimental evidence in avian species remains comparatively limited. Here, we tested African penguins using a preferential choice paradigm in which individuals chose between two cubes of different sizes after hearing either a high- or low-pitched sound. Following passive exposure to congruent pitch-size pairings, penguins chose larger objects following low-pitched sounds and smaller objects following high-pitched sounds, indicating that auditory pitch guided their visual size choices. Given that individuals were pre-exposed to a limited set of pitch-size pairings, this effect may reflect either a preexisting bias consistent with cross-modal correspondences or the generalization of a learned association. Nevertheless, these findings demonstrate that penguins can integrate auditory and visual information to guide their behavior and generalize a systematic pitch-size relationship across sensory dimensions.
Background: Parasitic infections of the central nervous system are still a health problem in low- and middle-income countries and due to international travels and migration can affect even opulent countries. Parasites can modulate host immunity to ensure their long-term survival without inflammatory symptoms; therefore, infection of the brain parenchyma by Taenia solium cysticerci (parenchymal neurocysticercosis) may be asymptomatic, or on the other hand lead to severe inflammation that initiates glial activation with production of pro-inflammatory cytokines, with mild to severe neurological symptoms. Besides, when cysticerci are localized in the ventricles or in the subarachnoid space (extraparenchymal neurocysticercosis) severe symptoms and treatment difficulties occur. Summary: Here we review how the nervous, the immune, and the endocrine systems interact with T. solium and crassiceps cysticerci and influence the course and individualities of the disease that the parasites trigger in humans and animals. For example, a clear sexual dimorphism in cysticercosis has been found in experimental models of the disease, but the influence of gender in human patients needs further investigation. The synthesis of steroids by the brain cells and the cysticerci might influence the local immune response elicited by the presence of the parasites. Remarkably, cultured cysticerci can synthesize sex steroids and deoxycorticosterone, suggesting that these parasites can influence the local brain microenvironment, especially by producing dehydroepiandrosterone, estrogens, and androgens, which could modify the immune response. Treatment of neurocysticercosis includes cysticidal drugs and corticosteroids intended to control the inflammation caused by the parasite; however, these steroids represent a double-edged tool due to their side effects during prolonged administration and also because of some beneficial effects for the parasite itself. Key Messages: Parasite survival in the host depends on the inflammatory response and the local microenvironment, including steroid hormones that can promote their survival and even their development and proliferation. New strategies should be designed to manage the severe symptoms induced by the chronic presence or the death of parasites and the poor response to treatment that occurs in extraparenchymal neurocysticercosis.
Chronic pancreatitis (CP) is characterized by progressive fibrosis, inflammation, and pancreatic atrophy. Here, we evaluate a milder CP model using only 42 cerulein injections administered in both male and female C57BL/6J (BL6) and BALB/c mice. We further assess the therapeutic potential of the RORγt inhibitor GSK805. We employed a multi-tiered analytical approach, including the robustness of conclusion (RC), unit fragility index, and robustness index, to evaluate consistency and numerical stability of conclusions. The model reliably produced key hallmarks of CP: reduced pancreas-to-body weight ratio, elevated collagen I deposition, and tubular complex formation with an RC of 100%. In contrast, the induction of Tnf, Ifng, Il10, Il23r, Il6, and Il1b expression was less robust and partially strain specific. Il23r and Il10 were significantly induced during CP in female and male BL6 but not in BALB/c mice. Il6 was significantly induced in female and male BALB/c but only reached significance in BL6 when sexes were combined. Treatment with GSK805 reduced Il23r expression level significantly in BL6 mice, but no reliable improvements in other disease characteristics were observed. Overall, this study validates a simplified, robust CP model and advocates for the integration of complementary statistical metrics to strengthen the reliability of scientific conclusion.
A widely observed phenomenon across cultures involves the use of rhythmic auditory stimulation in intricate rituals to achieve dissociative mental states. While several physiological mechanisms link repetitive auditory stimuli to nonordinary states of consciousness (NSCs), entrainment-the brainwave synchronization through periodic external stimuli-has received particular attention. However, there is limited experimental evidence on this relationship, and the influence of certain personality traits that shape the strength of NSCs remains underexplored. In our study, 27 participants with no prior experience of rhythm-induced NSCs listened to 12 min of both rhythmic and nonrhythmic drum sounds. Following each type of stimulation, they engaged in cognitive tasks and reported their phenomenological experiences related to NSCs through questionnaires. Electroencephalography was employed to record brain activity, evaluating whether entrainment to the drum sounds affected both objective and subjective proxies of NSCs. Our findings show that higher trait absorption was associated with stronger experiences of disembodiment and spirituality during drumming listening. Also, rhythmic drum sounds increased experiences of unity compared to nonrhythmic ones, and for individuals with low trait absorption, it also increased spiritual experiences. These findings suggest that rhythm influences the characteristics of the resulting phenomenological experience.
Promoting consumer adoption of high-efficiency energy-saving home appliances (ESHA) is critical for reducing residential energy consumption. China has implemented a portfolio of incentive policies, yet policy effects vary across regions, sales channels, and information environments. Based on panel data of 30 provincial-level regions in China from 2015 to 2022, this study adopts gradient boosting regression trees (GBRTs) and panel models to explore online and offline policy-sales associations. The online sample includes three major appliance categories: air conditioners, refrigerators, and washing machines, whereas, constrained by data availability, the offline analysis covers only air conditioners and washing machines. Results show that more policy instruments do not always strengthen online associations, with evident heterogeneity across instrument types and product groups. Offline policy performance also exhibits marked regional differentiation. This study reveals channel- and product-differentiated policy roles and provides empirical implications for targeted ESHA policy design, with its conclusions limited to China's institutional and market context and the scope of the available data.
Can rodents form a categorical face concept or is their ability to discriminate faces from objects driven solely by visual features? To answer this question, we trained C57BL/6J mice on a touchscreen face-object discrimination task and examined their behavior in two experiments. We show that: (i) after training, mice generalized face-object classification to novel exemplars but lost the ability to discriminate when stimuli were inverted or contrast‑negated, consistent with the classic effects of these manipulations on humans performing categorically face-specific tasks; (ii) along a continuum from low‑similarity pareidolia to real faces, choice performance followed a sigmoidal rather than a linear or quadratic function, which again suggests a categorical face concept recognition boundary. These behavioral results in mice resemble how humans visually categorize faces and nonfaces. The work provides evidence that a face concept can emerge even in a species whose social communication is not primarily visual, paving the way for future investigations on neural and genetic substrates of categorical pattern recognition.
Recent data show that loneliness is more prevalent in lower- and middle-income countries (LMICs), compared to higher-income countries (HICs). This evidence suggests that loneliness is not simply an issue in HICs or a result of living alone. Instead, loneliness is closely tied to structural factors, some of which may be more salient in LMICs. In this perspective article, the contextual aspects that are closely tied to loneliness in research from LMICs, where the majority of the world's population resides, are presented. The discussed aspects go beyond the differentiation between individualism versus collectivism found in loneliness literature from HICs. Instead, the article sheds light on the often-cyclical relationships between loneliness and poverty, political instability, stigma, migration, culture, religion, and climate change. Shedding light on loneliness research from LMICs, this perspective provides novel and exciting directions for loneliness research in both HICs and LMICs. As these structural influences are often entangled and mostly affect those populations who are already socially and economically disadvantaged, this perspective echoes scholars who view loneliness as a social justice issue and, additionally, calls for recognizing loneliness as a truly global phenomenon.
