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Hippocampal theta distinguishes between memory-guided and exploratory saccades in humans
Memory shapes how we explore the visual world, but the neural mechanisms linking mnemonic processes to eye movements during naturalistic viewing are not well understood. Theta-band oscillatory activity in the hippocampus is time-locked with eye movements in primates, suggesting a putative mechanism for coordinating mnemonic processing and oculomotor behaviour. Yet, it remains unknown whether this coupling generalises to episodic memory-guided viewing in humans, whether slow (3–6 Hz) and fast (6–10 Hz) theta bands play dissociable functions, and whether this coupling is sensitive to the direction of upcoming eye movements. Here, we used intracranial EEG and eye-tracking data from 11 neurosurgical patients of either sex (Keles et al., 2024) to address these questions. Using fixation-locked analyses, we found that hippocampal theta dynamics differentiate memory-guided from memory-independent fixations of episodically encoded naturalistic scenes (i.e., movies) through power and coherence mechanisms that are both temporally and spectrally dissociable. First, immediately after fixations (∼0 to 250 ms), slow-theta power was more strongly suppressed during memory-guided trials (i.e., true positive, TP) than correct memory-independent trials (i.e., true negative, TN). Second, in the period around fixations (-80 to 60 ms), theta phase coherence increased independent of power during TP vs TN trials. This increase in coherence was most pronounced for contraversive relative to ipsiversive fixations, consistent with direction-sensitive hippocampal–oculomotor coordination during memory-guided viewing. Together, these findings suggest that hippocampal theta plays dissociable, time-locked roles in memory-guided fixations during naturalistic visual retrieval, supporting an ecologically relevant role for the hippocampus in coordinating memory and active visual behaviour. Significance statement Memory influences how we sample the visual environment, but the brain signals that link memory systems to eye movements are poorly understood. Using intracranial recordings from the human hippocampus during visual exploration of naturalistically encoded scenes, we demonstrate that theta-band activity differentiates memory-guided from memory-independent fixations in two ways: increased theta synchrony around fixation onset and reduced theta power modulations after fixation onset. These results reveal novel insights into how hippocampal theta helps coordinate memory-guided visual exploration.
Design and validation of an immersive virtual rehabilitation system for individuals with vestibular disorders: A feasibility study
Background Vestibular rehabilitation is an essential part of managing balance disorders, but traditional exercises can often be repetitive and demotivating for patients. This can reduce adherence and limit treatment outcomes. Objective This study aimed to assess the feasibility, usability, patient satisfaction, and safety of DizzyVR, an immersive virtual reality system designed to support vestibular rehabilitation. Preliminary data on its potential effects on clinical outcomes were also collected. Methods A prospective, single-arm feasibility study was conducted with ten participants diagnosed with various vestibular disorders. Each participant completed eight weekly sessions using DizzyVR. Feasibility was assessed through session attendance and completion rates. Usability, satisfaction, and safety were measured using the System Usability Scale, the User Satisfaction Evaluation Questionnaire, and the Simulator Sickness Questionnaire. Clinical measures included the Dizziness Handicap Inventory (DHI), Timed Up and Go (TUG) test, Activities-specific Balance Confidence (ABC) scale, and Functional Gait Assessment (FGA). Results Ten participants completed the training, with a high adherence rate (91.25%). Usability scores indicated good ease of use, and satisfaction scores were high. Mild adverse events such as nausea or disorientation were reported by three participants, but improved over time. Exploratory pre–post changes were observed in gait speed (TUG: p = 0.002), balance confidence (ABC: p = 0.007), and gait stability (FGA: p = 0.012). While DHI scores demonstrated a trend toward improvement, the change did not reach statistical significance (p = 0.081). Overall, participants reported feeling safe and expressed willingness to recommend and reuse the system. Conclusions The findings suggest that DizzyVR is a feasible, usable, and well-accepted tool that may complement conventional vestibular rehabilitation. The system appears to support patient motivation and safe participation while showing promising exploratory changes in balance and gait. Further studies with larger samples, control groups, and longer follow-up are recommended to confirm and expand on these promising preliminary results.
A multi-objective optimization framework for sustainable automotive interior design integrating enhanced triple bottom line, fuzzy decision-making, and BO-BiLSTM-driven NSGA-II
Retailer’s inventory-based financing with bounded advance rates: Interplay between wholesale price contract and loan menu
We examine a supply chain comprising a capital-constrained retailer, a supplier, and a bank. The retailer adopts inventory-based financing with bounded advance rates (IBF-B) to procure products through wholesale price contracts offered by the supplier. The bank is viewed as a strategic decision-maker with market power over the retailer when designing a loan menu that includes interest rates and inventory advance rates. By analyzing how inventory advance rates influence the retailer’s financing decisions, we derive upper and lower bounds for these rates to balance profitability and credit risk. Furthermore, we explore the interplay between the loan menu and wholesale price contracts. For the retailer intending to borrow up to the loan limit, the highest feasible wholesale price is offered if the supplier can obtain more profits, while the bank consistently charges the highest feasible interest rate. The upper bound of inventory advance rates is offered only when it yields a positive margin; otherwise, the interior advance rate within medium range is preferred. Numerical results illustrate the value of IBF-B, the motivations of all participants, and the impact of key economic parameters on financing decisions and supply chain performance.
Inhalable ligustrazine powders relieve inflammation of COPD via regulation of neutrophil extracellular traps and gut-lung axis microbiota
Detection and Removal of Hyper-synchronous Artifacts in Massively Parallel Spike Recordings
Contemporary electrophysiology experiments often involve massively parallel recordings of neuronal activity using multi-electrode arrays. While researchers have been aware of artifacts arising fromelectric cross-talk between channels in setups for such recordings, systematic and quantitative assessment of the effects of those artifacts on the data quality has never been reported. Here we present, based on examination of electrophysiology recordings from multiple laboratories, that multi-electrode recordings of spiking activity commonly contain extremely precise (at the data sampling resolution) spike coincidences far above the chance level. The recordings analyzed here were obtained from two rhesus macaques ( Macaca mulatta ; one male, one female) and one male mouse (C57BL/6J).We derive, throughmodeling of the electric cross-talk, a systematic relation between the amount of such hyper-synchronous events (HSEs) in channel pairs and the correlation between the raw signals of those channels in the multi-unit activity frequency range (500-7500 Hz). We show that whitening the band-pass filtered raw signals removes the above chance HSEs; strongly suggesting they originate from linear mixing of signals. Whitening should therefore be performed prior to spike sorting and any further analysis of precise spike correlation, otherwise analysis results may be considerably affected. Significance statement Artifacts are widespread in electrophysiological recordings. To mitigate their impact, these artifacts need to be detected and they should be removed from the data without impacting the quality of the data. This work presents measures to identify and quantify the amount of artifacts within a multichannel recording by evaluating the occurrence of hyper-synchronous events i.e., spikes that are synchronous on a sub-millisecond time scale, and further introduces zero-phase component analysis (ZCA) as a method to remove these artifacts from the data. Thus, we recommend to use ZCA as a general preprocessing for electrophysiological recordings.
Bayesian hierarchical mixture modelling to derive probabilistic iELISA thresholds for bovine brucellosis in endemic dairy systems
Background In endemic dairy systems, the interpretation of serological tests for bovine brucellosis is compromised using fixed diagnostic cut-offs, which fail to account for continuous antibody distributions and population heterogeneity. This study aimed to apply a Bayesian hierarchical Gaussian mixture model (BHGMM) to resolve diagnostic uncertainty by deriving probabilistic, biologically informed thresholds for indirect ELISA (iELISA). Methods A cross-sectional dataset comprising 2,696 milk samples from large-scale dairy herds was analysed. Log-transformed and standardised antibody values were modelled using a three-component hierarchical mixture representing healthy, latent, and diseased populations. Posterior class distributions, herd-specific cut-offs, and prevalence were estimated, and model performance was evaluated using convergence diagnostics, posterior predictive checks, and ROC analysis. Results Three distinct serological populations were identified. Mean antibody levels (S/P%) were 5.29 in healthy, 17.07 in latent, and 299.84 in diseased animals. Dual diagnostic thresholds were estimated at 10.7 S/P% and 82.2 S/P%. Estimated class proportions were 23.5% healthy, 43.6% latent, and 32.9% diseased. Substantial between-herd heterogeneity was observed, with confirmatory cut-offs ranging from approximately 68–133 S/P% and herd-level true prevalence varying from about 1% to 67%. The model demonstrated high diagnostic accuracy (AUC = 84.5%) and stability across prior specifications. Conclusions Bayesian modelling captures intermediate serological “gray zones” and herd-level variability overlooked by standard binary interpretations. This probabilistic approach supports targeted control strategies in complex endemic environments.
Case-based evaluation of emergency parking bay installation in three-lane loess tunnels in the loess plateau of Shaanxi Province
The neural correlates of parallel and serial search
For decades, target–distractor similarity has been known to induce distinct visual search modes. A highly salient target can pop out, suggesting parallel processing of all items irrespective of set size. By contrast, high similarity among items requires item-by-item assessment, a characteristic of serial search. Despite this long-standing distinction, search modes remain poorly defined due to confounding of behavioural measures by differences in local contrasts and display density just as neural correlates are confounded by distinct displays used to prompt different search modes. Here, we biased search mode by manipulating target–distractor similarity in inducer trials, while embedded test trials afforded both modes, allowing us to isolate neural signatures of serial and parallel search under visually identical displays. Behavioral results from 24 participants (21 female, 3 male) confirmed successful induction of distinct search modes. EEG decoding reliably discriminated search modes and generalized across inducer and test trials. Attentional deployment toward the target differed across search modes, revealing topographical differences in target location representations. The representation of target location was associated with response times, indicating when subjects swapped search mode from parallel to serial if target was not detected quickly. Moreover, the representation of search target diverged between search modes: A temporally stable pattern emerged during serial search, suggesting the maintenance of conjunction item in working memory, whereas the representations were dynamic in parallel search, likely reflecting the relevant feature. These findings demonstrate that search history shapes search mode, giving rise to clearly distinct neural dynamics even under visually identical stimulation. Significance statement Serial and parallel search distinction is recognized half a century ago. However, search modes remain poorly defined. This is because visual displays used to prompt distinct search modes confound behavioural measures and neural correlates of search modes. Here, we biased search modes in subsequent blocks by manipulating target-distractor similarity in a set of inducer trials. Embedded among inducer trials, test trials afforded both search modes, allowing us to isolate neural signatures of serial and parallel search under visually identical displays. We used EEG decoding to distinguish neural correlates of search modes and their influence on the modulation of target location and the representation of the target itself.
Association of troponin-defined myocardial injury with adverse long-term survival among patients with chronic kidney disease
Objective Chronic kidney disease (CKD) is associated with increased mortality, however, the impact of troponin-defined myocardial injury within this population remains poorly understood. This study aimed to investigate the associations between troponin-defined myocardial injury and long-term mortality in CKD patients. Methods This observational study analyzed 22,772,953 weighted records of adult CKD patients from National Health and Nutrition Examination Survey (1999–2004) databases. Myocardial injury was defined by at least one elevated high-sensitivity troponin (hs-cTn) assay, present in 26.6% of the cohort. Cox regression models adjusted for baseline characteristics and comorbidities were used to assess the associations between troponin-defined myocardial injury and all-cause and cardiovascular mortality. Sensitivity analyses excluding patients with known cardiovascular disease (CVD) were performed to evaluate the robustness of the findings. Results Patients with troponin-defined myocardial injury were older and had a higher prevalence of CVD, hypertension, diabetes, as well as a lower estimated glomerular filtration rate (eGFR), compared with those without troponin-defined myocardial injury. Over a median follow-up of 11.6 years, survival was significantly worse among patients with troponin-defined myocardial injury at 1, 5, 10, and 15 years. The adjusted hazard ratios (aHR) for all-cause mortality and cardiovascular mortality in patients with troponin-defined myocardial injury were 1.81 (95% CI 1.51–2.17) and 2.03 (95% CI 1.47–2.79), respectively. Sensitivity analysis excluding records with pre-existing CVD showed similar trends, with an aHR of 1.86 (95% CI 1.56–2.21) for all-cause mortality and 2.44 (95% CI 1.83–3.24) for cardiovascular mortality. Conclusion As a marker for troponin-defined myocardial injury, hs-cTns were independently associated with worse long-term survival among CKD patients. However, the observational design precludes causal inference, and single time-point troponin measurements limit the assessment of dynamic changes in myocardial injury.
A machine learning and agent-based modeling framework for tourism crisis management
Abstract This study proposes and tests a new Destination Resilience Assessment Framework (DRAF) to overcome the weaknesses of existing models which have a limited focus on multi-hazard prediction and on multi-layered interactions of stakeholders/infrastructure/markets during recovery in the context of cascading crises (pandemics, natural disasters and geopolitical shocks). The research employs a mixed-methods design that combines decision-tree based machine learning (random forests), an LSTM-based neural network, and ensemble approaches with agent-based modeling in NetLogo. Simulations are informed and calibrated using real-time streams from 847 sources globally (2019–2024), such as economic indicators, tourist flows, infrastructure capacity and stakeholder sentiment, combined with case data for 12 crises. DRAF achieves 94.7% accuracy in predicting recovery trajectories, identifies key resilience variables with 89.3% accuracy, and forecasts recovery time within ± 2.3 months. Simulation-based counterfactual analyses indicate that destinations implementing DRAF would recover an estimated 67% faster and regain visitor confidence an estimated 43% more quickly than the simulated baseline scenario.The five principal resilience factors are adaptive governance (β = 0.847), stakeholder collaboration networks (β = 0.723), infrastructure flexibility (β = 0.692), market diversification (β = 0.634), and community engagement (β = 0.587). Conceptually, the framework advances tourism crisis management models and, practically, provides transparent decision support that empowers stakeholders to assess impacts and coordinate evidence-based recovery actions.
Brain-wide circuitry underlying altered auditory habituation in zebrafish models of autism
Auditory processing is widely understood to occur differently in autism, though the patterns of brain activity underlying these differences are not well understood. The diversity of autism also means brain-wide networks may change in various ways to produce similar behavioral outputs. We used larval zebrafish to investigate auditory habituation in three genetic lines relevant to autism: fmr1 , mecp2 , and cntnap2 . In free-swimming behavioral tests, we found each line had a unique profile of auditory hyper-responsiveness and/or reduced habituation compared to wild types. Combining the optical transparency of larval zebrafish with genetically encoded calcium indicators and light-sheet microscopy, we then observed brain-wide activity at cellular resolution during repeated sound stimuli. Each line showed unique alterations in brain-wide spontaneous activity, auditory processing, and adaptation in response to repetitive acoustic stimuli. We also observed commonalities in activity across our genetic lines that indicate shared circuit changes underlying certain aspects of their behavioral phenotypes. These were predominantly in regions involved in sensory integration and sensorimotor gating rather than primary auditory areas. Overlapping phenotypes include differences in the activity and functional connectivity of the telencephalon, dopaminergic regions, and the locus coeruleus. Unique phenotypes include increased activity in auditory regions and excitatory/inhibitory imbalance in the cerebellum in fmr1, and differences in network activity over time in mecp2 and cntnap2 . Comparing these distinct but overlapping brain-wide auditory networks suggests that diverse genetic factors may contribute to similar behavioral effects through a range of circuit- and network-scale mechanisms. Significance statement Wilde et al. compare auditory habituation phenotypes in three genetic zebrafish models of autism. Of particular interest, several lines had overlapping behavioral phenotypes despite distinct patterns of brain-wide activity and network organization. Rather than pointing to a single mechanism underlying altered sensory responses, the data instead suggest there may be multiple neural routes to superficially similar sensory behaviors. This fits with growing discussions in human research that auditory processing in autism is unlikely to reflect one unified phenotype, but instead a diverse set of sensory profiles and underlying neural processes. Comparing across multiple genetic models and levels of neural organization may therefore help strengthen links between mechanistic animal work and the variability described in human sensory research in autism.
An innovative quantum–fuzzy paradigm for time- and context-sensitive membership: Quantive logic
Uncertainty in real-world decision problems is rarely static or one-dimensional: the relevance of evidence changes over time, depends on context, and is shaped by interactions between multiple criteria. Classical fuzzy logic provides a flexible scalar notion of membership, but it typically treats each criterion in isolation and does not natively encode temporal or contextual dynamics. Quantum-inspired models, on the other hand, offer rich Hilbert-space representations but are often difficult to integrate with everyday decision-making tasks. This paper proposes Quantive Logic (QL), a quantum-inspired fuzzy framework for time- and context-sensitive membership. In QL, each element is assigned a quantive membership state, represented as a vector in a complex Hilbert space. Conventional fuzzy degrees are recovered as suitable projections of this state, while phase and superposition capture interactions and context effects between criteria. We formalize how quantive membership states are initialized from classical information and updated through linear operators that model temporal evolution and contextual shifts. To illustrate the framework, we outline a multi-criteria credit-risk assessment scenario in which applicant profiles are encoded as quantive membership states and updated under changing economic conditions. This example shows how QL can refine risk judgments when interactions between criteria and scenario-dependent effects are important. Rather than competing with existing fuzzy or probabilistic models, QL is intended as a complementary layer that enriches membership representation wherever time, context, and interaction effects cannot be ignored.
Hibiscus derived nitrogen doped carbon nanochains for visual pH sensing and catalytic methyl orange degradation
Abstract The rapid expansion of synthetic azo dye pollution requires the development of multifunctional nanomaterials capable of simultaneous real-time monitoring and active chemical remediation. Herein, we report the one-pot, microwave-assisted hydrothermal synthesis of nitrogen-doped carbon nano-chains (N-CNCs) using Hibiscus sabdariffa botanical waste as a sustainable precursor. Transmission electron microscopy (TEM) confirmed the fabrication of an interconnected, one-dimensional (1D) beads-on-a-string morphology composed of monodisperse beads (2.08–2.96 nm). Selected area electron diffraction (SAED) verified a short-range turbostratic amorphous carbon framework. The synthesized N-CNCs function as a high-performance dual-mode environmental platform, serving as a high-contrast naked-eye pH sensor and an ultra-rapid catalyst for methyl orange (MO) degradation. Catalytic trials demonstrated a clean, systematic elimination of the chromophore within seconds (< 1 s) at environmental extremes, reaching degradation efficiencies of 79.30% (pH 3) and 74.67% (pH 12). Computational insights from Density Functional Theory (DFT) and Density of States (DOS) analysis decoded the underlying quantum logic, revealing a dramatic collapse of the frontier molecular orbital energy gap (E g ) from 8.5416 eV in native N-CNCs to an ultra-reactive 0.8816 eV within the hybrid matrix. DOS spectra confirmed intense orbital crowding near the Fermi level, which drives instantaneous, non-radiative intramolecular electron transfer for irreversible azo-bond cleavage. This metal-free, circular-economy platform successfully bridges real-time optical tracking with high-capacity chemical remediation, offering a highly competitive blueprint for advanced wastewater treatment.
Optoretinography in R9AP-Bradyopsia Reveals an Essential role of G-protein Activation and Deactivation in the Human Cone Elongation Response
Photoreceptor outer segments (OS) shorten and elongate in response to bleaching stimuli: these responses are measurable optically at nanometer scale resolution with OCT and collectively known as the optoretinogram (ORG). The molecular mechanisms underlying the ORG remain unresolved. Here we examine the role of G-protein in cone elongation by measuring ORGs in 2 female bradyopsia subjects caused by mutation in R9AP, the membrane anchor protein of RGS9, necessary for the latter’s transport to the OS and for normal deactivation of phototransduction by the GTPase-activating protein (GAP) complex. The ORGs of bradyopsia subjects had normal activation kinetics, amplitude and photosensitivity, but markedly slowed recovery compared to controls (2 males, 1 female). The slowed recovery is attributable to a reduced level of RGS9 in the OS and localizes the molecular basis of the OS elongation in the G-protein cascade sequence at, or prior to, formation of the GAP complex. The recovery of the ORG, measured in a paired-flash paradigm, revealed that the elongation requires a substrate that is depleted and recovers in a bleach level-dependent manner. Recovery from the highest bleach (75%) tracked the time course of cone opsin regeneration, implying that unregenerated cone opsin produces “ dark light ”, known to arise in rods from activation of G-protein by unregenerated rhodopsin. Overall, our results identify holo-trimeric G-protein as an essential and rapidly recyclable substrate for the ORG elongation response, and establish the ORG as a non-invasive, molecularly interpretable optical assay of G-protein signaling and dark adaptation suitable for evaluating diseases and therapies. Significance statement Photoreceptor outer segments shorten and elongate in response to bleaching stimuli: these responses are measurable optically at nanometer scale resolution with OCT and known as the optoretinogram (ORG). The molecular mechanisms underlying the ORG remain unresolved. By comparing control ORGs against subjects with a mutation in the anchor protein of regulator of G-protein signaling RGS9, we identified G-protein as an essential and rapidly recyclable substrate for the ORG elongation response. The recovery from exposures isomerizing 75% opsins tracked the time-course of pigment regeneration, indicating persistent activation of G-protein by unregenerated opsin. By linking ORG dynamics to defined molecular reactions, this work establishes the ORG as a quantitative, noninvasive assay of G-protein signaling and cone dark adaptation suitable for clinical translation.
Assessing the effects of virtual reality-based positive psychotherapy on emotion, life satisfaction, and suicidal ideation in major depression: A mixed-methods randomized controlled trial
Background Positive psychotherapy (PPT) targets the enhancement of well‑being in individuals with major depressive disorder (MDD), and virtual reality (VR) offers an immersive medium for delivering such experiential interventions. However, most VR-based approaches for depression are grounded in cognitive‑behavioral frameworks, leaving the application of PPT within VR environments largely unexplored. This study examined the effects of VR-based PPT on emotional experiences, life satisfaction, and suicidal ideation in individuals with MDD. Methods In this sequential explanatory mixed‑methods study, 78 patients were randomly assigned to VR-based positive psychotherapy (intervention; n = 39) or an equivalent face-to-face format (control; n = 39). Both groups received three sessions of positive psychotherapy, differing only in delivery mode. The quantitative phase assessed changes in affect, life satisfaction, and suicidal cognitions before and after each session using the PANAS, SWLS, and B-SCS. A subsequent qualitative analysis of the intervention group was conducted to contextualize and further interpret the quantitative findings. Results The results demonstrated a significant multivariate effect over time (Wilks’ Lambda = 0.316, F(20,57) = 6.176, ɳ² = 0.684, P < 0.001), indicating significant improvements in the outcome measures across sessions. Within‑group effect sizes ranged from small to moderate (d = 0.02–0.53), with comparable improvements observed in both the VR-supported and face-to-face formats. Qualitative findings further enriched the interpretation of these patterns, yielding two overarching themes: “user-friendly program” and “efficient psychotherapy program.” Conclusion Both VR-based and face-to-face positive psychotherapy were associated with improvements in emotional experiences, life satisfaction, and suicidal ideation in individuals with major depressive disorder. VR-based delivery appeared feasible and acceptable, with outcomes comparable to the traditional face-to-face format in this preliminary trial. Further studies with larger samples and longer follow-up are needed to confirm these findings and clarify their clinical implications. Trial registration: This trial was prospectively registered in the Iranian Registry of Clinical Trials (IRCT20201001048893N7, registration date: 16 November 2022, URL: https://irct.behdasht.gov.ir/trial/66424 ) prior to the enrollment of the first participant.
Microbacterium pollutisoli sp. nov., isolated from HCH-contaminated soil, exhibits genomic potential for bioactive compounds
Common and distinct neural substrates for approach- and avoidance-motivated actions
The motivation to approach rewards and avoid negative outcomes often guides human action. However, whether these opposing motivations for actions engage common or distinct neural pathways in humans remains unresolved. To address this, we conducted a functional magnetic resonance imaging study using a ready–set–go task with potential monetary gains (approach) and losses (avoidance) in 29 healthy individuals (18 males and 11 females). At the prefrontal level, the ventromedial prefrontal cortex and dorsomedial prefrontal cortex were preferentially activated by the anticipation of gains and losses, respectively, indicating distinct cortical representations of approach and avoidance motivations. At the subcortical level, the dorsolateral ventral midbrain (VM) was engaged during the anticipation of both gains and losses, whereas the ventromedial VM was selectively activated by gain anticipation. Crucially, dorsolateral VM activity was positively correlated with the subsequent peak grip force but not the reaction time (RT), suggesting its role in transmitting motivational signals to downstream motor circuits. At the motor cortical level, the activity of the primary motor cortex was correlated with both the grip force and RT. Together, these findings suggest a hierarchical circuit in which approach and avoidance motivations are distinctly represented in the prefrontal cortex, partially converge in the VM, and ultimately influence motor cortex activity to generate motor output. This framework provides evidence that opposing motivations engage both distinct and shared neural pathways and that their integration through subcortical–cortical interactions enables motivational signals to shape human motor action. Significance statement Human actions are energized by both approaching rewards and avoiding punishments, but how these opposing motivated actions converge in the brain remains unclear. Using fMRI during a motivational ready–set–go task, we discovered that approach and avoidance motivations engage distinct prefrontal representations that partially converge in the dorsolateral ventral midbrain. This midbrain region encoded motivational intensity regardless of valence and selectively predicted peak grip force, but not reaction time, suggesting its role in scaling motor output strength, a key component of motor vigor. These findings reveal a hierarchical circuit in which opposing motivations are differentiated cortically, integrated subcortically, and transformed into motor output through mesocortical pathways. This framework advances understanding of motivation‒motor interactions, with implications for treating disorders affecting motivated action.
Overexpression of CD97 in intestinal epithelial cells attenuates LPS-induced pro-inflammatory cytokine induction via stabilization of β-catenin early in life
Acute inflammatory conditions in the intestine of preterm infants are linked to increased susceptibility due to the immature degree of the gut’s epithelial barrier, microbiota, and pattern recognition receptors. Toll-like receptor 4 (TLR4) plays a pivotal role in recognizing lipopolysaccharides (LPS) from gram-negative bacteria, triggering pro-inflammatory cytokine responses (TNF-α, IL-1β, CXCL1) via nuclear factor kappa B (NF-κB) signaling. These processes are implicated in necrotizing enterocolitis (NEC), a severe gastrointestinal condition in premature infants. CD97, an adhesion G-protein coupled receptor (aGPCR), has emerged as a modulator of immune responses influencing inflammatory signaling pathways. CD97 expression is typically low in intestinal epithelial cells (IECs); however, protective effects of increased CD97 levels have been described in experimentally induced colitis. In this study, we examined the role of CD97 in modulating the inflammatory response in the immature gut, utilizing wild-type (WT) and transgenic CD97-overexpressing mice (TgCD97) with epithelial-specific expression in the intestinal epithelium. LPS was administered to IECs and organ segments isolated from the small intestine of mice of specific ages, modeling certain stages of human perinatal/postnatal gut development. CD97 overexpression attenuated LPS-induced TNF-α expression in IECs during early intestinal development while IECs from adult mice remained unaffected. This effect was attributed specifically to ileal tissue. Attenuation was mediated by β-catenin stabilization, leading to suppressed LPS/NF-κB signaling. Inhibition of β-catenin in TgCD97 IECs reversed the anti-inflammatory phenotype restoring pro-inflammatory gene expression. These findings suggest that CD97 overexpression modulates the inflammatory response in the developing gut by stabilizing β-catenin and interacting with the LPS/NF-κB axis. This effect was restricted to early developmental stages and ileal tissue, highlighting a previously unrecognized role of CD97 in age-dependent endotoxin tolerance. These findings identify a novel CD97-β-catenin-NF-κB regulatory axis in the immature small intestine and highlight its potential as a therapeutic target to protect the immature neonatal gut from inflammatory damage.