Biology and Life Sciences

Abstract: We introduce a neurophysiological adaptation of the Double Covariance Model (DCM) to provide a generative, fourth-order statistical framework for brain dynamics. Moving beyond descriptive sliding-window methods, the proposed theory implements a two-scale temporal scheme that explicitly separates fast micro-time stochastic neural fluctuations from the macro-time scale of emergent cognitive states. By treating the variance of covariance as a first-class mathematical object, the model computes the fourth-order moment of localized micro-signals to directly reconstruct a complex-valued network density matrix ($\rho$). This architecture transitions classical neurophysiological data into a quantum-like state representation, enabling the direct application of quantum information measures—such as concurrence and von Neumann entropy—to model macroscopic integration. Ultimately, this framework establishes a principled, non-phenomenological link between low-level stochastic network dynamics and the unified macroscopic phenomenon of "mental entanglement".

Abstract: The dominant narrative of autonomic nervous function remains essentially that proposed by Walter B. Cannon over a hundred years ago. It emphasizes sympathetic mediation of “fight-or-flight” responses and catabolism and associates the parasympathetic system with “rest-and-digest” functions and anabolism. Dual innervation of tissues and an antagonistic relationship between the divisions is presented as the rule, with minor exceptions. Extensive evidence accumulated over the past century renders these generalizations untenable, as autonomic neuroscientists have been pointing out for decades. Yet such critiques have not changed how the system is taught or understood. To remedy this situation, it is proposed that an alternative framework is needed that aptly summarizes sympathetic and parasympathetic functions, respectively. Here, following a systematic critique of the traditional approach, such an alternative is developed based on a consideration, first, of functions in tissues innervated by only one branch, such as the kidneys, and then, of specific functions in tissues receiving dual innervation where distinct regulatory responsibilities of one or the other branch is clear, e.g. respiratory sinus arrhythmia and the pupillary light reflex. The proposed schema describes the sympathetic division as the body’s “quartermaster,” responsible for regulating physico-chemical conditions and distributing metabolic resources to meet, and where necessary adjust, current and anticipated demand, under all circumstances. In contrast, the parasympathetic division is described as the body’s “coordinator,” regulating secretory and smooth muscle function involved in interactions and exchanges with the outside world—eating, breathing, speaking, voiding, looking, mating, moving, etc—often closely articulated with specific patterns of associated somatic motor activity. The schema emphasizes that the actions of the respective branches in each tissue relates to their respective regulatory responsibilities, and not to a generically counterbalancing relationship to the other. The proposed alternative leads to novel hypotheses regarding the function of autonomic innervation in cases where its physiological importance remains obscure, such as the parasympathetic supplies to airway smooth muscle and the pulmonary and cerebral vasculature. It is offered to stimulate debate directed toward the creation of a consensus alternative narrative that can displace the misleading traditional narrative and advance a more realistic view of autonomic function.

Abstract: The inclusion of landmarks in navigation aids is an effective strategy for mitigating spatial deskilling; however, increasing landmark density may also increase cognitive load during locomotion. This study investigates how landmark density (LM5, LM6, and LM7 corresponding to five, six, and seven landmarks respectively) influences cognitive load and brain activity during navigational locomotion using a combination of blink-related event-related potentials (bERPs) and EEG microstate analysis. EEG data were analysed using the EEGLAB Microstate Toolbox, where group-level clustering based on global field power identified four canonical microstate classes (A–D). Micros-tate temporal parameters (mean duration, occurrence, and coverage) were extracted through backfitting, and topographic differences were assessed using topographic analysis of variance (TANOVA), while bERPs were used to examine localized neural responses. Linear mixed-effects modelling revealed that the LM7 condition produced significantly longer duration and greater coverage of Microstate D compared to LM5, indicating increased engagement of attentional and visuospatial networks under higher landmark density. In contrast, traditional ERP components showed limited sensitivity to changes in cognitive load. TANOVA further confirmed significant topographic differ-ences across conditions (p = .001). These findings indicate that cognitive load increases non-linearly with landmark density and demonstrate that EEG microstate analysis pro-vides a more sensitive measure of large-scale brain dynamics than traditional ERP approaches.

Abstract: Traumatic exposure does not uniformly lead to persistent posttraumatic symptoms, suggesting that vulnerability depends on more than event intensity or arousal magnitude alone. The Symbolic Objectification Hypothesis (SOH) proposes that traumatic persistence is shaped by the stability of a representational gate: the capacity to hold threat as a bounded, labelable, temporally situated object of awareness while executive continuity remains intact. When this capacity fails during encoding or later reactivation, threat may shift from object-mode representation into immersive action mode, increasing defensive capture and weakening contextual updating. SOH does not replace established accounts of contextual integration, appraisal, decentering, cognitive defusion, mentalization, or dual representation. Rather, it proposes a proximal representational condition that helps explain when these downstream processes remain available during threat activation. The manuscript defines symbolic objectification, distinguishes it from adjacent constructs, proposes operational markers for measurement, and identifies falsifiable predictions concerning intrusion quality, defensive capture, and treatment-related change.

Abstract: Despite ethical constraints and strict oversight by local Institutional Animal Care and Use Committees, animal models still permit molecular investigations that would never be acceptable to humans. Nevertheless, experimental outcomes depend on species, strain, sex, age, hormonal status, diet, exposure to hypoxia, toxins, radiation, external stimuli, stress, and even housing conditions. Further complications stem from the heterogeneous cellular composition of tissues and from the procedures required to isolate and eventually immortalize specific cell subtypes. Moreover, most diseases are multi-factorial and associated with altered structure or/and expression of several genes. A major problem with genetically engineered animals is that together with the targeted gene numerous other genes are mutated or/and regulated owing to their interlinkage in functional pathways. However, animal models have the important advantage of allowing the investigator to control most of the regulating factors and produce biological replicates, while every human is a dynamic unique. This review examines the challenges, accuracy and limitations of the mouse, rat and rabbit models we used to decipher the transcriptomic alterations associated with several neurological disorders. Links to publicly accessible databases presenting the experimental protocols and expression profiles are provided for readers interested in reanalyzing our data and comparing with their own results.

Abstract: Fibromyalgia (FMS) is a chronic widespread pain syndrome characterized by hyperalgesia, sleep disturbances, fatigue and cognitive dysfunction. Its complex etiology may involve endocannabinoid system (ECS) dysfunction, modulating nociception, inflammation, and sleep. This review examines key ECS components, including CB1 and CB2 receptors, endocannabinoids such as anandamide and 2-AG, and degradative enzymes FAAH and MAGL, focusing on their roles in chronic pain and inflammation.This review explores sex differences in ECS components, including CB1 and CB2 receptors, endocannabinoids, and degradative enzymes such as FAAH. Evidence from human studies and animal models indicates sex-specific variations in receptor expression and responses to cannabinoids, influenced by sex hormones and epigenetic regulators such as the long non-coding RNA FAAH-OUT. CB1 receptors mediate antinociceptive effects through central pain pathways, whereas CB2 receptors modulate immune and inflammatory responses, which may contribute to the higher prevalence and symptom severity of FMS in women. Overall, the ECS represents a promising therapeutic target for FMS. However, no animal model fully replicates the clinical complexity of the syndrome, and human studies are limited. Further research is needed to elucidate sex-specific mechanisms, validate treatment strategies, and develop more personalized approaches to FMS management.

Abstract: Background/Objectives: Clinically overt Alzheimer disease (AD) is associated with significant changes of personality factors. Earlier studies indicated that personality factors do not remain stable in elderly controls. Whether the early presence of AD neuroimaging markers may predict subsequent changes in personality factors is still debatable. Methods: To address this issue, we examined the association between Big Five factor scores and baseline AD and vascular imaging markers in a previously established cohort of 58 elderly controls with a 4.5-year follow-up. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised scale at inclusion and 55 months follow-up. Regression models were used to identify predictors of personality factor changes including time, age, sex, APOE epsilon 4 allele, baseline MMSE scores, amyloid PET positivity, abnormal FDG-PET patterns, mesial temporal lobe atrophy and Fazekas scores, and number of microbleeds. Results: In both univariate and multivariable models, the decrease of openness was related to abnormal FDG PET patterns. This single variable explained 15% of the variance of this personality factor. In univariate models, lower MMSE scores and amyloid positivity at baseline were associated with subsequent decrease of agreeableness scores. In multivariable models, these two parameters explained 11% and 8% of its variance respectively. The other personality factors were not associated with AD and cerebrovascular imaging markers. Conclusions: Our findings support the idea of the reverse causality. Personality patterns at baseline may impact on the emergence of AD pathology but they may also change rapidly as a function of the presence of early AD-related PET abnormalities.

Abstract: The Brief Advanced Computerized Neuropsychological Battery (BACNB) was developed as a compact protocol to investigate, in a fully in silico environment, the functional geometry produced by four classical tasks: the Sustained Attention to Response Task, Stop-Signal Task, Flanker Task, and Digit Span. The study does not establish clinical norms or diagnostic validity. Its aim is to test whether synthetic agents completing all four tasks produce a coherent, reproducible, and theoretically interpretable state structure. We simulated 200,000 agents, each with continuous latent microparameters and observable metrics extracted from the four tasks. Measures were standardized into an oriented functional scale so that higher values represented greater cost under the task ecology, without implying biological inferiority. Variable clustering yielded 8 emergent cognitive parameters; agent clustering yielded 4 phenotypic-functional attractors. The main result is the BACNB Cognitive State Space: each agent is described by a compositional vector of relative approximation to attractors P1-P4. Because the weights sum to 1.00, the system has three degrees of freedom and can be visualized as a tetrahedron. The external comparison with Inhibitory Control, Working Memory, and Cognitive Flexibility showed partial convergence but did not literally reconstruct the Miyake model. The proposed interpretation shifts the battery from a taxonomy of deficits to a contextual cognitive kinematics in which functional cost depends on the relation among organism, task, and environment. This framing treats simulation as theoretical instrumentation for generating falsifiable hypotheses and clarifying which assumptions require empirical tests.

Abstract:

Glutamatergic neuron-to-glioma signaling mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) has emerged as an important mechanism in glioma progression. We analyzed the expression of the AMPAR subunit genes GRIA1, GRIA2, GRIA3, and GRIA4 in lower-grade glioma (LGG). Expression of GRIA1–GRIA4 was highest in IDH-mutant/1p19q-codeleted tumors and lowest in IDH-wildtype tumors across both The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts. High expression of each GRIA gene was associated with longer overall survival (OS). Transcriptome-wide analyses identified positive correlations between an AMPAR score and genes involved in synaptic organization, neuronal connectivity, and neurotransmission. Co-expression analyses demonstrated coordinated expression between GRIA1-GRIA4 and genes encoding AMPAR auxiliary proteins. Gene Ontology (GO) enrichment revealed overrepresentation of synaptic signaling, trans-synaptic communication, and synapse organization. Although the AMPAR score was associated with favorable survival in univariate analyses, it did not retain independent prognostic significance after adjustment for key clinicomolecular variables. Elevated expression of AMPAR subunit genes in LGG was associated with favorable molecular subtypes, prolonged survival, and a synaptic transcriptional program. These findings suggest that GRIA1–GRIA4 expression may serve as a marker of a neuron-like, synaptically enriched biological state in LGG.

Abstract: (1) Background/Objectives: Blood-based biomarkers have emerged as practical tools for identifying Alzheimer’s disease (AD) pathology in patients with mild cognitive impairment (MCI). Among them, plasma phosphorylated tau217 (p-tau217) demonstrates strong associations with cerebral amyloid deposition. In parallel, the easy Z-score Imaging System (eZIS), a quantitative brain perfusion SPECT analysis tool, has been widely used to detect characteristic AD-related hypoperfusion patterns. Although both measures reflect distinct AD processes, the relationship between plasma p-tau217 and eZIS in MCI remains unclear. (2) Methods: This retrospective study included 62 patients with MCI who underwent plasma p-tau217 testing and brain perfusion SPECT with eZIS analysis. Associations between plasma p-tau217 and the three eZIS indices (severity, extent, and ratio) were evaluated. Exploratory subgroup analyses were performed using a previously reported plasma p-tau217 threshold of 0.63 pg/mL. In addition, a validation sub-cohort of 21 participants who underwent plasma p-tau217 testing, eZIS, and amyloid PET was analyzed to assess concordance with cerebral amyloid pathology. (3) Results: Among the three eZIS indices, severity demonstrated the highest sensitivity relative to elevated plasma p-tau217 levels. However, all eZIS indices showed limited discriminative performance. Optimal eZIS cutoff values derived from the present cohort were higher than previously reported thresholds. In the amyloid PET-validated sub-cohort, plasma p-tau217 demonstrated closer concordance with amyloid positivity than any individual eZIS parameter. The reduced performance of eZIS appeared to be associated with advanced age, substantial vascular burden, white matter lesions, and cerebral atrophy. (4) Conclusions: Plasma p-tau217 showed a stronger association with cerebral amyloid pathology than eZIS indices in this elderly MCI cohort. Nevertheless, eZIS may provide complementary information regarding downstream neurodegenerative and cerebrovascular processes that are not directly captured by plasma biomarkers. This integrated approach highlights plasma p-tau217 as a primary screening tool for amyloid pathology to guide disease-modifying therapies (DMTs), alongside eZIS for tracking follow-up mixed co-pathologies.

Abstract: Accurate sleep staging is fundamental to the diagnosis of sleep disorders, the evaluation of therapeutic interventions, and the understanding of sleep’s role in health and disease. While polysomnography (PSG) remains the clinical gold standard, its cost, technical complexity, and reliance on controlled laboratory settings have motivated the development of wearable alternatives capable of continuous, home-based monitoring. This comprehensive review spans the full translational pipeline - from the neurophysiological foundations of sleep architecture through signal acquisition, preprocessing, and algorithmic classification to device-level validation and population-specific clinical evidence. We begin by establishing the physiological basis of sleep stages, including macro-architectural organization, microstructural markers (spindles, K-complexes, cyclic alternating pattern), and the autonomic, respiratory, and movement correlates that wearable sensors can capture. We then examine the signal processing chain — artifact removal, filtering, feature extraction, and data augmentation — that underpins reliable staging from noisy, real-world recordings. Building on this foundation, we evaluate the performance of consumer and clinical-grade wearable devices across diverse populations, including healthy adults, children and adolescents, older adults, clinical cohorts (insomnia, obstructive sleep apnea, neurodegenerative disease), pregnant individuals, shift workers, and athletes. Finally, we identify persistent challenges — signal quality gaps between laboratory and consumer sensors, algorithmic opacity, population bias, and the emerging phenomenon of orthosomnia — and outline future directions encompassing multimodal sensing, standardized benchmarking, digital sleep biomarkers, and equitable regulatory frameworks. By synthesizing evidence from review articles published from 2018 onward, this work provides a single, integrated reference for researchers, engineers, and clinicians working to advance robust, generalizable, and clinically meaningful wearable sleep monitoring. A companion paper (OstadSharif Memar et al., 2026) offers a detailed algorithmic analysis of computational models for wearable-based sleep stage detection.

Abstract: Post-stroke cognitive impairment (PSCI) affects up to half of survivors and is a leading cause of long-term disability, making it the norm rather than the exception. Despite its prevalence and impact, PSCI remains largely unaddressed in rehabilitation programs, which focus primarily on physical recovery. The subtle nature of cognitive deficits in the acute stages renders them difficult to detect and address, yet they often worsen over time, highlighting the need to understand the biological processes driving PSCI. Growing evidence implicates inflammation not as a singular event, but as a dynamic, phase-specific process that evolves from acute injury to chronic maladaptation, driving cognitive decline. Acute neuroinflammation, involving microglial activation and cytokine release, initiates secondary brain injury and evolves to a chronic state with sustained glial activation and peripheral immune cell involvement, leading to synaptic loss, white matter injury, and network dysfunction. Preclinical models demonstrate that immunomodulatory interventions can mitigate cognitive deficits, highlighting their therapeutic potential. The future management of PSCI will therefore require a dual approach by suppressing maladaptive inflammation through phase-specific immunomodulation, integrated with cognitively focused rehabilitation. Developing inflammatory biomarkers for patient stratification will be essential to personalize these strategies and translate them into successful clinical outcomes.

Abstract: Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), which encodes Insulin Receptor Substrate Protein 53 (IRSp53), has emerged as a brain-disease gene. BAIAP2 involvement in pathogenic CNS disorders is due to its roles in molecular architecture, synaptic signaling, circuit computation, and human neurodevelopmental pathology can be examined within a single mechanistic framework. Unlike many synaptic risk genes that are assigned broad scaffolding functions, IRSp53 is distinguished by the convergence of membrane-shaping capacity, actin control, and postsynaptic condensate organization, through which N-methyl-D-aspartate receptor (NMDAR) -dependent signaling is tuned rather than merely supported. Across mouse models, disrupted IRSp53 has been linked to altered postsynaptic density assembly, abnormal glutamatergic physiology, reduced prefrontal population activity, and impaired social behavior. These phenotypes have not only been observed across scales but, in part, have been reversed in adulthood, indicating that pathogenic effects are not fixed once development has ended. In parallel, emerging human studies have extended BAIAP2 beyond idiopathic neuropsychiatric association toward defined neurodevelopmental disorders, including cortical migration defects and developmental epileptic encephalopathy. A multi-scale view is that the BAIAP2 is not considered as a synaptic organizer, but a causal bridge between nanoscale postsynaptic structure, systems-level dysfunction, and disease expression.

Abstract: Colostrum extracellular vesicles (C-EVs) are nanoscale, bioactive vesicles with therapeutic potential. Mechanisms of action include their control of cellular and tissue homeostasis. These make C-EVs a novel means to control inflammatory and cellular dysfunctions. However, a limitation to their broad use is the ease of C-EV isolation and stability. Standard ultracentrifugation and gradient techniques used for EV isolation are costly, cumbersome, and time-consuming. Such isolation procedures require repeated ultracentrifugation. Exodus dual-frequency ultrasonic nanofiltration (UNF) isolation system can produce pure vesicles at high concentrations. Due to the need to recover C-EVs at clinical grade at high concentrations while preserving vesicle structural integrity and broad biological functions. Large-scale recovery is preserved within hours. We now affirm UNF C-EV purity by the presence of Alix, CD63, Tsg101, and Flotillin antigens. EVs’ sizes were from 50-200 nm, maintaining intact bilayer structures. Functional tests showed preservation of the vesicles’ anti-inflammatory activities with suppression of pro-inflammatory cytokines and the NLRP3 inflammasome, caspase 1, interleukin-1, and 18. These were maintained at baseline levels, sustaining cellular homeostasis. Processing time, high yields, and functional responses served to sustain cellular homeostasis. These data support that UNF-isolated C-EVs were recovered safely at high-yields and reproducibly for future clinical applications.

Abstract: Aberrant signalling by leucine-rich repeat kinase 2 (LRRK2) is a major driver of Parkinson’s disease (PD) biology, linking Rab phosphorylation to vesicular trafficking, endolysosomal dysfunction and immune-cell regulation. However, how LRRK2-linked trafficking programs intersect with metabolic and mitochondrial remodeling within vulnerable human substantia nigra cell states remains poorly defined. Here, phosphatome-wide systems analysis, single-nucleus transcriptomics, structural modelling and deep-phosphoproteomic validation were integrated to identify the glycolytic regulator PFKFB2 as a phosphorylation-regulated metabolic node in the Parkinsonian substantia nigra. Sample-level pseudobulk profiling of the GSE184950 human substantia nigra single-nucleus RNA-seq dataset revealed distributed phosphatome remodeling across the PD spectrum, with PFKFB2 emerging as a transcriptionally reduced and dynamically rewired systems hub. Full-atlas analysis across 390,360 nuclei showed that this tissue-level decrease resolved into disease-stage-specific cellular redistribution: PFKFB2 was reduced across oligodendrocyte-lineage and neuronal compartments in PD, whereas Parkinson’s disease dementia (PDD) showed microglial induction alongside astrocytic, astrocyte/glial-intermediate and neuronal loss. Stratification by PFKFB2 expression revealed marked transcriptional polarity, with PFKFB2-positive cellular states enriched for PD-associated genes, LRRK2–Rab trafficking, lysosomal/autophagy and glycolytic programs, while PFKFB2-negative states retained stronger mitochondrial/OXPHOS-associated signatures. Mechanistically, sequence-based phosphosite prioritization and AlphaFold-guided peptide docking identified the flexible, putatively disordered C-terminal regulatory tail of PFKFB2 as a kinase-accessible region, prioritizing the conserved Ser483 locus as the strongest LRRK2-compatible structural candidate. Independent phosphoproteomic interrogation of human and mouse LRRK2 perturbation datasets further supported the orthologous PFKFB2/Pfkfb2 Ser483/Ser486 region as a conserved LRRK2-responsive phosphosite candidate, including inhibitor-sensitive reduction and inhibitor-resistant retention under A2016T LRRK2 conditions. Together, these findings position the PFKFB2 signalling axis as a cell-state-resolved metabolic bridge linking LRRK2–Rab trafficking programs with the mitochondrial–endolysosomal disease architecture of the Parkinsonian substantia nigra.

Abstract: Post-Traumatic Stress Disorder (PTSD) is associated with well-documented alterations in reactive brain processing of stimuli or events, while yet little is known about proactive/anticipatory neural dynamics preceding and preparing for task execution. This study aimed at investigating both proactive and reactive brain control of PTSD patients during a cognitive task, using event-related potentials (ERPs) method. Twenty-one PTSD patients have been matched to thirty healthy controls. Proactive ERPs components, such as the Bereitschaftspotential (BP), prefrontal Negativity (pN) and visual Negativity (vN) were analysed to assess motor, cognitive, and sensory preparation, respectively. Reactive components such as the P1, N1, and P3 were also analysed to evaluate perceptual, attentional and decisional processes, respectively. Results revealed in PTSD patients a strong reduction in the amplitudes of all anticipatory components, suggesting a general compromission of top-down control in task preparation. Analysis of post-stimulus reactive processing revealed no differences in early components associated with sensorial and attentional processing (P1, N1), but a reduction of the P3 in the PTSD group, indicating impaired high-level cognitive processing as task closure and decision-making. Behaviourally, patients exhibited longer and more variable response times, though accuracy remained unaffected, consistent with a speed-accuracy trade-off. These results provide evidence of widespread proactive processing deficits in PTSD, supporting the documented hypoactivity in prefrontal, cingulate, and visual associative areas. Moreover, new findings about anticipatory components can represent a potential biomarker in clinical assessment.

Abstract: Light acutely affects human alertness, cognitive performance, and neural activity. These effects are often attributed to melanopic stimulation mediated by short-wavelength-sensitive, melanopsin-containing intrinsically photosensitive retinal ganglion cells. However, long-wavelength exposure, brightness-related mechanisms, visual-task demands, and individual differences may also influence observed alerting responses. This structured evidence synthesis evaluated whether melanopic stimulation alone is sufficient to explain spectrum-dependent alerting effects. Studies were tiered by evidentiary role, and quantitative pooling was restricted to clearly defined light contrasts, alertness-relevant outcomes, and extractable effect sizes. Separate analyses were conducted for behavioral performance, subjective alertness or sleepiness, EEG/physiology, and field or operational evidence. In inverse-variance models restricted to strict primary evidence, light condition showed a moderate association with behavioral performance, r = 0.355, 95% CI [0.189, 0.501]. Red or long-wavelength behavioral contrasts, r = 0.402, 95% CI [0.171, 0.591], and short-wavelength or high-melanopic contrasts, r = 0.306, 95% CI [0.061, 0.516], were both positive, but overlapping confidence intervals did not support subgroup differences. The strict subjective model was inconclusive, whereas the strict red-light EEG model produced the largest estimate. Overall, the evidence supports melanopic relevance but does not provide a clean confirmation of melanopic sufficiency; red and long-wavelength findings remain small but unresolved empirical signals.

Abstract: Background: Autism spectrum disorder (ASD) affects approximately 1-2% of children worldwide, yet its etiology remains incompletely understood. Emerging evidence suggests that offspring of parents with autoimmune diseases show elevated autism prevalence. Notably, children of parents or mothers with immune-related conditions, including psoriasis (OR 1.59), maternal type 1 diabetes (HR 2.36 in one large cohort study), and rheumatoid arthritis (OR 1.51), show elevated ASD-associated risk estimates.Hypothesis: I propose that autism may be conceptualized as an immune-metabolic disorder in which multiple pro-inflammatory cytokines—including TNF-α, IL-6, IL-1β, and IFN-γ—act through distinct molecular pathways yet converge on a common endpoint of mitochondrial dysfunction and cerebral energy deficiency. This convergence implies that it is the cumulative prenatal inflammatory burden, rather than any single cytokine, that drives the energy deficit. The resulting energy shortage may impair four critical processes: (1) synaptic pruning during neurodevelopment, (2) real-time social cognition including gaze processing and emotion recognition, (3) protein synthesis of critical synaptic scaffolding molecules, and (4) flexible hierarchical predictive inference. The last domain offers a unifying bioenergetic interpretation of restricted repetitive behaviors and insistence on sameness as a behavioral compensation for chronic cerebral energy constraint. Crucially, the resulting mitochondrial dysfunction is proposed to persist beyond birth, with the gap between cerebral energy demand and supply widening during the rapid brain growth of the first postnatal years. This developmental trajectory may help explain the typical emergence of clinical symptoms between 12 and 24 months of age, the selective vulnerability of high-metabolism brain regions, and the regressive pattern observed in a substantial subset of ASD cases.The proposed mechanism is a chronic low-grade pro-inflammatory cytokine state—clinically silent, yet biologically consequential—arising from inherited inflammatory susceptibility and/or direct fetal exposure to elevated maternal inflammatory signaling during pregnancy. Unlike high-grade inflammatory states in which maternal and fetal survival are acutely threatened, low-grade cytokine elevations may proceed without conspicuous symptoms or detectable clinical signs, particularly when chronic. Although seemingly quiet, such a state may be insufficient to endanger maternal or fetal survival, yet sufficient to disrupt fetal brain bioenergetics during sensitive gestational windows—producing neonates who appear outwardly healthy at term while their neurodevelopmental trajectories have already been altered.I further propose that the well-documented "firstborn effect" in autism reflects maternal immune maladaptation during primigravid pregnancies. Additionally, for cases without parental autoimmune history, a speculative secondary mechanism is proposed: mitonuclear incompatibility, in which paternally inherited nuclear genes encoding mitochondrial proteins may be imperfectly matched to the maternally inherited mitochondrial genome, impairing mitochondrial function and thereby generating endogenous pro-inflammatory (DAMP-driven) signaling.Implications: This framework may provide an integrative account of disparate observations about autism pathophysiology by uniting prenatal initiation with postnatal persistence into a single developmental trajectory. It suggests that pro-inflammatory immune pathways and mitochondrial dysfunction merit further investigation as candidate targets for risk modification, with the prenatal period offering opportunities for identification of high-risk pregnancies through parental autoimmune or inflammatory disease, and the early postnatal period offering an additional window for longitudinal characterization of mitochondrial and bioenergetic trajectories. If supported by sufficient subsequent evidence, prenatal cytokine monitoring and prospective postnatal mitochondrial assessment—neither of which is currently part of routine care—may merit consideration by the medical community as complementary candidate strategies for autism risk research.

Abstract: Neuroinflammation is considered as one of the core pathogenic factors of neurodegeneration in Alzheimer disease (AD) and related dementias (RD). It is also associated with other two hallmarks of AD dementia, i.e., amyloid beta (Ab) and neurofibrillary tangles (NFT), and increasingly considered as the third hallmark of AD. Abnormality in microglial pathway plays a crucial role in the neuroinflammation of AD and RD. Microglia dysfunction is linked to many neuroinflammatory signaling pathways towards the progress of developing neurodegeneration resulting to cognitive deficits or dementia. Currently, several therapeutic approaches aim to target inflammatory regulators for AD treatment, and microglia is considered as one of the vital targets. In this article we intend to highlight and discuss various microglia mediated signaling pathways that link to chronic neuroinflammation and cognitive dysfunction/dementia in AD and other diseases. This could help us to understand the degree of microglial association with the disease pathophysiology through analyzing various studies in last few decades including the latest reports. We also aim to highlight the pathways that are more and less conclusively established and determine possible pathways which may help in further exploration and narrowing down or expanding the area of studies that requires further research. AD and RD are one of the most leading causes of death in the world and there is no appropriate drug available for cure or prevention of the disease. Further research is an absolute requirement for better understanding the mechanisms underlying the disease pathophysiology and better planning of basic/therapeutic research and clinical trials. We also provide up-to-date clinical trials that used inflammatory targeting drugs and discuss the failures and promising drug targets.

Abstract: Peripheral nerve injuries represent significant clinical challenges, often resulting in lifelong motor function loss and disability. Evidence suggests regenerating axons cannot cross nerve gaps without Schwann Cell (SC) assistance. However, FDA-approved bio-material conduits for peripheral nerve repair lack bioactivity and structural complexity needed to facilitate SC migration. To address this, we developed a three-dimensional biomimetic in vitro model to simulate complex cellular interactions within the nerve bridge. The model features lyophilized hydrogel bioscaffolds with longitudinal channels to recapitulate the nerve microenvironment. To encourage directional SC migration, the top ~30% of the lyophilized hydrogel was conjugated with macrophage inflammatory protein-1α (MIP-1α). Cell line-derived SCs were seeded within no-MIP-1α- and MIP-1α-conjugated bioscaffold channels as spheroids and cultured for nine days. Histology demonstrated that MIP-1α Conjugation retained more SC spheroids during culture with greater cellular distribution. Cytokine profiling revealed MIP-1α conjugation activated SCs into a pro-repair phenotype characterized by increases in VEGF, ICAM-1, IL-6, and CINC-1 production, alongside downregulation of IL-1β, IL-10, and IL-13. The SC-derived pro-inflammatory and pro-angiogenic mediators did not inhibit NSC-34 motor neurite extension compared to controls. This study establishes an in vitro model that serves as both a screening platform and mechanistic tool, advancing our understanding of peripheral nerve repair.