Search Results (234)

The striatum is the principal input structure of the basal ganglia, central to selecting behaviour and learning from its consequences. Its output is conventionally described through D1-associated direct and D2-associated indirect pathways. Striosome–matrix organisation provides a second, intersecting division. Together, these two divisions define four principal striatal output populations: matrix D1, matrix D2, striosomal D1 and striosomal D2. Mouse studies identify striosomal pathways that regulate dopamine neurons alongside the canonical pathways controlling basal ganglia output. We propose that these populations perform complementary functions: matrix routes predominantly support behavioural selection, while striosomal routes shape the dopamine signal that influences selection and learning. The key principle is that a receptor’s functional significance depends on its circuit position. Inhibiting a basal ganglia output neuron and inhibiting a dopamine neuron have different consequences, even when the cells defining each route express the same dopamine receptor. This distinction connects pathway anatomy with parallel basal ganglia loops, dopamine coding and a proposed relative weighting of content and value across compartments. The two coordinates describe preferential circuit organisation within a broader diversity of cell types, overlapping connections and regional specialisations. Parkinson’s disease and schizophrenia illustrate how neuronal degeneration and circuit dysregulation affect different parts of this organisation, while systemic treatments act beyond the circuits requiring correction. The framework yields specific predictions about pathway connectivity, compartmental information processing and dopamine feedback, providing an experimentally testable link between cellular organisation, behaviour and clinical function. Full article

Alzheimer’s disease (AD) has traditionally been conceptualized as a disorder driven primarily by cerebral amyloid-β accumulation, tau pathology, synaptic failure, vascular dysfunction, and chronic neuroinflammation. However, emerging evidence suggests that AD pathobiology may also involve extracerebral cranial compartments positioned at the interface between the brain, meninges, cerebrospinal fluid, and skull bone marrow. Recent anatomical and experimental studies have identified direct vascular and osseous channels connecting skull bone marrow with the dura mater, allowing bidirectional exchange of immune cells, soluble mediators, and cerebrospinal fluid-derived signals. These findings support the concept that skull bone marrow functions as a specialized cranial immune reservoir capable of sensing central nervous system-derived molecular cues and supplying myeloid and lymphoid cells to meningeal and brain-border compartments. In AD models and human imaging studies, amyloid-β-related signals have been detected in skull marrow, where they may promote IL-6-dependent B lymphopoiesis, expansion of age-associated B cells, microglial activation, and amplification of cerebral amyloid pathology. In parallel, AD-related amyloid precursor protein and amyloid-β signaling may remodel the skull marrow niche through osteoblast dysfunction, altered osteoclast activity, vascular channel expansion, marrow adiposity, and inflammatory reprogramming. Human PET and MRI studies indicate that skull marrow-associated inflammatory, amyloid-related, and cerebrospinal-fluid drainage signals can be detected in vivo; however, these observations remain indirect, method-dependent, and insufficiently validated for diagnostic or prognostic use. Importantly, much of the anatomical foundation for skull marrow–meninges–brain communication derives from non-AD studies of CNS-border physiology, stroke, meningitis, spinal cord injury, and infection, whereas the strongest AD-specific mechanistic evidence is currently derived from transgenic mouse models. Accordingly, we frame the skull marrow–meninges–brain axis as a testable conceptual model rather than an established causal pathway in human AD. This review integrates anatomical, immunological, osteoimmune, and imaging evidence while explicitly distinguishing AD-specific findings from evidence extrapolated from other neurological or inflammatory contexts. Determining whether skull marrow alterations represent a cause, consequence, compensatory response, or amplifier of AD pathology will require longitudinal, biomarker-defined human studies and further mechanistic validation. The review also compares the principal in vivo strategies used to distinguish skull-marrow-derived immune cells from circulating leukocytes and examines ischemic stroke and brain tumors as comparator CNS conditions. These disease models demonstrate that cranial marrow responses can be rapid, spatially organized, and either protective or pathogenic depending on cellular phenotype and disease context, reinforcing the interpretation of skull marrow as a general CNS-border immune organ rather than an AD-specific compartment. Full article

In the field of new-energy electric vehicles, lithium battery cells need to be connected in series and parallel to meet the requirements of high voltage and high power. Aiming at the high cost of traditional active equalizer, a half/full-bridge converter is developed, which integrates lithium battery equalization technology into the auxiliary power module of an electric vehicle. The asymmetric modulation strategy is realized by introducing DC duty ratio adjustment at the half-bridge side to improve the balancing speed. In order to suppress the backflow power of the whole bridge side, an extended phase-shift control strategy is proposed based on the single-phase-shift control strategy. The working principle and mode of the half/full-bridge converter under the proposed control strategy are analyzed, and the mathematical models of transmission power and reflux power of the converter under the two control strategies are compared. The experiments show that the modular half/full-bridge converter functions using lithium battery equalization and an auxiliary power module; they also verify the correctness of the proposed extended phase-shift control strategy. Full article

Exosomes are small extracellular vesicles (EVs) generated through the endosomal pathway that mediate intercellular communication by transferring proteins, lipids, and regulatory RNAs. In parallel, the NLRP3 inflammasome is a key signaling platform of the innate immune system that integrates cellular stress signals to drive inflammatory responses. Recent studies suggest that exosome biology and NLRP3 signaling intersect at fundamental levels of cell organization. On one hand, inflammasome activation can promote exosome biogenesis and secretion through caspase-1-dependent remodeling of intracellular trafficking, including cleavage of Rab-interacting lysosomal protein (RILP) and redistribution of multivesicular bodies (MVBs). These processes influence the selective loading of exosomal cargo, notably miRNAs, through sequence-dependent mechanisms involving RNA-binding proteins and the endosomal sorting machinery. Conversely, exosomes can modulate inflammasome activity in recipient cells by delivering regulatory molecules that affect NLRP3 priming and signaling. Although exosome release is increased in several inflammatory disorders, including ischemia/reperfusion injury, diabetes and neurodegenerative disease, the mechanistic relationship between exosome pathways and NLRP3 remains incompletely understood. In addition to their pathogenic and diagnostic relevance, exosomes are increasingly being explored as innovative acellular biologics and therapeutic delivery platforms due to their immunomodulatory and regenerative properties. In particular, mesenchymal stem cell (MSC)-derived exosomes have shown promising anti-inflammatory effects through modulation of NLRP3 pathways in preclinical models of kidney, cardiovascular, neurological and inflammatory diseases. Here, we review current evidence connecting NLRP3 inflammasome activation to EV trafficking, exosome formation, and cargo selection, and discuss how exosome-mediated communication shapes inflammasome signaling across cells and tissues in health and disease. Full article

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription–translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine–methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles—where oocyte quality is controlled for—show reduced implantation rates in several but not all cohorts—a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention. Full article

Ubiquitin-related modifier 1 (URM1) defines a distinctive ubiquitin-like system in which URM1 functions both as a covalent protein modifier and a sulfur carrier required for wobble uridine (U34) thiolation of cytosolic tRNAs. This dual role places URM1 signaling at the intersection of protein post-translational modification and codon-sensitive translational control. Although URM1 remains less well characterized than ubiquitin and other ubiquitin-like modifiers, accumulating evidence links URM1-associated processes to oxidative-stress tolerance, proteostasis, and tumorigenesis. In this review, we summarize the molecular architecture and biochemical regulation of URM1 signaling, distinguish the biological significance of protein URMylation from URM1-dependent tRNA U34 thiolation, and evaluate evidence connecting these pathways to cancer biology. Notably, stress-inducible protein URMylation has been demonstrated in mammalian cells, although endogenous mammalian URM1 substrates and their cancer-relevant functions remain incompletely defined to date. In parallel, URM1-dependent tRNA thiolation has been linked to selective translational programs that support metastatic progression and adaptation to targeted therapy. We further discuss emerging therapeutic opportunities associated with redox and translational dependencies, as well as the potential limitations and challenges of pathway selectivity, biomarker development, and normal-tissue toxicity. Together, these studies position URM1 signaling as a context-dependent stress-adaptive network with emerging relevance to cancer biology and precision oncology. Full article

Current distribution in serial–parallel battery packs is commonly assumed to be uniform in the absence of cell-to-cell variations. However, in practical systems, the electrical topology and finite resistance of current-collecting busbars can introduce significant inhomogeneities even when all cells are identical. In this work, a matrix-based modeling framework is developed to analyze the current and voltage distribution in large battery packs with arbitrary serial–parallel configurations. The results reveal that the resistance of current-supplying busbars plays a dominant role in shaping current distribution, leading to pronounced current imbalance that increases with both resistance and operating C-rate. To quantify this effect, a current non-uniformity factor is introduced and used to define an illustrative criterion for acceptable operation. Based on this metric, together with a maximum-cell-voltage constraint, design maps are constructed to identify operating regions that are acceptable or critical with respect to current overload and localized overvoltage as a function of busbar resistance and charging rate. The analysis further demonstrates that topology-induced current inhomogeneity can lead to cell-level voltage divergence and localized overcharge under high-current operation. Such local effects may remain hidden when only the pack voltage or the voltage of a series-connected cell group is monitored, because conventional battery management systems (BMSs) typically do not resolve individual cell currents or local voltage drops within parallel-connected cell groups. The proposed approach enables the derivation of design-oriented constraints linking electrical performance to physical parameters such as busbar resistance and cell spacing. The resulting design maps provide a practical tool for battery pack engineering, enabling the determination of the maximum allowable busbar resistance or operating current to ensure safe, homogeneous pack operation. Full article

Interactions among molecular recognition systems, neuronal activity, and glial regulation transform early neuronal connectivity into precise functional circuits during brain development. The cerebellum is a powerful model for studying these mechanisms due to its stereotyped and accessible circuitry. Two major excitatory afferent pathways—climbing fibers (CFs), which convey error-related signals to Purkinje cells (PCs), and mossy fibers (MFs), which transmit sensorimotor information via granule cells (GCs) and parallel fibers (PFs)—undergo strengthening, competition, and refinement during postnatal development. Synaptic specificity is established by general and pathway-specific organizers. The neurexin–neuroligin system broadly regulates synapse formation, while the neurexin–CBLN1–GluD2 complex specifies PF–PC synapses and C1qL1–BAI3 signaling stabilizes the dominant CF input during competitive refinement. CF–PC synapse elimination serves as a classic model of activity-dependent competition, where weaker inputs are removed through calcium-dependent mechanisms. In parallel, glial cells regulate synaptic maturation: microglia shape inhibitory environments, and Bergmann glia support glutamate homeostasis, dendritic organization, and synapse stability. PCs integrate CF and PF inputs and provide inhibitory output to the cerebellar nuclei, where convergent excitatory collaterals from CFs and MFs are combined with PC inhibition to generate cerebellar output. Together, these coordinated molecular, cellular, and circuit-level mechanisms establish the synaptic architecture underlying cerebellar computation, motor coordination, and adaptive learning, which are the central focus of this review. Full article

The rapid electrification of transportation has accelerated the demand for high-power electric vehicle (EV)-charging systems with high efficiency, compact size, galvanic isolation, and flexible scalability. Conventional isolated EV chargers typically adopt cascaded AC–DC and DC–DC conversion stages, which require additional semiconductor devices, passive components, and bulky dc-link capacitors, thereby increasing system complexity and limiting power density. This paper proposes a scalable three-phase modular parallel quasi-single-stage isolated single-ended primary-inductor converter (SEPIC) for high-power EV fast-charging applications. The proposed converter integrates power factor correction, voltage regulation, and high-frequency isolation within a unified SEPIC-based conversion cell, eliminating the intermediate dc-link capacitor while reducing the number of magnetic components and power conversion stages. By employing a Δ-connected three-phase input and input/output-parallel modular configuration, the proposed architecture provides a flexible power expansion approach based on a 9 kW basic module, with the potential to extend to higher power levels, such as 54 kW, through paralleling multiple identical modules. The operating principle, steady-state characteristics, continuous conduction mode (CCM)/discontinuous conduction mode (DCM) transition mechanism, current-sharing behavior, and control strategy are systematically investigated. An 18 kW prototype consisting of two parallel modules is experimentally validated under 380 V three-phase AC input and 400 V DC output conditions. The experimental results demonstrate a peak efficiency of 97.5%, a rated efficiency of 97.3%, a power factor (PF) of 0.999, and an input current total harmonic distortion (THD) of 2.55%, confirming the effectiveness and scalability of the proposed converter for high-power EV fast-charging applications. Full article

Reliable pack-level battery systems capable of safely handling instantaneous high-C-rate discharge above 10C during take-off, climb, and hovering are required for the commercialization of urban air mobility (UAM) aircraft. However, pack-level studies on wide-range C-rate characteristics of battery systems for UAM applications remain very limited, and most previous studies have been restricted to single-cell experiments or battery-pack simulations. In this study, a 24S1P test battery pack using nickel–cobalt–manganese (NCM) pouch cells, with a nominal voltage of 88.8 V and a capacity of 22 Ah, was designed and fabricated. A two-level battery management system (BMS) based on the LTC6803G-4 was also developed. To evaluate the charge–discharge characteristics of the battery system, constant-current discharge tests were conducted under five conditions ranging from 0.2C (4.4 A) to 10.68C (235 A), and charging tests were performed over the range of 0.2C–2C. The discharge test results showed that the capacity retention remained within 97.5–100.0% in the 1C–5C range, confirming excellent power capability. Continuous discharge operation was confirmed at 10.68C, the maximum discharge condition considered for vertical take-off and climb. Under this condition, the capacity decreased to 16.26 Ah, corresponding to 74.2% of the rated capacity, owing to internal-resistance-induced voltage drop, electrochemical polarization, and early attainment of the cut-off voltage. The Peukert exponent was estimated to be 1.113. An apparent pack-level direct-current internal resistance (DCIR) of approximately 40.3 mΩ was estimated from the initial voltage-drop analysis under different discharge-current conditions. In addition, the maximum temperature during 10.68C discharge was measured as 55.1 °C, providing a thermal margin of 4.9 °C relative to the operational temperature limit of 60 °C adopted in this study. Finally, a 24S4P battery system with a capacity of 88 Ah, consisting of four 24S1P battery packs connected in parallel, was installed in the VS-210, a 210 kg-class maximum take-off weight (MTOW) eVTOL aircraft. An in-flight test was conducted by repeating six take-off–hovering–landing cycles during a total test session of 15 min 20 s, and a stable propulsion power supply was maintained throughout all flight cycles. This study provides experimental baseline data for the design and preliminary safety assessment of high-power battery systems for UAM applications by presenting both the electrical and thermal characteristics of a 24S NCM battery pack over a wide discharge-rate range of 0.2C–10.68C and in-flight eVTOL data. Full article

Diffuse midline glioma (DMG) is one of the most aggressive paediatric brain tumours and remains almost universally fatal despite decades of research. The defining molecular feature of approximately 80% of DMG tumours is H3K27M, which disrupts PRC2 activity and profoundly remodels chromatin architecture. Increasing evidence suggests that this epigenetic alteration not only rewires transcriptional programs but also influences tumour metabolism. Several studies indicate that H3K27M-mutant tumours exhibit altered mitochondrial metabolism, oxidative phosphorylation activity, redox regulation, and cellular stress responses, although the extent of oxidative phosphorylation dependence varies between models, tumour subtypes, and cellular states. In parallel, dopaminergic signalling has been implicated in cancer stem cell maintenance, metabolic regulation, and tumour survival across multiple malignancies, including glioma. The imipridone compound ONC201/dordaviprone, initially described as a dopamine receptor D2/3 antagonist and subsequently characterised as a mitochondrial ClpP agonist, demonstrates clinical activity in H3K27M-mutant DMG and induces mitochondrial stress responses. In this review, we examine emerging connections between epigenetic dysregulation, mitochondrial metabolism, and dopamine signalling in DMG. We propose that H3K27M-driven epigenetic reprogramming may impose metabolic constraints that increase tumour reliance on mitochondrial bioenergetics and stress-buffering pathways. Within this context, dopamine signalling may function as a metabolic rheostat that contributes to mitochondrial homeostasis; however, this remains a hypothesis requiring direct experimental validation in DMG models. Pharmacologic disruption of this axis may destabilise tumour metabolism and expose therapeutically exploitable vulnerabilities in this otherwise treatment-resistant disease. Full article

Unc-51-like kinase 3 (ULK3) is a key member of the ULK serine/threonine kinase family. Aberrant ULK3 expression has been increasingly linked to tumorigenesis and malignant progression in multiple cancer types. However, the precise role of ULK3 in tumor initiation and progression remains incompletely understood. Leveraging integrated multi-omics data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) project, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC), we systematically characterized the expression of ULK3 at both the transcript and protein levels across 33 cancer types. We also evaluated genomic alterations, prognostic significance, alternative splicing, pathway enrichment, tumor stemness, immune infiltration, and immunotherapy-related biomarkers. In parallel, we investigated the function of ULK3 in prostate cancer PC-3 cells using cellular localization analysis, wound-healing assays, and MTT assays. We further applied Connectivity Map (CMap) screening and molecular docking to identify candidate ULK3 activators. ULK3 was significantly upregulated in 13 cancer types, including Bladder Urothelial Carcinoma, Breast Invasive Carcinoma, and Lung Adenocarcinoma. In contrast, ULK3 was downregulated in Cholangiocarcinoma and Head and Neck Squamous Cell Carcinoma. High ULK3 expression was associated with poor overall survival in Adrenocortical Carcinoma, Kidney Renal Clear Cell Carcinoma, and Skin Cutaneous Melanoma. Copy number amplification contributed to ULK3 overexpression. A recurrent A206V missense mutation was detected in the protein kinase (Pkinase) domain. Genes co-expressed with ULK3 were enriched in RNA splicing, methylation, oxidative phosphorylation, and energy metabolism. ULK3 expression showed positive correlations with tumor stemness indices and m1A/m5C/m6A RNA modification regulators. From an immunological perspective, high ULK3 expression was associated with lower Immune Score, increased M2 macrophage infiltration, and co-expression of PD-L1, CTLA4, and LAG3 in most cancers. ULK3 expression was also correlated with Tumor Mutational Burden in Kidney Renal Clear Cell Carcinoma and Rectum Adenocarcinoma. In addition, ULK3 expression was associated with Microsatellite Instability in Brain Lower Grade Glioma, Lung Adenocarcinoma, and Uterine Corpus Endometrial Carcinoma. ULK3 overexpression promoted proliferation and migration in PC-3 cells. Cephaeline was screened as a putative ULK3 activator. Overall, ULK3 expression and amplification were associated with poor clinical outcomes, tumor stemness, immunosuppression, and RNA dysregulation. These findings highlight the potential value of ULK3 as a pan-cancer diagnostic and prognostic biomarker and as a predictor of immunotherapy response, particularly in prostate cancer. Full article

Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation. Full article

The autism spectrum disorder-associated SCN2A, ANK2, and SHANK-family genes encode molecularly distinct proteins that converge functionally on dendritic integration. Recent work established that ankyrin-B, encoded by ANK2, acts as an obligate dendritic scaffold for NaV1.2, encoded by SCN2A, in neocortical pyramidal neurons. Loss of this module mislocalizes dendritic NaV1.2, reduces dendritic Na⁺ influx, weakens backpropagating action potentials, and impairs synaptic maturation and long-term potentiation. SHANK proteins organize a complementary postsynaptic receptor scaffold within dendritic spines, coupling N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and metabotropic glutamate receptor (e.g., mGluR5) signaling to the actin cytoskeleton through layered PSD-95/GKAP/Homer interactions. Disruption of this scaffold can destabilize excitatory transmission, spine morphology, and plasticity. We propose that these dendritic shaft and spine-associated modules jointly regulate dendritic input–output gain and that their disruption may contribute to autism spectrum disorder by destabilizing, rather than uniformly shifting, excitatory integration across cortico-subcortical circuits relevant to sensory reactivity, behavioral flexibility, and social-valence processing. Here, we review the cortical evidence for this layered dendritic convergence and evaluate its potential relevance beyond the cortex. We assess the striatum, thalamus, and amygdala as subcortical sites where related dendritic scaffolding mechanisms may operate. The striatum provides the strongest current test case, with established roles for both NaV1.2 and SHANK3 in medium spiny neuron physiology and corticostriatal connectivity. Thalamic and amygdalar extensions are supported mainly by SHANK-related circuit and channelopathy data but lack direct evidence for ANK2–SCN2A involvement. The framework is experimentally testable: conditional Ank2 deletion in striatal, thalamic, and amygdalar cell types; dendritic Na⁺/Ca²⁺ imaging across Scn2a, Ank2, and Shank3 models; adult rescue experiments; and genetic-interaction designs would determine whether ankyrin-B supports dendritic excitability beyond the cortex and whether these genes converge on, rather than merely parallel, dendritic input–output gain. Validation in human subcortical tissue would then establish whether this dendritic scaffolding logic represents a shared point of convergence through which genetically distinct autism spectrum disorder-risk variants alter circuit function. Full article

Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine. Full article