摘要: Neuronal intranuclear inclusion disease(NIID) is a rare autosomal dominant neurodegenerative disorder defined by the presence of eosinophilic intranuclear inclusions across both central and peripheral components of the nervous system, as well as multiple visceral organs,resulting in pronounced clinical heterogeneity. Following the discovery of pathogenic GGC repeat expansions in the NOTCH2NLC gene as the underlying genetic driver, a diverse array of experimental platforms has been established to probe NIID pathogenesis, including adenoassociated virus-mediated expression systems, transgenic animal models, and patient-derived cellular systems such as brain organoids. Collectively, these models recapitulate key histopathological and behavioral phenotypes observed in NIID and have elucidated multiple molecular and cellular pathways implicated in disease progression. This review systematically examines the current landscape of NIID model systems, highlighting their respective contributions to understanding disease pathogenesis, evaluating their experimental limitations, and identifying avenues for future refinement. Such integrative analysis is critical for advancing the development of more faithful disease models and facilitating the identification of therapeutic targets for NIID.

摘要: Transfer ribonucleic acid–derived small ribonucleic acids(ts RNAs) are an emerging class of regulatory noncoding RNAs produced through the precise cleavage of mature or precursor t RNAs(pre-t RNAs). Once considered degradation byproducts, ts RNAs are now recognized as key modulators of gene expression, epigenetic regulation,and cellular stress responses. In recent years, growing evidence has implicated ts RNAs in the aging process of the brain and in the pathogenesis of age-related neurodegenerative diseases, such as Alzheimer's disease(AD), Parkinson's disease(PD), and amyotrophic lateral sclerosis(ALS). These small RNAs are involved in modulating synaptic function, neuronal survival, and neuroinflammation, and their expression profiles are dynamically altered in response to aging and diseaseassociated stressors. This review summarizes the biogenesis, classification, and molecular and cellular mechanisms of ts RNAs, with an emphasis on their subcellular locations and associated biological functions.We further explore their roles in brain aging and agerelated neurodegenerative diseases and the emerging potential of ts RNAs as biomarkers and therapeutic targets for age-related neurological disorders while highlighting current challenges and future directions in this rapidly advancing field.

摘要: Epilepsy, a prevalent neurological disorder, is characterized by recurrent, self-sustained seizures resulting from abnormal neuronal hyperexcitability.Epilepsy encompasses a wide spectrum of etiologies,pathophysiological mechanisms, and treatment responses,resulting in considerable phenotypic heterogeneity. Over the past few decades, animal models, ranging from simple organisms to complex species, have played a pivotal role in elucidating the cellular, molecular, and circuit mechanisms underlying seizure generation and propagation, while also facilitating the development of antiseizure medication and other therapeutic interventions.This review first outlines the mechanistic basis of epilepsy and systematically summarizes existing seizure and epilepsy models across diverse taxa, including zebrafish,rodents, and non-human primates(NHPs), with a focus on model-specific features, translational relevance, and therapeutic utility. Despite substantial progress, limitations persist in recapitulating the full complexity of human epilepsy. Recent advances in genetic engineering,neuromodulation technology, and brain organoids are refining model fidelity and enhancing alignment with precision medicine approaches. Cross-species integration offers a promising avenue for bridging preclinical findings with clinical application, advancing mechanistic insight,and the development of targeted therapies.

摘要: Polycystic ovary syndrome(PCOS), a common female endocrine disorder marked by disrupted folliculogenesis and hyperandrogenism, is increasingly linked to oxidative stress. Despite this association, the mechanistic basis remains poorly characterized. C-Phycocyanin(C-PC), a cyanobacteria-derived protein with potent antioxidant properties, has demonstrated therapeutic potential for treating PCOS, though the molecular pathways mediating its effects have yet to be delineated. This study employed both a dehydroepiandrosterone(DHEA)-induced murine model and DHEA-challenged human granulosa cells(KGN) to elucidate the regulatory role of C-PC. In vivo, oral administration of C-PC restored estrous cyclicity, reduced the prevalence of cystic follicles, and normalized circulating levels of testosterone, estradiol, progesterone,and luteinizing hormone(LH). In vitro, C-PC treatment activated the NRF2/x CT/GPX4 pathway, enhanced antioxidant activity, improved mitochondrial function, and suppressed ferroptotic death. Direct molecular interaction between C-PC and NRF2 was validated through molecular docking and cellular thermal shift assays(CETSA).Correspondingly, in vivo administration alleviated oxidative stress, inhibited ferroptosis, and increased GPX4 and x CT expression, effects reversed by pharmacological inhibition(ML385) and genetic silencing(AAV-sh-NRF2) of NRF2.C-PC also reduced DHEA-induced phosphorylation of AMPK, while co-treatment with an AMPK activator attenuated its effects on GPX4 and x CT, abolishing its anti-ferroptotic protection against granulosa cells. These findings suggest that C-PC mitigates PCOS pathology by repressing granulosa cell ferroptosis through coordinated activation of NRF2 and modulation of redox-sensitive AMPK signaling, highlighting its potential as a redoxtargeted therapeutic strategy for PCOS.

摘要: Precise shaping of the sperm head is essential for successful fertilization, and defects in this process are frequently associated with severe forms of male infertility.Sperm head morphology is coordinated by several testisspecific structures, including the apical ectoplasmic specialization(ES), manchette, and perinuclear theca(PT)—a dense cytoskeletal layer that envelops the nucleus during spermiogenesis. However, the molecular components and physiological functions of the PT remain incompletely understood. This study identified FNDC8 as a testis-enriched protein primarily localized to the PT.Genetic disruption of Fndc8 resulted in male infertility characterized by spermatozoa exhibiting acrosome detachment from the nuclear membrane and sperm head surface collapse. FNDC8 interacted with CCIN and ACTL7A during spermiogenesis, and its depletion destabilized both proteins. Together, these results indicate that FNDC8 is integral to the structural integrity of the PT by mediating protein interactions critical for sperm head morphogenesis, implicating FNDC8 dysfunction as a potential contributor to teratozoospermia in humans.

摘要: The sublaterodorsal tegmental nucleus(SLD) is a critical hub for regulating rapid eye movement(REM) sleep and muscle atonia, with its dysfunction linked to various disorders such as REM sleep behavior disorder(RBD) and cataplexy. Despite its physiological significance, the presynaptic patterns influencing SLD γ-aminobutyric acid(GABA)ergic neurons—one of the primary neuronal subtypes within the SLD—remain poorly understood. This study applied a modified rabies virus tracing system combined with a Cre/lox P-based genetic approach to map and quantify the whole-brain monosynaptic afferents to SLD GABAergic neurons in mice. In total, 139 anatomically distinct nuclei were identified as sources of direct input,with predominant projections originating from the midbrain,pons, and medulla. Ipsilateral contributions accounted for67.99% of all traced inputs, while 32.01% were contralateral. Prominent sources included the mesencephalic reticular nucleus, superior colliculus, oral part of the pontine reticular nucleus, gigantocellular reticular nucleus, lateral hypothalamic area, and zona incerta neurons. Several nuclei displayed contralateral projection biases. Immunofluorescence staining revealed molecular diversity among input neurons, suggesting that SLD GABAergic neurons integrate signals from anatomically and functionally distinct neuronal populations.These findings provide a comprehensive anatomical framework for understanding how SLD GABAergic neurons integrate multisource inputs and offer new perspectives for investigating their involvement in regulating complex physiological functions, including sleep and motor control.

摘要: Hypobaric hypoxia encountered at high altitudes impairs reproductive health and fertility across species. Previous findings have demonstrated that maternal hypoxia exposure disrupts granulosa cell(GC) viability and oocyte maturation in female offspring; however, its transgenerational impact on male reproductive outcomes remains poorly elucidated. In this study, pregnant mice(F0) were subjected to hypoxic conditions, and male progeny across four generations(F1-F4) were evaluated.Results revealed that maternal hypoxia induced mild alterations in sperm DNA methylation in F1 males but caused profound developmental defects in F2 embryos,predominantly affecting males. Following mating of F1males with control females, a substantial proportion of male F2 fetuses were lost at embryonic day(E) 13.5,attributed to placental malformations. Integrated RNA sequencing and whole-genome bisulfite sequencing of placentas from male fetuses revealed aberrant expression of imprinted genes, including Gnas, Slc38a4, Jade1, and Kcnq1, which also exhibited differential methylation in F1sperm. These findings demonstrate that maternal hypoxia disrupts epigenetic programming in F1 germ cells,impairing placental development and fetal viability in F2males, thereby leading to an unbalanced sex ratio. Overall,this study elucidates the mechanisms by which environmental hypoxia influences sex ratios and offers critical insights into hypoxia-induced reproductive impairments in mammals.

摘要: Microplastics have been detected in the brain, raising concerns regarding their neurological health impacts.However, the specific cellular targets and functional consequences of their accumulation remain understudied.This study explored the primary brain cell types that internalize polystyrene nanoparticles(PSNs) and investigated their immunological responses. Results showed that PSNs preferentially localized to primary microglia and astrocytes. Functional assays revealed divergent effects on lipopolysaccharide(LPS)-stimulated immune responses in the two cell types: PSNs potentiated LPS-induced activation of microglia, whereas they suppressed activation in astrocytes. Apoptotic responses were likewise cell-type specific, with PSN reducing apoptosis in microglia independently of LPS, but enhancing it in astrocytes. In vivo, adult mice exposed to both PSNs and LPS exhibited increased microglial numbers in the hippocampus compared to those receiving LPS alone. These findings demonstrate that PSNs disrupt the immune homeostasis of brain-resident glial cells through cell-type-specific mechanisms, highlighting a potential neurotoxic risk associated with nanoparticulate plastic exposure.

摘要: Current evidence supports high temperature-induced masculinization as the primary temperature-dependent sex determination(TSD) pattern in fish. To date, no study has reported bidirectional TSD in a fish species, in which low temperature induces masculinization while high temperature induces feminization. In this study,Onychostoma macrolepis exhibited a distinctive bidirectional TSD pattern, with a balanced 1:1 sex ratio at24°C(moderate temperature), over 80% female development at 28°C(high temperature), and approximately 75% male development at 20°C(low temperature). Transcriptomic analyses revealed kdm6bb and calcium channel genes as key regulators of TSD among the differentially expressed genes between high and low temperature groups. Consistently, administration of calcium influx and Kdm6bb inhibitors effectively blocked high temperature-induced feminization and low temperature-induced masculinization, respectively. These findings indicate that temperature perception in O.macrolepis is mediated through calcium signaling, which regulates the expression of the epigenetic modifier kdm6bb and consequently modulates sex determination.Unexpectedly, canonical male pathway genes such as dmrt1 and gsdf showed higher expression in the high temperature group than in the low temperature group at 50days after fertilization(daf). Administration of aromatase inhibitors failed to induce sex reversal at either temperature, whereas extremely low concentrations of testosterone/methyltestosterone(T/MT) and 17β-estradiol(E2) successfully induced sex reversal under high and low temperature conditions, respectively. These results suggest that downstream regulatory pathways controlling sexual differentiation in O. macrolepis are distinct from conventional TSD models. The discovery of this bidirectional mechanism establishes O. macrolepis as an exceptional model for elucidating the molecular and physiological bases of temperature-driven sex determination and underscores the ecological risks of global warming for aquatic vertebrates.

摘要: Snakes exhibit extraordinary ecological diversity and occupy a broad range of terrestrial, aquatic, and intermediate environments. Despite their widespread capacity for swimming, quantitative assessments of their aquatic locomotion remain scarce. Furthermore, the roles of intraspecific variation in shaping swimming performance and kinematics have been largely overlooked, hindering robust interspecific comparisons. This study systematically investigated intraspecific and interspecific variation in 287individuals representing seven snake species along a terrestrial to aquatic continuum. Nine conventional swimming traits were quantified, including swimming speed and undulation characteristics such as frequency,wavelength, lateral velocities(head, body and tail) and amplitudes(head, body and tail). Undulation frequency and lateral velocity exhibited strong positive correlations with swimming speed, whereas wavelength showed a strong negative correlation. Semi-aquatic taxa attained the highest swimming speeds, while fully aquatic snakes displayed the lowest speeds. Intraspecific variation in swimming performance and kinematics was moderately reduced in aquatic species. Morphological traits, sex, and reproductive status significantly influenced both speed and kinematic profiles within species. Principal component analyses further revealed distinct kinematic domains among certain species(e.g., no overlap between aspic viper and sea snakes), while others, such as the green whip snake, exhibited broad overlap with all taxa examined. These findings demonstrate that ecological specialization to aquatic habitats does not unilaterally dictate swimming speed or kinematic patterns. Moreover,conventional kinematic parameters alone are insufficient to study the evolutionary trajectories of aquatic locomotion in snakes. Integrating hydrodynamic, endurance capacity,and diving performance will be essential to better understand how natural selection has shaped locomotion in aquatic snakes.