Sleep apnea syndrome (SAS) is a prevalent disorder characterized by recurrent respiratory pauses during sleep; however, the neural mechanisms governing respiratory stability remain poorly understood. In this study, we identify the ratio of sigh expiratory volume to eupneic expiratory volume as a potential predictor of post-sigh apnea in susceptible C57BL/6J mice. We demonstrate that leptin signaling within the nucleus tractus solitarius (NTS) is critical for maintaining respiratory drive and suppressing apnea. Chemogenetic activation of Leptin receptor b-expressing NTS (NTSLepRb) neurons significantly reduced apnea incidence, whereas their ablation exacerbated respiratory dysfunction. Moreover, NTSLepRb neurons mediate these effects through anatomically and functionally segregated projections to the dorsomedial hypothalamus and the lateral parabrachial nucleus. These findings define a specific leptin-mediated brainstem circuit that stabilizes respiratory output, providing new mechanistic insights and potential therapeutic targets for sleep-disordered breathing.

Background and Objectives: IQSEC2-related neurodevelopmental disorder is an X-linked condition characterized by developmental delay and epilepsy, with substantial phenotypic heterogeneity. Although sex-dependent clinical differences have been reported in western population, the population-specific genetic architecture and epilepsy treatment outcomes of IQSEC2 -related disorder remain incompletely characterized, particularly in East Asian populations. This study aims to delineate the clinical features, variant spectrum and epilepsy outcomes in a Chinese pediatric cohort with IQSEC2 -associated disorders. Methods We retrospectively analyzed the clinical manifestations, genetic findings, antiseizure medication use, and follow-up outcomes of 35 Chinese children with potential disease causing by variants in IQSEC2. Variants were identified by WES and classified according to ACMG/AMP guidelines, with additional analysis of variant inheritance and intragenic copy-number variants. Results The cohort included 20 males and 15 females, with symptom onset predominantly between 1 and 7 years of age. Females were diagnosed at a significantly later age than males (Mann-Whitney U test, P = 0.0161). All patients exhibited developmental delay, and epilepsy was observed in 17 of 35 individuals (48.57%), with a high proportion of refractory epilepsy 47.05% (8/17). Females generally demonstrated milder epilepsy phenotypes and more favorable seizure control compared with males, including higher rates of seizure freedom at follow-up. Genetic analysis identified a distinct variant spectrum, with a predominance of truncating variants, and one intragenic exon 5–9 deletion, of which 68.57% were de novo , highlighting population-specific differences from previously reported Western cohorts. Among patients with epilepsy, seizure control was achieved in ten individuals during follow-up, with substantial variability in response to antiseizure medications. Conclusions This Chinese cohort study delineates the clinical and genetic spectrum of disease in the IQSEC2 -related X-linked intellectual disability population, revealing notable sex-related differences in disease manifestation.

Objective: This study explored the protective effects of Anemoside B4 (AB4) against septic cardiomyopathy (SCM) and investigated the underlying mechanisms involving mitochondrial dysfunction and cellular senescence.Methods: LPS-induced and cecal ligation and puncture (CLP)-induced SCM models were established in C57BL/6 mice, with LPS-stimulated H9c2 cardiomyocytes used for in vitro validation. AB4 was administered in graded doses, and the SRC-specific inhibitor PP2 was used in rescue experiments. AB4's effects were assessed using echocardiography, histopathology, Western blotting, RT-qPCR, and molecular docking to evaluate AB4-SRC binding.Results: AB4 exhibited dose-dependent protection in both LPS- and CLP-induced SCM models, enhancing cardiac function and mitigating myocardial damage. High-dose AB4 (AB4-H) demonstrated the most pronounced enhancements, reinstating myocardial integrity and diminishing inflammation, as indicated by echocardiogram and HE staining. AB4 directly interacted with SRC in both in vivo and in vitro settings, activating the PI3K/AKT/mTOR pathway, which reinstated mitochondrial function by diminishing mitochondrial reactive oxygen species (ROS) levels, augmenting ATP generation, and increasing mitochondrial morphology. AB4 also suppressed cardiomyocyte senescence, as indicated by diminished senescence markers and factors associated with the senescence-associated secretory phenotype (SASP). Significantly, PP2, a selective SRC inhibitor, nullified AB4's protective effects, thereby indicating that AB4 operates through the SRC-mediated PI3K/AKT/mTOR pathway.Conclusions: AB4 was a promising therapeutic candidate for SCM, with its protective effects mediated through the SRC-mediated PI3K/AKT/mTOR pathway, which in turn enhanced mitochondrial function and inhibited cardiomyocyte senescence. These findings highlighted the potential of targeting this pathway in treating sepsis-induced cardiac injury.

Background Rich-club organization is a fundamental topological feature supporting global information integration in the brain. However, its hierarchical alterations in comorbid insomnia with anxiety (CI-A) remain poorly understood. Methods Diffusion tensor imaging was performed in 61 patients with CI-A and 35 matched healthy controls. Whole-brain structural networks were reconstructed and categorized into rich-club, feeder, and local connections. Group differences in diffusion metrics and connectivity strength were examined, and their associations with the Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAMA-14), Hyperarousal Scale (HAS), and Montreal Cognitive Assessment (MoCA) were evaluated. Results In feeder connections, CI-A patients showed elevated radial diffusivity, which correlated with HAS (r = 0.304, p = 0.003), and higher fiber number was associated with PSQI (r = 0.335, p = 0.001). In local connections, increased radial diffusivity correlated with HAS (r = 0.308, p = 0.002), and heightened axial diffusivity was linked to PSQI (r = 0.299, p = 0.003). Conclusion These findings reveal a selective vulnerability pattern in CI-A, with peripheral connections showing more pronounced microstructural abnormalities than the rich-club connections, providing novel insights into the hierarchical disruption of white matter networks in this condition.

Metabolic state strongly shapes social and reproductive behaviors, yet the neural circuits that convert internal energy signals into behavioral responses remain poorly defined. The ventral premammillary nucleus (PMv) of the hypothalamus has been implicated in this process, particularly through leptin receptor-expressing (LepRb) neurons, but its brain-wide circuit organization is still unclear. Here, we used Cre-dependent retrograde (RV) and anterograde (HSV) viral tracing techniques in LepRb-Cre mice to construct a comprehensive, single-cell-resolution input-output map of PMvLepRb neurons. 3D reconstruction showed that these neurons receive dense convergent inputs, mainly from hypothalamic and forebrain regions involved in energy balance, motivation, and limbic processing. In contrast, their outputs extend not only back to several input regions but also prominently to midbrain and pontine autonomic centers, including the periaqueductal gray (PAG) and parabrachial nucleus (PB). Quantitative analysis revealed that forebrain regions were more likely to participate in reciprocal connectivity, whereas brainstem regions were dominated by outgoing projections. This organization suggests that PMvLepRb neurons are positioned to integrate metabolic and motivational signals and relay them to downstream systems controlling instinctive behavioral and autonomic responses. These findings provide a structural basis for understanding how energy state can influence decisions related to social competition and reproduction.

Abstract Purpose Post-operative sleep disturbance affects more than 60% of surgical patients and impedes recovery. Although general anesthesia itself may profoundly remodel brain function and contribute to this pathology, the underlying neural mechanisms remain unclear. We previously identified the dorsomedial hypothalamus (DMH) as a key modulator of emergence and arousal. Here, we investigated the distinct roles of DMH glutamatergic neurons (DMH Glu ) and GABAergic neurons (DMH GABA ) in the pathophysiology of post-anesthesia sleep disturbance (PSD). Methods Using a mouse model of PSD induced by 2 h of 1.4% isoflurane anesthesia, we used chemogenetics to selectively activate or inhibit DMH neurons. Sleep–wake architecture was assessed using wireless electroencephalography (EEG) and electromyography (EMG) biotelemetry, complemented by fiber photometry for neuronal activity monitoring and single-nucleus RNA sequencing for molecular profiling. Results Isoflurane anesthesia induced a delayed-onset sleep disturbance characterized by increased wakefulness and reduced, fragmented sleep during the subsequent rest phase. Notably, DMH Glu neurons showed heightened activity specifically during rest-phase wakefulness, whereas DMH GABA neurons were predominantly active during wakefulness and non-rapid eye movement sleep in the post-anesthesia active phase. Activation of DMH Glu neurons reversed PSD in a circadian phase-dependent manner, while both activation and inhibition of DMH GABA neurons improved PSD without significant phase variation. Single-nucleus RNA sequencing revealed the involvement of retrograde endocannabinoid signaling in both DMH Glu and DMH GABA neurons. Administration of a type 1 cannabinoid receptor (CB1R) antagonist alleviated PSD, potentially by disinhibiting DMH Glu neurons and remodeling the integration of excitatory and inhibitory inputs onto DMH GABA neurons. Conclusions DMH Glu and DMH GABA neurons differentially regulate PSD through distinct, CB1R-mediated presynaptic modulation, providing novel mechanistic insights into PSD and identifying potential therapeutic targets for its treatment.

Self-limited epilepsy with centrotemporal spikes (SeLECTS) is the most common form of focal epilepsy in childhood, accounting for 20-25 % of all childhood epilepsy cases and may be associated with cognitive dysfunction and behavioral issues. Accurate detection and assessment of epileptic discharges in EEG signals, particularly the spike-wave index (SWI), are crucial for timely intervention and treatment. Manual analysis of EEG data is laborintensive and prone to errors, underscoring the need for automated methods. In the present study, we propose a novel Dual-Stream Spatial-Spectral-Temporal Large model (DeaSTL) that leverages a large-scale EEG architecture to effectively capture the multidimensional characteristics of EEG signals associated with SeLECTS syndrome. Our model integrates multi-view temporal representations and spatial-spectral representations through a dual-stream approach, enhancing the learning of complex patterns in EEG data. We introduce the SJTU SeLECTS EEG Dataset (SLED), a comprehensive EEG dataset from 212 patients diagnosed with SeLECTS, including annotations for abnormal discharge detection, wake-sleep period classification, and SWI estimation. Addressing the previously unexplored problem of SWI prediction, we provide a novel method for quantifying the severity of epileptic discharges during sleep. Extensive experiments demonstrate that our DeaSTL model significantly outperforms several state-of-the-art methods across multiple tasks, showcasing its potential for clinical application in assisting diagnosis and treatment planning.

Background: Triclosan (TCS), a widely used environmental antimicrobial agent, is associated with cardiovascular risks such as coronary heart disease; however, its effect on post-myocardial infarction (MI) prognosis remains unclear. This study investigated whether TCS exacerbated post-MI outcomes and the underlying mechanisms, with the goal of identifying potential preventive strategies. Methods: MI models were established using mice with left anterior descending coronary artery ligation, alongside hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and human AC16 cardiomyocytes. A comprehensive set of methodologies was employed, including RNA sequencing, echocardiography, Western blotting, co-immunoprecipitation, dual-luciferase reporter assays, molecular docking, quantitative real-time PCR, histological/immunofluorescence staining, and oxidative stress parameter analyses. Mechanistic investigations utilized Nur77 knockout mice, AAV9-based viral vectors targeting Nur77 and NTRK2, adenoviruses, plasmids, and small-molecule inhibitors/activators. Results: Exposure to environmentally relevant TCS concentrations dose-dependently aggravated short- and long-term post-MI cardiac dysfunction and ventricular remodeling in both male and female mice. Mechanistically, TCS induced TRIM13-mediated K48-linked ubiquitination and proteasomal degradation of the nuclear receptor Nur77, leading to reduced transcription of NTRK2. Downregulated NTRK2 suppressed the AKT/mTOR/YY1 signaling cascade, ultimately decreasing PGC-1α expression and impairing mitochondrial function—specifically mitochondrial oxidative phosphorylation. This bioenergetic deficit triggered excessive reactive oxygen species (ROS) production, promoting lipid peroxidation and exacerbating cardiomyocyte ferroptosis, cellular senescence, and the senescence-associated secretory phenotype (SASP). These pathological effects collectively exacerbated acute post-MI injury and facilitated the progression of long-term ventricular remodeling. Validation in NRCMs and human AC16 cardiomyocytes confirmed conserved phenotypes and mechanisms. Pharmacological activation of PGC-1α with ZLN005 mitigated TCS-induced deterioration of short- and long-term post-MI cardiac function and attenuated ventricular remodeling. Conclusions: TCS exacerbates post-MI injury by disrupting the Nur77/NTRK2/PGC-1α axis, triggering mitochondrial dysfunction-mediated ferroptosis and senescence in cardiomyocytes of both male and female mice. Pharmacological activation of PGC-1α represents a potential strategy to counteract TCS-induced adverse outcomes after MI.

Objective: To address various issues associated with electroencephalography (EEG) interpretation for pediatric epilepsy diagnosis, this study proposes a deep learning model for automatically quantifying the spike-wave index (SWI), a critical marker representing the percentage of spike-and-slow-wave discharges during non-rapid eye movement (NREM) sleep and a key biomarker for detecting electrical status epilepticus during sleep (ESES) and atypical evolution in self-limited epilepsy with centrotemporal spikes (SeLECTS). Methods: An EEG database derived from 221 children diagnosed with SeLECTS was constructed. We propose a spatial-temporal attention transformer for evaluating the spike-wave index (STATFS) with deep learning methods to automatically classify EEG-based data and predict the SWI. The model demonstrates optimal performance by more effectively extracting features from the original signal, yielding better classification results in the low-dimensional space. Results: STATFS outperformed existing deep learning models in SWI prediction tasks, demonstrating enhanced ability to extract spatiotemporal features from raw EEG signals. Compared with traditional manual interpretation, STATFS enabled real-time SWI prediction within seconds. Conclusion: STATFS supports reliable clinical decision-making and offers valuable assistance for early intervention. STATFS addresses the low efficiency and subjectivity of EEG interpretations, thereby significantly conserving medical resources; providing convenience; and offering prospects for personalized treatments with substantial clinical.

Central respiratory chemoreception is a vital homeostatic mechanism maintaining arterial blood gas levels. Central respiratory chemoreceptors in the retrotrapezoid nucleus (RTN) and nucleus tractus solitarius (NTS) form interconnected circuits to regulate respiratory homeostasis. We hypothesized that NTS GABAergic neurons (NTSGABA) modulate hypercapnic ventilatory responses by targeting ventrolateral medulla Phox2b neurons (VLMPhox2b), particularly Phox2b-expressing RTN neurons. Stimulation of NTSGABA neurons significantly attenuated CO2-evoked ventilatory responses, accompanied by a reduction in CO2-activated Phox2b-expressing RTN neurons. Neural tracing revealed that monosynaptic inputs to the VLMPhox2b neurons primarily originate from the ventrolateral and dorsolateral subdivisions of the NTS. Photostimulation of NTSGABA neurons retrogradely labeled from the VLM markedly suppressed respiratory drive, while chemogenetic activation of these neurons induced hypoventilation, increased spontaneous apnea, and attenuated hypercapnic ventilatory response. These findings demonstrate that activation of the NTS-VLM inhibitory circuit diminishes respiratory motor output, offering novel insights into the regulatory mechanisms of respiratory homeostasis.

Breathing rhythms bidirectionally modulate affective states, yet the underlying neural pathways remain elusive. Here, we identified an ascending neural circuit that integrates respiratory patterning with affective state in male mice. This circuit originates from glutamatergic neurons in the preBötzinger complex (preBötC), projecting to the paraventricular thalamic nucleus (PVT) and subsequently targeting the central amygdala (CeA). We reveal that photostimulation of the preBötC→PVT circuit significantly alleviates acute restraint stress-induced anxiety-like phenotypes and reduces respiratory frequency variability. Conversely, inhibition of this circuit exacerbates anxiety-like phenotypes and respiratory dysfunction. These effects are significantly abolished by inhibition or ablation of PVT neurons projecting to the CeA. Additionally, this anxiolytic effect is mediated by PVT projections that preferentially excite centrolateral amygdala neurons, thereby inhibiting centromedial amygdala output. Translating these findings, we show that volitional slow breathing reduces anxiety in healthy humans and suppresses anxiety-related beta/high-gamma oscillations in the amygdala of epilepsy patients. This work delineates a conserved respiratory-limbic circuit that mechanistically explains the anxiolytic effect of controlled breathing.

Introduction: Odontogenic brain abscess is an uncommon but potentially fatal intracranial infection, and its diagnosis is often delayed because of nonspecific symptoms and difficulty identifying the primary source of infection. Microbiological confirmation of oral pathogens is rare, particularly in anaerobic infections. Case Presentation: A 66-year-old man was admitted with dizziness, headache, and progressive right-sided weakness. Brain magnetic resonance imaging (MRI) revealed a left parietal abscess with surrounding edema. Cerebrospinal fluid (CSF) analysis showed marked inflammatory changes, whereas routine cultures were negative. Metagenomic next-generation sequencing (mNGS) of the CSF identified Porphyromonas gingivalis, Fusobacterium nucleatum, and Actinomyces israelii. An oral examination revealed severe periodontal disease, supporting an odontogenic source. Despite broad-spectrum antimicrobial therapy, the abscess ruptured into the ventricular system. The patient was successfully treated with targeted antibiotics combined with ventricular drainage and intraventricular lavage, resulting in substantial neurological recovery. No recurrence was observed during 6 months of follow-up. Conclusions: This case provides direct microbiological evidence linking chronic periodontal disease to brain abscess formation and highlights the diagnostic utility of CSF mNGS for identifying anaerobic odontogenic pathogens. Early recognition of oral infection as a potential source, and timely multidisciplinary intervention, are critical for improving outcomes in patients with high-risk brain abscesses.

BACKGROUND:Diabetic cognitive dysfunction (DCD) is one of the chronic complications of diabetes, but its mechanism is currently unknown. Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD. Blocking calcium overload and restoring calcium homeostasis are key steps in treatment. Transient receptor potential melastatin 7 (TRPM7) is a novel player in causing calcium overload. Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function, but the specific mechanism remains unclear. Troxerutin, extracted from the flowers of Sophora japonica, is one of the derivatives of rutin and has been shown to have neuroprotective effects. However, its association with TRPM7 remains unclear. AIM:To use animal and cellular models, we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin (CaN)/dynamin-related protein 1 (Drp1)ser637 in DCD, and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division. METHODS:In this study, we used db/db mice and hippocampal neuronal cell lines (HT22) treated with high-concentration glucose as our study subjects. We evaluated cognitive function using Morris water maze, novel object recognition tasks, and Nesting tests. We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer. We also detected mRNA and protein expression of TRPM7, CaN, p-Drp1ser637, caspase-3, B-cell lymphoma 2 associated X protein, and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. RESULTS:In the db/db diabetic mice with cognitive dysfunction, as well as in hippocampal neurons exposed to high-concentration glucose, TRPM7 and CaN expression were upregulated, phosphorylated Drp1ser637 expression was downregulated, and mitochondrial fission was increased. By modulating (inhibiting or overexpressing) TRPM7, it was further validated that TRPM7 activates the CaN/Drp1ser637 pathway, resulting in an increase in mitochondrial fission and neuronal cell apoptosis. Troxerutin downregulated TRPM7/CaN/Drp1ser637, reduced mitochondrial fission, and improved DCD. CONCLUSION:TRPM7 promotes mitochondrial fission via the CaN/Drp1ser637 pathway. Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway, suggesting TRPM7 as a potential therapeutic target for DCD.

BACKGROUND:Treatment of disorders of consciousness (DOC) remains a clinical challenge. Electroacupuncture (EA) was shown to have the potential to promote the recovery of consciousness. This trial aims to explore the therapeutic effects and mechanisms of EA in patients with DOC due to traumatic brain injury (TBI) through a multimodal approach. METHODS:A total of 50 adult patients with DOC due to TBI and 25 healthy subjects will be enrolled in the study. Patients enrolled in the study will be assigned to the EA group or the sham-EA group through stratified randomization. All patients receive behavioral assessments (CRS-R and brain-computer interface), neurophysiological evaluations (EEG, somatosensory evoked potentials, brainstem auditory evoked potentials), and neuroimaging evaluations (rs-fMRI, amide proton transfer, intravoxel incoherent motion, neurite orientation dispersion and density imaging) before and after the 14-day EA or sham-EA treatment. Each healthy subject will receive a set of neurophysiological and neuroimaging examinations but no treatments. The practitioner administering EA and sham-EA is the only one aware of the grouping results. In the sham-EA group, sham-acupoints, sham-acupuncture, and sham-wire are utilized. The primary outcome measurement is the change in CRS-R score after 14 days of treatment compared with the baseline CRS-R score. DISCUSSION:The AcuDoc trial will be the first randomized sham-controlled study to investigate the clinical benefits of EA in patients with DOC. This trial will elucidate the role of EA in the treatment of DOC due to TBI and provide evidence of its therapeutic mechanisms.

Background Aldosterone overactivity intensifies central sodium sensitivity and sympathetic output, driving salt-sensitive hypertension, but specific mechanisms remain incompletely defined. Herein, we aimed to explore the role of organum vasculosum of the lamina terminalis glutamatergic neurons (OVLTGlut) and their hyperexcitability mechanisms in hyperaldosteronism-associated hypertension. Methods Adult age matched male TASK−/− mice (primary aldosteronism model) and wild-type controls (TASK+/+) mice were used. Neuronal excitability was assessed via patch-clamp techniques. Arterial blood pressure (BP) monitored via telemetry or carotid catheterization. Chronic drug delivery used minipumps. RNA-seq/qPCR profiled gene expression, and intracerebroventricular hypertonic saline tested sodium sensitivity. Results In TASK−/− mice, heightened OVLTGlut activity increased sympathetic outflow and hypertension, mitigated by OVLTGlut neuron ablation. Optogenetic activation of these neurons or their paraventricular nucleus (PVN) / rostral ventrolateral medulla (RVLM) projections acutely elevated BP, with ablation reducing BP selectively in TASK−/− mice. Aldosterone dependence of OVLTGlut-PVN/RVLM neuron hyperactivity was evident in both TASK−/− mice and TASK+/+ mice with chronic aldosterone infusion. Aldosterone chronic infusion enhanced central sodium pressor effects, that were nullified by OVLTGlut-PVN/RVLM neuron lesioning. RNA-seq indicated that aldosterone-induced ion channel expression spectrum changes, including potassium channels and the epithelial sodium channel, underlie the neuronal hyperexcitability. Conclusion Overactivation of OVLTGlut neurons contributes to hypertension in TASK−/− mice through regulation of OVLTGlut-PVN/RVLM circuits. The hyperexcitability of these neurons, possibly due to aldosterone-induced changes in ion channel expression spectrum, contribute to hypertension by amplifying central sodium sensitivity. ### Competing Interest Statement The authors have declared no competing interest. * OVLT : organum vasculosum of the lamina terminalis BP : blood pressure SFO : subfornical organ MnPO : median preoptic nucleus PVN : the paraventricular nucleus RVLM : rostral ventrolateral medulla aCSF : artificial cerebrospinal fluid AP : Action potential AHP : afterhyperpolarization HR : heart rate MAP : mean arterial pressure MR : mineralocorticoid receptor AVP : arginine vasopressin TH : tyrosine hydroxylase TASK : TWIK-related acid sensitive potassium channel RMP : resting membrane potential ENaC : epithelial sodium channel

INTRODUCTION:Refractory status epilepticus (RSE) usually requires admission in an intensive care unit (ICU). Available specific prognostic scores for SE do not account for refractoriness, life support dependency, or related comorbidities, and usually fail to accurately predict outcome in RSE. Our goal was to develop a daily severity score, like existing scores used for critical illness, to follow patients' trajectory in the ICU and predict their outcome at discharge. METHODS:Retrospective observational study of two independent prospectively identified cohorts (derivation and validations cohorts) of RSE episodes admitted in the ICU of two tertiary-care centers, between January 2015 and May 2023. The sequential organ failure assessment (SOFA) score, additional neurological, EEG, treatment-related and biological variables were collected and compared between poor and good outcome groups (modified Rankin Scale (mRS) ≥ 4 or <4), on admission and during the first week of ICU stay, using Mann-Whitney tests and generalized linear mixed models. Based on significant univariate variables, we derived the SE daily severity (SEDS) score and measured its predictive performance for functional outcome using the area under the receiver operating characteristic curve (AUC). RESULTS:54 episodes and 71 episodes were included in derivation and validation cohorts, respectively. In the derivation cohort, no difference was found at ICU admission. The course of the SOFA score over the first week differed (p < 0.001) between groups, especially their cardiovascular and respiratory components, C-reactive protein (p < 0.001), SE-related and EEG variables. The SEDS score, which includes cardiovascular and respiratory components of SOFA score, CRP levels, GCS, EEG patterns and the use of continuous intravenous anesthetic drugs, had better AUCs than each components considered separately, ranging from 0.70 to 0.83 in the derivation cohort from 0.72 to 0.84 in the validation cohort. CONCLUSION:In the absence of differences in existing scores on ICU admission, the SEDS score achieved an AUC >0.70 throughout the first week of ICU stay, indicating good performance to predict poor outcome at hospital discharge.

OBJECTIVE:Astrocytes within the preBötzinger complex (preBötC) critically regulate respiratory rhythmogenesis and pattern formation. However, the molecular mechanisms underlying their contributions remain poorly understood. This study aims to investigate whether connexin 43 (Cx43) channels, a prominent subtype of connexin proteins expressed in preBötC astrocytes, are essential for stabilizing breathing patterns. METHODS:We employed a multidisciplinary approach, integrating whole-body plethysmography, in vivo fiber photometry, phrenic nerve discharge (PND) recordings, photostimulation, RNAscope fluorescence in situ hybridization, and RNA sequencing to elucidate the functional role of Cx43 channels in respiratory regulation. RESULTS:Elevated activation levels of preBötC astrocytes were synchronized with specific respiratory events, including sighs and transiently augmented breathing. RNA-sequencing analysis demonstrated that Gja1 (encoding Cx43) was identified as the predominant connexin transcript in preBötC astrocytes. Photostimulation of preBötC astrocytes significantly increased PND frequency in anesthetized mice, an effect replicated by pharmacological blockade of Cx43 hemichannels. Conditional knockdown of astrocytic Gja1 in the preBötC considerably increased resting breathing frequency and minute ventilation. Blockade of Cx43 hemichannels enhanced astrocytic activation and induced ATP accumulation around somatostatin-expressing preBötC neurons (preBötCSST). Furthermore, Cx43 hemichannel blockade activated preBötCSST neurons, an effect mediated by P2Y1 but not P2X receptors. CONCLUSION:We identify an astrocyte-to-neuron signaling cascade involving Cx43 hemichannel-dependent ATP release, P2Y1 receptor activation on preBötCSST neurons, and subsequent modulation of respiratory motor output. These findings establish Cx43 hemichannels as critical molecular determinants for stabilizing breathing patterns.

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NHK), is a rare inherited disease caused by an inborn error of glycine metabolism, resulting in elevated glycine concentration in plasma and cerebrospinal fluid. Clinical manifestations mainly include varying degrees of hypotonia, apneic episodes, epilepsy, psychomotor delay during the neonatal period or early infancy. Biallelic variants in GLDC account for up to 80 % of classical NKH cases. Here we describe the clinical, biochemical, and molecular characteristics of two Chinese siblings with severe NHK. Their phenotypes included severe symptoms in neonatal period, seizures, and psychomotor delay. The siblings carry novel compound heterozygous variants in GLDC, c.1740C > G (p.His580Gln) and c.1023G > A (p.Val341=). Based on previous literature reports and pathogenicity prediction, the c.1740C > G (p.His580Gln) variant is classified as likely pathogenic. By minigene analysis, we confirmed the synonymous mutation c.1023G > A (p.Val341=) led to abnormal splicing, with 38 bp missing in exon 7 in the GLDC gene. These findings highlight the pathogenic nature of a novel synonymous mutation c.1023G > A, expand the genetic spectrum of GLDC and provide crucial guidance for both the patient's clinical management and family's reproductive genetic counseling.

OBJECTIVE:The globus pallidus externa (GPe) is involved in mediating physiological functions and contains two types of neurons: Forkhead box protein P2-expressing (GPeFoxP2) neurons which inhibit motor, and parvalbumin-expressing (GPePV) neurons which improve motor. The functional complexity of the GPe, directly linked to its neuronal heterogeneity, necessitates exploring the neuroanatomical circuits of its distinct neuron types as a foundation for functional research. METHODS:In this study, we employed specific, modified rabies viruses and adeno-associated viruses to investigate the monosynaptic inputs of GPeFoxP2 and GPePV neurons. RESULTS:We found that the input projections to both types of neurons are widespread, including the cortex, subcortical structures, amygdala, thalamus, hypothalamus, and brainstem. These inputs exhibit significant similarity, with 49 nuclei simultaneously innervating both types of neurons. However, GPePV neurons receive a lower proportion of inputs from the cortex and a higher proportion of inputs from the thalamus, compared to GPeFoxP2 neurons. Clustering analysis indicates that GPeFoxP2 neurons receive extensive afferent inputs from four nuclear clusters in the brain, whereas GPePV neurons receive afferent inputs from only three clusters, suggesting GPeFoxP2 neurons may be involved in more diverse functional regulations than GPePV. CONCLUSION:Collectively, our results reveal the similarities and differences in the input projections to the two types of neurons in the GPe and lay the neuroanatomic groundwork for further studies to explore the critical physiological functions of GPe.