AIMS:To characterize the clinical, electrophysiological, and genetic spectrum of pediatric CMS and evaluate genotype-informed outcomes using an integrated phenotype-electrophysiology-genomics approach. METHODS:We retrospectively reviewed 36 pediatric CMS patients evaluated at a single center between 2015 and 2025. Clinical features, RNS, targeted NGS/WES variants, ventilator use, treatments, ACMG/AMP classifications, and MG-ADL outcomes were analyzed. RESULTS:Of 36 patients, 28 (77.8%) developed symptoms in the neonatal period or infancy. Biallelic variants involved 17 CMS genes; postsynaptic CMS was most common (55.6%, 20/36). COLQ and CHRNE were the most frequent genes (13.9%, 5/36 each), followed by CHAT (11.1%, 4/36). VUS were detected in 19 patients (52.8%, 19/36), including 8 with biallelic VUS supported by phenotype, neuromuscular transmission findings, treatment response, and follow-up. RNS showed a ≥ 10% decrement in 16/21 tested patients (76.2%). CHAT-CMS was associated with higher ventilator use (3/4 vs. 6/32; p = 0.041) and early mortality (3/4 vs. 1/32; p = 0.002). Median MG-ADL improved from 5 to 3 after genotype-informed therapy. CONCLUSION:Pediatric CMS shows marked genetic heterogeneity and frequent VUS-related uncertainty. Integrating phenotype, electrophysiology, and genomics supports diagnosis and mechanism-guided therapy. CHAT-CMS is high risk for early respiratory failure and mortality.
Aims To evaluate the diagnostic performance and non-inferiority of an abbreviated, non–intravenous contrast-enhanced magnetic resonance enterography (MRE) protocol compared with a standard gadolinium-enhanced protocol for the assessment of Crohn's disease activity, extent and complications. Materials and Methods This retrospective, single-centre study included 50 consecutive patients (mean age 42.7±16.9 years) with suspected or established Crohn’s disease who underwent standard MRE. Two radiologists, blinded to clinical data and reference reports, independently evaluated abbreviated protocol sequences (BTFE, T2-weighted SPAIR and TSE, DWI/ADC). Diagnostic performance was assessed against the report as reference standard. Interobserver agreement for categorical variables was analysed using Cohen’s and Fleiss’ kappa coefficients, while continuous variables were evaluated using intraclass correlation coefficients (ICC), with 95% confidence intervals. Bland–Altman analysis was performed. Results Agreement for disease activity was almost perfect (κ = 0.83, 95% CI: 0.64–0.96)(Reader A: sensitivity 93.5% (95% CI: 78.6–99.2), specificity 84.2% (60.4–96.6); reader B: sensitivity 90.3% (74.2–98.0), specificity 94.7% (74.0–99.9)). Agreement for anatomical location was also almost perfect. Substantial agreement was observed for stenosis detection (κ from 0.66 (95% CI: 0.29–0.89) to 0.73 (0.44–0.92)), whereas agreement for ulceration and penetrating complications was lower and heterogeneous. Quantitative measurements demonstrated excellent reproducibility (ICC>0.87, 95% CI: 0.79–0.93). Conclusion The abbreviated, non–intravenous contrast-enhanced MRE protocol demonstrates non-inferior diagnostic performance for the evaluation of disease activity, extent and stenosis in Crohn’s disease. Its implementation may reduce examination time and contrast exposure, although contrast-enhanced imaging remains indicated for ulcerations and penetrating complications assessment.
BACKGROUND:The posterior insular cortex (PIC) is a multimodal sensory integration center, and the GABAergic neurons are associated with functions such as pain perception, emotional regulation, and fear memories encoding. However, the whole-brain connectivity to PIC GABAergic neurons remains unclear. OBJECTIVE:To map the whole-brain input-output connectivity of PIC GABAergic neurons. METHODS:This study combined cell-type-specific retrograde/anterograde viral tracing systems with Cre/loxP genetic technology to perform a comparative analysis of the localization and quantification of monosynaptic inputs and axonal projections of PIC GABAergic neurons. RESULTS:Retrograde tracing identified 45 input nuclei, with densest inputs from the piriform cortex (Pir) and secondary somatosensory cortex (S2) of the isocortex, thalamic nuclei including the posterior thalamic nuclear group (PO) and parafascicular thalamic (PAF), exhibiting ipsilateral preference. Anterograde tracing revealed 18 output targets, with densest projections to the caudate putamen (CPu), external globus pallidus (GPe), and ventral pallidum (VP) of the basal ganglia and multiple subnuclei of the amygdala. CONCLUSIONS:PIC GABAergic neurons receive dense inputs from the isocortex and thalamus and send prominent projections to the basal ganglia and amygdala, with these brain regions constituting key hubs of the whole-brain connectivity network. This connectivity pattern provides a novel anatomical perspective for elucidating their roles in physiological behavior regulation.
BACKGROUND:P7C3 compounds are aminopropyl carbazole derivatives identified through phenotypic screening for proneurogenic activity. They directly activate nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. However, a comprehensive synthesis of their mechanisms and therapeutic potential across neurological disorders is currently lacking. METHODS:A systematic literature review was conducted in PubMed, Web of Science, and Scopus to synthesize the discovery trajectory, structure-activity relationships, molecular mechanisms, and preclinical efficacy of P7C3 compounds. The following keyword combinations were used: ("P7C3" OR "P7C3 compound") AND ("NAMPT" OR "NAD+" OR "sirtuin" OR "mitochondria") AND ("neuroprotection" OR "neurodegenerative"). RESULTS:P7C3 elevates intracellular NAD+ levels, engages SIRT1 and SIRT3 deacetylase cascades, enhances mitochondrial quality control and attenuates oxidative stress. This review discusses the discovery, structure-activity relationships, and molecular mechanisms of P7C3, with a particular emphasis on mitochondrial dynamics and redox homeostasis. The efficacy of P7C3 in preclinical studies was evaluated across Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), ischemic stroke, depression, and chemotherapy-induced neuropathy. These neuroprotective effects occur independently of disease-specific aggregates. Challenges hindering clinical application include the on-target safety of NAMPT activation given the concurrent development of NAMPT inhibitors for tumorigenesis, the absence of validated predictive biomarkers, and the failure of prior NAMPT-targeting trials. CONCLUSIONS:P7C3 illustrates how phenotypic screening coupled with target deconvolution can yield therapeutic candidates with potential applications across a broad spectrum of neurological disorders.
BACKGROUND:Synaptic loss is a neuropathological feature of depression. OBJECTIVE:Cerebello-cerebral synaptic function was evaluated in female first-episode major depressive disorder (MDD) patients using [18F]UCB-H positron emission tomography (PET). MATERIALS AND METHODS:PET was performed on female first-episode MDD patients (FMD group, n = 7), healthy controls (HC group, n = 9), and chronic restraint stress (CRS) mice (n = 9). Standardized uptake value ratios (SUVR), voxel-wise tracer uptake analysis, functional connectivity (FC), and network analysis were performed at the cerebello-cerebral level. Associations with Hamilton depression scale (HAMD) and Hamilton anxiety scale (HAMA) scores were assessed by Pearson correlation and logistic regression analysis. RESULTS:In the FMD group, SUVR in the left cerebellum 7b was significantly reduced and negatively correlated with HAMD (r = -0.57) and HAMA (r = -0.55) scores. The cluster centered on the left cerebellar lobule VIII showed reduced tracer uptake and was negatively correlated with HAMD scores. FC was significantly reduced in the right frontal lobe but enhanced in the midbrain and occipital regions. The network was characterized by bilateral frontal lobe concentration in the FMD group, while the cerebellar network was more uniform. Cerebello-cerebral uncoupling between the left cerebellum and the right frontal lobe was observed, manifested as reduced SUVR correlation and weakened FC. CRS mice also showed reduced brain [18F]UCB-H uptake. CONCLUSIONS:Left cerebellar-right frontal uncoupling may serve as a potential neural correlate of first-episode MDD in females.
BACKGROUND:Dynamic analysis of resting-state fMRI (rs-fMRI) offers a novel approach to differentiate Parkinson's disease (PD) from progressive supranuclear palsy (PSP) by capturing temporal features of brain network activity, which may shed light on the mechanisms underlying non-motor symptoms. OBJECTIVES:To characterize differences in brain dynamics between PD and PSP using dynamic brain metrics, evaluate their exploratory discriminative performance, and investigate associations with non-motor symptoms. METHODS:Sixty-nine healthy controls, 82 PD patients, and 29 PSP patients underwent standardized clinical assessment and rs-fMRI. Hidden Markov models extracted temporal features including fraction occurrence (FO), dwell time, and transition probability. These metrics were used for group comparisons, correlation analyses, and machine learning classification. RESULTS:PD and PSP showed opposite trends in fraction occurrence of unimodal network-dominant states. Compared to PD and controls, PSP exhibited prolonged duration in the dorsal attention and limbic network (DAN&LIM) state and increased occurrence in the dorsal attention and frontoparietal control network (DAN&FPCN) state. Reduced unimodal state occupancy correlated with cognitive decline in both groups, while increased DAN&LIM and unimodal persistence linked to worse mood and sleep disturbances in PSP. Machine learning with these metrics achieved moderate accuracy in differentiating PD from PSP. CONCLUSIONS:Temporal features of brain network dynamics may provide candidate imaging markers for distinguishing PD and PSP while offering mechanistic insights into non-motor symptomatology. However, their diagnostic applicability requires validation in independent external multicenter cohorts.
BACKGROUND:Branch atheromatous disease (BAD) carries a high risk of early neurological deterioration (END). We evaluated the efficacy of preemptive tirofiban administration within 72 h compared with reactive rescue therapy following END. METHODS:This retrospective, single-center study enrolled 221 patients with BAD-associated stroke. Based on the timing of tirofiban administration, patients were assigned to a preemptive intervention group (n = 127) or a conventional intervention group (n = 94). Preemptive intervention was defined as preemptive administration after clinical risk assessment, whereas conventional intervention was delayed until an increase of ≥ 2 points on the NIHSS score. Inverse probability of treatment weighting (IPTW) was applied to balance baseline covariates. Multivariable regression analysis was performed to identify independent predictors of an excellent 90-day outcome, defined as a modified Rankin Scale (mRS) score ≤ 1. RESULTS:After IPTW adjustment, the preemptive intervention group showed a significantly higher rate of excellent 90-day outcomes (76.6% vs. 44.6%, p < 0.001) and a shorter median hospital stay (10 vs. 11 days, p = 0.02) compared with the conventional group. No between-group differences were observed in mortality or stroke recurrence (p > 0.05). Early tirofiban use (adjusted OR = 4.411, 95% CI: 2.349-8.283) and a lower baseline NIHSS score (adjusted OR = 0.832, 95% CI: 0.707-0.980) independently predicted favorable outcomes. Subgroup analyses confirmed consistent benefits across most strata, with patients aged over 65 years deriving greater neuroprotection (p = 0.004 for age-treatment interaction). CONCLUSION:Preemptive administration of tirofiban within the initial 72 h significantly improves 90-day neurological outcomes and reduces hospital stay length in patients with BAD-related stroke.
AIMS:Melatonin has shown neuroprotective potential in various models of cerebrovascular diseases, but its effects on mitophagy in vascular dementia (VaD) induced by chronic cerebral hypoperfusion (CCH) remain unclear. METHODS:Eighteen adult male Sprague-Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) to induce CCH. Animals were randomly assigned to three groups (n = 6 per group): sham-operated controls, BCCAO model animals receiving vehicle injection, and BCCAO animals treated with daily melatonin (10 mg/kg, intraperitoneally for 14 days). Cognitive performance was evaluated using the Morris water maze. Regional cerebral blood flow (rCBF) was measured with high-resolution laser Doppler imaging. Mitophagy was assessed via Western blot analysis of LC3BII/I, TOMM20, COX IV, caspase-3, and immunofluorescence colocalization of LC3B with TOMM20 in the hippocampal CA1 subfield. RESULTS:BCCAO rats exhibited significant cognitive deficits in the Morris water maze, along with persistently reduced rCBF. BCCAO also induced a significant upregulation of hippocampal mitophagy, as indicated by an elevated LC3BII/I, decreased TOMM20 and COX IV levels, and increased colocalization of TOMM20 and LC3B immunofluorescence signals. Caspase-3 expression was markedly higher in the BCCAO group. Melatonin treatment improved rCBF recovery at day 14, mitigated the spatial learning and memory impairments, decreased the LC3BII/I, increased mitochondrial protein markers (TOMM20, COX IV), reduced the colocalization of TOMM20 and LC3B puncta, and attenuated caspase-3 levels. CONCLUSION:These findings indicate that CCH in the VaD model induces excessive hippocampal mitophagy and cognitive impairment. The cognitive improvement observed with melatonin treatment is closely correlated with restored cerebral perfusion and attenuated mitophagic activity.
AIMS:Absence seizures, characterized by spike-and-wave discharges (SWDs), are mediated by reciprocal thalamocortical interactions; however, the contribution of developing inhibitory networks to SWDs remains unclear. We investigated the developmental trajectory of inhibitory interneurons in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) by analyzing their distribution across postnatal development in the somatosensory (S1) and motor (M1) cortices, the hippocampus, and striatum. METHODS:The neurodevelopmental trajectory of parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons was quantified at three critical stages: postnatal day 14 (P14), when SWDs were not yet observed, P21 when immature SWDs appear, and adulthood (P90), when mature SWDs are established. Wistar rats served as controls. Brain sections were processed immunohistochemically to quantify interneuron density. RESULTS:PV+ interneuron density across S1 and M1 was significantly higher in GAERS at P14 than control. However, this difference was not maintained at P21 and adults. Conversely, SST+ interneurons exhibited a delayed increase in M1. GAERS displayed higher PV+ interneuron density in the dentate gyrus and CA1 at P14, whereas SST+ interneuron density remained unchanged across hippocampal subfields. Striatal PV+ and SST+ interneurons increased at later developmental stages, suggesting altered inhibition in basal ganglia. CONCLUSION:These findings demonstrate a temporally dynamic and region-specific reorganization of interneurons in GAERS that may underlie absence epileptogenesis.
BACKGROUND:Uveal melanoma (UVM) is an aggressive intraocular tumor with limited effective treatments for metastatic disease. This study explored the pathways through which fatty acid-binding protein 5 (FABP5) promoted UVM progression. METHODS:Single-cell RNA sequencing datasets were preprocessed by the Seurat package, and prognostic genes were screened using the survival package. A prognostic model was constructed via LASSO Cox regression, followed by Kaplan-Meier (KM) survival analysis. To characterize the tumor immune microenvironment, we evaluated immune cell infiltration using ssGSEA, ESTIMATE, and CIBERSORT algorithms, while GSEA was applied to identify enriched pathways. Additionally, immunotherapy response was predicted by TIDE, and tumor mutation burden (TMB) was calculated using Maftools. For in vivo validation, a nude mouse xenograft model was established, and Western blotting was performed on tumor tissues harvested from the xenograft assay. RESULTS:SPON2, MATK, and FABP5 were identified as hub genes in UVM and used to construct a prognostic model with a high AUC. Immune infiltration analysis revealed that high-risk patients exhibited features of immune evasion. Enrichment analysis further revealed that cytotoxic T-cell-related genes (MATK and FABP5) were enriched in the PI3K/AKT/mTOR pathway. FABP5 was overexpressed in UVM cells, whereas FABP5 silencing suppressed cell viability, proliferation, migration, and invasion, reduced MMP2 and MMP9 levels, promoted apoptosis, downregulated PI3K/AKT/mTOR pathway-related molecules, and upregulated apoptosis-related proteins. Notably, these effects could be reversed by the PI3K agonist 740Y-P. CONCLUSION:FABP5 promoted UVM cell proliferation and migration through the PI3K/AKT/mTOR pathway. Though the immune-infiltration analysis was hypothesis-generating, it may help identify patients likely to benefit from immunotherapy.
BACKGROUND:Hearing loss primarily results from irreversible cochlear hair cell (HC) damage caused by factors such as noise, aging, genetics, and ototoxic drugs including cisplatin. Currently, there are no effective clinical otoprotective agents available. The natural compound paeonol, derived from Paeonia suffruticosa, exhibits potential anti-inflammatory and antioxidant properties, positioning it as a promising therapeutic candidate given the central roles of oxidative stress and inflammation in hearing loss pathogenesis. METHODS AND RESULTS:Using mouse cochlear explant cultures, we demonstrated that paeonol protects against cisplatin-induced HC damage in a concentration-dependent manner and reduces the accumulation of MitoSOX, TNF-α, and IL-6. In vivo, paeonol administration not only prevented cisplatin-induced HC loss and inner HC synaptic degeneration but also conferred protection against noise-induced HC damage and hearing loss, demonstrating broad otoprotective efficacy. Mechanistically, RNA-seq analysis revealed that paeonol exerts its protective effect partly by preventing ribosome biogenesis dysfunction, thereby ensuring normal protein synthesis in HCs. CONCLUSIONS:Together, our work demonstrates the efficacy of paeonol across multiple models and reveals a potential protective mechanism, paving the way for its development as a much-needed otoprotective drug.
OBJECTIVE:To evaluate the clinical efficacy of dual transcranial direct current stimulation (tDCS) in patients with post-stroke cognitive impairment (PSCI) and to explore the effects on the hierarchical organization of functional brain networks, ranging from regional synchronization to inter-regional connectivity and global network topology. METHODS:In this randomized, double-blind, sham-controlled trial, 74 PSCI patients received conventional therapy alongside either active dual-tDCS (n = 38) or sham stimulation (n = 36). Active tDCS targeted the dorsolateral prefrontal cortex (DLPFC) via anodal-left/cathodal-right nodes (2.0 mA, 20 min/day, 20 sessions). The primary outcome was the Montreal Cognitive Assessment (MoCA). Secondary outcomes included the Mini-Mental Status Examination (MMSE), Stroop Test (ST), Trail Making Test (TMT), Wechsler Memory Scale (WMS), and Barthel Index (BI). A subgroup of 36 participants (18 per group) underwent resting-state functional magnetic resonance imaging (rs-fMRI) to analyze regional homogeneity (ReHo), functional connectivity (FC), and network topology. Partial correlations assessed the association between neuroimaging alterations and clinical improvements. RESULTS:The tDCS group showed significantly greater improvements in MoCA scores (tDCS: 5.74 ± 2.76 vs. sham: 2.69 ± 2.69; t = 4.799, p < 0.001) as well as in attention and memory domains compared to the sham group. The rs-fMRI changes included increased ReHo in the right middle temporal gyrus (MTG) and the left inferior frontal gyrus (IFG), and reduced FC between the right MTG-left superior frontal gyrus and left IFG-cerebellum (p < 0.05, FWE-corrected). Additionally, small-worldness and global efficiency increased (p < 0.05) with these alterations correlating with clinical recovery. Adverse events were rare and self-limiting. CONCLUSION:Dual-tDCS over bilateral DLPFC safely improves cognitive recovery in PSCI. These clinical gains are associated with rs-fMRI alterations, specifically in regional synchronization, inter-regional connectivity, and global topology, which suggest a potential biomarker for monitoring tDCS efficacy, offering a rationale for precision neuromodulation in stroke rehabilitation.
BACKGROUND:Mild cognitive impairment (MCI) is a clinically recognized condition, often being a prodromal dementia state with a risk of further cognitive decline. While there is currently no definitive diagnostic test for MCI, early identification and intervention are important. METHODS:To assist clinicians in the diagnosis and treatment of MCI, the ASian Clinical Expert group on Neurocognitive Disorders (ASCEND) convened to identify ongoing gaps in MCI management primarily in Asia, and to discuss the existing body of literature with a view to providing evidence-based expert recommendations. RESULTS:Two novel algorithms and a set of expert recommendations were formulated, addressing the cognitive assessment and clinical diagnosis of MCI, and optimal MCI management approaches. Because many risk factors for cognitive decline are modifiable, the mainstay of intervention comprises a multi-domain approach involving optimizing metabolic health, mitigating cerebrovascular risk, correcting hearing and vision loss, treating depression, encouraging engagement in cognitive exercises and social connection, and avoiding harmful substances. Digital interventions are becoming increasingly important as tools for cognitive assessment, as well as for cognitive stimulation and to help patients self-manage and maintain their independence. Pharmacologic approaches for MCI management include medical management of cardiovascular risk, reducing cholinergic burden and the use of drugs known to sedate or affect cognitive function, and evidence-based medications that have demonstrated benefit specifically in MCI. CONCLUSIONS:These evidence-based recommendations are intended to support clinicians, particularly in primary care, to identify MCI and plan an intervention strategy to help slow age-related cognitive decline.
INTRODUCTION:The efficacy of awake craniotomy (AC) with intraoperative mapping for glioblastoma (GBM) in eloquent regions remains debated. This study aims to evaluate functional and survival outcomes of GBM patients undergoing AC stratified by tumor locations. METHODS:A combined retrospective (2015-2023, n = 114: 43 AC vs. 71 standard craniotomy) and prospective cohort (2023-2025, n = 28: 13 AC vs. 15 standard craniotomy) of GBM patients with motor/language-eloquent tumors was analyzed. Tumors were classified into motor subtypes (I: precentral gyrus; II: premotor/supplementary motor; III: internal capsule posterior limb; IV: other) and language subtypes (I: Broca's/precentral; II: postcentral/supramarginal gyrus; III: Wernicke's; IV: insular; V: other). Outcomes included extent of resection (EOR), postoperative motor/language recovery, overall survival (OS), and progression-free survival (PFS). RESULTS:The retrospective cohort demonstrated that AC has advantages in functional preservation across various motor/language subtypes. However, AC was associated with significantly deteriorated survival outcomes specifically in precentral gyrus GBMs. A prospective cohort study, enrolling only precentral gyrus GBMs for validation, yielded results consistent with the retrospective findings: worsened OS and PFS (OS: HR = 3.223, p = 0.0450; PFS: HR = 2.374, p = 0.0476); reduced EOR (AC: 74.3% ± 5.3%; standard craniotomy: 86.9% ± 12.3%, p = 0.0470); and better motor recovery. CONCLUSIONS:Functional preservation and survival outcomes of AC in GBM exhibited subtype-specific correlations with tumor locations. AC with intraoperative mapping effectively preserves neurological function in GBM patients. However, for tumors involving the precentral gyrus, the AC approach carries greater risks than benefits and should be considered with caution. TRIAL REGISTRATION:Strategic Intervention on Preserving Motor Function During Awake Craniotomy: NCT05143788. Strategic Intervention on Preserving Language Function During Awake Craniotomy: NCT05143775.
BACKGROUND:Exosomes derived from mesenchymal stem cells (MSCs) and their cargo contribute to the protective properties of MSCs in spinal cord injury (SCI). This study aimed to explore the role of Proteasome 26S subunit non-ATPase 1 (PSMD1), delivered via exosomes derived from dental pulp mesenchymal stem cells (DPMSCs-Exo), in SCI repair. METHODS:Proteomic profiling was conducted to identify proteins enriched in DPMSCs-Exo. M1/M2 microglial polarization was assessed using flow cytometry, immunofluorescence, and western blotting. The apoptotic rates of BV2 microglia and NE-4C neural stem cells were measured by flow cytometry, whereas cell viability was determined using the CCK-8 assay. Western blotting was performed to analyze proteins involved in autophagy and apoptosis. Pro-inflammatory cytokine levels were quantified using ELISA. Additionally, a mouse SCI model treated with DPMSCs-Exo was established to assess therapeutic effects in vivo. RESULTS:DPMSCs-Exo enriched with PSMD1 suppressed M1-associated inflammatory activation, promoted M2 microglial polarization, and suppressed inflammation in BV2 cells following LPS exposure by activating the JAK2/STAT3 pathway. The shift toward an anti-inflammatory microglial phenotype indirectly enhanced survival, reduced apoptosis, and inhibited autophagy in NE-4C neural stem cells. In SCI mice, exosomal PSMD1 improved locomotor recovery, promoted spinal tissue regeneration at the injury site, reduced inflammation and astrocyte activation, and increased M2 microglial polarization. CONCLUSIONS:DPMSCs-Exo carrying PSMD1 suppressed M1-type inflammatory responses while promoting M2 microglial polarization, thereby attenuating inflammation and astrocyte activation and facilitating SCI repair. These findings suggest that DPMSCs-Exo may be a promising therapeutic candidate for the treatment of SCI.
BACKGROUND:Ischemic stroke (IS) is an acute cerebrovascular disease characterized by high morbidity and mortality, with limited current treatment options. Tumor protein p53-inducible nuclear protein 2 (Tp53inp2) is known to be a positive regulator of autophagy under physiological conditions, but the mechanism of Tp53inp2 in IS remains unclear. In this study, we aimed to explore the mechanism of Tp53inp2 in IS. METHODS:Primary neural stem cells (NSCs) were extracted and identified. An OGD/R cell model was constructed. Tp53inp2 was knocked down and rapamycin was added. A middle cerebral artery occlusion (MCAO) animal model was constructed, and then 5 μL of 5 × 105 NSCs, either untreated or transfected with sh-NC or sh-Tp53inp2, were injected. Additionally, at the cellular level, Ptgs2 or Tp53inp2 was overexpressed, and METTL14 was knocked down. RESULTS:Inhibition of Tp53inp2 mitigated OGD/R-induced mitophagy and ROS levels in vitro. Moreover, inhibition of Tp53inp2 mediated neuronal differentiation of OGD/R treated NSCs by suppressing mitophagy. At the animal level, the transplantation of NSCs with a knockdown of Tp53inp2 increased neuronal differentiation, thereby alleviating the effects of MCAO and mitigating cognitive impairments in MCAO model mice. Ptgs2 was further screened and validated as a downstream target mediating the effect of Tp53inp2 on NSCs. At the cellular level, Tp53inp2 alleviated OGD/R-induced mitophagy and ROS levels by regulating Ptgs2 expression. METTL14 could regulate Tp53inp2 expression by modulating the functional m6A modification sites on Tp53inp2 mRNA. Inhibition of METTL14 alleviated OGD/R-induced mitophagy and the rise of ROS levels in NSCs by inhibiting the Tp53inp2/Ptgs2 axis. CONCLUSIONS:Inhibition of METTL14 alleviated OGD/R-induced neuronal differentiation injury in NSCs by inhibiting the Tp53inp2/Ptgs2 axis. By elucidating the mechanisms involving Tp53inp2, Ptgs2, and METTL14, this research offers a foundation for developing new strategies to enhance neuronal differentiation and mitigate cognitive impairments in stroke patients.
INTRODUCTION:Cortical plasticity is essential for functional recovery after peripheral nervous injury (PNI). Different injury types, from compressive to metabolic neuropathies, lead to distinct patterns of cortical reorganization, calling for a better understanding of the mechanisms and treatment options for each injury type. METHODS:This review summarizes current evidence from preclinical, neuroimaging, electrophysiological, and clinical studies on the link between cortical plasticity and PNI. RESULTS:The review describes the key molecular pathways that shape adaptive and maladaptive cortical reorganization across injury types, examines the value of neuroimaging and blood-based biomarkers for tracking plasticity, and evaluates the current evidence for drug and rehabilitation treatments. Major gaps remain, including the limited testing of biomarkers across different injury types, the lack of PNI-specific clinical trials, and the difficulty of applying laboratory findings to personalized treatment. CONCLUSIONS:Moving forward, progress depends on validating biomarkers for each injury type, conducting well-designed trials in PNI patients, and combining drug, rehabilitation, and whole-body treatment approaches. This review offers a practical guide for turning mechanistic knowledge into clinical focus in PNI-related cortical plasticity.
BACKGROUND:In Alzheimer's disease (AD), neurodegeneration is primarily attributed to the accumulation of tau neurofibrillary tangles. However, the distribution patterns of both tau pathology and neurodegeneration vary across different brain regions and among individuals. Moreover, multiple factors may influence the relationship between tau burden and neurodegenerative processes. Identifying the genetic architecture associated with deviation in the tau-neurodegeneration relationship can provide deeper mechanistic insights and guide the development of precision medicine strategies. METHODS:Here, I perform a genome-wide association study (GWAS) of cortical tau and thickness quantified by positron emission tomography (PET) and magnetic resonance imaging (MRI) in 794 participants from two cohorts of Alzheimer's disease Neuroimaging Initiative (ADNI) and A4. RESULTS:A GWAS was identified between the Tau/Neurodegeneration residual and two novel loci on chromosomes 7 and 14, with two SNPs (rs9323573 and rs9784993) exceeding the genome-wide significance threshold (p ≤ 5 × 10-8). SNP rs9323573 is located in STXBP6 on chromosome 14, while rs9784993 is in AKAP9 on chromosome 7, both of which were directly genotyped. The minor allele G of both SNPs (rs9323573, MAF = 0.221, p = 2.60 × 10-8; rs9784993, MAF = 0.197, p = 4.92 × 10-8) was associated with lower Tau/Neurodegeneration residuals, indicating higher-than-expected neurodegeneration given tau levels. CONCLUSION:GWAS of tau-related neurodegeneration identified two novel genetic variants in the loci AKAP9 and STXBP6 leading to higher than expected regional neurodegeneration given the tau level. Identifying genetic factors involved in tau-neurodegeneration mismatch may improve our understanding regarding the potential mechanistic downstream leading to susceptibility or resilience to tau pathology.
AIMS:This study aims to systematically dissect how MYCN amplification shapes the immunosuppressive tumor microenvironment (TME) in high-risk neuroblastoma, elucidating key mechanisms underlying immune evasion. METHODS:We performed an integrated multi-omics analysis of bulk RNA-seq (n = 721), single-cell RNA-seq (n = 9), proteomic data (n = 49) and spatial transcriptomics (Visium, with external validation in melanoma). Analyses included unsupervised clustering, cell-cell communication inference, transcriptional regulatory network reconstruction, and spatial proximity assessment to map the immune landscape. RESULTS:A distinct molecular subtype (Class C), defined by MYCN amplification and poor prognosis, exhibited a comprehensive "immune desert" phenotype characterized by low immune scores and minimal leukocyte infiltration. Single-cell analysis confirmed significant depletion of T and B lymphocytes within the Class C TME. Dysregulated transcriptional networks were identified, including upregulation of REL and EOMES in T cells-with EOMES potentially driving exhaustion via regulation of Transient Receptor Potential (TRP) genes, and REL inhibition enhancing cytotoxic function in vitro. A unique immunosuppressive B-cell subset (B7) engaged in enhanced crosstalk with exhausted T cells and harbored a MYC-centered network linked to cell cycle dysregulation and poor survival. Spatial transcriptomics revealed significant proximity between B7-active regions and Treg/exhaustion-enriched areas, externally validated in melanoma. Proteomic data validated elevated REL expression in MYCN-amplified tumors. CONCLUSION:This work delineates the immunosuppressive architecture of MYCN-driven neuroblastoma, revealing novel regulatory nodes within specific lymphocyte compartments. Integrating single-cell, spatial, and proteomic evidence, we propose REL inhibition as a therapeutic candidate, the EOMES/TRP axis as a bioinformatically supported hypothesis, and the B7/MYC hub as a hypothesis supported by transcriptomic and spatial evidence.
BACKGROUND:Fluoxetine is an established pharmacological intervention for bulimia nervosa (BN); however, the macroscopic functional network remodeling underlying its efficacy in suppressing eating impulsivity remains poorly understood. METHODS:Fifty-eight patients with BN and 58 healthy controls assessed at both baseline and follow-up underwent resting-state functional magnetic resonance imaging (rs-fMRI). Network-Based Statistic (NBS) analysis with edgewise paired comparisons was used to identify whole-brain connectivity changes in patients with BN. The resulting BN-derived component was subsequently examined in both groups using a Group × Time analysis. Exploratory brain-behavior associations within BN were examined using Spearman and partial Spearman correlations. RESULTS:During follow-up, patients with BN showed significant improvements in depressive symptoms and externally driven eating behavior. Within-group NBS analysis identified a 23-edge component showing reduced functional connectivity in BN at follow-up, with network-level family-wise error correction (p < 0.05). This component primarily involved dorsal attention, ventral attention/salience, and somatomotor networks. Whole-brain NBS analysis in healthy controls did not identify a significant longitudinal component. When mean connectivity of the BN-derived component was extracted in both groups, connectivity decreased more strongly in BN than in healthy controls (Group × Time β = -0.053, p = 0.027). CONCLUSIONS:The follow-up period in patients with BN was accompanied by clinical improvement and reduced functional connectivity among attention-, salience-, and sensorimotor-related systems. These findings provide preliminary evidence of treatment-period-associated functional network reconfiguration in BN. TRIAL REGISTRATION:ChiCTR2200066885.
