Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer's disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle-vascular-brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.
The Brain-Heart axis regulates cardiovascular and cerebral function through bidirectional neural communication, integrating autonomic reflexes such as respiratory sinus arrhythmia and postural blood pressure regulation. Despite a growing body of literature, the quantitative dynamics of Brain-Heart interplay (BHI) underlying respiratory and baroreflex-mediated changes to postural challenges remain incompletely understood. This study aims to elucidate this relationship by investigating postural and controlled respiratory changes. Seventeen healthy volunteers (average age: 22 ± 1.83 years) participated in the study, performing a 5-minute resting state in both supine and upright positions, with breathing patterns categorized as either spontaneous or slow-paced (6 cycles/min). Throughout the experiment, we recorded high-density electroencephalography (EEG), arterial blood pressure, and electrocardiogram signals to derive RR interval series and calculate baroreflex sensitivity (BRS). Results indicate that postural changes reduced the power of EEG delta (δ) oscillations and cardiac vagal activity while enhancing EEG beta (β) and gamma (γ) oscillations and increasing diastolic blood pressure. Slow-paced breathing amplified EEG beta (β) and gamma (γ) oscillations but reduced sympathovagal activity. Finally, the upright position enhanced bidirectional BHI information transfer while weakening the functional coupling between BRS and BHI. In contrast to slow-paced breathing, spontaneous breathing is characterized by negative heart-brain correlations in both the high- and low-frequency bands across all EEG spectral bands. These findings underscore the contributions of respiratory sinus arrhythmia and baroreflex-mediated cardiovascular regulation to BHI, demonstrating that both postural and respiratory changes influence BHI directionality and autonomic cardiovascular regulation.
The gut-brain axis (GBA) plays a critical role in regulating neurocognitive and gastrointestinal functions through integrated neuronal, immune, endocrine, and microbial pathways. Estrogen deficiency causes gut dysbiosis and associated GBA dysfunction. Strategies that may modulate GBA dysfunction in the postmenopausal phase need to be explored. Our present research aimed to examine the synergistic effect of soy isoflavone (SIF) and fructooligosaccharide (FOS) in combination on GBA dysfunction in an estrogen-deprived rat model. To induce similar postmenopausal complications, female SD rats were bilaterally ovariectomized (OVX) and were orally administered a combination of FOS (50 mg/kg) & SIF (40 mg/kg) and 17β-estradiol (10 μg/kg) for 28 days. At the end, the uterus, hippocampus, & proximal colon health was measured. Co-supplementation of FOS with SIF in estrogen-deprived rats synergistically improves body weight, neurobehavior, brain-derived neurotrophic factor levels, and monoamine neurotransmission. We also observed marked restoration of oxidative stress, inflammation, and apoptosis in the hippocampus and colon. With this, we also observed restoration of gut health as indicated by increased mucosal layer integrity, promoting tight junction (TJ) genes, and rebalancing the gut microbiome (GM). The combination approach also selectively activates ER-β expression in the hippocampus without affecting serum estradiol levels & uterine weight. Collectively, the combination approach acts as a selective estrogen receptor modulator and improves GBA functioning. Thus, the combination approach may attenuate GBA dysfunction in estrogen-deprived rats by selectively activating the ER-β receptor and modulating oxidative stress, inflammation, and apoptosis while preserving the mucosal layer, TJ genes, and GM.
There is a growing number of research suggesting that there is an association between gut microbiota and central nervous system (CNS) tumor. However, the causal relationships and the mediation effects of inflammatory proteins in the associations are unclear. We extracted genetic variants associated with gut microbiota, inflammatory proteins, and 4 subtypes of CNS tumors from published genome-wide association studies and performed a Mendelian randomization analysis to identify potential causal effects. The inverse variance weighted method was used as the main method. Mediation analysis and single-cell RNA-seq analysis were performed to explore the mediation effects and the expression in cells. This study identified 73 gut microbial taxa and 11 inflammatory proteins that were significantly associated with CNS tumors. The inflammatory proteins may act as intermediate mediators in the potential causal association between gut microbiota and 4 CNS tumor subtypes. Mediation analysis suggested that CX3CL1 may partially mediate the relationship between gut microbiota and Glioblastoma, while Eotaxin, CSF-1, IL-15RA and the other 5 cytokines may serve as subtype-specific potential mediators for the remaining 3 tumor types. Our research supports a hypothesized "gut-immune-brain" axis that may mediate the effects of gut microbiota on different CNS tumor subtypes, with distinct immune proteins implicated for each. These findings strongly suggest potential targets for microbiome therapy and immune therapy, though the underlying mechanistic links require experimental validation.
The identification of quantitative non-invasive imaging biomarkers, including radiomics, may complement molecular characterization and thereby improve clinical management of neuro-oncological patients. We aimed to identify imaging predictors with improved performance over clinical parameters to stratify patients with brain metastases into high and low-risk groups for overall survival (OS). 422 patients recruited by two neuro-oncological centers were included with first diagnosis of brain metastases from different primary tumors. From each patient, 15 clinical parameters and a total of 321 radiomic features extracted from cerebral MRI were employed in prediction models to classify patients into low- and high-risk groups for OS. The best performing model was a bootstrap aggregating model including only clinical features (test set: macro F-1 = 0.62, accuracy = 0.72), while the combined and radiomic datasets led to poorer results (test set: macro F-1 = 0.60, accuracy = 0.67; test set: macro F-1 = 0.62, accuracy = 0.52, respectively). However, in the subgroup of melanoma patients (n = 54), the radiomic dataset showed better predictive power over clinical and combined dataset (test set: macro F-1 score = 0.71, accuracy = 0.77). 80% and 67% of melanoma patients were correctly classified into the low- and the high-risk group for OS, respectively. Clinical features remained the strongest predictors of risk across patients with brain metastases from different primary tumors. Although, in melanoma patients, radiomic features provided better prediction of the survival outcome compared to clinical parameters alone.
Leptomeningeal disease (LMD) is a devastating complication of metastatic breast cancer that leads to severe neurologic symptoms and a poor prognosis. Current treatment options, including radiation and intrathecal chemotherapy, offer limited efficacy and are associated with significant toxicity. Generally, systemic therapy in LMD poorly penetrates the blood-brain barrier (BBB). Leveraging the L-type amino acid transporter 1 (LAT1) represents a unique therapeutic strategy, as LAT1 facilitates transport of medications across the BBB, and is also highly expressed in metastatic cancer cells. QBS72S is a first-in-class BBB-penetrant bifunctional molecule targeting overexpression of LAT1 to selectively eliminate cancer cells. It has shown preclinical efficacy in a mouse model of breast cancer LMD. This Phase 2a, single-arm, open-label clinical trial (NCT05305365) investigated the safety, cerebrospinal fluid (CSF) concentration, pharmacokinetics, and preliminary efficacy of QBS72S in participants with breast cancer brain metastases. Secondary endpoints included progression-free survival, overall survival, and duration of response. Correlative analyses included LAT1 immunohistochemistry and CSF cell-free RNA sequencing. In this analysis, we report results from breast cancer patients with LMD (n = 10) treated with QBS72S. QBS72S was reliably detected in CSF, adequately tolerated, and two participants exhibited long-term radiographic stability or improvement lasting 6-7 months. These early findings support further investigation of QBS72S as a targeted therapy for LMD, addressing an urgent unmet need in metastatic breast cancer. Leptomeningeal metastases (LMD) are a deadly complication of breast cancer, where cancer cells travel to the brain’s covering and the spinal fluid. Most chemotherapy does not enter the brain or spinal fluid. LAT-1 is a protein that helps molecules enter the brain and spinal fluid. Breast cancer cells in the brain have high LAT-1 levels. We studied a new chemotherapy, QBS72S, that uses LAT-1 to enter the brain and spinal fluid. Some patients felt better and lived longer while getting QBS72S. We also showed LAT-1 levels can be detected in the spinal fluid. Our research suggests QBS72S should be studied more in patients with breast cancer LMD.
Large-scale imaging of multiple dynamic behaviors and quantitative neurochemical concentrations with high spatiotemporal resolution is essential for understanding complex brain functions. Two-photon microscopy (TPM) is ideally suited for in vivo brain function imaging because of its high resolution and deep tissue penetration. However, conventional TPM is limited by a restricted field-of-view (FOV), an inherent trade-off between the imaging area and temporal resolution, and an insufficient amount of information obtained using only intensity recording. Here, we propose large-FOV, dual-region, two-photon fluorescence lifetime imaging microscopy (LD-2P-FLIM) for multiparameter and quantitative brain function imaging, with a 3 × 3 mm2 FOV, a uniform lateral resolution of 0.7 μm, and a FLIM throughput of up to 15.73 megapixels/s (512 × 512 pixels, 30 Hz, two regions). We extend the FOV by breaking the limit of commercial objectives with an effective adaptive optics strategy. To alleviate the trade-off between the imaging area and temporal resolution, we use a temporal multiplexing system that enables simultaneous and flexible two-region imaging across the large FOV. Furthermore, we develop a field programmable gate array module to demultiplex fluorescence signals from different regions and perform high-throughput, two-region FLIM. We demonstrate the superior performance of LD-2P-FLIM by simultaneous monitoring of neural activities across multiple cortical areas, synchronous recording of neurovascular coupling under both physiological and pathological conditions, long-term observation of the microglial response to local neuron injury, and quantitative imaging of calcium concentrations across a large neuronal population in vivo.
To compare motor recovery in children with severe traumatic brain injury (TBI) with findings from functional and imaging diagnostic techniques based on the age-dependent theory of motor development. The study included 43 children (26 boys and 17 girls), aged 5 to 17 years, with severe TBI who underwent rehabilitation at the Department of Rehabilitation of the Research Institute of Emergency Pediatric Surgery and Traumatology (Dr. Roshal Clinic) from 2023 to 2024. The clinical evaluation used the Muscle Strength Scale, the Modified Ashworth Scale, and a classification system for gross motor function. Instrumental assessments of the anatomical and functional state of the corticospinal tract (CST) included diagnostic single-pulse transcranial magnetic stimulation (sTMS) and magnetic resonance (MR) tractography, which analyzed corticomotor neuronal pathways originating from the primary motor cortex (PMC) and supplementary motor area. Improvement in motor deficits during both intermediate and long-term phases post-injury was associated with a reduction in the threshold for motor evoked responses (MER) (AUCs of 0.583 and 0.548, respectively) and an increase in MER amplitude (AUCs of 0.5 and 0.508, respectively). A significant correlation was noted between the deviation of the MER threshold from reference values and the patient's age at the time of injury, with deviations of 9.27% for ages 6-12 years and 26.1% for ages 12-18 years (p<0.05). Additionally, an increase in the fractional anisotropy coefficient of CST was observed in children with various degrees of motor impairment following severe TBI within the first-year post-trauma. The findings suggest that instrumental diagnostic methods can effectively assess the severity of motor deficits in children with severe TBI and diminished consciousness. The interpretation of these results should incorporate the age-dependent theory of locomotor behavior development. Сопоставить клиническое восстановление моторной функции у детей с черепно-мозговой травмой (ЧМТ) тяжелой степени с результатами функциональных и лучевых методов исследования с учетом возрастзависимой теории формирования двигательного поведения. В исследование включены 43 ребенка (26 мальчиков и 17 девочек) в возрасте от 5 до 17 лет с ЧМТ тяжелой степени, проходивших реабилитацию на базе отделения восстановительного лечения НИИ «НДХиТ — Клиника доктора Рошаля» в период 2023—2024 гг. Оценка клинического статуса проводилась с использованием шкалы оценки мышечной силы, модифицированной шкалы оценки спастичности Эшворта и системы классификации больших моторных функций. Инструментальные методы оценки анатомо-функционального состояния кортикоспинального тракта (КСТ) включали диагностическую одностимульную транскраниальную магнитную стимуляцию (ос ТМС) и магнитно-резонансную (МР) трактографию кортико-мотонейрональных проекций от первичной моторной коры (ПМК) и дополнительной моторной зоны. Регрессу моторного дефицита в промежуточном и отдаленном периодах болезни сопутствовали снижение порога вызванного моторного ответа (ВМО) (AUC 0,583 и 0,548) и увеличение его амплитуды (AUC 0,5 и 0,508). Установлена взаимосвязь между отклонением порога ВМО от нормативных значений и возрастом ребенка на момент повреждающего события (9,27% в возрасте 6—12 лет и 26,1% в возрасте 12—18 лет, (p<0,05)). Выявлено повышение коэффициента фракционной анизотропии КСТ у детей с разной степенью выраженности моторного дефицита после ЧМТ тяжелой степени в течение 1-го года болезни. Полученные данные указывают на возможность объективизации степени выраженности моторного дефицита у детей с ЧМТ тяжелой степени и сниженным уровнем сознания инструментальными методами диагностики. Интерпретацию результатов исследования необходимо проводить с учетом возрастзависимой теории формирования локомоторного акта.
Effective intraoperative speech mapping requires specific test with standardized linguistic material. The last one should capture speech function supported by brain region targeted for resection. It is necessary to develop a test tailored to specific patient's needs and document intraoperative linguistic support. The objective of this report was to describe the procedure of intraoperative speech testing and battery of intraoperative tests for Russian language. We correlated intraoperative tests with brain regions and speech functions, as well as presented an application for intraoperative linguistic testing. Для эффективного проведения процедуры интраоперационного картирования речи важно подобрать специфический речевой тест со стандартизированным лингвистическим материалом, чтобы он вовлекал непосредственно речевую функцию, которую обеспечивает участок мозга, находящийся в зоне резекции. Необходимо подготовить тест с учетом особенностей конкретного пациента и протоколировать проведение лингвистического интраоперационного сопровождения. Описать процедуру проведения речевого интраоперационного тестирования, представить батарею разработанных интраоперационных тестов для русского языка, соотнести интраоперационные тесты с зонами головного мозга и вовлекаемыми речевыми функциями и представить приложение, разработанное для проведения лингвистического интраоперационного тестирования.
Electroencephalography (EEG) research systematically excludes participants with textured hair, limiting generalizability. While inclusive hardware offers a solution, it remains unvalidated in dynamic settings. This study bridges this ecological gap by determining if equitable data quality is achievable across racial groups during a complex Mobile Brain/Body Imaging (MoBI) paradigm. We recruited 17 older adults from racially and ethnically underrepresented groups (REUG) and 17 age-and-sex-matched White older adults. Participants completed an auditory oddball task while sitting and during active standing. EEG was recorded using a dry-brush-electrode system paired with culturally sensitive procedures. The primary outcome was event-related potential (ERP) data quality, quantified using the Standardized Measurement Error (SME) for P3 amplitude and latency. Total data loss was comparable between White (8.29%) and REUG participants (9.88%), with no group differences (p = 0.91) or group×condition interactions (p = 0.82). We found no significant main effects of group or group-by-condition interactions on any SME measure (all p > 0.05), and equivalence testing confirmed that SME for P3 amplitude and latency was statistically equivalent in 16 of 18 stimulus × postural comparisons. A sensitivity analysis restricting the REUG group to participants with textured hair (REUG-T, n = 9) yielded a near-identical pattern (15 of 18 comparisons). Signal‑to‑noise ratio at Fz for frequent stimuli increased from sitting to standing (F = 10.33, p = 0.002, adjusted p = 0.036). Behavioral performance was similar across groups. This study provides the first evidence that equitable ERP data quality is achievable across racial groups during active MoBI by combining inclusive hardware with culturally sensitive protocols. These findings confirm that the technological incompatibility underlying historical underrepresentation is surmountable when paired with culturally sensitive protocols, enabling more inclusive and generalizable cognitive neuroscience.
Tuberculous meningitis (TBM), caused by Mycobacterium tuberculosis, is the most severe form of extrapulmonary tuberculosis and isassociated with high morbidity and mortality, particularly when diagnosis is delayed. Improved understanding of the metabolic alterations associated withTBM may support the development of novel diagnostic biomarkers and provide insights into disease pathophysiology. In this study, we applied anuntargeted two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOFMS) metabolomics approach to formalin-fixed, paraffin-embedded (FFPE) postmortem human brain tissue from 41 TBM cases and 36 tissue sections from 6 non-TBM control cases. Metabolomics data wereprocessed, normalized, and analyzed using multivariate and univariate statistical approaches, including principal component analysis (PCA) and partialleast squares-discriminant analysis (PLS-DA), with variable importance in projection (VIP) scores. These results were further correlated with patient clinical data. Distinct metabolic profiles were observed between TBM and control tissues. Several metabolites were significantly reduced in TBM samples, particularly within the alkane and alkene classes, with additional decreases observed in metabolites associated with alcohols, fatty acids, lipids, carbohydrates, and amino acids. These metabolic alterations suggest substantial perturbations, primarily in the host lysine degradation pathway (linked to the kynurenine pathway), in TBM-affected brain tissue. Collectively, these findings provide insight into the metabolic landscape of terminalTBM and suggest potential metabolic pathways that may contribute to disease pathophysiology. Further investigation of these metabolic signatures in accessible patient tissue and biofluids may support the development of biomarkers and inform future therapeutic strategies for TBM.
In the US, deep brain stimulation (DBS) is accessible to pediatric patients with dystonia who are 7 years of age and older through an FDA Humanitarian Device Exemption (HDE). The aim of this study was to assess the safety, feasibility, and outcomes of DBS for dystonia in children younger than 7 years of age who are excluded from the FDA HDE. Data were collected (February 2015-December 2025) through The Child & Youth Comprehensive Longitudinal Database for DBS, which is a prospective registry of pediatric DBS from 5 tertiary pediatric hospitals in North America. Participants younger than 7 years of age who underwent DBS targeting the globus pallidus internus for the treatment of dystonia were included. Demographics, operative details, and postoperative outcomes and complications were analyzed. Twelve children underwent 14 DBS-related surgeries, with a mean follow-up duration of 2.66 years (range 0.50-10.85 years). The mean age at the time of surgery was 4.72 years (range 2.96-6.83 years), and the mean weight was 16.5 kg (range 9.3-30.8 kg). Half of the children had prior ICU admissions for status dystonicus, and 9 DBS surgeries (64.3%) were performed urgently. Three children had transgression of stereotactic frame pins beyond the inner table of the skull, while 4 other children had wound complications requiring surgical intervention. No patients experienced neurological sequelae, and those requiring explantation of infected hardware were reimplanted successfully once the infections were treated. Overall, there was a mean reduction of 40.1% in the Burke-Fahn-Marsden movement subscale at 6 months postoperatively (p < 0.05), which persisted to 12 months. Three children died due to underlying conditions > 6 months from their respective surgeries. DBS had demonstrable benefits in children younger than 7 years of age with severe refractory dystonia, albeit with higher surgical risks compared with older children. Further research is warranted to better inform treatment decisions and regulatory oversight.
Studies on VEGF responses to brain stimulation (BS) are inconsistent. We systematically reviewed and meta-analyzed these data. Overall meta-analyses for the three main models (time, group, time×group) showed no significant effects (p>0.05). Given the high heterogeneity across interventions and populations, we conducted extensive exploratory subgroup analyses to generate hypotheses. These revealed several within-subgroup effects, but they were based on limited data constraining their interpretability, with several single studies and others on 2-4 observations. For time-difference analyses, higher post-BS VEGF emerged in older rTMS patients (k=4, g=2.14), responders (k=3, g=0.58), and remitters (k=2, g=0.56), but not in other subgroups. Group-difference analyses showed higher post-BS VEGF in tDCS (k=1, g=1.01) and DBS (k=1, g=6.03) groups vs. controls; at baseline, non-responders had lower VEGF than controls (k=3, g=-0.31). Time×group analyses favored rTMS over non-rTMS (k=3, g=1.95), responders over non-responders (k=4, g=0.54), and remitters over non-remitters (k=3, g=0.72). Meta-regression (k=19) identified age as a major variability source (β=1.12, R²=88.9%). HCA ranked the top eight VEGF correlates: PANSS, MADRS, HDRS/HAM-D, HAMA, treatment outcome, age, SHAPS, and BPRS-5. These significant subgroup findings derive from post-hoc exploratory analyses with small sample sizes and should not be interpreted as confirmatory. We provide an early meta-analytical framework, but the small number of observations per BS technique, psychiatric condition, and timepoint precludes definitive conclusions. Future updates with larger, more homogenous datasets are essential to rigorously test whether VEGF can serve as a reliable biomarker of differential BS responses. These exploratory results are hypothesis-generating and require confirmation in future studies.
Synapse formation and function are coordinated spatially and temporally by a host of synaptic proteins that regulate neuronal signaling, synapse specificity, and plasticity, many of which are implicated in neuropsychiatric disorders. Many members of the C1q/TNF superfamily function as synaptic organizers, shaping synapse assembly and maintenance. Among them, C1QL3 plays a putative role in trans-synaptic adhesion and modulation of synaptic strength, but the lack of a reliable antibody to detect it has severely limited the ability to map its endogenous localization and study its biochemical properties. Here, we present a novel epitope-tagged knock-in mouse line (C1ql32HA), in which two hemagglutinin (HA) epitopes were inserted near the N-terminus of the endogenous C1QL3 protein. This model enables purification, detection, and subcellular localization of native C1QL3 protein (C1QL3-2HA) with high specificity, eliminating the need for overexpression or custom antibodies. We validated that C1ql32HA mice maintain normal mRNA expression, biochemical properties, and behavior. Using native PAGE, we determined the endogenous oligomeric state of C1QL3-2HA. Brain-wide light-sheet microscopy uncovered an expanded neuroanatomical map of C1QL3-2HA expression, including newly identified populations in cortical and subcortical regions as well as the retina. Dual immunohistochemistry confirmed cell-type-specific expression patterns, and super-resolution STED microscopy localized C1QL3-2HA to hippocampal mossy fiber synapses, positioned between pre- and postsynaptic markers, supporting its hypothesized role in trans-synaptic complexes. This knock-in mouse line is a valuable tool for studying the anatomical, molecular, and synaptic biology of C1QL3 in all cellular/tissue contexts, enabling future studies into its potential roles in the nervous system and beyond.
Brain natriuretic peptide (BNP) and global longitudinal strain (GLS) are emerging biomarkers used to risk-stratify patients with asymptomatic severe aortic regurgitation (AR) and preserved ejection fraction (EF). Although numerous clinical trials have investigated the efficacy of these biomarkers in patients with aortic stenosis, only a limited number have examined these biomarkers in patients with AR. Therefore, the proposed systematic review and meta-analysis seeks to assess the prognostic value of BNP and/or GLS in patients with severe asymptomatic AR and preserved EF. This is a protocol for a systematic review and meta-analysis that will aggregate and synthesize high-quality clinical data on the usefulness of BNP and GLS as prognostic indicators for asymptomatic severe AR with preserved EF. By providing a comprehensive review, our study will have a significant impact in determining surgical candidacy in this patient population. In accordance with the PRISMA-S (Preferred Reporting Items for Systematic reviews and Meta-Analyses literature search extension), which is an extension of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement for reporting literature searches in systematic reviews, a comprehensive search of databases, including PubMed, Cochrane, and Embase, will be performed to retrieve peer-reviewed, English-language, observational, and experimental studies published from inception to November 2024. Studies that investigated patients aged ≥18 years with severe AR and preserved EF will be included. The National Heart, Lung, and Blood Institute tool will be used to assess the quality of the studies. Search strategy development for this systematic review began in November 2024. A Peer Review of Electronic Search Strategies review of the search strategy with 2 academic librarians occurred in December 2024, and the final search strategy was finalized by the team of investigators in January 2025. Database queries and screening of studies began in January 2025 with title screening, followed by abstract screening in January and February 2025. Full-text screening took place from February to April 2025. Data extraction occurred between April and May 2025. Synthesis and risk of bias assessment occurred between April and May 2026, followed by data analysis between June and July 2026. Manuscript drafting will begin between June 2026 and July 2026, with manuscript writing and data dissemination continuing from May 2026 to August 2026. Findings will be submitted to a peer-reviewed journal by August 2026. This systematic review will synthesize the existing evidence to determine the prognostic value of BNP and GLS in patients with asymptomatic severe AR and preserved EF, which could inform future clinical guidelines for the management of this population.
Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
THAP domain-containing protein 6 (THAP6) is a member of the THAP family and contains a conserved THAP zinc-finger domain, allowing it to regulate gene expression as a transcription factor. Previous studies have shown that THAP6 may be involved in macrophage activation and transcriptional regulation related to social stimuli; however, whether THAP6 affects emotional behavior and brain tissue structure has not yet been reported. This study aims to clarify the effects of Thap6 gene deletion on emotional behaviors in mice, preliminarily explore the effects of Thap6 gene knockout on mouse brain tissue, and provide experimental evidence for revealing the potential role of THAP6 in neuropsychiatric disorders. A whole-body Thap6 knockout mouse model was generated using CRISPR/Cas9 technology. Genotyping was performed to select heterozygous Thap6 knockout (Thap6+/-; n=8) and wild-type (WT; n=10) male C57BL/6J mice as study subjects. After the mice reached adulthood, motor and balance abilities were assessed using the rotarod test; general locomotor activity and exploratory ability were evaluated using the open-field test; depression-like behaviors were assessed using the sucrose preference test and tail suspension test; anxiety-like behavior was evaluated using the elevated plus-maze test; and social behavior was assessed using the three-chamber social test. After behavioral assessments, mouse brain tissues were collected, and hematoxylin and eosin (HE) staining and Nissl staining were used to observe changes in brain microstructure and neuronal number. Behavioral results showed that, compared with WT mice, Thap6+/- mice had a significantly lower percentage of entries into the open arms in the elevated plus maze test (t=2.516, P=0.024) and a significantly higher average movement speed in the open arms (t=3.045, P=0.013). In the three-chamber social test, the sociability index (t=4.350, P<0.001) and social preference index (t=2.732, P=0.014) of Thap6+/- mice were significantly lower than those of WT mice. No statistically significant differences were observed between the 2 groups in other behavioral indicators (all P>0.05). HE staining of brain tissues showed scattered abnormal cell morphology, loose cytoplasm, and blurred nuclei in the cortex of Thap6⁺/⁻ mice; loosely arranged neurons, enlarged intercellular spaces, and extensive vacuole formation in the amygdala; disordered arrangement of cerebellar Purkinje cells, unclear boundaries, swelling and dissolution of some nuclei, and cell loss; and loss of neuronal nucleoli and partial cellular pyknosis in the substantia nigra. In the hippocampus of Thap6⁺/⁻ mice, neurons were orderly arranged, with relatively good cell morphology, a larger number of cells, and compact arrangement. Nissl staining showed that the number of neurons in the hippocampal dentate gyrus region was significantly increased in Thap6⁺/⁻ mice (U=0, P=0.029), whereas morphological abnormalities and reduced neuronal numbers were observed in the cortex, amygdala, cerebellum, and substantia nigra (all U=0, P=0.029). Thap6 gene knockout leads to anxiety-like behavior and social behavioral deficits in mice. It also causes structural abnormalities and reductions in neuronal number across multiple brain regions. This study systematically reveals, for the first time, the important role of THAP6 in the regulation of emotional and social behaviors, provides new evidence for understanding the functional differentiation of THAP family proteins in the central nervous system, and suggests that Thap6 knockout mice may serve as a novel animal model for studying neuropsychiatric disorders related to anxiety and social deficits. 目的: THAP结构域蛋白6(THAP domain-containing protein 6，THAP6)是THAP家族成员之一，含保守的THAP锌指结构域，可作为转录因子调控基因表达。既往研究表明THAP6可能参与巨噬细胞激活及社会刺激相关的转录调控，但THAP6是否影响情绪和社交行为及脑组织结构，目前未见报道。本研究旨在明确Thap6基因缺失对小鼠情绪和社交行为的影响，初步探讨Thap6基因敲除对小鼠脑组织的影响，为揭示THAP6在神经精神疾病中的潜在作用提供实验依据。方法: 采用CRISPR/Cas9技术构建Thap6基因全身敲除小鼠模型，通过基因型鉴定筛选Thap6基因敲除杂合子(Thap6+/-，n=8)和野生型(wild-type，WT;n=10)C57BL/6J雄性小鼠作为研究对象。在小鼠成年后，采用转棒实验评估运动和平衡能力，采用旷场实验评估一般活动性和探索能力，采用糖水偏好实验和悬尾实验评估抑郁样行为，采用高架十字迷宫实验评估焦虑样行为，采用三箱社交实验评估社交行为。在行为评估结束后，收集小鼠脑组织，采用苏木精-伊红(hematoxylin and eosin，HE)染色和尼氏染色观察脑组织微结构和神经元数量的改变情况。结果: 行为学结果显示，与WT小鼠相比，Thap6+/-小鼠在高架十字迷宫中进入开放臂的次数百分比显著降低(t=2.516，P=0.024)、在开放臂中的平均运动速度显著增快(t=3.045，P=0.013);在三箱社交实验中，Thap6+/-小鼠的社交能力指数 (t=4.350，P<0.001)和社交偏好指数(t=2.732，P=0.014)均显著低于WT组;其他行为实验各指标2组间的差异均无统计学意义(均P>0.05)。脑组织HE染色结果显示，Thap6+/-小鼠皮质散在细胞形态异常、细胞质疏松、细胞核模糊;杏仁核神经元排列松散、细胞间隔增大、大量空泡形成;小脑浦肯野细胞排列不齐、边界不清、部分细胞核肿胀溶解、细胞缺失;黑质神经元核仁丢失、部分细胞固缩;Thap6+/-组小鼠海马神经元排列有序，细胞形态较好，数目较多，排列紧密。尼氏染色结果显示，Thap6+/-小鼠海马齿状回区域神经元数量显著增多(U=0，P=0.029)，皮质、杏仁核、小脑、黑质4个脑区均出现形态异常和神经元数量减少(均U=0，P=0.029)。结论: Thap6基因敲除导致小鼠焦虑样行为和社交行为缺陷，同时导致小鼠多个脑区脑结构异常和神经元数量减少。本研究首次系统揭示了THAP6在情绪与社交行为调控中的重要作用，为理解THAP家族蛋白在中枢神经系统中的功能分化提供了新证据，并提示Thap6基因敲除小鼠可能作为研究焦虑和社交障碍相关神经精神疾病的新型动物模型。.
Sleep loss is a public health concern requiring widely accessible cost-effective interventions to counteract the cognitive and brain health impairments caused by it. Sleep loss impairs the brain's capacity to form new episodic memories, which is critical for everyday cognition, future planning, and decision-making. In this study, we compared the protective effect of a 20-min exercise and a 90-min nap against a no-intervention control condition on the capacity to encode episodic memory after 30 h of uninterrupted wakefulness and examined underlying neural mechanisms using electroencephalography. Both exercise and nap preserved episodic memory after sleep loss, with an average of 22% higher memory performance than the control condition. Electroencephalography revealed distinct neural mechanisms within the intervention groups, which significantly contributed to memory performance. After napping, the brain-state markers of neural fatigue and sleep pressure determined memory performance more than episodic memory markers and after exercise, only episodic memory markers significantly contributed to memory performance. In contrast, in the control group, none of these markers explained memory performance. Instead, those markers were associated with fatigue, suggesting compensatory neural efforts. Consistent with the principle of neural degeneracy, in which different brain mechanisms can yield similar outcomes, after sleep loss exercise facilitates efficient neural processing while napping makes the brain state conducive to new learning. These results warrant implementation studies within safety-critical occupations such as healthcare, shiftwork, mining, and transportation, where implementing sleep hygiene recommendations to counteract sleep loss is not effective or practical, but preserving brain and cognitive health is of global importance.