Changes on Cognition and Brain Network Temporal Variability After Pediatric Neurosurgery.

BACKGROUND AND OBJECTIVES: Pediatric intracranial space-occupying lesions are common, with prognoses improving markedly in recent years, significantly extending survival. As such, there is an imperative to pay increased attention to the postoperative cognitive functions and brain network alterations in these children because these factors significantly influence their quality of life. Temporal variability (TV) analysis of brain networks captures the full extent of resting-state activities, reflecting cognitive functions and rehabilitation potential. However, previous research rarely uses TV analyses and most focus on adults or children after multidisciplinary treatments, not reflecting the combined effect caused by neurosurgery only and self-repair. This study gives our insights into this field from a holistic perspective. METHODS: We studied 35 children with intracranial space-occupying lesions, analyzing pre- and postsurgery MRI and cognitive tests. We used TV analysis to assess changes and correlated imaging indicators with cognitive performance. RESULTS: We observed a tendency for cognitive recovery after about 3 months postsurgery, primarily in the domains of social cognition and nonverbal reasoning. TV analysis of brain networks indicated increased nodal variability within systems such as the visual and sensorimotor networks, which are integral to external interactions. Correlative analysis showed that alterations in certain occipital regions were associated with changes in social cognition and nonverbal reasoning. CONCLUSION: These findings suggest significant intrinsic repair in cognitive functions and brain networks at around 3 months postneurosurgery in children. This study not only enriches our comprehension of postoperative cognitive and brain network self-repair processes in children but also furnishes potential therapeutic targets for rehabilitation interventions and establishes a theoretical foundation for proactive surgical interventions.

Structural and functional changes following brain surgery in pediatric patients with intracranial space-occupying lesions.

We explored the structural and functional changes of the healthy hemisphere of the brain after surgery in children with intracranial space-occupying lesions. We enrolled 32 patients with unilateral intracranial space-occupying lesions for brain imaging and cognitive assessment. Voxel-based morphometry and surface-based morphometry analyses were used to investigate the structural images of the healthy hemisphere. Functional images were analyzed using regional homogeneity, amplitude of low-frequency fluctuations, and fractional-amplitude of low-frequency fluctuations. Voxel-based morphometry and surface-based morphometry analysis used the statistical model built into the CAT 12 toolbox. Paired t-tests were used for functional image and cognitive test scores. For structural image analysis, we used family-wise error correction of peak level (p < 0.05), and for functional image analysis, we use Gaussian random-field theory correction (voxel p < 0.001, cluster p < 0.05). We found an increase in gray matter volume in the healthy hemisphere within six months postoperatively, mainly in the frontal lobe. Regional homogeneity and fractional-amplitude of low-frequency fluctuations also showed greater functional activity in the frontal lobe. The results of cognitive tests showed that psychomotor speed and motor speed decreased significantly after surgery, and reasoning increased significantly after surgery. We concluded that in children with intracranial space-occupying lesions, the healthy hemisphere exhibits compensatory structural and functional effects within six months after surgery. This effect occurs mainly in the frontal lobe and is responsible for some higher cognitive compensation. This may provide some guidance for the rehabilitation of children after brain surgery.

The combined signatures of telomere and immune cell landscape provide a prognostic and therapeutic biomarker in glioma.

Background: Gliomas, the most prevalent primary malignant tumors of the central nervous system in adults, exhibit slow growth in lower-grade gliomas (LGG). However, the majority of LGG cases progress to high-grade gliomas, posing challenges for prognostication. The tumor microenvironment (TME), characterized by telomere-related genes and immune cell infiltration, strongly influences glioma growth and therapeutic response. Therefore, our objective was to develop a Telomere-TME (TM-TME) classifier that integrates telomere-related genes and immune cell landscape to assess prognosis and therapeutic response in glioma. Methods: This study encompassed LGG patients from the TCGA and CCGA databases. TM score and TME score were derived from the expression signatures of telomere-related genes and the presence of immune cells in LGG, respectively. The TM-TME classifier was established by combining TM and TME scores to effectively predict prognosis. Subsequently, we conducted Kaplan-Meier survival estimation, univariate Cox regression analysis, and receiver operating characteristic curves to validate the prognostic prediction capacity of the TM-TME classifier across multiple cohorts. Gene Ontology (GO) analysis, biological processes, and proteomaps were performed to annotate the functional aspects of each subgroup and visualize the cellular signaling pathways. Results: The TM_low+TME_high subgroup exhibited superior prognosis and therapeutic response compared to other subgroups (P<0.001). This finding could be attributed to distinct tumor somatic mutations and cancer cellular signaling pathways. GO analysis indicated that the TM_low+TME_high subgroup is associated with the neuronal system and modulation of chemical synaptic transmission. Conversely, the TM_high+TME_low subgroup showed a strong association with cell cycle and DNA metabolic processes. Furthermore, the classifier significantly differentiated overall survival in the TCGA LGG cohort and served as an independent prognostic factor for LGG patients in both the TCGA cohort (P<0.001) and the CGGA cohort (P<0.001). Conclusion: Overall, our findings underscore the significance of the TM-TME classifier in predicting prognosis and immune therapeutic response in glioma, shedding light on the complex immune landscape within each subgroup. Additionally, our results suggest the potential of integrating risk stratification with precision therapy for LGG.

Single-cell RNA sequencing to track novel perspectives in HSC heterogeneity.

As the importance of cell heterogeneity has begun to be emphasized, single-cell sequencing approaches are rapidly adopted to study cell heterogeneity and cellular evolutionary relationships of various cells, including stem cell populations. The hematopoietic stem and progenitor cell (HSPC) compartment contains HSC hematopoietic stem cells (HSCs) and distinct hematopoietic cells with different abilities to self-renew. These cells perform their own functions to maintain different hematopoietic lineages. Undeniably, single-cell sequencing approaches, including single-cell RNA sequencing (scRNA-seq) technologies, empower more opportunities to study the heterogeneity of normal and pathological HSCs. In this review, we discuss how these scRNA-seq technologies contribute to tracing origin and lineage commitment of HSCs, profiling the bone marrow microenvironment and providing high-resolution dissection of malignant hematopoiesis, leading to exciting new findings in HSC biology.

The adipokine orosomucoid alleviates adipose tissue fibrosis via the AMPK pathway.

The excess deposition of underlying extracellular matrix (ECM) in adipose tissue is defined as adipose tissue fibrosis that is a major contributor to metabolic disorder such as obesity and type 2 diabetes. Anti-fibrosis therapy has received much attention in the treatment of metabolic disorders. Orosomucoid (ORM) is an acute-phase protein mainly produced by liver, which is also an adipokine. In this study, we investigated the effects of ORM on adipose tissue fibrosis and the potential mechanisms. We showed that ORM1-deficient mice exhibited an obese phenotype, manifested by excessive collagen deposition in adipose tissues and elevated expression of ECM regulators such as metalloproteinases (MMP-2, MMP-13, MMP-14) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3). Administration of exogenous ORM (50 mg· kg-1· d-1, ip) for 7 consecutive days in high-fat diet (HFD)-fed mice and leptin receptor (LepR)-deficient db/db mice attenuated these abnormal expressions. Meanwhile, ORM administration stimulated AMP-activated protein kinase (AMPK) phosphorylation and decreased transforming growth factor-ß1 (TGF-ß1) level in adipose tissues of the mice. In TGF-ß1-treated 3T3-L1 fibroblasts, ORM (10 µg/mL) improved the impaired expression profiles of fibrosis-related genes, whereas a selective AMPK inhibitor dorsomorphin (1 µmol/mL) abolished these effects. Together, our results suggest that ORM exerts a direct anti-fibrosis effect in adipose tissue via AMPK activation. ORM is expected to become a novel target for the treatment of adipose tissue fibrosis.

Analysis of the effects of magnetic levitation to simulate microgravity environment on the Arp2/3 complex pathway in macrophage.

With dwindling natural resources on earth, current and future generations will need to explore space to new planets that will require travel under no or varying gravity conditions. Hence, long-term space missions and anticipated impacts on human biology such as changes in immune function are of growing research interest. Here, we reported new findings on mechanisms of immune response to microgravity with a focus on macrophage as a cellular model. We employed a superconducting magnet to generate a simulated microgravity environment and evaluated the effects of simulated microgravity on RAW 264.7 mouse macrophage cell line in three time frames: 8, 24, and 48 h. As study endpoints, we measured cell viability, phagocytosis, and used next-generation sequencing to explore its changing mechanism. Macrophage cell viability and phagocytosis both showed a marked decrease under microgravity. The differentially expressed genes (DEG) were identified in two ways: (1) gravity-dependent DEG, compared µg samples and 1 g samples at each time point; (2) time-dependent DEG, compared time-point samples within the same gravitational field. Through transcriptome analysis and confirmed by molecular biological verification, our findings firstly suggest that microgravity might affect macrophage phagocytosis by targeting Arp2/3 complex involved cytoskeleton synthesis and causing macrophage immune dysfunction. Our findings contribute to an emerging body of scholarship on biological effects of space travel.

Wood-Derived Hybrid Scaffold with Highly Anisotropic Features on Mechanics and Liquid Transport toward Cell Migration and Alignment.

Fantastic structures in nature have inspired much incredible research. Wood, a typical model of anisotropy and hierarchy, has been widely investigated for its mechanical properties and water extraction abilities, although applications in biological areas remain challenging. Delignified wood composite with in situ deposited hydroxyapatite (HAp) and infiltrated polycaprolactone (PCL) is hereby fabricated in an attempt to mimic natural bone. The inherent structure and properties of wood are carefully preserved during the fabrication, showing anisotropic mechanical properties in the radial direction (420 MPa) and longitudinal direction (20 MPa). In addition, it also performs directional liquid transport, effectively inducing the migration and alignment of cells to simulate the uniform seeding behavior of various cells in natural bone. Moreover, the synergistic effect of blended HAp and PCL largely promotes cell proliferation and osteogenic differentiation, providing a promising candidate for bone regeneration materials.

Role of acute-phase protein ORM in a mice model of ischemic stroke.

The only Food and Drug Administration-approved treatment for acute ischemic stroke is tissue plasminogen activator, and the discovery of novel therapeutic targets is critical. Here, we found orosomucoid (ORM), an acute-phase protein mainly produced by the liver, might act as a treatment candidate for an ischemic stroke. The results showed that ORM2 is the dominant subtype in mice normal brain tissue. After middle cerebral artery occlusion (MCAO), the level of ORM2 is significantly increased in the ischemic penumbra compared with the contralateral normal brain tissue, whereas ORM1 knockout did not affect the infarct size. Exogenous ORM could significantly decrease infarct size and neurological deficit score. Inspiringly, the best administration time point was at 4.5 and 6 hr after MCAO. ORM could markedly decrease the Evans blue extravasation, and improve blood-brain barrier-associated proteins expression in the ischemic penumbra of MACO mice and oxygen-glucose deprivation (OGD)-treated bEnd3 cells. Meanwhile, ORM could significantly alleviate inflammation by inhibiting the production of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α), reduce oxidative stress by improving the balance of malondialdehyde (MDA) and superoxide dismutase (SOD), inhibit apoptosis by decreasing caspase-3 activity in ischemic penumbra of MCAO mice and OGD-treated bEnd.3 cells. Because of its protective role at multiple levels, ORM might be a promising therapeutic target for ischemic stroke.

Estrogen weakens muscle endurance via estrogen receptor-p38 MAPK-mediated orosomucoid (ORM) suppression.

Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females.

Protective cerebrovascular effects of hydroxysafflor yellow A (HSYA) on ischemic stroke.

The purpose of the present work was designed to explore protective cerebrovascular effects of hydroxysafflor yellow A (HSYA), and provide preclinical efficacy and mechanism data for its possible application in patients with cerebral ischemia. The protective effect of HSYA on ischemic stroke was evaluated by infarct sizes and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Cerebrovascular permeability was detected by Evans blue dye leakage in MCAO rats. Cerebral blood flow, as well as blood pressure and heart rate were monitored using flow probes in Beagle dogs. Basilar artery tension isolated from Beagle dogs was evaluated with an MPA 2000 data-acquisition system. Coagulation-related function was also judged, including rabbit platelet aggregation by adenosine diphosphate (ADP) and platelet-aggregating factor (PAF), rabbit blood viscosity by a blood viscometer, and thrombus formation by rat arterial-venous shunts. Results showed that HSYA treatment significantly decreased the infarct sizes, neurological scores and cerebrovascular permeability in rats with MCAO. However, cerebral blood flow, blood pressure and heart rate were not affected by HSYA. In vitro, HSYA had a strong effect on cerebrovascular vasodilatation, and significantly decreased platelet aggregation, blood viscosity, and thrombogenesis. Besides well-known anti-coagulation effects, HSYA protects against ischemic stroke by dilating cerebral vessels and improving cerebrovascular permeability.

Microwave-assisted extraction and a new determination method for total steroid saponins from Dioscorea zingiberensis C.H. Wright.

An efficient microwave-assisted extraction (MAE) technique was applied to isolate total steroid saponins from Dioscorea zingiberensis C.H. Wright (DZW). The optimal extracting conditions were established as 75% ethanol as solvent, ratio of solid/liquid 1:20 (g/ml), temperature 75 °C, irradiation power 600 W and three extraction cycles of 6 min each. Scanning electron microscopy (SEM) images of DZW processed by four different extractions provided visual evidence of the disruption effect on DZW. Diosgenin was quantified by HPLC and examined further by LC-ESI/MS after acid hydrolysis. Total steroid saponins were calculated using diosgenin from total steroid saponins. The MAE procedure was optimized, validated and compared with other conventional extraction processes. This report provides a convenient technology for the extraction and quantification of total saponins of DZW combining MAE with HPLC and LC-ESI/MS for the first time.