Human Brain Research Articles

Repetitive transcranial magnetic stimulation enhanced by neuronavigation in the treatment of depressive disorder and schizophrenia

This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment. Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability. Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting. This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders. This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.

Paracetamol overdose associated with cortical blindness-complicated acute leukoencephalopathy: a case report

Abstract Background Paracetamol is one of the most used antipyretics and analgesics among pediatrics, and its overdose is highly encountered among pediatrics especially in the pre-school age. While it is well-known that paracetamol overdose may lead to toxicities including severe hepatic toxicity, some recent reports have highlighted its “in situ” toxicity on brain tissue at high doses, even in the absence of hepatotoxicity. This can result in acute leukoencephalopathy (AL), coma, or even death. This report describes a case of a child who developed cortical blindness-complicated AL, following a paracetamol overdose. Case presentation An 18-month-old previously healthy girl accidentally ingested 300 mg/kg of paracetamol suspension. After ingestion, the child was in an initial bad condition that has gradually improved. Several days after ingestion, the patient lost her vision, and she remained blind since then despite a newer appreciation to light. The initial brain magnetic resonance imaging (MRI) suggested AL demonstrated as a faint high T2/fluid-attenuated inversion recovery (FLAIR) signal intensity in the cortical and subcortical regions of both parieto-occipital lobes with sulcal effacement and restricted diffusion. After around 3 months, the subsequent brain MRI showed involutional changes that were manifested as a brain volume loss in the same areas with evidence of gyri-form laminar necrosis in both parieto-occipital regions without restricted diffusion. Other brain MRI findings include right cerebral convexity hyperacute subdural hematoma with prominent subarachnoid spaces. Conclusions The child developed cortical blindness-complicated AL following a paracetamol overdose. It is well- known that AL may result from several toxins by their direct and/or indirect effect on the cerebral white matter. However, there is still no enough data in the literature clearly explaining the relation of paracetamol overdose to AL. The generally proposed effect of paracetamol on the brain is mainly justified by the excessive oxidative stress. Further studies at the cellular and genetic levels are still needed to investigate the exact association between paracetamol overdose and AL, as well as the underlying mechanisms involved.

Patch-walking, a coordinated multi-pipette patch clamp for efficiently finding synaptic connections

Significant technical challenges exist when measuring synaptic connections between neurons in living brain tissue. The patch clamping technique, when used to probe for synaptic connections, is manually laborious and time-consuming. To improve its efficiency, we pursued another approach: instead of retracting all patch clamping electrodes after each recording attempt, we cleaned just one of them and reused it to obtain another recording while maintaining the others. With one new patch clamp recording attempt, many new connections can be probed. By placing one pipette in front of the others in this way, one can ‘walk’ across the mouse brain slice, termed ‘patch-walking.’ We performed 136 patch clamp attempts for two pipettes, achieving 71 successful whole cell recordings (52.2%). Of these, we probed 29 pairs (i.e. 58 bidirectional probed connections) averaging 91 μm intersomatic distance, finding three connections. Patch-walking yields 80–92% more probed connections, for experiments with 10–100 cells than the traditional synaptic connection searching method.

Patch-walking, a coordinated multi-pipette patch clamp for efficiently finding synaptic connections

Significant technical challenges exist when measuring synaptic connections between neurons in living brain tissue. The patch clamping technique, when used to probe for synaptic connections, is manually laborious and time-consuming. To improve its efficiency, we pursued another approach: instead of retracting all patch clamping electrodes after each recording attempt, we cleaned just one of them and reused it to obtain another recording while maintaining the others. With one new patch clamp recording attempt, many new connections can be probed. By placing one pipette in front of the others in this way, one can ‘walk’ across the mouse brain slice, termed ‘patch-walking.’ We performed 136 patch clamp attempts for two pipettes, achieving 71 successful whole cell recordings (52.2%). Of these, we probed 29 pairs (i.e. 58 bidirectional probed connections) averaging 91 μm intersomatic distance, finding three connections. Patch-walking yields 80–92% more probed connections, for experiments with 10–100 cells than the traditional synaptic connection searching method.

Abstract A039: Characterization of the heterogeneous nature of the peritumoral zone of glioblastomas and its relevance for the clinical progression of the disease

Abstract Glioblastoma (GBM) is one of the most aggressive forms of cancer, with a recurrence rate of nearly 100% within 12 months of diagnosis. This is attributable to the persistence of residual tumor cells following surgical resection, which can repopulate the tumor even after the administration of aggressive chemoradiotherapy. These cells are embedded in a specific microenvironment in the peritumoral zone (PTZ), which is formed by their interaction with the brain parenchyma. The PTZ can be classified radiologically into two distinct categories: areas of clear tumor infiltration (non-contrast-enhancing (non-CE) tumor) and areas of vascular edema. Recent data suggest that the extent of surgical resection to non-CE regions may confer substantial benefits to patients with GBM. However, while the tumor core niche has been the subject of extensive study, there is a paucity of knowledge regarding the nature of the PTZ. In this study, we prospectively collected a large cohort of radiologically guided biopsies from GBM patients and performed a comprehensive cellular analysis. To this end, we initially integrated publicly available single-cell RNA sequencing (scRNA-seq) datasets from non-pathogenic human brains and gliomas, resulting in an integrated atlas representing the major cell types: immune (myeloid cells and T cells), astrocytic, oligodendroglial, and vascular. By means of a meticulous multi-stage examination of differentially expressed genes in glioma and cell type-specific markers, we were able to identify several genes that could serve to characterize the cellular content of the biopsies obtained from the tumor core and the periphery, comprising non-CE tumor, edema, and what was deemed "normal" tissue. The application of unsupervised clustering enabled the separation of the most pathogenic samples (including CE and non-CE tumor biopsies) based on the enrichment of proliferative markers and the pronounced absence of normal endothelial and oligodendrocyte expression. The tumorigenic samples were clustered into two main groups: one group that was enriched in astrocytic and proliferative markers and another one that was enriched in myeloid cells. Furthermore, our findings indicate the existence of inter- and intra-tumor heterogeneity in the cellular composition of the PTZ in GBM, with observed differences associated with the degree of tumor infiltration, but also patient age and gender. In particular, a distinct pathological pattern was discerned in select edema and normal biopsies from multiple patients, particularly those of an advanced age. Moreover, several markers of neural and immune cells associated with a favorable prognosis were identified, though only when expressed in the periphery. In conclusion, our study offers a comprehensive scRNA-seq resource for investigating the involvement of diverse cell types in the pathobiology of GBM. Additionally, it highlights the heterogeneous nature of the glioma periphery, which could explain the gender and age-related prognostic differences that have been observed among patients with GBM. Citation Format: Olaya de Dios, María de los Ángeles Ramírez-González, Beatriz Herranz, Juan Romero, Ana Ramos, Juan Manuel Sepúlveda-Sánchez, Ricardo Gargini, Aurelio Hernández-Laín, Pedro González, Luis Jiménez-Roldán, Guillermo García-Posadas, Ángel Pérez-Núñez, Pilar Sánchez-Gómez. Characterization of the heterogeneous nature of the peritumoral zone of glioblastomas and its relevance for the clinical progression of the disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A039.

Effects of 1800MHz and 2100MHz mobile phone radiation on the blood-brain barrier of New Zealand rabbits.

In this study, the impact of mobile phone radiation on blood-brain barrier (BBB) permeability was investigated. A total of 21 New Zealand rabbits were used for the experiments, divided into three groups, each consisting of 7 rabbits. One group served as the control, while the other two were exposed to electromagnetic radiation at frequencies of 1800MHz with a distance of 14.5cm and 2100MHz with a distance of 17cm, maintaining a constant power intensity of 15 dBm, for a duration equivalent to the current average daily conversation time of 38min. The exposure was conducted under non-thermal conditions, with RF radiation levels approximately ten times lower than normal values. Evans blue (EB) dye was used as a marker to assess BBB permeability. EB binds to plasma proteins, and its presence in brain tissue indicates a disruption in BBB integrity, allowing for a quantitative evaluation of radiation-induced permeability changes. Left and right brain tissue samples were analyzed using trichloroacetic acid (TCA) and phosphate-buffered solution (PBS) solutions to measure EB amounts at 620nm via spectrophotometry. After the experiments, BBB tissue samples were collected from the right and left brains of all rabbits in the three groups and subjected to a series of medical procedures. Samples from Group 1 were compared with those from Group 2 and Group 3 using statistical methods to determine if there were any significant differences. As a result, it was found that there was no statistically significant difference in the BBB of rabbits exposed to 1800MHz radiation, whereas there was a statistically significant difference at a 95% confidence level in the BBB of rabbits exposed to 2100MHz radiation. A decrease in EB values was observed upon the arithmetic examination of the BBB.

Genotoxic impact of agricultural insecticides as contaminants of river Teesta on the resident fish Pethia Conchonius.

Fish, being highly sensitive to changes in the physico-chemical parameters of water, are good indicators of contamination. Teesta, a prominent northern West Bengal River system, is increasingly contaminated due to anthropogenic activities. This study aims to determine agricultural pesticide contamination and its genotoxic impact on the resident fish, Pethia conchonius, as an experimental organism. Sample water analysis from three riverine sites I, II & III, showed the presence of the insecticides imidacloprid (IMI), chlorpyrifos (CPF), bifenethrin (BF), cypermethrin (CP), difenthiuron, acetamiprid (AC) in the sites II and III only with adjoining agricultural lands. Comet assay revealed a significantly lower % Head DNA (~ 1.2 times), higher %Tail DNA (~ 16 times), and %Tail length (~ 3.1 times) in the gills of Pethia conchonius from sites II and III. About 4 and 10 times increase of micronuclei and other nuclear abnormalities were also noted in the erythrocytes of the fish from sites II and III than I, which was not contaminated. The antioxidant enzymes SOD, CAT, and GST activity and MDA levels were significantly higher (p < 0.05) in the liver samples from sites II and III, while AChE activity was significantly decreased (p < 0.001) in the brain tissues. Moreover, the sod, cat, and gpx expression in the hepatic cells were significantly upregulated compared to the β actin mRNA indicating increased oxidative stress. Increased genomic damage, antioxidant enzyme activity, higher MDA levels, decreased AChE activity in the brain, and the upregulation of hepatic genes strongly suggested the genotoxic effects of the detected insecticides in combination with other contaminants.

Legal and economic assessment of Neuralink: Between today's challenges and future aspirations analytical descriptive study

This research explores the legal and economic challenges associated with Neuralink’s innovative technology that merges artificial intelligence with the human brain. This technology allows individuals to control devices with their thoughts and addresses neurological disorders, thereby enhancing human capabilities. Legal concerns focus on privacy issues arising from brain data collection, necessitating new laws to protect individual rights. Questions of liability for damages also arise, determining whether responsibility lies with Neuralink or the users. Additionally, the ethical implications of enhancing human abilities and their effects on identity are examined. Economically, Neuralink could drive innovation, increase productivity, and create specialized jobs while transforming the labor market. It holds promise for improving healthcare and education, thus enhancing overall quality of life. It highlights that protecting rights is vital for innovation and meeting societal needs. It emphasizes safeguarding individual rights to promote innovation and ensure technology benefits society.

Neuroprotective Role of Zingerone: Investigating the Effective Doses of Zingerone in Lead Acetate-Induced Brain Dysfunctions in Rats

This experiment was designed to determine the effective dose of zingerone against the sublethal dose of lead acetate that induced brain dysfunctions in rats through using different successive doses of zingerone on some parameters related to oxidative stress for 28 days. Thirty-six adult male rats were randomly selected and divided equally into six experimental groups and treated for 28 days as follows: Control group: administered (orally) sterile distilled water. G1 group: administered (orally) (1/280 from LD50) of lead acetate and treated with 25mg/kg for 4 weeks, the rats were then dissected. G2 group: administered (orally) (1/280 from LD50) of lead acetate and treated with 50mg/kg for 4 weeks, the rats were then dissected. G3 group: administered (orally) (1/280 from LD50) of lead acetate and treated with 100mg/kg for 4 weeks, the rats were then dissected. G4 group: administered (orally) (1/280 from LD50) of lead acetate and treated with 150mg/kg for 4 weeks, the rats were then dissected. G5 group: administered (orally) (1/280 from LD50) of lead acetate and treated with 200mg/kg for 4 weeks, the rats were then dissected. Blood samples were collected, by heart punched under anesthesia, at the end of the experiment for measuring the serum malondialdehyde, neuroglobulin, and dopamine concentrations. The result showed a significant (P&lt;0.05) positive correlation between successive doses of zingerone and dopamine and neuroglobulin concentrations, while a significant (P&lt;0.05) negative correlation between successive doses of zingerone and the concentration of malondialdehyde in all animals that are treated with lead acetate compared to the control group. Concluded from this research show that the zingerone has potent antioxidants and neuroprotective effects at the dose 125 mg/kg BW may result in a significant improvement of the neurotransmitter levels and decrease in the production of oxidative stress to the brain tissue.

Morin Ameliorates Lipopolysaccharides-Induced Sepsis-Associated Encephalopathy and Cognitive Impairment in Albino Mice.

Sepsis-associated encephalopathy is a common neurological complication of sepsis that is characterized by neuroinflammation, oxidative stress and apoptosis, which results in cognitive impairments in septic survivors. Despite numerous treatment options for this condition, none of them are definite. Therefore, this study aimed to investigate the impact of morin, a flavone known for its neuroprotective and anti-inflammatory effects, against lipopolysaccharides-induced sepsis-associated encephalopathy in albino mice for 7 days. Mice were divided into 4 groups: Negative control, morin, septic, and septic morin-treated mice. Sepsis was induced by a single injection of lipopolysaccharides (5mg/kg, intraperitoneally), morin (50mg/kg b. wt.) was given orally, starting from 5h after sepsis induction, then daily for 4 other days. Morin ameliorated septic structural and functional alternations as manifested by improving the survival rate, the behavioral functions, in addition to preserving and protecting the brain tissue. This was accompanied with the augmentation of the total antioxidant capacity, as well as the suppression of tissue levels of the lipid peroxidation marker malondialdehyde, apoptosis (cleaved-caspase-3), glial fibrillary acidic protein, and the proinflammatory cytokine tumor necrosis factor. In conclusion, morin has a promising ameliorative effect to counteract the sepsis-associated encephalopathy via its anti-inflammatory and antioxidant effects and to prevent the associated cognitive impairments.

Alterations of gray matter asymmetry in internet gaming disorder.

Structural asymmetry is a subtle but pervasive property of the human brain, which has been found altered in various psychiatric and neurocognitive disorders. However, little is known regarding potential alterations of structural asymmetry underlying internet gaming disorder (IGD). Therefore, this study aimed to investigate the structural features of gray matter asymmetry in IGD. High-resolution structural magnetic resonance imaging data were collected from 104 individuals with IGD and 104 recreational game users (RGUs). We applied a whole-brain voxel-based asymmetry (VBA) approach to determine the asymmetrical aberrations of gray matter in relation to IGD. Furthermore, the local abnormalities of structural asymmetry were employed as features to examine the effect of classification using a support vector machine (SVM). The results indicated that individuals with IGD as compared to RGUs showed asymmetrical alterations of gray matter in the medial prefrontal cortex (mPFC), orbitofrontal cortex, precuneus, middle temporal gyrus, superior parietal lobule and inferior temporal gyrus, regions implicated in hedonic motivation, self-reflection, information integration and visuospatial attention processing. Moreover, these atypical asymmetrical features can distinguish IGD subjects from RGUs with high accuracy. These results suggested that disrupted structural asymmetry of motivational reward, visuospatial and default mode circuits might be potential biomarkers for identifying pathological gaming dependence. These findings extended our understanding of structural underpinnings of IGD and provided new insights for developing effective interventions to alleviate compulsive gaming usage.

Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure.

Analyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive, dendrite-targeting GABAergic interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons (induced by Cre-mediated deletion of the γ2 GABAA receptor subunit gene selectively from SST neurons, SSTCre:γ2f/f mice) results in stress resilience. Similarly, chronic chemogenetic activation of SST neurons in the medial prefrontal cortex (mPFC) results in stress resilience but only in male and not in female mice. Here, we used RNA sequencing of the mPFC of SSTCre:γ2f/f mice to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female SSTCre:γ2f/f mice is characterized by resilience to chronic stress-induced transcriptome changes in the mPFC. Interestingly, the transcriptome of non-stressed SSTCre:γ2f/f (stress-resilient) male mice resembled that of chronic stress-exposed SSTCre (stress-vulnerable) mice. However, the behavior and the serum corticosterone levels of non-stressed SSTCre:γ2f/f mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of SSTCre:γ2f/f mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes suggesting stress-induced enhancement of mRNA translation. Behaviorally, the SSTCre:γ2f/f mice were not only resilient to chronic stress-induced anhedonia - they also showed an inversed, anxiolytic-like behavioral response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in the expression of putative stress resilience genes, through a sex-specific brain substrate.

Eleutheroside B alleviates oxidative stress and neuroinflammation by inhibiting the JAK2/STAT3 signaling pathway in a rat high altitude cerebral edema model

BackgroundHigh altitude cerebral edema (HACE) is a condition where the central nervous system experiences severe impairment as a result of sudden oxygen deprivation at high elevations. At present, effective measures for preventing and treating this condition are still lacking. Eleutheroside B (EB), the primary natural active compound found in the Eleutheroside senticosus, has demonstrated various biological functions. It has also shown significant potential in addressing acute mountain sickness and various neurological disorders. However, additional investigation is required to explore the potential protective effects and its underlying mechanisms of EB on HACE.MethodsThe male rats received pre-treatment with either vehicle, EB 100 mg/kg or 50 mg/kg, Dexamethasone 4 mg/kg, or coumermycin A1 100 μg/kg. To simulate the hypobaric hypoxia environment at a plateau of 6,000 m, a hypobaric hypoxia chamber was utilized. The therapeutic effects of EB were assessed through measurements of brain water content, histopathological observation, and evaluation of oxidative stress and inflammatory factors using immunofluorescence and ELISA. Furthermore, molecular docking, molecular dynamics simulation and Western blot were employed to clarify its molecular mechanism. Through these analyses, the underlying mechanism by which EB on HACE was identified.ResultsPre-treatment with EB demonstrated a significant protective effect against HACE by effectively reducing brain water content, down-regulating HIF-1α and AQP4 protein expression induced by hypoxia and reversing pathological changes in brain tissue and neuron damage. Compared to the group treated with HACE alone, the group pre-treated with EB showed a significant reduction in levels of ROS and MDA, as well as an increase in GSH. In addition, pre-treatment with EB led to a significant decrease in the levels of IL-1β, IL-6, and TNF-α. Molecular docking and dynamics simulations indicated that EB has a strong binding affinity to the JAK2/STAT3 signaling pathway. Western blot further confirmed that EB significantly downregulated the expression of JAK2/STAT3 related proteins in the brain tissue of HACE rats. Additionally, coumermycin A1, an agonist of the JAK2, reversed the anti-oxidative stress and neuroinflammation against HACE of EB.ConclusionEB exerts its antioxidant stress and anti-neuroinflammatory effects by inhibiting the JAK2/STAT3 signaling pathway in a rat HACE model.

Changing dynamics in daily rhythms of oxidative stress indicators in SCN and extra-SCN brain regions with aging in male Wistar rats.

The suprachiasmatic nucleus (SCN) in the hypothalamus regulates circadian timing system (CTS) by co-ordinating peripheral tissue clocks and extra-SCN oscillators in the brain. Aging disrupts the CTS, impairing physiological functions and reducing antioxidant defences, which contribute to neurodegeneration. The brain is vulnerable to oxidative damage due to its high metabolic activity, oxygen consumption, and levels of iron and lipids. Antioxidant enzymes, such as catalase (CAT), glutathione S-transferase (GST), superoxide dismutase (SOD), and lipid peroxidation (LPO), help against oxidative damage. In this study, we examined the temporal patterns of these antioxidant stress indicators in the SCN and extra-SCN brain regions (frontal cortex, cerebellum, and hippocampus) at various time points in male Wistar rats 3, 12, and 24months. The rhythmicity of GST and LPO levels persisted across brain regions with aging, while CAT rhythmicity was lost in the SCN and hippocampus of older rats. SOD rhythmicity persisted in cortex, cerebellum, and hippocampus but was lost in the SCN. The daily rhythm parameters of CAT were affected most significantly, followed by SOD, GST, and LPO. Our findings demonstrate that aging leads to desynchronization of oxidative stress indicators potentially contributing to neurodegeneration and circadian dysfunction with varying effects across different brain tissues.

BRD4 Degradation Enhanced Glioma Sensitivity to Temozolomide by Regulating Notch1 via Glu-Modified GSH-Responsive Nanoparticles.

Temozolomide (TMZ) serves as the principal chemotherapeutic agent for glioma; nonetheless, its therapeutic efficacy is compromised by the rapid emergence of drug resistance, the inadequate targeting of glioma cells, and significant systemic toxicity. ARV-825 may play a role in modulating drug resistance by degrading the BRD4 protein, thereby exerting anti-glioma effects. Therefore, to surmount TMZ resistance and achieve efficient and specific drug delivery, a dual-targeted glutathione (GSH)-responsive nanoparticle system (T+A@Glu-NP) is designed and synthesized for the co-delivery of ARV-825 and TMZ. As anticipated, T+A@Glu-NPs significantly enhanced penetration of the blood-brain barrier (BBB), facilitated drug uptake by glioma cells, and exhibited efficient accumulation in brain tissue. Additionally, T+A@Glu-NPs exhibited augmented efficacy against glioma both in vitro and in vivo through the induction of apoptosis, inhibition of proliferation, and cell cycle arrest. Furthermore, mechanistic exploration revealed that T+A@Glu-NPs degraded the BRD4 protein, leading to the downregulation of Notch1 gene transcription and the inhibition of the Notch1 signaling pathway, thereby augmenting the therapeutic efficacy of glioma chemotherapy. Taken together, the findings suggest that T+A@Glu-NPs represents a novel and promising therapeutic strategy for glioma chemotherapy.

Chronic implantable flexible serpentine probe reveals impaired spatial coding of place cells in epilepsy

Abstract Developing minimally invasive and reliable electrode probes for neural signal recording is crucial for advancing neuroscience and treating major brain disorders. Flexible neural probes offer superior long-term recording capabilities over traditional rigid probes. This study introduces a parylene-based serpentine electrode probe for stable, long-term neural monitoring. Inspired by the flexibility and morphology of snakes, the probe's serpentine design ensures stable anchorage within the brain tissue during subject movement. The probe features a hydrophilic surface and is combined with a biodegradable silk fibroin-PEG coating, significantly enhancing biocompatibility and mitigating inflammatory responses. In vivo experiments demonstrate that these probes maintain stable, high-quality neural recordings for over eight months. The probes are also used to investigate the neural bases of epilepsy-induced cognitive deficits. By analyzing place cell dynamics in mice pre- and post-epileptic events, we identified the correlation between impaired spatial encoding and the observed cognitive deficits in epileptic mice. This study highlights the potential of our flexible probes in neurological research and medical applications.

X-ray fluorescence mapping of brain tissue reveals the profound extent of trace element dysregulation in stroke pathophysiology.

The brain is a privileged organ with regards to its trace element composition and maintains a robust barrier system to sequester this specialized environment from the rest of the body and the vascular system. Stroke is caused by loss of adequate blood flow to a region of the brain. Without adequate blood flow ischemic changes begin almost immediately, triggering an ischemic cascade, characterized by ion dysregulation, loss of function, oxidative damage, cellular degradation, and break down of the barrier that helps maintain this environment. Ion dysregulation is a hallmark of stroke pathophysiology and we observe that most elements in the brain are dysregulated after stroke. X-ray fluorescence-based detection of physiological changes in the neurometallome after stroke reveals profound ion dysregulation within the lesion and surrounding tissue. Not only are most elements significantly dysregulated after stroke, but the level of dysregulation cannot be predicted from a cell-level description of dysregulation. X-ray fluorescence imaging reveals that the stroke lesion retains<25% of essential K+ after stroke, but this element is not concomitantly elevated elsewhere in the organ. Moreover, elements like Na+, Ca2+, and Cl- are vastly elevated above levels available in normal brain tissue (>400%, >200%, and>150%, respectively). We hypothesize that weakening of the blood-brain-barrier after stroke allows elements to freely diffuse down their concentration gradient so that the stroke lesion is in equilibrium with blood (and the compartments containing brain interstitial fluid and cerebrospinal fluid). The changes observed for the neurometallome likely has consequences for the potential to rescue infarcted tissue, but also presents specific targets for treatment.

SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development.

Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These individuals have severe developmental brain malformations, including microcephaly and cerebellar hypoplasia. The disease mechanism of SMPD4 was not known and so we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells lacking SMPD4 exhibit neural progenitor cell death and have shortened primary cilia, which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.

EXPLORING INTELLECTUAL AND EDUCATIONAL MIGRATION IN KAZAKHSTAN: DOCUMENTARY ANALYSIS

Background: Addressing brain drain and fostering human capital development are critical for sustaining a nation's long-term economic growth, innovation capacity, and global competitiveness. Kazakhstan has faced significant brain drain, particularly following the dissolution of the Soviet Union, as many skilled professionals sought better opportunities abroad. Despite government efforts to retain talent, the country continues to experience a negative migration balance, with a substantial portion of emigrants being highly educated and skilled. This study examines the challenges posed by brain drain and evaluates Kazakhstan's current policy initiatives aimed at addressing intellectual migration and fostering human capital development. Methods: The study employs a qualitative research approach using documentary analysis to explore intellectual and educational migration in Kazakhstan. The methodology involves systematically reviewing key government policy documents and reports, such as the Concept of Migration Policy of the Republic of Kazakhstan for 2023-2027. Documentary analysis was selected for its ability to provide in-depth insights into government initiatives and policy frameworks, enabling an assessment of their long-term effectiveness. Content analysis was applied to identify recurring themes and policy shifts related to human capital development and brain drain. Results and conclusions: The findings highlight the government’s efforts to attract skilled professionals, retain domestic talent, and foster international collaboration through streamlined visa processes, academic partnerships, and the establishment of international branch campuses. The analysis highlights educational immigration as a core component of Kazakhstan's migration strategy, shaped by regional factors and geopolitical considerations. Despite these efforts, the study identifies ongoing challenges in creating attractive domestic career opportunities and competitive research environments, which are crucial for the longterm retention of talent. By leveraging international best practices and fostering collaboration between the government, academia, and industry, Kazakhstan can enhance its position in the global knowledge economy while addressing demographic and economic challenges. The paper concludes by discussing the potential policy implications and recommendations for sustaining Kazakhstan’s human capital development in the context of global intellectual migration trends.

Microglia contribute to the production of the amyloidogenic ABri peptide in familial British dementia.

Mutations in ITM2B cause familial British, Danish, Chinese, and Korean dementias. In familial British dementia (FBD), a mutation in the stop codon of the ITM2B gene (also known as BRI2) causes a C-terminal cleavage fragment of the ITM2B/BRI2 protein to be extended by 11 amino acids. This fragment, termed amyloid-Bri (ABri), is highly insoluble and forms extracellular plaques in the brain. ABri plaques are accompanied by tau pathology, neuronal cell death and progressive dementia, with striking parallels to the aetiology and pathogenesis of Alzheimer's disease. The molecular mechanisms underpinning FBD are ill-defined. Using patient-derived induced pluripotent stem cells, we show that expression of ITM2B/BRI2 is 34-fold higher in microglia than neurons and 15-fold higher in microglia compared with astrocytes. This cell-specific enrichment is supported by expression data from both mouse and human brain tissue. ITM2B/BRI2 protein levels are higher in iPSC-microglia compared with neurons and astrocytes. The ABri peptide was detected in patient iPSC-derived microglial lysates and conditioned media but was undetectable in patient-derived neurons and control microglia. The pathological examination of post-mortem tissue supports the presence of ABri in microglia that are in proximity to pre-amyloid deposits. Finally, gene co-expression analysis supports a role for ITM2B/BRI2 in disease-associated microglial responses. These data demonstrate that microglia are major contributors to the production of amyloid forming peptides in FBD, potentially acting as instigators of neurodegeneration. Additionally, these data also suggest ITM2B/BRI2 may be part of a microglial response to disease, motivating further investigations of its role in microglial activation. These data have implications for our understanding of the role of microgliaand the innate immune response in the pathogenesis of FBD and other neurodegenerative dementias including Alzheimer's disease.