Neural Cells Research Articles

Analysis of human neuronal cells carrying ASTN2 deletion associated with psychiatric disorders

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558.

Molecular characterization of nodose ganglia development reveals a novel population of Phox2b+ glial progenitors in mice.

The vagal ganglia, comprised of the superior (jugular) and inferior (nodose) ganglia of the vagus nerve, receive somatosensory information from the head and neck, or viscerosensory information from the inner organs, respectively. Developmentally, the cranial neural crest gives rise to all vagal glial cells and to neurons of the jugular ganglia, while the epibranchial placode gives rise to neurons of the nodose ganglia. Crest-derived nodose glial progenitors can additionally generate autonomic neurons in the peripheral nervous system, but how these progenitors generate neurons is unknown. Here, we found that some Sox10+ neural crest-derived cells in, and surrounding, the nodose ganglion transiently expressed Phox2b, a master regulator of autonomic nervous system development, during early embryonic life. Our genetic lineage tracing analysis in mice of either sex revealed that despite their common developmental origin and extreme spatial proximity a substantial proportion of glial cells in the nodose, but not in the neighboring jugular ganglia, have a history of Phox2b expression. We used single cell RNA-sequencing (scRNA-seq) to demonstrate that these progenitors give rise to all major glial subtypes in the nodose ganglia, including Schwann cells, satellite glia and glial precursors, and mapped their spatial distribution by in situ hybridization. Lastly, integration analysis revealed transcriptomic similarities between nodose and dorsal root ganglia glial subtypes, and revealed immature nodose glial subtypes. Our work demonstrates that these crest-derived nodose glial progenitors transiently express Phox2b, give rise to the entire complement of nodose glial cells and display a transcriptional program that may underlie their bipotent nature.Significance statement The nodose ganglia contain sensory neurons that innervate inner organs and play key roles in homeostatic behaviors like digestion, regulation of blood pressure and heart rate, and breathing. Nodose sensory neurons are supported by nodose glial cells, which are understudied compared to their neuronal neighbors. Specifically, the genetic program governing their development is not fully understood. Here, we uncover a transcriptional program unique to nodose glial cells (transient expression of Phox2b) that resolves the 40-year-old finding that nodose glial progenitors can also give rise to autonomic neurons (whose development depends on Phox2b expression). Lastly, we leveraged single cell RNA-sequencing to identify the four major subtypes of nodose glial cells and used subtype specific marker genes to map their spatial distribution.

Facile Surface Functionalization of Electrospun Elastic Nanofibers Via Initiated Chemical Vapor Deposition for Enhanced Neural Cell Adhesion and Alignment

Facile Surface Functionalization of Electrospun Elastic Nanofibers Via Initiated Chemical Vapor Deposition for Enhanced Neural Cell Adhesion and Alignment

Revolutionizing Stroke Care: Nanotechnology-Based Brain Delivery as a Novel Paradigm for Treatment and Diagnosis.

Stroke, a severe medical condition arising from abnormalities in the coagulation-fibrinolysis cycle and metabolic processes, results in brain cell impairment and injury due to blood flow obstruction within the brain. Prompt and efficient therapeutic approaches are imperative to control and preserve brain functions. Conventional stroke medications, including fibrinolytic agents, play a crucial role in facilitating reperfusion to the ischemic brain. However, their clinical efficacy is hampered by short plasma half-lives, limited brain tissue distribution attributed to the blood-brain barrier (BBB), and lack of targeted drug delivery to the ischemic region. To address these challenges, diverse nanomedicine strategies, such as vesicular systems, polymeric nanoparticles, dendrimers, exosomes, inorganic nanoparticles, and biomimetic nanoparticles, have emerged. These platforms enhance drug pharmacokinetics by facilitating targeted drug accumulation at the ischemic site. By leveraging nanocarriers, engineered drug delivery systems hold the potential to overcome challenges associated with conventional stroke medications. This comprehensive review explores the pathophysiological mechanism underlying stroke and BBB disruption in stroke. Additionally, this review investigates the utilization of nanocarriers for current therapeutic and diagnostic interventions in stroke management. By addressing these aspects, the review aims to provide insight into potential strategies for improving stroke treatment and diagnosis through a nanomedicine approach.

Simultaneous isolation of intact brain cells and cell-specific extracellular vesicles from cryopreserved Alzheimer’s disease cortex

BackgroundThe neuronal and gliaI populations within the brain are tightly interwoven, making isolation and study of large populations of a single cell type from brain tissue a major technical challenge. Concurrently, cell-type specific extracellular vesicles (EVs) hold enormous diagnostic and therapeutic potential in neurodegenerative disorders including Alzheimer’s disease (AD). New MethodPostmortem AD cortical samples were thawed and gently dissociated. Following filtration, myelin and red blood cell removal, cell pellets were immunolabeled with fluorescent antibodies and analyzed by flow cytometry. The cell pellet supernatant was applied to a triple sucrose cushion for brain EV isolation. ResultsNeuronal, astrocyte and microglial cell populations were identified. Cell integrity was demonstrated using calcein AM, which is retained by cells with esterase activity and an intact membrane. For some experiments cell pellets were fixed, permeabilized, and immunolabeled for cell-specific markers. Characterization of brain small EV fractions showed the expected size, depletion of EV negative markers, and enrichment in positive and cell-type specific markers. Comparison with existing methods and conclusionsWe optimized and integrated established protocols, aiming to maximize information obtained from each human autopsy brain sample. The uniqueness of our method lies in its capability to isolate cells and EVs from a single cryopreserved brain sample. Our results not only demonstrate the feasibility of isolating specific brain cell subpopulations for RNA-seq but also validate these subpopulations at the protein level. The accelerated study of EVs from human samples is crucial for a better understanding of their contribution to neuron/glial crosstalk and disease progression.

Replication of Akabane virus and related orthobunyaviruses in a fetal-bovine-brain-derived cell line.

Akabane virus (AKAV), Aino virus, Peaton virus, Sathuperi virus, and Shamonda virus are arthropod-borne viruses belonging to the order Elliovirales, family Peribunyaviridae, genus Orthobunyavirus. These viruses cause or may cause congenital malformations in ruminants, including hydranencephaly, poliomyelitis, and arthrogryposis, although their pathogenicity may vary among field cases. AKAV may cause relatively severe congenital lesions such as hydranencephaly in calves. Furthermore, strains of AKAV genogroups I and II exhibit different disease courses. Genogroup I strains predominantly cause postnatal viral encephalomyelitis, while genogroup II strains are primarily detected in cases of congenital malformation. However, the biological properties of AKAV and other orthobunyaviruses are insufficiently investigated in hosts in the field and in vitro. Here, we used an immortalized bovine brain cell line (FBBC-1) to investigate viral replication efficiency, cytopathogenicity, and host innate immune responses. AKAV genogroup II and Shamonda virus replicated to higher titers in FBBC-1 cells compared with the other viruses, and only AKAV caused cytopathic effects. These results may be associated with the severe congenital lesions in the brain caused by AKAV genogroup II. AKAV genogroup II strains replicated to higher titers in FBBC-1 cells than AKAV genogroup I strains, suggesting that genogroup II strains replicated more efficiently in fetal brain cells, accounting for the detection of the latter strains mainly in fetal infection cases. Therefore, FBBC-1 cells may serve as a valuable tool for investigating the virulence and tropism of the orthobunyaviruses for bovine neonatal brain tissues in vitro.

Zika virus as a new pathogenic agent within the Toxoplasma gondii, Rubella virus, Cytomegalovirus, and Herpes simplex (TORCH) virus family: where do we stand?

Viral infections in low-income countries such as Brazil pose a significant challenge for medical authorities, with epidemics such as Zika virus infection having lasting effects. The increase in microcephaly among newborns has prompted investigations into the association between Zika virus and this congenital syndrome. The severity and prevalence of microcephaly led to the declaration of national and international emergencies. Extensive research has been conducted to understand the teratogenic effects of Zika virus, particularly its impact on neural progenitor cells in the fetal brain. Various pre- and postnatal imaging techniques, such as ultrasound, magnetic resonance imaging (MRI), and postnatal computed tomography (CT), have played crucial roles in diagnosing and monitoring malformations linked to congenital Zika virus infection in the central nervous system (CNS). These modalities can detect brain parenchymal abnormalities, calcifications, cerebral atrophy, and callosal anomalies. Additionally, three-dimensional ultrasound and fetal MRI provide detailed anatomical images, while CT can identify calcifications that are not easily detected by other methods. Despite advancements in imaging, there are still unanswered questions and ongoing challenges in comprehending the long-term effects and developmental impairments in children affected by Zika virus. Radiologists continue to play a crucial role in diagnosing and assisting in the management of these cases.

Demographic factors of prognosis in pediatric neuroblastoma.

10041 Background: Neuroblastoma is a rare type of pediatric tumor derived from neural crest progenitor cells. It can arise anywhere along the sympathetic chain but is most commonly found in the retroperitoneum from the adrenal glands. At diagnosis, approximately 50% of patients have hematogenous spread of metastases and so timely, aggressive treatment may be life-saving. The National Cancer Database (NCDB) is an oncology database that collects data from over 1500 cancer centers in the United States. This study will utilize the NCDB to analyze how demographic factors may impact prognosis in patients with pediatric neuroblastoma. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) and identified patients diagnosed with pediatric neuroblastoma under the age of 18 between 2004-2020 with ICD code 9500/3 (n = 2323). Multivariate Cox regression analysis was used to calculate hazard ratios (HR) analyzing race, Spanish/Hispanic origin, facility type, education, income, insurance status, age at diagnosis, distance traveled to the facility, and urban characteristics of the facility on prognosis. Results: The median age at diagnosis was one year-old. Patients aged greater than one year-old composed 48% of the sample and had a less favorable prognosis compared to patients younger than one-year old (HR 1.99, 95% CI 1.69-2.35, p < 0.001). The median distance to the facility was 21.4 miles. 50% of the sample patients lived greater than 21.4 miles of their chosen facility and had a poorer prognosis compared to patients who lived closer (HR 1.25, 95% CI 1.06-1.47, p = 0.008). Conversely, patients with private insurance composed 59% of the sample and had a more favorable prognosis (HR 0.54, 95% CI 0.30-0.99, p = 0.046) compared to patients with no insurance. Conclusions: To our knowledge, this study provides the most updated analysis on how demographic factors impact prognosis in patients with pediatric neuroblastoma. We highlight potential barriers to care including age, distance to facility, and insurance. We hope this study may serve as a foundation for further investigation into the systemic barriers that affect patients with pediatric neuroblastoma.

Palliative effect of abalone insulin-related peptide 2 on emersion stress-induced hyperglycemia in the Pacific abalone (Haliotis discus hannai)

The Pacific abalone (Haliotis discus hannai), an economically important marine mollusk in East Asia, is often exposed to extreme environments, such as high water temperatures during summer and air exposure during handling or transportation. These stressful conditions lead to hyperglycemia and the generation of reactive oxygen species (ROS), resulting in oxidative stress and subsequent cell damage in the organism. To understand the role of insulin-related peptides in the regulation of elevated hemolymph glucose, hyperglycemia was confirmed in abalone under high water temperature and air (emersion) exposure (p < 0.05). To prove the existence of a glucose regulatory system in abalone, changes in hemolymph glucose were measured after bovine insulin injection, and hemolymph glucose was lowered by bovine insulin injection in hyperglycemia caused by both stressors (p < 0.05), supporting the existence of a glucose regulatory system functionally similar to that of vertebrates. Among the three abalone insulin-related peptides (AIPs), which were previously reported to be upregulated along with hemolymph glucose levels upon feeding, the relative mRNA expression of AIP2 in the cerebral ganglion showed a close correlation with high water temperature and emersion stress, which peaked 12 h after treatment (p < 0.05). Based on these results, we focused on the function of AIP2 in glucose homeostasis and characterized the localization of AIP2 mRNA-expressing cells in the cerebral ganglion using in situ hybridization. Positive signals from RNA probes were detected in neural cortex cells in the cerebral ganglion. Furthermore, suppressing AIP2 mRNA expression using RNA interference with double-stranded RNA (dsRNA) revealed that dsRNA-AIP2 injected abalone maintained high hemolymph glucose levels after 24 h of recovery following 1 h of emersion stress (p < 0.01). In contrast, abalones that received dsRNA-GFP and molluscan saline showed relatively rapid clearance of hemolymph glucose. This study demonstrates that AIP2 gene expression affects the recovery rate from emersion stress-induced hyperglycemia by regulating hemolymph glucose.

Role of NEDD9 expression in non-metastatic HER2-positive breast cancer.

e12645 Background: Neural Precursor Cell Expressed Developmentally Downregulated Protein 9 (NEDD9) is a member of the associated substrate family. Our previous studies demonstrated the role of NEDD9 overexpression in early tumorigenesis in HER2-positive (HER2+) breast cancer in vivo. Tissue microarray-based analysis showed a strong correlation between NEDD9 mRNA and relapse-free survival (RFS) and pathologic complete response (pCR) rate in HER2+ breast cancers. In this study, NEDD9 expression in non-metastatic HER2+ breast cancer was evaluated by tissue microarray. Methods: A total of 64 patients with non-metastatic HER2+ cancer of the breast who had received neoadjuvant chemotherapy and had sufficient pathology specimens were included in the study. NEDD9 was stained by tissue microarray, and the expression was subclassified as low, intermediate, and high based on the NEDD9 expression score. The correlations of NEDD9 expression with the clinical/biological characteristics, treatment, and treatment response were analyzed by Fisher Exact test. Results: A total of 64 patients were included in the study, with a medium follow-up duration of 4.6 years. The median age was 54, 1 patient was male, 79.3% of patients had stage 2 disease, 1 patient had inflammatory breast cancer, and 37.5% of patients had ER/PR negative disease. The most common neoadjuvant chemotherapy regimen was TCHP (82.5%), 44.4% of patients underwent lumpectomy, and 67.7% of patients underwent axillary lymph node dissection (ALND). 54% of patients achieved complete pathologic response (pCR), all patients received adjuvant anti-HER2 treatment, 85.7% received adjuvant radiotherapy, and 74.6% received adjuvant endocrine therapy. The NEDD9 expression distribution for low, intermediate, and high were 37.5%, 50.0%, and 12.5%, respectively. NEDD9-high patients had higher tumor stage and grade than NEDD9-low/ intermediate patients (p = 0.004, p= 0.041). More NEDD9-high patients underwent ALND compared to NEDD9- low/intermediate patients (p = 0.09). There is no statistically significant difference in pCR rate between NEDD9 expression groups, although numerically more NEDD9-high patients achieved pCR (75%, 56.2%, and 43.5% in NEDD9-high, intermediate, and low patients). Conclusions: In non-metastatic HER2+ breast cancer, NEDD9 expression is associated with more advanced tumor grade and stage. There is no statistically significant difference in pCR rate between groups, although more patients achieved pCR with a higher level of NEDD9 expression. The sample size limits our study. Additional study is needed to evaluate the correlation between NEDD9 expression and pCR rate following neoadjuvant chemotherapy in HER2+ breast cancer.

An Update on Parkinson's Disease and its Neurodegenerative Counterparts.

Neurodegenerative disorders are a group of diseases that cause nerve cell degeneration in the brain, resulting in a variety of symptoms and are not treatable with drugs. Parkinson's disease (PD), prion disease, motor neuron disease (MND), Huntington's disease (HD), spinal cerebral dyskinesia (SCA), spinal muscle atrophy (SMA), multiple system atrophy, Alzheimer's disease (AD), spinocerebellar ataxia (SCA) (ALS), pantothenate kinase-related neurodegeneration, and TDP-43 protein disorder are examples of neurodegenerative diseases. Dementia is caused by the loss of brain and spinal cord nerve cells in neurodegenerative diseases. Even though environmental and genetic predispositions have also been involved in the process, redox metal abuse plays a crucial role in neurodegeneration since the preponderance of symptoms originates from abnormal metal metabolism. Hence, this review investigates several neurodegenerative diseases that may occur symptoms similar to Parkinson's disease to understand the differences and similarities between Parkinson's disease and other neurodegenerative disorders based on reviewing previously published papers. Based on the findings, the aggregation of alpha-synuclein occurs in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. Other neurodegenerative diseases occur with different protein aggregation or mutations. We can conclude that Parkinson's disease, Multiple system atrophy, and Dementia with Lewy bodies are closely related. Therefore, researchers must distinguish among the three diseases to avoid misdiagnosis of Multiple System Atrophy and Dementia with Lewy bodies with Parkinson's disease symptoms.

Cell-type-specific effects of age and sex on human cortical neurons.

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes withadvanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Identification of a novel neurovirulence factor encoded by the cryptic orphan gene UL31.6 of herpes simplex virus 1.

Although the herpes simplex virus type 1 (HSV-1) genome was thought to contain approximately 80 different protein coding sequences (CDSs), recent multi-omics analyses reported HSV-1 encodes more than 200 potential CDSs. However, few of the newly identified CDSs were confirmed to be expressed at the peptide or protein level in HSV-1-infected cells. Furthermore, the impact of the proteins they encode on HSV-1 infection is largely unknown. This study focused on a newly identified CDS, UL31.6. Re-analyzation of our previous chemical proteomics data verified that UL31.6 was expressed at the peptide level in HSV-1-infected cells. Antisera raised against a viral protein encoded by UL31.6 (pUL31.6) reacted with a protein with an approximate molecular mass of 37 kDa in lysates of Vero cells infected with each of three HSV-1 strains. pUL31.6 was efficiently dissociated from virions in high-salt solution. A UL31.6-null mutation had a minimal effect on HSV-1 gene expression, replication, cell-to-cell spread, and morphogenesis in Vero cells; in contrast, it significantly reduced HSV-1 cell-to-cell spread in three neural cells but not in four non-neural cells including Vero cells. The UL31.6-null mutation also significantly reduced the mortality and viral replication in the brains of mice after intracranial infection, but had minimal effects on pathogenic manifestations in and around the eyes, and viral replication detected in the tear films of mice after ocular infection. These results indicated that pUL31.6 was a tegument protein and specifically acted as a neurovirulence factor by potentially promoting viral transmission between neuronal cells in the central nervous system.IMPORTANCERecent multi-omics analyses reported the herpes simplex virus type 1 (HSV-1) genome encodes an additional number of potential coding sequences (CDSs). However, the expressions of these CDSs at the peptide or protein levels and the biological effects of these CDSs on HSV-1 infection remain largely unknown. This study annotated a cryptic orphan CDS, termed UL31.6, an HSV-1 gene that encodes a tegument protein with an approximate molecular mass of 37 kDa, which specifically acts as a neurovirulence factor. Our study indicates that HSV-1 proteins important for viral pathogenesis remain to be identified and a comprehensive understanding of the pathogenesis of HSV-1 will require not only the identification of cryptic orphan CDSs using emerging technologies but also step-by-step and in-depth analyses of each of the cryptic orphan CDSs.

Enhanced electrophysiological activity and neurotoxicity screening of environmental chemicals using 3D neurons from human neural precursor cells purified with PSA-NCAM

The assessment of neurotoxicity for environmental chemicals is of utmost importance in ensuring public health and environmental safety. Multielectrode array (MEA) technology has emerged as a powerful tool for assessing disturbances in the electrophysiological activity. Although human embryonic stem cell (hESC)-derived neurons have been used in MEA for neurotoxicity screening, obtaining a substantial and sufficiently active population of neurons from hESCs remains challenging. In this study, we successfully differentiated neurons from a large population of human neuronal precursor cells (hNPC) purified using a polysialylated neural cell adhesion molecule (PSA-NCAM), referred to as hNPCPSA-NCAM+. The functional characterization demonstrated that hNPCPSA-NCAM+-derived neurons improve functionality by enhancing electrophysiological activity compared to total hNPC-derived neurons. Furthermore, three-dimensional (3D) neurons derived from hNPCPSA-NCAM+ exhibited reduced maturation time and enhanced electrophysiological activity on MEA. We employed subdivided population analysis of active mean firing rate (MFR) based on electrophysiological intensity to characterize the electrophysiological properties of hNPCPSA-NCAM+-3D neurons. Based on electrophysiological activity including MFR and burst parameters, we evaluated the sensitivity of hNPCPSA-NCAM+-3D neurons on MEA to screen both inhibitory and excitatory neuroactive environmental chemicals. Intriguingly, electrophysiologically active hNPCPSA-NCAM+-3D neurons demonstrated good sensitivity to evaluate neuroactive chemicals, particularly in discriminating excitatory chemicals. Our findings highlight the effectiveness of MEA approaches using hNPCPSA-NCAM+-3D neurons in the assessment of neurotoxicity associated with environmental chemicals. Furthermore, we emphasize the importance of selecting appropriate signal intensity thresholds to enhance neurotoxicity prediction and screening of environmental chemicals.

Predicting Postoperative Speech Perception and Audiometric Thresholds Using Intracochlear Electrocochleography in Cochlear Implant Recipients.

Electrocochleography (ECochG) appears to offer the most accurate prediction of post-cochlear implant hearing outcomes. This may be related to its capacity to interrogate the health of underlying cochlear tissue. The four major components of ECochG (cochlear microphonic [CM], summating potential [SP], compound action potential [CAP], and auditory nerve neurophonic [ANN]) are generated by different cochlear tissue components. Analyzing characteristics of these components can reveal the state of hair and neural cell in a cochlea. There is limited evidence on the characteristics of intracochlear (IC) ECochG recordings measured across the array postinsertion but compared with extracochlear recordings has better signal to noise ratio and spatial specificity. The present study aimed to examine the relationship between ECochG components recorded from an IC approach and postoperative speech perception or audiometric thresholds. In 113 human subjects, responses to 500 Hz tone bursts were recorded at 11 IC electrodes across a 22-electrode cochlear implant array immediately following insertion. Responses to condensation and rarefaction stimuli were then subtracted from one another to emphasize the CM and added to one another to emphasize the SP, ANN, and CAP. Maximum amplitudes and extracochlear electrode locations were recorded for each of these ECochG components. These were added stepwise to a multi-factor generalized additive model to develop a best-fit model predictive model for pure-tone audiometric thresholds (PTA) and speech perception scores (speech recognition threshold [SRT] and consonant-vowel-consonant phoneme [CVC-P]) at 3- and 12-month postoperative timepoints. This best-fit model was tested against a generalized additive model using clinical factors alone (preoperative score, age, and gender) as a null model proxy. ECochG-factor models were superior to clinical factor models in predicting postoperative PTA, CVC-P, and SRT outcomes at both timepoints. Clinical factor models explained a moderate amount of PTA variance ( r2 = 45.9% at 3-month, 31.8% at 12-month, both p < 0.001) and smaller variances of CVC-P and SRT ( r2 range = 6 to 13.7%, p = 0.008 to 0.113). Age was not a significant predictive factor. ECochG models explained more variance at the 12-month timepoint ( r2 for PTA = 52.9%, CVC-P = 39.6%, SRT = 36.4%) compared with the 3-month one timepoint ( r2 for PTA = 49.4%, CVC-P = 26.5%, SRT = 22.3%). The ECochG model was based on three factors: maximum SP deflection amplitude, and electrode position of CM and SP peaks. Adding neural (ANN and/or CAP) factors to the model did not improve variance explanation. Large negative SP deflection was associated with poorer outcomes and a large positive SP deflection with better postoperative outcomes. Mid-array peaks of SP and CM were both associated with poorer outcomes. Postinsertion IC-ECochG recordings across the array can explain a moderate amount of postoperative speech perception and audiometric thresholds. Maximum SP deflection and its location across the array appear to have a significant predictive value which may reflect the underlying state of cochlear health.

Emerging Pro-neurogenic Therapeutic Strategies for Neurodegenerative Diseases: A Review of Pre-clinical and Clinical Research.

The neuroscience community has largely accepted the notion that functional neurons can be generated from neural stem cells in the adult brain, especially in two brain regions: the subventricular zone of the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus. However, impaired neurogenesis has been observed in some neurodegenerative diseases, particularly in Alzheimer's, Parkinson's, and Huntington's diseases, and also in Lewy Body dementia. Therefore, restoration of neurogenic function in neurodegenerative diseases emerges as a potential therapeutic strategy to counteract, or at least delay, disease progression. Considering this, the present study summarizes the different neuronal niches, provides a collection of the therapeutic potential of different pro-neurogenic strategies in pre-clinical and clinical research, providing details about their possible modes of action, to guide future research and clinical practice.

Actin depolymerizing factor destrin governs cell migration in neural development during Xenopus embryogenesis

The actin-based cytoskeleton is considered a fundamental driving force for cell differentiation and development. Destrin (dstn), a member of the actin depolymerizing factor family, regulates actin dynamics by treadmilling actin filaments and increasing globular actin pools. However, the specific developmental roles of dstn have yet to be fully elucidated. Here, we investigated the physiological functions of dstn during early embryonic development using Xenopus laevis as an experimental model organism. dstn is expressed in anterior neural tissue and neural plate during Xenopus embryogenesis. Depleting dstn promoted morphants with short body axes and small heads. Moreover, dstn inhibition extended the neural plate region, impairing cell migration and distribution during neurulation. In addition to the neural plate, dstn knockdown perturbed neural crest cell migration. Our data suggest new insights for understanding the roles of actin dynamics in embryonic neural development, simultaneously presenting a new challenge for studying the complex networks governing cell migration involving actin dynamics.

Human post-mortem organotypic brain slice cultures: a tool to study pathomechanisms and test therapies

Human brain experimental models recapitulating age- and disease-related characteristics are lacking. There is urgent need for human-specific tools that model the complex molecular and cellular interplay between different cell types to assess underlying disease mechanisms and test therapies. Here we present an adapted ex vivo organotypic slice culture method using human post-mortem brain tissue cultured at an air-liquid interface to also study brain white matter. We assessed whether these human post-mortem brain slices recapitulate the in vivo neuropathology and if they are suitable for pathophysiological, experimental and pre-clinical treatment development purposes, specifically regarding leukodystrophies. Human post-mortem brain tissue and cerebrospinal fluid were obtained from control, psychiatric and leukodystrophy donors. Slices were cultured up to six weeks, in culture medium with or without human cerebrospinal fluid. Human post-mortem organotypic brain slice cultures remained viable for at least six weeks ex vivo and maintained tissue structure and diversity of (neural) cell types. Supplementation with cerebrospinal fluid could improve slice recovery. Patient-derived organotypic slice cultures recapitulated and maintained known in vivo neuropathology. The cultures also showed physiologic multicellular responses to lysolecithin-induced demyelination ex vivo, indicating their suitability to study intrinsic repair mechanisms upon injury. The slice cultures were applicable for various experimental studies, as multi-electrode neuronal recordings. Finally, the cultures showed successful cell-type dependent transduction with gene therapy vectors. These human post-mortem organotypic brain slice cultures represent an adapted ex vivo model suitable for multifaceted studies of brain disease mechanisms, boosting translation from human ex vivo to in vivo. This model also allows for assessing potential treatment options, including gene therapy applications. Human post-mortem brain slice cultures are thus a valuable tool in preclinical research to study the pathomechanisms of a wide variety of brain diseases in living human tissue.

Does Getting Sick More Often Impact the Way Our Brain Cells Work and How We Learn and Remember?

Does Getting Sick More Often Impact the Way Our Brain Cells Work and How We Learn and Remember?

CNN and XGBoost for Automatic Segmentation of Stroke Lesions using CT Data

The negative impact of stroke on society has led to a concerted effort to improve stroke management and diagnosis. Technological advances have led to the development of deep learning techniques that can be used to accurately detect and characterize brain damage caused by stroke. The ubiquitous growth of artificial intelligence and its medical applications has improved the efficiency of healthcare systems for patients requiring rapid care. Today, chronic diseases such as stroke are the leading cause of death worldwide. A stroke is a type of brain injury. Stroke lesions occur when a group of brain cells dies due to a lack of blood supply. Stroke damage can disrupt brain function, causing a wide range of symptoms such as weakness, disturbance of one or more senses and confusion. It is important to detect and characterize the damaged areas of brain tissue caused by stroke accurately, quickly and effectively in order to save the patient. Stroke diagnosis often relies on expensive imaging techniques such as CT and magnetic resonance imaging (MRI), which are expensive nevertheless CT is more available and accessible in some African hospitals in general and in Senegal in particular. We therefore use a CT dataset to automatically segment stroke lesions. We find that CNN combined with XGBoost can effectively detect, classify and characterize stroke-damaged areas.