Complex Central Nervous System Research Articles

Exploring the feasibility of integrating ultra‐high field magnetic resonance imaging neuroimaging with multimodal artificial intelligence for clinical diagnostics

AbstractBackgroundThe integration of 7 Tesla (7T) magnetic resonance imaging (MRI) with advanced multimodal artificial intelligence (AI) models represents a promising frontier in neuroimaging. The superior spatial resolution of 7TMRI provides detailed visualizations of brain structure, which are crucial forunderstanding complex central nervous system diseases and tumors. Concurrently, the application of multimodal AI to medical images enables interactive imaging‐based diagnostic conversation.MethodsIn this paper, we systematically investigate the capacity and feasibility of applying the existing advanced multimodal AI model ChatGPT‐4V to 7T MRI under the context of brain tumors. First, we test whether ChatGPT‐4V has knowledge about 7T MRI, and whether it can differentiate 7T MRI from 3T MRI. In addition, we explore whether ChatGPT‐4V can recognize different 7T MRI modalities and whether it can correctly offer diagnosis of tumors based on single or multiple modality 7T MRI.ResultsChatGPT‐4V exhibited accuracy of 84.4% in 3T‐vs‐7T differentiation and accuracy of 78.9% in 7T modality recognition. Meanwhile, in a human evaluation with three clinical experts, ChatGPT obtained average scores of 9.27/20 in single modality‐based diagnosis and 21.25/25 in multiple modality‐based diagnosis. Our study indicates that single‐modality diagnosis and the interpretability of diagnostic decisions in clinical practice should be enhanced when ChatGPT‐4V is applied to 7T data.ConclusionsIn general, our analysis suggests that such integration has promise as a tool to improve the workflow of diagnostics in neurology, with a potentially transformative impact in the fields of medical image analysis and patient management.

Possible roles of neuropeptide/transmitter and autoantibody modulation in emotional problems and aggression.

The theoretical foundations of understanding psychiatric disorders are undergoing changes. Explaining behaviour and neuroendocrine cell communication leaning towards immunology represents a different approach compared to previous models for understanding complex central nervous system processes. One such approach is the study of immunoglobulins or autoantibodies, and their effect on peptide hormones in the neuro-endocrine system. In the present review, we provide an overview of the literature on neuropeptide/transmitter and autoantibody modulation in psychiatric disorders featuring emotional problems and aggression, including associated illness behaviour. Finally, we discuss the role of psycho-immunology as a growing field in the understanding of psychiatric disorders, and that modulation and regulation by IgG autoAbs represent a relatively new subcategory in psycho-immunology, where studies are currently being conducted.

Flexible scaffold-based cheminformatics approach for polypharmacological drug design

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

Navigating the complexities of encephalocraniocutaneous lipomatosis: a case series and review

IntroductionEncephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with complex skin, eye, and central nervous system (CNS) symptoms. Diagnosis and treatment are challenging due to its rarity and diverse manifestations. It often involves issues like porencephalic cysts, cortical atrophy, and low-grade gliomas in the CNS, resulting in developmental delays. The spinal cord is frequently affected, leading to problems like medullary compression and radiculopathy, causing back pain and sensory/motor deficits. Surgical interventions are reserved for symptomatic cases to address hydrocephalus or alleviate spinal lipomas. This article reviews a case series to assess surgical risks and neurological outcomes.Case seriesWe present a case series ECCL, focusing on the diffuse lipomatosis of the spinal cord and the intricate surgical procedures involved. A multi-stage surgical approach was adopted, with continuous neuromonitoring employed to safeguard motor pathways. We discuss clinical characteristics, imaging studies, and indications for neurosurgical interventions.DiscussionECCL is a complex syndrome. Diagnosis is challenging and includes clinical evaluation, neuroimaging, and genetic testing. Treatment targets specific symptoms, often requiring surgery for issues like lipomas or cerebral cysts. Surgery involves laminectomies, spinal fusion, and motor pathway monitoring. Thorough follow-up is crucial due to potential CNS complications like low-grade gliomas. Hydrocephalus occurs in some cases, with endoscopic third ventriculostomy (ETV) preferred over ventriculoperitoneal shunt placement.ConclusionNeurosurgery for ECCL is for symptomatic cases. ETV is preferred for hydrocephalus, while the treatment for lipoma is based on the presence of symptoms; the follow-up should assess growth and prevent deformities.

The protective effects of hesperidin as an antioxidant against quinolinic acid-induced toxicity on oligodendroglia cells: An in vitro study

Introduction: Multiple sclerosis (MS) is a complex central nervous system disorder, marked by neurodegenerative and inflammatory processes, where overproduction of reactive oxygen species (ROS) is a key factor in demyelination and neurodegeneration. The current study aims to investigate the effect of hesperidin and Quinolinic acid (QA) on ROS and antioxidant levels, and cell viability of OLN-93 cells. Methods: OLN-93 cell lines were treated with hesperidin and QA. OLN-93 cells were cultured in Dulbecco's modified Eagle's medium under controlled conditions. Cell viability assays were performed using resazurin to assess the toxicity of hesperidin and QA. Additionally, ROS levels were measured using DCFDA, and malondialdehyde (MDA) levels were determined to evaluate oxidative stress. Superoxide dismutase (SOD) activity and cell viability were assessed by trypan blue staining after exposure to hesperidin and QA. Results: The results of the current study showed that co-administration of 8 mM QA with 50, 100, and 200 μM hesperidin significantly reduced both ROS and MDA levels, demonstrating a substantial attenuation in comparison to the elevated ROS and MDA levels induced by 8 mM QA (p-value < 0.01). Furthermore, 8 mM QA + 50, 100, and 200 μM hesperidin significantly increased SOD levels compared with QA alone (p-value < 0.01). In addition, treatment of OLN cells with 8 mM QA + 50, 100, and 200 μM hesperidin led to higher cell viability compared to QA alone (p value <0.0001). Conclusion: The current study demonstrated the antioxidant effect of hesperidin on OLN-93 cells suggesting new insights into the clinical application of hesperidin as an effective treatment for patients with MS. Future in vivo studies, focusing on cellular mechanisms are recommended.

Outcome Disparities Among Hispanic and Non-Hispanic Patients with Acute Lymphoblastic Leukemia

Introduction: Acute lymphoblastic leukemia (ALL) is the predominant type of leukemia diagnosed in children and accounts for approximately 20% of all cases of acute leukemia in adults. In pediatric cases, ALL generally exhibits a favorable prognosis and outcome. Unfortunately, this optimistic scenario does not extend to adults, as the majority of deaths related to ALL occur in this age group. The outcomes observed in children with ALL are linked to the favorable cytogenetic profile of their leukemia. However, as individuals age, the cytogenetic profile progressively shifts towards high-risk groups. Furthermore, several epidemiologic studies have identified ethnicity, specifically Hispanic and African American backgrounds, as independent factors associated with worse outcomes. The factors contributing to these outcomes are diverse and include limited healthcare access, insurance coverage, immigration status, treatment adherence, socioeconomic status, and timeliness of treatment initiation, among others. Additionally, individuals of Hispanic ethnicity are more prone to complex cytogenetics and Central Nervous System involvement, both of which are commonly associated with a poor prognosis. Our study aimed to assess the differences in treatment outcomes among adults diagnosed with ALL by conducting a specific comparison between non-Hispanic and Hispanic individuals. Methods: In this retrospective observational study, we collected data from the electronic medical records (EMR) of patients aged 18 years and older who received a diagnosis of Acute Lymphoblastic Leukemia between February 1, 2011, and February 28, 2020 at Ascension Seton Hospitals in Texas. The collected data included sociodemographic factors such as gender, ethnicity, and age at diagnosis, as well as clinical characteristics such as cytogenetics, immunophenotype, treatment, and overall survival. Bivariate and multivariate analyses were conducted using a chi-squared test. Statistical significance was defined as a P-value less than 0.05. Results: A total of 56 patients with ALL were identified, with 45% being non-Hispanic and 55% being Hispanic. The incidence of ALL did not show significant variation based on gender or age, but it exhibited a significant difference depending on insurance status. The analysis revealed that Hispanic patients had a significantly higher likelihood of lacking insurance coverage (75%) compared to non-Hispanic patients (25%), with a statistically significant p-value of 0.001. With the exception of one non-Hispanic patient diagnosed with T-cell ALL, almost all participants in the study had B-cell ALL. Among the patients who received chemotherapy, 44% were non-Hispanic, while 56% were Hispanic. Among patients with t(9;22)/BCR-ABL1 positive ALL, non-Hispanics represented 76% and Hispanics represented 23%. Other cytogenetic abnormalities, including CRLF2-IGH fusion, IgH rearrangement, CRLF2 rearrangement, PBX1/TCF3 fusion, t(1;19) with PBX1/TCF3 fusion, ETV6 deletion, near haploidy, and 9p deletion, were more prevalent in Hispanic patients (79%) compared to non-Hispanic patients (21%). The overall survival rates at 1 year were 64% for non-Hispanic patients and 67.7% for Hispanic patients. However, at 3 years, the overall survival rates decreased to 32% for non-Hispanic patients and 25.8% for Hispanic patients. Conclusions: Our study provides important insights into the demographic and clinical characteristics of patients with ALL and highlights notable disparities between non-Hispanic and Hispanic patients. A higher proportion of Hispanic patients lacked any form of health insurance coverage at the time of diagnosis. Interestingly, the incidence of Philadelphia-positive ALL was found to be higher among non-Hispanic patients, whereas other cytogenetic abnormalities were more prevalent among Hispanic patients. Additionally, Hispanic patients experienced lower rates of overall survival at 3 years, suggesting potential disparities in outcomes. The differences observed between Hispanic and non-Hispanic patients highlight the necessity for additional investigation and tailored interventions to address the specific challenges faced by Hispanic patients, including access to healthcare, insurance coverage, and the prevalence of unfavorable cytogenetic abnormalities.

Advancements in the Application of Nanomedicine in Alzheimer's Disease: A Therapeutic Perspective.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood-brain and blood-cerebrospinal fluid barriers are two barriers that protect the central nervous system, their presence has severely restricted the efficacy of many treatments that have been studied for AD diagnosis and/or therapy. The use of nanoparticles for the diagnosis and treatment of AD is the focus of an established and rapidly developing field of nanomedicine. Recent developments in nanomedicine have made it possible to effectively transport drugs to the brain. However, numerous obstacles remain to the successful use of nanomedicines in clinical settings for AD treatment. Furthermore, given the rapid advancement in nanomedicine therapeutics, better outcomes for patients with AD can be anticipated. This article provides an overview of recent developments in nanomedicine using different types of nanoparticles for the management and treatment of AD.

West syndrome and multiple sclerosis association

Introduction. West syndrome is a rare and severe infantile epileptic encephalopathy, beginning around the age of six months, characterized by a classic electro-clinical triad. This is a pathology totally different from multiple sclerosis (MS) which is a demyelinating disease of the central nervous system caused, affecting young adults, especially females. The association of these two pathologies has never been described. Observation. We report here an exceptional presentation of MS in a 14-year-old girl with a history of West syndrome. She had normal development until the age of six months, when she began to have flexion spasms. The diagnosis of West syndrome was made with a normal MRI. The infantile spasms disappeared after treatment with vigabatrin and adrenocorticotropic hormone (ACTH). It had generally progressed to Lennox Gastaut encephalopathy, with delayed psychomotor development and epileptic sequelae. At 14, she presented with left hemiparesis within a few days. A cerebral MRI showed multiple nodular hyperintensities of the supra and infratentorial white matter, with the presence of an active lesion, fulfilling the diagnostic criteria for multiple sclerosis. CSF analysis was normal. Anti-AQP4, anti-MOG, anti-NMDA and anti-GABA (AB) antibodies were absent in the blood. Antibodies against HIV and viral hepatitis were. Biotinidase activity and autoimmunity tests were correct. The patient received high doses of methylprednisolone IV (1g/day) for three days with remarkable clinical improvement after 15 days. Discussion. MS is a complex and heterogeneous central nervous system (CNS) demyelinating disease. It is not uncommon for epilepsy to be the first symptom of multiple sclerosis. Seizures, on the other hand, are more common after disease progression. Although the disease is characterized by inflammatory lesions of the white matter, various neuropathological and radiological studies have shown that the disease also affects the grey matter. Several studies have shown that seizures are three to six times more common in MS patients than in the general population. Even though MS can start with epilepsy and a seizure may be the only symptom of a relapse of MS, it is still not known whether the two diseases coexist or whether MS predisposes to seizures. Conclusion. The association of these two totally different pathologies can lead us to say that the mechanism of multiple sclerosis may begin in childhood and that the clinical signs appear in adulthood.

Recording electrical activity from the brain of behaving octopus

Octopuses, which are among the most intelligent invertebrates,1,2,3,4 have no skeleton and eight flexible arms whose sensory and motor activities are at once autonomous and coordinated by a complex central nervous system.5,6,7,8 The octopus brain contains a very large number of neurons, organized into numerous distinct lobes, the functions of which have been proposed based largely on the results of lesioning experiments.9,10,11,12,13 In other species, linking brain activity to behavior is done by implanting electrodes and directly correlating electrical activity with observed animal behavior. However, because the octopus lacks any hard structure to which recording equipment can be anchored, and because it uses its eight flexible arms to remove any foreign object attached to the outside of its body, invivo recording of electrical activity from untethered, behaving octopuses has thus far not been possible. Here, we describe a novel technique for inserting a portable data logger into the octopus and implanting electrodes into the vertical lobe system, such that brain activity can be recorded for up to 12h from unanesthetized, untethered octopuses and can be synchronized with simultaneous video recordings of behavior. In the brain activity, we identified several distinct patterns that appeared consistently in all animals. While some resemble activity patterns in mammalian neural tissue, others, such as episodes of 2Hz, large amplitude oscillations, have not been reported. By providing an experimental platform for recording brain activity in behaving octopuses, our study is a critical step toward understanding how the brain controls behavior in these remarkable animals.

P-786 Perinatal outcomes of assisted reproduction technology (ART) pregnancies after transfer of mosaic blastocysts: a single centre matched cohort study

Abstract Study question Do viable pregnancies after transfer of mosaic blastocysts present different perinatal outcomes as compared to those deriving from transfer of euploid blastocysts? Summary answer Pregnancies from transfer of mosaic vs. euploid blastocysts showed an increased rate of fetal structural malformations and postpartum haemorrhages (PPH). What is known already The incidence of mosaicisms in the trophoectoderm is a relatively frequent event and most true embryo mosaicisms result in spontaneous intrauterine demise. The confirmation of the mosaic aneuploidy in the fetus is related to the type and grade of the aneuploidy with higher risk for chromosomes 13, 14, 15, 16, 18 and 21 and X monosomy. On the other hand, selected mosaic blastocysts have been transferred with subsequent birth of healthy neonates. However, the risk of abnormal obstetric outcomes after transfer of mosaic embryos remains to be completely elucidated. Study design, size, duration Explorative cohort study between 2016 and 2021 including consecutive viable ART pregnancies developing from transfer of mosaic blastocysts (n = 39 cases). Transfer of available mosaic embryos was considered for patients with a poor response to ovarian stimulation or recurrent implantation failures and no available euploid blastocysts, after genetic counselling. Cases were matched for maternal age, parity and body mass index to women with viable pregnancies after transfer of euploid blastocysts (n = 39, controls) and followed-up until delivery. Participants/materials, setting, methods All patients recruited at San Raffaele, Scientific Institute of Milan, underwent a prenatal genetic testing by trophoectoderm biopsy and next-generation sequencing analysis. Patients with a viable fetus at 12 weeks gestation were included and underwent detailed ultrasound assessment at 12, 20 and 32 weeks including fetal biometry and anatomical survey. Frequency of adverse pregnancy and perinatal outcomes including maternal, fetal and delivery complications were compared between patients who received a mosaic versus a euploid blastocyst. Main results and the role of chance No difference in indications to preimplantation diagnosis was found between cases and controls. In the group who transferred mosaic embryos, median rate of mosaicisms was 35% (IQR 30%-40%) and they were characterized by heterogeneous anomalies including complex aneuploidies (n = 12), autosomal monosomies (n = 13), trisomies (n = 8) and duplications/deletions (n = 6). Invasive testing was performed in 62.0% of mosaics (5 chorion villous samplings; 19 amniocenteses; 2 anomalies: confined placental mosaicism trisomy 15 after transfer of mosaic monosomy 6 and fetal microduplication 6p after transfer of mosaic deletion 10p) vs 2.5% of controls (p &amp;lt; 0.001). Structural malformations were observed in 6 neonates in the study group (tanatophoric skeletal dysplasia, complex central nervous system anomaly, congenital diaphragmatic hernia, cerebral arteriovenous fistulae, pyeloureteral junction stenosis, diffuse haemangiomatosis) compared to 1 in controls (pulmonary stenosis) (p = 0.04). One neonate per group was followed-up for future surgery. PPH rate was significantly higher in cases vs controls (15 vs 7; p = 0.04). Neonatal survival at hospital discharge was not different in the two groups (p = 0.30). No significant differences were recorded in rates of preterm birth, small or large for gestational age, fetal growth restriction, miscarriage, preeclampsia and median birthweight centile or gestational age at birth. Limitations, reasons for caution Data from our exploratory study should be interpreted cautiously given the limited sample size which makes it challenging to infer a causal relationship between the association found and transfer of mosaic blastocysts. Wider implications of the findings The higher rates of structural malformations and PPH in ART pregnancies after transfer of mosaic embryos strongly suggest the need for strict monitoring of these patients. First and second trimester ultrasound screening for structural defects, and preventive measures to minimize bleeding at delivery should be implemented. Trial registration number not applicable

Identifying Gene Signature in RNA Sequencing Multiple Sclerosis Data

Objectives: Multiple Sclerosis (MS) is a complex central nervous system disease; it is the result of a combination of genetic predispositions and a nongenetic trigger. This study aims to find the gene signatures using a Pareto optimization algorithm for MS RNA sequencing (RNA-seq) data. Methods: This case-control study involved 50 samples (25 MS patients and 25 age-matched healthy individuals) and their GSE profiles (GSE123496) were selected from the National Center for Biotechnology Information Gene Expression Omnibus database. We used Pareto-optimal cluster size identification to find the gene signatures in the RNA-seq data. After prefiltering and normalizing the data, we used the Limma package to find the differentially expressed genes (DEGs). The Pareto-optimal cluster size for these DEGs was then determined using the technique, multi-objective optimization for collecting the clusters alternatives. Afterward, the RNA-seq data were clustered via k-means with suitable cluster size. The best cluster, as a signature, was found by calculating the mean of the Spearman correlation coefficients (SCCs) of whole genes in the module in a pairwise manner. All analysis was performed in the R software, 4.1.1 package, under virtual space with 100 GB RAM. Results: In total, 960 DEGs were identified by the Limma analysis. Among them, 720 were up-regulated genes and 240 were down-regulated genes. Meanwhile, 6 Pareto-optimal clusters were obtained. Two clusters that had the greatest average SCCs score (0.88 and 0.74, respectively) were chosen as the gene signatures. Discussion: A total of 9 metabolic prognostic genes and 3 biological pathways were identified. These can provide more potent prognostic information for MS patients.

The Effect of Peripheral Immune Cell Counts on the Risk of Multiple Sclerosis: A Mendelian Randomization Study.

ObjectivesMultiple sclerosis (MS) is a complex central nervous system (CNS) demyelinating disease, the etiology of which involves the interplay between genetic and environmental factors. We aimed to determine whether genetically predicted peripheral immune cell counts may have a causal effect on MS.MethodsWe used genetic variants strongly associated with cell counts of circulating leukocyte, lymphocyte, monocyte, neutrophil, eosinophil, and basophil, in addition to some subpopulations of T and B lymphocyte, as instrumental variables (IVs) to perform Mendelian randomization (MR) analyses. The effect of immune cell counts on MS risk was measured using the summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) genome-wide association studies (GWAS).ResultsOur findings indicated that higher leucocyte count [odds ratio (OR), 1.24; 95% confidence interval (CI), 1.07 - 1.43; p = 0.0039] and lymphocyte count (OR, 1.17; 95% CI, 1.01 – 1.35; p = 0.0317) were causally associated with MS susceptibility. In addition, we also found that increase of genetically predicted natural killer T (NKT) cell count is also associated with an increase MS risk (OR, 1.24; 95% CI, 1.06 - 1.45; p = 0.0082).ConclusionsThese findings show that the genetic predisposition to higher peripheral immune cell counts can exert a causal effect on MS risk, which confirms the crucial role played by peripheral immunity in MS. Particularly, the causal association between NKT cell count and MS underscores the relevance of exploring the functional roles of NKT cells in disease pathogenesis in future.

ANXIOGENIC EFFECT OF AN ATYPICAL ANTIPSYCHOTIC, OLANZAPINE IN PRE-CLINICAL MODELS

Introduction: Atypical antipsychotics, such as olanzapine, act on multiple neurotransmitter pathways and produce complex central nervous system effects. Pre-clinical and clinical studies conducted in the past, to study their effects on anxiety, have come up with confusing and contradictory observations. Some studies have even indicated anxiogenic effect of these novel drugs. These observations are significant, because anxiety symptoms are known to be present in about 65% of schizophrenia patients. Any possible anxiogenic effect by one of the extensively used antipsychotic can have adverse impact on these patients. Hence, this study was undertaken with the aim of evaluating olanzapine for its effects on anxiety, in preclinical models. Methods: Rats of either sex weighing between 150 and 300 g were placed into three groups of six each. For 10 days, oral doses of the test drug (olanzapine 2 mg/kg), the control drug (distilled water), and the standard drug (diazepam 1 mg/kg) were given. The animals were taken for the elevated plus maze (EPM) and light dark arena (LDA) screening tests on the 10th day, 1 h after the compounds were administered. Results: Olanzapine treatment significantly reduced the amount of time that animals spent in open arms (p&lt;0.05) of the EPM, and highly lighted compartments (p&lt;0.05) of LDA, as compared to animals receiving control treatment, showing a significant anxiogenic impact. Conclusions: Olanzapine has exhibited potential to produce anxiogenic effect in preclinical models. Hence, it is suggested to use olanzapine with caution in patients of schizophrenia with anxiety symptoms.

A High-Throughput Chemical Screen in DJ-1\u03b2 Mutant Flies Identifies Zaprinast as a Potential Parkinson\u2019s Disease Treatment

Dopamine replacement represents the standard therapy for Parkinson’s disease (PD), a common, chronic, and incurable neurological disorder; however, this approach only treats the symptoms of this devastating disease. In the search for novel disease-modifying therapies that target other relevant molecular and cellular mechanisms, Drosophila has emerged as a valuable tool to study neurodegenerative diseases due to the presence of a complex central nervous system, the blood–brain barrier, and a similar neurotransmitter profile to humans. Human PD-related genes also display conservation in flies; DJ-1β is the fly ortholog of DJ-1, a gene for which mutations prompt early-onset recessive PD. Interestingly, flies mutant for DJ-1β exhibit PD-related phenotypes, including motor defects, high oxidative stress (OS) levels and metabolic alterations. To identify novel therapies for PD, we performed an in vivo high-throughput screening assay using DJ-1β mutant flies and compounds from the Prestwick® chemical library. Drugs that improved motor performance in DJ-1ß mutant flies were validated in DJ-1-deficient human neural-like cells, revealing that zaprinast displayed the most significant ability to suppress OS-induced cell death. Zaprinast inhibits phosphodiesterases and activates GPR35, an orphan G-protein-coupled receptor not previously associated with PD. We found that zaprinast exerts its beneficial effect in both fly and human PD models through several disease-modifying mechanisms, including reduced OS levels, attenuated apoptosis, increased mitochondrial viability, and enhanced glycolysis. Therefore, our results support zaprinast as a potential therapeutic for PD in future clinical trials.

The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application.

Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studies show that exosomal miRNA plays an important role in glioma occurrence, development, invasion, metastasis, and treatment resistance. However, the association of exosomal miRNA between glioma has not been systemically characterized. This will provide a theoretical basis for us to further explore the relationship between exosomal miRNAs and glioma and also has a positive clinical significance in the innovative diagnosis and treatment of glioma.

Molecular and morphological analysis of the developing nemertean brain indicates convergent evolution of complex brains in Spiralia

BackgroundThe brain anatomy in the clade Spiralia can vary from simple, commissural brains (e.g., gastrotrichs, rotifers) to rather complex, partitioned structures (e.g., in cephalopods and annelids). How often and in which lineages complex brains evolved still remains unclear. Nemerteans are a clade of worm-like spiralians, which possess a complex central nervous system (CNS) with a prominent brain, and elaborated chemosensory and neuroglandular cerebral organs, which have been previously suggested as homologs to the annelid mushroom bodies. To understand the developmental and evolutionary origins of the complex brain in nemerteans and spiralians in general, we investigated details of the neuroanatomy and gene expression in the brain and cerebral organs of the juveniles of nemertean Lineus ruber.ResultsIn the juveniles, the CNS is already composed of all major elements present in the adults, including the brain, paired longitudinal lateral nerve cords, and an unpaired dorsal nerve cord, which suggests that further neural development is mostly related with increase in the size but not in complexity. The ultrastructure of the juvenile cerebral organ revealed that it is composed of several distinct cell types present also in the adults. The 12 transcription factors commonly used as brain cell type markers in bilaterians show region-specific expression in the nemertean brain and divide the entire organ into several molecularly distinct areas, partially overlapping with the morphological compartments. Additionally, several of the mushroom body-specific genes are expressed in the developing cerebral organs.ConclusionsThe dissimilar expression of molecular brain markers between L. ruber and the annelid Platynereis dumerilii indicates that the complex brains present in those two species evolved convergently by independent expansions of non-homologous regions of a simpler brain present in their last common ancestor. Although the same genes are expressed in mushroom bodies and cerebral organs, their spatial expression within organs shows apparent differences between annelids and nemerteans, indicating convergent recruitment of the same genes into patterning of non-homologous organs or hint toward a more complicated evolutionary process, in which conserved and novel cell types contribute to the non-homologous structures.

Bioengineered optogenetic model of human neuromuscular junction

Functional human tissues engineered from patient-specific induced pluripotent stem cells (hiPSCs) hold great promise for investigating the progression, mechanisms, and treatment of musculoskeletal diseases in a controlled and systematic manner. For example, bioengineered models of innervated human skeletal muscle could be used to identify novel therapeutic targets and treatments for patients with complex central and peripheral nervous system disorders. There is a need to develop standardized and objective quantitative methods for engineering and using these complex tissues, in order increase their robustness, reproducibility, and predictiveness across users. Here we describe a standardized method for engineering an isogenic, patient specific human neuromuscular junction (NMJ) that allows for automated quantification of NMJ function to diagnose disease using a small sample of blood serum and evaluate new therapeutic modalities. By combining tissue engineering, optogenetics, microfabrication, optoelectronics and video processing, we created a novel platform for the precise investigation of the development and degeneration of human NMJ. We demonstrate the utility of this platform for the detection and diagnosis of myasthenia gravis, an antibody-mediated autoimmune disease that disrupts the NMJ function.

Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease

The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC50 = 3.08 ± 0.29 μM) and exhibited good anti-neuroinflammatory activity (IC50 = 2.91 ± 0.47 μM) against NO production through remarkably blocking the NF-κB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 μM concentration. Furthermore, possessing significant self-mediated Aβ1-42 aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood–brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents.

Noncanonical Transmission of a Measles Virus Vaccine Strain from Neurons to Astrocytes.

Viruses, including members of the herpes-, entero-, and morbillivirus families, are the most common cause of infectious encephalitis in mammals worldwide. During most instances of acute viral encephalitis, neurons are typically the initial cell type that is infected. However, as replication and spread ensue, other parenchymal cells can become viral targets, especially in chronic infections. Consequently, to ascertain how neurotropic viruses trigger neuropathology, it is crucial to identify which central nervous system (CNS) cell populations are susceptible and permissive throughout the course of infection, and to define how viruses spread between distinct cell types. Using a measles virus (MV) transgenic mouse model that expresses human CD46 (hCD46), the MV vaccine strain receptor, under the control of a neuron-specific enolase promoter (NSE-hCD46+ mice), a novel mode of viral spread between neurons and astrocytes was identified. Although hCD46 is required for initial neuronal infection, it is dispensable for heterotypic spread to astrocytes, which instead depends on glutamate transporters and direct neuron-astrocyte contact. Moreover, in the presence of RNase A, astrocyte infection is reduced, suggesting that nonenveloped ribonucleoproteins (RNP) may cross the neuron-astrocyte synaptic cleft. The characterization of this novel mode of intercellular transport offers insights into the unique interaction of neurons and glia and may reveal therapeutic targets to mitigate the life-threatening consequences of measles encephalitis.IMPORTANCE Viruses are the most important cause of infectious encephalitis in mammals worldwide; several thousand people, primarily the very young and the elderly, are impacted annually, and few therapies are reliably successful once neuroinvasion has occurred. To understand how viruses contribute to neuropathology, and to develop tools to prevent or ameliorate such infections, it is crucial to define if and how viruses disseminate among the different cell populations within the highly complex central nervous system. This study defines a noncanonical mode of viral transmission between neurons and astrocytes within the brain.

Interaction between Neurons and the Oligodendroglial Lineage in Multiple Sclerosis and Its Preclinical Models.

Multiple sclerosis (MS) is a complex central nervous system inflammatory disease leading to demyelination and associated functional deficits. Though endogenous remyelination exists, it is only partial and, with time, patients can enter a progressive phase of the disease, with neurodegeneration as a hallmark. Though major therapeutic advances have been made, with immunotherapies reducing relapse rate during the inflammatory phase of MS, there is presently no therapy available which significantly impacts disease progression. Remyelination has been shown to favor neuroprotection, and it is thus of major importance to better understand remyelination mechanisms in order to promote them and hence preserve neurons. A crucial point is how this process is regulated through the neuronal crosstalk with the oligodendroglial lineage. In this review, we present the current knowledge on neuron interaction with the oligodendroglial lineage, in physiological context as well as in MS and its experimental models. We further discuss the therapeutic possibilities resulting from this research field, which might allow to support remyelination and neuroprotection and thus limit MS progression.