scholarly journals Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion

2018 ◽  
Author(s):  
Yuchen Chen ◽  
Ningxin Ma ◽  
Zifei Pei ◽  
Zheng Wu ◽  
Fabricio H. Do-Monte ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Cortical Neurons ◽  
High Efficiency ◽  
Therapeutic Potential ◽  
Ischemic Injury ◽  
Memory Deficits ◽  
Neural Regeneration ◽  
Novel Treatment ◽  
Regeneration Capability

ABSTRACTMammalian brains have largely lost internal neural regeneration capability except for a few discrete neurogenic niches. After brain injury, the cerebral cortex is especially difficult to repair due to its extremely low rate of adult neurogenesis. Previous studies have converted glial cells into neurons, but the total number of neurons generated is rather limited, casting doubt about its therapeutic potential. Here, we demonstrate that high-efficiency neuroregeneration can be achieved in adult mammalian brains by making use of an engineered AAV Cre-FLEX system to convert a large number of reactive astrocytes into functional neurons. Specifically, using a combination of GFAP::Cre and FLEX-NeuroD1 AAV system, we were able to regenerate enough new neurons from astrocytes to cover about 40% of the neurons lost from an ischemic injury (400 NeuN+ new neurons/mm2), compared to previously reported an average of <1% of cortical neurons (2-8 NeuN+ neurons/mm2) in an ischemic-injured adult mammalian cortex. Importantly, this in situ astrocyte-to-neuron conversion process also improved survival of injured pre-existing neurons, (additional 400 neurons/mm2), leading to a repaired motor cortex with layered cortical structures. Moreover, NeuroD1-converted neurons not only form functional neural circuits but also rescue motor and memory deficits after ischemic injury. Our results establish the proof-of-principle that a highly efficient in situ astrocyte-to-neuron conversion approach provides a novel treatment for neurological disorders that are in need of new neurons.

scholarly journals The Expanding Therapeutic Potential of Neuronal KCC2

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 240 ◽  
Author(s):  
Bor Luen Tang
Keyword(s):  
Spinal Cord ◽  
Mouse Model ◽  
Neurological Disorders ◽  
Healthy Adult ◽  
Therapeutic Potential ◽  
Reversal Potential ◽  
Memory Deficits ◽  
Inhibitory Input ◽  
Disease Phenotype ◽  
Neural Transmission

Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

Nano-Neurotherapeutics (NNTs): An Emergent and Multifaceted Tool for CNS Disorders

2020 ◽  
Vol 21 ◽  
Author(s):  
Aashish Sharma ◽  
Romila Manchanda ◽  
Faheem Hyder Pottoo ◽  
Ghulam Md. Ashraf
Keyword(s):  
Central Nervous System ◽  
Neurological Disorders ◽  
Driving Force ◽  
Treatment Options ◽  
Clinical Aspects ◽  
Future Scenarios ◽  
Cns Disorders ◽  
Drug Conjugates ◽  
Novel Treatment ◽  
Pharmacological Targets

: Impressive research steps have been taken for the treatment of neurological disorders in the last few decades. Still effective treatments of brain related disorders are very less due to problems associated with crossing the blood brain barrier (BBB), non-specific therapies, and delay in functional recovery of central nervous system (CNS) after treatment. Striving for novel treatment options for neurological disorders, nanotechnology-derived materials, and devices have gained the ground due to inherent features of derivatization/encapsulation with drugs as per the neurological ailments and pharmacological targets. Facile developments/syntheses of the nanomaterials-drug conjugates have also been the driving force for researchers to get into this field. Moreover, the tunable size and hydro/lipophilicity of these nanomaterials are the added advantages that make these materials more acceptable for CNS disorders. These nano-neurotherapeutics (NNTs) systems provide the platform for diagnosis, theranostics, treatments, restoration of CNS disorders, and encourage the translation of NNTs from “bench to bedside”. Still, these techniques are in primary stages of medical development. This review describes the latest advancements and future scenarios of developmental and clinical aspects of polymeric NNTs.

scholarly journals mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1043 ◽  
Author(s):  
Phil Jun Kang ◽  
Daryeon Son ◽  
Tae Hee Ko ◽  
Wonjun Hong ◽  
Wonjin Yun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Urine ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Patient Specific ◽  
Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

scholarly journals The Bacterial Enzyme Cas13 Interferes with Neurite Outgrowth from Cultured Cortical Neurons

Toxins ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 262
Author(s):  
Qin-Wei Wu ◽  
Josef P. Kapfhammer
Keyword(s):  
Rna Editing ◽  
Cortical Neurons ◽  
High Efficiency ◽  
Primary Cultures ◽  
Cultured Neurons ◽  
Therapeutic Tool ◽  
Bacterial Enzyme ◽  
Rna Targeting ◽  
Cultured Cortical Neurons ◽  
New Generation

The CRISPR-Cas13 system based on a bacterial enzyme has been explored as a powerful new method for RNA manipulation. Due to the high efficiency and specificity of RNA editing/interference achieved by this system, it is currently being developed as a new therapeutic tool for the treatment of neurological and other diseases. However, the safety of this new generation of RNA therapies is still unclear. In this study, we constructed a vector expressing CRISPR-Cas13 under a constitutive neuron-specific promoter. CRISPR-Cas13 from Leptotrichia wadei was expressed in primary cultures of mouse cortical neurons. We found that the presence of CRISPR-Cas13 impedes the development of cultured neurons. These results show a neurotoxic action of Cas13 and call for more studies to test for and possibly mitigate the toxic effects of Cas13 enzymes in order to improve CRISPR-Cas13-based tools for RNA targeting.

scholarly journals Influence of Casting Solvents on CO2/CH4 Separation Using Polysulfone Membranes

Membranes ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 286
Author(s):  
Roba M. Almuhtaseb ◽  
Ahmed Awadallah-F ◽  
Shaheen A. Al-Muhtaseb ◽  
Majeda Khraisheh
Keyword(s):  
High Efficiency ◽  
In Situ Synthesis ◽  
Separation Process ◽  
Polymeric Membranes ◽  
Gas Mixture ◽  
Manufacturing Cost ◽  
Binary Gas Mixture ◽  
Maximum Permeability ◽  
Polysulfone Membranes

Polysulfone membranes exhibit resistance to high temperature with low manufacturing cost and high efficiency in the separation process. The composition of gases is an important step that estimates the efficiency of separation in membranes. As membrane types are currently becoming in demand for CO2/CH4 segregation, polysulfone will be an advantageous alternative to have in further studies. Therefore, research is undertaken in this study to evaluate two solvents: chloroform (CF) and tetrahydrofuran (THF). These solvents are tested for casting polymeric membranes from polysulfone (PSF) to separate every single component from a binary gas mixture of CO2/CH4. In addition, the effect of gas pressure was conducted from 1 to 10 bar on the behavior of the permeability and selectivity. The results refer to the fact that the maximum permeability of CO2 and CH4 for THF is 62.32 and 2.06 barrer at 1 and 2 bars, respectively. Further, the maximum permeability of CF is 57.59 and 2.12 barrer at 1 and 2 bars, respectively. The outcome selectivity values are 48 and 36 for THF and CF at 1 bar, accordingly. Furthermore, the study declares that with the increase in pressure, the permeability and selectivity values drop for CF and THF. The performance for polysulfone (PSF) membrane that is manufactured with THF is superior to that of CF relative to the Robeson upper bound. Therefore, through the results, it can be deduced that the solvent during in-situ synthesis has a significant influence on the gas separation of a binary mixture of CO2/CH4.

High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

2021 ◽  
pp. jmedgenet-2020-107369
Author(s):  
Quentin Thomas ◽  
Antonio Vitobello ◽  
Frederic Tran Mau-Them ◽  
Yannis Duffourd ◽  
Agnès Fromont ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
High Efficiency ◽  
Neuromuscular Disorders ◽  
Daily Practice ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Cerebellar Ataxias ◽  
Mitochondrial Origin ◽  
Second Tier

ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

scholarly journals Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jesús David Urbano-Gámez ◽  
Juan José Casañas ◽  
Itziar Benito ◽  
María Luz Montesinos
Keyword(s):  
Intellectual Disability ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Memory Deficits ◽  
Prenatal Treatment ◽  
Hippocampal Pyramidal Neurons ◽  
Metabotropic Glutamate ◽  
Mushroom Spines

AbstractDown syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

Study on Mechanical Automation with Design of Rapid Milk Detector Based on Freezing Point

2013 ◽  
Vol 703 ◽  
pp. 282-286
Author(s):  
Ren Cai Zhang ◽  
Xiang Yu ◽  
Xing Ju Liu ◽  
Jin Hai Zhai ◽  
Zhen Wu Ning
Keyword(s):  
Integrated Circuit ◽  
Temperature Sensor ◽  
High Efficiency ◽  
Freezing Point ◽  
Electronic Control ◽  
Freezing Point Depression ◽  
Electronic Control System ◽  
Freezing Curve ◽  
Rack Mechanism

An efficient automated milk detector based on freezing point depression is designed. This detector shares characters of high efficiency and good stability with accuracy and automation. Its main parts include temperature sensor of IC (Integrated Circuit), pinion-rack mechanism and crank-rocker mechanism and electronic control system. Monitoring in-situ change of milk freezing curve and developing efficiency of sampling can be available by means of pinion-rack mechanism and IC temperature sensor mechatronics design. As a result, adulterating status of milk can be discriminated in a rapid and accurate and automated way. The detector may be employed to detect liquid foods other than milk as well.

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