Search

Mutations in Adenosine deaminase acting on RNA 1 (ADAR1) gene encoding RNA editing enzyme ADAR1 results in the neuroinflammatory leukodystrophy Aicardi Goutières Syndrome (AGS). AGS is an early onset leukoencephalopathy with an exacerbated interferon response leading to neurological regression with intellectual disability, spasticity, and motor deficits. We have generated three induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of individuals with ADAR1G1007R mutation. The generated iPSCs were investigated to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The reprogrammed iPSCs will allow us to model AGS, dissect the cellular mechanisms and testing different treatment targets.

Mutations in tubulin alpha 4a (TUBB4A) result in a spectrum of leukodystrophies, including Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC), resulting from a recurring mutation p.Asp249Asn (TUBB4AD249N). H-ABC presents with dystonia, motor and cognitive impairment and pathological features of hypomyelination and loss of cerebellar and striatal neurons. We have generated three induced pluripotent stem cell (iPSC) lines from fibroblast and peripheral blood mononuclear cells (PBMCs) of individuals with TUBB4AD249N mutation. The iPSCs were assessed to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The iPSCs will allow for disease modeling, understanding mechanisms and testing of therapeutic targets.

The goal of this research is to investigate the behaviours of porosity and squeezing phenomena in the presence of time-dependent heat flow that affect the flow rate and improve the system’s heating/cooling mechanism, reduce non-Newtonian fluid turbulence and scale-up flow tracers. Squeezing discs in the presence of no-slip velocity and convective surface boundary conditions induces a laminar, unstable and incompressible non-Newtonian fluid. The convective form of the momentum, concentration and energy equations are modelled for smooth discs to evaluate and offer an analytical and numerical examination of the flow for heat and mass transfer, which are further transformed to a highly non-linear system of ordinary differential equation using similarity transformations. In the case of smooth disks, the self-similar equations are solved using Homotopy Analysis Method (HAM) with appropriate initial guesses and auxiliary parameters to produce an algorithm with an accelerated and assured convergence. The comparison of HAM solutions with numerical solver programme BVP4 c proves the validity and correctness of HAM results. It is found that increasing or bypassing the Hartman number reduces the capillary region, making the Lorentz force effect more visible for small values of non-Newtonian parameter. The concentration rate at the bottom disc rises rapidly as the thermal diffusivity rises. In addition, because the rate of outflow from the flow domain increases, the suction/injection parameter lowers the radial velocity. Additionally, as the non-Newtonian parameter is increased, skin friction and heat/mass flux rise. In the suction/injection situation, all physical characteristics have the opposite effect on flow field profiles.

Glia cells are often viewed as support cells in the central nervous system, but recent discoveries highlight their importance in physiological functions and in neurological diseases. Central to this are leukodystrophies, a group of progressive, neurogenetic disease affecting white matter pathology. In this review, we take a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected. While white matter diseases involve oligodendrocyte and myelin loss, we discuss how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology. We provide an overview of the leukodystrophies covering their hallmark features, clinical phenotypes, diverse molecular pathways, and potential therapeutics for clinical trials. Glial cells are gaining momentum as cellular therapeutic targets for treatment of demyelinating diseases such as leukodystrophies, currently with no treatment options. Here, we bring the much needed attention to role of glia in leukodystrophies, an integral step towards furthering disease comprehension, understanding mechanisms and developing future therapeutics.

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.

Connexin 43 (Cx43) gap junctions and hemichannels mediate astrocyte intercellular communication in the central nervous system under normal conditions and contribute to astrocyte-mediated neurotoxicity in amyotrophic lateral sclerosis (ALS). Here, we show that astrocyte-specific knockout of Cx43 in a mouse model of ALS slows disease progression both spatially and temporally, provides motor neuron (MN) protection, and improves survival. In addition, Cx43 expression is up-regulated in human postmortem tissue and cerebrospinal fluid from ALS patients. Using human induced pluripotent stem cell-derived astrocytes (hiPSC-A) from both familial and sporadic ALS, we establish that Cx43 is up-regulated and that Cx43-hemichannels are enriched at the astrocyte membrane. We also demonstrate that the pharmacological blockade of Cx43-hemichannels in ALS astrocytes using GAP 19, a mimetic peptide blocker, and tonabersat, a clinically tested small molecule, provides neuroprotection of hiPSC-MN and reduces ALS astrocyte-mediated neuronal hyperexcitability. Extending the in vitro application of tonabersat with chronic administration to SOD1G93A mice results in MN protection with a reduction in reactive astrocytosis and microgliosis. Taking these data together, our studies identify Cx43 hemichannels as conduits of astrocyte- mediated disease progression and a pharmacological target for disease-modifying ALS therapies. [ABSTRACT FROM AUTHOR]

Mutations in Adenosine deaminase acting on RNA 1 (ADAR1) gene encoding RNA editing enzyme ADAR1 results in the neuroinflammatory leukodystrophy Aicardi Goutières Syndrome (AGS). AGS is an early onset leukoencephalopathy with an exacerbated interferon response leading to neurological regression with intellectual disability, spasticity, and motor deficits. We have generated three induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of individuals with ADAR1G1007R mutation. The generated iPSCs were investigated to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The reprogrammed iPSCs will allow us to model AGS, dissect the cellular mechanisms and testing different treatment targets. [ABSTRACT FROM AUTHOR]

In order to collect and study the morphological- phenological characteristics and ecological requirements of different poplars, 40 most successful clones were selected from Selection Nursery and transferred into Mother Individual collection by 5*5 and 4*4 m intervals for open and closed crown species, respectively, using five seedlings for each planting line. The collection is located in western Iran, near Yasooj in Kohgiluye and Buyerahmad province. The studied growth characteristics contained of diameter and height which recorded at the end of growth period. The phenological phenomena consisted of were flower, leaf, seed development and leaf fall. Furthermore, daily maximum and minimum temperature data was recorded all over the growth period. The results showed that the poplar biotic activity usually starts at March and ends at November. The phenological phenomena at different poplar species and clones started in different dates due to variation in species and clones genetic characteristics and climate condition which varied from few days to few weeks. Beginning of phenological phenomena of a species is usually correlated to air temperature (maximum, minimum and average) at beginning of growth period, whereas its end is often correlated to photoperiodism and minimum air temperature. Leaf discolor and fall date at different poplar species varied from 6th September to 6th November due to shorter day time and cooler air temperature. The species P. alba and P. euramericana started their phenological activities earlier than the other species and the clones of P. alba and P. deltoides had longest biotic activities. The clones of P. alba were more sensetive to forest, whereas the clones of P. euramericana and P. deltoides were very sensetive to pests, particularly to beetle xylophagus (Melanophila sp.). About 70% of P. euramericana clones were complete died due to damage caused by this pest.

Our understanding of astrocytes and their role in neurological diseases has increased considerably over the past two decades as the diverse roles of these cells have become recognized. Our evolving understanding of these cells suggests that they are more than support cells for neurons and that they play important roles in CNS homeostasis under normal conditions, in neuroprotection and in disease exacerbation. These multiple functions make them excellent candidates for targeted therapies to treat neurological disorders. New technological advances, including in vivo imaging, optogenetics and chemogenetics, have allowed us to examine astrocytic functions in ways that have uncovered new insights into the dynamic roles of these cells. Furthermore, the use of induced pluripotent stem cell-derived astrocytes from patients with a host of neurological disorders can help to tease out the contributions of astrocytes to human disease. In this Review, we explore some of the technological advances developed over the past decade that have aided our understanding of astrocyte function. We also highlight neurological disorders in which astrocyte function or dysfunction is believed to have a role in disease pathogenesis or propagation and discuss how the technological advances have been and could be used to study each of these diseases. [ABSTRACT FROM AUTHOR]

Abstract: Aicardi–Goutières syndrome (AGS) is an early‐onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over‐production of the cytokine Interferon–alpha (IFN‐α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood‐brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases—Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)—has been well‐established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN‐α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell‐autonomous and non‐cell‐autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS. [ABSTRACT FROM AUTHOR]

• Tubulin beta 4A (TUBB4A) is a brain-specific β-tubulin. • β- and α-tubulins dimerize forming microtubules, critical to cell development. • Severe TUBB4A mutations result in progressive motor and cognitive decline. • Generated patient-derived iPSCs exhibit hallmark pluripotency characteristics. • iPSC derived cells serve as an in vitro model to study mechanisms and therapeutics. Mutations in tubulin alpha 4a (TUBB4A) result in a spectrum of leukodystrophies, including Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC), resulting from a recurring mutation p.Asp249Asn (TUBB4AD249N). H-ABC presents with dystonia, motor and cognitive impairment and pathological features of hypomyelination and loss of cerebellar and striatal neurons. We have generated three induced pluripotent stem cell (iPSC) lines from fibroblast and peripheral blood mononuclear cells (PBMCs) of individuals with TUBB4AD249N mutation. The iPSCs were assessed to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The iPSCs will allow for disease modeling, understanding mechanisms and testing of therapeutic targets. [ABSTRACT FROM AUTHOR]

Therapeutic strategies using stem cells for treating neurological diseases are receiving more attention as the scientifi c community appreciates cell-autonomous contributions to several diseases of the central nervous system. The transplantation of stem cells from various sources is now being employed for both neuronal and glial replacement. This review provides an assessment of glial contributions to some of the central nervous system diseases and the advancements in cellular replacement approaches. The rationale for glial replacement in individual diseases and the potential hurdles for cell-replacement strategies are also emphasized. The signifi cant progress in the fi eld of stem cell biology with the advent of tools such as induced pluripotent stem cells and imaging techniques holds promise for the clinical application of cell therapeutics. [ABSTRACT FROM AUTHOR]

Background: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population. We provide extended phenotypic classification of this disorder based on clinical history of a further seven affected individuals, assess carrier frequency in the Ashkenazi Jewish population, and provide a neuropathological study.Methods: Clinical information, neuroimaging, and biosamples were collected. Brain autopsy was performed for one case.Results: Individuals with HIKESHI-related disease share common clinical features: early axial hypotonia evolving to dystonia or with progressive spasticity, hyperreflexia and clonus, feeding difficulties with poor growth, and nystagmus. Severe morbidity or death during febrile illness occurred in five of the nine affected individuals. Magnetic resonance images of seven patients were analyzed and demonstrated diffuse hypomyelination and thin corpus callosum. Genotyping data of more than 125,000 Ashkenazi Jewish individuals revealed a carrier frequency of 1 in 216. Gross pathology examination in one case revealed abnormal white matter. Microscopically, there was a near-total absence of myelin with a relative preservation of axons. The cerebral white matter showed several reactive astrocytes and microglia.Conclusions: We provide pathologic evidence for a primary disorder of the myelin in HIKESHI-related leukodystrophy. These findings are consistent with the hypomyelination seen in brain magnetic resonance imaging and with the clinical features of early-onset spastic/dystonic quadriplegia and nystagmus. The high carrier rate of the recurrent variant seen in the Ashkenazi Jewish population requires increased attention to screening and diagnosis of this condition, particularly in this population. [ABSTRACT FROM AUTHOR]

The article presents a study on the occurrence of chronic remyelination for all spared axons after spinal cord injury in mouse. A study examined the myelin status and simulated functional properties of spared axons chronically after injury. They studied actively transporting rubrospinal tract (RST) axons in C57BL/6 mice at select time points after contusive spinal cord injury.

Abstract: In multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), relapses are markedly reduced during pregnancy. Exosomes are lipid-bound vesicles and are more abundant in the serum during pregnancy. Using murine EAE, we demonstrate that serum exosomes suppress T cell activation, promote the maturation of oligodendrocyte precursor cells (OPC), and pregnancy exosomes facilitate OPC migration into active CNS lesions. However, exosomes derived from both pregnant and non-pregnant mice reduced the severity of established EAE. Thus, during pregnancy, serum exosomes modulate the immune and central nervous systems and contribute to pregnancy-associated suppression of EAE. [Copyright &y& Elsevier]

Glia cells are often viewed as support cells in the central nervous system, but recent discoveries highlight their importance in physiological functions and in neurological diseases. Central to this are leukodystrophies, a group of progressive, neurogenetic disease affecting white matter pathology. In this review, we take a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected. While white matter diseases involve oligodendrocyte and myelin loss, we discuss how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology. We provide an overview of the leukodystrophies covering their hallmark features, clinical phenotypes, diverse molecular pathways, and potential therapeutics for clinical trials. Glial cells are gaining momentum as cellular therapeutic targets for treatment of demyelinating diseases such as leukodystrophies, currently with no treatment options. Here, we bring the much needed attention to role of glia in leukodystrophies, an integral step towards furthering disease comprehension, understanding mechanisms and developing future therapeutics. [ABSTRACT FROM AUTHOR]