Search results for "NCEP"

Gatekeeper role of brain antigen‐presenting CD11c + cells in neuroinflammation

2015

Multiple sclerosis is the most frequent chronic inflammatory disease of the CNS. The entry and survival of pathogenic T cells in the CNS are crucial for the initiation and persistence of autoimmune neuroinflammation. In this respect, contradictory evidence exists on the role of the most potent type of antigen-presenting cells, dendritic cells. Applying intravital two-photon microscopy, we demonstrate the gatekeeper function of CNS professional antigen-presenting CD11c(+) cells, which preferentially interact with Th17 cells. IL-17 expression correlates with expression of GM-CSF by T cells and with accumulation of CNS CD11c(+) cells. These CD11c(+) cells are organized in perivascular clusters…

TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

2017

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune ence…

Hypoxia in CNS Pathologies: Emerging Role of miRNA-Based Neurotherapeutics and Yoga Based Alternative Therapies

2017

Cellular respiration is a vital process for the existence of life. Any condition that results in deprivation of oxygen (also termed as hypoxia) may eventually lead to deleterious effects on the functioning of tissues. Brain being the highest consumer of oxygen is prone to increased risk of hypoxia-induced neurological insults. This in turn has been associated with many diseases of central nervous system (CNS) such as stroke, Alzheimer's, encephalopathy etc. Although several studies have investigated the pathophysiological mechanisms underlying ischemic/hypoxic CNS diseases, the knowledge about protective therapeutic strategies to ameliorate the affected neuronal cells is meager. This has au…

An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephal…

2019

N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or…

Role of the epigenetic factor Sirt7 in neuroinflammation and neurogenesis.

2017

Epigenetic regulators are increasingly recognized as relevant modulators in the immune and nervous system. The class of sirtuins consists of NAD+-dependent histone deacetylases that regulate transcription. Sirtuin family member Sirt1 has already been shown to influence the disease course in an animal model of autoimmune neuroinflammation (experimental autoimmune encephalomyelitis (EAE). A role of Sirt7, a related epigenetic regulator, on immune system regulation has been proposed before, as these mice are more susceptible to develop inflammatory cardiomyopathy. Sirt7-/- animals showed no differences in clinical score compared to wild-type littermates after EAE induction with myelin oligoden…

Wnt-Dependent Oligodendroglial-Endothelial Interactions Regulate White Matter Vascularization and Attenuate Injury

2020

Recent studies have indicated oligodendroglial-vascular crosstalk during brain development, but the underlying mechanisms are incompletely understood. We report that oligodendrocyte precursor cells (OPCs) contact sprouting endothelial tip cells in mouse, ferret and human neonatal white matter. Using transgenic mice, we show that increased or decreased OPC density results in cognate changes in white matter vascular investment. Hypoxia promoted both increased OPC numbers and higher white matter vessel density, and endothelial cell expression of the Wnt pathway targets Apcdd1 and Axin2, suggesting paracrine OPC-endothelial signaling. Conditional knockout of OPC Wntless resulted in diminished w…

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test

2016

The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations a…

Specific mosaicKRASmutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis

2016

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four…

2017

Despite rapid progress, many problems and limitations persist and limit the applicability of gene-editing techniques. Making use of meganucleases, TALENs, or CRISPR/Cas9-based tools requires an initial step of pre-screening to determine the efficiency and specificity of the designed tools. This step remains time consuming and material consuming. Here we propose a simple, cheap, reliable, time-saving, and highly sensitive method to evaluate a given gene-editing tool based on its capacity to induce chromosomal translocations when combined with a reference engineered nuclease. In the proposed technique, designated engineered nuclease-induced translocations (ENIT), a plasmid coding for the DNA-…

A multidimensional approach to frailty in older people

2020

Frailty is an important factor determining a higher risk of adverse health outcomes in older adults. Although scientific community in the last two decades put a lot of effort for its definition, to date no consensus was reached on its assessment. The mainstream thinking describes frailty as a loss of physical functions or as accumulation of multiple deficits. Recently, a novel conceptual model of frailty has emerged based on the loss of harmonic interaction between multiple domains (also referred as dimensions) including genetic, biological, functional, cognitive, psychological and socio-economic domain that ultimately lead to homeostatic instability. Therefore, the multidimensional aspects…