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Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
Although disruption of AJs can result in increased BBB permeability, TJs are primarily responsible for restricting paracellular permeability at the BBB (Hawkins and Davis 2005, Zlokovic 2008). TJs form the primary physical barrier component of the BBB and function to greatly restrict paracellular entry of various endogenous and exogenous substances that can potentially be neurotoxic. TJs are dynamic complexes of multiple protein constituents including junctional adhesion molecules (JAMs), occludin, claudins (i.e., claudin-1, -3, and -5), and membrane-associated guanylate kinase (MAGUK)-like proteins (i.e., ZO-1, -2, and -3) (Hawkins and Davis 2005) (Figure 15.3).
Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
CARD14 is represented by several isoforms.8 Full-length CARD14 (CARD14fl, also known as CARD14 isoform 1) encodes both an N-terminal CARD domain necessary for activation of NF-κB and a C-terminal tripartite membrane-associated guanylate kinase (MAGUK) domain (PDZ/SH3/GUK) that is involved in relaying external signals to the inside of the cell. This is the only isoform that harbors the p.R820W polymorphism. A shorter isoform, CARD14sh, encodes the CARD domain but not the MAGUK domain. CARD14sh is the most abundant isoform in all tissues where it is expressed, including skin. Another isoform, CARD14cl, lacks the CARD and the tripartite domain and is unable to activate NF-κB.8,78CARD14cl has a very restricted pattern of expression, which is confined to the epidermis, thymus, and placenta8 and possibly lung and cervix.78 CARD14-induced activation of NF-κB is dependent on TRAF278 and might also require TRAF3 or TRAF6. Moreover, CARD14 may fit into other known Ps associated pathways such as IL-17/Act1. Figure 4.3 provides possible signaling pathways involving CARD14 that are operating in the keratinocyte and endothelial cell in Ps. Genes in regions identified through GWAs are highlighted.
Viral-Specific and Immune-Based Nonspecific Antiviral Therapies for CFS
Published in Roberto Patarca-Montero, Treatment of Chronic Fatigue Syndrome in the Antiviral Revolution Era, 2014
Acyclovir is an acyclic analog of guanosine. The inhibitory activity of acyclovir is highly selective. The enzyme thymidine kinase (TK) of normal uninfected cells does not effectively use acyclovir as a substrate. However, TK encoded by the herpes simplex virus converts acyclovir into acyclovir monophosphate, a nucleotide analog. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. Acyclovir triphosphate interferes with herpes simplex virus DNA polymerase and inhibits viral replication. Acyclovir is preferentially taken up and selectively converted to the active triphosphate form by herpes virus-infected cells. Acyclovir triphosphate binds viral DNA polymerase, acting as a DNA chain terminator. Because acyclovir is taken up selectively by virus-infected cells, the concentration of acyclovir triphosphate is forty to 100 times higher in infected cells than in uninfected cells. Furthermore, viral DNA polymerase exhibits a ten- to thirtyfold greater affinity for acyclovir triphosphate than do cellular DNA polymerases. The higher concentration of the active triphosphate metabolite in infected cells plus the affinity for viral polymerases result in the very low toxicity of acyclovir for normal host cells.
Current techniques to accurately measure anti-retinal autoantibodies
Published in Expert Review of Ophthalmology, 2020
Phage immunoprecipitation sequencing (PhIP-Seq) is a new technique for autoantigen discovery that is based on a synthetic representation of a complete human peptidome [44,45]. This method has been used to identify novel autoantigens in neurologic paraneoplastic disorders, multiple sclerosis, and rheumatoid arthritis. PhIP-Seq was also used for an identification of novel autoantigens expressed in the retina in AR patients (RTN3, PRPF6, TRPC6, and B3GNT8), but not in healthy controls [46]. A human proteome (HuProt) microarray, representing >80% of all protein-coding genes, was screened with serum from a patient with suspected CAR [25]. This method identified aryl hydrocarbon receptor-interacting protein-like (AIPL)-1, a protein specifically restricted to the retina and the pineal gland. The array also identified lipocalin 8, membrane-associated guanylate kinase WW, PDZ-containing domain 1, and doublecortin domain-containing 2 [25]. Those procedures are limited to the analysis of linear epitopes and the expression of some epitopes in bacteria is difficult.
Gene networks associated with non-syndromic intellectual disability
Published in Journal of Neurogenetics, 2018
Soohyun Lee, Stephen Rudd, Jacob Gratten, Peter M. Visscher, Johannes B. Prins, Paul A. Dawson
PPI network analyses identified DLG3 (Disc large homolog 3), DLG4 (Disc large homolog 4) and CASK (calcium/calmodulin-dependent serine protein kinase 3), all of which are members of the membrane-associated guanylate kinase (MAGUK) superfamily, to be highly interconnected within this network (Supplementary Figure 2). Their direct/indirect binding partners include neuroligin-neurexin (encoded by NLGN and NRXN), NMDA receptors (encoded by GRIN1) and AMPA receptors and potassium channels (encoded by KCNA1), which form multimeric scaffolds for PPI and signal transduction. Of particular interest is the role of DLG4 in dopaminergic-glutamatergic systems. DLG4 provides a direct link between dopamine and glutamate receptors by multiple PPI and indirectly by crosstalk between their respective signalling pathways allowing reciprocal interaction between dopaminergic-glutamatergic systems (de Bartolomeis & Tomasetti, 2012). Dysfunction of dopamine and glutamate interaction has been implicated in the aetiology of schizophrenia (2014), and mutations in the genes DLG4, EPB41L1, GRIK2, GRIN1 and NRXN1 that we identified within the NS-ID network have also been linked with schizophrenia in the diseases ontology within the GeneGO database (Figure 2). The common aberration of dopaminergic and glutamatergic systems in schizophrenia (Network & Pathway Analysis Subgroup of Psychiatric Genomics Consortium, 2015) and NS-ID suggest that this network may be an underlying contributor to NS-ID.
Genetic analysis for cognitive flexibility in the trail-making test in attention deficit hyperactivity disorder patients from single nucleotide polymorphism, gene to pathway level
Published in The World Journal of Biological Psychiatry, 2019
Kunlin Zhang, Zili Fan, Yufeng Wang, Stephen V. Faraone, Li Yang, Suhua Chang
The top result related gene DLGAP1 encodes the protein guanylate kinase-associated protein (GKAP). It interacts with PSD95 protein, which is encoded by DLG4 and has been reported to be a prediction of cognitive deficits (Sultana et al. 2009; Whitfield et al. 2014). Such interaction also contributes to the synaptic plasticity in obsessive-compulsive disorder (OCD) (Kim et al. 1997; Welch et al. 2007). In addition, DLGAP1 is also reported to be associated with schizophrenia, major depression disorder and Alzheimer’s disease (Bertram et al. 2008; Li et al. 2013; Mathias et al. 2016). All these psychiatric disorders were reported to have impaired cognitive flexibility (Ebmeier et al. 2006; Thoma et al. 2007; Pooragha et al. 2013; Francazio and Flessner 2015). So, DLGAP1 may be associated with these mental disorders through the underlying impaired cognitive flexibility. The top result in the gene-level analysis CADPS2 is a member of the CAPS/CADPS protein family. It is widely expressed in the brain, especially the cerebellum, and is involved in monoamine and neurotrophin neurotransmission (Sadakata et al. 2017). CADPS2 mediates BDNF release in neurons as it was reported that mice with the deficiency of CADPS2 expressed less BDNF (Sadakata et al. 2007). It is also reported to be associated with several psychiatric disorders, such as schizophrenia, intellectual disability, autism spectrum disorder and Alzheimer's disease (Hattori et al. 2011; Velez et al. 2013; Bonora et al. 2014). Interval-enrichment analysis for potential candidate SNPs with P < e-4 highlighted another candidate gene ADCY2. This gene codes an important enzyme involved in cyclic adenosine monophosphate cAMP signalling. ADCY2 has been reported to be a risk locus for bipolar disorder in a GWAS (Muhleisen et al. 2014). Given that impairment of cognitive flexibility is a cross-disorder phenotype, the association of DLGAP1, CADPS2 and ADCY2 with cognitive flexibility deserves further validation in a replication study.