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https://www.readbyqxmd.com/read/28221369/chemistry-based-molecular-signature-underlying-the-atypia-of-clozapine
#1
T Cardozo, E Shmelkov, K Felsovalyi, J Swetnam, T Butler, D Malaspina, S V Shmelkov
The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions...
February 21, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28176268/no-genetic-association-between-attention-deficit-hyperactivity-disorder-adhd-and-parkinson-s-disease-in-nine-adhd-candidate-snps
#2
Julia M Geissler, Marcel Romanos, Manfred Gerlach, Daniela Berg, Claudia Schulte
Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13)...
February 7, 2017: Attention Deficit and Hyperactivity Disorders
https://www.readbyqxmd.com/read/28138806/drd4-variants-moderate-the-impact-of-parental-characteristics-on-child-attention-deficit-hyperactivity-disorder-exploratory-evidence-from-a-multiplex-family-design
#3
Molly A Nikolas, Allison M Momany
Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD...
January 30, 2017: Journal of Abnormal Child Psychology
https://www.readbyqxmd.com/read/28138201/asenapine-for-the-control-of-physical-aggression-a-prospective-naturalist-pilot-study
#4
Jin Shi Amon, Sarah B Johnson, Rif S El-Mallakh
It has been previously purported that higher relative affinity to the dopamine D4 receptor compared to D2 (i.e., D4/D2 affinity ratio > 1) may underlie unique antiaggression potency. Asenapine is a newer antipsychotic that also has D4/D2 affinity ratio > 1. It has demonstrated efficacy in reducing acute agitation in a placebo-controlled study. We performed a prospective naturalistic, pilot, proof of concept study on an inpatient psychiatric unit. Among patients with aggression at time of admission (≥ 12 on Refined Aggression Questionnaire [RAQ], or ≥ 2 on Modified Overt Aggression Scale [MOAS]), asenapine treatment was associated with a significant reduction in total aggression as measured by the MOAS (-14...
January 26, 2017: Psychopharmacology Bulletin
https://www.readbyqxmd.com/read/28115217/cysteinyl-leukotriene-e4-activates-human-ilc2s-and-enhances-the-effect-of-prostaglandin-d2-and-epithelial-cytokines
#5
Maryam Salimi, Linda Stöger, Wei Liu, Simei Go, Ian Pavord, Paul Klenerman, Graham Ogg, Luzheng Xue
BACKGROUND: Group 2 innate lymphoid cells (ILC2) are a potential innate source of type-2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25 and TSLP) and mast cell mediators (PGD2) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs) including leukotriene C4 (LTC4), D4 and E4 are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. OBJECTIVES: We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s...
January 20, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28098359/m2-like-macrophages-induce-colon-cancer-cell-invasion-via-matrix-metalloproteinases
#6
Katyayni Vinnakota, Yuan Zhang, Benson Chellakkan Selvanesan, Geriolda Topi, Tavga Salim, Janna Sand-Dejmek, Gunilla Jönsson, Anita Sjölander
The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors...
January 18, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28097219/key-role-of-the-dopamine-d4-receptor-in-the-modulation-of-corticostriatal-glutamatergic-neurotransmission
#7
Jordi Bonaventura, César Quiroz, Ning-Sheng Cai, Marcelo Rubinstein, Gianluigi Tanda, Sergi Ferré
Polymorphic variants of the dopamine D4 receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4 receptor and the functional differences of the products of DRD4 polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4 receptor with the long intracellular domain of a human DRD4 polymorphic variant associated with attention deficit hyperactivity disorder (ADHD)...
January 2017: Science Advances
https://www.readbyqxmd.com/read/28060819/an-anti-human-lutheran-glycoprotein-phage-antibody-inhibits-cell-migration-on-laminin-511-epitope-mapping-of-the-antibody
#8
Yurie Enomoto-Okawa, Yuka Maeda, Nozomi Harashima, Yumika Sugawara, Fumihiko Katagiri, Kentaro Hozumi, Kam Man Hui, Motoyoshi Nomizu, Yuji Ito, Yamato Kikkawa
The Lutheran glycoprotein (Lu), also known as basal cell adhesion molecule (B-CAM), is an Ig superfamily (IgSF) transmembrane receptor for laminin α5. Although Lu is not present in normal hepatocytes, its expression is significantly increased in hepatocellular carcinoma (HCC). In this study, we isolated thirteen phage antibodies to Lu from a phage library of peripheral blood from HCC patients, suggesting that these patients produced autoantibodies against endogenous Lu. To characterize the phage antibodies, we determined the Lu domains they recognize...
2017: PloS One
https://www.readbyqxmd.com/read/28051998/prex1-integrates-g-protein-coupled-receptor-and-phosphoinositide-3-kinase-signaling-to-promote-glioblastoma-invasion
#9
Alexander Gont, Manijeh Daneshmand, John Woulfe, Sylvie J Lavictoire, Ian A J Lorimer
A defining feature of the brain cancer glioblastoma is its highly invasive nature. When glioblastoma cells are isolated from patients using serum free conditions, they accurately recapitulate this invasive behaviour in animal models. The Rac subclass of Rho GTPases has been shown to promote invasive behaviour in glioblastoma cells isolated in this manner. However the guanine nucleotide exchange factors responsible for activating Rac in this context have not been characterized previously. PREX1 is a Rac guanine nucleotide exchange factor that is synergistically activated by binding of G protein αγ subunits and the phosphoinositide 3-kinase pathway second messenger phosphatidylinositol 3,4,5 trisphosphate...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/27992450/association-between-age-and-the-7-repeat-allele-of-the-dopamine-d4-receptor-gene
#10
Anna Szekely, Eszter Kotyuk, Julianna Bircher, Andrea Vereczkei, David A Balota, Maria Sasvari-Szekely, Zsolt Ronai
Longevity is in part (25%) inherited, and genetic studies aim to uncover allelic variants that play an important role in prolonging life span. Results to date confirm only a few gene variants associated with longevity, while others show inconsistent results. However, GWAS studies concentrate on single nucleotide polymorphisms, and there are only a handful of studies investigating variable number of tandem repeat variations related to longevity. Recently, Grady and colleagues (2013) reported a remarkable (66%) accumulation of those carrying the 7 repeat allele of the dopamine D4 receptor gene in a large population of 90-109 years old Californian centenarians, as compared to an ancestry-matched young population...
2016: PloS One
https://www.readbyqxmd.com/read/27932423/integrated-genomic-analysis-of-survival-outliers-in-glioblastoma
#11
Sen Peng, Harshil Dhurv, Brock Armstrong, Bodour Salhia, Christophe Legendre, Jeffrey Kiefer, Julianna Parks, Selene Virk, Andrew E Sloan, Quinn T Ostrom, Jill S Barnholtz-Sloan, Nhan L Tran, Michael E Berens
BACKGROUND: To elucidate molecular features associated with disproportionate survival of glioblastoma (GB) patients, we conducted deep genomic comparative analysis of a cohort of patients receiving standard therapy (surgery plus concurrent radiation and temozolomide); "GB outliers" were identified: long-term survivor of 33 months (LTS; n = 8) versus short-term survivor of 7 months (STS; n = 10). METHODS: We implemented exome, RNA, whole genome sequencing, and DNA methylation for collection of deep genomic data from STS and LTS GB patients...
December 8, 2016: Neuro-oncology
https://www.readbyqxmd.com/read/27907150/molecular-characterization-of-two-monoclonal-antibodies-against-the-same-epitope-on-b-cell-receptor-associated-protein-31
#12
Won-Tae Kim, Saemina Shin, Hyo Jeong Hwang, Min Kyu Kim, Han-Sung Jung, Hwangseo Park, Chun Jeih Ryu
Previously, we showed that B-cell receptor associated protein 31 (BAP31), an endoplasmic reticulum (ER) membrane chaperone, is also expressed on the cell surface by two monoclonal antibodies (MAbs) 297-D4 and 144-A8. Both MAbs recognize the same linear epitope on the C-terminal domain of BAP31, although they were independently established. Here, flow cytometric analysis showed that 144-A8 had additional binding properties to some cells, as compared to 297-D4. Quantitative antigen binding assays also showed that 144-A8 had higher antigen binding capacity than 297-D4...
2016: PloS One
https://www.readbyqxmd.com/read/27905471/evidence-of-genotypic-adaptation-to-the-exposure-to-volcanic-risk-at-the-dopamine-receptor-drd4-locus
#13
Charlotte Faurie, Clement Mettling, Mohamed Ali Bchir, Danang Sri Hadmoko, Carine Heitz, Evi Dwi Lestari, Michel Raymond, Marc Willinger
Humans have colonized and adapted to extremely diverse environments, and the genetic basis of some such adaptations, for example to high altitude, is understood. In some cases, local or regional variation in selection pressure could also cause behavioural adaptations. Numerous genes influence behaviour, such as alleles at the dopamine receptor locus D4 (DRD4), which are associated with attitude toward risk in experimental settings. We demonstrate genetic differentiation for this gene, but not for five unlinked microsatellite loci, between high- and low risk environments around Mount Merapi, an active volcano in Java, Indonesia...
December 1, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27874231/stability-of-domain-4-of-the-anthrax-toxin-protective-antigen-and-the-effect-of-the-vwa-domain-of-cmg2-on-stability
#14
Sireesha Mamillapalli, Masaru Miyagi, James G Bann
The major immunogenic component of the current anthrax vaccine, anthrax vaccine adsorbed (AVA) is protective antigen (PA). We have shown recently that the thermodynamic stability of PA can be significantly improved by binding to the Von-Willebrand factor A (VWA) domain of capillary morphogenesis protein 2 (CMG2), and improvements in thermodynamic stability may improve storage and long-term stability of PA for use as a vaccine. In order to understand the origin of this increase in stability, we have isolated the receptor binding domain of PA, domain 4 (D4), and have studied the effect of the addition of CMG2 on thermodynamic stability...
February 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/27830016/effects-of-leukotriene-d4-on-adenoidal-t-cells-in-children-with-obstructive-sleep-apnea-syndrome
#15
Yan Shu, Da-Zhi Yang, Jia Liang, Feng Zhang, Bing Wang, Hong-Bing Yao, En-Mei Liu
PURPOSE: This study aims to determine whether leukotriene D4 (LTD4) can promote T cell proliferation in adenoid tissues via activation of CysLT1 receptors in children with OSAS. METHODS: CD4(+) and CD8(+) T cell proliferation was assessed by flow cytometry in adenoid mononuclear cells (AdMCs) stimulated with LTD4 from children with OSAS. The activation of mitogen-activated protein kinase pathways and their effects on the proliferation of CD4(+) and CD8(+) T cells in AdMCs were observed by western blotting...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27821512/dopamine-d4-receptor-gene-polymorphism-in-a-sample-of-egyptian-children-with-attention-deficit-hyperactivity-disorder-adhd
#16
Farida ElBaz Mohamed, Tarek Mostafa Kamal, Sally Soliman Zahra, Mona Abdel Hakiem Khfagy, Azza Mohamed Youssef
This study aimed to detect DRD4 receptor gene polymorphisms in attention-deficit hyperactivity disorder (ADHD) children and to correlate their phenotype-genotype. Fifty children with ADHD were diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria and were subjected to Conners Parent Rating Scale. All cases and controls were subjected to history taking, physical examination, IQ assessment, and dopamine receptor D4 (DRD4) exon 3 genotyping. The 7-repeat allele was present only in controls, whereas 2-repeat allele was present in the ADHD children (heterozygous 2-repeat allele in 16% and homozygous in 26% of cases)...
November 7, 2016: Journal of Child Neurology
https://www.readbyqxmd.com/read/27793671/antiferroptotic-activity-of-non-oxidative-dopamine
#17
Ding Wang, Yingpeng Peng, Yangchun Xie, Borong Zhou, Xiaofang Sun, Rui Kang, Daolin Tang
Dopamine is a neurotransmitter that has many functions in the nervous and immune systems. Ferroptosis is a non-apoptotic form of regulated cell death that is involved in cancer and neurodegenerative diseases. However, the role of dopamine in ferroptosis remains unidentified. Here, we show that the non-oxidative form of dopamine is a strong inhibitor of ferroptotic cell death. Dopamine dose-dependently blocked ferroptosis in cancer (PANC1 and HEY) and non-cancer (MEF and HEK293) cells following treatment with erastin, a small molecule ferroptosis inducer...
October 25, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27760989/mechanisms-underlying-the-endogenous-dopaminergic-inhibition-of-spinal-locomotor-circuit-function-in-xenopus-tadpoles
#18
Laurence D Picton, Keith T Sillar
Dopamine plays important roles in the development and modulation of motor control circuits. Here we show that dopamine exerts potent effects on the central pattern generator circuit controlling locomotory swimming in post-embryonic Xenopus tadpoles. Dopamine (0.5-100 μM) reduced fictive swim bout occurrence and caused both spontaneous and evoked episodes to become shorter, slower and weaker. The D2-like receptor agonist quinpirole mimicked this repertoire of inhibitory effects on swimming, whilst the D4 receptor antagonist, L745,870, had the opposite effects...
October 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27755061/lassbio-1422-a-new-molecular-scaffold-with-efficacy-in-animal-models-of-schizophrenia-and-disorders-of-attention-and-cognition
#19
Andresa H Betti, Camila B Antonio, Thais E T Pompeu, Thaise S Martins, Vivian Herzfeldt, Eveline D Stolz, Carlos A M Fraga, Eliezer Barreiro, François Noël, Stela M K Rates
Aiming to identify new antipsychotic lead-compounds, our group has been working on the design and synthesis of new N-phenylpiperazine derivatives. Here, we characterized LASSBio-1422 as a pharmacological prototype of this chemical series. Adult male Wistar rats and CF1 mice were used for in-vitro and in-vivo assays, respectively. LASSBio-1422 [1 and 5 mg/kg, postoperatively (p.o.)] inhibited apomorphine-induced climbing as well as ketamine-induced hyperlocomotion (1 and 5 mg/kg, p.o.), animal models predictive of efficacy on positive symptoms...
October 13, 2016: Behavioural Pharmacology
https://www.readbyqxmd.com/read/27727308/circadian-and-dopaminergic-regulation-of-fatty-acid-oxidation-pathway-genes-in-retina-and-photoreceptor-cells
#20
Patrick Vancura, Tanja Wolloscheck, Kenkichi Baba, Gianluca Tosini, P Michael Iuvone, Rainer Spessert
The energy metabolism of the retina might comply with daily changes in energy demand and is impaired in diabetic retinopathy-one of the most common causes of blindness in Europe and the USA. The aim of this study was to investigate putative adaptation of energy metabolism in healthy and diabetic retina. Hence expression analysis of metabolic pathway genes was performed using quantitative polymerase chain reaction, semi-quantitative western blot and immunohistochemistry. Transcriptional profiling of key enzymes of energy metabolism identified transcripts of mitochondrial fatty acid β-oxidation enzymes, i...
2016: PloS One
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