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Miko Valori, Lilja Jansson, Anna Kiviharju, Pekka Ellonen, Hanna Rajala, Shady Adnan Awad, Satu Mustjoki, Pentti J Tienari
Somatic mutations have a central role in cancer but their role in other diseases such as autoimmune disorders is poorly understood. Earlier work has provided indirect evidence of rare somatic mutations in autoreactive T-lymphocytes in multiple sclerosis (MS) patients but such mutations have not been identified thus far. We analysed somatic mutations in blood in 16 patients with relapsing MS and 4 with other neurological autoimmune disease. To facilitate the detection of somatic mutations CD4+, CD8+, CD19+ and CD4-/CD8-/CD19- cell subpopulations were separated...
December 5, 2016: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Jianjun Gao, Lea K Davis, Amy B Hart, Sandra Sanchez-Roige, Lide Han, John T Cacioppo, Abraham A Palmer
Loneliness is a complex biological trait that has been associated with numerous negative health outcomes. The measurement and environmental determinants of loneliness are well understood, but its genetic basis is not. Previous studies have estimated the heritability of loneliness between 37 and 55% using twins and family-based approaches, and have explored the role of specific candidate genes. We used genotypic and phenotypic data from 10 760 individuals aged ⩾50 years that were collected by the Health and Retirement Study (HRS) to perform the first genome-wide association study of loneliness...
October 12, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Suzana Elena Voiculescu, Diana Le Duc, Adrian Eugen Roșca, Vlad Zeca, Diana Maria Chiţimuș, Andreea Letiţia Arsene, Cristina Manuela Drăgoi, Alina Crenguţa Nicolae, Leon Zăgrean, Torsten Schöneberg, Ana-Maria Zăgrean
Disruption of the maternal environment during pregnancy leads to behavioral changes and diseases in the adult offspring. To explore the influence of prenatal continuous light exposure (PCLE) on the adult offspring, we exposed pregnant Wistar rats to constant light during late gestation. Adult PCLE offspring showed an anxiety-like behavior and impairment of short-term memory in different tests. Measurements in the whole brain homogenates from newborn and adult offspring indicated decreased melatonin and serotonin levels and increased reactive oxygen species level in PCLE offspring...
November 1, 2016: Brain Research
Yuwei Zhang, Yulan Liu, Yin Liu, Yanjie Zhang, Zhiguang Su
Retinoic acid receptor-related orphan receptor alpha (RORA) plays a key role in the regulation of lipid and glucose metabolism and insulin expression that are implicated in the development of type 2 diabetes mellitus (T2DM). However, the effects of genetic variants in the RORA gene on the susceptibility to T2DM remain unknown. Nine tagging single-nucleotide polymorphisms (SNPs) were screened by using the SNaPshot method in 427 patients with T2DM and 408 normal controls. Association between genotypes and haplotypes derived from these SNPs with T2DM was analyzed using different genetic models...
2016: Genes
Alicja Majewska, Małgorzata Gajewska, Kourou Dembele, Henryk Maciejewski, Adam Prostek, Michał Jank
BACKGROUND: Canine atopic dermatitis (cAD) is a common chronic and pruritic skin disease in dogs. The development of cAD involves complex interactions between environmental antigens, genetic predisposition and a number of disparate cell types. The aim of the present study was to perform comprehensive analyses of peripheral blood of AD dogs in relation to healthy subjects in order to determine the changes which would be characteristic for cAD. RESULTS: The number of cells in specific subpopulations of lymphocytes was analyzed by flow cytometry, concentration of chosen pro- and anti-inflammatory cytokines (IL-4, IL-10, IL-13, TNF-α, TGF-β1) was determined by ELISA; and microarray analysis was performed on RNA samples isolated from peripheral blood nuclear cells of AD and healthy dogs...
2016: BMC Veterinary Research
Louise Nicol, Hazel Wilkie, Anton Gossner, Craig Watkins, Robert Dalziel, John Hopkins
Two different forms of clinical paratuberculosis in sheep are recognised, related to the level of bacterial colonization. Paucibacillary lesions are largely composed of lymphocytes with few bacteria, and multibacillary pathology is characterized by heavily-infected macrophages. Analysis of cytokine transcripts has shown that inflammatory Th1/Th17 T cells are associated with development of paucibacillary pathology and Th2 cytokines are correlated with multibacillary disease. The master regulator T cell transcription factors TBX21, GATA3, RORC2 and RORA are critical for the development of these T cell subsets...
2016: Veterinary Research
Andrea Ghelli Luserna Di Rorà, Ilaria Iacobucci, Enrica Imbrogno, Cristina Papayannidis, Enrico Derenzini, Anna Ferrari, Viviana Guadagnuolo, Valentina Robustelli, Sarah Parisi, Chiara Sartor, Maria Chiara Abbenante, Stefania Paolini, Giovanni Martinelli
During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A...
July 11, 2016: Oncotarget
V V Miroshnikova, A A Panteleeva, E A Bazhenova, E P Demina, T S Usenko, M A Nikolaev, I A Semenova, A E Neimark, J He, O D Belyaeva, O A Berkovich, E I Baranova, S N Pchelina
Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis - LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels...
March 2016: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
Brennan Smith, Stuart Schwartz
Recharge estimation is an important and challenging element of groundwater management and resource sustainability. Many recharge estimation methods have been developed with varying data requirements, applicable to different spatial and temporal scales. The variability and inherent uncertainty in recharge estimation motivates the recommended use of multiple methods to estimate and bound regional recharge estimates. Despite the inherent limitations of using daily gauged streamflow, recession curve displacement methods provide a convenient first-order estimate as part of a multimethod hierarchical approach to estimate watershed-scale annual recharge...
July 8, 2016: Ground Water
Xi-Shan Wu, Rui Wang, Yan-Li Xing, Xiao-Qian Xue, Yan Zhang, Yong-Zhi Lu, Yu Song, Xiao-Yu Luo, Chun Wu, Yu-Lai Zhou, Jian-Qin Jiang, Yong Xu
AIM: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. METHODS: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized...
November 2016: Acta Pharmacologica Sinica
P A Geoffroy, B Etain, M Lajnef, E-H Zerdazi, C Brichant-Petitjean, U Heilbronner, L Hou, F Degenhardt, M Rietschel, F J McMahon, T G Schulze, S Jamain, C Marie-Claire, F Bellivier
Preliminary studies suggest that lithium (Li) response might be associated with some circadian gene polymorphisms, we therefore performed a pharmacogenetic study on the core clock genes in two independent samples suffering from bipolar disorder (BD) and thoroughly characterized for their Li response. Two independent Caucasian samples (165 and 58 bipolar patients) treated with Li were selected from samples recruited in a French multicenter study and assessed for their Li response using the Alda scale. The two samples were genotyped using the Human660 (H660) and OmniExpress (OE) BeadChips and gene-based association analyses of 22 core clock genes were conducted...
September 2016: Genes, Brain, and Behavior
A D Sawle, M Kebschull, R T Demmer, P N Papapanou
Analytic approaches confined to fold-change comparisons of gene expression patterns between states of health and disease are unable to distinguish between primary causal disease drivers and secondary noncausal events. Genome-wide reverse engineering approaches can facilitate the identification of candidate genes that may distinguish between causal and associative interactions and may account for the emergence or maintenance of pathologic phenotypes. In this work, we used the algorithm for the reconstruction of accurate cellular networks (ARACNE) to analyze a large gene expression profile data set (313 gingival tissue samples from a cross-sectional study of 120 periodontitis patients) obtained from clinically healthy (n = 70) or periodontitis-affected (n = 243) gingival sites...
August 2016: Journal of Dental Research
Hisao Kano, Tadatoshi Takayama, Yutaka Midorikawa, Hiroki Nagase
Retinoic acid receptor-related orphan receptor α (RORA) is a tumor-specific differentially methylated region. RORA mRNA expression is frequently downregulated in colorectal cancer (CRC) due to promoter methylation, and this methylation is correlated with the development of CRC. Here we investigated the correlation between the methylation status of the RORA promoter region and clinical CRC stages. The methylation status of RORA isoform 1 (RORA1) and isoform 4 (RORA4) promoters was investigated in 43 paired CRC specimens and adjacent normal tissues by quantitative DNA methylation analysis using the Sequenom MassARRAY system and bisulfite sequencing...
July 19, 2016: Bioscience Trends
E Molinari, H Bar, A M Pyle, P Patrizio
STUDY QUESTION: Can RNA sequencing of human cumulus cells (CC) reveal molecular pathways involved in the physiology of reproductive aging? STUDY FINDING: Senescent but not young CC activate gene pathways associated with hypoxia and oxidative stress. WHAT IS KNOWN ALREADY: Shifts in socioeconomic norms are resulting in larger numbers of women postponing childbearing. The reproductive potential is sharply decreased with aging, and the reasons are poorly understood...
August 2016: Molecular Human Reproduction
Chunfang Qiu, Bizu Gelaye, Marie Denis, Mahlet G Tadesse, Daniel A Enquobahrie, Cande V Ananth, Percy N Pacora, Manuel Salazar, Sixto E Sanchez, Michelle A Williams
The genetic architecture of placental abruption (PA) remains poorly understood. We examined variations in SNPs of circadian clock-related genes in placenta with PA risk. We also explored placental and maternal genomic contributions to PA risk. Placental genomic DNA samples were isolated from 280 PA cases and 244 controls. Genotyping was performed using the Illumina Cardio-MetaboChip. We examined 116 SNPs in 13 genes known to moderate circadian rhythms. Logistic regression models were fit to estimate odds ratios (ORs)...
2016: International Journal of Molecular Epidemiology and Genetics
Eirik Ikdahl, Silvia Rollefstad, Jonny Hisdal, Inge C Olsen, Terje R Pedersen, Tore K Kvien, Anne Grete Semb
OBJECTIVE: Patients with inflammatory joint diseases (IJD) have a high prevalence of hypertension and increased arterial stiffness. The aim of the present study was to evaluate the effect of long-term rosuvastatin treatment on arterial stiffness, measured by augmentation index (AIx) and aortic pulse wave velocity (aPWV), and blood pressure (BP) in IJD patients with established atherosclerosis. METHODS: Eighty-nine statin naïve IJD patients with carotid atherosclerotic plaque(s) (rheumatoid arthritis n = 55, ankylosing spondylitis n = 23, psoriatic arthritis n = 11) received rosuvastatin for 18 months to achieve low-density lipoprotein cholesterol goal ≤1...
2016: PloS One
M Soták, J Bryndová, P Ergang, K Vagnerová, P Kvapilová, M Vodička, J Pácha, A Sumová
Glucocorticoids are considered to synchronize the rhythmicity of clock genes in peripheral tissues; however, the role of circadian variations of endogenous glucocorticoids is not well defined. In the present study, we examined whether peripheral circadian clocks were impaired by adrenalectomy. To achieve this, we tested the circadian rhythmicity of core clock genes (Bmal1, Per1-3, Cry1, RevErbα, Rora), clock-output genes (Dbp, E4bp4) and a glucocorticoid- and clock-controlled gene (Gilz) in liver, jejunum, kidney cortex, splenocytes and visceral adipose tissue (VAT)...
2016: Chronobiology International
Hazel Wilkie, Anton Gossner, Stephen Bishop, John Hopkins
This study used selected lambs that varied in their resistance to the gastrointestinal parasite Teladorsagia circumcincta. Infection over 12 weeks identified susceptible (high adult worm count, AWC; high fecal egg count, FEC; low body weight, BW; low IgA) and resistant sheep (no/low AWC and FEC, high BW and high IgA). Resistance is mediated largely by a Th2 response and IgA and IgE antibodies, and is a heritable characteristic. The polarization of T cells and the development of appropriate immune responses is controlled by the master regulators, T-bet (TBX21), GATA-3 (GATA3), RORγt (RORC2) and RORα (RORA); and several inflammatory diseases of humans and mice are associated with allelic or transcript variants of these transcription factors...
2016: PloS One
Stefania Trino, Ilaria Iacobucci, Daniela Erriquez, Ilaria Laurenzana, Luciana De Luca, Anna Ferrari, Andrea Ghelli Luserna Di Rorà, Cristina Papayannidis, Enrico Derenzini, Giorgia Simonetti, Annalisa Lonetti, Claudia Venturi, Federica Cattina, Emanuela Ottaviani, Maria Chiara Abbenante, Domenico Russo, Giovanni Perini, Pellegrino Musto, Giovanni Martinelli
MDM2 is an important negative regulator of p53 tumor suppressor. In this study, we sought to investigate the preclinical activity of the MDM2 antagonist, Nutlin-3a, in Philadelphia positive (Ph+) and negative (Ph-) leukemic cell line models, and primary B-acute lymphoblastic leukemia (ALL) patient samples. We demonstrated that Nutlin-3a treatment reduced viability and induced p53-mediated apoptosis in ALL cells with wild-type p53 protein, in a time and dose-dependent manner, resulting in the increased expression of pro-apoptotic proteins and key regulators of cell cycle arrest...
March 15, 2016: Oncotarget
Melanie Vanessa Halbach, Suzana Gispert, Tanja Stehning, Ewa Damrath, Michael Walter, Georg Auburger
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum...
February 11, 2016: Cerebellum
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