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https://www.readbyqxmd.com/read/28212402/graph-gpa-a-graphical-model-for-prioritizing-gwas-results-and-investigating-pleiotropic-architecture
#1
Dongjun Chung, Hang J Kim, Hongyu Zhao
Genome-wide association studies (GWAS) have identified tens of thousands of genetic variants associated with hundreds of phenotypes and diseases, which have provided clinical and medical benefits to patients with novel biomarkers and therapeutic targets. However, identification of risk variants associated with complex diseases remains challenging as they are often affected by many genetic variants with small or moderate effects. There has been accumulating evidence suggesting that different complex traits share common risk basis, namely pleiotropy...
February 17, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28212315/developmental-programming-of-adult-disease-reprogramming-by-melatonin
#2
REVIEW
You-Lin Tain, Li-Tung Huang, Chien-Ning Hsu
Adult-onset chronic non-communicable diseases (NCDs) can originate from early life through so-called the "developmental origins of health and disease" (DOHaD) or "developmental programming". The DOHaD concept offers the "reprogramming" strategy to shift the treatment from adulthood to early life, before clinical disease is apparent. Melatonin, an endogenous indoleamine produced by the pineal gland, has pleiotropic bioactivities those are beneficial in a variety of human diseases. Emerging evidence support that melatonin is closely inter-related to other proposed mechanisms contributing to the developmental programming of a variety of chronic NCDs...
February 16, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28209983/generation-and-quantitative-proteomics-analysis-of-ck2%C3%AE-%C3%AE-cells
#3
Christian Borgo, Cinzia Franchin, Stefano Scalco, Valentina Bosello-Travain, Arianna Donella-Deana, Giorgio Arrigoni, Mauro Salvi, Lorenzo A Pinna
CK2 is a ubiquitous, constitutively active, highly pleiotropic, acidophilic Ser/Thr protein kinase whose holoenzyme is composed of two catalytic (α and/or α') subunits and a dimer of a non-catalytic β subunit. Abnormally high CK2 level/activity is often associated with malignancy and a variety of cancer cells have been shown to rely on it to escape apoptosis. To gain information about the actual "druggability" of CK2 and to dissect CK2 dependent cellular processes that are instrumental to the establishment and progression of neoplasia we have exploited the CRISPR/Cas9 genome editing technology to generate viable clones of C2C12 myoblasts devoid of either both the CK2 catalytic subunits or its regulatory β-subunit...
February 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28209135/marv-a-tool-for-genome-wide-multi-phenotype-analysis-of-rare-variants
#4
Marika Kaakinen, Reedik Mägi, Krista Fischer, Jani Heikkinen, Marjo-Riitta Järvelin, Andrew P Morris, Inga Prokopenko
BACKGROUND: Genome-wide association studies have enabled identification of thousands of loci for hundreds of traits. Yet, for most human traits a substantial part of the estimated heritability is unexplained. This and recent advances in technology to produce high-dimensional data cost-effectively have led to method development beyond standard common variant analysis, including single-phenotype rare variant and multi-phenotype common variant analysis, with the latter increasing power for locus discovery and providing suggestions of pleiotropic effects...
February 16, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28206986/in-situ-generated-d-peptidic-nanofibrils-as-multifaceted-apoptotic-inducers-to-target-cancer-cells
#5
Xuewen Du, Jie Zhou, Huainin Wang, Junfeng Shi, Yi Kuang, Wu Zeng, Zhimou Yang, Bing Xu
Nanofibrils of small molecules, as a new class of biofunctional entities, exhibit emergent properties for controlling cell fates, but the relevant mechanism remains to be elucidated and the in vivo effect has yet to be examined. Here, we show that D-peptide nanofibrils, generated by enzyme-instructed self-assembly (EISA), pleiotropically activate extrinsic death signaling for selectively killing cancer cells. Catalyzed by alkaline phosphatases and formed in situ on cancer cells, D-peptide nanofibrils present autocrine proapoptotic ligands to their cognate receptors in a juxtacrine manner, as well as directly cluster the death receptors...
February 16, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28202597/histone-lysine-to-methionine-mutations-reduce-histone-methylation-and-cause-developmental-pleiotropy
#6
Dean Sanders, Shuiming Qian, Rachael Fieweger, Li Lu, James A Dowell, John M Denu, Xuehua Zhong
Epigenetic modifications play critical roles in diverse biological processes. Histone lysine to methionine (K-to-M) mutations act as gain-of-function mutations to inhibit a wide range of histone methyltransferases and are thought to promote tumorigenesis. However, it is largely unknown whether K-to-M mutations impact development at the whole organismal level. Using Arabidopsis as a model system, we discovered that a transgene exogenously expressing histone 3 lysine 36 to methionine mutation (K36M) acts in a dominant negative manner to cause global reduction of H3K36 methylation...
February 15, 2017: Plant Physiology
https://www.readbyqxmd.com/read/28199350/25-hydroxyvitamin-d3-and-1-25-dihydroxyvitamin-d3-exert-distinct-effects-on-human-skeletal-muscle-function-and-gene-expression
#7
Zaki K Hassan-Smith, Carl Jenkinson, David J Smith, Ivan Hernandez, Stuart A Morgan, Nicola J Crabtree, Neil J Gittoes, Brian G Keevil, Paul M Stewart, Martin Hewison
Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers...
2017: PloS One
https://www.readbyqxmd.com/read/28196480/genome-wide-detection-of-genetic-markers-associated-with-growth-and-fatness-in-four-pig-populations-using-four-approaches
#8
Yuanmei Guo, Yixuan Huang, Lijuan Hou, Junwu Ma, Congying Chen, Huashui Ai, Lusheng Huang, Jun Ren
BACKGROUND: Genome-wide association studies (GWAS) have been extensively used to identify genomic regions associated with a variety of phenotypic traits in pigs. Until now, most GWAS have explored single-trait association models. Here, we conducted both single- and multi-trait GWAS and a meta-analysis for nine fatness and growth traits on 2004 pigs from four diverse populations, including a White Duroc × Erhualian F2 intercross population and Chinese Sutai, Laiwu and Erhualian populations...
February 14, 2017: Genetics, Selection, Evolution: GSE
https://www.readbyqxmd.com/read/28195387/baseline-adiponectin-concentration-and-clinical-outcomes-among-patients-with-diabetes-and-recent-acute-coronary-syndrome-in-the-examine-trial
#9
Brian A Bergmark, Christopher P Cannon, William B White, Petr Jarolim, Yuyin Liu, Marc P Bonaca, Faiez Zannad, David A Morrow
INTRODUCTION: Adiponectin is a pleiotropic adipocytokine with a strong inverse (protective) association with obesity, diabetes, and cardiovascular outcomes in stable patients. However, this relationship may be reversed in the setting of acute coronary syndrome (ACS). Given this possible complex relationship, we investigated adiponectin and cardiovascular (CV) outcomes in patients with diabetes and recent ACS. MATERIALS AND METHODS: We analyzed baseline adiponectin concentration and CV outcomes in 5,213 patients with type 2 diabetes enrolled 15-90 days (median 45 days) after ACS in the EXAMINE trial of alogliptin vs placebo...
February 14, 2017: Diabetes, Obesity & Metabolism
https://www.readbyqxmd.com/read/28195185/microglia-preconditioned-by-oxygen-glucose-deprivation-promote-functional-recovery-in-ischemic-rats
#10
Masato Kanazawa, Minami Miura, Masafumi Toriyabe, Misaki Koyama, Masahiro Hatakeyama, Masanori Ishikawa, Takashi Nakajima, Osamu Onodera, Tetsuya Takahashi, Masatoyo Nishizawa, Takayoshi Shimohata
Cell-therapies that invoke pleiotropic mechanisms may facilitate functional recovery in stroke patients. We hypothesized that a cell therapy using microglia preconditioned by optimal oxygen-glucose deprivation (OGD) is a therapeutic strategy for ischemic stroke because optimal ischemia induces anti-inflammatory M2 microglia. We first delineated changes in angiogenesis and axonal outgrowth in the ischemic cortex using rats. We found that slight angiogenesis without axonal outgrowth were activated at the border area within the ischemic core from 7 to 14 days after ischemia...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28193458/inactivation-of-the-olfactory-marker-protein-omp-gene-in-river-dolphins-and-other-odontocete-cetaceans
#11
Mark S Springer, John Gatesy
Various toothed whales (Odontoceti) are unique among mammals in lacking olfactory bulbs as adults and are thought to be anosmic (lacking the olfactory sense). At the molecular level, toothed whales have high percentages of pseudogenic olfactory receptor genes, but species that have been investigated to date retain an intact copy of the olfactory marker protein gene (OMP), which is highly expressed in olfactory receptor neurons and may regulate the temporal resolution of olfactory responses. One hypothesis for the retention of intact OMP in diverse odontocete lineages is that this gene is pleiotropic with additional functions that are unrelated to olfaction...
February 10, 2017: Molecular Phylogenetics and Evolution
https://www.readbyqxmd.com/read/28192415/immune-regulation-by-glucocorticoids
#12
REVIEW
Derek W Cain, John A Cidlowski
Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive...
February 13, 2017: Nature Reviews. Immunology
https://www.readbyqxmd.com/read/28188805/sphingosine-1-phosphate-signaling-axis-mediates-fibroblast-growth-factor-2-induced-proliferation-and-survival-of-murine-auditory-neuroblasts
#13
Marina Bruno, Ilaria Maria Rizzo, Ricardo Romero-Guevara, Caterina Bernacchioni, Francesca Cencetti, Chiara Donati, Paola Bruni
Hearing loss affects millions of people in the world. In mammals the auditory system comprises diverse cell types which are terminally differentiated and with no regenerative potential. There is a tremendous research interest aimed at identifying cell therapy based solutions or pharmacological approaches that could be applied therapeutically alongside auditory devices to prevent hair cell and neuron loss. Sphingosine 1-phosphate (S1P) is a pleiotropic bioactive sphingolipid that plays key role in the regulation of many physiological and pathological functions...
February 7, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28183357/proangiogenic-effects-of-soluble-%C3%AE-klotho-on-systemic-sclerosis-dermal-microvascular-endothelial-cells
#14
Celestina Mazzotta, Mirko Manetti, Irene Rosa, Eloisa Romano, Jelena Blagojevic, Silvia Bellando-Randone, Cosimo Bruni, Gemma Lepri, Serena Guiducci, Lidia Ibba-Manneschi, Marco Matucci-Cerinic
BACKGROUND: Systemic sclerosis (SSc) is characterized by endothelial cell (EC) apoptosis, impaired angiogenesis and peripheral microvasculopathy. Soluble α-Klotho (sKl) is a pleiotropic molecule with multiple effects on ECs, including antioxidant and vasculoprotective activities. On the EC surface, sKl interacts with vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) and transient receptor potential canonical-1 (TRPC-1) cation channel to control EC homeostasis. Here, we investigated whether sKl might act as a protective factor to improve angiogenesis in dermal microvascular endothelial cells (MVECs) from SSc patients (SSc-MVECs)...
February 10, 2017: Arthritis Research & Therapy
https://www.readbyqxmd.com/read/28182617/statins-in-hiv-infected-patients-potential-beneficial-effects-and-clinical-use
#15
Enrique Bernal, Mar Masiá, Irene Marín, Félix Gutiérrez
Patients living with HIV have an increased risk of cardiovascular disease that is considered to be the result of an interaction between traditional cardiovascular risk factors, particularly smoking and dyslipidemia, and persistent chronic inflammation and immune activation associated with HIV infection, along with side effects of antiretroviral therapy. In the general population, the administration of statins has been associated with a reduction in cardiovascular disease-associated mortality, and these drugs are among the most common class of medication prescribed in high-income countries...
February 9, 2017: AIDS Reviews
https://www.readbyqxmd.com/read/28181907/the-role-of-interleukin-15-in-neoplasia
#16
Małgorzata Chłopek, Artur Kowalik, Stanisław Góźdź, Katarzyna Koziak
Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL‑15Rα‑chain and IL-2/IL-15Rβ and IL‑2Rγ chains, IL‑15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL‑15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL‑15 on the immune system provides new opportunities for development of anti‑cancer therapies...
January 10, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28181315/emodin-a-natural-inhibitor-of-protein-kinase-ck2-suppresses-growth-hyphal-development-and-biofilm-formation-of-candida-albicans
#17
Monika Janeczko, Maciej Masłyk, Konrad Kubiński, Hieronim Golczyk
Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural secondary plant product, originally isolated from the rhizomes of Rheum palmatum. Many reports show its diuretic, vasorelaxant, anti-bacterial, anti-viral, anti-ulcerogenic, immunosuppressive, hepatoprotective, anti-inflammatory, and anti-cancer potential. Emodin is a pleiotropic molecule capable of interacting with several major molecular targets, e.g. NF-κB, AKT/mTOR, and STAT3. The compound can also act as an inhibitor of some protein kinases, with special affinity to protein kinase CK2...
February 8, 2017: Yeast
https://www.readbyqxmd.com/read/28181297/induction-of-oxidative-stress-by-bisphenol-a-and-its-pleiotropic-effects
#18
REVIEW
Natalie R Gassman
Bisphenol A (BPA) has become a target of intense public scrutiny since concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer have emerged. BPA is a highly prevalent chemical in consumer products, and human exposure is thought to be ubiquitous. Numerous studies have demonstrated its endocrine disrupting properties and attributed exposure with cytotoxic, genotoxic, and carcinogenic effects; however, the results of these studies are still highly debated and a consensus about BPA's safety and its role in human disease has not been reached...
February 9, 2017: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/28181108/circulating-levels-of-fibroblast-growth-factor-21-in-early-stage-diabetic-kidney-disease
#19
A Esteghamati, A Khandan, A Momeni, A Behdadnia, A Ghajar, M S Nikdad, S Noshad, M Nakhjavani, M Afarideh
AIMS/PURPOSE: Fibroblast growth factor 21 (FGF21), a hepatoadipokine with pleiotropic metabolic regulatory actions, is emerging as a novel biomarker of progressive nephropathy. We sought to evaluate circulating FGF21 and its association with clinical and biochemical characteristics as well as the urinary albumin excretion (UAE) rates in a population of patients with type 2 diabetes (T2D) with or without microalbuminuria and their matched healthy controls. METHODS: Cross-sectionally, 130 consecutive individuals comprising patients with T2D with (n = 44) or without (n = 44) microalbuminuria and their healthy controls (n = 42) were recruited for analysis...
February 8, 2017: Irish Journal of Medical Science
https://www.readbyqxmd.com/read/28179965/primary-care-based-investigation-of-the-effect-of-sitagliptin-on-blood-pressure-in-hypertensive-patients-with-type-2-diabetes
#20
Shouhei Yuasa, Kazuyoshi Sato, Takamoto Furuki, Kosuke Minamizawa, Hiroyuki Sakai, Yuichi Numata, Keiichi Chin, Jisho Kojima, Masaaki Miyakawa, Ikuro Matsuba
BACKGROUND: The influence of long-term sitagliptin therapy on office blood pressure (BP) and home BP has been unclear. METHODS: In a retrospective cohort study of 454 patients with type 2 diabetes, the following variables were analyzed before and at 3, 6, 9, and 12 months after initiation of sitagliptin therapy: office systolic blood pressure (SBP), office diastolic blood pressure (DBP), office pulse rate, morning home SBP, morning home DBP, morning home pulse rate, evening home SBP, evening home DBP, evening home pulse rate, hemoglobin A1c (HbA1c), plasma glucose, lipid profile, and renal function parameters...
March 2017: Journal of Clinical Medicine Research
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