Home About us Contact
|
Home About us Contact | ||
|
|
||
Genes Relevant (gene + relevant)
Selected AbstractsAMP-activated protein kinase in contraction regulation of skeletal muscle metabolism: necessary and/or sufficient?ACTA PHYSIOLOGICA, Issue 1 2009T. E. Jensen Abstract In skeletal muscle, the contraction-activated heterotrimeric 5,-AMP-activated protein kinase (AMPK) protein is proposed to regulate the balance between anabolic and catabolic processes by increasing substrate uptake and turnover in addition to regulating the transcription of proteins involved in mitochondrial biogenesis and other aspects of promoting an oxidative muscle phenotype. Here, the current knowledge on the expression of AMPK subunits in human quadriceps muscle and evidence from rodent studies suggesting distinct AMPK subunit expression pattern in different muscle types is reviewed. Then, the intensity and time dependence of AMPK activation in human quadriceps and rodent muscle are evaluated. Subsequently, a major part of this review critically examines the evidence supporting a necessary and/or sufficient role of AMPK in a broad spectrum of skeletal muscle contraction-relevant processes. These include glucose uptake, glycogen synthesis, post-exercise insulin sensitivity, fatty acid (FA) uptake, intramuscular triacylglyceride hydrolysis, FA oxidation, suppression of protein synthesis, proteolysis, autophagy and transcriptional regulation of genes relevant to promoting an oxidative phenotype. [source] Designing mouse behavioral tasks relevant to autistic-like behaviors,DEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 4 2004Jacqueline N. Crawley Abstract The importance of genetic factors in autism has prompted the development of mutant mouse models to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (1) face validity, i.e., resemblance to the human symptoms; (2) construct validity, i.e., similarity to the underlying causes of the disease; and (3) predictive validity, i.e., expected responses to treatments that are effective in the human disease. There is a growing need for mouse behavioral tasks with all three types of validity for modeling the symptoms of autism. We are in the process of designing a set of tasks with face validity for the defining features of autism: deficits in appropriate reciprocal social interactions, deficits in verbal social communication, and high levels of ritualistic repetitive behaviors. Social approach is tested in an automated three-chambered apparatus that offers the subject a choice between a familiar environment, a novel environment, and a novel environment containing a stranger mouse. Preference for social novelty is tested in the same apparatus, with a choice between the start chamber, the chamber containing a familiar mouse, and the chamber containing a stranger mouse. Social communication is evaluated by measuring the ultrasonic distress vocalizations emitted by infant mouse pups and the parental response of retrieving the pup to the nest. Resistance to change in ritualistic repetitive behaviors is modeled by forcing a change in habit, including reversal of the spatial location of a reinforcer in a T-maze task and in the Morris water maze. Mouse behavioral tasks that may model additional features of autism are discussed, including tasks relevant to anxiety, seizures, sleep disturbances, and sensory hypersensitivity. Applications of these tests include (1) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism, (2) characterization of mutant mice derived from random chemical mutagenesis, (3) DNA microarray analyses of genes in inbred strains of mice that differ in social interaction, social communication and resistance to change in habit, and (4) evaluation of proposed therapeutics for the treatment of autism. Published 2004 Wiley-Liss, Inc. MRDD Research Reviews 2004;10:248,258. [source] Autism-like behavioral phenotypes in BTBR T+tf/J miceGENES, BRAIN AND BEHAVIOR, Issue 2 2008H. G. McFarlane Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms. [source] The aetiology of sperm protamine abnormalities and their potential impact on the sperm epigenomeINTERNATIONAL JOURNAL OF ANDROLOGY, Issue 6 2008Douglas T. Carrell Summary During the elongating spermatid stage of spermatogenesis, there is a step-wise replacement of nuclear histones with protamines 1 and 2. In fertile men, the ratio of protamine 1/protamine 2 (P1/P2) is within the narrow range of 0.8,1.2. Ratios above or below that range are associated with infertility, exhibiting a wide range of defects including decreased sperm counts, morphology, fertilization ability, and embryo implantation capacity. In this review, we highlight studies evaluating potential causes of abnormal protamine expression, including the sequencing of genes relevant to protamine expression in both affected patients and controls. While the variants of the protamine genes themselves do not appear to be responsible for most observed defects, variants of the Contrin gene, a transcription factor and translation repressor, appear to be contributory to some cases of abnormal expression. Additionally, we explore the potential effects of abnormal protamine replacement on the epigenome of human sperm. Ongoing studies are evaluating the role of retained histones and DNA methylation in sperm, which may be affected in sperm with aberrant protamine replacement. This important area of epigenetic research has profound clinical implications. [source] Periodontal therapy alters gene expression of peripheral blood monocytesJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 9 2007Panos N. Papapanou Abstract Aims: We investigated the effects of periodontal therapy on gene expression of peripheral blood monocytes. Methods: Fifteen patients with periodontitis gave blood samples at four time points: 1 week before periodontal treatment (#1), at treatment initiation (baseline, #2), 6-week (#3) and 10-week post-baseline (#4). At baseline and 10 weeks, periodontal status was recorded and subgingival plaque samples were obtained. Periodontal therapy (periodontal surgery and extractions without adjunctive antibiotics) was completed within 6 weeks. At each time point, serum concentrations of 19 biomarkers were determined. Peripheral blood monocytes were purified, RNA was extracted, reverse-transcribed, labelled and hybridized with AffymetrixU133Plus2.0 chips. Expression profiles were analysed using linear random-effects models. Further analysis of gene ontology terms summarized the expression patterns into biologically relevant categories. Differential expression of selected genes was confirmed by real-time reverse transcriptase-polymerase chain reaction in a subset of patients. Results: Treatment resulted in a substantial improvement in clinical periodontal status and reduction in the levels of several periodontal pathogens. Expression profiling over time revealed more than 11,000 probe sets differentially expressed at a false discovery rate of <0.05. Approximately 1/3 of the patients showed substantial changes in expression in genes relevant to innate immunity, apoptosis and cell signalling. Conclusions: The data suggest that periodontal therapy may alter monocytic gene expression in a manner consistent with a systemic anti-inflammatory effect. [source] Platelet hyperreactivity generalizes to multiple forms of stimulationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2006D. L. YEE Summary.,Background:,Although platelet hyperreactivity constitutes an important cardiovascular risk factor, standardized methods for its measurement are lacking. We recently reported that aggregometry using a submaximal concentration of epinephrine identifies individuals with in vitro platelet hyperreactivity; this hyperreactivity was reproducible on multiple occasions over long periods of time. Objective and methods:,To better understand this aberrant reactivity, we studied in a large group of subjects (n = 386) the relationship between healthy individuals' platelet reactivity to epinephrine and their platelet phenotype as measured by other functional assays. Results:,Subjects with hyperreactivity to epinephrine were more likely to exhibit hyperfunction in each major aspect of platelet activity, including adhesion (response to low-dose ristocetin; P < 0.001), activation (surface P-selectin expression and PAC-1 binding after stimulation; P , 0.003) and aggregation to other agonists [no agonist, adenosine diphosphate (ADP), arachidonic acid, collagen, collagen-related peptide and ristocetin; P , 0.025] and to applied shear stress (PFA-100 and cone-and-plate viscometer; P < 0.05). These differences persisted after adjusting for demographic and hematologic differences between groups. We studied candidate genes relevant to epinephrine-mediated platelet activation and found that hyperreactivity to epinephrine was associated with a polymorphism on the gene (GNB3) encoding the beta-3 subunit of G proteins (P = 0.03). Conclusions:,Robust aggregation to a submaximal concentration of epinephrine establishes a true hyperreactive platelet phenotype that is ,global' as opposed to agonist specific; detection of this phenotype could be useful for studying patients at risk for arterial thrombosis. The mechanisms underlying hyperreactivity to different types of platelet stimulation may share common signaling pathways, some of which may involve specific G protein subunits. [source] NSAID-induced antral ulcers are associated with distinct changes in mucosal gene expressionALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2009J. C. DESAI Summary Background, The basis for individual variation in gastroduodenal vulnerability to NSAIDs is not well understood. Aim, To assess whether a gene expression signature is associated with susceptibility to gastroduodenal ulcerations. Methods, Twenty-five Helicobacter pylori negative adults were treated for 7 days with naproxen 500 mg b.d. Subjects underwent baseline and post-treatment endoscopy, during which biopsies were taken from antrum and duodenum. RNA extraction and cDNA synthesis were performed, followed by PCR of 23 genes relevant to mucosal injury and repair. Fold changes in gene expression were compared between subjects who developed ulcers and those who did not. Results, Compared with subjects who did not develop ulcers (n = 18), subjects who developed antral ulcers (n = 7) had significantly greater mucosal up-regulation of interleukin-8 [Fold change = 33.5 (S.E.M. = 18.5) vs. ,7.7 (3.2)] and of cyclo-oxygenase-2 [2.3 (1.7) vs. ,10.8 (2.2)]. Conversely, non-ulcer subjects had significantly greater up-regulation of toll-like receptor-4, cyclo-oxygenase-1 and hepatocyte growth factor [14.0 (2.2) vs. ,0.8 (1.0), 9.8 (2.4) vs. 0.0 (0.7) and 8.2 (2.6) vs. ,2.2 (0.3) respectively]. Conclusions, NSAID-induced antral ulcers are associated with a specific pattern of gastroduodenal mucosal gene expression. These patterns may provide an insight into the molecular basis of individual susceptibility to mucosal injury. [source] Analysis of bile acid-induced regulation of FXR target genes in human liver slicesLIVER INTERNATIONAL, Issue 1 2007Diana Jung Abstract Information about the role of nuclear receptors has rapidly increased over the last decade. However, details about their role in human are lacking. Owing to species differences, a powerful human in vitro system is needed. This study uses for the first time precision-cut human liver slices in the nuclear receptor field. The farnesoid X receptor (FXR) was chosen as a model. We were able to demonstrate that human liver slices efficiently take up bile acids and show a stable expression of a wide variety of genes relevant for bile acid metabolism, including bile acid transporters, cytochrome P450 enzymes and transcription factors. Treatment with chenodeoxycholate induced small heterodimer partner, bile salt export pump and p-glycoprotein, ABCB4 and repressed cholesterol 7, hydroxylase, hepatocyte nuclear factor (HNF)1, HNF4 and organic anion transporting peptide (OATP)1B1. OATP1B3, FXR, HNF3, and cytochrome P450 enzyme remained relatively constant. In contrast to what has been observed in mice and rat studies, SHP induction did not result in repression of sodium-dependent bile acid cotransporter expression. Further, regulation of genes seemed to be dependent on concentration and time. Taken together, the study shows that the use of liver slices is a powerful technique that enables to study nuclear receptors in the human liver. [source] A network analysis of the single nucleotide polymorphisms in acute allergic diseasesALLERGY, Issue 1 2010J. Renkonen Abstract Background:, Genetics of acute allergies has focused on identifying single nucleotide polymorphisms (SNPs) within genes relevant in the pathogenesis. In this study, we begin a systems biology analysis of the interconnectivity and biological functions of these genes, their transcripts and their corresponding proteins. Methods:, The literature (Pubmed) was searched for SNPs within genes relevant in acute allergic diseases. The SNP-modified genes were converted to corresponding proteins and their protein,protein interactions were searched from six different databases. This interaction network was analysed with annotated vocabularies (ontologies), such as Gene Ontology, Reactome and Nature pathway interaction database. Time-series transcriptomics was performed with nasal epithelial cells obtained from allergic patients and their healthy control subjects. Results:, A total of 39 genes with SNPs related to acute allergic diseases were found from a literature search. The corresponding proteins were then hooked into a large protein,protein interaction network with the help of various databases. Twenty-five SNP-related proteins had more than one interacting protein and a network contained 95 proteins, and 182 connections could be generated. This network was 10-fold enriched with protein kinases and proteins involved in the host,virus interaction compared with background human proteome. Finally, eight of the 95 nodes on our network displayed nasal epithelial transcriptomal regulation in a time-series analysis collected from birch allergic patients during the spring pollen season. Conclusions:, Signal transduction with special reference to host,virus interactions dominated in the allergy-related protein interaction network. Systems level analysis of allergy-related mutation can provide new insights into pathogenetic mechanisms of the diseases. [source] Alterations of chaperone protein expression in presenilin mutant neurons in response to glutamate excitotoxicityPATHOLOGY INTERNATIONAL, Issue 9 2002Izumi Maezawa Mutations in the presenilin-1 (PS1) gene underlie the most common form of familial dementia of the Alzheimer type (DAT). We demonstrated previously that the expression of PS1 with a M146V mutation in transgenic mice potentiates glutamate toxicity to neurons, due to an altered calcium homeostasis. Here, using a subtractive cDNA library approach, we report the identification of several genes, the altered expression of which may be associated with this unique PS1 -related vulnerability to glutamate. The identified genes, including chaperonin subunit 2 and nucleophosmin 1/B23, are involved in the intracellular trafficking of proteins and ions. Northern blot analysis revealed that the effect of glutamate on calcium-binding proteins was augmented in neurons from PS1 mutation mice, compared with neurons from mice lacking other genes relevant to the pathogenesis of DAT (FE65 and APOE) or neurons from control wild-type mice. Interestingly, mRNA for two chaperone proteins were expressed at lower levels specifically in neurons from PS1 mutant mice. These findings suggest that PS1 mutations may, in part, contribute to the development of DAT via altered expression of chaperone proteins. [source] Chemopreventive Action of Xanthone Derivatives on Photosensitized DNA Damage,PHOTOCHEMISTRY & PHOTOBIOLOGY, Issue 2 2005Kazutaka Hirakawa ABSTRACT Photosensitized DNA damage participates in solar-UV carcinogenesis, photogenotoxicity and phototoxicity. A chemoprevention of photosensitized DNA damage is one of the most important methods for the above phototoxic effects. In this study, the chemopreventive action of xanthone (XAN) derivatives (bellidifolin [BEL], gentiacaulein [GEN], norswertianin [NOR] and swerchirin [SWE]) on DNA damage photosensitized by riboflavin was demonstrated using [32P]-5,-end-labeled DNA fragments obtained from genes relevant to human cancer. GEN and NOR effectively inhibited the formation of piperidine-labile products at consecutive G residues by photoexcited riboflavin, whereas BEL and SWE did not show significant inhibition of DNA damage. The four XAN derivatives decrease the formation of 8-oxo-7,8-dihydro-2,-deoxyguanosine (8-oxodGuo), an oxidative product of G, by photoexcited riboflavin. The preventive action for the 8-oxodGuo formation of these XAN derivatives increased in the following order: GEN > NOR , BEL > SWE. A fluorescence spectroscopic study and ab initio molecular orbital calculations suggested that the prevention of DNA photodamage is because of the quenching of the triplet excited state of riboflavin by XAN derivatives through electron transfer. This chemoprevention is based on neither antioxidation nor a physical sunscreen effect; rather, it is based on the quenching of a photosensitizer. In conclusion, XAN derivatives, especially GEN, may act as novel chemopreventive agents by the quenching mechanism of an excited photosensitizer. [source] MicroRNAs as Immune Regulators: Implications for TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010A. Harris The explosion of genetic information from recent advances in sequencing technologies, bioinformatics and genomics highlights the importance of understanding mechanisms involved in gene expression and regulation. Over the last decade, it has become clear that small ribonucleic acids (RNAs) are a central component of the cellular gene regulatory network. MicroRNAs (miRNAs) are a family of endogenous, small, noncoding single-stranded RNA of ,22 nucleotides in length that act as posttranscriptional gene regulatory elements. MicroRNAs can inhibit de novo protein synthesis by blocking translation through base-pairing with complementary messenger RNA (mRNA) and also suppress translation by promoting degradation of target mRNA. MicroRNAs are intimately involved in a variety of biologic processes including development, hematopoietic cell differentiation, apoptosis and proliferation. To date, over 800 human miRNAs have been identified, though the biologic function of only a fraction of miRNAs has been elucidated. Here, we discuss how miRNAs are produced, identified and quantitated, and focus on several key miRNAs that govern expression of genes relevant to allograft rejection, tolerance induction and posttransplant infection. Finally, we discuss potential ways in which the miRNA network can be modulated that ultimately may offer new strategies to promote long-term graft survival. [source] Der Zebrafisch als vielseitiges Modellsystem.BIOLOGIE IN UNSERER ZEIT (BIUZ), Issue 6 2009Vom Zierfisch zum Forschungsobjekt Abstract In den vergangenen Jahren hat sich der Zebrafisch vom Zierfisch zum weitverbreiteten Modellsystem der biomedizinischen Forschung entwickelt. Er ist einfach zu halten, produziert in rascher Folge viele Nachkommen, entwickelt sich schnell und außerhalb des Muttertiers und ist zudem in den frühen Entwicklungsphasen transparent. Entsprechend wurde er zuerst vor allem zur unmittelbaren Beobachtung von Entwicklungsvorgängen genutzt. Da er aber auch relativ einfach genetisch manipulierbar ist, wurde er in Folge zur Herstellung transgener Linien verwendet, in denen Fremd-DNA exprimiert und die Bedeutung des jeweiligen Genprodukts für die Biologie des Tieres untersucht werden kann. Außerdem kann er durch Zufalls-Mutagenese zur unvoreingenommenen Entdeckung krankheitsrelevanter Gene verwendet werden, zum Screening biologisch wirksamer Substanzen für die Entwicklung von Medikamenten und zunehmend auch als Modell in der Krebsforschung. Over the past years, the zebrafish rose from an aquarium fish to a widespread model of biomedical research. It is easily maintained, produces relatively large offspring, shows rapid extra maternal development, and is transparent during early development. Hence, it was initially primarily utilized for direct microscopic observation of developmental processes. However, as it is easily genetically manipulated, it was soon used to produce transgenic lines expressing DNA derived from other organisms. These lines could be used to study the importance of specific genes for biological processes. In addition, zebrafish is used for random mutagenesis screens, allowing the unbiased detection of genes relevant for diseases, for small molecule screens applied for the discovery of biologically active substances, and increasingly as a model for cancer research. [source] CARDIOVASCULAR AND METABOLIC EFFECTS OF OBESITYCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2008Margaret J Morris SUMMARY 1Obesity is an important risk factor for hypertension and its incidence is increasing around the world. 2The mechanisms underlying obesity-related hypertension include sympathetic activation, altered vascular responses, hormonal changes, enhanced inflammatory markers and structural changes. 3This review summarizes recent evidence of the underlying impact of obesity on blood pressure. A number of candidate mechanisms include increased sympathetic activity, activation of the renin-angiotensin system, altered vasoconstrictor or dilator responses and the attendant systemic inflammatory state. 4While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant hypertension, evidence suggests that the programming of obesity may occur following over-nutrition during development. A growing body of evidence links maternal obesity, offspring obesity and hypertension. 5Finally, epigenetic modification of genes relevant to hypertension may contribute to the development of hypertension following a suboptimal intrauterine environment. To date the cardiovascular effects of early nutritional changes have been largely investigated following maternal under-nutrition or protein restriction; further work is necessary to determine the impact of maternal obesity. [source] | |||||||||||||