Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Expression divergence”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 901 records · Page 50Linked to original sources

Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical phenotype of the disease is varied. It is proposed that this variation may be a result of differential functional disruption of ATPase7B (ATP7B) resulting from mutations in the gene ATP7B. We aimed to assess the relationship between specific mutational defects in ATP7B and divergence in the phenotypic expression of WD. One hundred and forty-two patients with clinically, biochemically and genetically diagnosed WD were included in the study. The phenotypic expression of WD was compared between patients with different types of mutations in ATP7B, detected by direct sequencing of exons 1-21 of the gene. Twenty-six mutations were identified in ATP7B; eleven of them were mutations predicted to result in the absence of a full-length normal protein [frameshift/nonsense mutations; classified as 'severe' mutations (SMs)], 14 were missense mutations (MMs) and one was a splice site mutation. Patients with one or two SMs on their alleles had lower serum copper and ceruloplasmin and were younger when the first symptoms of the disease appeared, compared with individuals with two MMs. The effect of SMs on the WD phenotype was dose-dependent. It is concluded that mutations within ATP7B are very heterogeneous. Frameshift and nonsense mutations are associated with a severe phenotype of WD.

Adenosine Triphosphatases↗

Matrix metalloproteinases and mesangial remodeling in light chain-related glomerular damage.

BACKGROUND: Matrix metalloproteinases (MMPs) belong to the zinc endopeptidase subgroup of the metalloproteinase superfamily and are primarily involved in extracellular matrix (ECM) remodeling. Alterations of the mesangial ECM in AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD) are crucial in their pathogeneses as two divergent entities. METHODS: Protein expression patterns of five MMPs (MMP-1, 2, 3, 7, and 9) in renal tissues obtained from autopsies and kidney biopsies, and cultured human mesangial cells (HMCs) treated with light chains obtained from the urines of patients with AL-Am and LCDD were analyzed. MMP mRNA expressions were determined in glomeruli following laser capture microdissection and selective MMP microarray. Zymography was used to assess MMP activity. RESULTS: The average glomerular MMP expression was 6 times greater in AL-Am than LCDD and negative control renal tissues with different expression profiles: MMP-1, 7 > 9 > 3 > 2, MMP-1 > 2, 9 > 3 > 7, and MMP-2, 3, 7 > 9 > 1, respectively. Microdissected glomeruli and HMCs treated with light chains expressed higher levels of MMP mRNA and proteins in AL-Am than LCDD. Zymography was used to assess activity demonstrating increased MMP-2 in AL-Am. CONCLUSION: Altered expressions of MMPs play a key role in the pathogenesis of AL-Am and LCDD. MMPs were more highly expressed in AL-Am compared to LCDD.

Amyloidosis↗

Cytokine profiles in peripheral blood mononuclear cells and lymph node cells from piglets infected in utero with porcine reproductive and respiratory syndrome virus.

The aim of the present study was to investigate at 2, 4, and 6 weeks after birth cytokine expression by peripheral blood mononuclear cells and bronchial lymph node cells from piglets infected in utero with porcine reproductive and respiratory syndrome virus (PRRSV). Technically, by flow cytometry we were able to measure gamma interferon (gamma-IFN), tumor necrosis factor alpha (TNF-alpha), interleukin-4 (IL-4), and IL-8 levels. In general, we found increases in the percentages of IL-4-, gamma-IFN-, and TNF-alpha-producing lymphocytes in the infected piglets compared to the percentages in the uninfected control animals, while there was a decrease in the percentage of IL-8-producing monocytes. We believe that these findings reflect a general lymphocyte activation stage that is created due to the infection and that occurs in combination with impairment of the monocyte function, possibly due to the ongoing viral replication in these cells. Single-cell bronchial lymph node preparations exhibited very much the same cytokine profiles as peripheral blood mononuclear cells except for a lack of IL-8 production. When the levels of the individual cytokines in the three groups of PRRSV-infected piglets were compared, the levels of cytokine expression at 4 weeks diverged from those at 2 and 6 weeks, in that there was a significant decrease in the numbers of lymphocytes producing gamma-IFN and TNF-alpha. This tendency was also observed among blood monocytes and lymph node macrophages. Possible reasons for this temporary immunosuppression in the piglets at 4 weeks are discussed.

Animals↗

Nucleotide sequence of the epidermolytic toxin A gene of Staphylococcus aureus.

The nucleotide sequence of the eta gene, which codes for the epidermolytic toxin serotype A of Staphylococcus aureus TC16, is reported. The coding sequence of 840 nucleotides specifies a protein which, when secreted, has a predicted molecular weight of 26,950. The sequence of eta and the deduced amino acid sequence of the toxin have been compared with those of epidermolytic toxin serotype B. The coding sequences have 52% identical residues, and the polypeptides have 40% identical residues. Amino acid residues have been conserved in the areas of the proteins which correspond to major hydrophobic domains, whereas the regions likely to specify antigenic determinants occur in hydrophilic sequences that have diverged. The level of expression of epidermolytic toxin A in S. aureus 8325-4 was shown to be dependent on the integrity of a regulatory gene called agr.

Amino Acid Sequence↗

Regulation of expression of the yiaKLMNOPQRS operon for carbohydrate utilization in Escherichia coli: involvement of the main transcriptional factors.

The yiaKLMNOPQRS (yiaK-S) gene cluster of Escherichia coli is believed to be involved in the utilization of a hitherto unknown carbohydrate which generates the intermediate L-xylulose. Transcription of yiaK-S as a single message from the unique promoter found upstream of yiaK is proven in this study. The 5' end has been located at 60 bp upstream from the ATG. Expression of the yiaK-S operon is controlled in the wild-type strain by a repressor encoded by yiaJ. No inducer molecule of the yiaK-S operon has been identified among over 80 carbohydrate or derivative compounds tested, the system being expressed only in a mutant strain lacking the YiaJ repressor. The lacZ transcriptional fusions in the genetic background of the mutant strain revealed that yiaK-S is modulated by the integration host factor and by the cyclic AMP (cAMP)-cAMP receptor protein (Crp) activator complex. A twofold increase in the induction was observed during anaerobic growth, which was independent of ArcA or Fnr. Gel mobility shift assays showed that the YiaJ repressor binds to a promoter fragment extending from -50 to +121. These studies also showed that the cAMP-Crp complex can bind to two different sites. The lacZ transcriptional fusions of different fragments of the promoter demonstrated that binding of cAMP-Crp to the Crp site 1, centered at -106, is essential for yiaK-S expression. The 5' end of the yiaJ gene was determined, and its promoter region was found to overlap with the divergent yiaK-S promoter. Expression of yiaJ is autogenously regulated and reduced by the binding of Crp-cAMP to the Crp site 1 of the yiaK-S promoter.

Amino Acid Sequence↗

Liver beta-adrenergic receptors, G proteins, and adenylyl cyclase activity in obesity-diabetes syndromes.

The ob and db genes produce similar hormonal anomalies in mice. Although the expression of the syndromes diverges with age, at 8-12 wk both ob/ob and db/db mice are hyperglycemic and hyperinsulinemic and show evidence of hypercorticoidism. Nevertheless, membranes isolated from livers of ob/ob and db/db mice behave differently in terms of adenylyl cyclase activity and beta-adrenergic receptor function. There are three times as many beta 2-adrenergic receptor binding sites and a threefold increase in the response to catecholamines in ob/ob mouse liver membranes than in comparable preparations from normal controls or db/db mice. By contrast, the two main G proteins of liver membranes (Gs alpha and Gi alpha 2) are less abundant in the mutants, ob/ob and db/db, than in their respective lean controls. Adrenalectomy normalizes the exaggerated response to beta-adrenergic agonists and the number of beta-adrenergic binding sites in the ob/ob mouse. This shows that the enhanced beta-adrenergic receptor response is linked to hypercorticoidism. Cellular maturation and differentiation (D. C. Watkins, J. K. Northrup, and C. C. Malbon, J. Biol. Chem. 262: 10651-10657, 1987) and diseases such as obesity and diabetes (cf. N. McFarlane-Anderson, J. Bailly, and N. Bégin-Heick, Biochem. J. 282: 15-23, 1992) have been associated with modifications in the complement of G proteins detected in cells. However, the relationship among levels, types, and intracellular localization of G proteins in tissues and their influence on the transduction of the message to an effector system, such as adenylyl cyclase, are not yet well understood.

Adenylyl Cyclases↗

Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current.

HERG, the human ether-a-go-go-related gene, encodes a K(+)-selective channel with properties similar to the rapidly activating component of the delayed rectifier K+ current (IKr). Mutations of HERG cause the autosomal-dominant long-QT syndrome (LQTS), presumably by disrupting the normal function of IKr. The current produced by HERG is not identical to IKr, however, and the mechanism by which HERG mutations cause LQTS remains uncertain. To better define the role of Erg in the heart, we cloned Merg1 from mouse genomic and cardiac cDNA libraries. Merg1 has 16 exons and maps to mouse chromosome 5 in an area syntenic to human chromosome 7q, the map locus of HERG. We isolated three cardiac isoforms of Merg1: Merg1a is homologous to HERG and is expressed in heart, brain, and testes, Merg1a' lacks the first 59 amino acids of Merg1a and is not expressed abundantly, and Merg1b has a markedly shorter divergent N-terminal cytoplasmic domain and is expressed specifically in the heart. The Merg1 isoforms, like HERG, produce inwardly rectifying E-4031-sensitive currents when heterologously expressed in Xenopus oocytes. Merg1a and HERG produce currents with slow deactivation kinetics, whereas Merg1a' and Merg1b currents deactivate more rapidly. Merg1b coassembles with Merg1a to form channels with deactivation kinetics that are more rapid than those of Merg1a or HERG and nearly identical to IKr. In addition, a homologue of Merg1b is present in human cardiac and smooth muscle. Thus, we have identified a novel N-terminal Erg isoform that is expressed specifically in the heart, has rapid deactivation kinetics, and coassembles with the longer isoform in Xenopus oocytes. This N-terminal Erg isoform may determine the properties of IKr and contribute to the pathogenesis of LQTS.

Amino Acid Sequence↗

Science, law, and politics in FDA's genetically engineered foods policy: scientific concerns and uncertainties.

The Food and Drug Administration's (FDA's) 1992 policy statement granted genetically engineered foods presumptive GRAS (generally recognized as safe) status. Since then, divergent views have been expressed concerning the scientific support for this policy. This paper examines four sources to better understand the basis for these claims: 1) internal FDA correspondence; 2) reports from the National Academy of Sciences; 3) research funded by US Department of Agriculture from 1981 to 2002; and 4) FDA's proposed rules issued in 2001. These sources reveal that little research has been conducted on unintended compositional changes from genetic engineering. Profiling techniques now make this feasible, but the new debate centers on the functional meaning of compositional changes.

Consumer Product Safety↗

The transcribed genome and the heritable basis of essential hypertension.

Gene expression can be now assessed quantitatively and comprehensively. In addition to reflecting the specialized differentiation of the cell or tissue type from which gene expression is sampled, it also manifests patterns determined by inheritance. Thus gene expression is a phenotypic trait, at least when assessed comprehensively. This trait shows familial aggregation and segregation patterns indicative of an inherited contribution. The molecular evolution of genes includes mutations affecting regulatory sequences in the genome that influence gene expression in cis and in trans. Such mutations may increase in frequency in a population either by genetic drift or by selection. Traits of gene expression, acting alone or in concert with other gene expression traits, may generate phenotypes that extend beyond transcript abundance. Indeed, the divergence of species and the traits that distinguish related species appear to rely importantly on inherited divergence in the control of gene expression. Variation in gene expression may contribute to the pathogenesis of a prevalent human disease trait that shows heritability--essential hypertension. Along with other common heritable diseases, hypertension susceptibility arises from the actions of multiple genome sequence variations. The identity of such variation has proven elusive when sought by methods that have been successfully applied to Mendelian diseases. This review explores the potential to uncover hypertension genes by exploiting quantitative variation in the heritable control of gene expression.

Animals↗

Transition from stochastic to deterministic behavior in calcium oscillations.

Simulation and modeling is becoming more and more important when studying complex biochemical systems. Most often, ordinary differential equations are employed for this purpose. However, these are only applicable when the numbers of participating molecules in the biochemical systems are large enough to be treated as concentrations. For smaller systems, stochastic simulations on discrete particle basis are more accurate. Unfortunately, there are no general rules for determining which method should be employed for exactly which problem to get the most realistic result. Therefore, we study the transition from stochastic to deterministic behavior in a widely studied system, namely the signal transduction via calcium, especially calcium oscillations. We observe that the transition occurs within a range of particle numbers, which roughly corresponds to the number of receptors and channels in the cell, and depends heavily on the attractive properties of the phase space of the respective systems dynamics. We conclude that the attractive properties of a system, expressed, e.g., by the divergence of the system, are a good measure for determining which simulation algorithm is appropriate in terms of speed and realism.

Adenosine Triphosphate↗

Expression of actin genes in the arrow worm Paraspadella gotoi (Chaetognatha).

Arrow worms (the phylum Chaetognatha), one of the major marine planktonic animals, exhibit features characteristic to both deuterostomes and protostomes, and their ancestry therefore remains unknown. As the first step to elucidate the molecular bases of arrow worm phylogeny, physiology and embryology, we isolated cDNA clones for three different actin genes (PgAct1, PgAct2 and PgAct3) from the benthic species Paraspadella gotoi, and examined their expression patterns in adults and juveniles. The amino acid sequences of the three actins resembled each other, with identities ranging from 86% to 92%. However, the patterns of the spatial expression of the genes were independent. The PgAct1 gene might encode a cytoplasmic actin and was expressed in oogenic cells, spermatogenic cells, and cells in the ventral ganglion. The PgAct2 and PgAct3 genes encoded actins of divergent types. The former was expressed in well-developed muscle of the head (gnathic) region and trunk muscle cells, whereas the latter was expressed in muscle of the trunk and tail regions and oogenic cells. These results suggest that, similarly to other metazoans, the chaetognath contains multiple forms of actins, which are expressed in various manners in the adult and juvenile arrow worm.

Actins↗

[Epidemiology and prognosis of peripheral obliterative arteriopathy].

Peripheral arterial disease has received less attention from epidemiologists than coronary and cerebrovascular disease. Prevalence and incidence data typically show that peripheral arterial disease increases with age, is more common in men than women, and that symptomatic disease is only the tip of the iceberg. Studies concerning the prevalence of peripheral arterial disease rely mainly on the Rose questionnaire, which is used to screen for intermittent claudication, and on the ankle/brachial index, used to detect asymptomatic disease. Although there is a certain parallel between the 2 sets of data, the figures for asymptomatic disease consistently surpass those for clinical disease, and there is a wide variation between frequencies obtained in individual studies. In general, the prevalence of peripheral arterial disease is estimated to be under 2% for men aged less than 50 years, increasing to over 5% in those aged more than 70 years. Women reach these rates almost 10 years after men, although this gender difference decreases with increasing age. Figures for incidence follow a similar trend. The incidence of chronic critical ischaemia is estimated to be between 0.05% and 0.1% of the population. Asymptomatic disease detected with noninvasive tests is 3 to 4 times more frequent than intermittent claudication: its prevalence increases from under 5% for individuals aged less than 50 years to over 20% for individuals aged more than 70 years. The classical risk factors for atherosclerosis also apply to peripheral arterial disease, although their order of importance may be different from that for coronary and carotid disease. Several studies have shown that peripheral arterial disease correlates most strongly with cigarette smoking. Smoking is also the single greatest predictor of the progression of peripheral arterial disease. Other risk factors include hypertension, raised lipid levels (cholesterol and triglycerides for severe disease), diabetes, increased plasma viscosity, fibrinogen and homocysteine levels. Divergent views have been expressed in individual epidemiological studies with regard to the respective contribution of these risk factors to the development and progression of peripheral arterial disease. The natural history of peripheral arterial disease is characterised by a relatively benign local evolution. It can be estimated that, in general, 3 of 4 men presenting with intermittent claudication will never have a serious problem necessitating vascular intervention, and that no more than 5% are ever likely to require a major amputation. However, the underlying atherosclerotic pathology progresses with time: nondiseased arteries become obliterated and disease with an initially unilateral pattern frequently progresses to become bilateral. In addition, the few patients who do progress to critical ischaemia are at a significantly higher risk of amputation. The general prognosis for patients with peripheral arterial disease is particularly negative. There is a high prevalence of coronary heart disease and cerebrovascular disease in such patients, although the exact percentages depend on the patient population selected and on the method used for their evaluation. Coronary heart disease is detected in 40 to 60% of patients through a medical history combined with electrocardiography, while systematic coronary angiography detects coronary heart disease in 90% of those undergoing surgery. Although few patients with peripheral arterial disease have a history of stroke, in studies of surgical patients almost 30% appear to have significant extracranial disease. Patients with peripheral arterial disease have a poor life expectancy: the mortality rate is 3 to 5% per year in those with intermittent claudication and 20% per year in those with critical ischaemia. Coronary heart disease accounts for half of the total mortality, while vascular disease in general accounts for almost two-thirds.

Arterial Occlusive Diseases↗

Autoregulatory sequences are revealed by complex stability screening of the mouse brn-3.0 locus.

The POU-IV or Brn-3 class of transcription factors exhibit conserved structure, DNA-binding properties, and expression in specific subclasses of neurons across widely diverged species. In the mouse CNS, Brn-3.0 expression characterizes specific neurons from neurogenesis through the life of the cell. This irreversible activation of expression suggests positive autoregulation. To search for cis-acting elements that could mediate autoregulation we used a novel method, complex stability screening, which we applied to rapidly identify functional Brn-3.0 recognition sites within a large genomic region encompassing the mouse brn-3.0 locus. This method is based on the observation that the kinetic stability of Brn-3.0 complexes with specific DNA sequences, as measured by their dissociation half-lives, is highly correlated with the ability of those sequences to mediate transcriptional activation by Brn-3.0. The principal Brn-3.0 autoregulatory region lies approximately 5 kb upstream from the Brn-3.0 transcription start site and contains multiple Brn-3.0-binding sites that strongly resemble the optimal binding site for this protein class. This region also mediates transactivation by the closely related protein Brn-3.2, suggesting a regulatory cascade of POU proteins in specific neurons in which Brn-3.2 expression precedes Brn-3.0.

Aging↗

Sites of plasticity in the neural circuit mediating tentacle withdrawal in the snail Helix aspersa: implications for behavioral change and learning kinetics.

The tentacle withdrawal reflex of the snail Helix aspersa exhibits a complex combination of habituation and sensitization consistent with the dual-process theory of plasticity. Habituation, sensitization, or a combination of both were elicited by varying stimulation parameters and lesion condition. Analysis of response plasticity shows that the late phase of the response is selectively enhanced by sensitization, whereas all phases are decreased by habituation. Previous data have shown that tentacle withdrawal is mediated conjointly by parallel monosynaptic and polysynaptic pathways. The former mediates the early phase, whereas the latter mediates the late phase of the response. Plastic loci were identified by stimulating and recording at different points within the neural circuit, in combination with selective lesions. Results indicate that depression occurs at an upstream locus, before circuit divergence, and is therefore expressed in all pathways, whereas facilitation requires downstream facilitatory neurons and is selectively expressed in polysynaptic pathways. Differential expression of plasticity between pathways helps explain the behavioral manifestation of depression and facilitation. A simple mathematical model is used to show how serial positioning of depression and facilitation can explain the kinetics of dual-process learning. These results illustrate how the position of cellular plasticity in the network affects behavioral change and how forms of plasticity can interact to determine the kinetics of the net changes.

Animals↗

Doctor-manager relationships in the United States and the United Kingdom.

In many developed countries, including the United States and the United Kingdom, the relationships between doctors and hospital managers are strained. The purposes of this article are to examine survey data from the United States and the United Kingdom on doctor-manager relationships and to identify the sources of strain common to both countries as well as those particular to each country's health system. The two countries exhibited many similarities. A very high proportion of respondents from both countries identified external factors-such as governmental budget cuts, pressure from third parties to increase physicians' workload, and the turbulence of the policy environment-as important barriers to improving doctor-manager relationships. Other common sources of strain were concerns over resource availability and the relative power of doctors and managers. Sources of relationship tension particular to each country were also found. Substantial divergence of opinion was expressed with respect to internal factors that affect doctor-manager relationships. Respondents from the United States were more negative than those from the United Kingdom in their ratings of teamwork and communication between doctors and managers, and they were also less likely to have confidence in the medical staff. Respondents from the United Kingdom were more likely to believe that hospital management is driven more by financial than clinical priorities. Managers can implement several strategies to improve doctor-manager relationships, including greater organizational transparency in decision making; more frequent communication between managers and doctors; and more physician involvement in decision making, especially with regard to important resource-related decisions, and in organizational governance.

Communication↗

Similarities in B cell repertoire development between autoimmune and aging normal mice.

B cell repertoire changes that characterize systemic autoimmune disease may be linked to an acceleration of normal immune aging. To examine this issue, the repertoires expressed by lupus-prone and geriatric normal mice were compared. An ELISA-spot assay was used to identify and quantitate individual lymphocytes secreting antibodies reactive with a panel of five autoantigens and three conventional Ag. Over half of autoimmune NZB and MRL/lpr mice developed repertoires biased toward the production of specific autoantibodies by 8 mo of age. The B cell repertoires expressed by normal BALB/c mice were stable over this period but developed a similar bias toward the production of autoantibodies by 18 to 22 mo of age. As both normal and autoimmune mice grew older, they expressed repertoires that increasingly diverged from those of other members of the same strain--a process whose onset and rate of development was accelerated in lupus-prone animals. By analyzing B cells from individual MRL/lpr mice at multiple time points, we found that 1) autoreactivity developed over a specific time period, 2) individual animals developed increased responsiveness against different autoantigens, and 3) this increased responsiveness persisted for life. These results suggest that the repertoires of adult autoimmune mice are generated and maintained by a process of continuous (auto)antigenic stimulation similar to that associated with normal immune aging.

Aging↗

The structure of the TATA-less rat tissue-type plasminogen activator gene. Species-specific sequence divergences in the promoter predict differences in regulation of gene expression.

The genomic region carrying the rat tissue-type plasminogen activator (tPA) gene including its 5'-flanking sequence has been isolated and characterized by restriction enzyme analysis, Southern blotting, and DNA sequencing of all coding parts and the promoter region. The gene is approximately 25 kilobase pairs in size and comprises 14 exons separated by 13 introns. All the exon/intron boundaries agree with the GT-AG rule. The organization of the rat tPA gene is very similar to its human counterpart, and the location of the introns in the protein structure is identical to the human tPA gene. To characterize the promoter region, the transcription initiation site was identified by S1 nuclease protection experiments. A DNA fragment carrying 621 nucleotides of the 5'-flanking sequence was found to confer basal promoter activity and hormone responsiveness to a reporter gene construct in primary cultures of rat granulosa cells. Analysis of the rat tPA promoter sequence and a comparison with the human and mouse counterparts reveal several species-specific differences: the rat and mouse tPA promoters lack typical TATA and CAAT sequences found in the human tPA gene. Furthermore, the rat tPA promoter contains a consensus cAMP-responsive element shown to be required for cAMP responsiveness in eucaryotic genes. At the same position as the cAMP-responsive element in the rat gene, the mouse and human tPA genes have a 12-O-tetradecanoylphorbol-13-acetate-responsive element known to mediate activation by phorbol esters. The differences in the promoter sequences of the rat, mouse, and human tPA genes may have implications for the regulation of the tPA gene in different species.

Amino Acid Sequence↗