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At least 991 records · Page 55Linked to original sources
PubMed1993

The divergent effect of RU 486 on adrenal function in the dog is related to differences in its pharmacokinetics.

This study has evaluated the relationship between the antiglucocorticoid effect of RU 486 and its pharmacokinetics in seven female mongrel dogs (weight 21-30 kg), all of which had appropriate responses to insulin-induced hypoglycemia and metyrapone. They were given RU 486 (50 mg.kg-1.d-1) for ten days. Three dogs (responders) demonstrated increased secretion of ACTH and cortisol which reached a maximum at the termination of RU 486 administration and returned to baseline by days 22 and 18, respectively. The remaining four dogs (non-responders) showed only transient non-sustained increases in ACTH and cortisol. Serum concentrations of RU 486 and its monodemethylated and di-demethylated (but not its hydroxylated) metabolites were significantly higher in the responder dogs. The ratios of the hydroxylated metabolite to RU 486 and its demethylated derivatives were higher in the non-responders, whereas the ratio of the di-demethylated to monodemethylated compound was higher in the responders. Since variations in the hydroxylation and reductive catabolism of steroids have been well documented in different strains of a species, it is possible that the differences in levels of RU 486 and its metabolites in the two groups are accounted for by variations in RU 486 metabolism. In the responder group the metabolism of RU 486 is directed to demethylation, and in the non-responder group to hydroxylation. Thus, differences in pharmacokinetics of RU 486 in the two groups of dogs may explain the variable biological response to this antiglucocorticoid.

Administration, Oral↗
PubMed2006

The consequences of genetic diversity in competitive communities.

Several lines of evidence suggest that the species diversity and composition of communities should depend on genetic diversity within component species, but there has been very little effort to directly assess this possibility. Here I use models of competition among genotypes and species to demonstrate a strong positive effect of the number of genotypes per species on species diversity across a range of conditions. Genetic diversity allows species to respond to selection imposed by competition, resulting in both functional convergence and divergence among species depending on their initial niche positions. This ability to respond to selection promotes species coexistence and contributes to a reduction in variation in species composition among communities. These models suggest that whenever individual fitness depends on the degree of functional similarity between a focal individual and its competitors, genetic diversity should promote species coexistence; this prediction is consistent with the few relevant empirical data collected to date. The results point to the importance of considering the genetic origin and diversity of material used in ecological experiments and in restoration efforts, in addition to highlighting potentially important community consequences of the loss of genetic diversity in natural populations.

Ecology↗
PubMed1993

Compartmentalization of the peripheral immune system.

The periphery of the immune system--as opposed to the central lymphoid organs--contains inhomogeneously distributed B and T cells whose phenotype, repertoire, developmental origin, and function are highly divergent. Nonconventional lymphocytes bearing a phenotype that is rare in the blood, spleen, or lymph nodes of undiseased individuals are encountered at high frequency in different localizations, e.g., alpha/beta TCR+CD4-CD8- cells in the bone marrow and gut epithelium, particular invariant gamma/delta TCR+CD4-CD8 alpha+CD8 beta- and gamma/delta TCR+CD4-CD8 alpha-CD8 beta- T cells in various epithelia, or CD5+ B cells in the peritoneum. The antigen receptor repertoire is different in each localization. Thus, different gamma/delta TCR gene products dominant in each site, and the proportion of cells expressing transgenic and endogenous alpha/beta TCR and immunoglobulin gene products follows a gradient, with a maximum of endogenous gene expression in the peritoneum, intermediate values in other peripheral lymphoid organs (spleen, lymph nodes), and minimum values in thymus and bone marrow. Forbidden T cells that bear self-superantigen-reactive V beta gene products are physiologically detected among alpha/beta TCR+CD4-CD8- lymphocytes of the bone marrow, as well as in the gut. Violating previous ideas on self-tolerance preservation, self-peptide-specific gamma/delta T cells are present among intestinal intraepithelial lymphocytes, and CD5+ B cells produce low-affinity crossreactive autoantibodies in a physiological fashion. It appears that, in contrast to the bulk of T and B lymphocytes, certain gamma/delta and alpha/beta T cells found in the periphery, as well as most CD5+ B cells, do not depend on the thymus or bone marrow for their development, respectively, but arise from different, nonconventional lineages. In addition to divergent lineages that are targeted to different organs guided by a spatiotemporal sequence of tissue-specific homing receptors, local induction or selection processes may be important in the diversification of peripheral lymphocyte compartments. Selection may be exerted by local antigens, antigen-presenting cells whose function varies in each anatomical localization, cytokines, and cell-matrix interactions, thus leading to the expansion and maintenance of some clones, whereas others are diluted out or deleted. The spatial compartmentalization of lymphocytes in different microenvironments has major functional consequences and leads to a partial fragmentation of immunoregulatory circuits at the local level. Lymphocytes residing in certain antigen-exposed compartments are likely to combat tissue-specific pathogens or self-proteins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2003

Endocannabinoids as autoregulatory signaling molecules: coupling to nitric oxide and a possible association with the relaxation response.

Endocannabinoid signaling processes are present in diverse organisms and in organisms 500 million years divergent in evolution. Cannabinoid receptor-1 expression (CB1), anandamide, and anandamide amidase have been found in invertebrates. Furthermore, this signaling system is coupled to constitutive nitric oxide synthase (cNOS)-derived nitric oxide (NO) release in both vertebrates and invertebrates, thereby regulating neural, immune, and vascular-like functions in these divergent organisms. In human endothelial cells from various blood vessels, CB1 immunoreactive components are present as is its coupling to anandamide-stimulated cNOS-derived NO production, which exerts an autoregulatory role on cNOS release. The modulation of vascular diameter and vascular tone represents a crucial point of interest in these pathways, and interactions between NO and the sympathetic nerve system are of importance, i.e, norepinephrine. Here, a possible association of NO and endocannabinoid signaling with the relaxation response, a physiological counterpart of the stress response, may exist.

Animals↗
PubMed2006

Global attraction and stability for Cohen-Grossberg neural networks with delays.

We consider a class of Cohen-Grossberg neural networks with delays. We prove the existence and global asymptotic stability of an equilibrium point and estimate the region of existence. Furthermore, we show that the trajectories of the neural networks with positive initial data will stay in the positive region if the amplification function satisfies a divergent condition. We also establish the existence of a globally attracting compact set for more general networks. We estimate this compact set explicitly in terms of the network parameters from physiological and biological models. Our results can be applied to neural networks with a wide range of activation functions which are neither bounded nor globally Lipschitz continuous such as the Lotka-Volterra model. We also give some examples and simulations.

Animals↗
PubMed1999

Quality of life in low-income patients with metastatic prostate cancer: divergent and convergent validity of three instruments.

Few studies have evaluated Quality Of Life (QOL) among low-income patients with cancer. Information is needed about the feasibility and psychometric characteristics of QOL instruments in these populations. The purpose of this study was to examine the convergent and discriminant relationships between scales of three QOL instruments: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC), Functional Assessment of Cancer Therapy--General (FACT), and Quality of Life Index (QLI). Participants included 110 men with metastatic prostate cancer of whom 94% were low income and 62% were African-American. Interviewers administered the questionnaires. Cronbach alpha internal consistency reliabilities were 0.57 to 0.90 for the EORTC, 0.65 to 0.86 for the FACT, and 0.63 for the QLI. Convergent validity was supported for the EORTC and FACT scales measuring emotional, physical, and role/functional dimensions (r = 0.54 to 0.72), but not on scales measuring social function (r = 0.12). Divergent validity was supported between dissimilar scales (r = 0.14 to 0.38). Analysis with receiver operating characteristics curves provided empirical support for the EORTC and FACT as multidimensional measures. These findings suggest that, even in busy clinical settings with low literacy patients, interviewer-administered EORTC and FACT QOL instruments can provide valid and reliable information.

Aged↗
PubMed2006

Discovery of eight novel divergent homologs expressed in cattle placenta.

Ten divergent homologs were identified using a subtractive bioinformatic analysis of 12,614 cattle placenta expressed sequence tags followed by comparative, evolutionary, and gene expression studies. Among the 10 divergent homologs, 8 have not been identified previously. These were named as follows: cattle cerebrum and skeletal muscle-specific transcript 1 (CSSMST1), cattle intestine-specific transcript 1 (CIST1), hepatitis A virus cellular receptor 1 amino-terminal domain-containing protein (HAVCRNDP), prolactin-related proteins 8, 9, and 11 (PRP8, PRP9, and PRP11, respectively) and secreted and transmembrane protein 1A and 1B (SECTM1A and SECTM1B, respectively). In addition, two previously known divergent genes were identified, trophoblast Kunitz domain protein 1 (TKDP1) and a new splice variant of TKDP4. Nucleotide substitution analysis provided evidence for positive selection in members of the PRP gene family, SECTM1A and SECTM1B. Gene expression profiles, motif predictions, and annotations of homologous sequences indicate immunological and reproductive functions of the divergent homologs. The genes identified in this study are thus of evolutionary and physiological importance and may have a role in placental adaptations.

Amino Acid Sequence↗
PubMed2003

Using mutant alleles to determine the structure and function of leucine-rich repeat receptor-like kinases.

The leucine-rich-repeat class of receptor-like kinase (RLK)-encoding genes represents the largest class of putative receptor-encoding genes in the Arabidopsis genome. The biological functions of several of these genes have been determined through genetic analysis. With dozens of mutant alleles described for various RLKs in Arabidopsis and other plants, comparisons of the mutations found in different receptors, as well as of structural features that are conserved between receptors, can provide insights into the common and/or divergent regulation and functions of these receptors.

Alleles↗
PubMed2001

Cold-induced changes in thyroid function in a poikilothermic mammal, the naked mole-rat.

Cold acclimation induces very divergent responses in thyroid function in reptiles and mammals reflective of their different thermoregulatory modes. Naked mole-rats, unlike other small mammals, are unable to effectively employ endothermy and are operatively poikilotherms. We therefore investigated changes in their thyroid status with chronic cold exposure. Under simulated burrow conditions, free thyroxine (T(4); 0.39 +/- 0.09 ng/dl) and thyroid stimulating hormone (TSH; 1.12 +/- 0.56 microIU/ml) levels fell within the reptilian range, one order of magnitude lower than mammalian levels. However, cold induced typical mammalian responses: free T(4) levels (0.55 +/- 0.09 ng/dl) and thyroid follicular cell height were significantly greater. Although TSH levels (1.28 +/- 0.83 microIU/ml) were not significantly elevated, thyrotrophs exhibited ultrastructural signs of increased secretory activity. Low thyroid hormone concentrations may contribute substantially to the unusual thermoregulatory mode exhibited by naked mole-rats.

Adaptation, Physiological↗
PubMed2005

Transcriptional reprogramming and backup between duplicate genes: is it a genomewide phenomenon?

Deleting a duplicate gene often results in a less severe phenotype than deleting a singleton gene, a phenomenon commonly attributed to functional compensation among duplicates. However, duplicate genes rapidly diverge in expression patterns after duplication, making functional compensation less probable for ancient duplicates. Case studies suggested that a gene may provide compensation by altering its expression upon removal of its duplicate copy. On the basis of this observation and a genomic analysis, it was recently proposed that transcriptional reprogramming and backup among duplicates is a genomewide phenomenon in the yeast Saccharomyces cerevisiae. Here we reanalyze the yeast data and show that the high dispensability of duplicate genes with low expression similarity is a consequence of expression similarity and gene dispensability, each being correlated with a third factor, the number of protein interactions per gene. There is little evidence supporting widespread functional compensation of divergently expressed duplicate genes by transcriptional reprogramming.

Genes, Duplicate↗
PubMed1979

Genetic variability and divergence in grayling, Thymallus arcticus.

In North America there are two disjunct forms of grayling, Montana and arctic, which have been separated for approximately 75,000 to 100,000 years. Electrophoretic analysis of thirty-six protein loci in these forms has revealed: (1) levels of gene duplication comparable to other salmonids, (2) a level of heterozygosity similar to other salmonids, (3) a fast and a slow evolving set of proteins, and (4) no obvious relationship between genetic variability and enzyme function. The genetic divergence between these populations may warrant subspecific designations for these two forms.

Animals↗
PubMed1994

Demand characteristics underlying differential ratings of sensory versus affective components of pain.

In several investigations, differential ratings of sensory and affective components of pain can be explained by the expectations conveyed to subjects to provide different ratings for each pain component under conditions where they could readily recall their ratings. In Experiment I, such demand characteristics were controlled in one group by having subjects rate each pain component in a separate session 1 week apart, so as to minimize recall. This group failed to differentiate between sensory and affective pain; however, another group with demand characteristics left uncontrolled, provided disparate and parallel functions for the two pain components. These results imply that recall during concurrent ratings of the two pain components contributes to a spurious separation of ratings for each component. In the second study, with demand characteristics controlled, a medication placebo led to ratings of affective pain that were significantly lower than those for sensory pain, and a divergence between the functions for each component. This offers an approach to the veridical separation of sensory and affective components of pain.

Analysis of Variance↗
PubMed1998

Evolution of new protein function: recombinational enhancer Fis originated by horizontal gene transfer from the transcriptional regulator NtrC.

New protein function is thought to evolve mostly by gene duplication and divergence. Here we present phylogenetic evidence that the multifunctional protein Fis of the gamma proteobacterial species derived from the COOH-terminal domain of an ancestral alpha proteobacterial NtrC transcriptional regulatory protein. All of the known enterobacterial fis genes are preceded by an open reading frame, named yhdG, that is highly similar to nifR3, a gene that forms an operon with ntrC in several alpha proteobacterial species. Thus, we propose that yhdG and fis were acquired by a lineage ancestral to the gamma proteobacteria in a single horizontal gene transfer event, and later diverged to their present functions.

Amino Acid Sequence↗
PubMed1997

Biochemical characterization and crystalization of human Zn-alpha2-glycoprotein, a soluble class I major histocompatibility complex homolog.

Zn-alpha2-glycoprotein (ZAG) is a 41-kDa soluble protein that is present in most bodily fluids. In addition, ZAG accumulates in fluids from breast cysts and in 40% of breast carcinomas, which suggests that ZAG plays a role in the development of breast diseases. However, the function of ZAG under physiological and cancerous conditions remains unknown. Because ZAG shares 30-40% sequence identity with the heavy chains of class I major histocompatibility complex (MHC) proteins, we compared the biochemical properties of ZAG with those of classical class I MHC molecules. We purified human ZAG from breast cyst fluid and serum and produced a panel of anti-ZAG monoclonal antibodies. Binding assays and acid elution experiments revealed that, in contrast to class I MHC proteins, ZAG does not bind peptides or the class I light chain, beta2-microglobulin (beta2m). Nevertheless, CD studies indicated that ZAG is thermally stable in the absence of bound peptide or associated beta2m, as opposed to class I MHC molecules, which require the presence of both beta2m and peptides for stability. These data indicate that the function of ZAG has diverged from the peptide presentation and T-cell interaction functions of class I molecules. To gain insight into the function of ZAG and to compare the three-dimensional structures of ZAG and class I MHC molecules, we produced ZAG crystals that diffract beyond 2.7 A and have initiated an x-ray structure determination.

Blood Proteins↗
PubMed2004

Pharmacogenomics of the OATP and OAT families.

Drug disposition is highly dependent on the interplay between drug metabolism and transport in organs such as the intestine, kidney, and liver. Genetically determined variation in drug transporter function or expression is now increasingly recognized to have a significant role as a determinant of intersubject variability in drug response. Similar to the discoveries of functional genetic variations in drug efflux transporters, such as multi-drug resistance proteins 1 and 2, there have been considerable advances in the identification of single nucleotide polymorphisms in transporters that facilitate cellular drug uptake. Among the uptake transporters, members of the organic anion-transporting polypeptides and organic anion transporters can mediate the cellular uptake of a large number of structurally divergent compounds. Accordingly, functionally relevant polymorphisms in these transporters may contribute to interindividual and interethnic variability in drug disposition and response. In this review, recent progress relating to pharmacogenomics of organic anion transporters will be outlined along with a compilation of currently known genetic polymorphisms.

Animals↗
PubMed2003

Partial conservation of LFY function between rice and Arabidopsis.

The LFY/FLO genes encode plant-specific transcription factors and play major roles in the reproductive transition as well as floral development. In this study, we reconstructed the phylogenetic tree of the 49 LFY/FLO homologs from various plant species. The tree clearly shows that the LFY/FLO genes from the eudicots and monocots formed the two monophyletic clusters with very high bootstrap probabilities, respectively. Furthermore, grass LFY/FLO genes have experienced significant acceleration of amino acid replacement rate compared with the eudicot homolog. To test whether grass LFY/FLO genes have a conserved function with those of eudicots, we introduced RFL, a rice LFY homolog, into the Arabidopsis lfy mutant. The RFL gene driven by LFY promoter partially rescued the lfy mutation, suggesting that the functions of LFY and RFL partly overlap. Interestingly, the RFL but not LFY, strongly activated the expression of AP1 and AG, the downstream targets of LFY, even in the vegetative tissues. The LFY::RFL transgenic Arabidopsis plants exhibited abnormal patterns of development such as leaf curling, bushy appearance and the transformation of ovules into carpels. All of the results indicate that both the partial conservation and divergence of LFY function between rice and Arabidopsis.

Amino Acid Sequence↗
PubMedDate not supplied

The role of pdx1 and HNF6 in proliferation and differentiation of endocrine precursors.

Ex vivo expansion of embryonic stem cells (ES cells) or pancreatic stem cells for insulin delivery to diabetic patients provides potential for the restoration of islet function in these individuals. Understanding the spatial and temporal requirements of crucial factors for endocrine progenitor specification, proliferation, and terminal differentiation remains a major challenge in the field of pancreas development. Here, we provide speculation as to the role of pdx1 and HNF6 in these different stages of pancreatic endocrine cell development. At the time when islets begin to form within the pancreas, the expression patterns of pdx1 and HNF6 diverge, suggesting distinct functions for each of the genes over the course of endocrine cell development. The current body of evidence provides support for a role of both factors in early endocrine specification as well as a requirement for pdx1 in the generation of mature pancreatic endocrine cells. The precise temporal requirement of HNF6 in the production of terminally differentiated endocrine cells remains unclear. Future studies in this area will rely on conditionally manipulatable systems in combination with lineage-tracing studies for a more accurate assessment of pdx1 and HNF6 function at different stages along the pathway of endocrine cell development.

Animals↗
PubMed2003

Treatment of cirrhosis and liver failure in rats by hepatocyte xenotransplantation.

BACKGROUND & AIMS: Hepatocyte transplantation has been proposed as an alternative to liver transplantation for the treatment of hepatic failure. A major limitation to this form of therapy is the availability of human livers as a source of hepatocytes. The use of porcine hepatocytes might address this problem; however, xenogeneic hepatocytes are thought to be functionally incompatible across species and susceptible to irreversible rejection. METHODS: Liver cirrhosis was induced with phenobarbital and carbon tetrachloride. Only rats with decompensated liver failure that did not correct 4 weeks after the discontinuation of carbon tetrachloride were subjected to intrasplenic rat or porcine hepatocyte transplantation. The immunologic integrity of cirrhotic rats was assessed by allogeneic skin grafting, and the immune response to transplanted porcine hepatocytes was assessed by enzyme-linked immunosorbent assay. RESULTS: Porcine hepatocytes restored metabolic function and prolonged the survival of cirrhotic rats, as well as rat hepatocytes. Cirrhotic rats retained the ability to reject allogeneic skin grafts and showed an immune response to the engrafted hepatocytes. Despite this, survival of transplanted porcine hepatocytes was accepted in cirrhotic rats for a period of weeks without immunosuppression. Conventional immunosuppression with FK506 allowed successful retransplantation with hepatocytes from a second porcine donor. CONCLUSIONS: Hepatocytes transplanted between widely divergent species can function to correct liver failure in cirrhotic rats and prolong their survival. Conventional immunosuppression allows long-term functioning of xenogeneic hepatocyte retransplants and suggests that hepatocyte xenotransplantation might be useful as a bridge to liver transplantation and could potentially provide long-term hepatic support.

Animals↗