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PubMed2002

Identification of genetic variants in endothelial lipase in persons with elevated high-density lipoprotein cholesterol.

BACKGROUND: Elevated high-density lipoprotein cholesterol (HDL-C) is associated with reduced risk of cardiovascular disease, and variation in HDL-C levels has been shown to be approximately 50% heritable. Overexpression of endothelial lipase (EL), a member of the lipoprotein lipase gene family, markedly reduces HDL-C levels in mouse models. We hypothesized that genetic variation in EL might be associated with elevated HDL-C. METHODS AND RESULTS: All exons and 1.2 kilobase of promoter of the EL gene were sequenced in 20 unrelated human subjects with high HDL-C levels. A total of 17 variants were identified. Six of these were potentially functional and were confirmed by restriction enzyme analysis. Four variants result in amino acid changes (Gly26Ser, Thr111Ile, Thr298Ser, and Asn396Ser,) and 2 variants were in the promoter (-303A/C and -410C/G). The genotype frequencies of each variant were determined in 176 black controls, 165 white controls, and 123 whites with high HDL-C. The Thr111Ile variant was the most common, with an allele frequency of 10.3% in blacks, 31.2% in white controls, and 32.6% in the high HDL-C group. The remaining variants all had allele frequencies <5.0% but differed in frequency among the 3 groups. Interestingly, Gly26Ser, Thr298Ser, and -303A/C were found in the black and high HDL-C white cohorts but were absent in the control white group. CONCLUSIONS: Six new potentially functional variants in EL were discovered through sequencing of the EL gene in subjects with high HDL-C levels. Differences in allele frequencies exist between blacks and whites and between control subjects and those with high HDL-C levels.

Black People↗
PubMed1995

Atomic solvation parameters in the analysis of protein-protein docking results.

Several sets of amino acid surface areas and transfer free energies were used to derive a total of nine sets of atomic solvation parameters (ASPs). We tested the accuracy of each of these sets of parameters in predicting the experimentally determined transfer free energies of the amino acid derivatives from which the parameters were derived. In all cases, the calculated and experimental values correlated well. We then chose three parameter sets and examined the effect of adding an energetic correction for desolvation based on these three parameter sets to the simple potential function used in our multiple start Monte Carlo docking method. A variety of protein-protein interactions and docking results were examined. In the docking simulations studied, the desolvation correction was only applied during the final energy calculation of each simulation. For most of the docking results we analyzed, the use of an octanol-water-based ASP set marginally improved the energetic ranking of the low-energy dockings, whereas the other ASP sets we tested disturbed the ranking of the low-energy dockings in many of the same systems. We also examined the correlation between the experimental free energies of association and our calculated interaction energies for a series of proteinase-inhibitor complexes. Again, the octanol-water-based ASP set was compatible with our standard potential function, whereas ASP sets derived from other solvent systems were not.

Amino Acids↗
PubMed2003

c-Met: structure, functions and potential for therapeutic inhibition.

Studies on signal transduction pathways have generated various promising molecular targets for therapeutic inhibition in cancer therapy. Receptor tyrosine kinases represent an important class of such therapeutic targets. c-Met is a receptor tyrosine kinase that has been shown to be overexpressed and/or mutated in a variety of malignancies. A number of c-Met activating mutations, many of which are located in the tyrosine kinase domain, have been detected in various solid tumors and have been implicated in invasion and metastasis of tumor cells. It is known that stimulation of c-Met via its natural ligand, hepatocyte growth factor (also known as scatter factor, HGF/SF) results in a plethora of biological and biochemical effects in the cell. Activation of c-Met signaling can lead to scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and eventual metastasis. In this review, the role of c-Met dysregulation in tumor progression and metastasis is discussed in detail with particular emphasis on c-Met mutations. Moreover, we summarize current knowledge on various pathways of c-Met signal transduction, highlighting the central role in the cytoskeletal functions. In this summary is included recent data in our laboratory indicating that phosphorylation of focal adhesion proteins, such as paxillin, p125FAK, and PYK2, occurs in response to c-Met stimulation in lung cancer cells. Most importantly, current data on c-Met suggest that when mutated or overexpressed in malignant cells, c-Met would serve as an important therapeutic target.

Cell Division↗
PubMed1991

Experimental and theoretical study of energetics of complex formation between nucleic acid bases and the bases with amide group.

A number of nucleic acid base pairs and complexes between the bases and the amide group of acrylamide have been studied experimentally by using mass spectrometry and theoretically by the method of atom-atom potential function calculations. It has been found from temperature dependencies of peak intensities in mass spectra of m2.2.9(3) Gua.m1Ura, m9 Ade.m1Cyt, m2.2.9(3) Gua.m1Gua.m1Cyt pairs that enthalpy values, delta H, of the complex formation are equal to 14.2 +/- 1.1, 13.5 +/- 1.3 and 16.4 +/- 1.4 kcal/M, respectively, and those of acrylamide with m1.3(2) Ura and m1Thy corresponds to 9.7 +/- 1.0 and 6.8 +/- 0.6 kcal/M. There is a good agreement of the experimental data with calculations when taking into account both the amino-oxo and the amino-hydroxy tautomeric forms of guanine. A combined use of the data allows us to determine the energy, the modes of interaction and the structure of the complexes. The results are discussed in connection with the modelling of molecular structure of biopolymers by the method of classical potential functions, protein-nucleic acids recognition and fidelity of nucleic acids biosynthesis.

Acrylamide↗
PubMed1994

Evaluation of the conformational free energies of loops in proteins.

In this paper we discuss the problem of including solvation free energies in evaluating the relative stabilities of loops in proteins. A conformational search based on a gas-phase potential function is used to generate a large number of trial conformations. As has been found previously, the energy minimization step in this process tends to pack charged and polar side chains against the protein surface, resulting in conformations which are unstable in the aqueous phase. Various solvation models can easily identify such structures. In order to provide a more severe test of solvation models, gas-phase conformations were generated in which side chains were kept extended so as to maximize their interaction with the solvent. The free energies of these conformations were compared to that calculated for the crystal structure in three loops of the protein E. coli RNase H, with lengths of 7, 8, and 9 residues. Free energies were evaluated with a finite difference Poisson-Boltzmann (FDPB) calculation for electrostatics and a surface area-based term for nonpolar contributions. These were added to a gas-phase potential function. A free energy function based on atomic solvation parameters was also tested. Both functions were quite successful in selecting, based on a free energy criterion, conformations quite close to the crystal structure for two of the three loops. For one loop, which is involved in crystal contacts, conformations that are quite different from the crystal structure were also selected. A method to avoid precision problems associated with using the FDPB method to evaluate conformational free energies in proteins is described.

Amino Acid Sequence↗
PubMed1985

Problem patients in general practice: identifying young women with recurrent abnormal illness behaviour.

The concept of recurrent illness behaviour and the importance of problem patients in general practice are discussed. The need for further research and the early identification of these patients is emphasized. The medical records of 1134 women between the ages of 16 and 25 years were analysed. The annual rate of potentially functional complaints was determined for each woman. The 51 women with the highest annual rates were selected as cases for interview, along with 51 randomly selected controls.Analysis showed there were significant differences between the cases and controls. The cases reported more health and emotional problems and had a higher dependence on alcohol and cigarettes than the controls. They had more social disadvantages, such as a history of parental death and unemployment; they were more likely to be housewives with children; they had fewer qualifications, held jobs for shorter periods of time and had a history of truancy from school. They were heavy users of primary care facilities and also hospital services but, despite this, were dissatisfied with the service provided and were less compliant with treatment. Finally, despite a need to discuss health problems, they experienced less family support in this area. Significant variables were entered into a step-wise multiple regression analysis to predict rates of potentially functional complaints and a logistic discriminant analysis was also carried out. The results of these analyses were used in a further discriminant function to form an index for the identification of recurrent abnormal illness behaviour.

Adolescent↗
PubMed1990

Global energy minimization by rotational energy embedding.

Given a sufficiently good empirical potential function for the internal energy of molecules, prediction of the preferred conformations is nearly impossible for large molecules because of the enormous number of local energy minima. Energy embedding has been a promising method for locating extremely good local minima, if not always the global minimum. The algorithm starts by locating a very good local minimum when the molecule is in a high-dimensional Euclidean space, and then it gradually projects down to three dimensions while allowing the molecule to relax its energy throughout the process. Now we present a variation on the method, called rotational energy embedding, where the descent into three dimensions is carried out by a sequence of internal rotations that are the multidimensional generalization of varying torsion angles in three dimensions. The new method avoids certain kinds of difficulties experienced by ordinary energy embedding and enables us to locate conformations very near the native for avian pancreatic polypeptide and apamin, given only their amino acid sequences and a suitable potential function.

Apamin↗
PubMed2004

Lectin chromatography of extrarenal renin protein in human plasma and tissues: potential endocrine function via the renin receptor.

Secretion of prorenin from extrarenal tissues comprises approximately half of the renin protein in plasma; its origin is unknown. The discovery of a prorenin/renin receptor that activates vascular tissue kinases raises interest in this otherwise inactive component. We have studied its glycosylation as this may distinguish it from renal renin. The binding of renin protein (active and prorenin) in human plasma and tissues to concanavalin (Con A) and wheat germ lectins was deployed. Immunoradiometric and enzyme kinetic assays were applied to column fractions. Mannosylated renin protein binds to Con A and has been shown to be taken up by human vascular and hepatic cells on mannose-6-phosphate receptors, possibly as a clearance mechanism. But the other binding sites of prorenin/renin that elicit a cellular phosphorylation response are apparently independent of glycosylation. The tissues examined (kidney, adrenal, ovary) each contain high proportions of Con A binding renin, but the plasma of normal resting males and females contain mainly non-binding renin, the proportion increasing as renal renin secretion decreases. The extreme of this relationship is seen in anephric patients and in some normal women on oral contraceptives with suppressed renal renin, in whom plasma renin is entirely non-binding to Con A. Conversely, when renal renin secretion was stimulated, the increased plasma active renin bound to Con A. However, extrarenal tissues containing exclusively Con A non-binding renin protein, and hence potential sources of anephric plasma renin protein, were not identified, but are unlikely to include adrenal or female reproductive tract. The findings are consistent with the view that normal human plasma contains a considerable amount of amannosylated prorenin of extrarenal origin that escapes hepatic clearance and has a longer half-life than renal renin. This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes.

Adrenal Glands↗
PubMed2001

The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions.

Grb7 family adaptor molecules consist of Grb7, Grb10 and Grb14, each of which has several splicing variants. Like other adaptor molecules, Grb7 family proteins function to mediate the coupling of multiple cell surface receptors to downstream signaling pathways in the regulation of various cellular functions. They share significant sequence homology with each other and a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, involved in embryonic migration, and a carboxyl-terminal SH2 domain. Grb7 family proteins are differentially expressed in a variety of tissues. They are phosphorylated on serine/threonine as well as tyrosine residues, although the kinases responsible have not been well characterized. Grb7 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7 family proteins, mostly through the SH2 domains. Various isoforms of Grb10 have been shown to regulate cell proliferation and apoptosis, whereas Grb7 has been found to regulate cell migration and also implicated in tumor progression. Future studies of interests will include identification of potential downstream effectors of Grb7 family proteins as well as understanding of the mechanisms of specificity of the different family members in signal transduction.

Animals↗
PubMed2005

Presence and potential signaling function of N-acylethanolamines and their phospholipid precursors in the yeast Saccharomyces cerevisiae.

N-acylethanolamines (NAEs) and N-acylphosphatidylethanolamines (NAPEs) are trace constituents of vertebrate cells and tissues and much is known about their metabolism and possible function in animals. Here we report for the first time the identification and quantification of NAEs and NAPEs in several strains of the yeast Saccharomyces cerevisiae. Gas chromatography-mass spectrometry of appropriate derivatives revealed 16:0, 16:1, 18:0 and 18:1 N-acyl groups in both NAE and NAPE whose levels, in wild-type cells, were 50 to 90 and 85 to 750 pmol/micromol lipid P, respectively (depending on the phase of growth). NAPE levels were reduced by 45 to 60% in a strain lacking three type B phospholipases, suggesting their involvement in NAPE synthesis by their known transacylation activity. A yeast strain lacking the YPL103c gene, which codes for a protein with 50.3% homology to human NAPE-specific phospholipase D, exhibited a 60% reduction in NAE, compared to wild-type controls. The exposure of various yeast strains to peroxidative stress, by incubation in media containing 0.6 mM H(2)O(2), resulted in substantial increases in NAE. Because yeast cells lack polyunsaturated fatty acids, they offer a useful system for the study of NAE generation and its potential signaling and cytoprotective effects in the absence of polyunsaturated ("endocannabinoid") congeners.

Acyltransferases↗
PubMed2006

The clinical potential of functional magnetic resonance imaging.

Functional magnetic resonance imaging (fMRI) has had a huge impact on understanding the healthy human brain. To date it has had much less impact in clinical neuroscience or clinical practice. The reasons for this are in part that the image acquisition, paradigm design, and data analysis strategies used presently are not sufficiently standardized. This makes the comparison of results across individuals, scanning sessions, and centers difficult. Nevertheless, there are emerging applications for clinical fMRI, and as the field matures the number of applications is likely to grow. It seems certain that fMRI has an important role to play in helping us understand the mechanisms of neuropsychiatric diseases and in helping to identify effective therapeutic strategies.

Animals↗
PubMed1990

The V kappa gene repertoire in the human germ line.

The question of how many V kappa gene segments exist in the human germ line was addressed. Seventy-five V kappa genes of the kappa locus and twenty-five V kappa genes localized outside of the locus ("orphons") had been cloned previously; 67 of the genes and 19 of the orphons had already been sequenced yielding 36 and 1 potentially functional V kappa genes, respectively, the remaining ones being pseudogenes. We now (a) determined the relative hybridization intensities of the cloned V kappa genes and orphons, (b) identified the bands in blot hybridizations of genomic DNA digests with the cloned genes and orphons, (c) determined the band intensities in the genomic DNA digests from two individuals and one cell line, (d) normalized the results with the help of the C kappa gene segment which is present in the haploid genome in one copy, (e) compared the genomic blot hybridization patterns with patterns of equimolar mixtures of the cloned V kappa genes and orphons, and (f) defined the bands and fractional intensities in bands that could not be assigned to cloned genes or orphons. From the resulting data we conclude that there are 5-7 still uncloned V kappa genes in germ-line DNA in addition to the 75 known V kappa genes and in addition to the 25 orphons 12-15 orphon candidates. It appears that the rheumatoid factor light chains of the Wa and 6B6.6 idiotypes are coded for by one V kappa III gene each. It is concluded that the kappa locus comprises no more than 50 potentially functional genes and no more than 85 V kappa genes altogether.

Blotting, Southern↗
PubMed1987

Changes in Doppler echocardiographic indexes of left ventricular function as potential markers of acute cardiac rejection.

Changes in left ventricular filling and ejection as potential markers of cardiac allograft rejection were evaluated by serial Doppler echocardiography performed in 23 normal volunteers and within 24 hr of endomyocardial biopsy in 22 patients aged 14 to 53 years (mean 37). Peak aortic velocity, left ventricular ejection time index (ETI), isovolumic relaxation time (IVRT), mitral valve pressure half-time (PHT), peak early mitral flow velocity (M1), and velocity following donor atrial systole (M2) were measured without prior knowledge of endomyocardial biopsy findings. Biopsy specimens were graded histologically as: no rejection, mild rejection (cellular infiltrate), and moderate rejection (myocyte necrosis). A total of 120 biopsy-correlated Doppler echocardiographic studies were performed during 16 weeks after cardiac transplantation. Heart rate and mean arterial pressure were significantly higher in transplant recipients than in normal subjects. IVRT and PHT were significantly longer, while M1 and M2 were similar. Peak aortic velocity was higher in normal subjects than in transplant recipients, while ejection time was similar. Rejection of increasing severity was associated with a progressive shortening of IVRT and PHT and with an increase in M1 (p less than .0005 for all comparisons). Peak aortic velocity and ejection time index did not change significantly with rejection. These data indicate that acute cardiac rejection is accompanied by alteration in left ventricular filling dynamics detectable by Doppler echocardiography, without measureable changes in systolic function. These changes may provide noninvasive markers for surveillance of rejection.

Acute Disease↗
PubMed1991

Alternatively spliced type II procollagen mRNAs define distinct populations of cells during vertebral development: differential expression of the amino-propeptide.

Type II collagen is a major component of cartilage providing structural integrity to the tissue. Type II procollagen can be expressed in two forms by differential splicing of the primary gene transcript. The two mRNAs either include (type IIA) or exclude (type IIB) an exon (exon 2) encoding the major portion of the amino (NH2)-propeptide (Ryan, M. C., and L. J. Sandell. 1990. J. Biol. Chem. 265:10334-10339). The expression of the two procollagens was examined in order to establish a potential functional significance for the two type II procollagen mRNAs. First, to establish whether the two mRNAs are functional, we showed that both mRNAs can be translated and the proteins secreted into the extracellular environment. Both proteins were identified as type II procollagens. Secondly, to test the hypothesis that differential expression of type II procollagens may be a marker for a distinct population of cells, specific procollagen mRNAs were localized in tissue by in situ hybridization to oligonucleotides spanning the exon junctions. Embryonic vertebral column was chosen as a source of tissue undergoing rapid chondrogenesis, allowing the examination of a variety of cell types related to cartilage. In this issue, each procollagen mRNA had a distinct tissue distribution during chondrogenesis with type IIB expressed in chondrocytes and type IIA expressed in cells surrounding cartilage in prechondrocytes. The morphology of the cells expressing the two collagen types was distinct: the cells expressing type IIA are narrow, elongated, and "fibroblastic" in appearance while the cells expressing type IIB are large and round. The expression of type IIB appears to be correlated with abundant synthesis and accumulation of cartilagenous extracellular matrix. The expression of type IIB is spatially correlated with the high level expression of the cartilage proteoglycan, aggrecan, establishing type IIB procollagen and aggrecan as markers for the chondrocyte phenotype. Transcripts of type II collagen, primarily type IIA, are also expressed in embryonic spinal ganglion. While small amounts of type II collagen have been previously detected in noncartilagenous tissues, the detection of this new form of the collagen in relatively high abundance in embryonic nerve tissue is unique. Taken together, these findings imply a potential functional difference between type IIA and type IIB procollagens and indicate that the removal of exon 2 from the pre-mRNA, and consequently the NH2-propeptide from the collagen molecule, may be an important step in chondrogenesis. In addition, type II procollagen, specifically type IIA, may function in noncartilage tissues, particularly during development.

Animals↗
PubMed1991

Effect of low dose iodide supplementation on thyroid function in potentially susceptible subjects: are dietary iodide levels in Britain acceptable?

OBJECTIVE The aim of the study was to evaluate the risk of exposure to an increase in dietary iodide intake amongst potentially susceptible population groups in Britain. DESIGN A randomized controlled trial was performed in healthy women and in women with underlying thyroid abnormalities due to subclinical Hashimoto's thyroiditis (diagnosed on the basis of antithyroid antibodies) or previous iodide deficiency of supplementation with 500 micrograms/day iodide (giving a total intake of approximately 750 micrograms/day) for 28 days versus placebo. PATIENTS Two hundred and twenty-five women aged 25-54, randomly selected from a general practice in Cardiff, were screened for thyroid microsomal antibody. Antibody positive women (n = 20), and antibody negative controls (n = 30) were recruited into the trial comparing iodide and placebo. In addition, groups of patients aged 60-75 randomly selected from the Cardiff practice (n = 29), an iodide sufficient area, and a practice in Dowlais (n = 35), a previously iodide deficient area, were also enrolled into the trial. MEASUREMENTS Changes in free thyroxine and thyrotrophin levels were measured after 14 and 28 days of iodide supplementation. RESULTS All the iodide supplemented groups responded in the same way with a small fall in free thyroxine and rise in thyrotrophin levels (combined fall in free thyroxine 14 days after the start of supplementation -1.22 (95% confidence interval -0.59 to -1.84) pmol/l and at 28 days -0.86 (-0.30 to -1.43) pmol/l and rise in thyrotrophin at 14 days 0.55 (0.19 to 0.92) mU/l and at 28 days 0.59 (0.12 to 1.07) mU/l). In two of the iodide supplemented subjects thyrotrophin levels rose above the laboratory reference range and in a further three subjects initially elevated thyrotrophin values increased further. In contrast, no changes in thyroid function were observed in the placebo treated controls and none developed biochemical hypothyroidism. CONCLUSIONS Dietary iodide intakes of 750 micrograms/day or more may adversely affect thyroid function, especially in individuals with borderline hypothyroidism.

Adult↗
PubMedDate not supplied

Opposite effects of serotonin and interferon-alpha on the membrane potential and function of human natural killer cells.

In an earlier article, we reported that serotonin (5-hydroxytryptamine, 5-HT) inhibits the natural killer cell (NK) cytotoxicity of human whole blood in a dose-dependent manner and that natural human interferon-alpha (IFN-alpha) partially eliminates this effect. Because natural IFN-alpha might contain factors other than IFN, we repeated these experiments with recombinant human interferon-alpha (rhIFN-alpha) and separated blood lymphocytes enriched with NK cells and then demonstrated that IFN really is responsible for this effect. Furthermore, this investigation was carried out to clarify the mechanisms of the action of 5-HT and of rhIFN-alpha on NK cells. The inhibition of the cytotoxicity was pronounced when 5-HT was added at the onset of the cytotoxic assay, whereas the pretreatment of lymphocytes for 18 h only led to a slight inhibition. Moreover, rhIFN-alpha applied 1 h before or 1 h after the addition of 5-HT decreased the inhibitory effect of 5-HT. Flow cytometric analysis involving the use of a voltage-sensitive dye, oxonol, revealed that 5-HT depolarized, whereas rhIFN-alpha hyperpolarized the plasma membrane of the lymphocytes. Thus, it seems likely that the inhibitory effect of 5-HT on the cytotoxicity of peripheral human lymphocytes is due to the depolarization on the plasma membrane of the effector cells and that rhIFN-alpha antagonizes this ability via its hyperpolarizing activity.

Cytotoxicity Tests, Immunologic↗
PubMed1999

Gene trap screening using negative selection: identification of two tandem, differentially expressed loci with potential hematopoietic function.

A fusion gene between Escherichia coli lacZ and herpes simplex virus thymidine kinase (HSV-tk) was constructed and used in a gene trap screen for hematopoietic loci in mouse embryonic stem (ES) cells. This gene, galtek, allowed both convenient histochemical detection of expression as well as ablation of expressing cells under 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) selection. Individual ES cell clones bearing gene trap insertions were differentiated in the presence of FIAU and scored for erythropoietic activity at day 9 of differentiation. Screening of a total of 235 independent gene trap lines identified one clone, F3, which consistently demonstrated FIAU-sensitive erythropoiesis during in vitro differentiation. Cloning of endogenous transcribed sequences from the F3 insertion site identified two distinct transcription units, F3-1 and F3-2, encoding mRNAs of approximately 1.3 kb and 3.35 kb, respectively. The transcripts were unrelated and did not exhibit similarity to known sequences. Both loci demonstrated similar relative levels of expression in the heart, testis, kidney, and lung as assessed by Northern blot hybridization. Whole-mount in situ hybridization detected F3-2 expression at multiple sites in embryonic day (E) 10.5 embryos, including the genital ridges, the aortic endothelium, and endothelium-associated cell clusters within the aortic lumen. Expression of F3-2 in the aortic endothelium and endothelium-associated clusters overlapped that of gata-2, a gene required for hematopoietic development. The FIAU sensitivity of hematopoiesis in F3 embryoid bodies may result from expression of galtek during the formation of early hematopoietic cells, directed by regulatory signals from one or both of these endogenous loci.

Amino Acid Sequence↗