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Biomedical subjects

J E Taylor

Publications and source records attributed to J E Taylor.

At least 37 records · Page 2Linked to original sources
PubMed2001

The role of calcium in ABA-induced gene expression and stomatal movements.

There is much interest in the transduction pathways by which abscisic acid (ABA) regulates stomatal movements (ABA-turgor signalling) and by which this phytohormone regulates the pattern of gene expression in plant cells (ABA-nuclear signalling). A number of second messengers have been identified in both the ABA-turgor and ABA-nuclear signalling pathways. A major challenge is to understand the architecture of ABA-signalling pathways and to determine how the ABA signal is coupled to the appropriate response. We have investigated whether separate Ca2+-dependent and -independent ABA-signalling pathways are present in guard cells. Our data suggest that increases in [Ca2+]i are a common component of the guard cell ABA-turgor and ABA-nuclear signalling pathways. The effects of Ca2+ antagonists on ABA-induced stomatal closure and the ABA-responsive CDeT6-19 gene promoter suggest that Ca2+ is involved in both ABA-turgor signalling and ABA-nuclear signalling in guard cells. However, the sensitivity of these pathways to alterations in the external calcium concentration differ, suggesting that the ABA-nuclear and ABA-turgor signalling pathways are not completely convergent. Our data suggest that whilst Ca2+-independent signalling elements are present in the guard cell, they do not form a completely separate Ca2+-independent ABA-signalling pathway.

Abscisic Acid↗
PubMed2001

Rash, abdominal pain and hyponatraemia.

Hypertriglyceridaemia is a rare precipitant of acute pancreatitis. We present a patient with acute pancreatitis and hyponatraemia in association with severe hyperlipidaemia, predominantly hypertriglyceridaemia. The patient was successfully treated with plasma exchange therapy.

Abdominal Pain↗
PubMed2001

Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt.

Somatostatin and its receptors (SSTR1 to SSTR5) are expressed in normal human parafollicular C cells and medullary thyroid carcinoma (MTC), but the role of SSTR subtypes in cell growth regulation is still not clear. The present study demonstrates that the human MTC cell line TT stably expresses all the SSTR subtypes and responds to SSTR2 and SSTR5 activation by subtype-selective agonists with two different patterns in terms of [(3)H]thymidine ([(3)H]thy) incorporation and cell number. The SSTR2 preferential agonists (BIM-23120, BIM-23197, BIM-23190, and BIM-23014; 10(-9)-10(-6) M), significantly suppressed [(3)H]thy incorporation (58-13%) and reduced cell proliferation (50-28%), whereas the SSTR5-selective agonist, BIM-23206 (10(-9)-10(-6) M), significantly increased [(3)H]thy incorporation in TT cells (80-175%), but failed to influence cell proliferation. SSTR2 antagonist (BIM-23627) counteracted the action of SSTR2 preferential agonists on TT cells. Furthermore, increasing concentrations of SSTR5-selective agonists, BIM-23206, dose-dependently prevented the suppression of TT cell [(3)H]thy incorporation and proliferation produced by SSTR2 preferential agonist, BIM-23120, showing an antagonism between these compounds. The following conclusions were reached: 1) the human MTC cell line TT expresses all SSTR subtypes; 2) SSTR2 activation inhibits DNA synthesis and cell proliferation, whereas SSTR5 activation increases DNA synthesis; and 3) SSTR2 preferential agonist (BIM-23120) can antagonise SSTR5-selective agonist (BIM-23206) action and vice versa. These findings suggest a tissue-specific function and a tissue-specific interaction between the two receptors.

Carcinoma, Medullary↗
PubMed2000

Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells.

In previous studies we have showed that somatostatin (SST) inhibits cell division, mitogen-activated protein (MAP) kinase and Ras activity in the human neuroblastoma cell line SY5Y. In the present study, we have assessed the role of a series of SST analogs, three of which were selective for SSTR1, SSTR2 or SSTR5, in these cellular events. All the analogs inhibited forskolin-induced cAMP accumulation. Selective stimulation of SSTR1 or SSTR2 but not of SSTR5 inhibited platelet-derived growth factor (PDGF)-induced [(3)H]thymidine incorporation. The three analogs inhibited PDGF-stimulated MAP kinase activity, at least at an early time. In contrast, none of the analogs used individually was able to inhibit PDGF-stimulated Ras activity. A combined stimulation of SSTR2 and SSTR5 was necessary to obtain a significant inhibitory effect, suggesting the possibility of receptor heterodimerization. These results indicate that SST inhibition of Ras and MAP kinase activities takes place via different pathways and that SST inhibition of PDGF-induced cell proliferation occurs via a Ras-independent pathway.

Animals↗
PubMed2000

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.

Animals↗
PubMed2000

Coping with multiple enemies: an integration of molecular and ecological perspectives.

How plants respond to attack by the range of herbivores and pathogens that confront them in the field is the subject of considerable research by both molecular biologists and ecologists. However, in spite of the shared focus of these two bodies of research, there has been little integration between them. We consider the scope for such integration, and how greater dialogue between molecular biologists and ecologists could advance understanding of plant responses to multiple enemies.

Animals↗
PubMed2000

Chemical synthesis and receptor binding of catfish somatostatin: a disulfide-bridged beta-D-Galp-(1-->3)-alpha-D-GalpNAc O-glycopeptide.

The glycopeptide hormone catfish somatostatin (somatostatin-22) has the amino acid sequence H-Asp-Asn-Thr-Val-Thr-Ser-Lys-Pro-Leu-Asn-Cys-Met-Asn-Tyr-Phe-Trp-Lys-Se r-Arg-Thr-Ala-Cys-OH; it includes a cyclic disulfide connecting the two Cys residues, and the major naturally occurring glycoform contains D-GalNAc and D-Gal O-glycosidically linked to Thr5. The linear sequence was assembled smoothly starting with an Fmoc-Cys(Trt)-PAC-PEG-PS support, using stepwise Fmoc solid-phase chemistry. In addition to the nonglycosylated peptide, two glycosylated forms of somatostatin-22 were accessed by incorporating as building blocks, respectively, Nalpha-Fmoc-Thr(Ac3-alpha-D-GalNAc)-OH and Nalpha-Fmoc-Thr(Ac4-beta-D-Gal-(1-->3)-Ac2-alpha-D-GalNAc)-O H. Acidolytic deprotection/cleavage of these peptidyl-resins with trifluoroacetic acid/scavenger cocktails gave the corresponding acetyl-protected glycopeptides with free sulfhydryl functions. Deacetylation, by methanolysis in the presence of catalytic sodium methoxide, was followed by mild oxidation at pH 7, mediated by Nalpha-dithiasuccinoyl (Dts)-glycine, to provide the desired monomeric cyclic disulfides. The purified peptides were tested for binding affinities to a panel of cloned human somatostatin receptor subtypes; in several cases, presence of the disaccharide moiety resulted in 2-fold tighter binding.

Amino Acid Sequence↗
PubMed1999

Chlamydia transmission: concurrency, reproduction number, and the epidemic trajectory.

To identify factors that influence individual and group transmission of Chlamydia, the authors conducted community-wide contact tracing of chlamydia cases in Colorado Springs, Colorado, from mid-1996 to mid-1997. Case patients identified persons with whom they had had contact during the 6 months preceding diagnosis; contacts were actively sought and offered DNA amplification testing. Sexual contact networks were used to identify "source cases" and "spread cases," permitting estimation of the basic reproduction number (R0) for individuals and groups. Network and epidemiologic factors influencing R0 were assessed using univariate and multivariate procedures. Of 1,309 case patients, 1,131 (86%) were interviewed, and 2,409 contacts were identified. The 1,131 interviewed cases yielded 623.9 computed spread cases, for an overall R0 of 0.55. Few subgroups analyzed yielded a mean R0 exceeding unity-an observation in keeping with routine surveillance information which suggests that chlamydia incidence is declining in Colorado Springs. Concurrency, a network measure of simultaneous partnerships, was the most powerful predictor of transmission. Direct estimation of basic reproduction numbers for chlamydia using contact tracing techniques is feasible and can produce useful data with which to prioritize control efforts, evaluate interventions, and gauge the place of chlamydia on the epidemic continuum.

Adolescent↗
PubMed1999

Highly potent cyclic disulfide antagonists of somatostatin.

The search for synthetic analogues of somatostatin (SRIF) which exhibit selective affinities for the five known receptor subtypes (sst1-5) has generated a large number of potent agonist analogues. Many of these agonists display good subtype selectivities and affinities for the subtypes 2, 3, and 5, with very few selective for sst1 or sst4. Until the recent report by Bass and co-workers (Mol. Pharmacol. 1996, 50, 709-715; erratum Mol. Pharmacol. 1997, 51, 170), no true antagonists of somatostatin had been discovered, let alone any displaying differential receptor subtype selectivity. In this present study, we further explore the effect of this putative L,5D6 antagonist motif on somatostatin octapeptide analogues with a cyclic hexapeptide core. The most potent antagonist found to date is H-Cpa-cyclo[DCys-Tyr-DTrp-Lys-Thr-Cys]-Nal-NH2, PRL-2970 (21), which has an IC50 of 1.1 nM in a rat pituitary growth hormone in vitro antagonist assay versus SRIF (1 nM). This analogue bound to cloned human somatostatin subtype 2 receptors with a Ki of 26 nM. The highest hsst2 affinity analogue was H-Cpa-cyclo[DCys-Pal-DTrp-Lys-Tle-Cys]-Nal-NH2, PRL-2915 (15), with a Ki of 12 nM (IC50 = 1.8 nM). This analogue was also selective for hsst2 over hsst3 and hsst5 by factors of 8 and 40, respectively, and had no agonist activity when tested alone at concentrations up to 10 microM. Regression analysis of the binding affinities versus the observed antagonist potencies revealed high correlations for hsst2 (r = 0.65) and hsst3 (r = 0.52) with a less significant correlation to hsst5 (r = 0.40). This is quite different from the somatostatin agonist analogues which show a highly significant correlation to hsst2 (r > 0.9). Receptor-selective somatostatin antagonists should provide valuable tools for characterizing the many important physiological functions of this neuropeptide.

Animals↗
PubMed1999

Inhibition of human pancreatic islet insulin release by receptor-selective somatostatin analogs directed to somatostatin receptor subtype 5.

Somatostatin (SS)-14 and SS28 are produced by pancreatic D cells and gut mucosa and inhibit pancreatic islet insulin and glucagon release. There are five distinct SS receptor (SSTR) subtypes, namely SSTR1-5, which show different affinities for SS14 and SS28. In order to identify the subtype responsible for inhibition of insulin release by human B cells, SSTR-selective SS analogs were tested in isolated human islets. Glucose-stimulated insulin secretion in human islets incubated for 1 hr at 20 mM glucose, and in islets cultured for 24 hr at a near-physiological (6.1 mM) glucose concentration, was inhibited (<50% of the control) by SSTR5-specific analogs and by SS14 and SS28. SS14, SS28, and different SSTR5 preferential analogs also inhibited islet amyloid polypeptide release during the 24-hr culture. On the other hand, a group of SSTR2-selective analogs failed to inhibit insulin release. Analysis by reverse transcription-polymerase chain reaction indicated that human islets express similar amounts of SSTR2 and SSTR5 mRNAs, while human pancreatic ductal cells express much lower levels of these mRNAs. In conclusion, our data suggest that SSTR5 is an important mediator of the insulin inhibitory action of SS in cultured human islets.

Amyloid↗
PubMed1999

Synthesis and binding properties of cyclohexapeptide somatostatin analogs containing naphthylalanine and arylalkyl peptoid residues.

We report the synthesis, binding affinities to the recombinant human somatostatin receptors, and structure-activity relationship studies of compounds related to the cyclic hexapeptide, c-[Pro6-Phe7-D-Trp8Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with the arylalkyl peptoid residues Nphe (N-benzylglycine), (S)betaMeNphe [(S)-N-[alpha(-methyl)benzyl]glycine] or (R)betaMeNphe [(R)-N-[(alpha-methyl)benzyl]glycine] and L-1-naphthylalanine is incorporated into either position 7 or 11 of the parent compound. The synthesis and binding data of the Nnal6 ([N-naphthylmethyl]glycine) analog of L-363,301 is also reported. The incorporation of the Nnal residue into position 6 of L-363,301 resulted in an analog with weaker binding affinities to all hsst receptors but enhanced selectivity towards the hsst2 receptor compared with the parent compound. The other compounds bind effectively to the hsst2 receptor but show some variations in the binding to the hsst3 and hsst5 receptors resulting in different ratios of binding affinities to the hsst5 and hsst2 or hsst3 and hsst2, respectively. The incorporation of the Nphe residue into position 6 and the Nal residue into position 7 of L-363,301 led to a compound which binds potently to the hsst2 and has increased selectivity towards this receptor (weaker binding to hsst3 and hsst5 receptors) compared with the parent compound. The analogs with beta-methyl chiral substitutions in the aromatic peptoid side chain and Nal in position 7 or 11 bind effectively to the hsst2 and hsst5 receptors. They exhibit similar ratios of binding affinities to the hsst5 and hsst2 receptors as observed for L-363,301. There are however minor differences in binding to the hsst3 receptor among these analogs. These studies allow us to investigate the influence of additional hydrophobic groups on the binding activity to the isolated human somatostatin receptors and the results are important for the design of other somatostatin analogs.

Alanine↗
PubMed1999

Acquisition and severity of driving-related fears.

Rachman's theory of fear acquisition proposes that directly-conditioned fears will differ from indirectly-conditioned fears in magnitude and anxiety response patterns, however the theory has received inconsistent empirical support. The aim of the present study was to describe the fear acquisition pathways for a community sample who reported driving-related fears, and to test Rachman's theory of fear acquisition. One hundred and ninety participants completed a questionnaire which assessed a variety of driving-related situations, reactions to motor vehicle accidents (MVAs), and anxiety response patterns. Professional psychological helpseeking and perceived need for treatment for driving-related fears were also assessed. Results failed to support Rachman's predictions. However, it was confirmed that respondents who had been involved in an MVA were more likely to ascribe their fears to a directly-conditioned pathway. The theoretical and methodological implications of the findings are discussed, along with suggestions for assessment of those with driving-related fears.

Accidents, Traffic↗
PubMed1999

Stability of driving fear acquisition pathways over one year.

The present study was conducted in response to increasing concerns about the potential unreliability of retrospective accounts in assessing the origins of fears and phobias. Some investigators [e.g. Menzies, R.G., & Clarke, J.C. (1993). The etiology of fear of heights and its relationship to severity and individual response patterns. Behaviour Research and Therapy, 31, 355-365; Kirkby, K.C., Menzies, R.G., Daniels, B.A., & Smith, K.L. (1995). Aetiology of spider phobia: Classificatory differences between two origins instruments. Behaviour Research and Therapy, 33, 955-958; King, N.J., Gullone, E., & Ollendick, T.H. (1998). Etiology of childhood phobias: current status of Rachman's three pathways theory. Behaviour Research and Therapy, 36, 297-309.] have questioned the reliability of retrospective reports at a single assessment point, although the test-retest reliability of such accounts has yet to be examined. The aim of the present study was to conduct a one-year follow-up of the subclinical driving-fearful sample studied by Taylor and Deane [Taylor, J. E., & Deane, F. P. (1999). Acquisition and severity of driving-related fears. Behaviour Research and Therapy, 37, 435-449.] to primarily investigate, the stability of fear onset ascriptions and fear severity over time. 85 respondents completed a questionnaire which assessed fear origins, anxiety response patterns, and additional fear-relevant events occurring over the year. The results suggest that retrospective accounts of fear onset may be quite unstable over time, although this instability does not clearly appear to be related to intervening events, and limitations of the study make these results inconclusive. Fear-relevant negative thinking worsened over time, while physiological reactions and general anxiety remained relatively stable. The theoretical, methodological and clinical implications of the findings are discussed, along with suggestions for future research.

Adult↗
PubMed1999

Determination of eletriptan in plasma and saliva using automated sequential trace enrichment of dialysate and high-performance liquid chromatography.

The use of the system, automated sequential trace enrichment of dialysates (ASTED), to prepare plasma and saliva prior to high pressure liquid chromatography of eletriptan (HPLC) is described. Chromatographic identification of one metabolite, UK-135,800 was also established. Using this technique the procedure was observed to be specific and linear over the range 0.50-250 ng/ml. The intra-batch imprecision (C.V.) of the method ranged from 0.56 to 5.70% at plasma eletriptan concentrations from 5.00 to 200 ng/ml, and the corresponding inter-batch imprecision ranged from 1.44 to 6.36%. At these plasma analyte concentrations, the overall inaccuracy (% bias) of the procedure ranged from -5.00 to 1.50%. Similar performances were observed for the estimation of eletriptan in saliva using near identical assay conditions. The application of the assay to a pharmacokinetic investigation during a clinical study is presented.

Chromatography, High Pressure Liquid↗
PubMed1999

Synthesis and binding potencies of cyclic hexapeptide analogs of somatostatin incorporating acidic and basic peptoid residues.

The synthesis, binding affinity, and structure-activity relationships of compounds related to the cyclic hexapeptide, c[Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residue in native somatostatin) is reported. The Pro residue in this compound is replaced with the peptoid residues Nasp [N-(2-carboxyethyl) glycine], Ndab [N-(2-aminoethyl) glycine] and Nlys [N-(4-aminobutyl) glycine]. This series of compounds enables us to draw conclusions about the influence of positively or negatively charged residues in the bridging region on the binding affinity towards the isolated human somatostatin receptors. A loss of binding to the recombinant human somatostatin (hsst) receptors in the Nasp analog compared with L-363,301 and compared with the Ndab and Nlys analogs clearly demonstrates that the presence of an acidic residue in the bridging region is unfavorable for binding to the hsst receptors. Comparison between the Ndab analog and the Nlys analog suggests that the presence of a basic residue in the bridging region might be advantageous for binding to the hsst5 receptor provided that the residue bearing the basic group extends far enough to allow for interaction with the receptor, while the length of the basic peptoid residue does not influence binding to the hsst2 receptor. These results are useful for the design of hsst5 selective somatostatin analogs.

Chromatography, High Pressure Liquid↗
PubMed1999

Prenatal onset spinal muscular atrophy.

Five patients with severe spinal muscular atrophy (SMA) type I, all of whom presented with reduced fetal movements in utero, severe weakness at birth, and short survival time were assessed to attempt to determine whether their phenotype could be explained by their genotype. The diagnosis was confirmed by clinical, electrophysiological and histopathological features. Polymerase chain reaction assays were used to define the molecular diagnosis. A gene-dosage assay was used to assess the quantity of centromeric survival motor neuron gene (SMNc) present. In all cases the telomeric survival motor neuron gene (SMNt) was absent. The SMNc gene was present but in reduced copy number compared with a control group of children with less severe type I SMA, so may be important in determining severity. In the differential diagnosis of reduced fetal movements, SMA should be considered. The clinical classification may in future be clarified by molecular genetic findings.

Cell Survival↗