Post-operative mortality related to waiting time for hip fracture surgery.
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Cohort Studies↗
Biomedical subjects
J P Cooper
Publications and source records attributed to J P Cooper.
Zenker's diverticulum and psychosis in the elderly.
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Aged↗
Buspirone for anxiety and agitation in dementia.
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Aged↗
The fission yeast Taz1 protein protects chromosomes from Ku-dependent end-to-end fusions.
A paramount role of telomeres is to prevent chromosome fusions. The fission yeast Taz1 protein regulates diverse telomere functions but is not essential for growth under stress-free conditions. Strikingly, however, taz1(-) cells exhibit lethal telomere fusions when subjected to nitrogen starvation, a treatment that induces an uncommitted G1 state. These fusions are formed by Ku-dependent nonhomologous end joining. Fusions also occur during normal growth in taz1(-) cells that lack rad22(+), a gene involved in homologous recombination. Our data suggest a model whereby taz1(-) telomeres are exposed to the prevailing mode of DNA repair, which is dictated by the cell cycle. Thus, Taz1 caps chromosome ends and provides the telomerespecific interaction that prevents Ku from treating telomeres as double-strand breaks.
Antigens, Nuclear↗
Peptide and peptide mimetic inhibitors of antigen presentation by HLA-DR class II MHC molecules. Design, structure-activity relationships, and X-ray crystal structures.
Molecular features of ligand binding to MHC class II HLA-DR molecules have been elucidated through a combination of peptide structure-activity studies and structure-based drug design, resulting in analogues with nanomolar affinity in binding assays. Stabilization of lead compounds against cathepsin B cleavage by N-methylation of noncritical backbone NH groups or by dipeptide mimetic substitutions has generated analogues that compete effectively against protein antigens in cellular assays, resulting in inhibition of T-cell proliferation. Crystal structures of four ternary complexes of different peptide mimetics with the rheumatoid arthritis-linked MHC DRB10401 and the bacterial superantigen SEB have been obtained. Peptide-sugar hybrids have also been identified using a structure-based design approach in which the sugar residue replaces a dipeptide. These studies illustrate the complementary roles played by phage display library methods, peptide analogue SAR, peptide mimetics substitutions, and structure-based drug design in the discovery of inhibitors of antigen presentation by MHC class II HLA-DR molecules.
Antigen Presentation↗
Telomere transitions in yeast: the end of the chromosome as we know it.
Telomere functions vary as the cell cycle progresses. Recent results highlight fluctuating associations between telomeres and DNA polymerases, DNA-damage repair proteins, and centrosome components. These associations reflect diverse roles of telomeres in chromosome maintenance and in the orchestration of chromosome movements during meiosis.
Animals↗
A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation.
The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPARgamma subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2, 4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPARgamma ligand that was a weak partial agonist of PPARgamma transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.
Adipocytes↗
Pulmonary embolus possibly associated with clozapine treatment.
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Aged↗
N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent.
3-¿4-[2-(Benzoxazol-2-ylmethylamino)ethoxy]phenyl¿-(2S)-((2- benzoylph enyl)amino)propionic acid (1) and (2S)-((2-benzoylphenyl)amino)-3-¿4-[2-(5-methyl-2-phenyloxazol-4-y l)e thoxy]phenyl¿propionic acid (2) are peroxisome proliferator-activated receptor gamma (PPARgamma) agonists and have antidiabetic activity in rodent models of type 2 diabetes. As part of an effort to develop the SAR of the N-2-benzoylphenyl moiety of 1 and 2, a series of novel carboxylic acid analogues, 23-66, modified only in the N-2-benzoylphenyl moiety were synthesized from L-tyrosine and evaluated as PPARgamma agonists. In general, only modest changes in the N-2-benzoylphenyl moiety of 1 and 2 are tolerated. More specifically, the best changes involve bioisosteric replacement of one of the two phenyl rings of this moiety. Addition of substituents to this moiety generally produced compounds that are less active in the cell-based functional assays of PPARgamma activity although binding affinity to PPARgamma may be maintained. A particularly promising set of analogues is the anthranilic acid esters 63-66 in which the phenyl ring in the 2-benzoyl group of 1 and 2 has been replaced by an alkoxy group. In particular, (S)-2-(1-carboxy-2-¿4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phen yl¿ ethylamino)benzoic acid methyl ester (63) has a pKi of 8.43 in the binding assay using human PPARgamma ligand binding domain and a pEC50 of 9.21 in the in vitro murine lipogenesis functional assay of PPARgamma activity. Finally, 63 was found to normalize glycemia when dosed at 3 mg/kg bid po in the Zucker diabetic fatty rat model of type 2 diabetes.
Administration, Oral↗
Two modes of survival of fission yeast without telomerase.
Deletion of the telomerase catalytic subunit gene trt1+ in Schizosaccharomyces pombe results in death for the majority of cells, but a subpopulation survives. Here it is shown that most survivors have circularized all of their chromosomes, whereas a smaller number maintain their telomeres presumably through recombination. When the telomeric DNA-binding gene taz1+ is also deleted, trt1- taz1- survivors use the recombinational mode more frequently. Moreover, the massive elongation of telomeres in taz1- cells is absent in the double mutant. Thus, Taz1p appears to regulate telomeric recombination as well as telomerase activity in fission yeast.
Chromosomes, Fungal↗
Fission yeast Taz1 protein is required for meiotic telomere clustering and recombination.
The alignment of homologous chromosomes during meiosis is essential for their recombination and segregation. Telomeres form and protect the ends of eukaryotic linear chromosomes, and are composed of tandem repeats of a simple DNA sequence and the proteins that bind to these repeats. A role for telomeres in meiosis was suspected from observations of telomere clustering in meiotic cells, and has now been supported experimentally by the dramatic rearrangement of telomere locations during premeiotic stages in fission yeast. Here we show that the fission yeast telomere protein, Taz1, is required for stable association between telomeres and spindle pole bodies during meiotic prophase. In the absence of Taz1, telomere clustering at the spindle pole bodies is disrupted, meiotic recombination is reduced, and both spore viability and the ability of zygotes to re-enter mitosis are impaired to a level that would be expected if chromosome segregation were occurring randomly. Such telomeric association mediated by telomere-specific proteins may also be important for proper chromosome alignment and recombination during meiosis in humans.
Chromosomes, Fungal↗
Design and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template.
The interleukin-1 proteins (IL-1 alpha and IL-1 beta) are key mediators of inflammatory and immunological responses, and several in vitro and in vivo studies with protein-based antagonists have demonstrated the potential usefulness of IL-1 receptor antagonists to treat various inflammation related diseases. Based on the X-ray crystal structures of IL-1 ligands and site-directed mutagenesis data, a noncontiguous binding epitope encompassing Arg4, Phe46, Ile56, Lys93, Lys103, and Glu105 for IL-1 beta was proposed. In this paper we describe the synthesis and binding assay results of small molecule IL-1 receptor antagonists designed on the basis of the three-dimensional structure of the binding epitope. Among these, the compound 45 was found to inhibit IL-alpha binding to the Type I receptor with an IC50 value of 3 microM. A hypothesis generated using BioCad CATALYST program is also presented to rationalize these observations.
Benzene Derivatives↗
Regulation of telomere length and function by a Myb-domain protein in fission yeast.
Telomeres, the specialized nucleoprotein structures that comprise the ends of eukaryotic chromosomes, are essential for complete replication, and regulation of their length has been a focus of research on tumorigenesis. In the budding yeast Saccharomyces cerevisiae, the protein Rap1p binds to telomeric DNA and functions in the regulation of telomere length. A human telomere protein, hTRF (human TTAGGG repeat factor) binds the telomere sequence in vitro and localizes to telomeres cytologically, but its functions are not yet known. Here we use a genetic screen to identify a telomere protein in fission yeast, Taz1p (telomere-associated in Schizosaccharomyces pombe), that shares homology to the Myb proto-oncogene DNA-binding domain with hTRF. Disruption or deletion of the taz1+ gene causes a massive increase in telomere length. Taz1p is required for the repression of telomere-adjacent gene expression and for normal meiosis or sporulation. It may be a negative regulator of the telomere-replicating enzyme, telomerase, or may protect against activation of telomerase-independent pathways of telomere elongation.
Amino Acid Sequence↗
Prolonged asystole induced by head up tilt test. Report of four cases and brief review of the prognostic significance and medical management.
Head up tilt is an established test for assessing patients with vasovagal syncope. Prolonged asystole during the test has previously been reported in patients suffering from the malignant form of this syndrome. Little is known about the prognostic significance of this response and there is no consensus about the optimum treatment. Four such patients are reported who were treated pharmacologically. During follow up they remained free from major events and their symptoms were well controlled. Conservative management is the initial method of choice and only if this fails should implantation of a dual chamber permanent pacemaker be considered.
Adolescent↗
Impaired matching of perfusion and ventilation in heart failure detected by 133xenon.
In severe chronic heart failure (CHF) the ventilatory cost of CO2 elimination during exercise (VE/VCO2) is increased, suggesting ventilation/perfusion (V/Q) mismatch. The relationship of exercise VE/VCO2 regression slope m to deadspace ventilation was studied in 15 patients with CHF who underwent cardiopulmonary exercise testing and arterial blood gas monitoring. Regional lung ventilation and perfusion was studied, using 133xenon, at rest and peak exercise in a further group of 10 CHF patients and in five normal subjects. VE/VCO2 slope m correlated well with deadspace ventilation at peak exercise in the 15 patients with CHF. We therefore used exercise VE/VCO2 slope m to categorize CHF patients undergoing 133xenon imaging into groups with increased (slope m > 36) or normal (slope m < 36) exercise deadspace ventilation. In normals, resting V/Q determined by 133xenon showed a gravitational gradient, which improved on exercise as a result of relative increases and of relative reductions in regional perfusion; no significant changes in regional ventilation distribution were detected. In patients with CHF who had normal slope m (n = 5), rest and exercise V/Q were similar to the normal subjects. In CHF patients with increased slope m (n = 5) however, the resting gravitational gradient of V/Q was lost, and there were no significant changes in relative perfusion distribution on exercise. These findings suggest that the increased ventilatory cost of CO2 elimination found in certain patients with CHF is related to inability to coordinate and optimise the relative distribution of lung perfusion with respect to ventilation during exercise.
Adult↗
Human isotype antibody responses to an Onchocerca volvulus glutathione S-transferase.
Human isotype specific antibody responses to a recombinant pi-class glutathione S-transferase (Ov24) from Onchocerca volvulus were assessed by ELISA, using a large and well-characterized bank sera (n = 238) from an hyper-endemic area of moderate intensity from Sierra Leone. IgG1, IgG4 and IgA responses, but neither IgG2 nor IgE response, to Ov24 were detected in infected subjects. The relationships between Ov24 antibody levels and skin microfilarial density, number of nodules, age, sex, eosinophil counts and clinical sign of reactive and chronic pathology were analysed using Pearson's correlation coefficient. Significant correlations between both IgA and IgG3 antibody levels and age were found (P < 0.01). Although no firm conclusions could be drawn from this study sample regarding the relationships between antibody levels and parasite load or clinical status, a negative correlation (P = 0.06) between Ov24 IgG3 antibody levels and microfilarodermia was found.
Adolescent↗
Bacterial endocarditis involving a subaortic membrane.
A subaortic membrane predisposes to bacterial endocarditis usually affecting the aortic valve and left ventricular outflow tract. Endocarditis involving the subaortic membrane itself has been described twice only; once at operation and once at postmortem. The case of a man with vegetations involving a subaortic membrane that were detected preoperatively and the echocardiographic appearances of these findings are reported.
Adult↗
Systemic sclerosis associated with right ventricular cardiomyopathy.
Systemic sclerosis is an uncommon multisystem disorder of unknown aetiology which predominantly affects the skin. Cardiac involvement, which is far more common than was originally realized, may affect any part of the heart but most frequently affects the left ventricular myocardium. Right ventricular dysfunction is usually associated with pulmonary vascular disease. We report a case of systemic sclerosis associated with right ventricular cardiomyopathy in whom pulmonary artery pressures were normal.
Adult↗