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Biomedical subjects

D Stock

Publications and source records attributed to D Stock.

At least 19 recordsLinked to original sources
PubMed1998

Postural sway and balance testing: a comparison of normal and anterior cruciate ligament deficient knees.

The purpose of this study was to assess postural sway and balance in normal and anterior cruciate ligament (ACL) deficient (ACLD) knees. Performance was assessed in 15 ACLD and 15 matched control (CON) subjects whilst standing on a postural sway meter and on a balance board. On both pieces of apparatus subjects attempted to maintain balance for 30 s under six different conditions; (1) and (2) standing on both legs with eyes open and closed; (3) and (4) standing on the injured leg with eyes open and closed; and (5) and (6) standing on the non-injured leg with eyes open and closed. Performance on the postural sway meter and balance board deteriorated significantly when both ACLD and CON stood on one leg (P<0.01), and when eyes were closed (P<0.01). This was independent of whether the leg was injured or not. The interaction of vision loss and single leg stance resulted in a significant deterioration in balance board performance on the injured leg compared to the non-injured leg in the ACLD group. Results suggest that use of a postural sway meter for predicting function and stability during dynamic activities in ACLD subjects may be inappropriate. Copyright 1998 Elsevier Science B.V.

Journal Article↗
PubMed1998

Crystal structure of the thermosome, the archaeal chaperonin and homolog of CCT.

We have determined to 2.6 A resolution the crystal structure of the thermosome, the archaeal group II chaperonin from T. acidophilum. The hexadecameric homolog of the eukaryotic chaperonin CCT/TRiC shows an (alphabeta)4(alphabeta)4 subunit assembly. Domain folds are homologous to GroEL but form a novel type of inter-ring contact. The domain arrangement resembles the GroEL-GroES cis-ring. Parts of the apical domains form a lid creating a closed conformation. The lid substitutes for a GroES-like cochaperonin that is absent in the CCT/TRiC system. The central cavity has a polar surface implicated in protein folding. Binding of the transition state analog Mg-ADP-AIF3 suggests that the closed conformation corresponds to the ATP form.

Adenosine Diphosphate↗
PubMed1998

Perspectives on genetic aspects of dental patterning.

Nearly a century of speculation and experimentation has gone into trying to understand the mechanisms that establish the pattern of the differentiated heterodont dentition. Regionally differing qualitative (combinatorial) expression of regulatory genes appears to be involved in this process. Work by our laboratory and others shows that the six members of the mammalian Dlx family of homeobox genes are expressed (a) at multiple times during dental development, (b) differently at different stages, (c) in a way that is related to their genomic organization as gene-pairs linked to three of the four Hox clusters of positional patterning genes. The expression appears to be involved in jaw regionalization, tooth initiation, and tooth development. However, this expression correlates with no single aspect of dental patterning or tooth development, involves redundant and complementary function, and developmental differences between the maxillary and mandibular dentition suggest that other elements remain to be identified. For example, the possibility that quantitative aspects of gene expression specify developmental fields in the dentition has not yet been investigated. Although the maxilla and mandible develop differently, indirect evidence suggests that, especially in the future midline (incisor) regions, both jaws may be patterned by a consistent process that occurs before neural crest migration takes place, and we hypothesize that signaling factors like Sonic hedgehog and Pax transcription factors may be involved.

Animals↗
PubMed1997

Structure of 20S proteasome from yeast at 2.4 A resolution.

The crystal structure of the 20S proteasome from the yeast Saccharomyces cerevisiae shows that its 28 protein subunits are arranged as an (alpha1...alpha7, beta1...beta7)2 complex in four stacked rings and occupy unique locations. The interior of the particle, which harbours the active sites, is only accessible by some very narrow side entrances. The beta-type subunits are synthesized as proproteins before being proteolytically processed for assembly into the particle. The proforms of three of the seven different beta-type subunits, beta1/PRE3, beta2/PUP1 and beta5/PRE2, are cleaved between the threonine at position 1 and the last glycine of the pro-sequence, with release of the active-site residue Thr 1. These three beta-type subunits have inhibitor-binding sites, indicating that PRE2 has a chymotrypsin-like and a trypsin-like activity and that PRE3 has peptidylglutamyl peptide hydrolytic specificity. Other beta-type subunits are processed to an intermediate form, indicating that an additional nonspecific endopeptidase activity may exist which is important for peptide hydrolysis and for the generation of ligands for class I molecules of the major histocompatibility complex.

Acetylcysteine↗
PubMed1997

Collision tumour of the ampulla of Vater: carcinoid and adenocarcinoma.

Obstructive jaundice is most commonly due to luminal stones or lesions of the head of the pancreas and more rarely ampullary and primary common bile duct lesions. Obstruction due to lesions of the ampulla of Vater may be due to adenocarcinoma which has a significantly better long term prognosis than carcinomas located in the head of the pancreas. A case is presented where two tumours were identified at the ampulla of Vater of the resected specimen one an adenocarcinoma and the other a carcinoid tumour representing a collision tumour.

Adenocarcinoma↗
PubMed1996

Probing the V1a vasopressin receptor binding site with pyroglutamate-substituted linear antagonists.

We have synthesized eight analogues of the linear vasopressin antagonist DTyr(Et)2-Phe3-Gln4-Asn5-Arg6-Pro7-Arg8-Tyr(NH2)9 substituted with L-, or D-, pyroglutamate at position-1, Asn or Val at position-4 and Arg or Met at position 6. All of these peptides bound to the V1a vasopressin receptor with affinities ranging 33.6-5, 470 nM. Of this series, only two peptides, [LpGlu1Val4Arg6Tyr(NH2)9]AVP Kd = 48.4 nM and [DpGlu1Val4Arg6Tyr(NH2)9]AVP Kd = 691 nM, bound to the V2 vasopressin receptor. All of the neurohypophysial hormone receptors studied (V1a VPR, V2 VPR and OTR) were found to be stereoselective with respect to the N-terminal pGlu residue. The effect on binding characteristics of L-pGlu1 and D-pGlu1 analogues was dependent on both the sequence of the peptide and on the receptor subtype in question. From these data we found that peptide 5, which has the structure DpGlu-DTyr(Et)-Phe-Val-Asn-Arg-Pro-ARg-Tyr(NH2), exhibited the highest V1a/OTR selectivity reported to date (V1aVPR Kd = 82 nM; OTR no binding at 10 microM). As such, peptide 5 will provide useful leads to the development of ligands with enhanced V1a/OTR selectivity. The binding affinity and hydrophobicity of pyroglutamate-substituted peptides was compared with previously characterized V1a receptor antagonists which contained a range of position-1 substitutions. The hydrophobicity of both cyclic and linear antagonists was markedly increased relative to the agonists AVP and [Phe2Orn8]VT but increased hydrophobicity alone did not exclusively lead to high affinity antagonists. Data presented support the contention that in addition to a general increase in hydrophobicity/lipophilicity, position-1 influences the pharmacophore of vasopressin antagonists by providing molecular determinants for ligand/receptor interaction.

Amino Acid Sequence↗
PubMed1996

Proteasome: from structure to function.

During the past two years, significant progress has been made in understanding the structure and function of the proteasome. Recent work has revealed the three-dimensional structure of the 700 kDa proteolytic complex at atomic resolution and elucidated its novel catalytic mechanism. Close relationships to a number of other amino-terminal hydrolases have emerged, making the proteasomal subunits the prototype of this newly discovered structural superfamily.

Animals↗
PubMed1996

Evaluation of reverse transcriptase and protease inhibitors in two-drug combinations against human immunodeficiency virus replication.

Current treatments for human immunodeficiency virus (HIV) include both reverse transcriptase and protease inhibitors. Results from in vitro and clinical studies suggest that combination therapy can be more effective than single drugs in reducing viral burden. To evaluate compounds for combination therapy, stavudine (d4T), didanosine (ddI), or BMS-186,318, an HIV protease inhibitor, were combined with other clinically relevant compounds and tested in a T-cell line (CEM-SS) that was infected with HIV-RF or in peripheral blood mononuclear cells infected with a clinical HIV isolate. The combined drug effects were analyzed by the methods described by Chou and Talalay (Adv. Enzyme Regul. 22:27-55, 1984) as well as by Prichard et al. (Antimicrob. Agents Chemother. 37:540-545, 1993). The results showed that combining two nucleoside analogs (d4T-ddI, d4T-zidovudine [AZT], and d4T-zalcitabine [ddC]), two HIV protease inhibitors (BMS-186,318-saquinavir, BMS-186,318-SC-52151, and BMS-186,318-MK-639) or a reverse transcriptase and a protease inhibitor (BMS-186,318-d4T, BMS-186,318-ddI, BMS-186,318-AZT, d4T-saquinavir, d4T-MK-639, and ddI-MK-639) yielded additive to synergistic antiviral effects. In general, analysis of data by either method gave consistent results. In addition, combined antiviral treatments involving nucleoside analogs gave slightly different outcomes in the two cell types, presumably because of a difference in phosphorylation patterns. Importantly, no strong antagonism was observed with the drug combinations studied. These data should provide useful information for the design of clinical trials of combined chemotherapy.

Cell Line↗
PubMed1996

Cardiovascular effects of beta-carbolines in conscious rats.

The beta-carbolines have a high affinity for the benzodiazepine receptor, where they demonstrate actions opposite to those of the benzodiazepines and elicit anxiogenic effects. We tested the acute cardiovascular effects of beta-carbolines in conscious unrestrained rats. Intravenous infusion of ethyl-beta-carboline-3-carboxylate (BCCE) or methyl-beta-carboline-3-carboxylate (BCCM) caused dose-related decreases in heart rate. Pretreatment with RO 15-1788 (10.0 mg/kg, i.v.), a benzodiazepine receptor antagonist, or atropine (1.0 mg/kg, i.v.) prevented the bradycardia elicited by BCCE (3.0 mg/kg, i.v.). In contrast, tetrahydro-beta-carboline (THBC; 3.0 mg/kg, i.v.) increased both heart rate and blood pressure significantly as compared with controls. However, larger doses of THBC failed to elicit further increases in heart rate or blood pressure. These experiments indicate that in conscious unrestrained rats, beta-carbolines given acutely do not routinely elicit the cardiovascular changes normally associated with stress or anxiety. We next extended our observations to rats given the beta-carboline noreleagnine, 2 mg/kg, or vehicle twice daily intraperitoneally for 4 weeks. The rats were fed either a high salt (8%) or a low salt (0.9%) diet. At 4 weeks, rats given noreleagnine and high salt had higher tail cuff pressures (146 +/- 4 vs. 134 +/- 4 mmHg) than those given noreleagnine and low salt. However, with direct arterial measurement, these differences disappeared. These data suggest that beta-carbolines do not provide a useful model for investigating the effects of chronic stress on cardiovascular function in rats.

Animals↗
PubMed1996

[Effects of patient education in type II diabetic patients after clinic admission. Results of a 3 month catamnesis after new patient-centered education].

The success of structured teaching programs trying to enable NIDDM patients to carry out effective self-management of their diabetes often does not last very long. Only few type-II-diabetes patients are able to both, control their nutritional behaviour, and maintain metabolic control in the long run. We added therefore a patient-centered motivational support training programme to a regular teaching programme. The underlying hypotheses being that the cognitions of patients with NIDDM frequently cause non-compliant behaviour concerning diet and sports. The motivational training programme aimed at systematic modification of patients' cognitions. 43 type-II-diabetes patients took part in a test of the motivationally supplemented diabetes training. As a result of the training a range of variables such as quality of life, glycosylated haemoglobin, body weight, etc. strongly supported the superiority of the motivational supplemented teaching programme. Unfortunately, effects of the motivational training programme disappeared within three month after completion of the training. These findings suggest that further support is needed to maintain the achieved level of motivation after the training. To address this problem we designed a self-help programme to be worked by the patients themselves whenever metabolic control cannot be maintained.

Aged↗
PubMed1995

Crystal structure of the 20S proteasome from the archaeon T. acidophilum at 3.4 A resolution.

The three-dimensional structure of the proteasome from the archaebacterium Thermoplasma acidophilum has been elucidated by x-ray crystallographic analysis by means of isomorphous replacement and cyclic averaging. The atomic model was built and refined to a crystallographic R factor of 22.1 percent. The 673-kilodalton protease complex consists of 14 copies of two different subunits, alpha and beta, forming a barrel-shaped structure of four stacked rings. The two inner rings consist of seven beta subunits each, and the two outer rings consist of seven alpha subunits each. A narrow channel controls access to the three inner compartments. The alpha 7 beta 7 beta 7 alpha 7 subunit assembly has 72-point group symmetry. The structures of the alpha and beta subunits are similar, consisting of a core of two antiparallel beta sheets that is flanked by alpha helices on both sides. The binding of a peptide aldehyde inhibitor marks the active site in the central cavity at the amino termini of the beta subunits and suggests a novel proteolytic mechanism.

Amino Acid Sequence↗
PubMed1995

Proteasome from Thermoplasma acidophilum: a threonine protease.

The catalytic mechanism of the 20S proteasome from the archaebacterium Thermoplasma acidophilum has been analyzed by site-directed mutagenesis of the beta subunit and by inhibitor studies. Deletion of the amino-terminal threonine or its mutation to alanine led to inactivation of the enzyme. Mutation of the residue to serine led to a fully active enzyme, which was over ten times more sensitive to the serine protease inhibitor 3,4-dichloroisocoumarin. In combination with the crystal structure of a proteasome-inhibitor complex, the data show that the nucleophilic attack is mediated by the amino-terminal threonine of processed beta subunits. The conservation pattern of this residue in eukaryotic sequences suggests that at least three of the seven eukaryotic beta-type subunit branches should be proteolytically inactive.

Amino Acid Sequence↗
PubMed1994

Expression, purification and crystallization of human phosphotyrosine phosphatase 1B.

Protein phosphotyrosine phosphatases are believed to be involved in the regulation of the activity of cellular proteins, such as receptor tyrosine kinases, by controlling their phosphorylation status. One of the best described and characterized protein of this class of enzymes is the phosphotyrosine phosphatase 1B. To obtain sufficient quantities for structural investigations, truncated forms of PTP1B encompassing the catalytic domain were over-expressed in Escherichia coli and purified to apparent homogeneity by conventional chromatography. The activity of these purified enzymes has been compared with the wild-type enzyme expressed in mammalian cells. By measuring the activities against p-nitrophenyl phosphate, the pH dependence of this activity, and responses to different modulators, it could be demonstrated that the truncated forms of PTP1B retained the same characteristics as the full-length mammalian enzyme, but are not subject to inhibition of enzymic activity mediated by the C-terminus. Due to their improved solubility, it can be assumed that the catalytic domains are advantageous for crystallization studies in comparison to the natural enzyme. In a screening for crystallization conditions, we obtained protein crystals indicating that the quality of the purified protein is sufficient for crystallographic studies.

Base Sequence↗
PubMed1993

Preliminary X-ray crystallographic study of the proteasome from Thermoplasma acidophilum.

Single cystals of proteasomes from the archaebacterium Thermoplasma acidophilum were obtained using the hanging-drop vapor diffusion method. The crystals diffract to better than 3.0 A and belong to the orthorhombic space group P2(1)2(1)2(1) with unit cell dimensions a = 308.9 A, b = 208.8 A and c = 116.9 A. There is one molecular complex in the asymmetric unit. Two potentially useful heavy-atom derivatives have been obtained. The self-rotation function of the native Patterson map shows local sevenfold symmetry, consistent with the low-resolution structure obtained by electron microscopic techniques. The unit cell dimensions and crystal symmetry together with the shape and size of the proteasome suggest a packing arrangement of proteasome molecules in the unit cell, with their cylinder axis nearly parallel to the crystallographic a-axis.

Crystallization↗
PubMed1992

Crystal structure of the factor for inversion stimulation FIS at 2.0 A resolution.

The factor for inversion stimulation (FIS) binds as a homodimeric molecule to a loose 15 nucleotide consensus sequence in DNA. It stimulates DNA-related processes, such as DNA inversion and excision, it activates transcription of tRNA and rRNA genes and it regulates its own synthesis. FIS crystallizes as a homodimer, with 2 x 98 amino acid residues in the asymmetric unit. The crystal structure was determined with multiple isomorphous replacement and refined to an R-factor of 19.2% against all the 12,719 X-ray data (no sigma-cutoff) extending to 2.0 A resolution. The two monomers are related by a non-crystallographic dyad axis. The structure of the dimer is modular, with the first 23 amino acid residues in molecule M1 and the first 24 in molecule M2 disordered and not "seen" in the electron density. The polypeptide folds into four alpha-helices, with alpha A, alpha A' (amino acid residues 26 to 40) and alpha B, alpha B' (49 to 69) forming the core of the FIS dimer, which is stabilized by hydrophobic forces. To the core are attached "classical" helix-turn-helix motifs, alpha C, alpha D (73 to 81 and 84 to 94) and alpha C', alpha D'. The connections linking the helices are structured by two beta-turns for alpha A/alpha B, and alpha C1 type extensions are observed at the C termini of helices alpha B, alpha C and alpha D. Helices alpha D and alpha D' contain 2 x 6 positive charges; they are separated by 24 A and can bind adjacent major grooves in B-type DNA if it is bent 90 degrees. The modular structure of FIS is also reflected by mutation experiments; mutations in the N-terminal part and alpha A interfere with FIS binding to invertases, and mutations in the helix-turn-helix motif interfere with DNA binding.

Amino Acid Sequence↗
PubMed1992

Auditory filter bandwidths as a function of level at low frequencies (125 Hz-1 kHz)

Auditory filter bandwidths were measured using the symmetric notched-noise method in five normally hearing listeners at four masker levels (40-70 dB SPL/Hz in 10-dB steps) and four probe frequencies (125-1000 Hz in octave steps). Accurate stimulus spectrum shape and level were ensured by use of a headphone monitoring technique. Auditory filter bandwidths decreased with decreasing frequency from 1 kHz down to 125 Hz. On the whole, bandwidths increased with increasing level, but the effect of level on bandwidth was greater as frequency increased, with little or no effect of level at 125 Hz. Insofar as the results from the notched-noise method reflect basilar membrane vibration patterns, basilar membrane mechanics appear to become less nonlinear as one approaches the apex of the cochlea.

Adult↗