An orally bioavailable pyrrolinone inhibitor of HIV-1 protease: computational analysis and X-ray crystal structure of the enzyme complex.
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Administration, Oral↗
Biomedical subjects
A B Smith
Publications and source records attributed to A B Smith.
Problems of reproducibility--does geologically ancient DNA survive in amber-preserved insects?
Apparently ancient DNA has been reported from amber-preserved insects many millions of years old. Rigorous attempts to reproduce these DNA sequences from amber- and copal-preserved bees and flies have failed to detect any authentic ancient insect DNA. Lack of reproducibility suggests that DNA does not survive over millions of years even in amber, the most promising of fossil environments.
Amber↗
Multiple calcium channels control neurotransmitter release from rat postganglionic sympathetic nerve terminals.
1. Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals of the rat isolated anococcygeus muscle. 2. Low concentrations of the N-type calcium channel blocker omega-conotoxin GVIA (omega-CgTX GVIA) irreversibly abolished excitatory junction potentials (EJPs) evoked by trains of < or = five stimuli at 10 Hz. When the frequency of stimulation was increased (10-50 Hz) trains of stimuli evoked EJPs even in the presence of 1 microM omega-CgTX GVIA. We have termed this omega-CgTX GVIA-resistant release 'residual release'. EJP amplitude in the presence of omega-CgTX GVIA depended on both the frequency and number of stimuli in a train. 3. Residual release was inhibited by the P-type calcium channel blocker omega-agatoxin IVA (100 nM). However, even in the presence of both toxins, longer trains of stimuli could still evoke neurotransmitter release. 4. Residual release was abolished by omega-conotoxin MVIIC and by the non-specific calcium channel antagonist omega-grammotoxin SIA. Therefore, it would appear that a heterogeneous population of calcium channels is involved in mediating neurotransmitter release from these sympathetic nerve terminals.
Animals↗
Can pressure overload cause sliding hiatal hernia? A case report and review of the literature.
We describe a hiatal hernia of moderate size in a 31-year-old competitive bodybuilder to raise the question of whether such hernias are more likely in young elite resistance-trained athletes as a consequence of attempts to increase intra-abdominal pressure and thus decrease the strain on the lumbar spine.
Adult↗
Special considerations for WEB-based clinical database applications.
The Hospital Information System at the University of Missouri-Columbia Veterinary Medical Teaching Hospital is implementing a web-based interface to the existing Hospital Information System. The "stateless" nature of HTML forms introduces a number of special considerations that, though not immediately obvious, nevertheless apply to any multi-user database application. Problems including identifying sessions and users, dealing with abandoned sessions or use of the "Back" arrow on the browser, record locking across multiple forms, state variables, and flow through "utility" forms. General solutions to each of these problems have been devised and are presented here.
Animals↗
Bringing a WEB-based interface to a hospital information system.
The Hospital Information System at the MU Veterinary Medical Teaching Hospital is a "home-grown" system written in MUMPS. The system has a "roll-and-scroll" user interface typical of terminal based systems from the 1970s and early 1980s. We are now introducing a new user interface that uses World Wide Web technology (HTML forms). Computers connected to the hospital's intranet can access the hospital system using the Web browser of the user's choice. The new user interface can run in parallel with the older interface (even on the same computer), and uses the same underlying database. This allows a smooth migration to the new interface which minimizes both user and programmer anguish. User acceptance has been good, and the ease and speed of development has been very promising.
Animals↗
Data model development as a prelude to implementing a hospital information system.
We developed a data model for use in a veterinary teaching hospital using modern object oriented database diagramming. Since we deal with more than one species and often with herds or flocks, the problem became even more complex than the situation in human medicine. We chose to follow, insofar as possible, standards set forth by the HL7 consortium and the American Society for Testing and Materials (ASTM), two organizations deeply involved in setting standards for the health care record. Some modifications became necessary in order to fit the veterinary medical record to these standards but these were straightforward and did not disrupt the overall model. As a first step in constructing a hospital information system we have developed, and present herein, a data model which adequately addresses our needs in both the clinical and financial arenas and which conforms to appropriate standards as completely as possible.
Animals↗
Ryanodine-sensitive calcium stores involved in neurotransmitter release from sympathetic nerve terminals of the guinea-pig.
1. Intracellular and focal extracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens. 2. High concentrations of the selective N-type calcium channel blocker omega-conotoxin GVIA abolished the release of the neurotransmitter ATP evoked by trains of low-frequency stimuli. However, in the presence of high concentrations of the blocker, a 'residual release' persisted at higher frequencies. 3. Residual release was dependent on calcium entry through a pharmacologically distinct voltage-dependent calcium channel. 4. Residual release was inhibited by ryanodine in a use- and time-dependent manner and this inhibitory effect was potentiated by caffeine. The inhibitory effect of ryanodine on residual release was reversed by 4-aminopyridine. 5. These findings indicate that calcium-induced calcium released from intraneuronal stores plays an important role in action potential-evoked neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals.
Adenosine Triphosphate↗
Chromosome 18 translocation (18;21) (p11.1;p11.1) associated with psychosis in one family.
In the course of recruiting families with 2 schizophrenic siblings for genome screening and linkage studies, a family was found with mental retardation, schizophrenia, and/or other related psychotic illnesses in individuals who also had an unbalanced or balanced translocation between chromosomes 21-18 [t(18;21)(p11.1;p11.1)]. The pericentric region of chromosome 18 has already been noted as a possible location of a gene for bipolar psychosis. The family described here provides further evidence that this region should be examined for a candidate psychosis gene.
Adult↗
Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.
The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.
Amino Acid Sequence↗
Acute and chronic liver toxicity resulting from exposure to chlorinated naphthalenes at a cable manufacturing plant during World War II.
Historical records were used to reconstruct an outbreak of chlorance and acute liver toxicity due to chlorinated naphthalene exposure at a New York State plant which manufactured "Navy cables" during World War II. A cohort mortality study was conducted of the population (n = 9,028) employed at the plant from 1940 to 1944. Vital status was followed through December 31, 1985. The study found an excess of deaths from cirrhosis of the liver [observed (OBS) = 150; standardized mortality ratio (SMR) = 1.84; 95% confidence interval (CI) = 1.56-2.16]; cirrhosis deaths were elevated to a similar degree in the 460 individuals who had chlorance (OBS = 8; SMR = 1.51; CI = 0.65-2.98). The SMR for "non-alcoholic cirrhosis" (OBS = 83; SMR = 1.67; CI = 1.33-2.07) was similar to the SMR for "alcoholic cirrhosis" (OBS = 59; SMR = 1.96; CI = 1.49-2.53). There was no evidence for increased alcoholism in the overall cohort based on mortality from alcohol-related causes of death other than cirrhosis (SMR for esophageal cancer = 1.01 and for deaths from alcoholism = 0.99). We conclude that the excess mortality from cirrhosis of the liver observed in this cohort is due to the chronic effect of chlorinated naphthalene exposure.
Acute Disease↗
Characterization of the delta-aminolevulinate synthase gene homologue in P. falciparum.
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5-Aminolevulinate Synthetase↗
Characterization of the delta-aminolevulinate synthase gene homologue in P. falciparum.
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5-Aminolevulinate Synthetase↗
The design and synthesis of 2,5-linked pyrrolinones. A potential non-peptide peptidomimetic scaffold.
The de novo design and initial synthetic studies directed toward construction of a novel non-peptide scaffold for beta-strand/sheet and related secondary peptide structural mimics are described. The scaffold, consisting of a repeating array of 2,5,5-trisubstituted pyrrolinone (enaminone) units punctuated with appropriate amino acid side chains, is conceptually related to our previously successful 3,5-linked polypyrrolinone non-peptide peptidomimetic scaffold. Construction of the 2,5,5-trisubstituted pyrrolinone ring system proceeds via intramolecular condensation of an N-protected amino dione. The latter is prepared from a protected alpha-amino ketone and aldehyde via an aldol-oxidation reaction sequence.
Crystallography, X-Ray↗
Vectorially oriented monolayers of detergent-solubilized Ca(2+) -ATPase from sarcoplasmic reticulum.
A method for tethering proteins to solid surfaces has been utilized to form vectorially oriented monolayers of the detergent-solubilized integral membrane protein Ca(2+) -ATPase from the sarcoplasmic reticulum (SR). Bifunctional, organic self-assembled monolayers (SAMs) possessing "headgroup" binding specificity for the substrate and "endgroup" binding specificity for the enzyme were utilized to tether the enzyme to the substrate. Specifically, an amine-terminated 11-siloxyundecaneamine SAM was found to bind the Ca(2+)-ATPase primarily electrostatically. The Ca(2+)-ATPase was labeled with the fluorescent probe 5-(2-[(iodoacetyl)amino]ethyl)aminonaphthalene-1-sulfonic acid before monolayer formation. Consequently, fluorescence measurements performed on amine-terminated SAM/enzyme monolayers formed on quartz substrates served to establish the nature of protein binding. Formation of the monolayers on inorganic multilayer substrates fabricated by molecular beam epitaxy made it possible to use x-ray interferometry to determine the profile structure for the system, which was proved correct by x-ray holography. The profile structures established the vectorial orientation of the Ca(2+)-ATPase within these monolayers, to a spatial resolution of approximately 12 A. Such vectorially oriented monolayers of detergent-solubilized Ca(2+)-ATPase from SR make possible a wide variety of correlative structure/function studies, which would serve to elucidate the mechanism of Ca(2+) transport by this enzyme.
Animals↗
Omega-conotoxin GVIA-resistant neurotransmitter release in postganglionic sympathetic nerve terminals.
Intracellular recording techniques were used to study neurotransmitter release in the guinea-pig isolated vas deferens. Low concentrations of the irreversible and selective N-type calcium channel blocker omega-conotoxin GVIA have previously been shown to block excitatory junction potentials evoked by low frequencies (< or = 1 Hz) of nerve stimulation. Here we report a component of action potential-evoked release which is insensitive to high concentrations of omega-conotoxin GVIA. We have termed this component "residual release" and show (i) it is positively frequency-dependent, (ii) its magnitude is dependent on both the train length and interval between trains, (iii) "residual release" can be modulated through prejunctional alpha 2-adrenoceptors and (iv) "residual release" is insensitive to many calcium entry blockers but abolished by omega-grammotoxin SIA and cadmium ions. Although noradrenaline is released by nerve action potentials, residual excitatory junction potentials were abolished by alpha,beta-methylene-ATP and therefore resulted entirely from the actions of neuronally released ATP acting through postjunctional P2x-purinoceptors. The results suggest that calcium entry through a novel, pharmacologically uncharacterized voltage-dependent calcium channel is responsible for "residual release" in sympathetic nerve terminals. It seems that in response to single or short trains of nerve action potentials, N-type calcium channels dominate the release process. However, at higher frequencies other voltage-dependent calcium channels are recruited and these may have an important role to play in triggering the mechanisms underlying frequency-dependent facilitation.
Adenosine Triphosphate↗
The role of support group facilitator: ensuring success.
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Adult↗
Identification of haptoglobin as a natural inhibitor of trypanocidal activity in human serum.
Trypanosomes are protozoan parasites of medical and veterinary importance. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense infect humans, causing African sleeping sickness. However, Trypanosoma brucei brucei can only infect animals, causing the disease Nagana in cattle. Man is protected from this subspecies of trypanosomes by a toxic subtype of high density lipoproteins (HDLs) called the trypanosome lytic factor (TLF). The toxic molecule in TLF is believed to be the haptoglobin-related protein that when bound to hemoglobin kills the trypanosome via oxidative damage initiated by its peroxidase activity. The amount of lytic activity in serum varies widely between different individuals with up to a 60-fold difference in activity. In addition, an increase in the total amount of lytic activity occurs during the purification of TLF, suggesting that an inhibitor of TLF (ITLF) exists in human serum. We now show that the individual variation in trypanosome lytic activity in serum correlates to variations in the amount of ITLF. Immunoblots of ITLF probed with antiserum against haptoglobin recognize a 120-kDa protein, indicating that haptoglobin is present in partially purified ITLF. Haptoglobin involvement is further shown in that it inhibits TLF in a manner similar to ITLF. Using an anti-haptoglobin column to remove haptoglobin from ITLF, we show that the loss of haptoglobin coincides with the loss of inhibitor activity. Addition of purified haptoglobin restores inhibitor activity. This indicates that haptoglobin is the molecule responsible for inhibition and therefore causing the individual variation in serum lytic activity.
Anemia, Hemolytic↗