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Biomedical subjects

J B Moon

Publications and source records attributed to J B Moon.

18 recordsLinked to original sources
PubMed1992

Crystal structure of a complex of HIV-1 protease with a dihydroxyethylene-containing inhibitor: comparisons with molecular modeling.

The structure of a crystal complex of recombinant human immunodeficiency virus type 1 (HIV-1) protease with a peptide-mimetic inhibitor containing a dihydroxyethylene isostere insert replacing the scissile bond has been determined. The inhibitor is Noa-His-Hch psi [CH(OH)CH(OH)]Vam-Ile-Amp (U-75875), and its Ki for inhibition of the HIV-1 protease is < 1.0 nM (Noa = 1-naphthoxyacetyl, Hch = a hydroxy-modified form of cyclohexylalanine, Vam = a hydroxy-modified form of valine, Amp = 2-pyridylmethylamine). The structure of the complex has been refined to a crystallographic R factor of 0.169 at 2.0 A resolution by using restrained least-squares procedures. Root mean square deviations from ideality are 0.02 A and 2.4 degrees, for bond lengths and angles, respectively. The bound inhibitor diastereomer has the R configurations at both of the hydroxyl chiral carbon atoms. One of the diol hydroxyl groups is positioned such that it forms hydrogen bonds with both the active site aspartates, whereas the other interacts with only one of them. Comparison of this X-ray structure with a model-built structure of the inhibitor, published earlier, reveals similar positioning of the backbone atoms and of the side-chain atoms in the P2-P2' region, where the interaction with the protein is strongest. However, the X-ray structure and the model differ considerably in the location of the P3 and P3' end groups, and also in the positioning of the second of the two central hydroxyl groups. Reconstruction of the central portion of the model revealed the source of the hydroxyl discrepancy, which, when corrected, provided a P1-P1' geometry very close to that seen in the X-ray structure.

Amino Acid Sequence↗
PubMed1991

Computer design of bioactive molecules: a method for receptor-based de novo ligand design.

The design of molecules to bind specifically to protein receptors has long been a goal of computer-assisted molecular design. Given detailed structural knowledge of the target receptor, it should be possible to construct a model of a potential ligand, by algorithmic connection of small molecular fragments, that will exhibit the desired structural and electrostatic complementarity with the receptor. However, progress in this area of receptor-based, de novo ligand design has been hampered by the complexity of the construction process, in which potentially huge numbers of structures must be considered. By limiting the scope of the structure-space examined to one particular class of ligands--namely, peptides and peptide-like compounds--the problem complexity has been reduced to the point that successful, de novo design is now possible. The methodology presented employs a large template set of amino acid conformations which are iteratively pieced together in a model of the target receptor. Each stage of ligand growth is evaluated according to a molecular mechanics-based energy function, which considers van der Waals and coulombic interactions, internal strain energy of the lengthening ligand, and desolvation of both ligand and receptor. The search space is managed by use of a data tree which is kept under control by pruning according to the energy evaluation. Ligands grown by this procedure are subjected to follow-up evaluation in which an approximate binding enthalpy is determined. This methodology has proven useful as a precise model-builder and has also shown the ability to design bioactive ligands.

Algorithms↗
PubMed1991

Inhibitors of the protease from human immunodeficiency virus: design and modeling of a compound containing a dihydroxyethylene isostere insert with high binding affinity and effective antiviral activity.

The peptidomimetic template and the dihydroxyethylene isostere insert that were applied successfully to the design of renin inhibitors have been extended to the related protease from human immunodeficiency virus (HIV). The present report describes the structure-activity study leading to the identification of an inhibitor with a Ki of less than 1 nM for the HIV type-1 protease (compound II). This compound, containing a diol insert, is highly effective in blocking polyprotein processing in in vitro cell culture assays. Results obtained from kinetic analysis, studies of the stereochemistry of the insert, and modeling have led to insights as to the requisites involved in the active site-inhibitor interaction.

Amino Acid Sequence↗
PubMed1991

The effects of auditory feedback on the regulation of intraoral air pressure during speech.

Previous experimental evidence has been interpreted as support for regulation of both acoustics and aerodynamics during speech production. One recent perspective is that although speech acoustics may be manipulated, regulation of aerodynamics is a central component of the processes that produce speech. From this perspective, it has been suggested that aerodynamic regulation is given priority over perceptual accuracy. The experiment attempted to test this hypothesis by forcing speakers into a choice between aerodynamic and acoustic regulation. The intensity level of frication (embedded in a carrier phrase) was selectively amplified or attenuated and fed back to the speaker on line. Intraoral air pressure was recorded in order to assess whether or not perturbed auditory feedback would result in aerodynamic compensation. Although compensatory changes in peak intraoral air pressure, pressure duration, and pressure curve area were seen in response to 30-dB alterations of frication, no systematic effects were seen for smaller auditory manipulations. Further, the compensations were less than what one might expect from a system controlling auditory output. Explanations of these findings and their implications for the control of speech production are offered.

Adult↗
PubMed1991

Motor control of velopharyngeal structures during vowel production.

This investigation was designed to measure the ability of normal adult speakers to exert voluntary control over velopharyngeal positioning. Speakers were asked to phonate the vowels [a] and [i] at 50 percent and 75 percent of complete velopharyngeal closure, using visual feedback of velopharyngeal opening and closing gestures from a phototransducer. The musculature of the velopharyngeal mechanism was hypothesized to act as a coordinated system that may demonstrate both motor flexibility and plasticity (Folkins, 1985) when forced to function in a novel way. Evidence of both motor system responses to a novel speaking condition was observed. Speakers were able either to phonate at intermediate closure levels without having to learn new motor rules, or to learn new rules for velopharyngeal muscle activation that resulted in the ability over time to position the velopharyngeal mechanism appropriately. As such, support is derived for the notion (Folkins, 1985) that speakers develop motor rules or coordinative structures involving the velopharyngeal mechanism that govern velopharyngeal movement. The characteristics of this coordinative structure framework has not yet been described, however, and are the subject of ongoing research efforts.

Adult↗
PubMed1991

A flexible system for vital signs monitoring in hospital general care wards based on the integration of UNIX-based workstations, standard networks and portable vital signs monitors.

The article describes a study conducted on general surgical and thoracic surgical floors of a 1000-bed hospital to assess the impact of a new network for portable patient care devices. This network was developed to address the needs of hospital patients who need constant, multi-parameter, vital signs surveillance, but do not require intensive nursing care. Bedside wall jacks were linked to UNIX-based workstations using standard digital network hardware, creating a flexible system (for general care floors of the hospital) that allowed the number of monitored locations to increase and decrease as patient census and acuity levels varied. It also allowed the general care floors to provide immediate, centralized vital signs monitoring for patients who unexpectedly became unstable, and permitted portable monitors to travel with patients as they were transferred between hospital departments. A disk-based log within the workstation automatically collected performance data, including patient demographics, monitor alarms, and network status for analysis. The log has allowed the developers to evaluate the use and performance of the system.

Boston↗
PubMed1990

Reversible covalent binding of peptide nitriles to papain.

The dissociation constants for reversible covalent binding of twelve peptide nitrile inhibitors to the active site of papain have been measured by means of fluorescence titration. The binding constants generally parallel the kinetic specificity constants (kcat/Km) for related papain substrates, supporting earlier suggestions that peptide nitriles behave as transition state analog inhibitors of papain. In ten cases the temperature dependence of binding was analyzed to determine the enthalpic and entropic contributions to the binding energy. A compensation plot of delta H vs. T delta S resulted in two parallel lines, one for 'specific' nitriles (i.e., N-Ac-L-aa-NHCH2CN; aa = Phe, Leu, Met) and the other for 'non-specific' nitriles (e.g., N-Ac-D-Phe-NHCH2CN, PhCH2CH2CONHCH2CN hippurylnitrile, etc.). For both specific and nonspecific nitriles representing an 1800-fold range of Kd values (0.27 microM-490 microM), the solvent deuterium isotope effect on binding (Kd(H2O)/Kd(D2O) = DKd) was very close to 2.0. This isotope effect could be accounted for entirely by the simple protonic change which occurs upon the reversible addition of the active site sulfhydryl of papain to the nitrile group of the peptide derivative to form a covalent thioimidate linkage. In contrast, six closely related non-nitrile ligands containing identical peptide side chains but having C-terminal groups incapable of binding covalently to papain had unmeasureably high dissociation constants. Collectively, these results indicate that strong binding of peptide nitrile substrate analogs to papain requires a combination of (1) hydrophobic interaction (especially at the P2 position), (2) specific intermolecular hydrogen bonding and (3) covalent interaction of the nitrile with the active site sulfhydryl group.

Chemical Phenomena↗
PubMed1990

A nursing home rotation in a family practice residency.

A nursing home rotation can be a complementary component of geriatrics education in a family practice residency curriculum. Using nursing homes in teaching geriatrics has been done for some time but has of late received more emphasis. This increasing emphasis has been brought about by the growing health care needs of an aging population and a concomitant focus on education in geriatrics. If implementation of a nursing home rotation is contemplated, both the positive and negative aspects of such action as it relates to the residents, the nursing home, and the nursing home patients should be explored. The rotation as incorporated into the geriatrics curriculum of the Family Practice Residency, Knoxville Unit, University of Tennessee College of Medicine, involves all second-year and third-year residents in the medical care for patients of a 222-bed long-term care facility. From an educational standpoint, overall evaluation of the rotation reflects satisfaction. The experience exemplifies personal and comprehensive continuity of patient care. Other educational benefits include desensitization to the nursing home environment, understanding the kinds of medical care that can be delivered in this setting, and appreciation for the cost not only to the patient and the family but also to the medical care system as well.

Family Practice↗
PubMed1989

A fast algorithm for generating smooth molecular dot surface representations.

The smooth molecular surface originally described by Richards and later implemented by Connolly in his MS program has become an important visualization technique in the field of molecular modeling. We describe here a new algorithm, called USURF, which approximates the MS dot surface, but with a twofold to sixfold enhancement of speed. The algorithm has been incorporated into our interactive modeling system, Mosaic, and is also available as a stand-alone program.

Algorithms↗
PubMed1987

Enthalpy and entropy of hippuraldehyde hydration and binding to papain.

In aqueous solution hippuraldehyde, PhCONHCH2CHO, is approx. 10-times more extensively hydrated than simple aliphatic aldehydes. Studies of the temperature dependence of the NMR spectrum of hippuraldehyde and its hydrate in 2H2O indicate that the dehydration is endothermic (delta H = 3.9 +/- 0.9 kcal/mol), but entropically favored (delta S = 7.9 +/- 1.9 cal/mol per deg). For simple aliphatic aldehydes the corresponding dehydration is slightly more endothermic, but somewhat more favorable entropically. Fluorescence titration studies show that Kd for the hemithioacetal adduct of hippuraldehyde with papain-SH (1.2 microM at 298 K) is approx. 3000-times smaller than that estimated for simple thiols. Dissociation of hippuraldehyde from papain is endothermic by 18.1 kcal/mol, and this is only partly offset by the favorable entropy change of 33.7 cal/mol per deg. Thus, at least in thermodynamic terms, the binding of this putative 'transition-state analog' to papain is not unlike the binding of other small ligands to the active site of chymotrypsin.

Hippurates↗
PubMed1987

Aerodynamic and myoelastic contributions to tracheoesophageal voice production.

Five laryngectomized, tracheoesophageal (TE) speakers completed a series of phonatory tasks developed to assess (a) aerodynamic and acoustic properties of TE voice and (b) aerodynamic and myoelastic contributions to the mediation of fundamental frequency change. These TE speakers' voices were characterized by increased trans-source airflow rates, comparable source driving pressures, and decreased airway resistances in comparison with standard esophageal speakers. TE speakers were capable of adjusting their voicing sources on a myoelastic basis to influence Fo change. This result, coupled with findings that confirm aerodynamic contributions to TE phonation, are interpreted to suggest that TE voice production should be regarded as an aerodynamic-myoelastic event. Findings are integrated with existing data to highlight fundamental differences among TE, esophageal, and normal voice production.

Airway Resistance↗
PubMed1987

Application of cine computed tomography to the assessment of velopharyngeal form and function.

The mechanism of velopharyngeal closure is clearly three-dimensional in nature. Numerous attempts have been made to obtain a comprehensive picture of velopharyngeal movement, with varying degrees of success. A computed tomography scan system has recently been developed that may be used for real-time motion study of various body systems. This preliminary study was designed to assess the applicability of multi-level cine computed tomography scanning as a tool in the three-dimensional analysis of the velopharynx. One normal speaker and one speaker with an unrepaired palatal cleft were asked to phonate while serial sections were taken at 650-millisecond intervals through a number of transverse sections in the velopharyngeal region. This paper includes an explanation of cine CT technology, examples of scans on two speakers with clearly different velopharyngeal mechanisms, and discussion of the potential use of cine computed tomography as a tool in the analysis of both normal and disordered velopharyngeal function.

Cineradiography↗
PubMed1987

Development of a second-generation phototransducer for the assessment of velopharyngeal activity.

There has been considerable interest in development of instrumental measures for quantifying velopharyngeal function. This paper describes the design and evaluation of a second-generation device that might be used to transduce opening magnitude and movement of the velopharyngeal valve. Miniature optoelectronic components were used to construct and evaluate the phototransducer on the basis of five a priori design objectives: (1) linear relationship between valve opening cross-sectional area and phototransducer output; (2) a response time quick enough to allow for accurate tracking of velopharyngeal movement; (3) insensitivity of the device to ambient light; (4) high sensitivity to valve opening magnitude; and (5) low cost. All five a priori design objectives were met. Potential usefulness of the device in both clinical and research applications and directions for future research are discussed.

Electronics, Medical↗
PubMed1986

Airway resistances of Blom-Singer and Panje Low Pressure tracheoesophageal puncture prostheses.

Airway resistances were calculated for two newly commercialized tracheoesophageal (TE) puncture prostheses: the Panje Low Pressure Voice Button and the Blom-Singer Low Pressure device. The airway resistances of newly commercialized Panje Low Pressure devices could not be distinguished from those calculated for previously commercialized, Regular Pressure Voice Button devices. Airway resistances of Blom-Singer Low Pressure devices increased systematically as a function of flow rate. Findings are compared with existing data to provide readers with an opportunity to evaluate the relative efficiency of air shunting among contemporary TE puncture prostheses. Results are interpreted in relation to their implications for selecting surgical-prosthetic options for laryngectomized patients.

Airway Resistance↗
PubMed1979

Ocular findings in thoracic-pelvic-phalangeal dystrophy.

Two unrelated patients with thoracic-pelvic-phalangeal dystrophy syndrome had retinal degeneration. A pathologic study of both eyes from one of the patients showed severe degeneration of the peripheral retina, with predominantly cone-type cells remaining.

Abnormalities, Multiple↗