Biomedical subjects

T A Jones

Publications and source records attributed to T A Jones.

At least 163 records · Page 9Linked to original sources

PubMed1989

Pulsed linear acceleration as a vestibular stimulus in electrophysiological investigations.

A simple method of generating precisely defined pulsed linear acceleration stimuli was developed and used to study vestibular responses to cranial acceleration. Electromechanical shakers were coupled to a stimulus platform. The platform, in turn, was used to couple stimuli to the skull. Movements were controlled by a voltage waveform (V(t] applied to shakers. Software algorithms were used to synthesize voltage functions (V(t]. The resulting acceleration was monitored [a(t)] and used to generate velocity [v(t)] and position [x(t)] functions (first and second integrals of a(t), respectively). The characteristics of stimuli used in physiological experiments are described. The system provides precise control of the timing and amplitude of acceleration, velocity and position pulses to the cranium and has proved to be valuable in developing noninvasive electrophysiological measures of peripheral and central vestibular function.

Acceleration↗

PubMed1989

Auditory thresholds in the American cockroach (Orthoptera: Blattidae): estimates using single-unit and compound-action potential recordings.

Recent commercial suggestions that insect populations can be controlled through the use of ultrasound raises the question of whether or not certain insects have receptors that are sensitive to high-frequency sound. Single neural unit discharges and compound-action potentials were recorded from the ventral nerve cord in the American cockroach, Periplaneta americana L., to constant rise time tone pulses from 100 to 40,000 hertz (Hz). Unit responses and compound-action potentials show that the cockroach is insensitive to sound above approximately 3,000 Hz. Data relating latency of the response to intensity of the stimulus suggest that the cockroach cercal system operates on the principle of energy envelope detection. Decreases in latency likely occur primarily as a result of increases in the rate of membrane depolarization in cercal dendrites.

Action Potentials↗

PubMed1989

Assignment of the gene coding for the alpha-subunit of prolyl 4-hydroxylase to human chromosome region 10q21.3-23.1.

Prolyl 4-hydroxylase, an alpha 2 beta 2 tetramer, catalyzes the formation of 4-hydroxyproline in collagens by the hydroxylation of proline residues in peptide linkages and plays a crucial role in the synthesis of these proteins. The gene for the beta-subunit of prolyl 4-hydroxylase has recently been mapped to the long arm of human chromosome 17, at band 17q25. We report here chromosomal localization of the gene for the catalytically and regulatorily important alpha-subunit of human prolyl 4-hydroxylase. Analysis of 24 rodent x human cell hybrids by Southern blotting with cDNA probes for the human alpha-subunit indicated complete cosegregation of the gene for the alpha-subunit with human chromosome 10. A cell hybrid containing only part of chromosome 10 mapped the gene to 10q11----qter. In situ hybridization mapped the gene to 10q21.3-23.1. The gene for the alpha-subunit is thus not physically linked to that for the beta-subunit of the enzyme.

Animals↗

PubMed1988

The solution conformation of the antibacterial peptide cecropin A: a nuclear magnetic resonance and dynamical simulated annealing study.

The solution conformation of the antibacterial polypeptide cecropin A from the Cecropia moth is investigated by nuclear magnetic resonance (NMR) spectroscopy under conditions where it adopts a fully ordered structure, as judged by previous circular dichroism studies [Steiner, H. (1982) FEBS Lett. 137, 283-287], namely, 15% (v/v) hexafluoroisopropyl alcohol. By use of a combination of two-dimensional NMR techniques the 1H NMR spectrum of cecropin A is completely assigned. A set of 243 approximate interproton distance restraints is derived from nuclear Overhauser enhancement (NOE) measurements. These, together with 32 distance restraints for the 16 intrahelical hydrogen bonds identified on the basis of the pattern of short-range NOEs, form the basis of a three-dimensional structure determination by dynamical simulated annealing [Nilges, M., Clore, G.M., & Gronenborn, A.M. (1988) FEBS Lett. 229, 317-324]. The calculations are carried out starting from three initial structures, an alpha-helix, an extended beta-strand, and a mixed alpha/beta structure. Seven independent structures are computed from each starting structure by using different random number seeds for the assignments of the initial velocities. All 21 calculated structures satisfy the experimental restraints, display very small deviations from idealized covalent geometry, and possess good nonbonded contacts. Analysis of the 21 converged structure indicates that there are two helical regions extending from residues 5 to 21 and from residues 24 to 37 which are very well defined in terms of both atomic root mean square differences and backbone torsion angles. For the two helical regions individually the average backbone rms difference between all pairs of structures is approximately 1 A. The long axes of the two helices lie in two planes, which are at an angle of 70-100 degrees to each other. The orientation of the helices within these planes, however, cannot be determined due to the paucity of NOEs between the two helices.

Anti-Bacterial Agents↗

PubMed1988

Necrotizing enterocolitis in full-term infants. A case-control study.

We performed a case-control investigation of 43 full-term infants with necrotizing enterocolitis (NEC) to identify possible risk factors and unique features of the disorder in the more mature infant. Two control groups were used. The first consisted of "healthy" term infants. The second was a group of "sick" term infants who did not develop NEC. The 43 term infants with NEC represented 12.7% of all 338 neonates with NEC. The median age at onset of symptoms was 2 days, and 18 infants developed NEC on the first day of life. Two (4.7%) of the 43 affected term infants died, while 35 (11.9%) of 295 preterm infants with the disorder died. Only three of the full-term infants who subsequently developed NEC had entirely unremarkable courses prior to the onset of symptoms. Sick infants, in particular those who are small for gestational age or require exchange transfusions, are at risk for NEC. Several other features that may be associated with the subsequent development of NEC include the following: perinatal asphyxia, presence of umbilical catheters, antecedent respiratory distress, polycythemia, and maternal preeclampsia. Full-term infants with these features should be treated with cautious observation and aggressive management early in the neonatal period should they develop signs and symptoms suggestive of NEC.

Enterocolitis, Pseudomembranous↗

PubMed1988

The three-dimensional structure of P2 myelin protein.

The three-dimensional structure of P2 protein from peripheral nervous system myelin has been determined at 2.7 A resolution by X-ray crystallography. The single isomorphous replacement/anomalous map was interpreted using skeletonized electron density on a computer graphics system. An atomic model was built using fragment fitting. The structure forms a compact 10-stranded up-and-down beta-barrel which encapsulates residual electron density that we interpret as a fatty acid molecule. This beta-barrel shows some similarity to, but is different from, the retinol binding protein family of structures. The relationship of the P2 structure to a family of cytoplasmic, lipid binding proteins is described.

Amino Acid Sequence↗

PubMed1988

Refined structure of human carbonic anhydrase II at 2.0 A resolution.

The structure of human erythrocytic carbonic anhydrase II has been refined by constrained and restrained structure-factor least-squares refinement at 2.0 A resolution. The conventional crystallographic R value is 17.3%. Of 167 solvent molecules associated with the protein, four are buried and stabilize secondary structure elements. The zinc ion is ligated to three histidyl residues and one water molecule in a nearly tetrahedral geometry. In addition to the zinc-bound water, seven more water molecules are identified in the active site. Assuming that Glu-106 is deprotonated at pH 8.5, some of the hydrogen bond donor-acceptor relations in the active site can be assigned and are described here in detail. The O gamma 1 atom of Thr-199 donates its proton to the O epsilon 1 atom of Glu-106 and can function as a hydrogen bond acceptor only in additional hydrogen bonds.

Binding Sites↗

PubMed1988

Crystallographic studies of inhibitor binding sites in human carbonic anhydrase II: a pentacoordinated binding of the SCN- ion to the zinc at high pH.

The binding of four inhibitors--mercuric ion, 3-acetoxymercuri-4-aminobenzenesulfonamide (AMS), acetazolamide (Diamox), and thiocyanate ion--to human carbonic anhydrase II (HCA II) has been studied with X-ray crystallography. The binding of mercury to HCA II at pH 7.0 has been investigated at 3.1 A resolution. Mercuric ions are observed at both nitrogens in the His-64 ring. One of these sites is pointing toward the zinc ion. The only other binding site for mercury is at Cys-206. The binding of the two sulfonamide inhibitors AMS and Diamox, has been reinvestigated at 2.0 and 3.0 A, respectively. Only the nitrogen of the sulfonamide group binds to the zinc ion replacing the hydroxyl ion. The sulfonamide oxygen closest to the zinc ion is 3.1 A away. Thus the tetrahedral geometry of the zinc is retained, refuting earlier models of a pentacoordinated zinc. The structure of the thiocyanate complex has been investigated at pH 8.5 and the structure has been refined at 1.9 A resolution using the least-squares refinement program PROLSQ. The crystallographic R factor is 17.6%. The zinc ion is pentacoordinated with the anion as well as a water molecule bound in addition to the three histidine residues. The nitrogen atom of the SCN- ion is 1.9 A from the zinc ion but shifted 1.3 A with respect to the hydroxyl ion in the native structure and at van der Waals' distance from the O gamma l atom of Thr-199. This is due to the inability of the O gamma l atom of Thr-199 to serve as a hydrogen bond donor, thus repelling the nonprotonated nitrogen. The SCN- molecule reaches into the deep end of the active site cavity where the sulfur atom has displaced the so-called "deep" water molecule of the native enzyme. The zinc-bound water molecule is 2.2 A from the zinc ion and 2.4 A from the SCN- nitrogen. In addition, this water is hydrogen bonded to the O gamma l atom of Thr-199 and to another water molecule. We have observed that solvent and inhibitor molecules have three possible binding sites on the zinc ion and their significance for the catalysis and inhibition of HCA II will be discussed. All available crystallographic data are consistent with a proposed catalytic mechanism in which both the OH moiety and one oxygen of the substrate HCO3- ion are ligated to the zinc ion.

Acetazolamide↗

PubMed1988

Bovine P2 myelin basic protein crystallizes in three different forms.

P2 protein is a minor component of the myelin membrane. We have crystallized this protein for high-resolution crystallographic study. Three crystal morphologies are available. Two of them are from ammonium sulfate, and one is from polyethyleneglycol (PEG). The unit cell of the most suitable crystals from PEG 4000 has the dimensions a = 91.3 A, b = 99.8 A, c = 56.0 A; is of space group P2(1)2(1)2(1); and contains up to four molecules per asymmetric unit. The limit of resolution is 2.7 A.

Ammonium Sulfate↗

PubMed1987

Crystallization of P2 myelin protein.

Single crystals of bovine P2 myelin protein have been grown in polyethylene glycol 4000 by the hanging-drop vapor diffusion method. Crystals belonging to space group P2(1)2(1)2(1) with cell dimensions a = 91.8 A, b = 99.5 A, c = 56.5 A (1 A = 0.1 nm). The diffraction pattern extends to better than 2.3 A resolution.

Amino Acid Sequence↗

PubMed1987

Peripheral and brainstem auditory function in paroxysmal (px) White Leghorn chicks.

The paroxysmal (px) chick is a mutant White Leghorn (Gallus domesticus) which appears normal at hatching and during the subsequent week. By ca. 8 days posthatching, various symptoms develop, of which the most obvious are depressed food intake (anorexia) and audiogenic seizures. Histological evidence suggests that central auditory and vestibular nuclei and fiber tracts begin to degenerate prior to seizure onset. This degeneration, which affects central and peripheral components of both systems, becomes increasingly severe over time although auditory stimulation continues to elicit seizures. Characterization and analysis of peripheral and brainstem auditory response to auditory stimuli indicated that major response differences between px and normal chicks exist in peaks reflecting brainstem activity (P3A, P3B, P4A, P5A). In 5 of 8 px chicks, these later response peaks were either grossly abnormal in terms of amplitude and latency (including amplitude input/output functions) or often entirely absent. Early peaks (P1A and P2A), however, in px waveforms were normal in morphology and amplitude, indicating normal function of peripheral auditory structures. Although lower body temperature of px chicks may account for some of the longer latencies observed, other abnormalities (e.g. absence of peaks) could not be produced in normal birds by induced hypothermia.

Animals↗

PubMed1987

Determination of three-dimensional protein structures from nuclear magnetic resonance data using fragments of known structures.

A method to build a three-dimensional protein model from nuclear magnetic resonance (NMR) data using fragments from a data base of crystallographically determined protein structures is presented. The interproton distances derived from the nuclear Overhauser effect (NOE) data are compared to the precalculated distances in the known protein structures. An efficient search algorithm is used, which arranges the distances in matrices akin to a C alpha diagonal distance plot, and compares the NOE distance matrices for short sequential zones of the protein to the data base matrices. After cluster analysis of the fragments found in this way, the structure is built by aligning fragments in overlapping zones. The sequentially long-range NOEs cannot be used in the initial fragments search but are vital to discriminate between several possible combinations of different groups of fragments. The method has been tested on one simulated NOE data set derived from a crystal structure and one experimental NMR data set. The method produces models that have good local structure, but may contain larger global errors. These models can be used as the starting point for further refinement, e.g., by restrained molecular dynamics or interactive graphics.

Crystallography↗

PubMed1987

Origins of peripheral and brainstem auditory responses in the White Leghorn chick.

1. Peripheral and central auditory projections were sectioned and far-field recordings measured to determine neural generators of the waveform in the White Leghorn chick. 2. The mesencephalicus lateralis p. dorsalis and more rostral structures do not contribute to the waveform. 3. Activity of N.VIII is reflected in peaks P1A and P2A; N2A appears to be central in origin but may be in part from the central stump of N.VIII. 4. The crossed dorsal cochlear tract but not the trapezoid body is necessary for P3A and P4A; it is therefore functionally homologous to mammalian trapezoid fibres. 5. P1A, P2A, N2A, P2B are not dependent on crossing fibres.

Acoustic Stimulation↗

PubMed1987

Far-field recordings of short latency auditory responses in the White Leghorn chick.

Far-field recordings of short latency auditory responses were characterized in the White Leghorn chick (Gallus domesticus, 2-3 weeks post hatch). Six to twelve positive peaks were normally present within the first 8 ms following the onset of a click stimulus (stimulus intensity = 99.0 +/- 6.3 dB pe SPL, 44.3 +/- 1.2 dB SL). Both cochlear microphonic (CM) and neural response components were distinguished based on functional criteria. Neural responses (P1a-P6b) were readily masked by white noise. CM responses were resistant to masking and inverted when click polarity was reversed. Systemic cooling produced shifts in neural response latencies such that later peaks (e.g. latencies greater than or equal to P3) were delayed to a greater extent than early peaks (P1a and P2a). The latencies of CM components were relatively unaffected by cooling. The mean latencies and amplitudes were described quantitatively for dominant positive peaks. The mean auditory response threshold for 18 animals was 54.5 +/- 7 dB pe SPL. Dominant later components (P3a and the P3b/P4a complex) were the first to disappear after lethal injection of anesthetic. These were followed immediately by earlier neural peaks. CM components were the last to disappear. A working hypothesis is advanced regarding the distinction between central (P3a, P3b and P4a) and peripheral (P1a, P2a) neural components.

Animals↗

PubMed1986

Molecular dynamics simulations of the holo and apo forms of retinol binding protein. Structural and dynamical changes induced by retinol removal.

The effects of removing retinol from the X-ray structure of holo-retinol binding protein are studied using the molecular dynamics technique. Structural and dynamical properties emerging from an 80 ps simulation of the apo form, for which no crystallographic structure is available, are compared with the results of a 70 ps trajectory of the holo-protein. Dynamical stationarity is attained after roughly 30 ps, and the resulting average structure is proposed as a reasonable model of the apo-protein. Conformational changes are observed for the loops at the beta-barrel entrance during the non-equilibrium part of the apo-trajectory. Tryptophan labelling experiments and retinoid reconstitution experiments point towards this part of the molecule as being involved in prealbumin binding. Structural changes in this region may therefore explain the differences in prealbumin affinity between the apo and holo forms. Furthermore, a change in the position of the alpha-helix, corresponding to a pivot around its C terminus, is observed for the apo-protein. The resulting conformation of the alpha-helix is found to be similar to that in apo-beta-lactoglobulin, which also can bind retinol and for which a crystal structure exists. The results from the holo simulation are compared to the crystallographic data and show good agreement. The dynamics of the secondary and tertiary structural elements are analysed and compared for the two forms. The beta-barrel is found to be extremely cooperative in its atomic motions in both simulations, and the top and bottom beta-sheets perform collective fluctuations with respect to each other in the low-frequency limit of the simulations. The dynamics of the alpha-helical region presents clear differences between the two forms; while the holo-protein has a well-defined spectrum for the longitudinal stretching mode, the apo form displays a fairly large bending of the alpha-helix at several points of the trajectory.

Computer Simulation↗

PubMed1986

Structural changes in retinol binding protein induced by retinol removal. A molecular dynamics study.

Relationships between structure and function for retinol binding protein (RBP) are elucidated with help of a 2.0 A resolution X-ray structure of the holo-protein and an average molecular dynamics (MD) structure of the apo-form. Comparisons between MD simulations of both the apo- and holo-forms with the X-ray holo-structure show conformational changes in apo-RBP that may be functionally significant. The average three dimensional structure obtained for apo-RBP is compared to the related protein apo-beta-lactoglobulin. Available biochemical information is consistent with structure/function relationships derived here.

Humans↗

PubMed1986

Using known substructures in protein model building and crystallography.

Retinol binding protein can be constructed from a small number of large substructures taken from three unrelated proteins. The known structures are treated as a knowledge base from which one extracts information to be used in molecular modelling when lacking true atomic resolution. This includes the interpretation of electron density maps and modelling homologous proteins. Models can be built into maps more accurately and more quickly. This requires the use of a skeleton representation for the electron density which improves the determination of the initial chain tracing. Fragment-matching can be used to bridge gaps for inserted residues when modelling homologous proteins.

Models, Molecular↗

PubMed1986

Effects of temperature and elevated intracranial pressure on peripheral and brain stem auditory responses in dogs.

Far-field recordings of central (P2 through P4) and peripheral (cochlear microphonic; and compound action potential of the eighth nerve) auditory responses were used to assess changes in auditory function resulting from elevated intracranial pressure. Normative data for eight dogs were obtained. The relationship between response latency and core temperature was examined. A mean slope of -0.17 ms/degrees C resulted for the temperature range of 35.0 to 40.0 degrees C. Systemic arterial pressure was measured in order to identify the cerebral ischemic response. Responses were not altered significantly unless the intracranial pressure approached within 15 to 30 mm Hg of mean systemic arterial pressure. Changes in the response consisted of both enhancement and deterioration during intracranial pressure elevation and were accompanied by increases in systemic arterial pressure during that elevation. Supernormal amplitudes of the action potential also occurred during recovery periods. Results suggest that: (i) during elevated intracranial pressure, changes in both central and peripheral auditory function result from ischemia rather than pressure-induced distortion of the cochlea or central neural assemblies. (ii) Far-field auditory responses may include an O2-dependent cochlear microphonic. (iii) An unknown process causing enhancement of central and peripheral neural responses exists and operates in connection with intracranial hypertension. Possible mechanisms underlying enhancement of response components are discussed.

Animals↗