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Biomedical subjects

P L Jackson

Publications and source records attributed to P L Jackson.

At least 19 recordsLinked to original sources
PubMed2005

QSAR of the anticonvulsant enaminones; molecular modeling aspects and other assessments.

The enaminones represent potentially useful agents for the clinical treatment in generalized tonic-clonic seizures (Epilepsia, 1993, 34(6), 1141-1145, Biopharm. Drug Disp. 2003, 397-407). A regression analysis was performed to provide a quantitative structure-activity relationship (QSAR) correlation model for prediction of activity for the anticonvulsant enaminones. Molecular modeling was performed to determine the molecular confluence of the Unverferth model (J. Med. Chem. 1998, 41, 63-73) to the enaminones. Conclusions related to the sodium channel model were assessed.

Animals↗
PubMed2001

Solution structure of an insect-specific neurotoxin from the New World scorpion Centruroides sculpturatus Ewing.

We report the high-resolution solution structure of the 6.3 kDa neurotoxic protein CsE-v5 from the scorpion Centruroides sculpturatus Ewing (CsE, range southwestern U.S.). This protein is the second example of an Old World-like neurotoxin isolated from the venom of this New World scorpion. However, unlike CsE-V, which is the first Old World-like toxin isolated and shows both anti-insect and anti-mammal activity, CsE-v5 shows high specificity for insect sodium channels. Sequence-specific proton NMR assignments and distance and angle constraints were obtained from 600 MHz 2D-NMR data. Distance geometry and dynamical simulated annealing refinements were performed to produce a final family of 20 structures without constraint violations, along with an energy-minimized average structure. The protein structure is well-defined (0.66 and 0.97 D rmsd for backbone and all heavy atoms, respectively) with a compact hydrophobic core and several extending loops. A large hydrophobic patch, containing four aromatic rings and other aliphatic residues, makes up a large area of one side of the protein. CsE-v5 shows secondary structural features characteristic of long-chain scorpion toxins: a two and a half-turn alpha-helix, a three-strand antiparallel beta-sheet, and four beta-turns. Among the proteins studied to date from the CsE venom, CsE-v5 is the most compact protein with nearly 50% of the amide protons having long exchange lifetimes, but CsE-v5 is unusual in that it has loop structures similar to both Old and New World toxins. Further, it also lacks prolines in its C-terminal 14 residues. It shows some important differences with respect to CsE-V not only in its primary sequence, but also in its electrostatic potential surface, especially around areas in register with residues 8, 9, 17, 18, 32, 43, and 57. The loss of anti-mammal activity in CsE-v5 and the differences in its anti-insect activity compared to that of other proteins such as CsE-V, v1, and v3 from this New World scorpion may be related to residue variations at these locations.

Amino Acid Sequence↗
PubMed2001

NMR conformational analysis of cis and trans proline isomers in the neutrophil chemoattractant, N-acetyl-proline-glycine-proline.

Alkaline hydrolysis of corneal proteins in the alkali-injured eye releases N-acetyl-proline-glycine-proline (Ac-Pro-Gly-Pro-OH) among other peptides. It has been shown that this tripeptide is a neutrophil chemoattractant. Existing data suggest that the release of this peptide is the catalytic event for early neutrophil invasion of the cornea leading to corneal ulcers. In order to design inhibitors of this tripeptide chemoattractant that would block neutrophil invasion and diminish corneal ulcers, we studied the solution properties of this tripeptide by NMR spectroscopy and compared this peptide to Ac-Pro-Gly-OH (a weaker chemoattractant), and to Ac-Pro-OH (inactive). The NMR data were consistent with Ac-Pro-Gly-Pro-OH existing in solution as a mixture of four isomers with different cis and trans conformations about the two X-proline amide bonds. The isomer with two trans conformations (trans-trans) was the most dominant (41%) in aqueous solution. This was followed by the isomers with mixed cis and trans conformations (trans-cis, 26% and cis-trans, 20%). The isomer with two cis conformations (cis-cis) was the least favored (13%). The populations of these isomers were investigated in DMSO and they were similar to those reported in aqueous solutions except that the ordering of the trans-cis and cis-trans isomers were reversed. NMR NH temperature coefficients and nuclear Overhauser effect (NOE) measurements as well as CD spectroscopy were used to demonstrate that the four isomers exist primarily in an extended conformation with little hydrogen bonding. The available (NOE) information was used with molecular dynamics calculations to construct a dominant solution conformation for each isomer of the tripeptide. This information will serve as a model for the design of peptide and nonpeptide inhibitors of the chemoattractant.

Alkalies↗
PubMed2001

Automatic assignment of NOESY cross peaks and determination of the protein structure of a new world scorpion neurotoxin using NOAH/DIAMOD.

The 3D NMR structures of the scorpion neurotoxin, CsE-v5, were determined from the same NOESY spectra with NOAH/DIAMOD, an automated assignment and 3D structure calculation software package, and with a conventional manual assignment combined with a distance geometry/simulated annealing (X-PLOR) refinement method. The NOESY assignments and the 3D structures obtained from the two independent methods were compared in detail. The NOAH/DIAMOD program suite uses feedback filtering and self-correcting distance geometry methods to automatically assign NOESY spectra and to calculate the 3D structure of a protein. NOESY cross peaks were automatically picked using a standard software package and combined with 74 manually assigned NOESY peaks to start the NOAH/DIAMOD calculations. After 63 NOAH/DIAMOD cycles, using REDAC procedures in the last 8 cycles, and final FANTOM constrained energy minimization, a bundle of 20 structures with the smallest target functions has a RMSD of 0.81 A for backbone atoms and 1.11 A for all heavy atoms to the mean structure. Despite some missing chemical shifts of side chain protons, 776 (including 74 manually assigned) of 1130 NOE peaks were unambiguously assigned, 150 peaks have more than one possible assignment compatible with the bundle structures, and only 30 peaks could not be assigned within the given chemical shift tolerance ranges in either the D1 or the D2 dimension. The remaining 174, mainly weak NOE peaks were not compatible with the final 20 best bundle structures at the last NOAH/DIAMOD cycle. The automatically determined structures agree well with the structures determined independently using the conventional method and the same NMR spectra, with the mean RMSD in well-defined regions of 0.84 A for bb and 1.48 A for all heavy atoms from residues 2-5, 18-26, 32-36, and 39-45. This study demonstrates the potential of the NOAH/DIAMOD program suite to automatically assign NMR data for proteins and determine their structure.

Amino Acids↗
PubMed2001

Potential role of mental practice using motor imagery in neurologic rehabilitation.

For many patients with damage to the central nervous system (CNS), execution of motor tasks is very difficult, sometimes impossible, even after early participation in an active rehabilitation program. Several investigators have recently proposed that mental practice could be used by these patients as a therapeutic tool to improve their performance of motor functions, yet very little empirical work addresses this issue directly. This article discusses the rationale for investigating mental practice as a means of promoting motor recovery in patients with a neurologic disorder. We first present evidence supporting the existence of a similarity between executed and imagined actions using data from psychophysical, neurophysiologic, and brain imaging studies. This parallel is then extended to the repetition of movements during physical and mental practice of a motor skill. Finally, a new model is proposed to emphasize the key role of motor imagery as an essential process of mental practice, and also to stimulate additional research on this type of training in the rehabilitation of patients with motor impairments of cerebral origin.

Brain↗
PubMed2000

De novo design of peptides targeted to the EF hands of calmodulin.

This report describes the use of the concept of inversion of hydropathy patterns to the de novo design of peptides targeted to a predetermined site on a protein. Eight- and 12-residue peptides were constructed with the EF hands or Ca(2+)-coordinating sites of calmodulin as their anticipated points of interaction. These peptides, but not unrelated peptides nor those with the same amino acid composition but a scrambled sequence, interacted with the two carboxyl-terminal Ca(2+)-binding sites of calmodulin as well as the EF hands of troponin C. The interactions resulted in a conformational change whereby the 8-mer peptide-calmodulin complex could activate phosphodiesterase in the absence of Ca(2+). In contrast, the 12-mer peptide-calmodulin complex did not activate phosphodiesterase but rather inhibited activation by Ca(2+). This inhibition could be overcome by high levels of Ca(2+). Thus, it would appear that the aforementioned concept can be used to make peptide agonists and antagonists that are targeted to predetermined sites on proteins such as calmodulin.

Amino Acid Sequence↗
PubMed1999

Chlorination and nitration of soy isoflavones.

Diets enriched in soy foods containing a high concentration of isoflavonoids are associated with a decrease in the incidence of several chronic inflammatory diseases. Studies with experimental models of diseases, such as atherosclerosis, suggest that these effects can be ascribed to the biological properties of the isoflavones. Since the isoflavones and tyrosine have structural similarities and modifications to tyrosine by inflammatory oxidants such as hypochlorous acid (HOCl) and peroxynitrite (ONOO(-)) have been recently recognized, we hypothesized that the isoflavones also react with HOCl and ONOO(-). Using an in vitro approach, we demonstrate in the present study that the isoflavones genistein, daidzein, and biochanin-A can be chlorinated and nitrated by these oxidants. These reactions were investigated using high-performance liquid chromatography, mass spectrometry, and nuclear magnetic resonance. In the reaction with HOCl, both mono- and dichlorinated derivatives of genistein and biochanin-A are formed, whereas with daidzein only a monochlorinated derivative was detected. The reaction between genistein or daidzein and ONOO(-) yielded a mononitrated product. However, no nitrated product was detected with biochanin-A. Furthermore, the reaction between genistein and sodium nitrite and HOCl yielded a chloronitrogenistein derivative, as well as a dichloronitrogenistein derivative. These results indicate that the ability of the isoflavones to react with these oxidant species depends on their structure and suggest that they could be formed under conditions where these reactive species are generated under pathological conditions.

Chromatography, High Pressure Liquid↗
PubMed1999

Solution structure of a beta-neurotoxin from the New World scorpion Centruroides sculpturatus Ewing.

We report the detailed solution structure of the 7.2 kDa protein CsE-I, a beta-neurotoxin from the New World scorpion Centruroides sculpturatus Ewing. This toxin binds to sodium channels, but unlike the alpha-neurotoxins, shifts the voltage of activation toward more negative potentials causing the membrane to fire spontaneously. Sequence-specific proton NMR assignments were made using 600 MHz 2D-NMR data. Distance geometry and dynamical simulated annealing refinements were performed using experimental distance and torsion angle constraints from NOESY and pH-COSY data. A family of 40 structures without constraint violations was generated, and an energy-minimized average structure was computed. The backbone conformation of the CsE-I toxin shows similar secondary structural features as the prototypical alpha-neurotoxin, CsE-v3, and is characterized by a short 2(1/2)-turn alpha-helix and a 3-strand antiparallel beta-sheet, both held together by disulfide bridges. The RMSD for the backbone atoms between CsE-I and CsE-v3 is 1.48 A. Despite this similarity in the overall backbone folding, the these two proteins show some important differences in the primary structure (sequence) and electrostatic potential surfaces. Our studies provide a basis for unravelling the role of these differences in relation to the known differences in the receptor sites on the voltage sensitive sodium channel for the alpha- and beta-neurotoxins.

Amino Acid Sequence↗
PubMed1999

The effectiveness of the Canadian Quality Daily Physical Education program on school physical education.

The effectiveness of the Canadian Quality Daily Physical Education (QDPE) program in creating awareness, support, and influencing school based physical education programs was determined using quantitative and qualitative methodologies. Participants included teachers, principals and vice principals, school board officials and trustees, professional agencies and association, and provincial ministry of education officials. Findings showed this national initiative increased awareness and support of QDPE among all participants. Although the influence of this increased awareness and support on school physical education programming was limited, the greatest impact was in time committed to instruction, development of curricula, instruction of classes, delivery of intramural programs, professional development, and student response to physical education. The least impact was on hiring of physical education specialists, the number of staff, and funding for physical education.

Adult↗
PubMed1995

A hybrid-hybrid matrix method for 3D NOE-NOE data analysis.

A hybrid-hybrid matrix method is described that quantitatively analyzes 3D NOE-NOE NMR data. Experimental 3D data are merged with simulated 3D data to create a hybrid 3D NOE-NOE spectrum. This is then deconvoluted into a 2D hybrid NOESY spectrum. The deconvoluted, 2D hybrid NOESY spectrum can then be merged with other 2D NOESY experimental data along with additional simulated 2D data as necessary to create a hybrid-hybrid 2D NOE volume matrix. This hybrid-hybrid volume matrix is then used with the complete relaxation program, MORASS, to calculate a rate matrix, and the resulting distances taken from the off-diagonal cross-relaxation rates can then be utilized in a distance geometry or restrained molecular-dynamics refinement of the structure. This process is repeated until a satisfactory agreement between the calculated and observed 3D volumes is obtained. This hybrid-hybrid matrix method retains computational efficiency and utilizes the resolution of the 3D data set while retaining any information content of the available 2D data. The initial tests of the deconvolution algorithm give high correlation results even with the introduction of random error into the 3D data set. Our results suggest that the hybrid-hybrid matrix method for analysis of 3D NOE-NOE spectra may provide a viable tool in the refinement of large molecules.

Algorithms↗
PubMed1990

Perceived self-esteem among children diagnosed with precocious puberty.

Self-esteem is known to be altered in children with chronic illness. Do accelerated normal changes, such as those that occur in children with precocious puberty, also alter the child's self-esteem? Twenty-eight children with precocious puberty participated in a nonrandomized descriptive pilot study using a structured interview, the Piers-Harris Children's Self-Concept Scale, and self-portrait drawings. Results indicate that the overall self-esteem of the majority of children was within normal limits as measured by the Piers-Harris Children's Self-Concept Scale, but closer analysis found that many of the children had difficulty with peer relationships and increased levels of anxiety. These findings were supported by the results of the structured interview and the children's self-portraits. Nursing implications from this pilot study are discussed.

Adolescent↗
PubMed1989

Precocious puberty: identifying early sexual development.

Primary care providers should have the ability to identify normal and abnormal variations of sexual development in children. The incidence of precocious puberty is approximately one child in every 10,000 children in the United States. While etiologies vary, precise differential diagnosis is essential because it will determine the course of treatment required. New forms of therapy using long-acting luteinizing releasing factor agonists are currently being investigated. Developmentally appropriate explanations for affected children regarding the diagnosis and treatment plan are a crucial component of care. Ongoing educational and emotional support for the child and family are essential as they learn to cope with early sexual development.

Adolescent↗
PubMed1983

Physical characteristics of the lips underlying vowel lipreading performance.

To evaluate the relationship between physical characteristics of the lips during vowel production and vowel lipreading confusions, four female talkers were videotaped producing 15 American English vowels and diphthongs in an /h/-V-/g/ context. Ten normal-hearing adults identified the stimuli through lipreading. Three analyses were performed. First, using confusion matrices for individual and pooled talkers, the stimuli were located in a two-dimensional space using multidimensional scaling. The ten monophthongs revealed a clear lip spreading/rounding dimension and a tongue height dimension, and while diphthongs also showed influence of lip rounding, more variability on the tongue height dimension was apparent. Second, tracings were made of the talkers' lips on a single videotape field representing the maximum opening or constriction for each of the 40 monophthong tokens (ten vowels X four talkers), and six physical measurements of the tokens were derived as descriptors of the vowel nuclei. Third, difference scores and other measures of physical pairwise similarity were used as predictors of two ways of representing the vowel lipreading confusions in a multiple regression paradigm. Results indicated that the physical measures were moderately successful as predictors of vowel perception (accounting for approximately 50% of the variance in the perceptual distance measure), although considerable differences in the strength of the prediction occurred among talkers.

Lip↗