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Biomedical subjects

J S Murray

Publications and source records attributed to J S Murray.

At least 19 recordsLinked to original sources
PubMed2006

Catalytic hydrodeoxygenation of methyl-substituted phenols: correlations of kinetic parameters with molecular properties.

The hydrodeoxygenation of methyl-substituted phenols was carried out in a flow microreactor at 300 degrees C and 2.85 MPa hydrogen pressure over a sulfided CoMo/Al(2)O(3) catalyst. The primary reaction products were methyl-substituted benzene, cyclohexene, cyclohexane, and H(2)O. Analysis of the results suggests that two independent reaction paths are operative, one leading to aromatics and the other to partially or completely hydrogenated cyclohexanes. The reaction data were analyzed using Langmuir-Hinshelwood kinetics to extract the values of the reactant-to-catalyst adsorption constant and of the rate constants characterizing the two reaction paths. The adsorption constant was found to be the same for both reactions, suggesting that a single catalytic site center is operative in both reactions. Ab initio electronic structure calculations were used to evaluate the electrostatic potentials and valence orbital ionization potentials for all of the substituted phenol reactants. Correlations were observed between (a) the adsorption constant and the two reaction rate constants measured for various methyl-substitutions and (b) certain moments of the electrostatic potentials and certain orbitals' ionization potentials of the isolated phenol molecules. On the basis of these correlations to intrinsic reactant-molecule properties, a reaction mechanism is proposed for each pathway, and it is suggested that the dependencies of adsorption and reaction rates upon methyl-group substitution are a result of the substituents' effects on the electrostatic potential and orbitals rather than geometric (steric) effects.

Journal Article↗
PubMed2002

Modeling alternative binding registers of a minimal immunogenic peptide on two class II major histocompatibility complex (MHC II) molecules predicts polarized T-cell receptor (TCR) contact positions.

Several major histocompatibility complex class II (MHC II) complexes with known minimal immunogenic peptides have now been solved by X-ray crystallography. Specificity pockets within the MHC II binding groove provide distinct peptide contacts that influence peptide conformation and define the binding register within different allelic MHC II molecules. Altering peptide ligands with respect to the residues that contact the T-cell receptor (TCR) can drastically change the nature of the ensuing immune response. Here, we provide an example of how MHC II (I-A) molecules may indirectly effect TCR contacts with a peptide and drive functionally distinct immune responses. We modeled the same immunogenic 12-amino acid peptide into the binding grooves of two allelic MHC II molecules linked to distinct cytokine responses against the peptide. Surprisingly, the favored conformation of the peptide in each molecule was distinct with respect to the exposure of the N- or C-terminus of the peptide above the MHC II binding groove. T-cell clones derived from each allelic MHC II genotype were found to be allele-restricted with respect to the recognition of these N- vs. C-terminal residues on the bound peptide. Taken together, these data suggest that MHC II alleles may influence T-cell functions by restricting TCR access to specific residues of the I-A-bound peptide. Thus, these data are of significance to diseases that display genetic linkage to specific MHC II alleles, e.g. type 1 diabetes and rheumatoid arthritis.

Alleles↗
PubMed2001

Comparison of quantum chemical parameters and Hammett constants in correlating pK(a) values of substituted anilines.

Historically, Hammett constants have been extremely effective in describing the influence of substituents on chemical reactivity and other physical and chemical properties, whereas variables derived from quantum chemical calculations have generally been less effective. Taking the experimental pK(a)s of substituted anilines as a representative physicochemical property, five ab initio quantum chemical indices are compared for effectiveness as one-parameter regression descriptors for pK(a). All of the tested descriptors performed well for a set of 19 mono-, 13 di-, and 4 trisubstituted anilines, and two performed somewhat better than the traditional Hammett sigma constants. Among the calculated quantities, the best representation of the aniline pK(a)s is produced by the minimum average local ionization energy on the molecular surface.

Journal Article↗
PubMed2000

Conducting psychosocial research with children and adolescents: a developmental perspective.

In the past 10 years, childhood has become a focal point of concern. Children are viewed as symbolizing an investment in the future of societies around the world. In the past, knowledge about children's views was realized through objective measures or from representative accounts by adults (e.g., parents and teachers) who were thought to know the child best. Current research suggests that most adult representations and interpretations are only attempts to describe something that more or less represents the child's world. The literature suggests that in the past, children have been perceived mainly as objects rather than subjects of research interest. This perhaps reflects the viewpoint held by many that children are unable to comprehend and describe their world and life experiences because of developmental immaturity and/or that there are intrinsic difficulties in researching children. The purpose of this article is to describe how a child's developmental level affects the research process. Specifically discussed are developmental differences in responses to research including psychosocial research methods, assent, and consent with children.

Adolescent↗
PubMed2000

A concept analysis of social support as experienced by siblings of children with cancer.

Social support is a complex phenomenon. The concept is variably defined by multiple disciplines. This article analyzes the concept of social support by using the methods outlined in the nursing literature. The concept analysis focuses on psychosocial support of siblings of children with cancer. Each step in the concept analysis is presented to show the relevance of the concept with siblings of children with cancer.

Adolescent↗
PubMed2000

Attachment theory and adjustment difficulties in siblings of children with cancer.

The demands of the childhood cancer experience on children and their parents has been investigated for a number of years. Despite this research, very little emphasis has been placed on well siblings. In the health care profession today, there is a growing perception that the psychosocial needs of the healthy siblings of children with cancer are less sufficiently met than those of other members of the family system. Previous research proposes that well siblings are especially susceptible to a number of adjustment difficulties (such as depression, anger, anxiety, feelings of guilt, and social isolation) (Murray, 1999). Given these findings, the question arises as to whether the adjustment difficulties seen in siblings are a result of the loss of, or separation from, the attachment figure--the mother who is busy caring for the child with cancer. The purpose of this article is to use attachment theory as a conceptual framework to try to understand the effects of the childhood cancer experience on siblings. Recent findings regarding siblings of children with cancer and some speculations regarding clinical implications are provided.

Adaptation, Psychological↗
PubMed2000

Development of two instruments measuring social support for siblings of children with cancer.

The literature on childhood cancer provides a very limited understanding of healthy siblings' perceptions of supportive interventions during the childhood cancer experience. The purpose of this article is to discuss the development of the Nurse-Sibling Social Support Questionnaire (NSSSQ). Instrument methodology for the study involved item development, face and content validation, and internal consistency reliability as described by Hockenberry-Eaton, Manteuffel, and Bottomley (1997). Item development for the research instrument evolved from an extensive review of the literature and clinical experience of the principal investigator. Content validity of the instrument was accomplished by five experienced pediatric oncology nurses according to the methodology described by Lynn (1986). Using the content validity index, each nurse rated each item as either 4 or 5, indicating 100% agreement among experts that these items measured the concept of social support. Readability for the instrument was determined by using a computerized program. Results showed that readability was concordant with the grade school level for all items. Twenty-five school-age siblings of children with cancer and their mothers were asked to complete the questionnaire. Instrument completion was accomplished in less than 1 hour. The NSSSQ showed high internal consistencies (alpha coefficients >.90). Results indicated that siblings' perceptions of social support differed from those of their mothers. Siblings perceive emotional and instrumental support as greater in importance, whereas mothers perceive emotional and informational support as more beneficial to siblings. Support issues for siblings of children with cancer have been difficult to assess because of the lack of appropriate instruments. This study finding provides exploratory evidence to suggest that the new instrument can help measure siblings' perceptions of social support during the childhood cancer experience.

Adolescent↗
PubMed2000

The role of resistance testing in clinical trial design and product labelling: a regulatory perspective.

Assays that attempt to characterize HIV susceptibility or resistance are among the latest technologies that are likely to impact HIV clinical trial design, antiretroviral drug development and patient management. However, at present the Food and Drug Administration (FDA) have yet to approve any phenotypic or genotypic HIV resistance assay and the role of resistance testing in clinical management of patients and in drug development is ill defined. In November 1999, the Division of Antiviral Drug Products at the FDA convened a meeting of its advisory committee to consider the available information about HIV resistance testing, and to generate some recommendations about how these assays could be utilized in antiretroviral drug development. In addition, the committee was presented with several hypothetical regulatory scenarios in order to illustrate how HIV resistance testing might be incorporated in antiretroviral drug development and drug labelling. In this article, we discuss the regulatory history of resistance testing in antimicrobial drug development, the current use of resistance testing for antiretrovirals, as well as a summary of the hypothetical scenarios that were presented to the committee and the discussion of the committee members regarding those scenarios.

Anti-HIV Agents↗
PubMed1999

The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs.

OBJECTIVES: To evaluate the utility of HIV RNA as an endpoint in antiretroviral efficacy studies. DESIGN: Data collected from antiretroviral efficacy trials were analyzed to explore relationships between clinical progression and the magnitude, nadir and duration of HIV RNA reductions. The proportion of patients suppressing HIV RNA below assay quantification, time to maximal virologic response, and loss of virologic response in relation to pretreatment characteristics were also analyzed. METHODS: Analyses were conducted using data from individual antiretoviral efficacy trials or groups of trials that studied similar types of drug regimens and used similar HIV RNA assays. Treatment regimens were pooled for most analyses. Clinical progression was defined as the occurrence of an AIDS-defining event (essentially Centers of Disease Control criteria) or death. RESULTS: Treatment-induced reductions in HIV RNA approximating total assay variability of about 0.5 log10 copies/ml were associated with decreases in the risk of clinical progression. Larger and more sustained reductions in HIV RNA were directly associated with lower risks for disease progression. Lower initial HIV RNA reductions were associated with more durable HIV RNA suppression. CONCLUSIONS: For antiretoviral efficacy studies, plasma HIV RNA is a suitable study endpoint that is likely to predict a decreased risk for AIDS progression and death. Because greater and more sustained reductions in HIV RNA appear to confer greater reductions in clinical risk, maintaining maximal suppression of plasma HIV RNA, particularly below the limits of assay quantification, appears to be a rigorous benchmark for assessing the efficacy of antiretroviral regimens.

Anti-HIV Agents↗
PubMed1999

Siblings of children with cancer: a review of the literature.

Research on siblings of children with cancer during the past 40 years has clearly shown that the childhood cancer experience is a stressor that may increase subjective feelings of stress by well siblings and in some cases lead to decreased psychosocial competencies and increased psychopathologies. Research has expanded from identifying psychosocial problems experienced by the sibling after the patient's death to identifying stressors during the illness experience. More recent studies have been targeted at identifying what action siblings take to cope with the stressors imposed since the cancer diagnosis and have addressed what interventions pediatric oncology nurses use in clinical practice to provide support to siblings of children with cancer. The current state of this body of literature, a review of 18 studies, is presented in this article along with a critique of the research studies and suggestions for future research.

Adaptation, Psychological↗
PubMed1999

Methodological triangulation in a study of social support for siblings of children with cancer.

Triangulation is an approach to research that is becoming increasingly popular among nurse researchers. Five types of triangulation are used in nursing research: data, methodological, theoretical, researcher, and analytical triangulation. Methodological triangulation is an attempt to improve validity by combining various techniques in one study. In this article, an example of quantitative and qualitative triangulation is discussed to illustrate the procedures used and the results achieved. The secondary data used as an example are from a previous study that was conducted by the researcher and investigated nursing interventions used by pediatric oncology nurses to provide social support to siblings of children with cancer. Results show that methodological triangulation was beneficial in this study for three reasons. First, the careful comparison of quantitative and qualitative data added support for the social support variables under investigation. Second, the comparison showed more in-depth dimensions about pediatric oncology nurses providing social support to siblings of children with cancer. Finally, the use of methodological triangulation provided insight into revisions for the quantitative instrument.

Child↗
PubMed1998

How the MHC selects Th1/Th2 immunity.

While the effects of cytokines on T helper 1 (Th1)/Th2 differentiation are well documented, it is less clear why a dichotomy of effector cytokine production would initiate from antigen-specific lymphocytes. Nevertheless, in defined experimental systems, the interaction between T-cell receptor (TCR), peptide and major histocompatibility complex (MHC) can determine Th1/Th2 dominance. Here, Joseph Murray discusses how TCR affinity and ligand density might interface with innate forces in the selection of CD4+ T-cell functions.

Animals↗
PubMed1996

MHC genotype controls the capacity of ligand density to switch T helper (Th)-1/Th-2 priming in vivo.

A quantitative mechanism for the differentiation of CD4 T cells into recognized subsets of Th1 and Th2 effectors is controversial. Here, we define the Ag dose more precisely to the density of a minimal immunogenic peptide presented on the surface of a specific APC type. Th1 and Th2 responder MHC genotypes differ by as much as an order of magnitude in the density of this peptide displayed on B7-2+ B cells. We asked whether such B cells presenting a low ligand density primed Th2 effectors in an MHC genotype with predisposed high-density presentation and Th1-type immunity, and whether high ligand density B cells primed Th1 effectors in an MHC genotype that normally presents a low density and the Th2 phenotype. While low ligand density had the capacity to switch phenotype in the Th1 responder, high-density presentation did not alter genetically determined Th2 responder status.

Animals↗
PubMed1996

Unique T cell antagonist properties of the exact self-correlate of a peptide antigen revealed by self-substitution of non-self-positions in the peptide sequence.

The role of self-peptides in shaping the T cell receptor (TCR) repertoire remains to be established. While TCR reactive to certain self-peptides are thought to be depleted in the thymus, the selection of TCR specificity for foreign peptide reactivity appears to require recognition of self-peptide(s) bound to the groove of thymic major histocompatibility complex (MHC) molecules. This dichotomy suggests that different TCR affinities, accessory signals, and/or different sets of self-peptides dictate the eventual fate of any given TCR-bearing clone. Recently, it has been established for several T cell epitopes that derivatives with substitutions in TCR-contact residues can antagonize the proliferation of T cell clones against the wild-type peptide antigen. Moreover, these altered peptide ligands have demonstrated activity in the positive selection of thymocytes with TCR reactive to the wild-type peptide antigen. We have investigated the specificity of T cell antagonism with step-wise substitution of self-amino acids into each nonconserved position of a 12-amino-acid foreign peptide antigen. Our data demonstrate that the ability to antagonize proliferation without competition for MHC binding is unique to the exact self-derivative, where all five of the self-substitutions are inserted. These properties may specifically allow certain self-peptides to downregulate T cell activation to the foreign ligand and/or provide a source of stimulation for immunologic memory.

Amino Acid Sequence↗
PubMed1995

Isolation, characterization and expression of the gene that encodes D-arabinitol dehydrogenase in Candida tropicalis.

The gene (ARD) that encodes NAD-dependent D-arabinitol dehydrogenase (ArDH) in the pathogenic fungus Candida tropicalis (Ct) was cloned by transforming Escherichia coli (Ec) BW31M (araCc) with a plasmid library of Ct genomic DNA and selecting for D-arabinitol-utilizing (D-arab+) clones. Plasmid DNA from a D-arab+ clone retransformed fresh Ec BW31M cells to D-arab+; these cells produced both ArDH catalytic activity and a 31-kDa protein recognized by antibodies to native Ct ArDH. The plasmid contained an 846-bp open reading frame (ORF) that encoded a deduced protein of 282 amino acids (aa) (30,748 Da). Four partial aa sequences from Ct ArDH were present in the deduced aa sequence, thus verifying that Ct ARD had been cloned. Ct ArDH was 95% identical to ArDH from Candida albicans (Ca), 85% identical to a xylitol dehydrogenase (XDH) from Pichia stipitis (Ps) and 20-25% identical to many other short-chain dehydrogenases. Ct ArDH, Ca ArDH and Ps XDH were typical short-chain dehydrogenases except that they lacked an N-terminal Gly that is conserved in other members of this family. Thus, these enzymes may represent a subclass of closely-related fungal pentitol dehydrogenases. Large amounts of recombinant ArDH (re-ArDH) were produced in Ec and purified by dye ligand affinity chromatography. The physical and catalytic properties of re-ArDH were similar to those of native Ct ArDH, and re-ArDH and native ArDH performed similarly in an automated enzymatic assay for D-arabinitol in human serum.

Amino Acid Sequence↗
PubMed1995

High-density presentation of an immunodominant minimal peptide on B cells is MHC-linked to Th1-like immunity.

Ligand-directed differences in the amount of peptide presented on a specific APC subset could influence the functional outcome of any given immune response. We have investigated this issue with a biochemically determined immunodominant peptide that is presented at a higher density on the APC of Th1 responders (I-As genotypes) than on the APC of Th2 responders (I-Ab genotypes). MHC-linked high peptide density is expressed on B lymphocytes, predominantly those that bear the B7-2 activation marker/costimulatory ligand. We further investigated the role of I-As-specific polymorphism with transfected cells bearing an R-->Q change at position-70 of A beta (found only in the I-As allele). Strikingly, I-Ab-restricted Th1 and Th2 clones proliferate at a peptide dose 10- to 100-fold lower than wild-type on transfected fibroblasts bearing this single s-like substitution in A beta b. Moreover, the shift in the clone dose response is sensitive to the peptide's C-terminus, as is MHC-linked Th1-like immunity to this peptide in vivo. Together, these data suggest that ligand-density can dictate Th1/Th2 selection via a single MHC polymorphism that determines the level of peptide presented to a given TCR on activated B cells.

Amino Acid Sequence↗