Biomedical subjects

Richard H Smith

Publications and source records attributed to Richard H Smith.

11 recordsLinked to original sources

PubMed2007

Comprehending envy.

The authors reviewed the psychological research on envy. The authors examined definitional challenges associated with studying envy, such as the important distinction between envy proper (which contains hostile feelings) and benign envy (which is free of hostile feelings). The authors concluded that envy is reasonably defined as an unpleasant, often painful emotion characterized by feelings of inferiority, hostility, and resentment caused by an awareness of a desired attribute enjoyed by another person or group of persons. The authors examined questions such as why people envy, why envy contains hostile feelings, and why it has a tendency to transmute itself. Finally, the authors considered the role of envy in helping understand other research domains and discussed ways in which people cope with the emotion.

Affect↗

PubMed2006

Relativistic origins of emotional reactions to events happening to others and to ourselves.

The purpose of the present study was to show that people's emotional reactions to both good and bad events happening to others can be influenced by how their own experiences compare with these events. Female undergraduate students took a test of intellectual ability and received false feedback suggesting that they had done well or poorly. Later, they viewed written feedback apparently given to another participant suggesting that she had performed well or poorly. Finally, participants gave their emotional reactions to their own performance as well as the performance of the other participant. Results showed that participants' relative performance influenced how happy they felt for the high performing other participant and how sad they felt for the low performing other participant. Participants' self-focused emotions of pride and shame were also affected by the relative performance of the other participant.

Adolescent↗

PubMed2006

Assault on resistance: the use of computational chemistry in the development of anti-HIV drugs.

While many inhibitors of the Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immunodeficiency Syndrome (AIDS), have been developed, the problem of drug resistance has continued to plague the fight against the disease. The ability of computers to aid in the drug discovery process, and by default the resistance problem, has increased dramatically as the speed of computers and sophistication of associated calculation programs has grown. In particular, the capability of predicting a compound's ability to combat resistance prior to synthesis of drug candidates has proven particularly desirable. Since resistance can develop against a specific drug designed to inhibit only one stage of the viral cycle, combinations of drugs directed at more than one step have proven to be more effective than a single drug given alone. While the introduction of this combination therapy (termed highly active antiretroviral therapy (HAART)) has significantly decreased the death rate from HIV infections, resistance problems still arise. This paper will review previous approaches and address current and future computational strategies used in the design of second-generation and beyond drugs.

Anti-HIV Agents↗

PubMed2003

Molecular modeling calculations of HIV-1 reverse transcriptase nonnucleoside inhibitors: correlation of binding energy with biological activity for novel 2-aryl-substituted benzimidazole analogues.

The energies and physical descriptors for the binding of 20 novel 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole analogues (BPBIs) to HIV-1 reverse transcriptase (RT) have been determined using Monte Carlo (MC) simulations. The crystallographic structure of the lead compound, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole, was used as a starting point to model the inhibitors in both the bound and the unbound states. The energy terms and physical descriptors obtained from the calculations were correlated with their respective experimental EC(50) values, resulting in an r(2) value of 0.70 and a root-mean-square deviation (rms) of 0.53 kcal/mol. The terms in the correlation include the change in total Coulombic energy and solvent-accessible surface area. Structural analysis of the data files from the BPBI calculations reveals that all of the analogues with good biological activity show the formation of a hydrogen bond between the ligand and the backbone nitrogen atom of lysine 103. By use of the structural results, two novel BPBI inhibitors have been designed and calculations have been carried out. The results show the formation of the desired hydrogen bonds, and the DeltaG(binding) values predict the compounds to be excellent RT inhibitors. Subsequent synthesis and biological activity testing of these analogues have shown the validity of the predictive calculations. If the BPBIs are modeled in a site constructed from the crystal coordinates of a member of another class of nonnucleoside inhibitors (the 4,5,6,7-tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione and -one (TIBO) compounds), the correlation with the same terms drops slightly, giving an r(2) value of 0.61 with an associated root-mean-square value of 0.53 kcal/mol. Conversely, if the TIBO compounds are modeled in a site constructed from the BPBI complex crystal coordinates, a correlation can be obtained using the drug-protein interaction energy and change in the total number of hydrogen bonds, giving an r(2) value of 0.63. These are the same descriptors that were used for the TIBO compounds modeled in their own sites, where the r(2) value was 0.72. These data suggest that it may be possible, in some cases, to design novel inhibitors utilizing structural data from related, but not identical, inhibitors.

Benzimidazoles↗

PubMed2003

Serum-free production and column purification of adeno-associated virus type 5.

Viral vectors derived from adeno-associated virus (AAV) are rapidly becoming the vehicles of choice for gene therapy applications. AAV-2 is the adeno-associated virus serotype most commonly employed in AAV-mediated gene therapy studies; however, recently developed vectors derived from alternative serotypes of AAV, such as AAV-5, are receiving special attention due to their disparate tissue tropisms and potential for serial administration. In this report, we describe a rapid and efficient method for the serum-free production and column purification of recombinant AAV-5 particles. This method utilizes a combination of anion-exchange chromatography and gel filtration chromatography to purify recombinant AAV particles to near homogeneity. Importantly, viral particles are captured directly from cellular extracts with high efficiency, and vector purification is achieved in less than one working day with a minimal amount of sample manipulation. The method described in this report does not require partial purification by density centrifugation, detergent treatment, or solvent extraction to achieve efficient levels of column binding and vector purification.

Animals↗

PubMed2003

The roles of praise and social comparison information in the experience of pride.

The authors examined the roles of social comparisons, publicity of success, and praise on the experience of pride in an experiment in which college students successfully completed a timed intelligence task in private and later received 1 of 4 types of feedback from the experimenter: no feedback (private), mere public acknowledgment of completion, general praise containing both a public and an evaluative component, or praise containing explicit comparison information. Half of the participants also received written normative information suggesting they performed at a high level. Participants then completed a number of dependent measures, including a key measure of pride. Overall, results suggest that the public aspect of a performance, together with the superior standing suggested by any praise accompanying this publicity, is important in the experience of pride.

Achievement↗

PubMed2003

HIV-1 reverse transcriptase variants: molecular modeling of Y181C, V106A, L100I, and K103N mutations with nonnucleoside inhibitors using Monte Carlo simulations in combination with a linear response method.

The energies and physical descriptors for the binding of 21 novel 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole (BPBI) analogs to HIV-1 reverse transcriptase (RT) variants Y181C, L100I, V106A, and K103N have been determined using Monte Carlo (MC) simulations. The crystallographic structure of the lead compound, 4-methyl BPBI, was used as a starting point to model the inhibitors in both the mutant bound and the unbound states. The energy terms and physical descriptors obtained from the calculations were reasonably correlated with the respective experimental EC50 values for the inhibitors against the various mutant RTs. Using the linear response correlations from the calculations, 2 novel BPBI inhibitors have been designed and simulations have been carried out. The results show the computed deltaG(binding) values match the experimental data for the analogs. Given the ongoing problem with drug resistance, the ability to predict the activity of novel analogs against variants prior to synthesis is highly advantageous.

Algorithms↗

PubMed2002

Prediction of activity for nonnucleoside inhibitors with HIV-1 reverse transcriptase based on Monte Carlo simulations.

Results of Monte Carlo (MC) simulations for more than 200 nonnucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) representing eight diverse chemotypes have been correlated with their anti-HIV activities in an effort to establish simulation protocols and methods that can be used in the development of more effective drugs. Each inhibitor was modeled in a complex with the protein and by itself in water, and potentially useful descriptors of binding affinity were collected during the MC simulations. A viable regression equation was obtained for each data set using an extended linear response approach, which yielded r(2) values between 0.54 and 0.85 and an average unsigned error of only 0.50 kcal/mol. The most common descriptors confirm that a good geometrical match between the inhibitor and the protein is important and that the net loss of hydrogen bonds with the inhibitor upon binding is unfavorable. Other physically reasonable descriptors of binding are needed on a chemotype case-by-case basis. By including descriptors in common from the individual fits, combination regressions that include multiple data sets were also developed. This procedure led to a refined "master" regression for 210 NNRTIs with an r(2) of 0.60 and a cross-validated q(2) of 0.55. The computed activities show an rms error of 0.86 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. Encouraging results were obtained for the predictions of 27 NNRTIs, representing a new chemotype not included in the development of the regression model. Predictions for this test set using the master regression yielded a q(2) value of 0.51 and an average unsigned error of 0.67 kcal/mol. Finally, additional regression analysis reveals that use of ligand-only descriptors leads to models with much diminished predictive ability.

Alkynes↗

PubMed2002

Transposase-mediated construction of an integrated adeno-associated virus type 5 helper plasmid.

Adeno-associated viruses (AAVs) are replication-defective parvoviruses that require helper virusfunctionsfor efficient productive replication. The AAVs are currently premier candidates as vectors for human gene therapy applications. In particular; much recent interest has been expressed concerning recombinant AAV serotype 5 (rAAV-5) vectors, as they appear to utilize cellular receptors distinctfrom those of the prototypical AAV serotype (AAV-2) and have been reported to have transduction properties in vivo that differ significantly from those of the prototype. One of the most popular current methodsfor the production of rAAVs involves co-transfection of human 293 cells with three plasmids: (i) an adenovirus (Ad)-derived helper plasmid containing Ad genes required for AAV replication, (ii) an AAV-derived plasmid encoding complementing AAV genes (ie., the viral rep and cap genes), and (iii) a target plasmid containing a transgene of interestflanked by AAV inverted terminal repeats (ITRs) that confer packaging and replication capabilities upon the ITR-flanked heterologous DNA. Here we describe novel plasmid reagents designed for convenient and efficient production of rAAV-S. An integrated helper plasmid containing all Ad genes requiredfor the efficient production of recombinant AAV as well as the complementing AAV genes on the same plasmid backbone, was constructed via transposase-mediated insertion into an Ad helper plasmid of a transposable element containing the AAV-5 rep and cap genes linked to a selectable marker This simple strategy can be used in the rapid and efficient construction of integrated helper plasmids derived from any reported AAV serotype for which a molecular clone exists.

Animals↗

PubMed2002

The role of public exposure in moral and nonmoral shame and guilt.

Although scholarly traditions assume that shame results more from the public exposure of a transgression or incompetence than guilt does, this distinction has little empirical support. Four studies, using either undergraduate participants' responses to hypothetical scenarios, their remembered experiences, or the coding of literary passages, reexamined this issue. Supporting traditional claims, public exposure of both moral (transgressions) and nonmoral (incompetence) experiences was associated more with shame than with guilt. Shame was also more strongly linked with nonmoral experiences of inferiority, suggesting 2 core features of shame: its links with public exposure and with negative self-evaluation. The distinctive features of guilt included remorse, self-blame, and the private feelings associated with a troubled conscience.

Female↗

PubMedDate not supplied

Doppler echocardiographic assessment of left ventricular filling pressures in elderly patients with moderate/severe aortic stenosis.

Doppler-derived mitral inflow indices reflect left ventricular (LV) filling pressures but often vary with age. Diastolic filling is impaired in LV pressure overload states. The objective of this study was to determine the influence of age on the relationship between mitral inflow indices and LV filling pressures in patients with aortic stenosis. The authors studied 57 consecutive patients (age, 77 years; 52% male) with moderate to severe aortic stenosis (aortic valve area < or =1.0 cm(2)) on cardiac catheterization and echocardiographic studies performed within 48 hours of catheterization. Patients with atrial fibrillation, aortic insufficiency, mitral stenosis, and paced rhythm were excluded. Echocardiographic variables obtained from five cardiac cycles were: E/A ratio and deceleration time (DT). Patients were subclassified by age (< and > or =75 years), ejection fraction ([EF] < and > or =50%), and coronary artery disease (CAD). Pulmonary capillary wedge pressure (PCWP) correlated with DT (r=-0.86; p=0.001) and with E/A (r=0.7; p=0.001) more strongly than did LV end-diastolic pressure. Age did not alter the relationship between DT and PCWP (r=-0.92; p=0.001 for < 75 years vs. r=-0.83; p=0.001 for > or =75 years). PCWP was predicted by the equation PCWP=-0.10DT+43, regardless of age. EF also had little influence on the correlation between PCWP and DT (r=-0.80; p=0.001 for EF < 50% vs. r=-0.94; p=0.001 for EF > or =50%). Similarly, there were no significant differences between the regression equations and correlations between the CAD and no-CAD groups: for CAD patients, PCWP=41.8-0.10DT; p < 0.0001; r=-0.84 (p < 0.0001). For no-CAD subjects, PCWP=46.2-0.12DT; p < 0.0001; r=20.92 (p < 0.0001). In patients with significant aortic stenosis, DT correlated strongly with PCWP but not with LV end-diastolic pressure. This relationship was independent of age, CAD, or EF.

Aged↗