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Biomedical subjects

D L Harris

Publications and source records attributed to D L Harris.

At least 19 recordsLinked to original sources

Mechanistic stoichiometry of mitochondrial oxidative phosphorylation.

P/O ratios of rat liver mitochondria were measured with particular attention to systematic errors. Corrections for energy loss during oxidative phosphorylation were made by measurement of respiration as a function of mitochondrial membrane potential. The corrected values were close to 1, 0.5, and 1 at the three coupling sites, respectively. These values are consistent with recent measurements of mitochondrial proton transport.

Adenosine Diphosphate

Binding of peptides to proteins: an exercise in molecular design.

Peptides coupled to solid supports were systematically tested for binding activity with a polyreactive immunoglobulin light chain dimer by the methods of Geysen and colleagues. Once identified, peptides of progressively increasing affinity for the dimer were synthesized in milligram quantities and diffused into crystals of the protein. The three-dimensional structures of the peptide-protein complexes were determined by X-ray analysis and crystallographic refinement. Criteria for the design of ligands to fill the binding cavity in incremental stages could be formulated from the combined results of peptide scanning and crystallographic analyses. Histidine proved to be an important substituent in the binding series. It was possible to manipulate the properties of this amino acid residue to alter the structures and binding patterns of the ligands. For example, if two beta-alanine residues were added to the carboxyl end of a tetrapeptide ligand, the terminal carboxyl group formed an intramolecular ion pair with the imidazolium group (N-3) of histidine. This interaction was accompanied by cleavage of the intra molecular hydrogen bond between N-1 of histidine and the amide group of a glutamine side chain. The shape of the ligand shifted from a compact to an extended form and the mode of binding changed from a lock-and-key to an induced-fit type. The direction of entry of dipeptides of histidine and proline into the binding cavity (normally amino end first) could be reversed (carboxyl end first) by protonation of the histidine ring.

Amino Acid Sequence

Computer simulation model of swine production systems: I. Modeling the growth of young pigs.

Theoretical concepts and relationships were used to develop a deterministic pig growth model. The model predicts, in a continuous form, growth and body composition of boars, barrows, and gilts according to genotype, diet, and management conditions. The model is aggregated at the whole-animal level with three main elements of body composition; total body DNA, total body protein mass (PT), and total body mass of lipids, with PT determining the secondary elements of ash and moisture. The primary factors regulating growth were associated with cellular hyperplasia and hypertrophy in agreement with the basic concepts described by Baldwin and Black (1979). Differential equations representing DNA accretion and protein synthesis and degradation were adapted from Oltjen et al. (1985). Normal pig protein growth was characterized from published data. Body PT was used to reflect several metabolic activities related to animal size and age, as in some prior models. Dietary energy and protein were used in sequence until requirements are satisfied, first for maintenance, then for protein growth, and finally for fat deposition. A comparison between experimental and simulated results illustrates that the model may simulate growth and body composition of young pigs adequately.

Animals

Computer simulation model of swine production systems: II. Modeling body composition and weight of female pigs, fetal development, milk production, and growth of suckling pigs.

Theoretical concepts and relationships used to develop a deterministic computer simulation model of female pigs during their reproductive life are described. The model predicts, in a continuous form, body composition and weight of female pigs, fetal development, sow milk yield, and growth of suckling pigs according to genotype, diet, and management conditions. The model simulates growth of adult female pigs. Dietary nutrients are used first for maintenance and second for fetal growth or milk production. Any surplus is retained in the body. Energy and protein body reserves are mobilized when a nutrient deficit occurs during gestation or lactation. However, the rates of body protein and fat accretion as well as the fat/protein ratio are limited by boundaries, the values of which depend on the nutritional and physiological status of the pig. The model's ability to simulate sow body weight changes and composition, fetal growth, milk production, and suckling pig's growth is illustrated.

Animals

Computer simulation model of swine production systems: III. A dynamic herd simulation model including reproduction.

A dynamic herd simulation model for a swine production unit has been developed. The model is discrete and stochastic and the appropriate random distributions have been defined from the literature or empirically estimated. Theoretical concepts and relationships presented previously are used to simulate growth and the overall life cycle of individual animals. Simulated animals are young pigs (from birth to slaughter age), gilts, and sows. Animal events are farrowing, weaning, mating, end-nursery (transfer from nursery to the growing-finishing facility), and slaughter and are processed individually using a next-event scheduling orientation package. Animals within the herd are culled for different health and reproductive reasons. Genetic parameters, diet composition, and herd management are input variables chosen by the user. The effects of nutrition, genetics, season, and other factors on several reproductive parameters are considered. Model evaluation is performed by studying the output of the model under specified herd situations. The herd model adequately simulates animal flow and dynamics of the herd.

Animal Nutritional Physiological Phenomena

Genetic improvement programs in livestock: swine testing and genetic evaluation system (stages).

Genetic evaluations for the U.S. swine industry are conducted by the eight purebred associations of the National Association of Swine Records. Within-herd evaluations of the growth traits (days to 105 kg [market] and backfat depth) were first reported in 1986. Analyses of the maternal traits (litter size at birth and weaning, and litter 21-d weight) were inaugurated in 1987. Expected progeny differences (EPD) are reported for all traits and for general, paternal, and maternal bioeconomic indexes. A sow productivity index combining only maternal traits is available. All records are adjusted according to National Swine Improvement Federation (NSIF) guidelines for effects such as number of pigs transferred at crossfostering and age at recorded observation prior to the BLUP evaluation. Within-herd analyses of individual contemporary groups are conducted immediately on receipt of performance records at each breed association office. All parents in the herd and the young pigs in the current group are evaluated. A report is returned to the breeder for use in herd selection and the EPD are placed in the pedigree file. The genetic base of each herd is defined as the first n tested pigs or litters, where n is the number of pigs registered annually within the herd. Change in mean EPD between groups is indicative of genetic trend. Periodic across-herd analyses are used to update interim within-herd analyses and a national sire summary is published.

Animals

The current and future need for minority medical faculty.

Little progress has been made in increasing the number of minority faculty members at US medical schools. From 1975 through 1989, underrepresented minority medical faculty increased only 0.3%--from 2.7% to 3.0%. In the field of medicine in general, only 3% of physicians are African-American and 3% are Hispanic, while the African-American and Hispanic populations are approximately 12% and 7%, respectively, of the total US population. A number of factors have caused the persistent underrepresentation of minority health professions trainees: inadequate or inappropriate career counseling, admissions policies, relatively high attrition rates after matriculation, substantial costs of education, and lack of appropriate mentors and role models. Helping minority students overcome these obstacles requires providing them with appropriate information, preparation, motivation, and opportunities at all stages of the educational process. Attention must focus on recruiting minority students into the scientific, academic professions if an increase is to occur in numbers of underrepresented minorities in all specialties of medicine. The Health Resources and Services Administration and private foundations have committed to providing funds to educational institutions to help encourage minority students to pursue academic careers. Leadership at these institutions must also commit to increasing the numbers of underrepresented minority faculty and senior administrators.

Ethnicity

AIDS awareness among rural Utah physicians.

Studies of physicians' attitudes and knowledge of the acquired immunodeficiency syndrome (AIDS) and the clinical precautions they take against exposure to the human immunodeficiency virus (HIV) have focused on urban physicians. To determine rural physicians' knowledge and attitudes about AIDS, a questionnaire was mailed to 321 physicians practicing in rural Utah. Of the 169 physicians who completed questionnaires, 96% thought that their community or area of service had only a minor or no problem with AIDS; 89%, however, thought that their chance of seeing a patient who was HIV-positive was fair to moderate. Of the 169 respondents, 3% were not sure whether they would even treat a patient who had AIDS, 67% said they would, and 30% said they would not. Although all physicians are at risk of seeing a patient who has had exposure to HIV and other blood-borne diseases such as hepatitis B, only 55% of the respondents felt a need to take clinical precautions to prevent their exposure to the virus. Our study shows the need for all rural Utah physicians to reevaluate their risk of exposure to HIV, to increase precautionary measures for their own protection, to consider the ethical responsibility of treating AIDS patients, and to take a more active role in teaching their patients how to protect themselves from exposure to the virus.

Acquired Immunodeficiency Syndrome

Photophysics of tryptophan in bacteriophage T4 lysozymes.

Bacteriophage T4 lysozyme contains three tryptophan residues in distinct environments. Lysozymes with one or two of these residues replaced by tyrosine are used to characterize the photophysics of tryptophan in these individual sites. The fluorescence spectra, average lifetimes, and quantum yields of these three single-tryptophan variants are understandable in terms of the neighboring residues. The emission spectra and radiative lifetimes are found to be the same for all three species while the quantum yield and decay kinetics are quite distinct. The variation of the average nonradiative rate constant is correlated with neighboring quenching groups. Quenching by I- correlates with exposure of the tryptophan residue based on the crystal structure. Complex behavior is observed for the time dependence of the fluorescence decay in all three cases, including that of the immobile tryptophan-138 residue. The complexity of the fluorescence decay is ascribed to heterogeneity in the nonradiative rate constant among microstates. Energy transfer between tryptophan residues is inferred to occur from comparison of the quantum yields of the two-tryptophan and single-tryptophan proteins and is discussed in terms of the Förster mechanism.

Muramidase

Outcome of pregnancies experienced during residency.

To investigate potential adverse effects of residency training on pregnancy outcome, a cohort study was conducted among 45 university-affiliated residency programs. Outcomes of the first pregnancy experienced during residency were compared between 92 female residents and 144 spouses of male residents. Despite long hours, sleep deprivation, and an increase in perceived stress, the female residents were as likely to give birth to a live, full-term newborn as the spouses of male residents. For white cohort members, an increased risk of premature labor without delivery was identified (RR = 12.3, 95% confidence interval 2.4-61.6). No significant differences were found in prematurity, spontaneous and therapeutic abortions, or presence of congenital abnormalities in the infants. Method of delivery and use of anesthetics and of other medications were similar in both groups. Pregnancy outcomes between the two groups were similar; however, the increased risk for premature labor among female residents is a cause for concern and should be further investigated.

Adult

Synthetic site-directed ligands.

Complexes of nucleotides, peptides and aromatic hapten-like compounds with immunoglobulin fragments were studied by X-ray analysis. After tri- or hexanucleotides of deoxythymidylate were diffused into triclinic crystals of a Fab (BV04-01) with specificity for single-stranded DNA, extensive changes were detected throughout the structure of the protein. The Fab co-crystallized with a tri- or pentanucleotide in a different space group (monoclinic), an observation sometimes correlated with alterations in the structure of the 'native' protein. Structural analyses of the co-crystals are in progress for direct comparisons with the unliganded Fab. In crystals of a human (Mcg) Bence-Jones dimer, synthetic opioid peptides, chemotactic peptides or dinitrophenyl (DNP) derivatives could be diffused into a large conical binding cavity. The conformations of both the ligand and the protein were usually altered during the binding process. At the base of the cavity tyrosine residues could be displaced like trap-doors to permit entry of some opioid peptides and DNP compounds into a deep binding pocket. In co-crystals of the dimer and bis(DNP)lysine, two ligand molecules were bound in tandem, one in the main cavity and the second in the deep pocket. One ligand adopted an extended conformation, with the epsilon-DNP ring near the floor of the main cavity and the alpha-DNP group in solvent outside the binding site. There were no significant conformational changes in the protein. In contrast, the second ligand was very compact, with DNP rings immersed in the deep pocket, and the binding site was expanded to accommodate the oversized ligand. Peptides designed to be specific for the main cavity were incrementally constructed from minimal binding units by M. Geysen, G. Trippick, S. Rodda and their colleagues. A pentapeptide optimized for binding by this method was diffused into a crystal of the dimer and found by Fourier difference analysis to lodge exclusively in the main cavity as predicted. Binding regions in the BV04-01 Fab and the Mcg dimer were markedly different in size and shape. The Fab had a groove-type site, in which a layer of sidechains acted like a false floor over regions analogous to the cavity and deep pocket of the Bence-Jones dimer.

Antibodies, Monoclonal

One-stage repair of hypospadias using split preputial flaps (Harris). The first 100 patients treated.

An analysis is presented of the outcome in the first 100 patients treated by a new technique for the repair of hypospadias and congenital short urethra associated with chordee. Further reconstructive surgery was required in 24 patients. The effect of the position of the meatus, the length of the reconstructed urethra and the method of urinary drainage are analysed. Minor complications are described. A significantly higher complication rate was associated with a perurethral than with a suprapubic catheter; 5 of the 38 patients in whom a suprapubic catheter was used developed complications requiring reconstructive surgery. Possible causes of the complications are discussed and the results compared with those of other methods. It was concluded that this is a satisfactory method of repair for hypospadias associated with chordee.

Adult

Adapting best linear unbiased prediction (BLUP) for timely genetic evaluation: I. Progeny traits in a single contemporary group for each sex.

The first step of a procedure to partially circumvent the voluminous calculations with extremely large matrices for the usual algorithms for a BLUP (best linear unbiased prediction) approach is presented. This procedure, specific for a hierarchical portion of a model relevant to many animal breeding populations, is pertinent especially for polytocous species such as swine and poultry. For these, the occurrence of full-sib families makes the inclusion of dam effects in the model more necessary than in dairy or beef cattle models, where dam effects often are omitted. The formulas are derived for the hierarchical model for sires, dams within sires, individuals within full-sib family, and records within individuals, showing a relatively simple structure for such predictors. These formulas provide the basis for an alternative computing algorithm for obtaining evaluations having the statistical properties of best linear unbiased prediction. Formulas also are developed to approximate the prediction error variances for such models. Following this, the methodology for combining separate BLUP predictors, both error-independent and correlated, is developed.

Algorithms

Adapting best linear unbiased prediction (BLUP) for timely genetic evaluation: II. Progeny traits in multiple contemporary groups within a herd.

The second step of a procedure to partially circumvent the voluminous calculations for some BLUP (Best Linear Unbiased Prediction) computing algorithms for genetic evaluation is presented. In addition, the procedure allows timely evaluations of each contemporary group. This procedure is pertinent especially for polytocous species such as swine and poultry, for which the occurrence of full-sib families makes the inclusion of dam effects in the model necessary and tests are completed throughout the year. Formulas are developed for a model including sires, dams, individuals within full-sib families and records within individuals. This model has a fundamentally hierarchical structure but includes some cross-classification. The formulas for predictors combine information across contemporary groups within a herd and incorporate relationships between sires and(or) dams in that herd. Formulas to approximate prediction error variances also are developed.

Algorithms

Computer modeling of sheep reproduction: I. An algorithm for quantifying anestrous cycles in ewes.

An algorithm that mathematically describes annual estrous activity in ewes is given. The function fitted as the ordinate is similar to a normal distribution function related to date as the abscissa. The data used were collected from literature on different breeds and from different locations of the world; all studies had been specifically conducted to study estrous activity in ewes in these locations. Parameters estimated in an iterative procedure from the algorithm were length of time during which estrous cycles occurred (SA), a measure of asymmetry (SD), day of mid-estrous (DE), highest incidence of estrus (MX) and lowest incidence of estrus (MN), day of lowest incidence of estrus (DN) and day of mid-anestrous season (DA). Incidence of estrus is defined as the proportion of ewes exhibiting an active estrus. These parameters were estimated for several breeds and locations. The data, as collected, were inadequately cross-classified to allow for unconfounded estimation. However, analyses of fitted parameters that describe the curves gave quantitative results about the influences of breed of sheep, location, latitude and altitude and indicated which parameters were associated with these factors. Breeds differed significantly for SA, DE, MX and DA. Locations differed for DE, MX and DA. Latitude was associated with differences in DE, DN and DA with altitude also associated with differences in DE and DA. There were no significant effects on SD even though breeds differed sizably in SD.

Algorithms

Computer modeling of sheep reproduction: II. Accelerated reproduction in sheep.

A computer simulation program was written in SLAM (Simulation Language for Alternative Modeling) to simulate certain biological aspects involved in alternative systems of reproduction in sheep. Four fundamental lambing schemes, once a year, three times in 2 yr, twice a year and continuous schemes, along with modifications of these schemes, are simulated. Parameters of greatest effect in this simulation were the average spread of the estrous season (SA), the measure of asymmetry (SD) and the maximum proportion of ewes exhibiting estrus (MX). It was demonstrated that the greater the SA values (longer estrous seasons and shorter anestrous seasons), the more advantageous it was to breed frequently. The SD and MX parameters influenced to a lesser degree the lambing results obtained from these simulations. The relative merits of certain breeds and locations for out-of-season breeding were studied and evaluated for annual and seasonal fertility.

Algorithms