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Biomedical subjects

R Hiller

Publications and source records attributed to R Hiller.

14 recordsLinked to original sources
PubMed1992

Induced peptide conformations in different antibody complexes: molecular modeling of the three-dimensional structure of peptide-antibody complexes using NMR-derived distance restraints.

Intramolecular interactions in bound cholera toxin peptide (CTP3) in three antibody complexes were studied by two-dimensional transferred NOE spectroscopy. These measurements together with previously recorded spectra that show intermolecular interactions in these complexes were used to obtain restraints on interproton distances in two of these complexes (TE32 and TE33). The NMR-derived distance restraints were used to dock the peptide into calculated models for the three-dimensional structure of the antibody combining site. It was found that TE32 and TE33 recognize a loop comprising the sequence VPGSQHID and a beta-turn formed by the sequence VPGS. The third antibody, TE34, recognizes a different epitope within the same peptide and a beta-turn formed by the sequence IDSQ. Neither of these two turns was observed in the free peptide. The formation of a beta-turn in the bound peptide gives a compact conformation that maximizes the contact with the antibody and that has greater conformational freedom than alpha-helix or beta-sheet secondary structure. A total of 15 antibody residues are involved in peptide contacts in the TE33 complex, and 73% of the contact area in the antibody combining site consists of the side chains of aromatic amino acids. A comparison of the NMR-derived models for CTP3 interacting with TE32 and TE33 with the previously derived model for TE34 reveals a relationship between amino acid sequence and combining site structure and function. (a) The three aromatic residues that interact with the peptide in TE32 and TE33 complexes, Tyr 32L, Tyr 32H, and Trp 50H, are invariant in all light chains sharing at least 65% identity with TE33 and TE32 and in all heavy chains sharing at least 75% identity with TE33. Although TE34 differs from TE32 and TE33 in its fine specificity, these aromatic residues are conserved in TE34 and interact with its antigen. Therefore, we conclude that the role of these three aromatic residues is to participate in nonspecific hydrophobic interactions with the antigen. (b) Residues 31, 31c, and 31e of CDR1 of the light chain interact with the antigen in all three antibodies that we have studied. The amino acids in these positions in TE34 differ from those in TE32 and TE33, and they are involved in specific polar interactions with the antigen. (c) CDR3 of the heavy chain varies considerably both in length and in sequence between TE34 and the two other anti-CTP3 antibodies. These changes modify the shape of the combining site and the hydrophobic and polar interactions of CDR3 with the peptide antigen.

Amino Acid Sequence↗
PubMed1992

Solution conformation of a peptide corresponding to the principal neutralizing determinant of HIV-1IIIB: a two-dimensional NMR study.

The 24 amino acid peptide RP135 corresponds in its amino acid sequence to the principal neutralizing determinant (PND) of the IIIB isolate of HIV-1. Although the sequence of the PND is highly variable, its central part, containing the sequence GPGR, is conserved in most HIV isolates. Using 2D NMR and CD spectroscopy, we have studied the conformation of RP135 and of two shorter versions: one (P547) that includes the GPGR sequence with the N-terminal part of the peptide and the other (P344) that includes GPGR and the C-terminal segment of RP135. In water, the C-terminal part of RP135 was found to exist in several transient turnlike conformations ("nascent helix"). A helical conformation was found to be stabilized by the addition of TFE. A transient turn was observed also in the GPGR sequence, both in water and in aqueous TFE solutions. While no nascent helix conformations could be observed in the N-terminal part of RP135 in water, a helical conformation was partially stabilized by the addition of TFE. The conformations of the two shorter versions of the peptide were similar to those of the corresponding parts of RP135, except that the transient turn in GPGR could not be detected in P547 dissolved in water. The turn in GPGR was previously predicted by Larosa et al. (1990) and was observed by Chandrasekhar et al. (1991) in the PND peptide of HIV-1MN (RP142), which shares only 56% identity with RP135. However, nascent helix conformations were not observed in aqueous solutions of RP142.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1990

Kinetic analysis of cooperative interactions induced by Mn2+ binding to the chloroplast H(+)-ATPase.

The kinetics of Mn2+ binding to three cooperatively interacting sites in chloroplast H(+)-ATPase (CF1) were measured by EPR following rapid mixing of the enzyme with MnCl2 with a time resolution of 8 ms. Mixing of the enzyme-bound Mn2+ with MgCl2 gave a measure of the rate of exchange. The data could be best fitted to a kinetic model assuming three sequential, positively cooperative binding sites. (1) In the latent CF1, the binding to all three sites had a similar on-rate constants of (1.1 +/- 0.04) X 10(4) M-1s-1. (2) Site segregation was found in the release of ions with off-rate constants of 0.69 +/- 0.04 s-1 for the first two and 0.055 +/- 0.003 s-1 for the third. (3) Addition of one ADP per CF1 caused a decrease in the off-rate constants to 0.31 +/- 0.02 and 0.033 +/- 0.008 s-1 for the first two and the third sites, respectively. (4) Heat activation of CF1 increased the on-rate constant to (4.2 +/- 0.92) X 10(4) M-1s-1 and the off-rate constants of the first two and the third site to 1.34 +/- 0.08 and 0.16 +/- 0.07 s-1, respectively. (5) The calculated thermodynamic dissociation constants were similar to those previously obtained from equilibrium binding studies. These findings were correlated to the rate constants obtained from studies of the catalysis and regulation of the H(+)-ATPase. The data support the suggestion that regulation induces sequential progress of catalysis through the three active sites of the enzyme.

Binding Sites↗
PubMed1989

Measurement error in assessing the size of posterior subcapsular cataracts from retroillumination photographs.

Twenty-six eyes with posterior subcapsular opacities of various sizes were photographed with the Neitz-Kawara Retroillumination camera. The outline of the opacity in a single photograph of each opacity was traced onto a transparent plastic overlay twice by two independent outliners. Two methods were used to estimate the area within the outlines of the opacities. In the first, a transparent overlay with a standard grid was used to count the number of boxes within the outlines. The second method used computer planimetry to estimate the area within the tracings. We estimated the measurement error associated with a single outlining of an opacity and the contribution of the measurement error to overall sample size requirements in studies comparing the mean areas of posterior subcapsular opacities. Variability in the measurement techniques contributed fewer than 20 additional subjects to overall sample size estimates, a small contribution to total sample size requirements in most studies. An outliner's inherent variability in outlining an opacity was a much larger contributor to the measurement error than was variability in assessing the area of the outline of the opacity. While within outliner variability was similar for the two persons outlining the opacities, there were systematic differences in the way the two traced the outlines. Variability from the use of separate photographs of the same opacity taken by different photographers was minimal.

Cataract↗
PubMed1988

Diabetic retinopathy and cardiovascular disease in type II diabetics. The Framingham Heart Study and the Framingham Eye Study.

Data from the Framingham Heart Study and the Framingham Eye Study were used to examine the association between diabetic retinopathy and the occurrence of cardiovascular events (coronary heart disease, intermittent claudication, congestive heart failure, and stroke). Among the 206 persons with Type II diabetes in the Framingham Eye Study, the odds ratios for diabetic retinopathy and cardiovascular disease were 14.3 (95% confidence interval (CI) = 2.7-101.9), 2.0 (95% CI = 0.5-8.1), and 0.3 (95% CI = 0.05-1.3) for ages 52-64, 65-74, and 75-85 years, respectively. The test for homogeneity indicated highly significant differences for the odds ratios across age groups. The associations were similar when sex, duration of diabetes, age at diagnosis of diabetes, and history of insulin treatment were accounted for by logistic regression. Our data suggest an association in younger diabetics between diabetic retinopathy, a small vessel complication of diabetes, and a group of cardiovascular events commonly thought to result from large vessel disease. The finding may merely indicate that diabetics with large vessel disease are also more likely to have small vessel disease. However, it is also consistent with the hypothesis, suggested by histologic data, that a more generalized microangiopathy affecting not only the eye but also organs such as the heart may play a role in the pathogenesis of cardiovascular disease in diabetics.

Age Factors↗
PubMed1985

Cooperativity among manganese-binding sites in the H+-ATPase of chloroplasts.

Coupling factor, isolated from lettuce chloroplasts, contained several binding sites for Mn2+ ions. Three of these sites showed strong cooperative interactions having a Hill coefficient of 2.9 +/- 0.20 and a Kd of 14.7 +/- 0.44 microM. Three additional non-interacting Mn2+-binding sites were found with a Kd of 46.7 +/- 2.3 microM. Chemical modification with naphthylglyoxal of 1 arginyl residue/chloroplast coupling factor 1, which inhibited ATPase activity, inhibited the cooperativity among the sites but did not prevent Mn2+ binding to the enzyme. It is suggested that the cooperative interaction among the Mn2+-binding sites is an expression of the interaction among the active sites of the enzyme which is required for catalysis.

Adenosine Triphosphate↗
PubMed1979

[Automatic regeneration of capillary dialysers].

First results of an automatically working regeneration apparatus for capillary dialysators in 200 dialyses allow the on an average tenfold use of the dialysator CDAK 4. In this case a reduction of the effective surface to 70% of the initial value must be taken into bargain. Pyrogenic reactions or bacterial contamination of the regenerated dialysators were not taken into consideration. This method is recommended as transitional solution up to the industrial production of cheap dialysators for a single use.

Kidneys, Artificial↗
PubMed1979

Prognosis for life in patients with diabetes: relation to severity of retinopathy.

In a group of 709 individuals with diabetes diagnosed prior to age 50 and followed for five to thirteen years a strong inverse relationship was demonstrated between the severity of the retinopathy at the initial visit and survival. Survival in patients with no retinopathy or with microaneurysms only was little different from that of the general population (five-year rate .99, SE .01). The five-year survival rate for patients with more severe nonproliferative retinopathy, characterized by the presence of hemorrhages and/or exudates, but without new vessels or vitreous hemorrhage (B2), was .81 (SE .04), and that for patients with proliferative retinopathy (PDR) was .56 (SE .03). After adjustment for age at diagnosis of diabetes, duration of diabetes and sex, the differences in survival between these three groups were highly statistically significant. Impairment of visual acuity was also shown to be inversely related to survival. The five-year survival rate for patients with visual acuity of 20/200 or worse in each eye was .42 (SE .05). In patients with B2 retinopathy there was a weak but statistically significant trend towards decreasing survival with increasing duration of diabetes. In patients with PDR survival decreased with increasing duration up to 20 years, but then improved for patients with 20 years or more of diabetes.

Adolescent↗
PubMed1977

Sunlight and cataract: an epidemiologic investigation.

Cataract prevalence data from two large U.S. sources were divided according to small geographic areas for which average annual sunlight hours were determined from a map prepared by the U.S. Weather Bureau. Several non-cataract disease controls were chosen from the same geographic locations (separately for each data set). It was found that the cataract-to-control ratios for persons aged 65 years or older were significantly larger in locations with large amounts of sunlight compared to those in locations with small amounts (P less than .05). Discussion of some possible biases in the data leads to the conclusion that the biases, if they exist, are probably not large. The authors believe, however, that more research should be done before the association between sunshine and cataract is considered established.

Aged↗
PubMed1976

Senile cataract extraction and diabetes.

A study of hospital discharge diagnoses from both national data and data from a local medical centre indicates that diabetes substantially increases the probability of cataract extraction at age 40-49, about doubles or triples the probability for age 50-69, and has little effect on risk at age 70 and over. Strengths and weaknesses of the data are discussed. Other reports, generally estimating a much stronger association between diabetes and probability of cataract extraction, at least at age 50 and above, are critically evaluated.

Adult↗
PubMed1975

Blindness from glaucoma.

We observed an overall ratio of 8:1 for nonwhite to white primary glaucoma blindness. Our fragmentary evidence suggested that the ratio of underlying disease, that is, nonblinding glaucoma or intraocular pressure differentials, may be closer to 2:1 than 8:1 as between nonwhites and whites. The remaining four fold differential can be explained by a combination of the following: more complete reporting for nonwhites, reporting for medical care later in the disease than whites, and poorer response to treatment for nonwhites compared to whites. The trend of new blindness from glaucoma for recent years was stationary in the United States, England, and Wales.

Adolescent↗