Biomedical subjects

Martina Keller

Publications and source records attributed to Martina Keller.

4 recordsLinked to original sources

PubMed2006

Effects of expectation and caffeine on arousal, well-being, and reaction time.

The objective of this study is to determine the impact of expectation associated with placebo and caffeine ingestion. We used a three-armed, randomized, double-blind design. Two three-armed experiments varying instruction (true, false, control) investigated the role of expectations of changes in arousal (blood pressure, heart rate), subjective well-being, and reaction time (RT). In Experiment 1 (N = 45), decaffeinated coffee was administered, and expectations were produced in one group by making them believe they had ingested caffeinated coffee. In Experiment 2 (N = 45), caffeinated orange juice was given in both experimental groups, but only one was informed about the true content. In Experiment 1, a significant effect for subjective alertness was found in the placebo treatment compared to the control group. However, for RT and well-being no significant effects were found. In Experiment 2, no significant expectancy effects were found. Caffeine produced large effects for blood pressure in both treatments compared to the control group, but the effects were larger for the false information group. For subjective well-being (alertness, calmness), considerable but nonsignificant changes were found for correctly informed participants, indicating possible additivity of pharmacologic effect and expectations. The results tentatively indicate that placebo and expectancy effects primarily show through introspection.

Adolescent↗

PubMed2005

Thrombin inhibitors identified by computer-assisted multiparameter design.

Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin.

Antithrombins↗

PubMed2004

Seasonality of energetic functioning and production of reactive oxygen species by lugworm (Arenicola marina) mitochondria exposed to acute temperature changes.

The influence of seasonal and acute temperature changes on mitochondrial functions were studied in isolated mitochondria of the eurythermal lugworm Arenicola marina (Polychaeta), with special emphasis on the interdependence of membrane potential and radical production. Acclimatisation of lugworms to pre-spawning/summer conditions is associated with rising mitochondrial substrate oxidation rates, higher proton leakage rates, elevated membrane potentials, and increased production of reactive oxygen species (ROS) in isolated mitochondria, compared with mitochondria from winter animals. However, a high ROS production was compensated for by higher activities of the antioxidant enzymes catalase and superoxide dismutase, as well as lower mitochondrial densities in summer compared with winter animals. In summer animals, a higher sensitivity of the proton leakage rate to changes of membrane potential will confer better flexibility for metabolic regulation (mild uncoupling) in response to temperature change. These seasonal alterations in mitochondrial functions suggest modifications of energy metabolism in eurythermal and euryoxic organisms on intertidal mudflats during summer. In winter, low and less changeable temperatures in intertidal sedimentary environments permit higher respiratory efficiency at low aerobic metabolic rates and lower membrane potentials in A. marina mitochondria.

Acclimatization↗

PubMed2003

Directed evolution towards protease-resistant hirudin variants.

Hirudin, a thrombin-specific inhibitor, is efficiently digested and inactivated by proteases with pepsin- and chymotrypsin-like specificity. Using a combination of phage display selection and high-throughput screening methods, several variants of recombinant hirudin were generated. Only very few variants comprising amino acid substitutions in the amino-terminal domain (residues 1-5) and in the carboxyl-terminal tail (residues 49, 50, and/or 56, 57, 62-64) were identified that showed thrombin inhibition activities similar to those of the wild-type polypeptide. Analysis of protease susceptibility, however, revealed that mutations, which conferred protease resistance, simultaneously diminish thrombin inhibition activity. This is particularly apparent for substitutions in the region of residues 56-64, which forms a large number of electrostatic and hydrophobic interactions with thrombin in the crystal structure of the complex. Unlike wild-type hirudin, the variant comprising Pro(50)- ...-His(56)-Asp(57)- ...-Pro(62)-Pro(63)-His(64) is completely resistant to pepsin and chymotrypsin cleavage; however, this is at the expense of thrombin inhibition activity where there is a 100-fold increase in the IC50 value. The frequent replacement of wild-type amino acids by proline at major protease cleavage sites indicates that at least pepsin- and chymotrypsin-like enzymes may exhibit a (conformational) specificity concerning the P1 and P2 positions. On the basis of these results, proline substitutions appear to be a general strategy to design polypeptides that are not susceptible to digestion by a broader range of different proteases.

Amino Acid Sequence↗