Peptidyl-prolyl cis-trans isomerases (immunophilins) and their roles in parasite biochemistry, host-parasite interaction and antiparasitic drug action.

Immunophilin is the collective name given to the cyclophilin and FK506-binding protein (FKBP) families. As the name suggests, these include the major binding proteins of certain immunosuppressive drugs: cyclophilins for the cyclic peptide cyclosporin A and FKBPs for the macrolactones FK506 and rapamycin. Both families, although dissimilar in sequence, possess peptidyl-prolyl <i>cis-trans</i> isomerase activity in vitro and can play roles in protein folding and transport, RNA splicing and the regulation of multiprotein complexes in cells. In addition to enzymic activity, many immunophilins act as molecular chaperones. This property may be conferred by the isomerase domain and/or by additional domains. Recent years have seen a great increase in the number of known immunophilin genes in parasitic protozoa and helminths and in many cases their products have been characterized biochemically and their temporal and spatial expression patterns have been examined. Some of these genes represent novel types: one example is a <i>Toxoplasma gondii</i> gene encoding a protein with both cyclophilin and FKBP domains. Likely roles in protein folding and oligomerisation, RNA splicing and sexual differentiation have been suggested for parasite immunophilins. In addition, unexpected roles in parasite virulence (Mip FKBP of <i>Trypanosoma cruzi</i>) and host immuno-modulation (e.g. 18-kDa cyclophilin of <i>Toxoplasma gondii</i>) have been established. Furthermore, in view of the potent antiparasitic activities of cyclosporins, macrolactones and nonimmunosuppressive derivatives of these compounds, immunophilins may mediate drug action and/or may themselves represent potential drug targets. Investigation of the mechanisms of action of these agents may lead to the design of potent and selective antimalarial and other antiparasitic drugs. This review discusses the properties of immunophilins in parasites and the 'animal model' <i>Caenorhabditis elegans</i> and relates these to our understanding of the roles of these proteins in cellular biochemistry, host-parasite interaction and the antiparasitic mechanisms of the drugs that bind to them

The energy transition in Europe: a vision of progress

Europe needs a new vision of progress. An energy transition has this potential. It can give the "European idea" a future-oriented content. The goal for 2050 is clear: a Europe without fossil and nuclear energy! This is not a utopia. Studies, resolutions of the EU and some member states prove that this vision is feasible and has many advantages: more jobs, more security of supply, fewer premature deaths due to air pollution, reduction of resource conflicts, falling energy costs. New green lead markets for renewable energies and resource efficiency are emerging. A European energy transition requires an alliance, ideally fuelled by neighbours France and Germany. Many are hoping for Germany as a driver of nuclear and coal phase-out. But deciding on "revolutionary goals" is not enough: finally implementing them is what Germany and Europe are waiting for. This report shows which concrete steps can advance this vision of progress

MEMS 411: Torsion Tester Design Report

The goal of this project is to provide the customer, Dr. James Jackson Potter, with a lightweight, inexpensive, and accurate alternative to modern, professional torsion-testing machines. The torsion tester developed by this team will be used in a classroom setting for design competitions on 3-D printed ABS plastic torsion bars; therefore the design also accommodate a range of functions which might be useful to the customer during testing competitions, potentially including automatic stopping at failure, a reset function, and the ability to create custom functions which can integrate into the existing function library

Bedeutung von Cytochrom-P450-Polymorphismen für Verlauf, Erfolg und Nebenwirkungen der Therapie mit Antidepressiva

Im Bereich der medikamentösen antidepressiven Therapie ist die Bedeutung von erblichen Polymorphismen arzneistoffmetabolisierender Enzyme bereits in vielen Studien untersucht und gezeigt worden. Die meisten Antidepressiva werden über polymorphe Cytochrom-P450-Enzyme verstoffwechselt. Diese Arbeit befasst sich mit der Fragestellung, ob die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Allele in der an Depression erkrankten Studienpopulation sich von der in der Normalbevölkerung unterscheidet und ob Veränderungen in der Pharmakokinetik, wie sie durch Cytochrom-P450-Polymorphismen verursacht werden, unter normalen klinischen Bedingungen Auswirkungen auf die Wirksamkeit der antidepressiven Therapie, die Nebenwirkungsrate und den Verlauf der Erkrankung haben. Im Rahmen dieser Arbeit wurden 334 Patienten auf die häufigsten CYP2D6-Allele (*3,*4,*5,*6 und Duplikation) und CYP2C19- und CYP2C9-Allele *2 und *3 mittels Genotypisierung untersucht. Die Bestimmung der seltener auftretender CYP2D6-Allele (*8,*9,*10,*17,*2 und *41) erfolgte zusätzlich bei 200 Patienten. Die entsprechenden klinischen Fragebögen mit Angaben zur Anamnese, Schwere der Erkrankung, Therapieverlauf und Nebenwirkungsprofil wurden von 233 Patienten in Abhängigkeit des CYP2D6- und CYP2C19-Genotyps ausgewertet. Für die Beurteilung des Langzeittherapieverlaufs standen jedoch deutlich weniger Patientendaten zur Verfügung, so dass die Ergebnisse zum Teil nur für den CYPD6-Genotyp ausgewertet werden konnten. Die genetischen Analysen ergaben, dass die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Polymorphismen in der untersuchten Studienpopulation keine signifikante Änderung im Vergleich zur Normalbevölkerung aufwies. Während der Einfluss der CYP2D6-Genotypen auf pharmakokinetische Parameter eindeutig nachgewiesen ist, konnten die Ergebnisse dieser Arbeit weitestgehend keinen Zusammenhang zwischen der Schwere der Depression, der Therapieresponse, der Häufigkeit und Schwere der Nebenwirkungen und dem CYP2D6- und CYP2C19-Genotyp herstellen.The importance of genetic polymorphisms of drug metablizing enzymes have been already investigated und proved in many studies before. Most of antidepressants are metabolized by cytochrome P450 enzymes. The aim of this study was to determine if there is a difference in the distribution of CYP2D6-, CYP2C19- and CYP2C9-allels in inpatients with major depression in comparison to the healthy population and if changes in the pharmacokinatic, created by cytochrome P450 polymorphisms, can be have effects on the efficacy of antidepressant therapy, rate of intolerable side effects and development of the depression. We examined 334 patients by genotyping for the most important CYP2D6-allels (*3,*4,*6,*5 und duplication) and the CYP2C19- and CYP2C9-allels *2 and *3. Further 200 patients were tested for the more infrequent CYP2D6-allels (*8,*9,*10,*17,*2 and *41). The corresponding clinical questionnaires containing informations about the anamnesis, severity of the desease, therapeutic outcome and intolerable side effects have been evaluated of 233 patients in dependence of the CYP2D6- and CYP2C19-genotype. There were significant less clinical datas for the evaluation of long term therapy response be available, so that the results could be partially only analysed for the CYP2D6-genotype. The genetic analysis detected that the distribution of the CYP2D6-, CYP2C19- and CYP2C9-polymorphismen in the study population didn´t reached significant changes in comparison to the healthy population. While the influence of CYP2D6-genotypes on pharmacokinatic parameters is clear demonstrated, the results of this study mainly couldn´t establish a relation between the severity of depression, therapeutic response, frequency and severity of side effects and the CYP2D6 and CYP2C19-genotype

ASME 2020 Design Challenge

Our project was to build a machine that would fulfill the requirements for the ASME 2020 design challenge, which was called, ”Building to the Sky.” The rules of the challenge were to build a machine that would take ordinary 8.5” x 11” sheets of paper and stack them into a tower. To accomplish this task, we decided to make our paper tower out of accordion-shaped folds that would be placed on top of each other, alternating in 90 degree orientations. Our device is divided into various sub-components, each which manipulate the paper in various ways. We first have a mechanism to cut the sheet of paper into two equal halves. Then, we have a conveyor mechanism which transports the paper. There is a press mechanism which folds the paper into the accordion pattern, and finally a ramp which assembles the paper into the final tower configuration. The cutting mechanism consists of a circular blade powered by an electric motor which both intakes the paper, and cuts it in half. We made our conveyor belt mechanism out of plastic wrap. This is also powered by an electric motor. The press consists of two saw-teeth presses which fold the paper through the downward motion of the upper press. One ramp comes after each of the two presses. One of the two ramps ejects the paper into a box, which holds the tower in place, and the other ramp spins the paper 90 degrees so that it can stack in alternating directions. Overall, our device was able to function successfully and we were able to meet all of the goals that we initially set for our device

Die Energiewende in Europa : eine Fortschrittsvision

Europa braucht eine neue Fortschrittsvision. Eine Energiewende hat dieses Potenzial. Sie kann der "Europäischen Idee" einen zukunftsorientierten Inhalt geben. Das Ziel für 2050 ist klar: ein Europa ohne fossile und nukleare Energie! Das ist keine Utopie. Studien, Beschlüsse der EU und einiger Mitgliedsländer belegen, dass diese Vision machbar und mit vielen Vorteilen verbunden ist: mehr Jobs, mehr Versorgungssicherheit, weniger vorzeitige Todesfälle durch Luftverschmutzung, Abbau von Ressourcenkonflikten, sinkende Energiekosten. Neue grüne Leitmärkte für erneuerbare Energien und Ressourceneffizienz entstehen. Eine europäische Energiewende erfordert eine Allianz, idealerweise angefeuert durch die Nachbarn Frankreich und Deutschland. Viele hoffen auf Deutschland als Treiber von Atom- und Kohleausstieg. Aber "revolutionäre Ziele" zu beschließen ist nicht genug: Sie endlich umzusetzen - darauf warten Deutschland und Europa. Dieses Buch zeigt, welche konkreten Schritte diese Fortschrittsvision voranbringen werden