Isolation and amino acid sequence analysis of a 4,000-dalton dynorphin from porcine pituitary

A 4,000-dalton dynorphin was isolated from porcine pituitary. It has 32 amino acids (Mr = 3,986), with the previously described heptadecapeptide (now called dynorphin A) at its amino terminus and a related tridecapeptide, dynorphin B, at its carboxyl terminus. The two peptides are separated by the "processing signal" Lys-Arg

Chirale Ökonomie

A short introduction illustrates the concept of chiral economical syntheses and the advantages of the corresponding approaches. Using the total synthesis of emetine according to the work of Openshaw and Whittaker and the total synthesis of the steroid skeleton accomplished by Roche and Schering research teams the chiral economical aspects of these syntheses are presented and discussed

Identification of a New Chemical Class of Antimalarials

The increasing spread of drug-resistant malaria strains underscores the need for new antimalarial agents with novel modes of action (MOAs). Here, we describe a compound representative of a new class of antimalarials. This molecule, ACT-213615, potently inhibits in vitro erythrocytic growth of all tested Plasmodium falciparum strains, irrespective of their drug resistance properties, with half-maximal inhibitory concentration (IC50) values in the low single-digit nanomolar range. Like the clinically used artemisinins, the compound equally and very rapidly affects all 3 asexual erythrocytic parasite stages. In contrast, microarray studies suggest that the MOA of ACT-213615 is different from that of the artemisinins and other known antimalarials. ACT-213615 is orally bioavailable in mice, exhibits activity in the murine Plasmodium berghei model and efficacy comparable to that of the reference drug chloroquine in the recently established P. falciparum SCID mouse model. ACT-213615 represents a new class of potent antimalarials that merits further investigation for its clinical potentia

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Empowering Digital Democracy

This article examines the role of digital technology in enabling and enhancing democratic practices and forms of governance. It contributes to emerging debates on democratic innovations by proposing a novel theoretical account of decentralized participatory democracy. To develop our account, we draw on the experience of two EU-funded projects, D-CENT and DECODE, which produced innovative citizen participation platforms and digital public infrastructure. Bringing democratic theory into conversation with critical data studies and the new municipalism movement, we theorize how these projects advanced three political aims: organizing political communities to build collective power, empowering citizens through direct participation in decision making, and transforming political institutions. The article then analyzes the strengths and limitations of these projects to draw lessons for policy makers and practitioners for future digital democratic experiments

Trix und Robert Haussmann

Die Monografie Robert & Trix Haussmann eröffnet die Publikationsreihe STUDIOLO / Edition Patrick Frey, eine Kollaboration des Verlags mit dem Ausstellungsraum STUDIOLO. Die Kuratoren Fredi Fischli und Niels Olsen betreiben in einem Atelierhaus in Zürich ein vielfältiges Programm gegenwärtiger Kunstproduktion. Die Ausstellung The Log-O-Rhythmic Slide Rule im Frühjahr 2012 widmete sich dem Werk von Trix und Robert Haussmann und ist Ausgangspunkt für die folgende Publikation, die mit Bildern, Essays, Künstlerbeiträgen und einem Gespräch vertieften Einblick in das reiche Schaffen des Schweizer Architekten- und Designerpaars bietet. Trix und Robert Haussmann gehören zu den wichtigsten Architekten, Designern und Theoretikern in der Prägung und Ablösung der klassischen Moderne in der Schweiz. Ihr Lebenswerk umfasst derzeit rund 650 realisierte Projekte; in Zürich u.a. die Da-Capo-Bar, den neuen Hauptbahnhof, die Boutique Weinberg und die Kronenhallenbar. Das Jahr 1967 markiert mit ihrer Heirat und der Gründung des Büros Allgemeine Entwurfsanstalt den Beginn ihrer langjährigen gemeinsamen Tätigkeit, aus der Arbeiten hervorgegangen sind, die mit den Dogmen erstarrter Architekturpraktiken brechen. Neben Bauten und Möbeln entstand ein reiches theoretisches OEuvre, das in dieser Publikation erstmals präsentiert wird und die Grundlage für eine zukünftige Auseinandersetzung mit ihrem Werk schafft

SAFO, FRAGMENTO 2: TRADUÇÃO E COMENTÁRIO

Safo destaca-se entre os maiores poetas da Lírica Grega Arcaica. Neste artigo, apresentamos uma tradução do Fragmento 2 (Lobel-Page) de um poema seu e oferecemos informações sobre essa lírica, uma biografia resumida da poetisa e sua obra. Descrevemos também como o Fragmento 2 chegou até nós. Por derradeiro, incluímos o texto grego original e um comentário