The influence of dipole moments on the mechanism of electron transfer through helical peptides

The life time of aromatic radical cations is limited by reactions like β-elimination, dimerization, and addition to the solvent. Here we show that the attachment of such a radical cation to the C-terminal end of an α-/3₁₀-helical peptide further reduces its life time by two orders of magnitude. For PPII-helical peptides, such an effect is only observed if the peptide contains an adjacent electron donor like tyrosine, which enables electron transfer (ET) through the peptide. In order to explain the special role of α-/3₁₀-helical peptides, it is assumed that the aromatic radical cation injects a positive charge into an adjacent amide group. This is in accord with quantum chemical calculations and electrochemical experiments in the literature showing a decrease in the amide redox potentials caused by the dipole moments of long α-/3₁₀-helical peptides. Rate measurements are in accord with a mechanism for a multi-step ET through α-/3₁₀-helical peptides that uses the amide groups or H-bonds as stepping stones

Rompiendo el techo de rendimiento del cultivo de arroz.

En 2012 se conformó un equipo de trabajo interinstitucional INIA-ACA-GMA con el fin de buscar respuestas a la preocupante tendencia a estabilización de los rendimientos nacionalesdel arroz, en el entorno de los 8 t/ha, que hacía presumir una aproximación al techo productivo. De esta iniciativa surgió un proyecto cofinanciado por ANII, INIA, GMA, COOPAR y ACA en el modelo de Alianza para la Innovación, que permitió desarrollar dos años de experimentos en campos de productores y un tercer año de validación de los resultados iniciales, en áreas comerciales manejadas por los propios productores. Al término de estos tres años de trabajo, se pudo comprobar que aún existe una brecha de rendimientos potenciales alcanzables a explorar por los productores uruguayos, a pesar de estar hoy entre los más altos del mundo. En un período en el cual el sector arrocero ha sufrido reducciones continuas de área sembrada por dificultades económicas asociadas a variables que en general no están al alcance del productor, éste es un mensaje fuerte y positivo, que sugiere que todavía hay espacio en los sistemas de producción para aplicar conocimientos y tecnologías de manejo que pueden contribuir a una mejora de los resultados productivos y los ingresos

Electron transfer in peptides: the influence of charged amino acids

International audienceThe ammonium group in the peptide shown leads to a tenfold increase of the electron‐transfer rate compared to that in a fully protected system. This is explained by Coulomb's law and the Marcus theory

Elektronentransfer in Peptiden: Bildung von Silbernanopartikeln

Einige Mikroorganismen zeigen anaerobe mineralische Respiration, bei der sie Metallionen zu Metallnanopartikeln reduzieren. Hierbei werden Peptide als Medium für den Elektronentransfer (ET) verwendet. Diese Reaktionsklasse wird anhand eines Modellpeptids und Silber als Metall diskutiert. Erstaunlicherweise können Silberionen, die von Peptiden mit Histidin als silberbindender Aminosäure und Tyrosin als photoinduziertem Elektronendonor gebunden sind, nicht unter ET-Bedingungen zu Ag-Nanopartikeln (AgNPs) reduziert werden, weil das Peptid die Aggregation von Ag- Atomen zu AgNPs verhindert. Nur in Gegenwart von Chloridionen, die zur Bildung von AgCl-Mikrokristallen führen, entstehen AgNPs. Diese Reaktion beginnt mit der Bildung von 100 nm großen Ag@AgCl-Peptid-Nanokompositen, die dann in 15 nm große AgNPs aufgebrochen werden. Diese kontrollierte Umwandlung von großen in kleinere Nanopartikeln kann detailliert in zeitaufgelösten UV/Vis-Spektren untersucht werden

Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2–25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2–24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3–4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76–95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30–400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. Blueprint Medicines