Similar Risks – Different Results

Analyzing the Inconsistent Application of the Precautionary Principle in European GMO Authorizatio

Directed Evolution of an Artificial Imine Reductase

Artificial metalloenzymes, resulting from incorporation of a metal cofactor within a host protein, have received increasing attention in the last decade. The directed evolution is presented of an artificial transfer hydrogenase (ATHase) based on the biotin-streptavidin technology using a straightforward procedure allowing screening in cell-free extracts. Two streptavidin isoforms were yielded with improved catalytic activity and selectivity for the reduction of cyclic imines. The evolved ATHases were stable under biphasic catalytic conditions. The X-ray structure analysis reveals that introducing bulky residues within the active site results in flexibility changes of the cofactor, thus increasing exposure of the metal to the protein surface and leading to a reversal of enantioselectivity. This hypothesis was confirmed by a multiscale approach based mostly on molecular dynamics and protein-ligand dockings

Совершенствование конструкции плоскореза глубокорыхлителя КПГ-250 в условиях КФХ "Правда" Беловского района, Кемеровской области

Объектом исследования является плоскорежущая лапа глубокорыхлителя КПГ-250. Цель работы – повышение качества обработки почвы, с совершенствованием конструкции глубокорыхлителя КПГ-250. повышение эффективности уборки зерновых культур, с разработкой конструкции В процессе исследования проводились технологические и конструкторские расчеты В результате исследования предложены мероприятия по снижению уплотнения почвы, а также конструкторские решения по повышению эффективности обработки почвы культиватором КПГ-250.The object of the study is flat-cutting paw cultivator KPG-250. Purpose – to improve the quality of the soil, by improving the design of the chisel KPG-250. Improving the efficiency of cleaning of grain crops, with the development of the design. In the process of research was conducted technological and design calculations The study proposed measures to reduce soil compaction, and design solutions for improving the effectiveness of soil treatment with cultivator KPG-250

A regio- and stereoselective ω-transaminase/monoamine oxidase cascade for the synthesis of chiral 2,5-disubstituted pyrrolidines

Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one-pot ω-transaminase (TA)/monoamine oxidase (MAO-N) cascade process for the synthesis of chiral 2,5-disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio- and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks

Switching the cofactor specificity of an imine reductase

Chiral amines have proven to be powerful building blocks for defining new pharmaceutical and agrochemicals due to their high density of structural information. In this light, the reduction of prochiral C=N double bonds is a well-established route in synthetic chemistry due to the easy accessibility of imines from their ketone precursors with the asymmetric addition of hydrogen or a hydride as the key stereo-differentiating step. Recently, we have witnessed remarkable advances in the enzyme-catalyzed asymmetric reduction of imines by NADPH-dependent imine reductases (IREDs).[1,2] Imine reductases were presented that catalyze the asymmetric reduction of various imines and the chemo- and stereoselective reductive amination as a useful method for the preparation of amines derived from aldehydes and ketones.[3,4] Please click Additional Files below to see the full abstract

The Infrared Light Curve of SN 2011fe in M101 and the Distance to M101

We present near infra-red light curves of supernova (SN) 2011fe in M101, including 34 epochs in H band starting fourteen days before maximum brightness in the B-band. The light curve data were obtained with the WIYN High-Resolution Infrared Camera (WHIRC). When the data are calibrated using templates of other Type Ia SNe, we derive an apparent H-band magnitude at the epoch of B-band maximum of 10.85 \pm 0.04. This implies a distance modulus for M101 that ranges from 28.86 to 29.17 mag, depending on which absolute calibration for Type Ia SNe is used.Comment: 9 pages, 3 figures, emulateapj style, accepted for publication in The Astrophysical Journa

Genetic Etiology of Parkinson Disease Associated with Mutations in the SNCA, PARK2, PINK1, PARK7, and LRRK2 Genes: A Mutation Update

To date, molecular genetic analyses have identified over 500 distinct DNA variants in five disease genes associated with familial Parkinson disease; α-synuclein (SNCA), parkin (PARK2), PTEN-induced putative kinase 1 (PINK1), DJ-1 (PARK7), and Leucine-rich repeat kinase 2 (LRRK2). These genetic variants include ∼82% simple mutations and ∼18% copy number variations. Some mutation subtypes are likely underestimated because only few studies reported extensive mutation analyses of all five genes, by both exonic sequencing and dosage analyses. Here we present an update of all mutations published to date in the literature, systematically organized in a novel mutation database (http://www.molgen.ua.ac.be/PDmutDB). In addition, we address the biological relevance of putative pathogenic mutations. This review emphasizes the need for comprehensive genetic screening of Parkinson patients followed by an insightful study of the functional relevance of observed genetic variants. Moreover, while capturing existing data from the literature it became apparent that several of the five Parkinson genes were also contributing to the genetic etiology of other Lewy Body Diseases and Parkinson-plus syndromes, indicating that mutation screening is recommendable in these patient groups. Hum Mutat 31:763–780, 2010. © 2010 Wiley-Liss, Inc

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation