Pregnancy rates of day 4 and day 5 embryos after culture in an integrated time-lapse incubator

Background: The aim of this study was to compare pregnancy rates in patients undergoing IVF/ICSI with embryo transfer after 4 and 5 days of culture in a closed incubation system with integrated time-lapse imaging. Methods: Out of n = 2207 in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) cycles performed between January 2011 and April 2016 at a tertiary referral university hospital, a total of n = 599 IVF/ICSI cycles with prolonged embryo culture in an integrated time-lapse system (EmbryoScope© (Vitrolife)) until day 4 or 5 were retrospectively analyzed with regard to embryo morphology and pregnancy rates. Results: A transfer on day 5 compared to a transfer on day 4 did not result in higher implantation and clinical pregnancy rates (IR 29.4% on day 4 versus 33.0% on day 5, p = 0.310; CPR 45.2% on day 4 versus 45.7% on day 5, p = 1.0). The percentage of ideal embryos transferred on day 4 was comparable to the rate of ideal embryos transferred on day 5 (41.6% versus 44.1%, p = 0.508). However, on day 4 a significantly higher number of embryos was transferred (1.92 on day 4 versus 1.84 on day 5, p = 0.023), which did not result in higher rates of multiple pregnancies. Conclusions: Pregnancy rates in IVF/ICSI cycles with integrated time-lapse incubation and transfer on day 4 and 5 are comparable. This finding provides the clinician, IVF laboratory and patient with more flexibility. Trial registration: This study was retrospectively registered by the local ethics committee of the University of Heidelberg on December 19, 2016 (registration number S-649/2016)

Odorant receptor phylogeny confirms conserved channels for sex pheromone and host plant signals in tortricid moths

The search for mates and food is mediated by volatile chemicals. Insects sense food odorants and sex pheromones through odorant receptors (ORs) and pheromone receptors (PRs), which are expressed in olfactory sensory neurons. Molecular phylogenetics of ORs, informed by behavioral and functional data, generates sound hypotheses for the identification of semiochemicals driving olfactory behavior. Studying orthologous receptors and their ligands across taxa affords insights into the role of chemical communication in reproductive isolation and phylogenetic divergence. The female sex pheromone of green budworm mothHedya nubiferana(Lepidoptera, Totricidae) is a blend of two unsaturated acetates, only a blend of both elicits male attraction. Females produce in addition codlemone, which is the sex pheromone of another tortricid, codling mothCydia pomonella. Codlemone also attracts green budworm moth males. Concomitantly, green budworm and codling moth males are attracted to the host plant volatile pear ester. A congruent behavioral response to the same pheromone and plant volatile in two tortricid species suggests co-occurrence of dedicated olfactory channels. In codling moth, one PR is tuned to both compounds, the sex pheromone codlemone and the plant volatile pear ester. Our phylogenetic analysis finds that green budworm moth expresses an orthologous PR gene. Shared ancestry, and high levels of amino acid identity and sequence similarity, in codling and green budworm moth PRs offer an explanation for parallel attraction of both species to the same compounds. A conserved olfactory channel for a sex pheromone and a host plant volatile substantiates the alliance of social and habitat signals in insect chemical communication. Field attraction assays confirm that in silico investigations of ORs afford powerful predictions for an efficient identification of behavior-modifying semiochemicals, for an improved understanding of the mechanisms of host plant attraction in insect herbivores and for the further development of sustainable insect control

Engineering novel complement activity into a pulmonary surfactant protein

Complement neutralizes invading pathogens, stimulates inflammatory and adaptive immune responses, and targets non- or altered-self structures for clearance. In the classical and lectin activation pathways, it is initiated when complexes composed of separate recognition and activation subcomponents bind to a pathogen surface. Despite its apparent complexity, recognition-mediated activation has evolved independently in three separate protein families, C1q, mannose-binding lectins (MBLs), and serum ficolins. Although unrelated, all have bouquet-like architectures and associate with complement-specific serine proteases: MBLs and ficolins with MBL-associated serine protease-2 (MASP-2) and C1q with C1r and C1s. To examine the structural requirements for complement activation, we have created a number of novel recombinant rat MBLs in which the position and orientation of the MASP-binding sites have been changed. We have also engineered MASP binding into a pulmonary surfactant protein (SP-A), which has the same domain structure and architecture as MBL but lacks any intrinsic complement activity. The data reveal that complement activity is remarkably tolerant to changes in the size and orientation of the collagenous stalks of MBL, implying considerable rotational and conformational flexibility in unbound MBL. Furthermore, novel complement activity is introduced concurrently with MASP binding in SP-A but is uncontrolled and occurs even in the absence of a carbohydrate target. Thus, the active rather than the zymogen state is default in lectin·MASP complexes and must be inhibited through additional regions in circulating MBLs until triggered by pathogen recognition

Klimafittes Österreich 2035: Eine gemeinsame Vision

Das vom Klima- und Energiefonds geförderte Forschungsprojekt "Tales of Tomorrow" richtete sich an potenzielle politische Entscheidungstragende von morgen, die für den Übergang zu einer kohlenstoffarmen und klimaresilienten Gesellschaft verantwortlich sein werden. Die Mitglieder des interdisziplinären Forschungsteams der Universität für Bodenkultur, Wien und der Umweltbundesamt GmbH mit Unterstützung von Narrata Consult hielten es für wichtig, einen Visionsprozess früh in der politischen Karriere der Beteiligten und über die politischen Überzeugungen hinweg zu gestalten. Die Idee war, die Teilnehmenden mit Fakten der Klimawissenschaft zu versorgen und sie in eine Diskussion über gemeinsame Werte und Interessen einzubeziehen, die durch den Kontext international vereinbarter Ziele (wie z.B. die Sustainable Development Goals oder das Pariser Abkommen) vorgegeben werden. Nur so kann ein gemeinsamer Visionsprozess etabliert, eine parteiübergreifende Zusammenarbeit initialisiert und der politische Wille gestärkt werden. Meilensteine, die so wichtig wären, um den zukünftigen Herausforderungen der Klimakrise nachzukommen. Im Rahmen eines zweitätigen Zukunftsdialogs haben sich im September 2020 über 20 VertreterInnen verschiedener politischer und zivilgesellschaftlicher Organisationen an der Universität für Bodenkultur in Wien getroffen, um eine klimafitte Zukunftsvision 2035 für Österreich Wirklichkeit werden zu lassen. Die Zielgruppe waren dabei junge politische Entscheidungstragende im Alter von 18 bis 35 Jahren

Mutations in UBA3 Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924 in Human Leukemic Cells

The NEDD8-activating enzyme (NAE) initiates neddylation, the cascade of post-translational NEDD8 conjugation onto target proteins. MLN4924, a selective NAE inhibitor, has displayed preclinical anti-tumor activity in vitro and in vivo, and promising clinical activity has been reported in patients with refractory hematologic malignancies. Here, we sought to understand the mechanisms of resistance to MLN4924. K562 and U937 leukemia cells were exposed over a 6 month period to MLN4924 and populations of resistant cells (R-K562MLN, R-U937MLN) were selected. R-K562MLN and R-U937MLN cells contain I310N and Y352H mutations in the NAE catalytic subunit UBA3, respectively. Biochemical analyses indicate that these mutations increase the enzyme’s affinity for ATP while decreasing its affinity for NEDD8. These mutations effectively contribute to decreased MLN4924 potency in vitro while providing for sufficient NAE function for leukemia cell survival. Finally, R-K562MLN cells showed cross-resistance to other NAE-selective inhibitors, but remained sensitive to a pan-E1 (activating enzyme) inhibitor. Thus, our work provides insight into mechanisms of MLN4924 resistance to facilitate the development of more effective second-generation NAE inhibitors

Validación del Timed Up and Go Test como Predictor de Riesgo de Caídas en Sujetos con Artritis Reumatoidea

Introducción: los sujetos con Artritis Reumatoidea (AR) tienen un elevado riesgo de caídas respecto a la población sana. El Timed Up and Go test (TUG) es utilizado para predecir el riesgo de caídas, pero no ha sido validado en sujetos con AR. Objetivos: el objetivo primario fue establecer la validez predictiva y la validez concurrente a velocidad habitual y máxima segura en sujetos con diagnóstico de AR. El objetivo secundario fue establecer si el TUG tiene mayor valor predictivo evaluado a velocidad habitual o a velocidad máxima segura

Muscle Mitochondrial ATP Synthesis and Glucose Transport/Phosphorylation in Type 2 Diabetes

BACKGROUND: Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM). METHODS AND FINDINGS: We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with (31)P/(1)H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%–99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%–42%; older: 11%, 95% CI 2%–25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux. CONCLUSIONS: Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients

Directed adenovirus evolution using engineered mutator viral polymerases

Adenoviruses (Ads) are the most frequently used viruses for oncolytic and gene therapy purposes. Most Ad-based vectors have been generated through rational design. Although this led to significant vector improvements, it is often hampered by an insufficient understanding of Ad’s intricate functions and interactions. Here, to evade this issue, we adopted a novel, mutator Ad polymerase-based, ‘accelerated-evolution’ approach that can serve as general method to generate or optimize adenoviral vectors. First, we site specifically substituted Ad polymerase residues located in either the nucleotide binding pocket or the exonuclease domain. This yielded several polymerase mutants that, while fully supportive of viral replication, increased Ad’s intrinsic mutation rate. Mutator activities of these mutants were revealed by performing deep sequencing on pools of replicated viruses. The strongest identified mutators carried replacements of residues implicated in ssDNA binding at the exonuclease active site. Next, we exploited these mutators to generate the genetic diversity required for directed Ad evolution. Using this new forward genetics approach, we isolated viral mutants with improved cytolytic activity. These mutants revealed a common mutation in a splice acceptor site preceding the gene for the adenovirus death protein (ADP). Accordingly, the isolated viruses showed high and untimely expression of ADP, correlating with a severe deregulation of E3 transcript splicing