Variable Metric Random Pursuit

We consider unconstrained randomized optimization of smooth convex objective functions in the gradient-free setting. We analyze Random Pursuit (RP) algorithms with fixed (F-RP) and variable metric (V-RP). The algorithms only use zeroth-order information about the objective function and compute an approximate solution by repeated optimization over randomly chosen one-dimensional subspaces. The distribution of search directions is dictated by the chosen metric. Variable Metric RP uses novel variants of a randomized zeroth-order Hessian approximation scheme recently introduced by Leventhal and Lewis (D. Leventhal and A. S. Lewis., Optimization 60(3), 329--245, 2011). We here present (i) a refined analysis of the expected single step progress of RP algorithms and their global convergence on (strictly) convex functions and (ii) novel convergence bounds for V-RP on strongly convex functions. We also quantify how well the employed metric needs to match the local geometry of the function in order for the RP algorithms to converge with the best possible rate. Our theoretical results are accompanied by numerical experiments, comparing V-RP with the derivative-free schemes CMA-ES, Implicit Filtering, Nelder-Mead, NEWUOA, Pattern-Search and Nesterov's gradient-free algorithms.Comment: 42 pages, 6 figures, 15 tables, submitted to journal, Version 3: majorly revised second part, i.e. Section 5 and Appendi

Regulation of cargo transfer between ESCRT-0 and ESCRT-I complexes by flotillin-1 during endosomal sorting of ubiquitinated cargo

Ubiquitin-dependent sorting of membrane proteins in endosomes directs them to lysosomal degradation. In the case of receptors such as the epidermal growth factor receptor (EGFR), lysosomal degradation is important for the regulation of downstream signalling. Ubiquitinated proteins are recognised in endosomes by the endosomal sorting complexes required for transport (ESCRT) complexes, which sequentially interact with the ubiquitinated cargo. Although the role of each ESCRT complex in sorting is well established, it is not clear how the cargo is passed on from one ESCRT to the next. We here show that flotillin-1 is required for EGFR degradation, and that it interacts with the subunits of ESCRT-0 and -I complexes (hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and Tsg101). Flotillin-1 is required for cargo recognition and sorting by ESCRT-0/Hrs and for its interaction with Tsg101. In addition, flotillin-1 is also required for the sorting of human immunodeficiency virus 1 Gag polyprotein, which mimics ESCRT-0 complex during viral assembly. We propose that flotillin-1 functions in cargo transfer between ESCRT-0 and -I complexes

A system for production of defective interfering particles in the absence of infectious influenza A virus

<div><p>Influenza A virus (IAV) infection poses a serious health threat and novel antiviral strategies are needed. Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. The antiviral activity of DIPs is exerted by a DI genomic RNA segment that usually contains a large deletion and suppresses amplification of wt segments, potentially by competing for cellular and viral resources. DI-244 is a naturally occurring prototypic segment 1-derived DI RNA in which most of the PB2 open reading frame has been deleted and which is currently developed for antiviral therapy. At present, coinfection with wt virus is required for production of DI-244 particles which raises concerns regarding biosafety and may complicate interpretation of research results. Here, we show that cocultures of 293T and MDCK cell lines stably expressing codon optimized PB2 allow production of DI-244 particles solely from plasmids and in the absence of helper virus. Moreover, we demonstrate that infectivity of these particles can be quantified using MDCK-PB2 cells. Finally, we report that the DI-244 particles produced in this novel system exert potent antiviral activity against H1N1 and H3N2 IAV but not against the unrelated vesicular stomatitis virus. This is the first report of DIP production in the absence of infectious IAV and may spur efforts to develop DIPs for antiviral therapy.</p></div

Zircon U-Pb Geochronology from the Wakhan Corridor, NE Afghanistan

Abstract HKT-ISTP 201

Democratizing glacier data – maturity of worldwide datasets and future ambitions

The creation and curation of environmental data present numerous challenges and rewards. In this study, we reflect on the increasing amount of freely available glacier data (inventories and changes), as well as on related demands by data providers, data users, and data repositories in-between. The amount of glacier data has increased significantly over the last two decades as remote sensing techniques have improved and free data access is much more common. The portfolio of observed parameters has increased as well, which presents new challenges for international data centers, and fosters new expectations from users. We focus here on the service of the Global Terrestrial Network for Glaciers (GTN-G) as the central organization for standardized data on glacier distribution and change. Within GTN-G, different glacier datasets are consolidated under one umbrella, and the glaciological community supports this service by actively contributing their datasets and by providing strategic guidance via an Advisory Board. To assess each GTN-G dataset, we present a maturity matrix and summarize achievements, challenges, and ambitions. The challenges and ambitions in the democratization of glacier data are discussed in more detail, as they are key to providing an even better service for glacier data in the future. Most challenges can only be overcome in a financially secure setting for data services and with the help of international standardization as, for example, provided by the CoreTrustSeal. Therefore, dedicated financial support for and organizational long-term commitment to certified data repositories build the basis for the successful democratization of data. In the field of glacier data, this balancing act has so far been successfully achieved through joint collaboration between data repository institutions, data providers, and data users. However, we also note an unequal allotment of funds for data creation and projects using the data, and data curation. Considering the importance of glacier data to answering numerous key societal questions (from local and regional water availability to global sea-level rise), this imbalance needs to be adjusted. In order to guarantee the continuation and success of GTN-G in the future, regular evaluations are required and adaptation measures have to be implemented

Bottlenose dolphins (Tursiops truncatus) do also cast neutrophil extracellular traps against the apicomplexan parasite Neospora caninum

Neutrophil extracellular traps (NETs) are web-like structures composed of nuclear DNA decorated with histones and cytoplasmic peptides which antiparasitic properties have not previously been investigated in cetaceans. Polymorphonuclear neutrophils (PMN) were isolated from healthy bottlenose dolphins (Tursiops truncatus), and stimulated with Neospora caninum tachyzoites and the NETs-agonist zymosan. In vitro interactions of PMN with the tachyzoites resulted in rapid extrusion of NETs. For the demonstration and quantification of cetacean NETs, extracellular DNA was stained by using either Sytox Orange® or Pico Green®. Scanning electron microscopy (SEM) and fluorescence analyses demonstrated PMN-derived release of NETs upon exposure to tachyzoites of N. caninum. Co-localization studies of N. caninum induced cetacean NETs proved the presence of DNA adorned with histones (H1, H2A/H2B, H3, H4), neutrophil elastase (NE), myeloperoxidase (MPO) and pentraxin (PTX) confirming the molecular properties of mammalian NETosis. Dolphin-derived N. caninum-NETosis were efficiently suppressed by DNase I and diphenyleneiodonium (DPI) treatments. Our results indicate that cetacean-derived NETs represent an ancient, conserved and relevant defense effector mechanism of the host innate immune system against N. caninum and probably other related neozoan parasites circulating in the marine environment