Align and Copy: UZH at SIGMORPHON 2017 Shared Task for Morphological Reinflection

This paper presents the submissions by the University of Zurich to the SIGMORPHON 2017 shared task on morphological reinflection. The task is to predict the inflected form given a lemma and a set of morpho-syntactic features. We focus on neural network approaches that can tackle the task in a limited-resource setting. As the transduction of the lemma into the inflected form is dominated by copying over lemma characters, we propose two recurrent neural network architectures with hard monotonic attention that are strong at copying and, yet, substantially different in how they achieve this. The first approach is an encoder-decoder model with a copy mechanism. The second approach is a neural state-transition system over a set of explicit edit actions, including a designated COPY action. We experiment with character alignment and find that naive, greedy alignment consistently produces strong results for some languages. Our best system combination is the overall winner of the SIGMORPHON 2017 Shared Task 1 without external resources. At a setting with 100 training samples, both our approaches, as ensembles of models, outperform the next best competitor.Comment: To appear in Proceedings of the 15th Annual SIGMORPHON Workshop on Computational Research in Phonetics, Phonology, and Morphology at CoNLL 201

A személyre szabott költségvetés – a felnőtt értelmileg akadályozott személyek társadalmi integrációjának egy eszköze

A felnőtt értelmileg akadályozott emberek számára bentlakást nyújtó intézményrendszer hazai átalakításának kapujában a lakók társadalmi integrációja kulcsfontosságú kérdés. A személyre szabott költségvetés Nyugat-Európában a szociálpolitika egy, már jól bevált eszköze. A személyre szabott költségvetés lényeges eleminek bemutatása után e szociálpolitikai eszköz történetét mutatja be a cikk. Németországi vizsgálatok is alátámasztják, hogy a személyre szabott költségvetés értelmileg akadályozott személyek esetén is alkalmazható. Ennek ellenére ma hazánkban a kitagolás során a személyre szabott költségvetés nem kap szerepet. Bevezetésének akadályait érintőlegesen tárgyaljuk

Mikroparticle and L-arginine Pathway Examinations in Stable and Exacerbated COPD Patients

Besides dr. Attila Kovács and dr. Viktor Vörös, dr. László Kovács inspired me to conduct research during my work in the Student Researchers' Society at university. I encountered patients' subjective complaints face-to-face for the first time during the treatment of chronic patients in his family physician's practice. My interest in chronic obstructive pulmonary disease was aroused by dr. Zoltán Balikó, who encouraged me to investigate COPD patients in the first years of my residency training. There has been many changes both in the management of COPD and in understanding the background of the disease in the 12 years that elapsed since then, but there are still many open issues remaining. In addition to the increase in the prevalence of COPD, the increase in the patient population and its ever more important role in the increasingly aging population, I have also witnessed individual human destinies and disease progressions in my professional career. Especially as the head of the Special Respiratory Care Unit of the Division of Pulmonology, I came in contact with the most severely ill COPD patients on a daily basis. Late dr. Tamás Magyarlaki encouraged me to investigate microparticles in this patient population and dr. Gitta Tőkés-Füzesi aided me in its practical implementation, while dr. Tihamér Molnár opened up my mind to the importance of NO pathways in diseases associated with chronic hypoxemia and inflammation. Therefore, with my research results I aim to contribute to the earliest possible screening of these patients, early recognition of their acute exacerbations, commencement of adequate therapy, and a better understanding of the patomechanisms of the disease. Nowadays, COPD is a leading cause of morbidity and mortality in developed countries. At a global level, COPD currently ranks between 4th and 6th places in the causes of death and is expected to be the third leading cause of death by 2020. This is caused by an increase in the environmental impacts damaging the respiratory system (mainly smoking), the aging population and improvement in the therapeutic outcomes in other major patient groups (e.g. cardiovascular patients). COPD constitutes a major social and economic burden due to its high prevalence and its chronic and progressive course. In the European Union, direct costs of respiratory diseases amount to 6 % of total healthcare costs, 56 % of which is allocated to the management of COPD. In the meantime, current pharmacotherapeutical options have a low efficacy on the progression of the disease, therefore prevention plays a major role in this patient population. Thus, in addition to markers used so far in clinical practice, it is important to determine new biomarkers, which aid in the assessment of factors involved in disease progression, in the early screening of patients at risk and in the follow-up of the individual course of the disease and the efficacy of the therapy

Genetic reconstitution of the human Adenovirus type 2 temperature-sensitive 1 mutant defective in endosomal escape

Human Adenoviruses infect the upper and lower respiratory tracts, the urinary and digestive tracts, lymphoid systems and heart, and give rise to epidemic conjunctivitis. More than 51 human serotypes have been identified to-date, and classified into 6 species A-F. The species C Adenoviruses Ad2 and Ad5 (Ad2/5) cause upper and lower respiratory disease, but how viral structure relates to the selection of particular infectious uptake pathways is not known. An adenovirus mutant, Ad2-ts1 had been isolated upon chemical mutagenesis in the past, and shown to have unprocessed capsid proteins. Ad2-ts1 fails to package the viral protease L3/p23, and Ad2-ts1 virions do not efficiently escape from endosomes. It had been suggested that the C22187T point mutation leading to the substitution of the conserved proline 137 to leucine (P137L) in the L3/p23 protease was at least in part responsible for this phenotype. To clarify if the C22187T mutation is necessary and sufficient for the Ad2-ts1 phenotype, we sequenced the genes encoding the structural proteins of Ad2-ts1, and confirmed that the Ad2-ts1 DNA carries the point mutation C22187T. Introduction of C22187T to the wild-type Ad2 genome in a bacterial artificial chromosome (Ad2-BAC) gave Ad2-BAC46 virions with the full Ad2-ts1 phenotype. Reversion of Ad2-BAC46 gave wild-type Ad2 particles indicating that P137L is necessary and sufficient for the Ad2-ts1 phenotype. The kinetics of Ad2-ts1 uptake into cells were comparable to Ad2 suggesting similar endocytic uptake mechanisms. Surprisingly, infectious Ad2 or Ad5 but not Ad2-ts1 uptake required CALM (clathrin assembly lymphoid myeloid protein), which controls clathrin-mediated endocytosis and membrane transport between endosomes and the trans-Golgi-network. The data show that no other mutations than P137L in the viral protease are necessary to give rise to particles that are defective in capsid processing and endosomal escape. This provides a basis for genetic analyses of distinct host requirements for Ad endocytosis and escape from endosomes

Ad 2.0: a novel recombineering platform for high-throughput generation of tailored adenoviruses

stranded DNA genome of 26-45 kb were broadly explored in basic virology, for vaccination purposes, for treatment of tumors based on oncolytic virotherapy, or simply as a tool for efficient gene transfer. However, the majority of recombinant adenoviral vectors (AdVs) is based on a small fraction of adenovirus types and their genetic modification. Recombineering techniques provide powerful tools for arbitrary engineering of recombinant DNA. Here, we adopted a seamless recombineering technology for high-throughput and arbitrary genetic engineering of recombinant adenoviral DNA molecules. Our cloning platform which also includes a novel recombination pipeline is based on bacterial artificial chromosomes (BACs). It enables generation of novel recombinant adenoviruses from different sources and switching between commonly used early generation AdVs and the last generation high-capacity AdVs lacking all viral coding sequences making them attractive candidates for clinical use. In combination with a novel recombination pipeline allowing cloning of AdVs containing large and complex transgenes and the possibility to generate arbitrary chimeric capsid-modified adenoviruses, these techniques allow generation of tailored AdVs with distinct features. Our technologies will pave the way toward broader applications of AdVs in molecular medicine including gene therapy and vaccination studies

A beta-herpesvirus with fluorescent capsids to study transport in living cells.

Fluorescent tagging of viral particles by genetic means enables the study of virus dynamics in living cells. However, the study of beta-herpesvirus entry and morphogenesis by this method is currently limited. This is due to the lack of replication competent, capsid-tagged fluorescent viruses. Here, we report on viable recombinant MCMVs carrying ectopic insertions of the small capsid protein (SCP) fused to fluorescent proteins (FPs). The FPs were inserted into an internal position which allowed the production of viable, fluorescently labeled cytomegaloviruses, which replicated with wild type kinetics in cell culture. Fluorescent particles were readily detectable by several methods. Moreover, in a spread assay, labeled capsids accumulated around the nucleus of the newly infected cells without any detectable viral gene expression suggesting normal entry and particle trafficking. These recombinants were used to record particle dynamics by live-cell microscopy during MCMV egress with high spatial as well as temporal resolution. From the resulting tracks we obtained not only mean track velocities but also their mean square displacements and diffusion coefficients. With this key information, we were able to describe particle behavior at high detail and discriminate between particle tracks exhibiting directed movement and tracks in which particles exhibited free or anomalous diffusion

Dominant-Negative Proteins in Herpesviruses – From Assigning Gene Function to Intracellular Immunization

Investigating and assigning gene functions of herpesviruses is a process, which profits from consistent technical innovation. Cloning of bacterial artificial chromosomes encoding herpesvirus genomes permits nearly unlimited possibilities in the construction of genetically modified viruses. Targeted or randomized screening approaches allow rapid identification of essential viral proteins. Nevertheless, mapping of essential genes reveals only limited insight into function. The usage of dominant-negative (DN) proteins has been the tool of choice to dissect functions of proteins during the viral life cycle. DN proteins also facilitate the analysis of host-virus interactions. Finally, DNs serve as starting-point for design of new antiviral strategies

A Capsid-Encoded PPxY-Motif Facilitates Adenovirus Entry

Viruses use cellular machinery to enter and infect cells. In this study we address the cell entry mechanisms of nonenveloped adenoviruses (Ads). We show that protein VI, an internal capsid protein, is rapidly exposed after cell surface attachment and internalization and remains partially associated with the capsid during intracellular transport. We found that a PPxY motif within protein VI recruits Nedd4 E3 ubiquitin ligases to bind and ubiquitylate protein VI. We further show that this PPxY motif is involved in rapid, microtubule-dependent intracellular movement of protein VI. Ads with a mutated PPxY motif can efficiently escape endosomes but are defective in microtubule-dependent trafficking toward the nucleus. Likewise, depletion of Nedd4 ligases attenuates nuclear accumulation of incoming Ad particles and infection. Our data provide the first evidence that virus-encoded PPxY motifs are required during virus entry, which may be of significance for several other pathogens