Biology subjects

Nagy, A.

Publications and source records attributed to Nagy, A..

24 records · Page 2Linked to original sources

bioRxiv2020

Multiple SARS-CoV-2 introductions shaped the early outbreak in Central Eastern Europe: comparing Hungarian data to a worldwide sequence data-matrix

Severe Acute Respiratory Syndrome Coronavirus 2 is the third highly pathogenic human coronavirus in history. Since the emergence in Hubei province, China, during late 2019 the situation evolved to pandemic level. Following China, Europe was the second epicenter of the pandemic. To better comprehend the detailed founder mechanisms of the epidemic evolution in Central-Eastern Europe, particularly in Hungary, we determined the full-length SARS-CoV-2 genomes from 32 clinical samples collected from laboratory confirmed COVID-19 patients over the first month of disease in Hungary. We applied a haplotype network analysis on all available complete genomic sequences of SARS-CoV-2 from GISAID database as of the 21th of April, 2020. We performed additional phylogenetic and phylogeographic analyses to achieve the recognition of multiple and parallel introductory events into our region. Here we present a publicly available network imaging of the worldwide haplotype relations of SARS-CoV-2 sequences and conclude the founder mechanisms of the outbreak in Central-Eastern Europe.

microbiology↗

bioRxiv2020

Trends in animal model preference for preclinical drug testing for type-2 diabetes and future directions

The importance of selecting accurate animal models of disease has become increasingly salient in recent years. This is particularly important for preclinical tests carried out to predict drug efficacy and safety for humans. We mapped past and current trends in animal model selection for type-2 Diabetes Mellitus (T2DM) antidiabetic drug research, and evaluate results in light of their implications for translational research. From data gathered from published studies on 41 orally administered antidiabetic drug classes from the MEDLINE Evaluator web service, we found animal model choice trends within - and across - drug classes to be substantially similar, with outbred rat strains being more prevalently used, since the 1990s. The observed consistency in choice of animal models in T2DM is advantageous for replicability and comparability of experiments, but prevalence of outbred strains raises a few concerns. In face of current criticism of the translational value of animal tests, predictive validity must be assessed on a case-by-case basis. We address some of the issues pertaining the most popular animal models in antidiabetic drug development and testing, including the lack of information on their predictive validity, and propose a back translation approach to estimate it retrospectively.

pharmacology and toxicology↗

bioRxiv2019

Usp14 is required for spermatogenesis and ubiquitin stress responses in Drosophila melanogaster

Deubiquitinating (DUB) enzymes free covalently linked ubiquitins from ubiquitin-ubiquitin and ubiquitin-protein conjugates, and thereby maintain the equilibrium between free and conjugated ubiquitins and regulate ubiquitin-mediated cellular processes. The present genetic analyses of mutant phenotypes demonstrate that loss of Usp14 function results in male sterility, with defects in spermatid individualization and reduced testicular free monoubiquitin levels. These phenotypes were rescued by germline specific overexpression of wild type Usp14. Synergistic genetic interactions with Ubi-p63E and cycloheximide sensitivity suggest that ubiquitin shortage is a primary cause of male sterility. In addition, Usp14 is predominantly expressed in testes in Drosophila, and differential expression patterns may be causative of testis-specific loss of function Usp14 phenotypes. Collectively, these results suggest a major role of Usp14 in maintaining normal steady state free monoubiquitin levels during the later stages of Drosophila spermatogenesis.

genetics↗

bioRxiv2019

Induction of long-term allogeneic cell acceptance and formation of immune privileged tissue in immunocompetent Hosts

A vast number of diseases could be treated with therapeutic cells derived from pluripotent stem cells (PSCs). However, cell products that come from non-autologous sources can be immune rejected by the recipients immune system. Here, we show that forced expression of eight immunomodulatory transgenes, including Ccl21, Pdl1, Fasl, Serpinb9, H2-M3, Cd47, Cd200, and Mfge8, allows mouse embryonic stem cells (mESCs) and their derivatives to escape immune rejection in fully immunocompetent, allogeneic recipients. Despite no genetic alterations to major histocompatibility complex (MHC) genes, immune-modified C57BL/6 mESCs could generate long-term, allogeneic tissues in inbred FVB/N, C3H, and BALB/c, as well as outbred CD-1 recipients. Due to the tandem incorporation of our safe-cell suicide system, which allows tight and drug-inducible control over proliferation in vivo, these allotolerated cells can generate safe and dormant ectopic tissues in the host. We show that these ectopic tissues maintain high expression of all eight immunomodulatory transgenes and are immune-privileged sites that can host and protect unmodified mouse and human cells from rejection in allogeneic and xenogeneic settings, respectively. If translated to human clinical settings, we envision the development of a single pluripotent cell line that can be used to generate allo-tolerated, off-the-shelf cell products to serve all humankind, as well as immune-privileged ectopic tissues to host and immune-protect any kind of therapeutic cell product.

bioengineering↗

bioRxiv2019

Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling

Microglia rapidly respond to changes in neural activity and inflammation to regulate synaptic connectivity. The extracellular signals, particularly neuron-derived molecules, that drive these microglial functions at synapses remains a key open question. Here, whisker lesioning, known to dampen cortical activity, induces microglia-mediated synapse elimination. We show that this synapse elimination is dependent on the microglial fractalkine receptor, CX3CR1, but not complement receptor 3, signaling. Further, mice deficient in the CX3CR1 ligand (CX3CL1) also have profound defects in synapse elimination. Single-cell RNAseq then revealed that Cx3cl1 is cortical neuron-derived and ADAM10, a metalloprotease that cleaves CX3CL1 into a secreted form, is upregulated specifically in layer IV neurons and microglia following whisker lesioning. Finally, inhibition of ADAM10 phenocopies Cx3cr1-/- and Cx3cl1-/- synapse elimination defects. Together, these results identify novel neuron-to-microglia signaling necessary for cortical synaptic remodeling and reveal context-dependent immune mechanisms are utilized to remodel synapses in the mammalian brain.

neuroscience↗

bioRxiv2017

Bipolar filaments of human nonmuscle myosin 2-A and 2-B have distinct motile and mechanical properties

Nonmuscle myosin 2 (NM-2) powers cell motility and tissue morphogenesis by assembling into bipolar filaments that interact with actin. Although the enzymatic properties of purified NM-2 motor fragments have been determined, the emergent properties of filament ensembles are unknown. Using single myosin filament in vitro motility assays, we report fundamental differences in filaments formed of different NM-2 motors. Filaments consisting of NM2-B moved processively along actin, while under identical conditions, NM2-A filaments did not. By more closely mimicking the physiological milieu, either by increasing solution viscosity or by copolymerization with NM2-B, NM2-A containing filaments moved processively. Our data demonstrate that both the kinetic and mechanical properties of these two myosins, in addition to the stochiometry of NM-2 subunits, can tune filament mechanical output. We propose altering NM-2 filament composition is a general cellular strategy for tailoring force production of filaments to specific functions such as maintaining tension or remodeling actin.

biophysics↗