Lineage A betacoronavirus NS2 proteins and the homologous torovirus Berne pp1a carboxy-terminal domain are phosphodiesterases that antagonize activation of RNase L

Viruses in the family Coronaviridae, within the order Nidovirales, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3′ ends of their genomes, that often act as host cell antagonists. We previously showed that 2′,5′-phosphodiesterases (2′,5′-PDEs) encoded by the prototypical Betacoronavirus, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2′,5′-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHV(Mut)) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2′,5′-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHV(Mut) in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHV(Mut) replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it. IMPORTANCE Viruses in the family Coronaviridae include important human and animal pathogens, including the recently emerged viruses severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome-associated coronavirus (MERS-CoV). We showed previously that two viruses within the genus Betacoronavirus, mouse hepatitis virus (MHV) and MERS-CoV, encode 2′,5′-phosphodiesterases (2′,5′-PDEs) that antagonize the OAS-RNase L pathway, and we report here that these proteins are furthermore conserved among additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses, suggesting that they may play critical roles in pathogenesis. As there are no licensed vaccines or effective antivirals against human coronaviruses and few against those infecting animals, identifying viral proteins contributing to virulence can inform therapeutic development. Thus, this work demonstrates that a potent antagonist of host antiviral defenses is encoded by multiple and diverse viruses within the family Coronaviridae, presenting a possible broad-spectrum therapeutic target

Mechanical properties of in-situ synthesis of Ti-Ti3Al metal composite prepared by selective laser melting

Titanium composite strengthened by Ti3Al precipitations is considered to be one of the excellent materials that is widely used in engineering. In this work, we prepared a kind of Ti-Ti3Al metallic composite by in-situ synthesis technology during the SLM (selective laser melting) process, and analyzed its microstructure, wear resistance, microhardness, and compression properties. The results showed that the Ti-Ti3Al composite, prepared by in-situ synthesis technology based on SLM, had more homogeneous Ti3Al-enhanced phase dispersion strengthening structure. The grain size of the workpiece was about 1 μm, and that of the Ti3Al particle was about 200 nm. Granular Ti3Al was precipitated after the aluminum-containing workpiece formed, with a relatively uniform distribution. Regarding the mechanical properties, the hardness (539 HV) and the wear resistance were significantly improved when compared with the Cp-Ti workpiece. The compressive strength of the workpiece increased from 886.32 MPa to 1568 MPa, and the tensile strength of the workpiece increased from 531 MPa to 567 MPa after adding aluminum. In the future, the combination of in-situ synthesis technology and SLM technology can be used to flexibly adjust the properties of Ti-based materials

Využití Pythonu při optimalizaci portfolia

Portfolio optimization is the approach to select the optimal portfolio that provides the most profitable rate of return for each unit of risk taken by an investor. An investment portfolio is the distribution of an investor's assets, alternatively, it is the selection pool of an investor's investments. The objective of this thesis is to validate and compare the out-of-sample performance of the following strategies: navie Strategy, minimum variance and maximum Sharpe ratio. Therefore, we chose thirty stocks that listed on the NASDAQ Composite Index during the past ten years. This thesis is divided into five chapters. The first chapter expounds on the content and structure of the thesis. The second chapter introduces Python. In Chapter 3 we describe the methodology for portfolio optimization. In the fourth chapter, we use Python to compute the naive Strategy, minimum variance and maximu Sharpe ratio portfolios. The last chapter is the conclusion.Optimalizace portfolia je přístup k výběru optimálního portfolia, který hledá nejvyšší míru výnosu za každou jednotku rizika, kterou investor podstupuje. Investiční portfolio je rozložení prostředků investora do aktiv, resp. je to soubor investic investora. Cílem této diplomové práce je ověřit a porovnat out-of-sample výkonnost následujících strategií: naivní strategie, strategie minimálního rozptylu a maximálního Sharpeho poměru. V aplikační části diplomové práce bylo vybráno třicet akcií, které byly v posledních deseti letech součástí indexu NASDAQ Composite. Tato diplomová práce je rozdělena do pěti kapitol. První kapitola objasňuje obsah a strukturu práce. Druhá kapitola popisuje jazyk Python. Ve třetí kapitole je popsána metodika optimalizace portfolia. Ve čtvrté kapitole je použit Python k sestavení a ověření výkonnosti strategií, konkrétně naivní strategie, strategie minimálního rozptylu a maximálního Sharpeho poměru. Poslední kapitolou je závěr.154 - Katedra financídobř