Viral RNA-dependent RNA polymerases (RdRps) play a central role not only in viral replication, but also in the genetic evolution of viral RNAs. After binding to an RNA template and selecting ...5'-triphosphate ribonucleosides, viral RdRps synthesize an RNA copy according to Watson-Crick base-pairing rules. The copy process sometimes deviates from both the base-pairing rules specified by the template and the natural ribose selectivity and, thus, the process is error-prone due to the intrinsic (in)fidelity of viral RdRps. These enzymes share a number of conserved amino-acid sequence strings, called motifs A-G, which can be defined from a structural and functional point-of-view. A co-relation is gradually emerging between mutations in these motifs and viral genome evolution or observed mutation rates. Here, we review our current knowledge on these motifs and their role on the structural and mechanistic basis of the fidelity of nucleotide selection and RNA synthesis by
RdRps.
Cellular and viral S-adenosylmethionine-dependent methyltransferases are involved in many regulated processes such as metabolism, detoxification, signal transduction, chromatin remodeling, nucleic ...acid processing, and mRNA capping. The Severe Acute Respiratory Syndrome coronavirus nsp16 protein is a S-adenosylmethionine-dependent (nucleoside-2'-O)-methyltransferase only active in the presence of its activating partner nsp10. We report the nsp10/nsp16 complex structure at 2.0 Å resolution, which shows nsp10 bound to nsp16 through a ∼930 Ų surface area in nsp10. Functional assays identify key residues involved in nsp10/nsp16 association, and in RNA binding or catalysis, the latter likely through a SN2-like mechanism. We present two other crystal structures, the inhibitor Sinefungin bound in the S-adenosylmethionine binding pocket and the tighter complex nsp10(Y96F)/nsp16, providing the first structural insight into the regulation of RNA capping enzymes in +RNA viruses.
Hendra virus (HeV) is a recently emerged severe human pathogen that belongs to the Henipavirus genus within the Paramyxoviridae family. The HeV genome is encapsidated by the nucleoprotein (N) within ...a helical nucleocapsid. Recruitment of the viral polymerase onto the nucleocapsid template relies on the interaction between the C-terminal domain, N(TAIL), of N and the C-terminal X domain, XD, of the polymerase co-factor phosphoprotein (P). Here, we provide an atomic resolution description of the intrinsically disordered N(TAIL) domain in its isolated state and in intact nucleocapsids using nuclear magnetic resonance (NMR) spectroscopy. Using electron microscopy, we show that HeV nucleocapsids form herringbone-like structures typical of paramyxoviruses. We also report the crystal structure of XD of P that consists of a three-helix bundle. We study the interaction between N(TAIL) and XD using NMR titration experiments and provide a detailed mapping of the reciprocal binding sites. We show that the interaction is accompanied by α-helical folding of the molecular recognition element of N(TAIL) upon binding to a hydrophobic patch on the surface of XD. Finally, using solution NMR, we investigate the interaction between intact nucleocapsids and XD. Our results indicate that monomeric XD binds to N(TAIL) without triggering an additional unwinding of the nucleocapsid template. The present results provide a structural description at the atomic level of the protein-protein interactions required for transcription and replication of HeV, and the first direct observation of the interaction between the X domain of P and intact nucleocapsids in Paramyxoviridae.
Betas and the myth of market neutrality Papageorgiou, Nicolas; Reeves, Jonathan J.; Xie, Xuan
International journal of forecasting,
04/2016, Letnik:
32, Številka:
2
Journal Article
Recenzirano
Market neutral funds are commonly advertised as alternative investments that offer returns which are uncorrelated with the broad market. Utilizing recent advances in financial econometrics, we ...demonstrate that using standard forecasting methods to construct market (beta) neutral funds is often very inaccurate. Our findings demonstrate that the econometric methods that are commonly employed for forecasting the beta (systematic) risk typically lack sufficient accuracy to permit the successful construction of market neutral portfolios. The results in this paper also highlight the need for higher frequency returns data to be utilized more commonly. Using daily returns over the past year, we demonstrate an approach that is easy to implement and delivers a substantial improvement, relative to other methods, when attempting to construct a market neutral portfolio.
is a family of viruses harbouring important emerging pathogens belonging to the
order. Like in other segmented negative strand RNA viruses, the nucleoprotein (NP) is a major actor of the viral life ...cycle being both (i) the necessary co-factor of the polymerase present in the L protein, and (ii) the last line of defence of the viral genome (vRNA) by physically hiding its presence in the cytoplasm. The NP is also one of the major players interfering with the immune system. Several structural studies of NP have shown that it features two domains: a globular RNA binding domain (NP-core) in its N-terminal and an exonuclease domain (ExoN) in its C-terminal. Further studies have observed that significant conformational changes are necessary for RNA encapsidation. In this review we revisited the most recent structural and functional data available on
NP, compared to other
nucleoproteins and explored the structural and functional implications. We review the variety of structural motif extensions involved in NP-NP binding mode. We also evaluate the major functional implications of NP interactome and the role of ExoN, thus making the NP a target of choice for future vaccine and antiviral therapy.
Higher-moment Risk Exposures in Hedge Funds Hübner, G.; Lambert, M.; Papageorgiou, N.
European financial management : the journal of the European Financial Management Association,
March 2015, Letnik:
21, Številka:
2
Journal Article, Web Resource
Recenzirano
This paper singles out the key roles of US equity skewness and kurtosis in the hedge fund return generating process. We propose a conditional higher‐moment model with location, trading, and ...higher‐moment factors to describe the dynamics of the equity hedge, event‐driven, relative value, and fund of funds styles. If the volatility, skewness, and kurtosis implied in US options are used by fund managers as instruments to anticipate market movements, managers should adjust their market exposure in response to variations in these moments. We indeed show that higher‐moment premia improve the conditional asset pricing model across all hedge fund styles.
Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single‐stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most abundant viral protein in infected ...cells and plays a critical role in both replication/transcription and virion assembly. The NP associates with RNA to form a ribonucleoprotein (RNP) complex, and this implies self‐assembly while the exact structure of this polymer is not yet known. Here, we report a measurement of the full‐length Mopeia virus NP by negative stain transmission electron microscopy. We observed RNP complex particles with diameter 15 ± 1 nm as well as symmetric circular heptamers of the same diameter, consistent with previous observations.
The nucleoprotein associates with RNA to form a ribonucleoprotein complex. The nucleoprotein trends to self‐assemble into heptameric rings. Theses rings represent stable intermediate states representative of the average full turn of the Arenaviridae ribonucleoprotein filament. They are the first observation of the complexed nucleoprotein‐RNA as a polymer and hint that oligomerization occurs as it happens for other Bunyavirales nucleoproteins.
This paper focuses on the structural arrangements, as seen in scanning tunneling microscopy, chemical and electric properties, as studied especially by high resolution synchrotron radiation ...photoelectron spectroscopy and energy loss spectroscopy of sub-monolayer up to few monolayer thin films of phthalocyanines adsorbed on narrow band gap III–V semiconductors where they form ordered superstructures, as well as on silicon surfaces. Special emphasis will be put on non-planar metal phthalocyanines where the central atom is either lead or tin. These molecules have been studied in detail from the experimental point of view as well as theoretically by ab initio quantum calculations. Comparison with metal free and metal substituted planar phthalocyanines (H
2Pc, CuPc, CoPc, …) adsorbed on semiconductors or noble metal surfaces is included. Perspectives and novel potential applications are finally outlined.
We examine whether performance persistence is suspicious. Top quintile portfolios formed on the Sharpe ratio, alpha, and information ratio persistently outperform similarly constructed mediocre third ...quintile portfolios throughout our sample period, but performance is more modest and less persistent when portfolios are formed on the excess manipulation‐proof performance measure (EMPPM). By selecting funds formed on ranking by Sharpe and information ratios, investors also select funds that have persistently doubtful performance according to the doubt ratio. In contrast, portfolios formed on alphas and especially the EMPPM have much less excess and persistent doubt.
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