The genomes of influenza viruses consist of multiple segments of single-stranded negative-sense RNA. Each of these segments is bound by the heterotrimeric viral RNA-dependent RNA polymerase and ...multiple copies of nucleoprotein, which form viral ribonucleoprotein (vRNP) complexes. It is in the context of these vRNPs that the viral RNA polymerase carries out transcription of viral genes and replication of the viral RNA genome. In this Review, we discuss our current knowledge of the structure of the influenza virus RNA polymerase, and insights that have been gained into the molecular mechanisms of viral transcription and replication, and their regulation by viral and host factors. Furthermore, we discuss how advances in our understanding of the structure and function of polymerases could help in identifying new antiviral targets.
Eukaryotes and bacteria can be infected with a wide variety of RNA viruses. On average, these pathogens share little sequence similarity and use different replication and transcription strategies. ...Nevertheless, the members of nearly all RNA virus families depend on the activity of a virally encoded RNA-dependent polymerase for the condensation of nucleotide triphosphates. This review provides an overview of our current understanding of the viral RNA-dependent polymerase structure and the biochemistry and biophysics that is involved in replicating and transcribing the genetic material of RNA viruses.
The mechanism of resistance to favipiravir in influenza Goldhill, Daniel H.; te Velthuis, Aartjan J. W.; Fletcher, Robert A. ...
Proceedings of the National Academy of Sciences - PNAS,
11/2018, Volume:
115, Issue:
45
Journal Article
Peer reviewed
Open access
Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, ...clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA virusesmight also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.
We demonstrate that magnetic properties of ultrathin Co films adjacent to Gd2O3 gate oxides can be directly manipulated by voltage. The Co films can be reversibly changed from an optimally oxidized ...state with a strong perpendicular magnetic anisotropy to a metallic state with an in-plane magnetic anisotropy or to an oxidized state with nearly zero magnetization, depending on the polarity and time duration of the applied electric fields. Consequently, an unprecedentedly large change of magnetic anisotropy energy up to 0.73 erg/cm(2) has been realized in a nonvolatile manner using gate voltages of only a few volts. These results open a new route to achieve ultralow energy magnetization manipulation in spintronic devices.
RNA viruses include many important human and animal pathogens, such as the influenza viruses, respiratory syncytial virus, Ebola virus, measles virus and rabies virus. The genomes of these viruses ...consist of single or multiple RNA segments that assemble with oligomeric viral nucleoprotein into ribonucleoprotein complexes. Replication and transcription of the viral genome is performed by ~250-450 kDa viral RNA-dependent RNA polymerases that also contain capping or cap-snatching activity. In this Review, we compare recent high-resolution X-ray and cryoelectron microscopy structures of RNA polymerases of negative-sense RNA viruses with segmented and non-segmented genomes, including orthomyxoviruses, peribunyaviruses, phenuiviruses, arenaviruses, rhabdoviruses, pneumoviruses and paramyxoviruses. In addition, we discuss how structural insights into these enzymes contribute to our understanding of the molecular mechanisms of viral transcription and replication, and how we can use these insights to identify targets for antiviral drug design.
Since the 1980s, efforts have been made to develop sensors that measure a parameter from an individual cow. The development started with individual cow recognition and was followed by sensors that ...measure the electrical conductivity of milk and pedometers that measure activity. The aim of this review is to provide a structured overview of the published sensor systems for dairy health management. The development of sensor systems can be described by the following 4 levels: (I) techniques that measure something about the cow (e.g., activity); (II) interpretations that summarize changes in the sensor data (e.g., increase in activity) to produce information about the cow's status (e.g., estrus); (III) integration of information where sensor information is supplemented with other information (e.g., economic information) to produce advice (e.g., whether to inseminate a cow or not); and (IV) the farmer makes a decision or the sensor system makes the decision autonomously (e.g., the inseminator is called). This review has structured a total of 126 publications describing 139 sensor systems and compared them based on the 4 levels. The publications were published in the Thomson Reuters (formerly ISI) Web of Science database from January 2002 until June 2012 or in the proceedings of 3 conferences on precision (dairy) farming in 2009, 2010, and 2011. Most studies concerned the detection of mastitis (25%), fertility (33%), and locomotion problems (30%), with fewer studies (16%) related to the detection of metabolic problems. Many studies presented sensor systems at levels I and II, but none did so at levels III and IV. Most of the work for mastitis (92%) and fertility (75%) is done at level II. For locomotion (53%) and metabolism (69%), more than half of the work is done at level I. The performance of sensor systems varies based on the choice of gold standards, algorithms, and test sizes (number of farms and cows). Studies on sensor systems for mastitis and estrus have shown that sensor systems are brought to a higher level; however, the need to improve detection performance still exists. Studies on sensor systems for locomotion problems have shown that the search continues for the most appropriate indicators, sensor techniques, and gold standards. Studies on metabolic problems show that it is still unclear which indicator reflects best the metabolic problems that should be detected. No systems with integrated decision support models have been found.
Abstract
The anomalous Hall effect (AHE) is an intriguing transport phenomenon occurring typically in ferromagnets as a consequence of broken time reversal symmetry and spin-orbit interaction. It can ...be caused by two microscopically distinct mechanisms, namely, by skew or side-jump scattering due to chiral features of the disorder scattering, or by an intrinsic contribution directly linked to the topological properties of the Bloch states. Here we show that the AHE can be artificially engineered in materials in which it is originally absent by combining the effects of symmetry breaking, spin orbit interaction and proximity-induced magnetism. In particular, we find a strikingly large AHE that emerges at the interface between a ferromagnetic manganite (La
0.7
Sr
0.3
MnO
3
) and a semimetallic iridate (SrIrO
3
). It is intrinsic and originates in the proximity-induced magnetism present in the narrow bands of strong spin-orbit coupling material SrIrO
3
, which yields values of anomalous Hall conductivity and Hall angle as high as those observed in bulk transition-metal ferromagnets. These results demonstrate the interplay between correlated electron physics and topological phenomena at interfaces between 3
d
ferromagnets and strong spin-orbit coupling 5
d
oxides and trace an exciting path towards future topological spintronics at oxide interfaces.
Transcription and replication of the influenza virus RNA genome is catalyzed by the viral heterotrimeric RNA-dependent RNA polymerase in the context of viral ribonucleoprotein (vRNP) complexes. ...Atomic resolution structures of the viral RNA synthesis machinery have offered insights into the initiation mechanisms of viral transcription and genome replication, and the interaction of the viral RNA polymerase with host RNA polymerase II, which is required for the initiation of viral transcription. Replication of the viral RNA genome by the viral RNA polymerase depends on host ANP32A, and host-specific sequence differences in ANP32A underlie the poor activity of avian influenza virus polymerases in mammalian cells. A failure to faithfully copy the viral genome segments can lead to the production of aberrant viral RNA products, such as defective interfering (DI) RNAs and mini viral RNAs (mvRNAs). Both aberrant RNA types have been implicated in innate immune responses against influenza virus infection. This review discusses recent insights into the structure-function relationship of the viral RNA polymerase and its role in determining host range and virulence.
Blowing magnetic skyrmion bubbles Jiang, Wanjun; Upadhyaya, Pramey; Zhang, Wei ...
Science (American Association for the Advancement of Science),
07/2015, Volume:
349, Issue:
6245
Journal Article
Peer reviewed
Open access
The formation of soap bubbles from thin films is accompanied by topological transitions. Here we show how a magnetic topological structure, a skyrmion bubble, can be generated in a solid-state system ...in a similar manner. Using an inhomogeneous in-plane current in a system with broken inversion symmetry, we experimentally "blow" magnetic skyrmion bubbles from a geometrical constriction. The presence of a spatially divergent spin-orbit torque gives rise to instabilities of the magnetic domain structures that are reminiscent of Rayleigh-Plateau instabilities in fluid flows. We determine a phase diagram for skyrmion formation and reveal the efficient manipulation of these dynamically created skyrmions, including depinning and motion. The demonstrated current-driven transformation from stripe domains to magnetic skyrmion bubbles could lead to progress in skyrmion-based spintronics.
An RNA-dependent RNA polymerase (RdRp) is the central catalytic subunit of the RNA-synthesizing machinery of all positive-strand RNA viruses. Usually, RdRp domains are readily identifiable by ...comparative sequence analysis, but biochemical confirmation and characterization can be hampered by intrinsic protein properties and technical complications. It is presumed that replication and transcription of the approximately 30-kb severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) RNA genome are catalyzed by an RdRp domain in the C-terminal part of nonstructural protein 12 (nsp12), one of 16 replicase subunits. However, thus far full-length nsp12 has proven refractory to expression in bacterial systems, which has hindered both the biochemical characterization of coronavirus RNA synthesis and RdRp-targeted antiviral drug design. Here, we describe a combined strategy involving bacterial expression of an nsp12 fusion protein and its in vivo cleavage to generate and purify stable SARS-CoV nsp12 (106 kDa) with a natural N-terminus and C-terminal hexahistidine tag. This recombinant protein possesses robust in vitro RdRp activity, as well as a significant DNA-dependent activity that may facilitate future inhibitor studies. The SARS-CoV nsp12 is primer dependent on both homo- and heteropolymeric templates, supporting the likeliness of a close enzymatic collaboration with the intriguing RNA primase activity that was recently proposed for coronavirus nsp8.
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