819 research outputs found
Mutations in the Poliovirus 3CD Proteinase S1-Specificity Pocket Affect Substrate Recognition and RNA Binding
AbstractSequence and structure comparisons with homologous trypsin-like serine proteases have predicted the S1-specificity pocket in picornavirus 3C proteinases. In this study, we examine the putative roles of such residues in poliovirus 3C substrate recognition. Single amino acid substitutions at 3C residues Thr-142, His-161, Gly-163, Gly-164, and Ala-172 were introduced into near full-length poliovirus cDNAs, and protein processing was examined in the context of authentic 3Cciscleavage activity. Our data are consistent with residues Thr-142, His-161, Gly-163, and Gly-164 acting as important determinants of 3C substrate specificity and support published models of 3C protein structure. Anin vivoanalysis of mutant viruses containing individual amino acid substitutions at 3C residues Thr-142 and Ala-172 suggests that such residues are important determinants for viral RNA replication. In addition, bacterially expressed, recombinant 3CD polypeptides containing amino acid substitutions at Thr-142 and Ala-172 show altered RNA binding properties in mobility shift assays that use a synthetic RNA corresponding to the poliovirus 5′-terminal sequences
The next detectors for gravitational wave astronomy
This paper focuses on the next detectors for gravitational wave astronomy
which will be required after the current ground based detectors have completed
their initial observations, and probably achieved the first direct detection of
gravitational waves. The next detectors will need to have greater sensitivity,
while also enabling the world array of detectors to have improved angular
resolution to allow localisation of signal sources. Sect. 1 of this paper
begins by reviewing proposals for the next ground based detectors, and presents
an analysis of the sensitivity of an 8 km armlength detector, which is proposed
as a safe and cost-effective means to attain a 4-fold improvement in
sensitivity. The scientific benefits of creating a pair of such detectors in
China and Australia is emphasised. Sect. 2 of this paper discusses the high
performance suspension systems for test masses that will be an essential
component for future detectors, while sect. 3 discusses solutions to the
problem of Newtonian noise which arise from fluctuations in gravity gradient
forces acting on test masses. Such gravitational perturbations cannot be
shielded, and set limits to low frequency sensitivity unless measured and
suppressed. Sects. 4 and 5 address critical operational technologies that will
be ongoing issues in future detectors. Sect. 4 addresses the design of thermal
compensation systems needed in all high optical power interferometers operating
at room temperature. Parametric instability control is addressed in sect. 5.
Only recently proven to occur in Advanced LIGO, parametric instability
phenomenon brings both risks and opportunities for future detectors. The path
to future enhancements of detectors will come from quantum measurement
technologies. Sect. 6 focuses on the use of optomechanical devices for
obtaining enhanced sensitivity, while sect. 7 reviews a range of quantum
measurement options
Viral CpG Deficiency Provides No Evidence That Dogs Were Intermediate Hosts for SARS-CoV-2.
Due to the scope and impact of the COVID-19 pandemic there exists a strong desire to understand where the SARS-CoV-2 virus came from and how it jumped species boundaries to humans. Molecular evolutionary analyses can trace viral origins by establishing relatedness and divergence times of viruses and identifying past selective pressures. However, we must uphold rigorous standards of inference and interpretation on this topic because of the ramifications of being wrong. Here, we dispute the conclusions of Xia (2020. Extreme genomic CpG deficiency in SARS-CoV-2 and evasion of host antiviral defense. Mol Biol Evol. doi:10.1093/molbev/masa095) that dogs are a likely intermediate host of a SARS-CoV-2 ancestor. We highlight major flaws in Xia's inference process and his analysis of CpG deficiencies, and conclude that there is no direct evidence for the role of dogs as intermediate hosts. Bats and pangolins currently have the greatest support as ancestral hosts of SARS-CoV-2, with the strong caveat that sampling of wildlife species for coronaviruses has been limited
HIV Capsid is a Tractable Target for Small Molecule Therapeutic Intervention
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need for additional novel mechanism inhibitors that will offer expanded therapeutic options in the clinic. We report a new class of small molecule antiretroviral compounds that directly target HIV-1 capsid (CA) via a novel mechanism of action. The compounds exhibit potent antiviral activity against HIV-1 laboratory strains, clinical isolates, and HIV-2, and inhibit both early and late events in the viral replication cycle. We present mechanistic studies indicating that these early and late activities result from the compound affecting viral uncoating and assembly, respectively. We show that amino acid substitutions in the N-terminal domain of HIV-1 CA are sufficient to confer resistance to this class of compounds, identifying CA as the target in infected cells. A high-resolution co-crystal structure of the compound bound to HIV-1 CA reveals a novel binding pocket in the N-terminal domain of the protein. Our data demonstrate that broad-spectrum antiviral activity can be achieved by targeting this new binding site and reveal HIV CA as a tractable drug target for HIV therapy
A Cryogenic Silicon Interferometer for Gravitational-wave Detection
The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument that will have 5 times the range of Advanced LIGO, or greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby universe, as well as observing the universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor
Gravitational Waves From Known Pulsars: Results From The Initial Detector Era
We present the results of searches for gravitational waves from a large selection of pulsars using data from the most recent science runs (S6, VSR2 and VSR4) of the initial generation of interferometric gravitational wave detectors LIGO (Laser Interferometric Gravitational-wave Observatory) and Virgo. We do not see evidence for gravitational wave emission from any of the targeted sources but produce upper limits on the emission amplitude. We highlight the results from seven young pulsars with large spin-down luminosities. We reach within a factor of five of the canonical spin-down limit for all seven of these, whilst for the Crab and Vela pulsars we further surpass their spin-down limits. We present new or updated limits for 172 other pulsars (including both young and millisecond pulsars). Now that the detectors are undergoing major upgrades, and, for completeness, we bring together all of the most up-to-date results from all pulsars searched for during the operations of the first-generation LIGO, Virgo and GEO600 detectors. This gives a total of 195 pulsars including the most recent results described in this paper.United States National Science FoundationScience and Technology Facilities Council of the United KingdomMax-Planck-SocietyState of Niedersachsen/GermanyAustralian Research CouncilInternational Science Linkages program of the Commonwealth of AustraliaCouncil of Scientific and Industrial Research of IndiaIstituto Nazionale di Fisica Nucleare of ItalySpanish Ministerio de Economia y CompetitividadConselleria d'Economia Hisenda i Innovacio of the Govern de les Illes BalearsNetherlands Organisation for Scientific ResearchPolish Ministry of Science and Higher EducationFOCUS Programme of Foundation for Polish ScienceRoyal SocietyScottish Funding CouncilScottish Universities Physics AllianceNational Aeronautics and Space AdministrationOTKA of HungaryLyon Institute of Origins (LIO)National Research Foundation of KoreaIndustry CanadaProvince of Ontario through the Ministry of Economic Development and InnovationNational Science and Engineering Research Council CanadaCarnegie TrustLeverhulme TrustDavid and Lucile Packard FoundationResearch CorporationAlfred P. Sloan FoundationAstronom
First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data
Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of
continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a
fully coherent search, based on matched filtering, which uses the position and rotational parameters
obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto-
noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch
between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have
been developed, allowing a fully coherent search for gravitational waves from known pulsars over a
fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of
11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial
outliers, further studies show no significant evidence for the presence of a gravitational wave signal.
Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of
the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for
the first time. For an additional 3 targets, the median upper limit across the search bands is below the
spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried
out so far
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