Characterization of SARS-CoV-2 replication complex elongation and proofreading activity

The replication complex (RC) of SARS-CoV-2 was recently shown to be one of the fastest RNA-dependent RNA polymerases of any known coronavirus. With this rapid elongation, the RC is more prone to incorporate mismatches during elongation, resulting in a highly variable genomic sequence. Such mutations render the design of viral protein targets difficult, as drugs optimized for a given viral protein sequence can quickly become inefficient as the genomic sequence evolves. Here, we use biochemical experiments to characterize features of RNA template recognition and elongation fidelity of the SARS-CoV-2 RdRp, and the role of the exonuclease, nsp14. Our study highlights the 2′OH group of the RNA ribose as a critical component for RdRp template recognition and elongation. We show that RdRp fidelity is reduced in the presence of the 3′ deoxy-terminator nucleotide 3′dATP, which promotes the incorporation of mismatched nucleotides (leading to U:C, U:G, U:U, C:U, and A:C base pairs). We find that the nsp10–nsp14 heterodimer is unable to degrade RNA products lacking free 2′OH or 3′OH ribose groups. Our results suggest the potential use of 3′ deoxy-terminator nucleotides in RNA-derived oligonucleotide inhibitors as antivirals against SARS-CoV-2

Photon Pair Generation in Silicon Micro-Ring Resonator with Reverse Bias Enhancement

Photon sources are fundamental components for any quantum photonic technology. The ability to generate high count-rate and low-noise correlated photon pairs via spontaneous parametric down-conversion using bulk crystals has been the cornerstone of modern quantum optics. However, future practical quantum technologies will require a scalable integration approach, and waveguide-based photon sources with high-count rate and low-noise characteristics will be an essential part of chip-based quantum technologies. Here, we demonstrate photon pair generation through spontaneous four-wave mixing in a silicon micro-ring resonator, reporting a maximum coincidence-to-accidental (CAR) ratio of 602 (+-) 37, and a maximum photon pair generation rate of 123 MHz (+-) 11 KHz. To overcome free-carrier related performance degradations we have investigated reverse biased p-i-n structures, demonstrating an improvement in the pair generation rate by a factor of up to 2, with negligible impact on CAR.Comment: 5 pages, 3 figure

HETDEX pilot survey for emission-line galaxies - I. Survey design, performance, and catalog

We present a catalog of emission-line galaxies selected solely by their emission-line fluxes using a wide-field integral field spectrograph. This work is partially motivated as a pilot survey for the upcoming Hobby-Eberly Telescope Dark Energy Experiment (HETDEX). We describe the observations, reductions, detections, redshift classifications, line fluxes, and counterpart information for 397 emission-line galaxies detected over 169 sq.arcmin with a 3500-5800 Ang. bandpass under 5 Ang. full-width-half-maximum (FWHM) spectral resolution. The survey's best sensitivity for unresolved objects under photometric conditions is between 4-20 E-17 erg/s/sq.cm depending on the wavelength, and Ly-alpha luminosities between 3-6 E42 erg/s are detectable. This survey method complements narrowband and color-selection techniques in the search for high redshift galaxies with its different selection properties and large volume probed. The four survey fields within the COSMOS, GOODS-N, MUNICS, and XMM-LSS areas are rich with existing, complementary data. We find 104 galaxies via their high redshift Ly-alpha emission at 1.9<z<3.8, and the majority of the remainder objects are low redshift [OII]3727 emitters at z<0.56. The classification between low and high redshift objects depends on rest frame equivalent width, as well as other indicators, where available. Based on matches to X-ray catalogs, the active galactic nuclei (AGN) fraction amongst the Ly-alpha emitters (LAEs) is 6%. We also analyze the survey's completeness and contamination properties through simulations. We find five high-z, highly-significant, resolved objects with full-width-half-maximum sizes >44 sq.arcsec which appear to be extended Ly-alpha nebulae. We also find three high-z objects with rest frame Ly-alpha equivalent widths above the level believed to be achievable with normal star formation, EW(rest)>240 Ang.Comment: 45 pages, 36 figures, 5 tables, submitted to ApJ

Point source in a phononic grating: stop bands give rise to phonon-focusing caustics

We use locally-excited gigahertz surface phonon wavepackets in microscopic line structures of different pitches to reveal profound anisotropy in the radiation pattern of a point source in a grating. Time-domain data obtained by an ultrafast optical imaging technique and by numerical simulations are Fourier transformed to obtain frequency-filtered real-space acoustic field patterns and k-space phononic band structure. The numerically-obtained k-space images are processed to reveal an intriguing double-horn structure in the lowest-order group-velocity surface, which explains the observed non-propagation sectors bounded by caustics, noted at frequencies above the bottom of the first stop band. We account for these phonon-focusing effects, analogous to collimation effects previously observed in two- and three-dimensional lattices, with a simple analytical model of the band structure based on a plane wave expansion. As the frequency is increased, a transition to dominant waveguiding effects along the lines is also documented

Smoking is associated with the concurrent presence of multiple autoantibodies in rheumatoid arthritis rather than with anti-citrullinated protein antibodies per se:a multicenter cohort study

BACKGROUND: The contribution of smoking to rheumatoid arthritis (RA) is hypothesized to be mediated through formation of anti-citrullinated protein antibodies (ACPA). In RA, however, autoantibodies such as ACPA, rheumatoid factor (RF), and anti-carbamylated protein antibodies (anti-CarP) often occur together, and it is thus unclear whether smoking is specifically associated with some autoantibodies rather than others. We therefore investigated whether smoking is only associated with ACPA or with the presence of multiple RA-related autoantibodies. METHODS: A population-based Japanese cohort (n = 9575) was used to investigate the association of smoking with RF and anti-cyclic citrullinated peptide antibodies (anti-CCP2) in individuals without RA. Furthermore, RA patients fulfilling the 1987 criteria from three early arthritis cohorts from the Netherlands (n = 678), the United Kingdom (n = 761), and Sweden (n = 795) were used. Data on smoking, RF, anti-CCP2, and anti-CarP were available. A total score of autoantibodies was calculated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by logistic regression. RESULTS: In the population-based non-RA cohort, no association was found between smoking and one autoantibody (RF or anti-CCP2), but smoking was associated with double-autoantibody positivity (OR 2.95, 95% CI 1.32-6.58). In RA patients, there was no association between smoking and the presence of one autoantibody (OR 0.99, 95% CI 0.78-1.26), but smoking was associated with double-autoantibody positivity (OR 1.32, 95% CI 1.04-1.68) and triple-autoantibody positivity (OR 2.05, 95% CI 1.53-2.73). CONCLUSIONS: Smoking is associated with the concurrent presence of multiple RA-associated autoantibodies rather than just ACPA. This indicates that smoking is a risk factor for breaking tolerance to multiple autoantigens in RA

The Cosmological Slingshot Scenario: A Stringy Early Times Universe

A cosmological model for the early time Universe is proposed. In this model, the Universe is a wandering brane moving in a warped throat of a Calabi-Yau space. A non-zero angular momentum induces a turning point in the brane trajectory, and leads to a bouncing cosmology as experienced by an observer living on the brane. The Universe undergoes a decelerated contraction followed by an accelerating expansion and no big-bang singularity. Although the number of e-folds of accelerated motion is low (less than 2), standard cosmological problems are not present in our model thanks to the absence of an initial singularity and the violation of energy conditions of mirage matter at high energies. Density perturbations are also calculated in our model and we find a slightly red spectral index with negligible tensorial perturbations in compatibility with WMAP data.Comment: v5: clarifications and references added, results unchanged, version accepted in Class. Quant. Grav. (2008), 34 pages, 5 figure

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks. © 2021 The Author

The paradox of tolerance: parasite extinction due to the evolution of host defence.

Host defence against parasite infection can rely on two broad strategies: resistance and tolerance. The spread of resistance traits usually lowers parasite prevalence and decreases selection for higher defence. Conversely, tolerance mechanisms increase parasite prevalence and foster selection for more tolerance. Here we examine the potential for the host to drive parasites to extinction through the evolution of one or other defence mechanism. We analysed theoretical models of resistance and tolerance evolution in both the absence and the presence of a trade-off between defence and reproduction. In the absence of costs, resistance evolves towards maximisation and, consequently, parasite extinction. Tolerance also evolves towards maximisation but the positive feedback between tolerance and disease prevents the disappearance of the parasite. On the contrary, when defence comes with costs it is impossible for the host to eliminate the infection through resistance, because costly resistance is selected against when parasites are at low prevalence. We uncover that the only path to disease clearance in the presence of costs is through tolerance. Paradoxically, however, it is by lowering tolerance -and hence increasing disease-induced mortality- that extinction can occur. We also show that such extinction can occur even in the case of parasite counter-adaptation. Our results emphasise the importance of tolerance as a defence strategy, and identify key questions for future research