Packaging signals in single-stranded RNA viruses: nature’s alternative to a purely electrostatic assembly mechanism

The formation of a protective protein container is an essential step in the life-cycle of most viruses. In the case of single-stranded (ss)RNA viruses, this step occurs in parallel with genome packaging in a co-assembly process. Previously, it had been thought that this process can be explained entirely by electrostatics. Inspired by recent single-molecule fluorescence experiments that recapitulate the RNA packaging specificity seen in vivo for two model viruses, we present an alternative theory, which recognizes the important cooperative roles played by RNA–coat protein interactions, at sites we have termed packaging signals. The hypothesis is that multiple copies of packaging signals, repeated according to capsid symmetry, aid formation of the required capsid protein conformers at defined positions, resulting in significantly enhanced assembly efficiency. The precise mechanistic roles of packaging signal interactions may vary between viruses, as we have demonstrated for MS2 and STNV. We quantify the impact of packaging signals on capsid assembly efficiency using a dodecahedral model system, showing that heterogeneous affinity distributions of packaging signals for capsid protein out-compete those of homogeneous affinities. These insights pave the way to a new anti-viral therapy, reducing capsid assembly efficiency by targeting of the vital roles of the packaging signals, and opens up new avenues for the efficient construction of protein nanocontainers in bionanotechnology

The spectral shift function and spectral flow

This paper extends Krein's spectral shift function theory to the setting of semifinite spectral triples. We define the spectral shift function under these hypotheses via Birman-Solomyak spectral averaging formula and show that it computes spectral flow.Comment: 47 page

Use of a penicillin allergy clinical decision rule to enable direct oral penicillin provocation: an international multicentre randomised control trial in an adult population (PALACE): study protocol

Introduction Penicillin allergies are highly prevalent in the healthcare setting and associated with the prescription of second-line inferior antibiotics. More than 85% of all penicillin allergy labels can be removed by skin testing and 96%–99% of low-risk penicillin allergy labels can be removed by direct oral challenge. An internally and externally validated clinical assessment tool for penicillin allergy, PEN-FAST, can identify a low-risk penicillin allergy without the need for skin testing; a score of less than 3 has a negative predictive value of 96.3% (95% CI, 94.1 to 97.8) for the presence of a penicillin allergy. It is hypothesised that PEN-FAST is a safe and effective tool for assessing penicillin allergy in an outpatient clinic setting. Methods and analysis This is an international, multicentre randomised control trial using the PEN-FAST tool to risk-stratify penicillin allergy labels in adult outpatients. The study’s primary objective is to evaluate the non-inferiority of using PEN-FAST score-guided management with direct oral challenge compared with standard care (defined as prick and intradermal skin testing followed by oral penicillin challenge). Participants will be randomised 1:1 to the intervention arm (direct oral penicillin challenge) or standard of care arm (skin testing followed by oral penicillin challenge, if skin testing is negative). The sample size of 380 randomised patients (190 per treatment arm) is required to demonstrate non-inferiority. Ethics and dissemination The study will be performed according to the guidelines of the Helsinki Declaration and is approved by the Austin Health Human Research Ethics Committee (HREC/62425/Austin-2020) in Melbourne Australia, Vanderbilt University Institutional Review Board (IRB #202174) in Tennessee, USA, Duke University Institutional Review Board (IRB #Pro00108461) in North Carolina, USA and McGill University Health Centre Research Ethics Board in Canada (PALACE/2022-7605). The results of this study will be published and presented in various scientific forums

Is cosmology consistent?

We perform a detailed analysis of the latest CMB measurements (including BOOMERaNG, DASI, Maxima and CBI), both alone and jointly with other cosmological data sets involving, e.g., galaxy clustering and the Lyman Alpha Forest. We first address the question of whether the CMB data are internally consistent once calibration and beam uncertainties are taken into account, performing a series of statistical tests. With a few minor caveats, our answer is yes, and we compress all data into a single set of 24 bandpowers with associated covariance matrix and window functions. We then compute joint constraints on the 11 parameters of the ``standard'' adiabatic inflationary cosmological model. Out best fit model passes a series of physical consistency checks and agrees with essentially all currently available cosmological data. In addition to sharp constraints on the cosmic matter budget in good agreement with those of the BOOMERaNG, DASI and Maxima teams, we obtain a heaviest neutrino mass range 0.04-4.2 eV and the sharpest constraints to date on gravity waves which (together with preference for a slight red-tilt) favors ``small-field'' inflation models.Comment: Replaced to match accepted PRD version. 14 pages, 12 figs. Tiny changes due to smaller DASI & Maxima calibration errors. Expanded neutrino and tensor discussion, added refs, typos fixed. Combined CMB data, window and covariance matrix at http://www.hep.upenn.edu/~max/consistent.html or from [email protected]

Sensitivity of the surface orographic gravity wave drag to vertical wind shear over Antarctica

The effects of vertical wind shear on orographic gravity wave drag derived previously from inviscid linear theory are evaluated using reanalysis data. Emphasis is placed on the relative importance of uniform and directional shear (associated with first and second vertical derivatives of the wind velocity), which are theoretically predicted, respectively, to reduce and enhance the surface drag. Two levels at which the wind derivatives are estimated are considered for evaluating the shear corrections to the drag: a height just above the parametrized boundary layer height in the ECMWF model (BLH), and a height of order the standard deviation of the subgrid-scale orography elevation (SDH), adopted by previous authors. A climatology of the Richardson number (Ri) computed for the decade 2006-2015 suggests that the Antarctic region has a high incidence of low Ri values, implying high shear conditions. Shear estimated at the BLH has a relatively modest impact on the drag, whereas shear estimated at the SDH has a stronger impact. Predicted drag enhancement is more widespread than drag reduction because terms involving second wind derivatives dominate the drag correction for a larger fraction of the time than terms involving first derivatives. A comparison of climatologies of the drag corrections for horizontally elliptical mountains (which represent anisotropic subgrid-scale orography in parametrizations) and axisymmetric mountains always results in drag enhancement over Antarctica, with a maximum during the JJA season, showing qualitative robustness to both calculation height and orography anisotropy. However, this enhancement is smaller when using elliptical instead of axisymmetric orography. This is because the shear vector is predominantly oriented along mountain ridges rather than across them when the orography is anisotropic

Tomato: a crop species amenable to improvement by cellular and molecular methods

Tomato is a crop plant with a relatively small DNA content per haploid genome and a well developed genetics. Plant regeneration from explants and protoplasts is feasable which led to the development of efficient transformation procedures. In view of the current data, the isolation of useful mutants at the cellular level probably will be of limited value in the genetic improvement of tomato. Protoplast fusion may lead to novel combinations of organelle and nuclear DNA (cybrids), whereas this technique also provides a means of introducing genetic information from alien species into tomato. Important developments have come from molecular approaches. Following the construction of an RFLP map, these RFLP markers can be used in tomato to tag quantitative traits bred in from related species. Both RFLP's and transposons are in the process of being used to clone desired genes for which no gene products are known. Cloned genes can be introduced and potentially improve specific properties of tomato especially those controlled by single genes. Recent results suggest that, in principle, phenotypic mutants can be created for cloned and characterized genes and will prove their value in further improving the cultivated tomato.

Physics of Solar Prominences: I - Spectral Diagnostics and Non-LTE Modelling

This review paper outlines background information and covers recent advances made via the analysis of spectra and images of prominence plasma and the increased sophistication of non-LTE (ie when there is a departure from Local Thermodynamic Equilibrium) radiative transfer models. We first describe the spectral inversion techniques that have been used to infer the plasma parameters important for the general properties of the prominence plasma in both its cool core and the hotter prominence-corona transition region. We also review studies devoted to the observation of bulk motions of the prominence plasma and to the determination of prominence mass. However, a simple inversion of spectroscopic data usually fails when the lines become optically thick at certain wavelengths. Therefore, complex non-LTE models become necessary. We thus present the basics of non-LTE radiative transfer theory and the associated multi-level radiative transfer problems. The main results of one- and two-dimensional models of the prominences and their fine-structures are presented. We then discuss the energy balance in various prominence models. Finally, we outline the outstanding observational and theoretical questions, and the directions for future progress in our understanding of solar prominences.Comment: 96 pages, 37 figures, Space Science Reviews. Some figures may have a better resolution in the published version. New version reflects minor changes brought after proof editin

Tests of sunspot number sequences: 1. Using ionosonde data

More than 70 years ago it was recognised that ionospheric F2-layer critical frequencies [foF2] had a strong relationship to sunspot number. Using historic datasets from the Slough and Washington ionosondes, we evaluate the best statistical fits of foF2 to sunspot numbers (at each Universal Time [UT] separately) in order to search for drifts and abrupt changes in the fit residuals over Solar Cycles 17-21. This test is carried out for the original composite of the Wolf/Zürich/International sunspot number [R], the new “backbone” group sunspot number [RBB] and the proposed “corrected sunspot number” [RC]. Polynomial fits are made both with and without allowance for the white-light facular area, which has been reported as being associated with cycle-to-cycle changes in the sunspot number - foF2 relationship. Over the interval studied here, R, RBB, and RC largely differ in their allowance for the “Waldmeier discontinuity” around 1945 (the correction factor for which for R, RBB and RC is, respectively, zero, effectively over 20 %, and explicitly 11.6 %). It is shown that for Solar Cycles 18-21, all three sunspot data sequences perform well, but that the fit residuals are lowest and most uniform for RBB. We here use foF2 for those UTs for which R, RBB, and RC all give correlations exceeding 0.99 for intervals both before and after the Waldmeier discontinuity. The error introduced by the Waldmeier discontinuity causes R to underestimate the fitted values based on the foF2 data for 1932-1945 but RBB overestimates them by almost the same factor, implying that the correction for the Waldmeier discontinuity inherent in RBB is too large by a factor of two. Fit residuals are smallest and most uniform for RC and the ionospheric data support the optimum discontinuity multiplicative correction factor derived from the independent Royal Greenwich Observatory (RGO) sunspot group data for the same interval

Demonstration of a novel technique to measure two-photon exchange effects in elastic e±pe^\pm p scattering

The discrepancy between proton electromagnetic form factors extracted using unpolarized and polarized scattering data is believed to be a consequence of two-photon exchange (TPE) effects. However, the calculations of TPE corrections have significant model dependence, and there is limited direct experimental evidence for such corrections. We present the results of a new experimental technique for making direct $e^\pm p$ comparisons, which has the potential to make precise measurements over a broad range in $Q^2$ and scattering angles. We use the Jefferson Lab electron beam and the Hall B photon tagger to generate a clean but untagged photon beam. The photon beam impinges on a converter foil to generate a mixed beam of electrons, positrons, and photons. A chicane is used to separate and recombine the electron and positron beams while the photon beam is stopped by a photon blocker. This provides a combined electron and positron beam, with energies from 0.5 to 3.2 GeV, which impinges on a liquid hydrogen target. The large acceptance CLAS detector is used to identify and reconstruct elastic scattering events, determining both the initial lepton energy and the sign of the scattered lepton. The data were collected in two days with a primary electron beam energy of only 3.3 GeV, limiting the data from this run to smaller values of $Q^2$ and scattering angle. Nonetheless, this measurement yields a data sample for $e^\pm p$ with statistics comparable to those of the best previous measurements. We have shown that we can cleanly identify elastic scattering events and correct for the difference in acceptance for electron and positron scattering. The final ratio of positron to electron scattering: $R=1.027\pm0.005\pm0.05$ for $=0.206$ GeV$^2$ and $0.830\leq \epsilon\leq 0.943$

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types