The emergence of SARS-CoV-2 variants has raised concerns about altered sensitivity to antibody-mediated immunity. The relative resistance of SARS-CoV-2 variants B.1.1.7 and B.1.351 to antibody ...neutralization has been recently investigated. We report that another emergent variant from Brazil, P.1, is not only refractory to multiple neutralizing monoclonal antibodies but also more resistant to neutralization by convalescent plasma and vaccinee sera. The magnitude of resistance is greater for monoclonal antibodies than vaccinee sera and evident with both pseudovirus and authentic P.1 virus. The cryoelectron microscopy structure of a soluble prefusion-stabilized spike reveals that the P.1 trimer adopts exclusively a conformation in which one of the receptor-binding domains is in the “up” position, which is known to facilitate binding to entry receptor ACE2. The functional impact of P.1 mutations thus appears to arise from local changes instead of global conformational alterations. The P.1 variant threatens current antibody therapies but less so protective vaccine efficacy.
Display omitted
•P.1 is refractory to multiple neutralizing mAbs, including three out of the four with EUA•P.1 is relatively resistant to neutralization by convalescent plasma and vaccinee sera•Cryo-EM structure of P.1 spike trimer reveals exclusively one-RBD-up conformation
Wang et al. report that an emergent SARS-CoV-2 variant, P.1, is relatively resistant to neutralization by multiple therapeutic monoclonal antibodies, convalescent plasma, and vaccinee sera. The cryoelectron microscopy structure reveals the P.1 trimer to adopt exclusively a conformation with one of the receptor-binding domains in the “up” position.
The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single ...and combination therapies with monoclonal antibodies have received emergency use authorization
, and more treatments are under development
. Furthermore, multiple vaccine constructs have shown promise
, including two that have an approximately 95% protective efficacy against COVID-19
. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK
and B.1.351 in South Africa
is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants
with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.
Epigenetics, the transgenerational transfer of phenotypic characters without modification of gene sequence, is a burgeoning area of study in many disciplines of biology. However, the potential impact ...of this phenomenon on the physiology of animals is not yet broadly appreciated, in part because the phenomenon of epigenetics is not typically part of the design of physiological investigations. Still enigmatic and somewhat ill defined is the relationship between the overarching concept of epigenetics and interesting transgenerational phenomena (e.g. 'maternal/parental effects') that alter the physiological phenotype of subsequent generations. The lingering effect on subsequent generations of an initial environmental disturbance in parent animals can be profound, with genes continuing to be variously silenced or expressed without an associated change in gene sequence for many generations. Known epigenetic mechanisms involved in this phenomenon include chromatin remodeling (DNA methylation and histone modification), RNA-mediated modifications (non-coding RNA and microRNA), as well as other less well studied mechanisms such as self-sustaining loops and structural inheritance. In this review we: (1) discuss how the concepts of epigenetics and maternal effects both overlap with, and are distinct from, each other; (2) analyze examples of existing animal physiological studies based on these concepts; and (3) offer a construct by which to integrate these concepts into the design of future investigations in animal physiology.
SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, ...particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval CI 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days 95% CI 7.9, 14.4) than for asymptomatic individuals (7.8 days 95% CI 6.1, 9.7). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient's infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient's progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious.
Advances in optical tweezers, coupled with the proliferation of two-photon polymerization systems, mean that it is now becoming routine to fabricate and trap non-spherical particles. The shaping of ...both light beams and particles allows fine control over the flow of momentum from the optical to mechanical regimes. However, understanding and predicting the behaviour of such systems is highly complex in comparison with the traditional optically trapped microsphere. In this Article, we present a conceptually new and simple approach based on the nature of the optical force density. We illustrate the method through the design and fabrication of a shaped particle capable of acting as a passive force clamp, and we demonstrate its use as an optically trapped probe for imaging surface topography. Further applications of the design rules highlighted here may lead to new sensors for probing biomolecule mechanics, as well as to the development of optically actuated micromachines.
By tracking the divergence of two initially close trajectories in phase space in an Eulerian approach to forced turbulence, the relation between the maximal Lyapunov exponent λ and the Reynolds ...number Re is measured using direct numerical simulations, performed on up to 2048^{3} collocation points. The Lyapunov exponent is found to solely depend on the Reynolds number with λ∝Re^{0.53} and that after a transient period the divergence of trajectories grows at the same rate at all scales. Finally a linear divergence is seen that is dependent on the energy forcing rate. Links are made with other chaotic systems.
Obtaining a burning plasma is a critical step towards self-sustaining fusion energy
. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, ...which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule
through two different implosion concepts
. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics
. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.
PDF
