In order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2, the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic ...machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an
system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation and/or insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum antiviral agents.This article has an associated First Person interview with the first author of the paper.
A new method is described which calculates the velocity of observed, quasi‐stationary structures at every moment in time from multi‐point magnetic field measurements. Once the magnetic gradient ...tensor G = ∇ and the time variation of the magnetic field have been estimated at every moment, the velocity can then be determined, in principle, as a function of time. One striking property of this method is that we can calculate the velocity of structures for any dimensionality: for three‐dimensional structures, all three components of the velocity vector can be calculated directly; for two‐dimensional (or one‐dimensional) structures, we can calculate the velocity along two (or one) directions. The advantage of this method is that the velocity is determined instantaneously, point by point through any structure, and so we can see the time variation of the velocity as the spacecraft traverse the structure. In this paper, the feasibility of the method is tested by calculating the motion velocity of a three‐dimensional, near cusp structure and a two‐dimensional magnetotail current sheet. The results for one‐dimensional structures in the magnetopause and cusp boundaries are compared to calculations for the standard techniques for analyzing discontinuities.
We report a first-principles study on the electronic structures of deformed graphene nanoribbons (GNRs). Our theoretical results show that the electronic properties of zigzag GNRs are not sensitive ...to uniaxial strain, while the energy gap modification of armchair GNRs (AGNRs) as a function of uniaxial strain displays a nonmonotonic relationship with a zigzag pattern. The subband spacings and spatial distributions of the AGNRs can be tuned by applying an external strain. Scanning tunneling microscopy dI/dV maps can be used to characterize the nature of the strain states, compressive or tensile, of AGNRs. In addition, we find that the nearest neighbor hopping integrals between pi-orbitals of carbon atoms are responsible for energy gap modification under uniaxial strain based on our tight binding approximation simulations.
Ecdysone 20‐monooxygenase (E20MO), a cytochrome P450 monooxygenase (CYP314A1), catalyses the conversion of ecdysone (E) to 20‐hydroxyecdysone (20E). We report here the cloning and characterization of ...the Halloween gene Shade (Shd) encoding E20MO in the Colorado potato beetle, Leptinotarsa decemlineata. LdSHD has five conserved motifs typical of insect P450s, ie the Helix‐C, Helix‐I, Helix‐K, PxxFxPE/DRF (PERF) and heme‐binding motifs. LdShd was expressed in developing eggs, the first to fourth instars, wandering larvae, pupae and adults, with statistically significant fluctuations. Its mRNA was ubiquitously distributed in the head, thorax and abdomen. The recombinant LdSHD protein expressed in Spodoptera frugiperda 9 (Sf9) cells catalysed the conversion of E to 20E. Dietary introduction of double‐stranded RNA (dsRNA) of LdShd into the second instar larvae successfully knocked down the LdShd expression level, decreased the mRNA level of the ecdysone receptor (LdEcR) gene, caused larval lethality, delayed development and affected pupation. Moreover, ingestion of LdShd‐dsRNA by the fourth instars also down‐regulated LdShd and LdEcR expression, reduced the 20E titre, and negatively influenced pupation. Introduction of 20E and a nonsteroidal ecdysteroid agonist halofenozide into the LdShd‐dsRNA‐ingested second instars, and of halofenozide into the LdShd‐dsRNA‐ingested fourth instars almost completely relieved the negative effects on larval performance. Thus, LdSHD functions to regulate metamorphotic processes by converting E to 20E in a coleopteran insect species Le. decemlineata.
Mirror‐mode structures are widely observed in space plasma environments. Although plasma features within the structures have been extensively investigated in theoretical models and numerical ...simulations, relatively few observational studies have been made, due to a lack of high‐cadence measurements of particle distributions in previous space missions. In this work, electron dynamics associated with mirror‐mode structures are studied based on Magnetospheric Multiscale observations of electron pitch angle distributions. We define mirror‐mode peaks/troughs as the region where the magnetic field strength is greater/smaller than the mean field. The observations show that most electrons are trapped inside the mirror‐mode troughs and display a donut‐like pitch angle distribution configuration. Besides the trapped electrons in mirror‐mode troughs, we find that electrons are also trapped between ambient mirror‐mode peaks and coexisting untrapped electrons within the mirror‐mode structure. Analysis shows that the observed donut‐like electron distributions are the result of betatron cooling and the spatial dependence of electron pitch angles within the structure.
Key Points
Electron PADs of magnetosheath mirror modes are observed by MMS
The PADs display a characteristic donut‐like configuration
Betatron cooling and spatial dependence of electron pitch angle are able to produce such a distribution
Data from the two‐spacecraft Acceleration, Reconnection, Turbulence and Electrodynamics of the Moon's Interaction with the Sun mission to the Moon have been exploited to characterize the lunar wake ...with unprecedented fidelity. The differences between measurements made by a spacecraft in the solar wind very near the Moon and concurrent measurements made by a second spacecraft in the near lunar wake are small but systematic. They enabled us to establish the perturbations of plasma density, temperature, thermal, magnetic and total pressure, field, and flow downstream of the Moon to distances of 12 lunar radii (RM). The wake disturbances are initiated immediately behind the Moon by the diamagnetic currents at the lunar terminator. Rarefaction waves propagate outward at fast MHD wave velocities. Beyond ~6.5 RM, all plasma and field parameters are poorly structured which suggests the presence of instabilities excited by counter‐streaming particles. Inward flowing plasma accelerated through pressure gradient force and ambipolar electric field compresses the magnetic field and leads to continuous increase in magnitude of magnetic perturbations. Besides the downstream distance, the field perturbation magnitude is also a function of the solar wind ion beta and the angle between the solar wind and the interplanetary magnetic field (IMF). Both ion and electron temperatures increase as a consequence of an energy dispersion effect, whose explanation requires fully kinetic models. Downstream of the Moon, the IMF field lines are observed to bulge toward the Moon, which is unexpected and may be caused by a plasma pressure gradient force or/and the pickup of heavy charged dust grains behind the Moon.
Key Points
The 3‐D lunar wake is studied with well‐determined solar wind conditions
The field lines bend in the wake due to flow deceleration
The 3‐D wake structure is investigated by observation data
To correlate elastic parameters with collagen fibre shape and arrangement features in breast lesions.
Shear-wave elastography (SWE) was used to measure the stiffness of breast lesions in 54 patients ...before surgical removal. The value of stiffness was expressed as the mean and maximum elasticity (Emean and Emax). Lesions were sliced and stained with picric acid–sirius red to display the extracellular matrix (ECM) collagen fibre. The categories of the collagen fibres were based on the shape and arrangement features, i.e., category 0, wavy collagen fibres similar to normal breast tissue; category 1, taut parallel collagen fibres around tumour nests; category 2, straightened and aligned collagen fibres tending to be perpendicular to the tumour boundary; category 3, collagen fibre in a honeycomb arrangement. Bivariate correlation analysis was used to analyse the relationship between elastic parameters and collagen fibre category.
For all 54 lesions, the correlation coefficient between Emean and category was 0.693 (p < 0.001), and between Emax and category was 0.794 (p < 0.001). For 36 malignant lesions, the correlation coefficient between Emean and category was 0.658 (p < 0.001), and between Emax and category was 0.771 (p < 0.001).
Emean and Emax of breast lesions evaluated by SWE were positively correlated with ECM collagen fibre shape and arrangement category. Changes of ECM collagen fibre shape and arrangement may account for the stiffness variations of breast lesions.
•Category of collagen fibres shape and arrangement features in breast lesions was developed.•The mean and maximum elasticity of breast lesions evaluated by SWE were positively correlated with the category of collagen fibre shape and arrangement.•Changes of ECM collagen fibre shape and arrangement may account for the stiffness variations of breast lesions.
A single line of dangling bonds (DBs) on Si(100)-2 × 1:H surface forms a perfect metallic atomic-wire. In this work, we investigate quantum transport properties of such dangling bond wires (DBWs) by ...a state-of-the-art first-principles technique. It is found that the conductance of the DBW can be gated by electrostatic potential and orbital overlap due to only a single DB center (DBC) within a distance of ∼16 Å from the DBW. The gating effect is more pronounced for two DBCs and especially, when these two DB “gates” are within ∼3.9 Å from each other. These effective length scales are in excellent agreement with those measured in scanning tunnelling microscope experiments. By analyzing transmission spectrum and density of states of DBC–DBW systems, with or without subsurface doping, for different length of the DBW, distance between DBCs and the DBW, and distance between DB gates, we conclude that charge transport in a DBW can be regulated to have both an on-state and an off-state using only one or two DBs.
A model for pore pressure-dependent cleat permeability is presented for gas-desorbing, linear elastic coalbeds under uniaxial strain conditions experienced in producing reservoirs. In the model, ...changes in the cleat permeability of coalbeds, which are idealised to have a bundled matchstick geometry, is controlled by the prevailing effective horizontal stresses normal to the cleats. Variations in the effective horizontal stresses under uniaxial strain conditions are expressed as a function of pore pressure reduction during drawdown, which includes a cleat compression term and a matrix shrinkage term that have competing effects on cleat permeability. A comprehensive analysis has revealed that the shape of the stress – pore pressure curve is predominantly determined by the magnitude of recovery pressure and rebound pressure relative to the initial reservoir pressure. A total of five possible scenarios have been identified with regard to response of the horizontal stress function to reservoir drawdown. When applied to four coalbed wells at two separate sites in the fairway of the San Juan basin, the model predictions at one site, where the three wells have shown increased absolute permeability during gas production, are in excellent agreement with the published pore pressure dependent permeability changes that were obtained independently from history matching the field production data. At a separate site the model correctly predicts, at least qualitatively, a strong permeability rebound at lower drawdown pressures that has been inferred through history matching the production data. An analysis of the effects of initial reservoir pressure on the response of effective horizontal stress to drawdown was carried out, with reference to the range of pressure likely to be encountered in the San Juan basin. The implications of this in terms of pore pressure dependent permeability are discussed.
We investigate the plasma sheet pressure variations in the near‐Earth magnetotail (radius distance, R, from 7.5 RE to 12 RE and magnetic local time, MLT, from 18:00 to 06:00) during substorm growth ...phase with Time History of Events and Macroscale Interactions during Substorms (THEMIS) observations. It is found that, during the substorm growth phase, about 39.4% (76/193) of the selected events display a phenomenon of equatorial plasma pressure (Peq) decrease. The occurrence rates of Peq decrease cases are higher in the dawn (04:00 to 06:00) and dusk (18:00 to 20:00) flanks (> 50%) than in the midnight region (20:00 to 04:00, < 40%). The mean values of the maximum percentages of Peq decrease during the substorm growth phases are larger in the dawn and dusk flanks (~ −20%) than in the midnight region (~ > −16%). The mean value of Peq increase percentages at the end of substorm growth phase is the highest (~ 40%) in the premidnight MLT bin (22:00 to 00:00) and is almost unchanged in the dawn and dusk flanks. Further investigations show that 13.0% of the events have more than 10% of Peq decrease at the end of substorm growth phase comparing to the value before the growth phase, and ~ 28.0% of the events have small changes (< 10%), and ~ 59.0% events have a more than 10% increase. This study also reveals the importance of electron pressure (Pe) in the variation of Peq in the substorm growth phase. The Pe variations often account for more than 50% of the Peq changes, and the ratios of Pe to ion pressure often display large variations (~ 50%). Among the investigated events, during the growth phase, an enhanced equatorial plasma convection flow is observed, which diverges in the midnight tail region and propagates azimuthally toward the dayside magnetosphere with velocity of ~ 20 km/s. It is proposed that the Peq decreases in the near‐Earth plasma sheet during the substorm growth phase may be due to the transport of closed magnetic flux toward the dayside magnetosphere driven by dayside magnetopause reconnection. Both solar wind and ionospheric conductivity effects may influence the distributions of occurrence rates for Peq decrease events and the Peq increase percentages in the investigated region.
Key Points
About 40% of the selected events in the near‐tail region display a phenomenon of equatorial plasma pressure decrease
An enhanced equatorial convection with speed of ~ 20 km/s is observed in our cases during the substorm growth phase
Statistical studies for the distributions of Peq properties and electron pressure variations are performed
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