Odorant binding proteins (OBPs) and chemosensory proteins (CSPs) play essential roles in insect chemosensory recognition. Here, we identified nine OBPs and nine CSPs from the Myzus persicae ...transcriptome and genome. Genomic structure analysis showed that the number and length of the introns are much higher, and this appears to be a unique feature of aphid OBP genes. Three M. persicae OBP genes (OBP3/7/8) as well as CSP1/4/6, CSP2/9 and CSP5/8 are tandem arrayed in the genome. Phylogenetic analyses of five different aphid species suggest that aphid OBPs and CSPs are conserved in single copy across all aphids (with occasional losses), indicating that each OBP and CSP class evolved from a single gene in the common ancestor of aphids without subsequent duplication. Motif pattern analysis revealed that aphid OBP and CSP motifs are highly conserved, and this could suggest the conserved functions of aphid OBPs and CSPs. Three OBPs (MperOBP6/7/10) are expressed antennae specifically, and five OBPs (MperOBP2/4/5/8/9) are expressed antennae enriched, consistent with their putative olfactory roles. M. persicae CSPs showed much broader expression profiles in nonsensory organs than OBPs. None of the nine MperCSPs were found to be antennae specific, but five of them (MperCSP1/2/4/5/6) showed higher expression levels in the legs than in other tissues. MperCSP10 mainly expressed in the antennae and legs. The broad and diverse expression patterns of M. persicae CSPs suggest their multifunctions in olfactory perception, development and other processes.
PDFfit2 is a program as well as a library for real-space refinement of crystal structures. It is capable of fitting a theoretical three-dimensional (3D) structure to atomic pair distribution function ...data and is ideal for nanoscale investigations. The fit system accounts for lattice constants, atomic positions and anisotropic atomic displacement parameters, correlated atomic motion, and experimental factors that may affect the data. The atomic positions and thermal coefficients can be constrained to follow the symmetry requirements of an arbitrary space group. The PDFfit2 engine is written in C++ and is accessible via Python, allowing it to inter-operate with other Python programs. PDFgui is a graphical interface built on the PDFfit2 engine. PDFgui organizes fits and simplifies many data analysis tasks, such as configuring and plotting multiple fits. PDFfit2 and PDFgui are freely available via the Internet.
We report observations of gamma-ray emissions with energies in the 100-TeV energy region from the Cygnus region in our Galaxy. Two sources are significantly detected in the directions of the Cygnus ...OB1 and OB2 associations. Based on their positional coincidences, we associate one with a pulsar PSR J2032 + 4127 and the other mainly with a pulsar wind nebula PWN G75.2 + 0.1, with the pulsar moving away from its original birthplace situated around the centroid of the observed gamma-ray emission. This work would stimulate further studies of particle acceleration mechanisms at these gamma-ray sources.
When deformed beyond their elastic limits, crystalline solids flow plastically via particle rearrangements localized around structural defects. Disordered solids also flow, but without obvious ...structural defects. We link structure to plasticity in disordered solids via a microscopic structural quantity, “softness,” designed by machine learning to be maximally predictive of rearrangements. Experimental results and computations enabled us to measure the spatial correlations and strain response of softness, as well as two measures of plasticity: the size of rearrangements and the yield strain. All four quantities maintained remarkable commonality in their values for disordered packings of objects ranging from atoms to grains, spanning seven orders of magnitude in diameter and 13 orders of magnitude in elastic modulus. These commonalities link the spatial correlations and strain response of softness to rearrangement size and yield strain, respectively.
We present sensitive 850 m imaging of the Cosmological Evolution Survey (COSMOS) field using 640 hr of new and archival observations taken with SCUBA-2 at the East Asian Observatory's James Clerk ...Maxwell Telescope. The SCUBA-2 COSMOS survey (S2COSMOS) achieves a median noise level of 850 m = 1.2 mJy beam−1 over an area of 1.6 sq. degree (main; Hubble Space Telescope/Advanced Camera for Surveys footprint), and 850 m = 1.7 mJy beam−1 over an additional 1 sq. degree of supplementary (supp) coverage. We present a catalog of 1020 and 127 sources detected at a significance level of >4 and >4.3 in the main and supp regions, respectively, corresponding to a uniform 2% false-detection rate. We construct the single-dish 850 m number counts at S850 > 2 mJy and show that these S2COSMOS counts are in agreement with previous single-dish surveys, demonstrating that degree-scale fields are sufficient to overcome the effects of cosmic variance in the S850 = 2-10 mJy population. To investigate the properties of the galaxies identified by S2COSMOS sources we measure the surface density of near-infrared-selected galaxies around their positions and identify an average excess of 2.0 0.2 galaxies within a 13″ radius (∼100 kpc at z ∼ 2). The bulk of these galaxies represent near-infrared-selected submillimeter galaxies and/or spatially correlated sources and lie at a median photometric redshift of z = 2.0 0.1. Finally, we perform a stacking analysis at submillimeter and far-infrared wavelengths of stellar-mass-selected galaxies (M = 1010-1012 M ) from z = 0-4, obtaining high-significance detections at 850 m in all subsets (signal-to-noise ratio, S/N = 4-30), and investigate the relation between far-infrared luminosity, stellar mass, and the peak wavelength of the dust spectral energy distribution. The publication of this survey adds a new deep, uniform submillimeter layer to the wavelength coverage of this well-studied COSMOS field.
Powerful terahertz (THz) radiation is observed from large-scale underdense preplasmas in front of a solid target irradiated obliquely with picosecond relativistic intense laser pulses. The radiation ...covers an extremely broad spectrum with about 70% of its energy located in the high frequency regime over 10 THz. The pulse energy of the radiation is found to be above 100 μJ per steradian in the laser specular direction at an optimal preplasma scale length around 40-50 μm. Particle-in-cell simulations indicate that the radiation is mainly produced by linear mode conversion from electron plasma waves, which are excited successively via stimulated Raman scattering instability and self-modulated laser wakefields during the laser propagation in the preplasma. This radiation can be used not only as a powerful source for applications, but also as a unique diagnostic of parametric instabilities of laser propagation in plasmas.
Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently ...demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited.
This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET FISH.
We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n = 10; pralsetinib, n = 7; pralsetinib followed by selpercatinib, n = 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months 95% confidence interval 3.6–10.8 months. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation.
RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.
•Resistance is a major challenge in RET fusion-positive lung cancer treated with RET tyrosine kinase inhibitors (TKIs).•RET mutations involving the solvent front residue G810 are a recurrent yet infrequent mechanism of resistance to RET TKIs.•The majority of resistance to selective RET inhibition is driven by RET-independent resistance, such as MET amplification.•RET TKIs with potency against RET solvent front mutations and combination strategies are needed to overcome resistance.
In the Earth's magnetotail, magnetic reconnection releases stored magnetic energy and drives magnetospheric convection. The rate at which magnetic flux is transferred from the reconnection inflow to ...outflow regions is determined by the reconnection electric field Er, which is often referred to as the unnormalized reconnection rate. To better quantify the efficiency of reconnection, this electric field Er is often normalized by the characteristic Alfvén speed and the reconnecting magnetic field. This parameter is generally called the normalized or dimensionless reconnection rate R. In this paper, we employ a two‐dimensional fully kinetic simulation to model a magnetotail reconnection event with weak geomagnetic activity (<200 nT of the AE index) observed by the Magnetospheric Multiscale (MMS) mission on 11 July 2017. We obtain R and Er from direct measurements in the diffusion region and indirect measurements of the rate at the separatrix using a recently proposed remote sensing technique. The measured normalized rate for this MMS event is R ∼0.15–0.2, consistent with theoretical and simulation models of fast collisionless reconnection. This corresponds to an unnormalized rate of Er ∼2–3 mV/m. Based on quantitative consistencies between the simulation and the MMS observations, we conclude that our estimates of the reconnection rates are reasonably accurate. Given that past studies have found Er of the order ∼10 mV/m during strong geomagnetic substorms, these results indicate that the local Er in magnetotail reconnection may be an important parameter controlling the amplitude of geomagnetic disturbances.
Key Points
Reliable reconnection rates are obtained based on virtual observations in a fully kinetic simulation of an MMS tail reconnection event
The normalized rates obtained from the simulation and MMS data are 0.15–0.2, indicating the occurrence of fast reconnection
The observed unnormalized rate is 2–3 mV/m, while higher rates were observed in other events with stronger geomagnetic activities
Physiologically based pharmacokinetic (PBPK) modeling and simulation is a tool that can help predict the pharmacokinetics of drugs in humans and evaluate the effects of intrinsic (e.g., organ ...dysfunction, age, genetics) and extrinsic (e.g., drug–drug interactions) factors, alone or in combinations, on drug exposure. The use of this tool is increasing at all stages of the drug development process. This report reviews recent instances of the use of PBPK in decision‐making during regulatory review. The examples are based on Center for Drug Evaluation and Research reviews of several submissions for investigational new drugs (INDs) and new drug applications (NDAs) received between July 2008 and June 2010. The use of PBPK modeling and simulation facilitated the following types of decisions: the need to conduct specific clinical pharmacology studies, specific study designs, and appropriate labeling language. The report also discusses the challenges encountered when PBPK modeling and simulation were used in these cases and recommends approaches to facilitating full utilization of this tool.
Clinical Pharmacology & Therapeutics (2011) 89 2, 259–267. doi:10.1038/clpt.2010.298
Amorphous solids lack long-range order. Therefore identifying structural defects -- akin to dislocations in crystalline solids -- that carry plastic flow in these systems remains a daunting ...challenge. By comparing many different structural indicators in computational models of glasses, under a variety of conditions we carefully assess which of these indicators are able to robustly identify the structural defects responsible for plastic flow in amorphous solids. We further demonstrate that the density of defects changes as a function of material preparation and strain in a manner that is highly correlated with the macroscopic material response. Our work represents an important step towards predicting how and when an amorphous solid will fail from its microscopic structure.
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