Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ...ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T lymphocyte-signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.
Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal ...cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes.
Large-scale, highly integrated and low-power-consuming hardware is becoming progressively more important for realizing optical neural networks (ONNs) capable of advanced optical computing. ...Traditional experimental implementations need N
units such as Mach-Zehnder interferometers (MZIs) for an input dimension N to realize typical computing operations (convolutions and matrix multiplication), resulting in limited scalability and consuming excessive power. Here, we propose the integrated diffractive optical network for implementing parallel Fourier transforms, convolution operations and application-specific optical computing using two ultracompact diffractive cells (Fourier transform operation) and only N MZIs. The footprint and energy consumption scales linearly with the input data dimension, instead of the quadratic scaling in the traditional ONN framework. A ~10-fold reduction in both footprint and energy consumption, as well as equal high accuracy with previous MZI-based ONNs was experimentally achieved for computations performed on the MNIST and Fashion-MNIST datasets. The integrated diffractive optical network (IDNN) chip demonstrates a promising avenue towards scalable and low-power-consumption optical computational chips for optical-artificial-intelligence.
Nb-bearing nickel-based superalloys were fabricated by laser additive manufacturing using both continuous-wave (CW) and quasi-continuous-wave (QCW) laser modes. Effects of laser modes on Nb ...segregation and Laves phase morphology were investigated. The responses to aging treatments of two different fabricated samples were also investigated. CW mode tends to develop columnar dendrites, relative severe Nb segregation and continuous distributed Laves phase, while QCW mode tends to produce fine equiaxed dendrites, less Nb segregations and fine discrete Laves phase. In addition, the QCW sample responses better to aging treatment than the CW sample.
•A quasi-continuous-wave laser additive manufacturing is proposed to control Laves phase formation of Inconel 718.•Fine and discrete Lave phase particles with reduced Nb segregation are obtained.•The mechanism relies on high cooling rate, high dendrite growth rate and improved solute trapping.•Good aging response indicates the effective control of Nb segregation.
Majorana zero-modes-a type of localized quasiparticle-hold great promise for topological quantum computing. Tunnelling spectroscopy in electrical transport is the primary tool for identifying the ...presence of Majorana zero-modes, for instance as a zero-bias peak in differential conductance. The height of the Majorana zero-bias peak is predicted to be quantized at the universal conductance value of 2e
/h at zero temperature (where e is the charge of an electron and h is the Planck constant), as a direct consequence of the famous Majorana symmetry in which a particle is its own antiparticle. The Majorana symmetry protects the quantization against disorder, interactions and variations in the tunnel coupling. Previous experiments, however, have mostly shown zero-bias peaks much smaller than 2e
/h, with a recent observation of a peak height close to 2e
/h. Here we report a quantized conductance plateau at 2e
/h in the zero-bias conductance measured in indium antimonide semiconductor nanowires covered with an aluminium superconducting shell. The height of our zero-bias peak remains constant despite changing parameters such as the magnetic field and tunnel coupling, indicating that it is a quantized conductance plateau. We distinguish this quantized Majorana peak from possible non-Majorana origins by investigating its robustness to electric and magnetic fields as well as its temperature dependence. The observation of a quantized conductance plateau strongly supports the existence of Majorana zero-modes in the system, consequently paving the way for future braiding experiments that could lead to topological quantum computing.
Systemic delivery of mRNA-based therapeutics remains a challenging issue for preclinical and clinical studies. Here, we describe new lipid-like nanoparticles (TT-LLNs) developed through an orthogonal ...array design, which demonstrates improved delivery efficiency of mRNA encoding luciferase in vitro by over 350-fold with significantly reduced experimental workload. One optimized TT3 LLN, termed O-TT3 LLNs, was able to restore the human factor IX (hFIX) level to normal physiological values in FIX-knockout mice. Consequently, these mRNA based nanomaterials merit further development for therapeutic applications.
We present X-ray timing results of the new black hole candidate MAXI J1535−571 during its 2017 outburst from Hard X-ray Modulation Telescope (Insight-HXMT) observations taken from 2017 September 6 to ...23. Following the definitions given by Belloni, we find that the source exhibits transitions from the low/hard state to the hard intermediate state, and eventually to the soft intermediate state. Quasi-periodic oscillations (QPOs) are found in the intermediate states, which suggest different types of QPOs. With the large effective area of Insight-HXMT at high energies, we are able to present the energy dependence of the QPO amplitude and centroid frequency up to 100 keV, which has rarely been explored by previous satellites. We also find that the phase lag at the type-C QPOs centroid frequency is negative (soft lag) and strongly correlated with the centroid frequency. Assuming a geometrical origin of type-C QPOs, the source is consistent with being a high-inclination system.
Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the ...accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of “dedifferentiated” vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsoninsensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don’t eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.
Abstract
The fast transitions between different types of quasi-periodic oscillations (QPOs) are generally observed in black hole transient sources (BHTs). We present a detailed study of the timing ...and spectral properties of the transitions of type-B QPOs in MAXI J1348–630, observed by Insight-HXMT. The fractional rms variability–energy relationship and energy spectra reveal that type-B QPOs probably originate from jet precession. Compared to a weak power-law dominated power spectrum, when type-B QPOs are present, the corresponding energy spectrum shows an increase in the Comptonization component and the need for the
xillverCp
component, and a slight increase in the height of the corona when using the
relxilllp
model. Therefore, we suggest that a coupled inner disk-jet region is responsible for the observed type-B QPO transitions. The timescale for the appearance/disappearance of type-B QPOs is either long or short (seconds), which may indicate instability of the disk-jet structure. For these phenomena, we hypothesize that the Bardeen–Petterson effect causes the disk-jet structure to align with the BH spin axis or that the disappearance of small-scale jets bound by the magnetic flux tubes leads to the disappearance of type-B QPOs. We observed three events regarding the B/C transitions, one of which occurred over a short time period from ∼9.2 Hz (C) to ∼4.8 Hz (B). The energy spectral analysis for the other two transitions shows that when type-C QPO is present, the Comptonization flux is higher, the spectrum is harder, and the inner radius of the disk changes insignificantly. We suggest that type-C QPOs probably originate from relatively stronger jets or the corona.
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