Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice ...display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of
ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.
Solidarity means strength: In new silole luminogens, the solid aggregates are stronger emitters than isolated molecules. The solid‐state emission is tunable by varying molecular structures of the ...luminogens. Increasing bulkiness of the substituents weakens intermolecular interactions and restricts intramolecular rotations, leading to a blue shift in emission color and a great increase in emission efficiency (see examples in picture).
The mechanisms by which AML1/ETO (A/E) fusion protein induces leukemogenesis in acute myeloid leukemia (AML) without mutagenic events remain elusive. Here we show that interactions between A/E and ...hypoxia-inducible factor 1α (HIF1α) are sufficient to prime leukemia cells for subsequent aggressive growth. In agreement with this, HIF1α is highly expressed in A/E-positive AML patients and strongly predicts inferior outcomes, regardless of gene mutations. Co-expression of A/E and HIF1α in leukemia cells causes a higher cell proliferation rate in vitro and more serious leukemic status in mice. Mechanistically, A/E and HIF1α form a positive regulatory circuit and cooperate to transactivate DNMT3a gene leading to DNA hypermethylation. Pharmacological or genetic interventions in the A/E-HIF1α loop results in DNA hypomethylation, a re-expression of hypermethylated tumor-suppressor p15(INK4b) and the blockage of leukemia growth. Thus high HIF1α expression serves as a reliable marker, which identifies patients with a poor prognosis in an otherwise prognostically favorable AML group and represents an innovative therapeutic target in high-risk A/E-driven leukemia.
ABSTRACT The events recorded by ARGO-YBJ in more than five years of data collection have been analyzed to determine the diffuse gamma-ray emission in the Galactic plane at Galactic longitudes 25° < l ...< 100° and Galactic latitudes . The energy range covered by this analysis, from ∼350 GeV to ∼2 TeV, allows the connection of the region explored by Fermi with the multi-TeV measurements carried out by Milagro. Our analysis has been focused on two selected regions of the Galactic plane, i.e., 40° < l < 100° and 65° < l < 85° (the Cygnus region), where Milagro observed an excess with respect to the predictions of current models. Great care has been taken in order to mask the most intense gamma-ray sources, including the TeV counterpart of the Cygnus cocoon recently identified by ARGO-YBJ, and to remove residual contributions. The ARGO-YBJ results do not show any excess at sub-TeV energies corresponding to the excess found by Milagro, and are consistent with the predictions of the Fermi model for the diffuse Galactic emission. From the measured energy distribution we derive spectral indices and the differential flux at 1 TeV of the diffuse gamma-ray emission in the sky regions investigated.
To investigate the health-related quality of life (HRQoL) of patients receiving allogeneic hematopoietic SCT (allo-HSCT) from HLA-haploidentical/partially matched related donors (HID/PMRD) and to ...compare this value with that of patients receiving allo-HSCT from HLA-identical sibling donor (ISD), a total of 350 patients receiving allo-HSCT were enrolled in a study (ISD: 173; HID/PMRD: 177). HRQoL post transplantation was evaluated by an SF-36 questionnaire. The effect of various factors on the HRQoL was analyzed through COX regression. Compared with the ISD group, patients in the HID/PMRD group had higher scores in physical functioning, general health, bodily pain, vitality and emotional role functioning, and these patients functioned significantly better on the physical and mental component summaries. Also, long-term survivors exhibit better HRQoL. Measured by multivariate analysis, extensive chronic GVHD was observed to have a strongly negative impact on patients' HRQoL, while male gender status, lower age when receiving allo-HSCT and returning to work or school were associated with positive impacts on at least one subscale. These results showed that the HRQoL of patients receiving HID/PMRD hematopoietic SCT (HSCT) is comparable to that of patients receiving ISD HSCT, and HLA disparity is not the factor affecting the HRQoL.
The effects of Ru on the tensile properties and deformation mechanism of the two alloys were investigated in detail at room temperature, 760 °C and 1100 °C. The microstructures of the two alloys ...after the tensile deformation were obtained via the TEM. Based on the microstructures, the increase of Ru further reduced the stacking faults energy at room temperature and 760 °C, which promoted the formation of stacking faults in the γ matrix and γ' phase. These stacking faults were seldom observed in the previous works. On the other hand, the slipping of dislocations was effectively hindered due to the stacking faults, which was contributed to tensile properties and work-hardening. Moreover, the dislocation pile-up groups were mainly shown on the γ/γ' interface of the alloy containing 2.5 wt % Ru at 760 °C, which was conducive to the work-hardening but harmful to the tensile properties. Hence, the yield strength and ultimate tensile stress were significantly improved with the increase of Ru at room temperature and 760 °C. The brittleness of the two alloys was improved with the increase of Ru at 760 °C due to the combined action of stacking faults, K–W locks, increase of the strength of γ' phase and high flow stress. Besides, the motion of the dislocations changed from cutting into the γ' phase to bowing out the γ' phase at 1100 °C. This movement mode of dislocations was promoted with the increase of Ru due to the wider γ matrix channels, which induced a slight decrease in tensile properties. Finally, the relation between deformation mechanisms and tensile behaviors was explained in detail according to the microstructures and tensile curves.
Proper immune responses are critical for successful biomaterial implantation. Here, four scales of honeycomb-like TiO
structures were custom made on titanium (Ti) substrates to investigate cellular ...behaviors of RAW 264.7 macrophages and their immunomodulation on osteogenesis. We found that the reduced scale of honeycomb-like TiO
structures could significantly activate the anti-inflammatory macrophage phenotype (M2), in which the 90-nanometer sample induced the highest expression level of CD206,
, and
and released the highest amount of
among other scales. Afterward, the resulting immune microenvironment favorably triggered osteogenic differentiation of murine mesenchymal stem cells in vitro and subsequent implant-to-bone osteointegration in vivo. Furthermore, transcriptomic analysis revealed that the minimal scale of TiO
honeycomb-like structure (90 nanometers) facilitated macrophage filopodia formation and up-regulated the Rho family of guanosine triphosphatases (
), which reinforced the polarization of macrophages through the activation of the RhoA/Rho-associated protein kinase signaling pathway.
High-energy photons from the Crab Nebula
The Crab Nebula contains a pulsar that excites the surrounding gas to emit high-energy radiation. The combination of the pulsar's youth and nearby location ...makes the nebula the brightest gamma-ray source in the sky. The LHAASO Collaboration report observations of this source at energies of tera– to peta–electron volts, extending the spectrum of this prototypical object. They combine these data with observations at lower energies to model the physics of the emission process. The multiwave-length data can be explained by a combination of synchrotron radiation and inverse Compton scattering.
Science
, abg5137, this issue p.
425
Detection of the Crab Nebula at peta–electron volt energies constrains the gamma-ray emission mechanism.
The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10
−4
to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10
36
ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.
Wind energy development in built environment is important for the future sustainable cities. The effects of corner modifications (benchmark, recessed, chamfered, and rounded roofs) and wind angles ...(θ = 0°, 22.5°, and 45°) over the flat rooftops of tall buildings were investigated through computational fluid dynamics (CFD) simulations. The velocity, turbulence intensity, skew angle, wind energy, and installation of wind turbines over roofs were also examined. The vertical wind profiles over the rooftops showed similar patterns at various corner modifications. The rounded and chamfered roofs showed higher velocities and lower turbulence intensities than the benchmark and recessed roofs, which can be attributed to the smooth flow separation from leading edges and the flow reattachment over the rounded and chamfered roofs. The hub heights were significantly lower at θ = 45° than those at 0° and 22.5°, due to the thinner boundary layer over roofs at θ = 45°. The highest wind energy amplification factor of 2.0 occurred over the rounded roof. The rounded roof was found to be ideal for the installation of wind turbines, due to the high velocity (more energy), low turbulence (small fatigue loads of wind turbines), and low installation height (low cost).
•Flow features and energy over roofs of tall buildings are investigated by CFD.•Effect of corner modification (sharp, recess, chamfer, and round) is examined.•larger wind angles induce larger zones of higher velocity and lower hub height.•Rounded roofs have a great potential for high energy yield and are idea for turbines.•Smooth flow separation and reattachment occur on rounded and chamfered roofs.
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