Aberrant activation of c-kit proto-oncogene contributes to abnormal cell proliferation by altering the tyrosine kinase signaling and constitutes a crucial impetus for leukemogenesis. Epigenetic ...silencing of tumor-suppressive microRNAs (miRNAs) is a key oncogenic mechanism for the activation of oncogenes in tumors. In this study, several miRNAs potentially binding to the 3'-untranslated region of human c-kit mRNA were screened by luciferase reporter assays. Among these miRNAs, miR-193a was embedded in a CpG island and epigenetically repressed by promoter hypermethylation in acute myeloid leukemia (AML) cell lines and primary AML blasts, but not in normal bone marrow cells. Importantly, miR-193a levels were inversely correlated with c-kit levels measured in 9 leukemia cell lines and 27 primary AML samples. Restoring miR-193a expression in AML cells harboring c-kit mutation and/or overexpression, either by synthetic miR-193a transfection or by DNA hypomethylating agent 5-azacytidine (5-aza) treatment, resulted in a significant reduction in c-kit expression at both RNA and protein levels and inhibition of cell growth. The growth-inhibitory activity of miR-193a was associated with apoptosis and granulocytic differentiation. Moreover, 5-aza-induced c-kit reduction could be partially blocked by miR-193a inhibitor, leading to a reversal of antiproliferative and proapoptotic effects of 5-aza. These data reveal a critical role for methylation-repressed miR-193a in myeloid leukemogenesis and the therapeutic promise of upregulating miR-193a expression for c-kit-positive AML.
Using combined data from the Relativistic Heavy Ion and Large Hadron Colliders, we constrain the shear and bulk viscosities of quark-gluon plasma (QGP) at temperatures of ∼ 150 – 350 MeV . We use ...Bayesian inference to translate experimental and theoretical uncertainties into probabilistic constraints for the viscosities. With Bayesian model averaging we propagate an estimate of the model uncertainty generated by the transition from hydrodynamics to hadron transport in the plasma's final evolution stage, providing the most reliable phenomenological constraints to date on the QGP viscosities.
We report on broadly based systematic investigations of the modeling components for open heavy-flavor diffusion and energy loss in strongly interacting matter in their application to heavy-flavor ...observables in high-energy heavy–ion collisions, conducted within an EMMI Rapid Reaction Task Force framework. Initial spectra including cold-nuclear-matter effects, a wide variety of space-time evolution models, heavy-flavor transport coefficients, and hadronization mechanisms are scrutinized in an effort to quantify pertinent uncertainties in the calculations of nuclear modification factors and elliptic flow of open heavy-flavor particles in nuclear collisions. We develop procedures for error assessments and criteria for common model components to improve quantitative estimates for the (low-momentum) heavy-flavor diffusion coefficient as a long-wavelength characteristic of QCD matter as a function of temperature, and for energy loss coefficients of high-momentum heavy-flavor particles.
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form ...heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1-RIP1 interaction is dispensable for necroptosis; RIP1-RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1-RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3-RIP3 interaction is required for necroptosis and RIP3-RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1-RIP3 heterodimer itself cannot induce necroptosis, the RIP1-RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1-RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.
An increasing number of reports have demonstrated enormous strength enhancements in titanium matrix composites (TiMCs) reinforced with graphene nanoflakes (GNFs) on account of the superior mechanical ...properties of GNFs. Unfortunately, the difficulty of uniform dispersion and severe interfacial reaction are simultaneously the most challenging and serious issues in GNFs reinforced TiMCs. In this work, we applied electroless plating method to prepare Ni decorated GNFs (Ni-GNFs) as a reinforcement in Ti matrix to uniformly disperse the GNFs in Ti matrix and relieve the severe interfacial reaction between metal and carbon nanophase. The composite reinforced by low content Ni-GNFs (0.05 wt%GNFs) exhibiting ultimate strength of 793 MPa (+40% compared to monolithic pure Ti), have been processed by short time ball milling process followed by spark plasma sintering (SPS) and hot-rolling (HR). Enormous strength increase of the composite can be attributed to a homogeneous distribution of Ni-GNFs in the Ti matrix coupled with the formation of special interface (Ti/Ti2Ni/nano-TiCX/Ni-GNFs). The load transfer mechanism of Ni-GNFs in composites was investigated by in-situ tensile test, which shows the great interfacial load transfer capability. This work provides a new strategy for dispersion and interface analysis of GNFs reinforced Ti matrix composites.
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Leptomeningeal metastases (LM) are more frequent in non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Due to limited access to leptomeningeal lesions, the ...purpose of this study was to explore the potential role of cerebrospinal fluid (CSF) as a source of liquid biopsy in patients with LM.
Primary tumor, CSF, and plasma in NSCLC with LM were tested by next-generation sequencing. In total, 45 patients with suspected LM underwent lumbar puncture, and those with EGFR mutations diagnosed with LM were enrolled.
A total of 28 patients were enrolled in this cohort; CSF and plasma were available in 26 patients, respectively. Driver genes were detected in 100% (26/26), 84.6% (22/26), and 73.1% (19/26) of samples comprising CSF cell-free DNA (cfDNA), CSF precipitates, and plasma, respectively; 92.3% (24/26) of patients had much higher allele fractions in CSF cfDNA than the other two media. Unique genetic profiles were captured in CSF cfDNA compared with those in plasma and primary tissue. Multiple copy number variations (CNVs) were mainly identified in CSF cfDNA, and MET copy number gain identified in 47.8% (11/23) of patients was the most frequent one, while other CNVs included ERBB2, KRAS, ALK, and MYC. Moreover, loss of heterozygosity (LOH) of TP53 was identified in 73.1% (19/26) CSF cfDNA, which was much higher than that in plasma (2/26, 7.7%; P<0.001). There was a trend towards a higher frequency of concomitant resistance mutations in patients with TP53 LOH than those without (70.6% versus 33.3%; P=0.162). EGFR T790M was identified in CSF cfDNA of 30.4% (7/23) of patients who experienced TKI progression.
CSF cfDNA could reveal the unique genetic profiles of LM and should be considered as the most representative liquid biopsy medium for LM in EGFR-mutant NSCLC.
Protein concentrates were prepared from heat-stabilized defatted rice bran and analyzed for their functional properties. Rice bran proteins were prepared by alkaline extracted and Alcalase 2.4L ...hydrolysis. The yield of rice bran proteins were 32.9% and 44.79%, respectively. Rice bran proteins had molecular sizes between 0.1 and over 97.4kDa; maximum solubilities of 72.5% and 84.56% at pH 11.0; maximum emulsifying capacities of 0.149 and 0.634; maximum emulsion stabilities of 24.26 and 25.96min; maximum foam capacities of 98% and 115%; maximum foam stabilities of 30.6 and 26.9mL at 30min; water absorption of 3.71 and 4.4g/g and oil absorption of 4.24 and 5.13g/g. These results demonstrate that the extracted rice bran protein has potential as a nutraceutical ingredient in food applications.
► Commercial microwave links are a novel method for measuring instantaneous rainfall. ► 676h of rainfall are evaluated using 2 different calculating methodologies. ► Correlation values compared with rain gauges reach 0.85 for 10min rainfall. ► Measuring skill improves as density of microwave link grid increases.
Evolution of crystalline quality of AlN
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high-temperature (HT) annealing induced by different sapphire pretreatments is investigated. It is found that after HT annealing at 1700 °C for one hour, ...an AlN film grown on a nitridation treated sapphire substrate presents a much lower threading dislocation density (TDD) than that grown on an alumination treated one, indicating that the combination of nitridation and HT annealing is a more effective approach to achieve high quality AlN. It is verified that the much greater grain density of the nucleation layer induced by nitridation can produce more columns with much smaller sizes so that they can more easily rotate during the HT annealing to reduce the TDD more effectively. A deep ultraviolet light-emitting diode (285 nm) with an output power over 10 mW has been demonstrated on a HT annealed AlN template with sapphire substrate nitridation pretreatment, showing great potential for applications.
Evolution of crystalline quality of AlN
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high-temperature (HT) annealing induced by different sapphire pretreatments is investigated.
Microplastics (plastic particles <5 mm) are an emerging concern in Arctic sea ice with measured concentrations orders of magnitude higher than in surface seawater. However, incorporation of ...microplastics into sea ice, and their impact on sea ice properties, is unknown. We added microplastic particles in a microcosm experiment to determine microplastic distributions and effects on sea ice properties. Microplastic additions did not affect sea ice growth, but high concentrations of microplastics at the ice surface resulted in high ice salinity and changes in sea ice albedo. Field studies in the Gulf of Bothnia (Baltic Sea) showed sea ice concentration of microplastics from 8 to 41 particles per liter of melted ice, wich were much lower than those found to impact sea ice properties in the microcosm experiments. However, should microplastic concentrations increase, microplastic incorporation in sea ice may impact sea ice albedo.
•Microplastics are concentrated within sea ice compared from underlying seawater.•Microplastic within sea ice does not affect the sea ice growth.•High microplastics concentration seems to affect sea ice salinity and albedo.
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