Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we ...show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.
Abstract
Wild teas are valuable genetic resources for studying domestication and breeding. Here we report the assembly of a high-quality chromosome-scale reference genome for an ancient tea tree. The ...further RNA sequencing of 217 diverse tea accessions clarifies the pedigree of tea cultivars and reveals key contributors in the breeding of Chinese tea. Candidate genes associated with flavonoid biosynthesis are identified by genome-wide association study. Specifically, diverse allelic function of
CsANR
,
CsF3’5’H
and
CsMYB5
is verified by transient overexpression and enzymatic assays, providing comprehensive insights into the biosynthesis of catechins, the most important bioactive compounds in tea plants. The inconspicuous differentiation between ancient trees and cultivars at both genetic and metabolic levels implies that tea may not have undergone long-term artificial directional selection in terms of flavor-related metabolites. These genomic resources provide evolutionary insight into tea plants and lay the foundation for better understanding the biosynthesis of beneficial natural compounds.
Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent ...immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin “inflammation-driven angiogenesis.” We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (αvβ3) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (αvβ3)-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (αvβ3) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, we provide an interactive and controllable GBM tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in GBM angiogenesis, paving a new direction of screening novel anti-angiogenic therapies.
A small nonaxisymmetric (3D) magnetic field can induce nonambipolar transport of the particle species confined in a tokamak and thus a significant change of plasma rotation. This process can be in a ...favor of instability control in the region where the tokamak plasma is sufficiently collisional and resistive, as observed in the applications of n=1 resonant magnetic perturbations to the KSTAR tokamak. The plasma rotation can be globally accelerated due to radially drifting electrons and constrained to the electron root, if the radial transport is enhanced by an amplified 3D response. This mechanism is verified by a kinetically self-consistent magnetohydrodynamic modeling for both response and transport, which offers the quantitative explanations on the internal n=1 structure detected by electron-cyclotron-emission imaging and the cocurrent plasma spinning observed in the experiments.
Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological ...databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica.edu.tw.
A theoretical and numerical investigation of non-ponderomotive absorption at laser intensities relevant to quantum electrodynamics is presented. It is predicted that there is a regime change in the ...dependence of fast electron energy on incident laser energy that coincides with the onset of pair production via the Breit-Wheeler process. This prediction is numerically verified via an extensive campaign of QED-inclusive particle-in-cell simulations. The dramatic nature of the power law shift leads to the conclusion that this process is a candidate for an unambiguous signature that future experiments on multi-petawatt laser facilities have truly entered the QED regime.
Zr65.5-xHfxNb3Cu13Ni11Al7.5 (x = 0.0, 0.5, 1.0, 1.5 and 2.0 at.%) bulk metallic glasses (BMGs) were successfully prepared by copper mold casting. The effects of minor Hf addition on the mechanical ...properties and fracture mechanisms were investigated. The quasi-static compressive mechanical properties of Zr65.5-xHfxNb3Cu13Ni11Al7.5 alloys were significantly improved by Hf addition. The optimum compressive fracture strength (σf) and fracture strain (εf) are 1516 MPa and 2.6%, respectively, for the Zr64.5Hf1.0Nb3Cu13Ni11Al7.5 alloy. The impact toughness of the Zr64Hf1.5Nb3Cu13Ni11Al7.5 alloy (Ak = 127 kJ/m2) is nearly four times than that of the Zr65.5Nb3Cu13Ni11Al7.5 alloy (Ak = 33 kJ/m2). The increase of the fracture surface area and the ratio of vein-like patterns regions caused by Hf addition play an important role in fracture energy dissipation under dynamic loading. The dependence of mechanical properties on the Hf content is closely related to the variation of free volume in the current alloys. The relationship between the Hf addition and the free volume change is discussed in detail. These results may provide new insights into simultaneously enhancing the plasticity and toughness of BMGs with minor alloying.
•Compressive properties and impact toughness could be simultaneously enhanced.•A model considering the bond shortening was proposed and discussed.•The free volume change caused by bond shortening was divided into two categories.•The correlation between free volume and mechanical properties is clearly described.
ABSTRACT
We analyse the physical properties of 121 SNR ≥ 5 sub-millimetre galaxies (SMGs) from the STUDIES 450 μm survey. We model their UV-to-radio spectral energy distributions using ...magphys+photo-z and compare the results to similar modelling of 850 μm-selected SMG sample from AS2UDS, to understand the fundamental physical differences between the two populations at the observed depths. The redshift distribution of the 450-μm sample has a median of z = 1.85 ± 0.12 and can be described by strong evolution of the far-infrared luminosity function. The fainter 450-μm sample has ∼14 times higher space density than the brighter 850-μm sample at z ≲ 2, and a comparable space density at z = 2–3, before rapidly declining, suggesting LIRGs are the main obscured population at z ∼ 1–2, while ULIRGs dominate at higher redshifts. We construct rest-frame ∼180-μm-selected and dust-mass-matched samples at z = 1–2 and z = 3–4 from the 450 and 850-μm samples, respectively, to probe the evolution of a uniform sample of galaxies spanning the cosmic noon era. Using far-infrared luminosity, dust masses, and an optically thick dust model, we suggest that higher redshift sources have higher dust densities due to inferred dust continuum sizes which are roughly half of those for the lower redshift population at a given dust mass, leading to higher dust attenuation. We track the evolution in the cosmic dust mass density and suggest that the dust content of galaxies is governed by a combination of both the variation of gas content and dust destruction time-scale.
The hot massive luminous blue variables (LBVs) represent an important evolutionary phase of massive stars. Here, we report the discovery of a new LBV-LAMOST J0037+4016 in the distant outskirt of the ...Andromeda galaxy. It is located in the southwestern corner (a possible faint spiral arm) of M31 with an unexpectedly large projection distance of ∼22 kpc from the center. The optical light curve shows a 1.2 mag variation in V band and its outburst and quiescence phases both last over several years. The observed spectra indicate an A-type supergiant at an epoch close to the outburst phase and a hot B-type supergiant with weak Fe ii emission lines at an epoch of much dimmer brightness. The near-infrared color-color diagram further shows that it follows the distribution of Galactic and M31 LBVs rather than Be supergiants. All the existing data strongly show that LAMOST J0037+4016 is an LBV. By spectral energy distribution fitting, we find it has a luminosity (4.42 1.64) × 105 L and an initial mass ∼30 M , indicating its nature of a less luminosity class of LBV.
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