Cancer associated fibroblasts (CAFs) are key stroma cells that play dominant roles in tumor progression. However, the CAFs-derived molecular determinants that regulate colorectal cancer (CRC) ...metastasis and chemoresistance have not been fully characterized.
CAFs and NFs were obtained from fresh CRC and adjacent normal tissues. Exosomes were isolated from conditioned medium and serum of CRC patients using ultracentrifugation method and ExoQuick Exosome Precipitation Solution kit, and characterized by transmission electronic microscopy, nanosight and western blot. MicroRNA microarray was employed to identify differentially expressed miRNAs in exosomes secreted by CAFs or NFs. The internalization of exosomes, transfer of miR-92a-3p was observed by immunofluorescence. Boyden chamber migration and invasion, cell counting kit-8, flow cytometry, plate colony formation, sphere formation assays, tail vein injection and primary colon cancer liver metastasis assays were employed to explore the effect of NFs, CAFs and exosomes secreted by them on epithelial-mesenchymal transition, stemness, metastasis and chemotherapy resistance of CRC. Luciferase report assay, real-time qPCR, western blot, immunofluorescence, and immunohistochemistry staining were employed to explore the regulation of CRC metastasis and chemotherapy resistance by miR-92a-3p, FBXW7 and MOAP1.
CAFs promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of CRC cells. Importantly, CAFs exert their roles by directly transferring exosomes to CRC cells, leading to a significant increase of miR-92a-3p level in CRC cells. Mechanically, increased expression of miR-92a-3p activates Wnt/β-catenin pathway and inhibits mitochondrial apoptosis by directly inhibiting FBXW7 and MOAP1, contributing to cell stemness, EMT, metastasis and 5-FU/L-OHP resistance in CRC. Clinically, miR-92a-3p expression is significantly increased in CRC tissues and negatively correlated with the levels of FBXW7 and MOAP1 in CRC specimens, and high expression of exosomal miR-92a-3p in serum was highly linked with metastasis and chemotherapy resistance in CRC patients.
CAFs secreted exosomes promote metastasis and chemotherapy resistance of CRC. Inhibiting exosomal miR-92a-3p provides an alternative modality for the prediction and treatment of metastasis and chemotherapy resistance in CRC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Topological Dirac and Weyl semimetals not only host quasiparticles analogous to the elementary fermionic particles in high-energy physics, but also have a non-trivial band topology manifested by ...gapless surface states, which induce exotic surface Fermi arcs1,2. Recent advances suggest new types of topological semimetal, in which spatial symmetries protect gapless electronic excitations without high-energy analogues3–11. Here, using angle-resolved photoemission spectroscopy, we observe triply degenerate nodal points near the Fermi level of tungsten carbide with space group \P\bar{6}m2\ (no. 187), in which the low-energy quasiparticles are described as three-component fermions distinct from Dirac and Weyl fermions. We further observe topological surface states, whose constant-energy contours constitute pairs of ‘Fermi arcs’ connecting to the surface projections of the triply degenerate nodal points, proving the non-trivial topology of the newly identified semimetal state.
High-energy cosmic-ray electrons and positrons (CREs), which lose energy quickly during their propagation, provide a probe of Galactic high-energy processes and may enable the observation of ...phenomena such as dark-matter particle annihilation or decay. The CRE spectrum has been measured directly up to approximately 2 teraelectronvolts in previous balloon- or space-borne experiments, and indirectly up to approximately 5 teraelectronvolts using ground-based Cherenkov γ-ray telescope arrays. Evidence for a spectral break in the teraelectronvolt energy range has been provided by indirect measurements, although the results were qualified by sizeable systematic uncertainties. Here we report a direct measurement of CREs in the energy range 25 gigaelectronvolts to 4.6 teraelectronvolts by the Dark Matter Particle Explorer (DAMPE) with unprecedentedly high energy resolution and low background. The largest part of the spectrum can be well fitted by a 'smoothly broken power-law' model rather than a single power-law model. The direct detection of a spectral break at about 0.9 teraelectronvolts confirms the evidence found by previous indirect measurements, clarifies the behaviour of the CRE spectrum at energies above 1 teraelectronvolt and sheds light on the physical origin of the sub-teraelectronvolt CREs.
Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin ...of cosmological FRBs is still not settled. Here we report the detection of1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref.9). These observations show irregular short-time variation ofthe Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (au; Earth-Sun distance) ofthe source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.
Summary
Background
Previous studies have implicated vascular destabilization and changes in extracellular matrix (ECM) composition in venous malformations (VMs).
Objectives
To evaluate the expression ...levels of the connective tissue growth factor (CCN) family of matricellular proteins in VMs and explore their association with vascular destabilization.
Methods
The expression levels of CCNs 1–6, transforming growth factor (TGF)‐β, phosphorylated Tie2 and phosphorylated platelet‐derived growth factor receptor β in normal human skin tissues and VMs were detected by immunohistochemistry. Correlation between tested proteins was explored using the Spearman rank correlation test, followed by clustering analysis. In vitro studies using human umbilical vein endothelial cells (HUVECs) were performed for mechanism investigation.
Results
Expression of CCN2 was found to be strongly positive in fibroblast‐like cells, endothelial cells and around blood vessels in normal human skin tissues, but it was significantly downregulated in VMs. Correlation analyses showed that expression levels of CCN2 and TGF‐β in VMs were positively correlated. The immunoreactivity of CCN2 was also closely correlated with perivascular α‐smooth muscle cell actin+ cell coverage in VMs. Moreover, in vitro studies in HUVECs indicated that CCN2 might act as a downstream target of TGF‐β, as demonstrated by the findings that treatment with exogenous TGF‐β or exogenous CCN2 could significantly upregulate the expression level of CCN2, and increase the expression levels of ECM components. Upregulation of the TGF‐β/CCN2 pathway was also detected in bleomycin‐treated VM specimens.
Conclusions
This study unmasks the downregulation of the TGF‐β/CCN2 pathway in VMs, and indicates its target potential for sclerotherapy.
What's already known about this topic?
Venous malformations (VMs) are made manifest by enlarged venous channels covered with few perivascular cells, indicating vascular destabilization.
The extracellular matrix (ECM) is closely associated with cell adhesion, smooth muscle cell proliferation, migration and differentiation, and thereby plays a pivotal role in vascular stability.
Changes in ECM composition in VMs have been demonstrated.
What does this study add?
The transforming growth factor (TGF)‐β/connective tissue growth factor (CCN)2 pathway is downregulated in VMs when compared with normal human skin tissues, and is closely correlated with vascular destabilization.
The sclerosant bleomycin A5 upregulates the TGF‐β/CCN2 pathway, and increases ECM production in human umbilical vein endothelial cells.
Upregulation of TGF‐β and CCN2 expression was found in bleomycin‐treated VMs, which was accompanied by increased perivascular α‐smooth muscle actin+ cell coverage.
Two-dimensional (2D) materials have been studied extensively as monolayers, vertical or lateral heterostructures. To achieve functionalization, monolayers are often patterned using soft lithography ...and selectively decorated with molecules. Here we demonstrate the growth of a family of 2D materials that are intrinsically patterned. We demonstrate that a monolayer of PtSe
can be grown on a Pt substrate in the form of a triangular pattern of alternating 1T and 1H phases. Moreover, we show that, in a monolayer of CuSe grown on a Cu substrate, strain relaxation leads to periodic patterns of triangular nanopores with uniform size. Adsorption of different species at preferred pattern sites is also achieved, demonstrating that these materials can serve as templates for selective self-assembly of molecules or nanoclusters, as well as for the functionalization of the same substrate with two different species.
Context.
Level population inversion of hydrogen atoms in ionized gas may lead to stimulated emission of hydrogen recombination lines, and the level populations can in turn be affected by powerful ...stimulated emissions.
Aims.
In this work the interaction of the radiation fields and the level population inversion of hydrogen atoms is studied. The effect of the stimulated emissions on the line profiles is also investigated.
Methods.
Our previous nl-model for calculating level populations of hydrogen atoms and hydrogen recombination lines is improved. The effects of line and continuum radiation fields on the level populations are considered in the improved model. By using this method the properties of simulated hydrogen recombination lines and level populations are used in analyses.
Results.
The simulations show that hydrogen radio recombination lines are often emitted from the energy level with an inverted population. The widths of Hn
α
lines can be significantly narrowed by strong stimulated emissions to be even less than 10 km s
−1
. The amplification of hydrogen recombination lines is more affected by the line optical depth than by the total optical depth. The influence of stimulated emission on the estimates of electron temperature and density of ionized gas is evaluated. We find that comparing multiple line-to-continuum ratios is a reliable method for estimating the electron temperature, while the effectiveness of the estimation of electron density is determined by the relative significance of stimulated emission.
The event rate, energy distribution and time-domain behaviour of repeating fast radio bursts (FRBs) contain essential information regarding their physical nature and central engine, which are as yet ...unknown
. As the first precisely localized source, FRB 121102 (refs.
) has been extensively observed and shows non-Poisson clustering of bursts over time and a power-law energy distribution
. However, the extent of the energy distribution towards the fainter end was not known. Here we report the detection of 1,652 independent bursts with a peak burst rate of 122 h
, in 59.5 hours spanning 47 days. A peak in the isotropic equivalent energy distribution is found to be approximately 4.8 × 10
erg at 1.25 GHz, below which the detection of bursts is suppressed. The burst energy distribution is bimodal, and well characterized by a combination of a log-normal function and a generalized Cauchy function. The large number of bursts in hour-long spans allows sensitive periodicity searches between 1 ms and 1,000 s. The non-detection of any periodicity or quasi-periodicity poses challenges for models involving a single rotating compact object. The high burst rate also implies that FRBs must be generated with a high radiative efficiency, disfavouring emission mechanisms with large energy requirements or contrived triggering conditions.
Electronic structures of graphene oxide (GO) and hydro-thermally reduced graphene oxides (rGOs) processed at low temperatures (120-180°C) were studied using X-ray absorption near-edge structure ...(XANES), X-ray emission spectroscopy (XES) and resonant inelastic X-ray scattering (RIXS). C K-edge XANES spectra of rGOs reveal that thermal reduction restores C = C sp(2) bonds and removes some of the oxygen and hydroxyl groups of GO, which initiates the evolution of carbonaceous species. The combination of C K-edge XANES and Kα XES spectra shows that the overlapping π and π* orbitals in rGOs and GO are similar to that of highly ordered pyrolytic graphite (HOPG), which has no band-gap. C Kα RIXS spectra provide evidence that thermal reduction changes the density of states (DOSs) that is generated in the π-region and/or in the gap between the π and π* levels of the GO and rGOs. Two-dimensional C Kα RIXS mapping of the heavy reduction of rGOs further confirms that the residual oxygen and/or oxygen-containing functional groups modify the π and σ features, which are dispersed by the photon excitation energy. The dispersion behavior near the K point is approximately linear and differs from the parabolic-like dispersion observed in HOPG.
Highlights • NRG1 protects against OGD-induced cortical neuronal apoptosis. • NRG1-mediated neuroprotection is blocked by neutralizing NRG1 and ErbB4 inhibition. • GABA receptor agonists have no ...synergistic effect with NRG1. • NRG1-mediated neuroprotection is partly blocked by GABA receptor antagonists. • The NRG1 neuroprotection against brain ischemia is abolished in PV-ErbB4−/− mice.
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