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
Cyclic period changes are a fairly common phenomenon in close binary systems and are usually explained as being caused either by the magnetic activity of one or both components or by the light travel ...time effect (LTTE) of a third body. We searched the orbital period changes in 182 EA-type (including the 101 Algol systems used by Hall), 43 EB-type and 53 EW-type binaries with known mass ratio and spectral type of the secondary component. We reproduced and improved the diagram in Hall according to the new collected data. Our plots do not support the conclusion derived by Hall that cyclic period changes are restricted to binaries having a secondary component with spectral type later than F5. The presence of period changes among systems with a secondary component of early type indicates that magnetic activity is one, but not the only, cause of the period variation. It is discovered that cyclic period changes, probably resulting from the presence of a third body, are more frequent in EW-type binaries among close systems. Therefore, the most plausible explanation of the cyclic period changes is the LTTE through the presence of a third body. Using the century-long historical record of the times of light minimum, we analysed the cyclic period change in the Algol binary WW Dra. It is found that the orbital period of the binary shows a ∼112.2-yr cyclic variation with an amplitude of ∼0.1977 d. The cyclic oscillation can be attributed to the LTTE by means of a third body with a mass no less than 6.43 M⊙. However, no spectral lines of the third body were discovered, indicating that it may be a candidate black hole. The third body is orbiting the binary at a distance closer than 14.4 au and may play an important role in the evolution of this system.
The primary circadian pacemaker, in the suprachiasmatic nucleus (SCN) of the mammalian brain, is photoentrained by light signals from the eyes through the retinohypothalamic tract. Retinal rod and ...cone cells are not required for photoentrainment. Recent evidence suggests that the entraining photoreceptors are retinal ganglion cells (RGCs) that project to the SCN. The visual pigment for this photoreceptor may be melanopsin, an opsin-like protein whose coding messenger RNA is found in a subset of mammalian RGCs. By cloning rat melanopsin and generating specific antibodies, we show that melanopsin is present in cell bodies, dendrites, and proximal axonal segments of a subset of rat RGCs. In mice heterozygous for tau-lacZ targeted to the melanopsin gene locus, β-galactosidase-positive RGC axons projected to the SCN and other brain nuclei involved in circadian photoentrainment or the pupillary light reflex. Rat RGCs that exhibited intrinsic photosensitivity invariably expressed melanopsin. Hence, melanopsin is most likely the visual pigment of phototransducing RGCs that set the circadian clock and initiate other non-image-forming visual functions.
The large-scale distribution of neutral hydrogen in the Universe will be luminous through its 21 cm emission. Here, for the first time, we use the auto-power spectrum of 21 cm intensity fluctuations ...to constrain neutral hydrogen fluctuations at z ∼ 0.8. Our data were acquired with the Green Bank Telescope and span the redshift range 0.6 < z < 1 over two fields totalling 41 deg2 and 190 h of radio integration time. The dominant synchrotron foregrounds exceed the signal by ∼103, but have fewer degrees of freedom and can be removed efficiently. Even in the presence of residual foregrounds, the auto-power can still be interpreted as an upper bound on the 21 cm signal. Our previous measurements of the cross-correlation of 21 cm intensity and the WiggleZ galaxy survey provide a lower bound. Through a Bayesian treatment of signal and foregrounds, we can combine both fields in auto- and cross-power into a measurement of ΩHI
bHI
= 0.62+0.23
−0.15 × 10−3 at 68 per cent confidence with 9 per cent systematic calibration uncertainty, where ΩHI
is the neutral hydrogen (H i) fraction and bHI
is the H i bias parameter. We describe observational challenges with the present data set and plans to overcome them.
This article aims at introducing triple shape memory polymers (SMPs) by four-dimensional (4D) printing technology and shaping adaptive structures for mechanical/bio-medical devices. The main approach ...is based on arranging hot-cold programming of SMPs with fused decomposition modeling technology to engineer adaptive structures with triple shape memory effect (SME). Experiments are conducted to characterize elasto-plastic and hyper-elastic thermo-mechanical material properties of SMPs in low and high temperatures at large deformation regime. The feasibility of the dual and triple SMPs with self-bending features is demonstrated experimentally. It is advantageous in situations either where it is desired to perform mechanical manipulations on the 4D printed objects for specific purposes or when they experience cold programming inevitably before activation. A phenomenological 3D constitutive model is developed for quantitative understanding of dual/triple SME of SMPs fabricated by 4D printing in the large deformation range. Governing equations of equilibrium are established for adaptive structures on the basis of the nonlinear Green-Lagrange strains. They are then solved by developing a finite element approach along with an elastic-predictor plastic-corrector return map procedure accomplished by the Newton-Raphson method. The computational tool is applied to simulate dual/triple SMP structures enabled by 4D printing and explore hot-cold programming mechanisms behind material tailoring. It is shown that the 4D printed dual/triple SMPs have great potential in mechanical/bio-medical applications such as self-bending gripers/stents and self-shrinking/tightening staples.
VZ Lib is a southern triple-lined system. By analyzing all available times of light minima, orbital period changes are revisited in detail. We discovered that the observed-calculated (O − C) curve ...shows a long-term period decrease at a rate of , revealing a mass transfer from the more massive component to the less massive one. A cyclic variation covering more than three cycles was discovered, which was analyzed for the light-travel-time effect via the presence of the tertiary companion. The cyclic variation has a short period of 2.96 ( 0.04) yr and a small semiamplitude of 0.0039 ( 0.0004) days. The mass of the third body was determined to be M and an orbital semimajor axis shorter than au was obtained. Orbital properties of this close-in companion should provide valuable information on the formation of close binaries and stellar dynamical interaction. New complete light curves of VZ Lib were obtained and modeled with the Wilson-Devinney code. The light curves show a small but significant O'Connell effect that was not detectable in 1981 and 2007 but in 2004, so we derived a new photometric solution with assuming spot and a third light in the system. It is found that the light-curve subtype changed from A-type to W-type, which was possibly caused by a dark spot on the massive component. Our photometric solutions are in agreement with the spectroscopic results given by previous authors.
Abstract V583 Lyr is an extremely low-mass-ratio Algol-type binary with an orbital period of 11.2580 days. We determined an effective temperature of T eff1 = 9000 ± 350 K from newly observed spectra, ...which might be an underestimate due to binary mass transfer. The binary mass ratio q = 0.1 ± 0.004 and the orbital inclination i = 85.°5 are determined based on the assumption that the secondary fills its Roche lobe and rotates synchronously. The radial velocity curve is obtained from time series spectra, allowing for improved estimation of stellar masses and radii: M 1 = 3.56 ± 0.5 M ⊙ , R 1 = 2.4 ± 0.2 R ⊙ ; and M 2 = 0.36 ± 0.02 M ⊙ , R 2 = 6.9 ± 0.4 R ⊙ . The variations in the double-peaked H α emission indicate the formation of a stable disk during mass transfer. V583 Lyr appears to be a post-mass-reversal system, according to the mass transfer estimated using O − C period analysis. Its orbital period is slowly increasing, from which the rate of mass accretion by the primary star is estimated to be M 1 ̇ = 3.384 × 10 −8 M ⊙ yr −1 . The pulsation analysis was conducted on the residuals of the light curve. The primary component was found to be a g -mode pulsating star with 26 frequencies extracted lower than 9 day −1 . The frequency groups and rotational splitting properties of the g mode were studied in detail. This study provides compelling evidence for an accretion disk surrounding the g -mode pulsating primary.
Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next‐generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely ...pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty‐three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox‐Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype‐phenotype correlations would provide insights into the underlying pathogenic mechanisms.
We identified 24 causative mutations (19 novel) in a cohort of 70 EE patients and delineated new phenotype associated with CLCN4 and KCNQ2.
The aim of this paper is to create adaptive structures capable of self-expanding and self-shrinking by means of four-dimensional printing technology. An actuator unit is designed and fabricated ...directly by printing fibers of shape memory polymers (SMPs) in flexible beams with different arrangements. Experiments are conducted to determine thermo-mechanical material properties of the fabricated part revealing that the printing process introduced a strong anisotropy into the printed parts. The feasibility of the actuator unit with self-expanding and self-shrinking features is demonstrated experimentally. A phenomenological constitutive model together with analytical closed-form solutions are developed to replicate thermo-mechanical behaviors of SMPs. Governing equations of equilibrium are developed for printed structures based on the non-linear Green-Lagrange strain tensor and solved implementing a finite element method along with an iterative incremental Newton-Raphson scheme. The material-structural model is then applied to digitally design and print SMP adaptive lattices in planar and tubular shapes comprising a periodic arrangement of SMP actuator units that expand and then recover their original shape automatically. Numerical and experimental results reveal that the proposed planar lattice as meta-materials can be employed for plane actuators with self-expanding/shrinking features or as structural switches providing two different dynamic characteristics. It is also shown that the proposed tubular lattice with a self-expanding/shrinking mechanism can serve as tubular stents and grippers for bio-medical or piping applications.
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