The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble ...form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.
Abstract
We carried out deep mapping observations of the atomic hydrogen (H
i
) 21 cm line emission in a field centered on the famous galaxy group Stephan's Quintet (SQ), using the Five-hundred-meter ...Aperture Spherical Telescope (FAST) equipped with a 19-beam receiver. The final data cube reaches an H
i
column density sensitivity of 5
σ
= 2.1 × 10
17
cm
−2
per 20 km s
−1
channel with an angular resolution of 4.′0. The discovery of a large diffuse feature of the H
i
emission in the outskirts of the intragroup medium of SQ was reported in a previous paper (Xu et al.). Here we present a new study of the total H
i
emission of SQ and the detection of several neighboring galaxies, exploiting the high sensitivity and the large sky coverage of the FAST observations. A total H
i
mass of
M
H I
= 3.48 ± 0.35 × 10
10
M
☉
is found for SQ, which is significantly higher than previous measurements in the literature. This indicates that, contrary to earlier claims, SQ is not H
i
deficient. The excessive H
i
gas is mainly found in the velocity ranges of 6200–6400 km s
−1
and 6800–7000 km s
−1
, which were undetected in previous observations that are less sensitive than ours. Our results suggest that the “missing H
i
” in compact groups may be hidden in the low-density diffuse neutral gas instead of in the ionized gas.
Stephan's Quintet (SQ, co-moving radial distance = 85 ± 6 Mpc, taken from the NASA/IPAC Extragalactic Database (NED)
) is unique among compact groups of galaxies
. Observations have previously shown ...that interactions between multiple members, including a high-speed intruder galaxy currently colliding into the intragroup medium, have probably generated tidal debris in the form of multiple gaseous and stellar filaments
, the formation of tidal dwarfs
and intragroup-medium starbursts
, as well as widespread intergalactic shocked gas
. The details and timing of the interactions and collisions remain poorly understood because of their multiple nature
. Here we report atomic hydrogen (H I) observations in the vicinity of SQ with a smoothed sensitivity of 1σ = 4.2 × 10
cm
per channel (velocity bin-width Δv = 20 km s
; angular resolution = 4'), which are about two orders of magnitude deeper than previous observations
. The data show a large H I structure (with linear scale of around 0.6 Mpc) encompassing an extended source of size approximately 0.4 Mpc associated with the debris field and a curved diffuse feature of length around 0.5 Mpc attached to the south edge of the extended source. The diffuse feature was probably produced by tidal interactions in early stages of the formation of SQ (>1 Gyr ago), although it is not clear how the low-density H I gas (N
≲ 10
cm
) can survive the ionization by the intergalactic ultraviolet background on such a long time scale. Our observations require a rethinking of properties of gas in outer parts of galaxy groups and demand complex modelling of different phases of the intragroup medium in simulations of group formation.
Raman spectroscopy uses visible light to acquire vibrational fingerprints of molecules, thus making it a powerful tool for chemical analysis in a wide range of media. However, its potential for ...optical imaging at high resolution is severely limited by the fact that the Raman effect is weak. Here, we report the discovery of a giant Raman scattering effect from encapsulated and aggregated dye molecules inside single-walled carbon nanotubes. Measurements performed on rod-like dyes such as α-sexithiophene and β-carotene, assembled inside single-walled carbon nanotubes as highly polarizable J-aggregates, indicate a resonant Raman cross-section of (3 ± 2) × 10-21 cm2 sr-1 , which is well above the cross-section required for detecting individual aggregates at the highest optical resolution. Free from fluorescence background and photobleaching, this giant Raman effect allows the realization of a library of functionalized nanoprobe labels for Raman imaging with robust detection using multispectral analysis.
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.
Human behaviour plays an important role in the spread of emerging infectious diseases, and understanding the influence of behaviour changes on epidemics can be key to improving control efforts. ...However, how the dynamics of individual behaviour changes affects the development of emerging infectious disease is a key public health issue. To develop different formula for individual behaviour change and introduce how to embed it into a dynamic model of infectious diseases, we choose A/H1N1 and Ebola as typical examples, combined with the epidemic reported cases and media related news reports. Thus, the logistic model with the health belief model is used to determine behaviour decisions through the health belief model constructs. Furthermore, we propose 4 candidate infectious disease models without and with individual behaviour change and use approximate Bayesian computation based on sequential Monte Carlo method for model selection. The main results indicate that the classical compartment model without behaviour change and the model with average rate of behaviour change depicted by an exponential function could fit the observed data best. The results provide a new way on how to choose an infectious disease model to predict the disease prevalence trend or to evaluate the influence of intervention measures on disease control. However, sensitivity analyses indicate that the accumulated number of hospital notifications and deaths could be largely reduced as the rate of behaviour change increases. Therefore, in terms of mitigating emerging infectious diseases, both media publicity focused on how to guide people's behaviour change and positive responses of individuals are critical.
Fracture healing is a well-orchestrated and coordinated process and begins with the inflammatory stage involving the infiltration of immune cells and the release of cytokines, including tumour ...necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10). Low-magnitude high-frequency vibration (LMHFV) stimulation is effective in promoting fracture healing. The study hypothesis was that the innate immune response was impaired in osteoporotic fracture and LMHFV could positively modulate it. 9-month-old ovariectomy (OVX)-induced osteoporotic rats were randomised into sham (SHAM), OVX control (OVX), OVX-vibration (OVX-VT) or OVX vibration plus administration of COX-2 specific non-steroid anti-inflammatory drugs (OVX-VT-NSAID). LMHFV (35 Hz, 0.3 g) was given 20 min/d and 5 d/week to the treatment groups. Healing and innate immune response were evaluated by weekly radiographs, endpoint micro-computed tomography (µCT), enzyme-linked immunosorbent assay (ELISA) and histomorphometry at weeks 1, 2, 4 and 8 post-treatment. Results showed that OVX slightly elevated systemic inflammation but impaired the innate immune response locally at the fracture site, with significantly lower expressions of TNF-α and IL-6 but higher IL-10 expression during the early stage of healing. LMHFV was effective in accelerating the delayed fracture healing in OVX bones by partly restoring the impaired innate immune response at the fracture site, accompanied by promoted progression of macrophage polarisation from M1 (pro-inflammatory) to M2 (anti-inflammatory) phenotype. In conclusion, vibration treatment could positively modulate the impaired innate immune response and promote macrophage polarisation in osteoporotic-fracture healing.
Vemurafenib, a selective inhibitor of BRAF(V600), has shown significant activity in BRAF(V600) melanoma but not in less than 10% of metastatic BRAF(V600) colorectal cancers (CRC), suggesting that ...studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAF(mut) CRC may provide combinatorial strategies.
We conducted comparative proteomic analysis of BRAF(V600E) melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models.
Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification.
We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAF(V600E) CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients.
A model with two channels of electrical transport (TCET) for perovskite manganites is proposed, and it is described by an equivalent device with two current-carrier channels. In one channel, there is ...a spin-independent resistor (
R
3
) with an equivalent resistivity of
ρ
3
. In the other channel, there are two spin-dependent resistors in series (
R
1
and
R
2
) with an equivalent resistivity of
ρ
1
+
ρ
2
. The component
ρ
1
includes residual resistivity and the resistivity contributed by crystal-lattice scattering. The other component of the equivalent resistivity,
ρ
2
, originates from the spin orientations of the itinerant electrons and the local electrons of the outer O 2p and Mn 3d orbits that deviate from the orientation of their ground states when the test temperature is close to the Curie temperature. Using this model, we fitted the experimental curves of the resistivity
versus
test temperature for single-crystalline La
1−
x
Sr
x
MnO
3
(0.00 ≤
x
≤ 0.40) and polycrystalline La
0.6
Sr
0.4
Mn
1−
x
Fe
x
O
3
(0.00 ≤
x
≤ 0.30). In addition, we investigated the effects of the fraction of the antiferromagnetic phase, scattering at the crystallite interfaces, and the crystal-cell constants on the samples' resistivity. The physical mechanism of the TCET model was explained using an O 2p itinerant-electron model, which has been used in other studies to explain the magnetic ordering of several series of spinel ferrites and perovskite manganites.
A model with two channels of electrical transport (TCET) for perovskite manganites is proposed, and it is described by an equivalent device with two current-carrier channels.
Real-time monitoring of flow turbulence is very difficult but extremely important in fluid dynamics, which plays an important role in flight safety and control. Turbulence can cause airflow to detach ...at the end of the wings, potentially resulting in the aerodynamic stall of aircraft and causing flight accidents. Here, we developed a lightweight and conformable system on the wing surface of aircraft for stall sensing. Quantitative data about airflow turbulence and the degree of boundary layer separation are provided in situ using conjunct signals provided by both triboelectric and piezoelectric effects. Thus, the system can visualize and directly measure the airflow detaching process on the airfoil, and senses the degree of airflow separation during and after a stall for large aircraft and unmanned aerial vehicles.
PDF
