L-ascorbate (L-ascorbic acid, vitamin C) clearly has an inhibitory effect on cancer cells. However, the mechanism underlying differential sensitivity of cancer cells from same tissue to L-ascorbate ...is yet to be clarified. Here, we demonstrate that L-ascorbate has a selective killing effect, which is influenced by sodium-dependent vitamin C transporter 2 (SVCT-2) in human breast cancer cells. Treatment of human breast cancer cells with L-ascorbate differentially induced cell death, dependent on the SVCT-2 protein level. Moreover, knockdown of endogenous SVCT-2 via RNA interference in breast cancer cells expressing high levels of the protein induced resistance to L-ascorbate treatment, whereas transfection with SVCT-2 expression plasmids led to enhanced L-ascorbate chemosensitivity. Surprisingly, tumor regression by L-ascorbate administration in mice bearing tumor cell xenograft also corresponded to the SVCT-2 protein level. Interestingly, SVCT-2 expression was absent or weak in normal tissues, but strongly detected in tumor samples obtained from breast cancer patients. In addition, enhanced chemosensitivity to L-ascorbate occurred as a result of caspase-independent autophagy, which was mediated by beclin-1 and LC3 II. In addition, treatment with N-acetyl-L-cysteine, a reactive oxygen species (ROS) scavenger, suppressed the induction of beclin-1 and LC3 II, implying that the differential SVCT-2 protein-dependent L-ascorbate uptake was attributable to intracellular ROS induced by L-ascorbate, subsequently leading to autophagy. These results suggest that functional SVCT-2 sensitizes breast cancer cells to autophagic damage by increasing the L-ascorbate concentration and intracellular ROS production and furthermore, SVCT-2 in breast cancer may act as an indicator for commencing L-ascorbate treatment.
This paper presents Magnetospheric Multiscale mission (MMS) observations of the exhaust region in the vicinity of the central reconnection site in Earth's magnetopause current sheet. ...High-time-resolution measurements of field and particle distributions enable us to explore the fine structure of the diffusion region near the X line. Ions are decoupled from the magnetic field throughout the entire current sheet crossing. Electron jets flow downstream from the X line at speeds greater than the E by B drift velocity. At or around the magnetospheric separatrix, large-amplitude electric fields containing field-aligned components accelerate electrons along the magnetic field toward the X line. Near the neutral sheet, crescent-shaped electron distributions appear coincident with (1) an out-of-plane electric field whose polarity is opposite to that of the reconnection electric field and (2) the energy transfer from bulk kinetic to field energy. The observations indicate that MMS passed through the edge of an elongated electron diffusion region (EDR) or the outer EDR in the exhaust region.
Coulomb collisions provide plasma resistivity and diffusion but in many low-density astrophysical plasmas such collisions between particles are extremely rare. Scattering of particles by ...electromagnetic waves can lower the plasma conductivity. Such anomalous resistivity due to wave-particle interactions could be crucial to many processes, including magnetic reconnection. It has been suggested that waves provide both diffusion and resistivity, which can support the reconnection electric field, but this requires direct observation to confirm. Here, we directly quantify anomalous resistivity, viscosity, and cross-field electron diffusion associated with lower hybrid waves using measurements from the four Magnetospheric Multiscale (MMS) spacecraft. We show that anomalous resistivity is approximately balanced by anomalous viscosity, and thus the waves do not contribute to the reconnection electric field. However, the waves do produce an anomalous electron drift and diffusion across the current layer associated with magnetic reconnection. This leads to relaxation of density gradients at timescales of order the ion cyclotron period, and hence modifies the reconnection process.
This paper reports on Magnetospheric Multiscale observations of whistler mode chorus and higher‐frequency electrostatic waves near and within a reconnection diffusion region on 23 November 2016. The ...diffusion region is bounded by crescent‐shaped electron distributions and associated dissipation just upstream of the X‐line and by magnetic field‐aligned currents and electric fields leading to dissipation near the electron stagnation point. Measurements were made southward of the X‐line as determined by southward directed ion and electron jets. We show that electrostatic wave generation is due to magnetosheath electron beams formed by the electron jets as they interact with a cold background plasma and more energetic population of magnetospheric electrons. On the magnetosphere side of the X‐line the electron beams are accompanied by a strong perpendicular electron temperature anisotropy, which is shown to be the source of an observed rising‐tone whistler mode chorus event. We show that the apex of the chorus event and the onset of electrostatic waves coincide with the opening of magnetic field lines at the electron stagnation point.
Key Points
Whistler mode chorus and higher‐frequency electrostatic waves were observed in the vicinity of a reconnection diffusion region at the dayside magnetopause
The location of the Earthward boundary of chorus and electrostatic waves coincides with the opening of magnetic field lines via reconnection
The causes of whistler mode chorus and electrostatic waves are shown to be electron temperature anisotropy and beam‐plasma interactions, respectively
Data from the NASA Magnetospheric Multiscale mission are used to investigate asymmetric magnetic reconnection at the dayside boundary between the Earth's magnetosphere and the solar wind. ...High‐resolution measurements of plasmas and fields are used to identify highly localized (~15 electron Debye lengths) standing wave structures with large electric field amplitudes (up to 100 mV/m). These wave structures are associated with spatially oscillatory energy conversion, which appears as alternatingly positive and negative values of J · E. For small guide magnetic fields the wave structures occur in the electron stagnation region at the magnetosphere edge of the electron diffusion region. For larger guide fields the structures also occur near the reconnection X‐line. This difference is explained in terms of channels for the out‐of‐plane current (agyrotropic electrons at the stagnation point and guide field‐aligned electrons at the X‐line).
Key Points
Energy conversion is highly localized within asymmetric reconnection electron diffusion regions
Oscillatory reconnection electric fields show characteristics of both spatial structures and propagating waves that are consistent with standing oblique quasi‐electrostatic whistlers
Both positive and negative values of J · E result from uniform current and oscillating electric fields
We present microlensing events in the 2015 Korea Microlensing Telescope Network (KMTNet) data and our procedure for identifying these events. In particular, candidates were detected with a novel ..."completed-event" microlensing event-finder algorithm. The algorithm works by making linear fits to a grid of point-lens microlensing models. This approach is rendered computationally efficient by restricting u0 to just two values (0 and 1), which we show is quite adequate. The implementation presented here is specifically tailored to the commission-year character of the 2015 data, but the algorithm is quite general and has already been applied to a completely different (non-KMTNet) data set. We outline expected improvements for 2016 and future KMTNet data. The light curves of the 660 "clear microlensing" and 182 "possible microlensing" events that were found in 2015 are presented along with our policy for their public release.
Preservative agents determining the shelf life of cosmetic products must have effective antimicrobial activity while meeting safety requirements for topical use. In this study, we determined the ...antimicrobial activity of 1,2‐hexanediol against several Gram‐positive and Gram‐negative bacteria. Antimicrobial susceptibility tests have shown that 1,2‐hexanediol exhibits broad‐spectrum activity against Gram‐positive and Gram‐negative bacteria with MICs of 0·5–2% (v/v). The bactericidal concentration of 1,2‐hexanediol was ranging from 1 to 2 × MIC as demonstrated by time‐kill curve assay. A membrane depolarization assay showed that 1,2‐hexanediol disrupted the cytoplasmic membrane potential. A checkerboard assay indicated that the effective concentration of 1,2‐hexanediol was reduced up to 0·25–0·5 × MIC when combined with macelignan and octyl gallate against Gram‐positive bacteria. However, this combination was not effective against Gram‐negative bacteria. A turbidity reduction assay demonstrated that the combination of a high concentration of 1,2‐hexanediol with food‐grade antimicrobial compounds could trigger lytic activity towards Bacillus cereus cells. The remaining cell turbidity was 24·6 and 22·2% when 2% of 1,2‐hexanediol was combined with 8 mg l⁻¹octyl gallate or with 32 mg l⁻¹macelignan respectively. This study showed that food‐grade antimicrobial compounds may be used in combination with 1,2‐hexanediol to increase its efficacy as a preservative agent in cosmetics. SIGNIFICANCE AND IMPACT OF THE STUDY: The antimicrobial activity of 1,2‐hexanediol against Gram‐positive and Gram‐negative bacteria was potentiated with food‐grade antimicrobials including xanthorrhizol, macelignan, panduratin A and octyl gallate, which have already been reported to display anti‐inflammatory and other beneficial activities related to cosmetics. Therefore, the combination of 1,2‐hexanediol and these food‐grade antimicrobial agents would have benefits not only for increasing the antimicrobial activity but also in cosmetics use.
Using MMS high‐resolution measurements, we present the first observation of fast electron jet (Ve ~2,000 km/s) at a dipolarization front (DF) in the magnetotail plasma sheet. This jet, with scale ...comparable to the DF thickness (~ 0.9 di), is primarily in the tangential plane to the DF current sheet and mainly undergoes the E × B drift motion; it contributes significantly to the current system at the DF, including a localized ring‐current that can modify the DF topology. Associated with this fast jet, we observed a persistent normal electric field, strong lower hybrid drift waves, and strong energy conversion at the DF. Such strong energy conversion is primarily attributed to the electron‐jet‐driven current (E ⋅ je ≈ 2 E ⋅ ji), rather than the ion current suggested in previous studies.
Key Points
For the first time, fast electron jet is observed at dipolarization front
This jet is responsible for current and energy conversion at dipolarization front
Quantitatively, the partition of energy conversion is E ⋅ je ≈ 2 E ⋅ ji
Aortic pulse wave velocity (AoPWV) and augmentation index (AIx) are commonly used measures of large elastic artery stiffness and wave reflection, respectively. Recently, a new cuff-based SphygmoCor ...device (Xcel) has been developed to measure both AoPWV and AIx. We sought to examine the following: (1) the validity of Xcel compared with the well-validated tonometry-based SphygmoCor device (MM3); (2) the intratest and day-to-day reliability of Xcel; (3) the influence of body side (right or left) on Xcel measurements; and (4) the relation of Xcel measurements to carotid artery compliance, distensibility and β-stiffness index. We found that measurements of AoPWV and AIx between Xcel and MM3 were not different (P=0.26 and P=0.43, N=22 and 26, respectively) and were strongly related (r=0.85 and 0.75, P<0.0001), and based on Bland-Altman plots there was good agreement between them. Intra-test (intraclass correlation=0.996 and 0.983, P<0.0001; AoPWV and AIx, N=24 and 26, respectively) and day-to-day reliability (intraclass correlation=0.979 and 0.939, P<0.0001) were high. Xcel AoPWV and AIx on the left versus right body side were not different (P=0.19 and P=0.58, N=14 and 15, respectively) and were highly correlated (r=0.99 and 0.94, P<0.0001). AoPWV and AIx measured with Xcel were positively related with β-stiffness index (r=0.62 and 0.51, P< or = 0.005, N=23 and 24, respectively) and negatively related with distensibility (r = -0.58 and -0.44, P < or = 0.02, N=23 and 24, respectively). In conclusion, Xcel measures of AIx and AoPWV are valid, highly reliable and not affected by body side. Xcel is a useful tool for use in research and the clinic.
Claudins (CLDNs) are a family of integral membrane proteins central to the formation of tight junctions, structures that are involved in paracellular transport and cellular growth and ...differentiation, and are critical for the maintenance of cellular polarity. Recent studies have provided evidence that CLDNs are aberrantly expressed in diverse types of human cancers, including hepatocellular carcinomas (HCCs). However, little is known about how CLDN expression is involved in cancer progression. In this study, we show that CLDN1 has a causal role in the epithelial-mesenchymal transition (EMT) in human liver cells, and that the c-Abl-Ras-Raf-1-ERK1/2 signaling axis is critical for the induction of malignant progression by CLDN1. Overexpression of CLDN1 induced expression of the EMT-regulating transcription factors Slug and Zeb1, and thereby led to repression of E-cadherin, β-catenin expression, enhanced expression of N-cadherin and Vimentin, a loss of cell adhesion, and increased cell motility in normal liver cells and HCC cells. In line with these findings, inhibition of either c-Abl or ERK clearly attenuated CLDN1-induced EMT, as evidenced by a reversal of N-cadherin and E-cadherin expression patterns, and restored normal motility. Collectively, these results indicate that CLDN1 is necessary for the induction of EMT in human liver cells, and that activation of the c-Abl-Ras-Raf-1-ERK1/2 signaling pathway is required for CLDN1-induced acquisition of the malignant phenotype. The present observations suggest that CLDN1 could be exploited as a biomarker for liver cancer metastasis and might provide a pivotal point for therapeutic intervention in HCC.
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