Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms.

Emerging evidence suggests the therapeutic role of autophagic modulators in cancer therapy. This study aims to identify novel traditional Chinese medicinal herbs as potential anti-tumor agents through autophagic induction, which finally lead to autophagy mediated-cell death in apoptosis-resistant cancer cells. Using bioactivity-guided purification, we identified tetrandrine (Tet) from herbal plant, Radix stephaniae tetrandrae, as an inducer of autophagy. Across a number of cancer cell lines, we found that breast cancer cells treated with tetrandrine show an increase autophagic flux and formation of autophagosomes. In addition, tetrandrine induces cell death in a panel of apoptosis-resistant cell lines that are deficient for caspase 3, caspase 7, caspase 3 and 7, or Bax-Bak respectively. We also showed that tetrandrine-induced cell death is independent of necrotic cell death. Mechanistically, tetrandrine induces autophagy that depends on mTOR inactivation. Furthermore, tetrandrine induces autophagy in a calcium/calmodulin-dependent protein kinase kinase-β (CaMKK-β), 5′ AMP-activated protein kinase (AMPK) independent manner. Finally, by kinase profiling against 300 WT kinases and computational molecular docking analysis, we showed that tetrandrine is a novel PKC-α inhibitor, which lead to autophagic induction through PKC-α inactivation. This study provides detailed insights into the novel cytotoxic mechanism of an anti-tumor compound originated from the herbal plant, which may be useful in promoting autophagy mediated- cell death in cancer cell that is resistant to apoptosis.published_or_final_versio

Unusual Location of the Geotail Magnetopause Near Lunar Orbit: A Case Study

The Earth's magnetopause is highly variable in location and shape and is modulated by solar wind conditions. On 8 March 2012, the ARTEMIS probes were located near the tail current sheet when an interplanetary shock arrived under northward interplanetary magnetic field conditions and recorded an abrupt tail compression at ∼(‐60, 0, ‐5) RE in Geocentric Solar Ecliptic coordinate in the deep magnetotail. Approximately 10 minutes later, the probes crossed the magnetopause many times within an hour after the oblique interplanetary shock passed by. The solar wind velocity vector downstream from the shock was not directed along the Sun‐Earth line but had a significant Y component. We propose that the compressed tail was pushed aside by the appreciable solar wind flow in the Y direction. Using a virtual spacecraft in a global magnetohydrodynamic (MHD) simulation, we reproduce the sequence of magnetopause crossings in the X‐Y plane observed by ARTEMIS under oblique shock conditions, demonstrating that the compressed magnetopause is sharply deflected at lunar distances in response to the shock and solar wind VY effects. The results from two different global MHD simulations show that the shocked magnetotail at lunar distances is mainly controlled by the solar wind direction with a timescale of about a quarter hour, which appears to be consistent with the windsock effect. The results also provide some references for investigating interactions between the solar wind/magnetosheath and lunar nearside surface during full moon time intervals, which should not happen in general

A direct examination of the dynamics of dipolarization fronts using MMS

Energy conversion on the dipolarization fronts (DFs) has attracted much research attention through the suggestion that intense current densities associated with DFs can modify the more global magnetotail current system. The current structures associated with a DF are at the scale of one to a few ion gyroradii, and their duration is comparable to a spacecraft's spin period. Hence, it is crucial to understand the physical mechanisms of DFs with measurements at a timescale shorter than a spin period. We present a case study whereby we use measurements from the Magnetospheric Multiscale (MMS) Mission, which provides full 3-D particle distributions with a cadence much shorter than a spin period. We provide a cross validation amongst the current density calculations and examine the assumptions that have been adopted in previous literature using the advantages of MMS mission (i.e., small-scale tetrahedron and high temporal resolution). We also provide a cross validation on the terms in the generalized Ohm's law using these advantageous measurements. Our results clearly show that the majority of the currents on the DF are contributed by both ion and electron diamagnetic drifts. Our analysis also implies that the ion frozen-in condition does not hold on the DF, while electron frozen-in condition likely holds. The new experimental capabilities allow us to accurately calculate Joule heating within the DF, which shows that plasma energy is being converted to magnetic energy in our event

β-Elemene-induced autophagy protects human gastric cancer cells from undergoing apoptosis

<p>Abstract</p> <p>Background</p> <p>β-Elemene, a compound found in an herb used in traditional Chinese medicine, has shown promising anti-cancer effects against a broad spectrum of tumors. The mechanism by which β-elemene kills cells remains unclear. The aim of the present study is to investigate the anti-tumor effect of β-elemene on human gastric cancer cells and the molecular mechanism involved.</p> <p>Results</p> <p>β-Elemene inhibited the viability of human gastric cancer MGC803 and SGC7901 cells in a dose-dependent manner. The suppression of cell viability was due to the induction of apoptosis. A robust autophagy was observed in the cells treated with β-elemene; it was characterized by the increase of punctate LC3 dots, the cellular morphology, and the increased levels of LC3-II protein. Further study showed that β-elemene treatment up-regulated Atg5-Atg12 conjugated protein but had little effect on other autophagy-related proteins. PI3K/Akt/mTOR/p70S6K1 activity was inhibited by β-elemene. Knockdown of Beclin 1 with small interfering RNA, or co-treatment with the autophagy inhibitor, 3-methyladenine or chlorochine enhanced significantly the antitumor effects of β-elemene.</p> <p>Conclusions</p> <p>Our data provides the first evidence that β-elemene induces protective autophagy and prevents human gastric cancer cells from undergoing apoptosis. A combination of β-elemene with autophagy inhibitor might thus be a useful therapeutic option for advanced gastric cancer.</p

On-demand semiconductor single-photon source with near-unity indistinguishability

Single photon sources based on semiconductor quantum dots offer distinct advantages for quantum information, including a scalable solid-state platform, ultrabrightness, and interconnectivity with matter qubits. A key prerequisite for their use in optical quantum computing and solid-state networks is a high level of efficiency and indistinguishability. Pulsed resonance fluorescence (RF) has been anticipated as the optimum condition for the deterministic generation of high-quality photons with vanishing effects of dephasing. Here, we generate pulsed RF single photons on demand from a single, microcavity-embedded quantum dot under s-shell excitation with 3-ps laser pulses. The pi-pulse excited RF photons have less than 0.3% background contributions and a vanishing two-photon emission probability. Non-postselective Hong-Ou-Mandel interference between two successively emitted photons is observed with a visibility of 0.97(2), comparable to trapped atoms and ions. Two single photons are further used to implement a high-fidelity quantum controlled-NOT gate.Comment: 11 pages, 11 figure

Inflammatory expression profiles in monocyte-to-macrophage differentiation in patients with systemic lupus erythematosus and relationship with atherosclerosis

Introduction: Our objectives were to examine mononuclear cell gene expression profiles in patients with systemic lupus erythematosus (SLE) and healthy controls and to compare subsets with and without atherosclerosis to determine which genes' expression is related to atherosclerosis in SLE.Methods: Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro-differentiated into macrophages. Subjects also underwent laboratory and imaging studies to evaluate for subclinical atherosclerosis. Whole-genome RNA expression microarray was performed, and gene expression was examined.Results: Gene expression profiling was used to identify gene signatures that differentiated patients from controls and individuals with and without atherosclerosis. In monocytes, 9 out of 20 patients with SLE had an interferon-inducible signature compared with 2 out of 16 controls. By looking at gene expression during monocyte-to-macrophage differentiation, we identified pathways which were differentially regulated between SLE and controls and identified signatures based on relevant intracellular signaling molecules which could differentiate SLE patients with atherosclerosis from controls. Among patients with SLE, we used a previously defined 344-gene atherosclerosis signature in monocyte-to-macrophage differentiation to identify patient subgroups with and without atherosclerosis. Interestingly, this signature further classified patients on the basis of the presence of SLE disease activity and cardiovascular risk factors.Conclusions: Many genes were differentially regulated during monocyte-to-macrophage differentiation in SLE patients compared with controls. The expression of these genes in mononuclear cells is important in the pathogenesis of SLE, and molecular profiling using gene expression can help stratify SLE patients who may be at risk for development of atherosclerosis

Current reduction in a pseudo-breakup event: THEMIS observations

Pseudo-breakup events are thought to be generated by the same physical processes as substorms. This paper reports on the cross-tail current reduction in an isolated pseudo-breakup observed by three of the THEMIS probes (THEMIS A (THA), THEMIS D (THD), and THEMIS E (THE)) on 22 March 2010. During this pseudo-breakup, several localized auroral intensifications were seen by ground-based observatories. Using the unique spatial configuration of the three THEMIS probes, we have estimated the inertial and diamagnetic currents in the near-Earth plasma sheet associated with flow braking and diversion. We found the diamagnetic current to be the major contributor to the current reduction in this pseudo-breakup event. During flow braking, the plasma pressure was reinforced, and a weak electrojet and an auroral intensification appeared. After flow braking/diversion, the electrojet was enhanced, and a new auroral intensification was seen. The peak current intensity of the electrojet estimated from ground-based magnetometers, ~0.7 × 105 A, was about 1 order of magnitude lower than that in a typical substorm. We suggest that this pseudo-breakup event involved two dynamical processes: a current-reduction associated with plasma compression ahead of the earthward flow and a current-disruption related to the flow braking/diversion. Both processes are closely connected to the fundamental interaction between fast flows, the near-Earth ambient plasma, and the magnetic field