Electrical charging of ash in Icelandic volcanic plumes

The existence of volcanic lightning and alteration of the atmospheric potential gradient in the vicinity of near-vent volcanic plumes provides strong evidence for the charging of volcanic ash. More subtle electrical effects are also visible in balloon soundings of distal volcanic plumes. Near the vent, some proposed charging mechanisms are fractoemission, triboelectrification, and the so-called "dirty thunderstorm" mechanism, which is where ash and convective clouds interact electrically to enhance charging. Distant from the vent, a self-charging mechanism, probably triboelectrification, has been suggested to explain the sustained low levels of charge observed on a distal plume. Recent research by Houghton et al. (2013) linked the self-charging of volcanic ash to the properties of the particle size distribution, observing that a highly polydisperse ash distribution would charge more effectively than a monodisperse one. Natural radioactivity in some volcanic ash could also contribute to self-charging of volcanic plumes. Here we present laboratory measurements of particle size distributions, triboelectrification and radioactivity in ash samples from the Gr\'{i}msv\"{o}tn and Eyjafjallaj\"{o}kull volcanic eruptions in 2011 and 2010 respectively, and discuss the implications of our findings.Comment: XV Conference on Atmospheric Electricity, 15-20 June 2014, Norman, Oklahoma, US

Measuring ionizing radiation in the atmosphere with a new balloon-borne detector

Increasing interest in energetic particle effects on weather and climate has motivated development of a miniature scintillator-based detector intended for deployment on meteorological radiosondes or unmanned airborne vehicles. The detector was calibrated with laboratory gamma sources up to 1.3 MeV, and known gamma peaks from natural radioactivity of up to 2.6 MeV. The specifications of our device in combination with the performance of similar devices suggest that it will respond to up to 17 MeV gamma rays. Laboratory tests show the detector can measure muons at the surface, and it is also expected to respond to other ionizing radiation including, for example, protons, electrons (>100 keV) and energetic helium nuclei from cosmic rays or during space weather events. Its estimated counting error is ±10%. Recent tests, when the detector was integrated with a meteorological radiosonde system, and carried on a balloon to ~25 km altitude, identified the transition region between energetic particles near the surface, which are dominated by terrestrial gamma emissions, to higher-energy particles in the free troposphere

Aspirated capacitor measurements of air conductivity and ion mobility spectra

Measurements of ions in atmospheric air are used to investigate atmospheric electricity and particulate pollution. Commonly studied ion parameters are (1) air conductivity, related to the total ion number concentration, and (2) the ion mobility spectrum, which varies with atmospheric composition. The physical principles of air ion instrumentation are long-established. A recent development is the computerised aspirated capacitor, which measures ions from (a) the current of charged particles at a sensing electrode, and (b) the rate of charge exchange with an electrode at a known initial potential, relaxing to a lower potential. As the voltage decays, only ions of higher and higher mobility are collected by the central electrode and contribute to the further decay of the voltage. This enables extension of the classical theory to calculate ion mobility spectra by inverting voltage decay time series. In indoor air, ion mobility spectra determined from both the novel voltage decay inversion, and an established voltage switching technique, were compared and shown to be of similar shape. Air conductivities calculated by integration were: 5.3 +- 2.5 fS/m and 2.7 +- 1.1 fS/m respectively, with conductivity determined to be 3 fS/m by direct measurement at a constant voltage. Applications of the new Relaxation Potential Inversion Method (RPIM) include air ion mobility spectrum retrieval from historical data, and computation of ion mobility spectra in planetary atmospheres.Comment: To be published in Review of Scientific Instrument

Fetal-derived trophoblast use the apoptotic cytokine tumor necrosis factor-alpha-related apoptosis-inducing ligand to induce smooth muscle cell death.

Remodeling of the uterine spiral arteries during pregnancy transforms them from high to low resistance vessels that lack vasoconstrictive properties. This process is essential to meet the demand for increased blood flow imposed by the growing fetus. Loss of endothelial and smooth muscle cells (SMC) is evident in remodeled arteries but the mechanisms underlying this transformation remain unknown. This study investigated the hypothesis that fetal trophoblast invading from the placenta instigate remodeling by triggering cell death in vascular SMC. Specifically, a role for trophoblast-derived death inducing cytokine tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL) was investigated. Expression of the activating TRAIL receptors R1 and R2 was detected by flow cytometry on human aortic SMC and by immunohistochemistry on spiral artery SMC. Recombinant human TRAIL induced human aortic SMC apoptosis, which was inhibited by antibodies against TRAIL-R1 or -R2. Perfusion of denuded spiral artery segments with recombinant human TRAIL also induced SMC apoptosis. Trophoblasts isolated from first trimester placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic SMC; apoptosis was significantly inhibited by a recombinant human TRAIL-R1:Fc construct. Trophoblast within the first trimester placental bed also expressed TRAIL. These data show that: 1) TRAIL causes SMC death; 2) trophoblast produce the apoptotic cytokine TRAIL; and 3) trophoblast induce SMC apoptosis via a TRAIL-dependent mechanism. We conclude that TRAIL produced by trophoblast causes apoptosis of SMC and thus may contribute to SMC loss during spiral artery remodeling in pregnancy

A STATement on vemurafenib-resistant melanoma.

Despite recent advancements in the treatment of late-stage mutant BRAF (V600E/K) melanomas, a major hurdle continues to be acquired resistance to BRAF inhibitors such as vemurafenib. The mechanisms for resistance have proven to be heterogeneous, emphasizing the need to use broad therapeutic approaches. In this issue, the study Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas by Liu et al. proposes that signal transducer and activator of transcription 3 (STAT3)-paired box 3 (PAX3) signaling may be a mechanism that is used by melanomas to resist RAF inhibitors

Targeting TBK1 inhibits migration and resistance to MEK inhibitors in mutant NRAS melanoma.

UNLABELLED: Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to 20% of patients with melanoma have an activating mutation in the GTPase, NRAS. The major downstream effectors of RAS are RAFs (ARAF, BRAF, and CRAF), phosphoinositide 3-kinase (PI3K), and the Ral guanine exchange factors (RalGEF). TANK-binding kinase 1 (TBK1) is an atypical IκB kinase family member that acts downstream of RalGEFs. Whereas many studies have analyzed RAF and PI3K signaling in mutant NRAS melanoma, the role of RalGEF/Ral is understudied and TBK1 has not been examined. To address this, TBK1 was modulated with knockdown approaches and targeted therapies to determine the role of TBK1 in motility, apoptosis, and signaling. In melanoma, NRAS overexpression increased TBK1 phosphorylation. TBK1 depletion inhibited migration and invasion, whereas its constitutive overexpression led to an increase in invasion. In three-dimensional systems that mimic the dermal microenvironment, TBK1 depletion or inhibition cooperated with MEK inhibitors to promote apoptosis, particularly in the context of MEK-insensitive mutant NRAS. This effect was absent in melanoma cells that are wild-type for NRAS. These results suggest the utility of TBK1 inhibitors as part of a treatment regimen for patients with mutant NRAS melanoma, for whom there are no current effective therapies. IMPLICATIONS: TBK1 promotes the malignant properties of NRAS-mutant melanoma and its targeting, in combination with MEK, promotes apoptosis, thus providing a potential novel targeted therapeutic option

The Broad Stroke of Hsp90 Inhibitors: Painting over the RAF Inhibitor Paradox.

The novel Hsp90 inhibitor XL888 is undergoing clinical investigation for use in conjunction with the rapidly accelerated fibrosarcoma (RAF) kinase inhibitor vemurafenib to treat unresectable melanoma. The addition of XL888 to current regimens may serve an additional purpose by blocking the RAF inhibitor paradox. Such activity could reduce adverse events in patients and provide a biomarker for the successful inhibition of Hsp90 target proteins

The natural resources of Bolinas Lagoon: their status and future

This publication is an integral part of the Department's high-priority inventory and assessment of coastal marshland and tideflat resources. It is intended as a guide for citizens, planners, administrators, and all others interested in the use and development of coastal lands and waters. Although the resources and problems of Bolinas Lagoon have probably been the subject of more biological and physical investigations than any small estuarine area of the California coast, many of the pertinent reports and information are not readily available to the public. Consequently, it is one purpose of this report to summarize the lagoon's history, ecological attractions, educational values and the problems facing its continued existence. At the same time, it should provide concerned citizens with a knowledge of the sources of additional and more specific information. Publication of this report is consistent with the obligation of the Department of Fish and Game to do everything in its power to protect and maintain the State's fish and wildlife resources. Therefore, its purpose transcends local issues on pollution and development, and the Department is, in fact, submitting a report to the people on the status and future of part of its inheritance and the dowry of coming generations. The report is the third of a scheduled series. It follows similar releases on Upper Newport Bay (Orange County) and Goleta Slough (Santa Barbara county) in March and June of 1970. Documentation of the resources of other critical areas is in progress. There will be future reports of this nature on Elkhorn Slough, Morro Bay, Tomales Bay, Humboldt Bay, and highly threatened marshlands in southern California. (137 pp.

Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation.

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway

Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.

Melanoma cells driven by mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) are highly resistant to chemotherapeutic treatments. Recent phase 1 results with PLX4032/RG7204/vemurafenib, which selectively inhibits B-RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field. Nearly all patients in the phase 1-3 studies saw at least some response and the overall response rates ranged from 48 and 81%. However, despite initial tumor shrinkage, most responders in the trial experienced tumor relapse over time. These findings indicate that both intrinsic and acquired resistance may affect the clinical efficacy of PLX4032. It is critical to optimize PLX4032 activity to improve response rates and understand why some patients with the B-RAF mutation do not respond. We have previously shown that the stemness factor, Forkhead box D3 (FOXD3), is upregulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that upregulation of FOXD3 following treatment with PLX4032 and PLX4720 (the non-clinical tool compound for PLX4032) confers resistance to cell death. Small interfering RNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032/4720 treatment in mutant B-RAF melanoma cell lines. Additionally, upregulation of FOXD3 after PLX4720 treatment was attenuated in non-adherent conditions and correlated with enhanced cell death. Ectopic expression of FOXD3 in non-adherent cells significantly reduced cell death in response to PLX4720 treatment. Together, these data indicate that upregulation of FOXD3 is an adaptive response to RAF inhibitors that promotes a state of drug resistance