Enhanced activation of an amino-terminally truncated isoform of the voltage-gated proton channel HVCN1 enriched in malignant B cells

The final published version can be found here: http://dx.doi.org/10.1073/pnas.1411390111M.C. is the recipient of a Bennett Fellowship from Leukaemia and Lymphoma Research (ref. 12002). M.A.B. is supported by a GlaxoSmithKline Oncology–Biotechnology and Biological Sciences Research Council Collaborative Awards in Science and Engineering PhD studentship. This work was supported by National Institutes of Health Grants GM087507 and GM102336 (to T.E.D.)

JDLL: A library to run Deep Learning models on Java bioimage informatics platforms

We present JDLL, an agile Java library that offers a comprehensive toolset/API to unify the development of high-end applications of DL for bioimage analysis and to streamline their installation and maintenance. JDLL provides all the functions required to consume DL models seamlessly, without being burdened by the configuration of the Python-based DL frameworks, within Java bioimage informatics platforms. Moreover, it allows the deployment of pre-trained models in the Bioimage Model Zoo (BMZ) by shipping the logic to connect to the BMZ website, download and run a selected model inference

Next-Generation Comprehensive Data-Driven Models of Solar Eruptive Events

Solar flares and coronal mass ejections are interrelated phenomena that together are known as solar eruptive events. These are the main drivers of space weather and understanding their origins is a primary goal of Heliophysics. In this white paper, we advocate for the allocation of sufficient resources to bring together experts in observations and modeling to construct and test next generation data-driven models of solar eruptive events. We identify the key components necessary for constructing comprehensive end-to-end models including global scale 3D MHD resolving magnetic field evolution and reconnection, small scale simulations of particle acceleration in reconnection exhausts, kinetic scale transport of flare-accelerated particles into the lower solar atmosphere, and the radiative and hydrodynamics responses of the solar atmosphere to flare heating. Using this modeling framework, long-standing questions regarding how solar eruptive events release energy, accelerate particles, and heat plasma can be explored. To address open questions in solar flare physics, we recommend that NASA and NSF provide sufficient research and analysis funds to bring together a large body of researchers and numerical tools to tackle the end-to-end modeling framework that we outline. Current dedicated theory and modeling funding programs are relatively small scale and infrequent; funding agencies must recognize that modern space physics demands the use of both observations and modeling to make rapid progress.Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 9 pages, 4 figure

Differential sensitivity of TREK-1, TREK-2 and TRAAK background potassium channels to the polycationic dye ruthenium red

BACKGROUND AND PURPOSE: Pharmacological separation of the background potassium currents of closely related K2P channels is a challenging problem. We previously demonstrated that ruthenium red (RR) inhibits TASK-3 (K2 P 9.1), but not TASK-1 (K2 P 3.1) channels. RR has been extensively used to distinguish between TASK currents in native cells. In the present study, we systematically investigate the RR sensitivity of a more comprehensive set of K2 P channels. EXPERIMENTAL APPROACH: K+ currents were measured by two-electrode voltage clamp in Xenopus oocytes and by whole-cell patch clamp in mouse dorsal root ganglion (DRG) neurons. KEY RESULTS: RR differentiates between two closely related members of the TREK subfamily. TREK-2 (K2 P 10.1) proved to be highly sensitive to RR (IC50 = 0.2 muM), whereas TREK-1 (K2 P 2.1) was not affected by the compound. We identified aspartate 135 (D135) as the target of the inhibitor in mouse TREK-2c. D135 lines the wall of the extracellular ion pathway (EIP), a tunnel structure through the extracellular cap characteristic for K2 P channels. TREK-1 contains isoleucine in the corresponding position. The mutation of this isoleucine (I110D) rendered TREK-1 sensitive to RR. The third member of the TREK subfamily, TRAAK (K2 P 4.1) was more potently inhibited by ruthenium violet, a contaminant in some RR preparations, than by RR. DRG neurons predominantly express TREK-2 and RR-resistant TREK-1 and TRESK (K2 P 18.1) background K+ channels. We detected the RR-sensitive leak K+ current component in DRG neurons. CONCLUSIONS AND IMPLICATIONS: We propose that RR may be useful for distinguishing TREK-2 (K2P 10.1) from TREK-1 (K2P 2.1) and other RR-resistant K2 P channels in native cells

The Focusing Optics X-ray Solar Imager (FOXSI)

FOXSI is a direct-imaging, hard X-ray (HXR) telescope optimized for solar flare observations. It detects hot plasma and energetic electrons in and near energy release sites in the solar corona via bremsstrahlung emission, measuring both spatial structure and particle energy distributions. It provides two orders of magnitude faster imaging spectroscopy than previously available, probing physically relevant timescales (<1s) never before accessible to address fundamental questions of energy release and efficient particle acceleration that have importance far beyond their solar application (e.g., planetary magnetospheres, flaring stars, accretion disks). FOXSI measures not only the bright chromospheric X-ray emission where electrons lose most of their energy, but also simultaneous emission from electrons as they are accelerated in the corona and propagate along magnetic field lines. FOXSI detects emission from high in the tenuous corona, where previous instruments have been blinded by nearby bright features and will fully characterizes the accelerated electrons and hottest plasmas as they evolve in energy, space, and time to solve the mystery of how impulsive energy release leads to solar eruptions, the primary drivers of space weather at Earth, and how those eruptions are energized and evolve.Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 14 pages, 4 figures, 1 tabl

VSOP/Hv1 proton channels sustain calcium entry, neutrophil migration, and superoxide production by limiting cell depolarization and acidification

Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltage-sensing domain only protein [VSOP]/Hv1) are required for high-level superoxide production by phagocytes, but the mechanism of this effect is not established. We show that neutrophils from VSOP/Hv1−/− mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1−/− neutrophils had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice. Hydrogen peroxide production was rescued by providing an artificial conductance with gramicidin. Loss of VSOP/Hv1 also aborted calcium responses to chemoattractants, increased neutrophil spreading, and decreased neutrophil migration. The migration defect was restored by the addition of a calcium ionophore. Our findings indicate that proton channels extrude the acid and compensate the charge generated by the oxidase, thereby sustaining calcium entry signals that control the adhesion and motility of neutrophils. Loss of proton channels thus aborts superoxide production and causes a severe signaling defect in neutrophils

Fundamentals of impulsive energy release in the corona

It is essential that there be coordinated and co-optimized observations in X-rays, gamma-rays, and EUV during the peak of solar cycle 26 (~2036) to significantly advance our understanding of impulsive energy release in the corona. The open questions include: What are the physical origins of space-weather events? How are particles accelerated at the Sun? How is impulsively released energy transported throughout the solar atmosphere? How is the solar corona heated? Many of the processes involved in triggering, driving, and sustaining solar eruptive events -- including magnetic reconnection, particle acceleration, plasma heating, and energy transport in magnetized plasmas -- also play important roles in phenomena throughout the Universe. This set of observations can be achieved through a single flagship mission or, with foreplanning, through a combination of major missions (e.g., the previously proposed FIERCE mission concept).Comment: White paper submitted to the Decadal Survey for Solar and Space Physics (Heliophysics) 2024-2033; 5 pages, 1 figur

The need for focused, hard X-ray investigations of the Sun

Understanding accelerated particles at the Sun is one of the most important problems in heliophysics. Flare-accelerated particles have huge energies; are an important source of particles in the heliosphere; and are the most important corollary to other areas of high-energy astrophysics. This paper describes the scientific motivation for X-ray studies of particle acceleration at the Sun