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Terrestrial gamma ray flashes (TGFs) are sub‐millisecond bursts of high energetic gamma radiation associated with intracloud flashes in thunderstorms. In this paper we use the simultaneity of lightning detections by World Wide Lightning Location Network to find TGFs in the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI) data that are too faint to be identified by standard search algorithms. A similar approach has been used in an earlier paper, but here we expand the data set to include all years of RHESSI + World Wide Lightning Location Network data and show that there is a population of observationally weak TGFs all the way down to 0.22 of the RHESSI detection threshold (three counts in the detector). One should note that the majority of these are “normal” TGFs that are produced further away from the subsatellite point (and experience a 1/r 2 effect) or produced at higher latitudes with a lower tropoause and thus experience increased atmospheric attenuation. This supports the idea that the TGF production rate is higher than currently reported. We also show that compared to lightning flashes, TGFs are more partial to ocean and coastal regions than over land., Key Points We show that there is a fluence distribution of TGFs down to 0.22 of the detection threshold, and we do not see a cutoff in the RHESSI TGF distributionWe find that there are six times as many TGFs inside of RHESSI's field of view, than can be identified by current search algorithmsWe find that observationally weak TGFs largely originate at larger radial distances and higher latitudes from the subsatellite point

International audience; Interparticle Coulombic Decay (ICD) is an efficient energy transfer process between two weakly interacting systems. ICD was recently proposed as the underlying fundamental mechanism for technological purposes based on quantum dot nanostructures, such as wavelength-sensitive detectors. Via ICD, an excited donor quantum dot releases its excess energy by ionizing a neighbouring acceptor dot. Here, we demonstrate that the presence of a third (ICD inactive) quantum dot can serve as a bridge between the two dots, which is shown to result in an enhancement of the efficiency of the ICD-mediated energy transfer. Furthermore, our results show that this enhancement is found to be robust against the change of the characteristics of the bridge quantum dot and particularly the depth and size. On the other hand, its relative position with respect to the donor and acceptor dots is found to foster the ICD when it is located in between the two dots. Our findings provide new insights for the development of ICD-based nanostructure technologies and particularly for rational design of three coupled quantum dots. 2

The Magnetospheric Multiscale (MMS) spacecraft encounter an electron diffusion region (EDR) of asymmetric magnetic reconnection at Earth’s magnetopause. The EDR is characterized by agyrotropic electron velocity distributions on both sides of the neutral line. Various types of plasma waves are produced by the magnetic reconnection in and near the EDR. Here we report large-amplitude electron Bernstein waves (EBWs) at the electron-scale boundary of the Hall current reversal. The finite gyroradius effect of the outflow electrons generates the crescent-shaped agyrotropic electron distributions, which drive the EBWs. The EBWs propagate toward the central EDR. The amplitude of the EBWs is sufficiently large to thermalize and diffuse electrons around the EDR. The EBWs contribute to the cross-field diffusion of the electron-scale boundary of the Hall current reversal near the EDR., Various types of plasma waves are generated around electron diffusion regions (EDRs). Here the authors show electron Bernstein waves (EBWs), at the electron-scale boundary of the Hall current reversal near EDR, are sufficiently strong to diffuse electrons and modify electron pressure tensor.

Electron inflow and outflow velocities during magnetic reconnection at and near the dayside magnetopause are measured using satellites from NASA's Magnetospheric Multiscale (MMS) mission. A case study is examined in detail, and three other events with similar behavior are shown, with one of them being a recently published electron-only reconnection event in the magnetosheath. The measured inflow speeds of 200–400 km/s imply dimensionless reconnection rates of 0.05–0.25 when normalized to the relevant electron Alfvén speed, which are within the range of expectations. The outflow speeds are about 1.5–3 times the inflow speeds, which is consistent with theoretical predictions of the aspect ratio of the inner electron diffusion region. A reconnection rate of 0.04 ± 25% was obtained for the case study event using the reconnection electric field as compared to the 0.12 ± 20% rate determined from the inflow velocity. publishedVersion

International audience; Baryonic matter in geospace is almost exclusively in a plasma state, with protons (H +) and to some extent ionized helium (He) and oxygen (O) being the dominant ion species. But also other heavier ion species and even molecular ions are present in geospace. The Research with Adaptive Particle Imaging Detectors (RAPID) on board the Cluster satellites can identify and characterize some of these ions by utilizing their measured time of flight and energy. Usually, the measurements are then assigned into three discrete species channels; protons (H +), helium (He), and a common channel for carbon, nitrogen, and oxygen (CNO), each with flux, energy, and angular information. But RAPID also has a Direct Event (DE) diagnostic mode in which the full time of flight and energy information for a limited number of incident particles are stored. With knowledge about energy losses in the various detector parts, it is then possible to derive the atomic mass of the incident particle. In this paper we report on results from a study of Cluster DE events during the years 2001-2018, with a particular emphasis of iron (Fe) ions. We show that suprathermal Fe ions can be found all over geospace covered by Cluster, and that the time variation is consistent with modulation by geomagnetic disturbances and solar activity. We do not find any clear correlations between detection of suprathermal Fe and meteor showers or sputtering off the moon.

Hydrophobic food ingredients sensitive to degradation can be protected from their environment by microencapsulation. In an O/W1/W2 system, these hydrophobic compounds are dissolved in oil droplets, dispersed within a gelled matrix microbead (W1), which forms a barrier. The stability and degree of protection delivered by the gel matrix depends on its structure and strength, which in turn depend on the gelling process. For heat sensitive ingredients this process is typically a cold-set gelling process. We investigated the effect of variations in matrix polymer (alginate and WPI aggregates), gelling agent (acid and calcium), and method of gelation (internal and external), on the ability of microbeads to retain oil droplets, and retain a spherical shape during the extraction from the oil phase. External gelation with CaCl2 nanoparticles gave the smoothest and strongest microbeads for both protein and alginate, which we attribute to the formation of a shell at the interface of the bead during gelation. Microbeads produced by internal calcium gelation (induced with CaCO3 nanoparticles and GDL) containing the same amount of calcium showed less integrity and gave a mixture of smooth and rough beads. About half of the microbeads produced by acid induced gelation of WPI aggregates (using GDL to lower the internal pH) remained intact. When the pH was brought further from the isoelectric point, fewer beads remained intact. The method of gelation proved to be more important for the microbead integrity than type of matrix polymer, and external gelling was clearly superior to internal and acid induced gelation.

International audience; In this study, we analyse the behaviour of antibubbles when subjected to an ultrasonic pulse. Specically, we derive oscillating behaviour of acoustic antibubbles with a negligible outer shell, resulting in a RayleighPlesset equation of antibubble dynamics. Furthermore, we compare theoretical behaviour of antibubbles to behaviour of regular gas bubbles. We conclude that antibubbles and regular bubbles respond to an acoustic wave in a very similar manner if the antibubble's liquid core radius is less than half the antibubble radius. For larger cores, antibubbles demonstrate highly harmonic behaviour, which would make them suitable vehicles in ultrasonic imaging and ultrasound-guided drug delivery.

International audience; The Arctic icescape is rapidly transforming from a thicker multiyear ice cover to a thinner and largely seasonal first-year ice cover with significant consequences for Arctic primary production. One critical challenge is to understand how productivity will change within the next decades. Recent studies have reported extensive phytoplankton blooms beneath ponded sea ice during summer, indicating that satellite-based Arctic annual primary production estimates may be significantly underestimated. Here we present a unique time-series of a phytoplankton spring bloom observed beneath snow-covered Arctic pack ice. The bloom, dominated by the haptophyte algae Phaeocystis pouchetii, caused near depletion of the surface nitrate inventory and a decline in dissolved inorganic carbon by 16 ± 6 g C m−2. Ocean circulation characteristics in the area indicated that the bloom developed in situ despite the snow-covered sea ice. Leads in the dynamic ice cover provided added sunlight necessary to initiate and sustain the bloom. Phytoplankton blooms beneath snow-covered ice might become more common and widespread in the future Arctic Ocean with frequent lead formation due to thinner and more dynamic sea ice despite projected increases in high-Arctic snowfall. This could alter productivity, marine food webs and carbon sequestration in the Arctic Ocean. Annual phytoplankton net primary production in the Arctic Ocean has increased by 30% since the late 1990's mainly due to the declining sea ice extent and an increasing phytoplankton growth season 1. However, there is considerable uncertainty about the future change in Arctic Ocean primary productivity largely attributed to the

International audience; Understanding the propagation of acoustic waves through a liquid-perfused porous solid framework such as cancellous bone is an important prerequisite to improve the diagnosis of osteoporosis by ultrasound. In order to elucidate the propagation dependence upon the material and structural properties of cancellous bone, several theoretical models have been considered to date, with Biot-based models demonstrating the greatest potential. This paper describes the fundamental basis of these models and reviews their performance.

International audience; Background: Pancreatic Adenocarcinoma (PDAC)represents one of the most lethal human cancers. Surgery is often unfeasible, and the tumors respond poorly to radiation or chemotherapeutic drugs. Consequently, pancreatic cancer represents a huge burden to society and the need for new therapeutic options is evident. Experimental research using ultrasound to improve therapeutic delivery has soared in the past decade. We aimed toevaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary goal was to develop a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance grade, and prolongation of survival. Methods: Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of enhancing therapeutic efficacy. Results: The combined therapeutic regimen did not induce any additional toxicity or increase side effect frequency when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients (n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls (n = 63 patients; average of 8.3±6.0 cycles, versus 13.8±5.6 cycles). In five patients, the maximum tumor diameter was decreased during treatment. The median survival in our patients was also increased from 7.0 months to 17.6 months (p = 0.0044). Conclusions: We perform the first-in-human study evaluating the toxicity and efficacy of ultrasound and microbubble enhanced chemotherapy. It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting with no additional toxicity. This combined treatment may improve the clinical efficacy of chemotherapeutic agents, prolong the quality of life, and extend survival in patients with PDAC. Clinical trial information: NCT01674556.

International audience; Experimental research of ultrasound to induce or improve delivery has snowballed in the past decade. In our work, we investigate the use of low-intensity ultrasound in combination with clinically approved microbubbles to enhance the therapeutic efficacy of chemotherapy. Ten voluntary patients with locally advanced or metastatic pancreatic adenocarcinoma were consecutively recruited. Following standard chemotherapy protocol (intravenous infusion of gemcitabine over 30 min), a clinical ultrasound scanner was targeted at the largest slice of the tumour using modified non-linear contrast imaging settings (1.9 MHz center frequency, 0.27 MPa peak-negative pressure), and SonoVue® was injected intravenously. Ultrasound and microbubble treatment duration was 31.5 min. The combined therapy did not induce any additional toxicity or increase side effect frequency when compared to chemotherapy alone. Combination treated patients were able to tolerate an increased amount treatment cycles when compare historical controls (n = 63); average of 8.3±6.0 cycles, versus 13.8±5.6 cycles. The median survival also increased from 7.0 months to 17.6 months (p = 0.0044). In addition, five patients showed a primary tumor diameter decrease. Combined treatment of ultrasound, microbubbles, and gemcitabine does not increase side effects and may have the potential to increase the therapeutic efficacy of chemotherapy in patients with pancreatic adenocarcinoma.

Published in: Михил Постема. Как выступают с докладами физики Западной Европы и физики из стран бывшего Советского Союза. СОВЕТСКИЙ ФИЗИК, Физический факультет Московский государственный университет имени М.В.Ломоносова, 2016, 117 (1), pp.47-49. Michiel Postema. Physics presentations in Western Europe and in the former Soviet Union. SOVIET PHYSICIST, Physics faculty of Moscow State University M.V. Lomonosov, 2016, 117 (1), pp. 47-49. The purpose of scientific research is to create, expand, and apply knowledge of Life, the Universe, and Everything. All over the world, Universities play a role in creating and transferring knowledge onto the next generation. Scientific merit is typically rewarded with academic titles, the first for understanding the basics of the field (BSc, Vordiplom), the second for mastering more complicated material and understanding how scientific research is done (MSc, Diplom), the third for proving independent thinking and research (PhD, kandidat), and the fourth for proving to initiate and transfer novel research (Habilitation, doktor nauka). (...)

The Universe is permeated by hot, turbulent, magnetized plasmas. Turbulent plasma is a major constituent of active galactic nuclei, supernova remnants, the intergalactic and interstellar medium, the solar corona, the solar wind and the Earth's magnetosphere, just to mention a few examples. Energy dissipation of turbulent fluctuations plays a key role in plasma heating and energization, yet we still do not understand the underlying physical mechanisms involved. THOR is a mission designed to answer the questions of how turbulent plasma is heated and particles accelerated, how the dissipated energy is partitioned and how dissipation operates in different regimes of turbulence. THOR is a single-spacecraft mission with an orbit tuned to maximize data return from regions in near-Earth space - magnetosheath, shock, foreshock and pristine solar wind - featuring different kinds of turbulence. Here we summarize the THOR proposal submitted on 15 January 2015 to the 'Call for a Medium-size mission opportunity in ESAs Science Programme for a launch in 2025 (M4)'. THOR has been selected by European Space Agency (ESA) for the study phase. Funding: The THOR science team thanks the Swedish National Space Board for support to carry out a technical assessment phase study before the proposal submission. We acknowledge the useful discussion and comments from the THOR team (http://thor.irfu.se/team) and particularly D. Delcourt, D. Fontaine, A. Kis, G. Lapenta, M. Maksimovic, M. Opher, G. Paschmann, A. Petrukovic, S. Schwartz. We acknowledge: the support of the UK Space Agency through grant ST/N003322/1 to ICL; the support of Agenzia Spaziale Italiana through contract ASI-INAF 2015-039-R.O to University of Calabria, Italy and at IAPS/INAF, Rome; the support of the Belgian Science Policy Office through PRODEX PEA 4000116805 to BIRA-IASB; the support of the Czech Science Foundation through project 16-04956S to Charles University, Prague; the support of ESA PRODEX to IAP Prague; the support of CNRS and CNES to IRAP, LPP, LP2CE and LESIA; the support of the German Space Agency through grant 50 00 1603 to CAU; the support of Swedish National Space Board through grants 232/15 and 257/15 to IRF, Uppsala; the support of Academy of Finland through grant 267144 and European Research Council Consolidator through grant 682068-PRESTISSIMO to FMI; the support of ISSI team 'Kinetic Turbulence and Heating in the Solar wind'; the support of FP7 projects STORM and SHOCK. Vlasiator (http://vlasiator.fmi.fi) has been developed with the support of Academy of Finland and European Research Council Starting grant 200141-QuESpace.

International audience; We study extremely intense substorms with SuperMAG AL (SML) peak intensities

International audience; Antibubbles are gas bubbles containing a liquid droplet core and, typically, a stabilising outer shell. It has been hypothesised that acoustically driven antibubbles can be used for active leakage detection from subsea production facilities. This paper treats the dynamics of spherically symmetric microscopic antibubbles, building on existing models of bubble dynamics. A more complete understanding of microbubble dynamics demands that the effects of the translational dynamics is included into the Rayleigh-Plesset equation, which has been the primary aim of this paper. Moreover, it is a goal of this paper to derive a theory that is not based on ad-hoc parameters due to the presence of a shell, but rather on material properties. To achieve a coupled set of differential equations describing the radial and translational dynamics of an antibubble, in this paper Lagrangian formalism is used, where a Rayleigh-Plesset-like equation allows for the shell to be modelled from first principles. Two shell models are adopted; one for a Newtonian fluid shell, and the other for a Maxwell fluid shell. In addition, a zero-thickness approximation of the encapsulation is presented for both models. The Newtonian fluid shell can be considered as a special case of the Maxwell fluid shell. The equations have been linearised and the natural and damped resonance frequencies have been presented for both shell models.

International audience; In research and industrial processes, it is increasingly common practice to combine multiple measurement modalities. Nevertheless, experimental tools that allow the colinear combination of optical and ultrasonic transmission have rarely been reported. The aim of this study was to develop and characterise a water-matched ultrasound transducer architecture using standard components, with a central optical window larger than 10 mm in diameter allowing for optical transmission. The window can be used to place illumination or imaging apparatus such as light guides, miniature cameras, or microscope objectives, simplifying experimental setups. Four design variations of a basic architecture were fabricated and characterised with the objective to assess whether the variations influence the acoustic output. The basic architecture consisted of a piezoelectric ring and a glass disc, with an aluminium casing. The designs differed in piezoelectric element dimensions: inner diameter, ID = 10 mm, outer diameter, OD = 25 mm, thickness, TH = 4 mm or ID = 20 mm, OD = 40 mm, TH = 5 mm; glass disc dimensions OD = 20-50 mm, TH = 2-4 mm; and details of assembly. The transducers' frequency responses were characterised using electrical impedance spectroscopy and pulse-echo measurements, the acoustic propagation pattern using acoustic pressure field scans, the acoustic power output using radiation force balance measurements, and the acoustic pressure using a needle hydrophone. Depending on the design and piezoelectric element dimensions, the resonance frequency was in the range 350-630 kHz, the-6 dB bandwidth was in the range 87-97%, acoustic output power exceeded 1 W, and acoustic pressure exceeded 1 MPa peak-to-peak. 3D stress simulations were performed to predict the isostatic pressure required to induce material failure and 4D acoustic simulations. The pressure simulations indicated that specific design variations could sustain isostatic pressures up to 4.8 MPa.The acoustic simulations were able to predict the behaviour of the fabricated devices. A total of 480 simulations, varying material dimensions (piezoelectric ring ID, glass disc diameter, glass thickness) and drive frequency indicated that the emitted acoustic profile varies nonlinearly with these parameters.

This article describes observations of a bursty bulk flow (BBF) in the outer central plasma sheet. The observations are made with the Cluster satellites, located approximately 19 RE downtail, close to the midnight sector in the Southern Hemisphere. 40–60 s after Cluster first detected the BBF, there was a large bipolar perturbation in the magnetic field. A Grad-Shafranov reconstruction has revealed that this is created by a field-aligned current at the flank of the BBF. Further analysis of the plasma moments has shown that the BBF has the properties of a depleted flux tube. Depleted flux tubes are an important theoretical model for how plasma and magnetic flux can be transported Earthward in the magnetotail as part of the Dungey cycle. The field aligned current is directed Earthward and is located at the dawn side of the BBF. Thus, it is consistent with the magnetic shear at the flank of an Earthward moving BBF. The total current has been estimated to be about 0.1 MA.

International audience; We report evidence for interference phenomena beyond Young-type in electron emission spectrum from the dimers by fast ions. Prior measurements for H2 have led to a wide discussion for which no definitive conclusions have been settled, whereas theoretical-side have failed to reproduce the phenomenon. The process under investigations is treated by using a nonperturbative semi-classical approach to solve the time-dependent Schrodinger equation. Our results are supported by an analytic model based on second- and third-order Born series.

International audience; The principles of an imaging technique for 2D materials are presented. It is based on the measurement of differential cross sections for electron capture induced by impact of keV-proton on such materials. We illustrate these principles for graphene target and demonstrate the selectivity of this technique upon materials, geometries and surface defects through the highly coherent phenomenon giving rise to the imaging pattern.

International audience; Microbubble oscillation at specific ultrasound settings leads to permeabilization of surrounding cells. This phenomenon, referred to as sonoporation, allows for the in vitro and in vivo delivery of extracellular molecules, including plasmid DNA. To date, the biological and physical mechanisms underlying this phenomenon are not fully understood. The aim of this study was to investigate the interactions between microbubbles and cells, as well as the intracellular routing of plasmid DNA and microbubbles, during and after sonoporation. High-speed imaging and fluorescence confocal microscopy of HeLa cells stably expressing enhanced green fluorescent protein fused with markers of cellular compartments were used for this investigation. Soft-shelled microbubbles were observed to enter cells during sonoporation using experimental parameters that led to optimal gene transfer. They interacted with the plasma membrane in a specific area stained with fluorescent cholera subunit B, a marker of lipid rafts. This process was not observed with hard-shelled microbubbles, which were not efficient in gene delivery under our conditions. The plasmid DNA was delivered to late endosomes after 3 h post-sonoporation, and a few were found in the nucleus after 6 h. Gene transfer efficacy was greatly inhibited when cells were treated with chlorpromazine, an inhibitor of the clathrin-dependent endocytosis pathway. In contrast, no significant alteration was observed when cells were treated with filipin III or genistein, both inhibitors of the caveolin-dependent pathway. This study emphasizes that microbubble-cell interactions do not occur randomly during sonoporation ; microbubble penetration inside cells affects the efficacy of gene transfer at specific ultrasound settings ; and plasmid DNA uptake is an active mechanism that involves the clathrin-dependent pathway.

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International audience; ObjectivesThe objectives of this Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and to possibly increase the overall survival in patients with pancreatic adenocarcinoma.Methods10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner (GE LOGIQ 9) over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T = 30.0, 33.5, 37.0, 40.5, 44.0, 47.5, 51.0, 54.5, and 58.0min. A single vial (4.5 ml) was used throughout each treatment. Treatment was stopped at T=61.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min.ResultsUsing the authors’ custom acoustic settings, the 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated (published data, ref below), the maximum tumor diameter was temporally decreased to 80 ± 5% and permanently to 70 ± 5% of their original size, while the other patients showed reduced growth. Compared to historical data, there was increased survival with 60% of patients surviving 12 months (versus 10% in literature).ConclusionsIt is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles. Our study also indicates increased survival in patients with inoperable pancreatic adenocarcinoma. Ref: Medical Physics, Vol. 40, No. 7, July 2013.

International audience; The bilayer sonophore model suggests that ultrasound induces a pulsating structure in the intra-membrane hydrophobic space between the two lipid monolayer leaets of the cell membrane, assembled by dissolved gas of the surrounding area, which absorbs acoustic energy and transforms it by creating intra-cellular structural changes. This void has been referred to as a bilayer sonophore. The bilayer sonophore inates and deates periodically when exposed to ultrasound and may itself radiate acoustic pressure pulses in the surrounding medium in the same way a gas bubble does: once exposed to ultrasound the bilayer sonophore becomes a mechanical oscillator and a source of intracellular cavitation activity. In this paper, we describe observations of the clustering behaviour of living cells and several other particles in a standing sound eld generated inside a ring transducer. Upon sonication, blood cells and monodisperse polystyrene particles were observed to have been trapped in the same locations, corresponding to nodes of the ultrasound eld. Because polystyrene is hydrophobic, it behaves like a particle trapped inside a thin gas shell. In fact, the sonophore model treats biological cells in a similar way. Microbubbles that form the ultrasound contrast agent Quantison behave dierently, however. These microbubbles accumulated in circles faster than blood cells and polystyrene particles. In addition, they form tightly packed clusters at the nodes, indicating very strong secondary Bjerknes forces. Cluster formation is not to be expected in cells with predicted sonophore sizes on the order of 10100 nm.

Studying the effects of ultrasound on biological cells requires extensive knowledge of both the physical ultrasound and cellular biology. Translating knowledge between these fields can be complicated and time consuming. With the vast range of ultrasonic equipment available, nearly every research group uses different or unique devices. Hence, recreating the experimental conditions and results may be expensive or difficult. For this reason, we have developed devices to combat the common problems seen in state-of-the-art biomedical ultrasound research. In this paper, we present the design, fabrication, and characterisation of an open-source device that is easy to manufacture, allows for parallel sample sonication, and is highly reproducible, with complete acoustic calibration. This device is designed to act as a template for sample sonication experiments. We demonstrate the fabrication technique for devices designed to sonicate 24-well plates and OptiCell™ using three-dimensional (3D) printing and low-cost consumables. We increased the pressure output by electrical impedance matching of the transducers using transmission line transformers, resulting in an increase by a factor of 3.15. The devices cost approximately €220 in consumables, with a major portion attributed to the 3D printing, and can be fabricated in approximately 8 working hours. Our results show that, if our protocol is followed, the mean acoustic output between devices has a variance of

Michiel Postema, Spiros Kotopoulis, Klaus-Vitold Jenderka. Basic Principles: Basic physical principles of medical ultrasound. In: Christoph F. Dietrich: EFSUMB Course Book, pp.9-26, 2012., {"references":["Hoskins P, Martin K, Thrush A (Eds). Diagnostic Ultrasound: Physics and Equipment. Cambridge: Cambridge University Press 2010.","Millner R, Jenderka K-V. Physik und Technik der Ultraschallanwendung in der Medizin. Studienbrief MPT0015. Kaiserslautern: Technische Universität Kaiserslautern 2010.","Postema M. Fundamentals of Medical Ultrasonics. London: Spon Press 2011.","Schmitz G. Ultrasound in medical diagnosis. In: Pike R, Sabatier P (Eds). Scattering: Scattering and Inverse Scattering in Pure and Applied Science. London: Academic Press 2002:162-174."]}

Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ~25e75 micron-wide microplanar beams separated by wider (100e400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper. © 2015 Published by Elsevier Ltd on behalf of Associazione Italiana di Fisica Medica. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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International audience; An antibubble consists of a liquid droplet, surrounded by a gas, often with an encapsulating shell. Antibubbles of microscopic sizes suspended in fluids are acoustically active in the ultrasonic range. Antibubbles have applications in food processing and guided drug delivery. We study the sound generated from antibubbles, with droplet core sizes in the range of 0–90% of the equilibrium antibubble inner radius. The antibubble resonance frequency, the phase difference of the echo with respect to the incident acoustic pulse, and the presence of higher harmonics are strongly dependent of the core droplet size. Antibubbles oscillate highly nonlinearly around resonance size. This may allow for using antibubbles in clinical diagnostic imaging and targeted drug delivery.

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International audience; BackgroundThere are over 217 000 new cases of pancreatic cancer each year. Pancreatic cancer is very difficult to treat due to aggressive biology, late diagnosis, encasement of large blood vessels and/or the presence of metastasis; hence surgery is rarely an option. Chemotherapy produces modest responses but is not curative in this setting, mainly because its use is severely hampered by toxic effects to vital organs. As a result, the survival is very low. The mortality of the inoperable patients is 50% within 3 months and 90% within 12 monthsObjectivesThe aims of this Phase I study were to investigate the safety and the ability of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ treatment cycles and to possibly increase the overall survival in patients with pancreatic adenocarcinoma.Methods10 Patients were treated using a customized configuration of a commercial clinical ultrasound scanner (GE LOGIQ 9) over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue was injected intravenously during the treatment with the aim of inducing sonoporation. To ensure microbubbles were present throughout the whole treatment, 0.5 ml of contrast agent followed by 5 ml saline were injected every 3.5 min, i.e., at T = 30.0, 33.5, 37.0, 40.5, 44.0, 47.5, 51.0, 54.5, and 58.0min. A single vial (4.5 ml) was used throughout each treatment. Treatment was stopped at T=61.5 min. The total cumulated ultrasound treatment time was only 18.9 s. Gemcitabine was administered by intravenous infusion at a dose of 1000 mg/m2 over 30 min.ResultsUsing the authors’ custom acoustic settings, the 10 patients were able to undergo an increased number of treatment cycles; from an average of 8 cycles, to an average of 14 cycles when comparing to a historical control group of 80 patients. In the first two out of five patients treated (published data, ref below), the maximum tumor diameter was temporally decreased to 80 ± 5% and permanently to 70 ± 5% of their original size, while the other patients showed reduced growth. Compared to historical data, there was increased survival with 60% of patients surviving 12 months.ConclusionsIt is feasible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using a commercially available clinical ultrasound scanner to increase the number of treatment cycles. Our study also indicates increased survival in patients with inoperable pancreatic adenocarcinoma.ReferenceMedical Physics, Vol. 40, No. 7, July 2013 DOI: 10.1118/1.4808149

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We present ground-based electromagnetic data from the MIRACLE and BEAR networks and satellite optical observations from the UVI and PIXIE instruments on the Polar satellite of an omega band event over Northern Scandinavia on 26 June 1998, which occured close to the morning side edge of a substorm auroral bulge. Our analysis of the data concentrates on one omega band period from 03:18-03:27UT, for which we use the method of characteristics combined with an analysis of the UVI and PIXIE data to derive a time series of instantaneous, solely data-based distributions of the mesoscale ionospheric electrodynamic parameters with a 1-min time resolution. In addition, the AMIE method is used to derive global Hall conductance patterns. Our results show that zonally alternating regions of enhanced ionospheric conductances ("tongues") up to ~60S and low conductance regions are associated with the omega bands. The tongues have a poleward extension of ~400km from their base and a zonal extension of ~380km. While they are moving coherently eastward with a velocity of ~770ms-1, the structures are not strictly stationary. The current system of the omega band can be described as a superposition of two parts: one consists of anticlockwise rotating Hall currents around the tongues, along with Pedersen currents, with a negative divergence in their centers. The sign of this system is reversing in the low conductance areas. It causes the characteristic ground magnetic signature. The second part consists of zonally aligned current wedges of westward flowing Hall currents and is mostly magnetically invisible below the ionosphere. This system dominates the field-aligned current (FAC) pattern and causes alternating upward and downward FAC at the flanks of the tongues with maximum upward FAC of ~25µAm-2. The total FAC of ~2MA are comparable to the ones diverted inside a westward traveling surge. Throughout the event, the overwhelming part of the FAC are associated with gradients of the ionospheric conductances, and 66-84% of the FAC are connected with ionospheric Hall currents.

International audience; Glass windowed ultrasound transducers have several potential uses ranging from multi-modal research (ultrasound and optics) to industrial application in oil and gas or chemistry. Fig. 1. Graphical representation showing the construction of (A.) a traditional transducer and (B. four different transparent transducer designs.) between the PZT-ring and glass disc was removed using a 87 scalpel to access the printed surface electrode of the PZT-ring. 88 A microcoaxial cable was bonded using conductive Ag-epoxy 89 (Agar Scientific, Essex, United Kingdom) as a side connection 90 on the PZT-glass interface and on the back electrode of the 91 PZT-ring. The microcoaxial cable was subsequently soldered 92 to a larger diameter 50-Ω RG174 cable for increased stability 93 and reliability. The stacked PZT-glass disc was then placed 94 centrally in an aluminium cylinder and bonded to adhesive 95 UV tape (Adwill D, LINTEC, Tokyo, Japan). The interface 96 between the PZT-glass stack and aluminium cylinder was then 97 bonded with Epofix epoxy and left to cure for 24 hours. The 98 RG174 cable threaded through a 3-mm hole drilled into the 99 aluminium case wall. The back side of the case was sealed 100 with a polycarbonate disc. Bonding and sealing was achieved 101 using generic 5-minute epoxy. 102 Design 2 was fabricated in a similar manner. The PZT 103 ring was first bonded to the aluminium case, and the front 104 face was connected to the aluminum case with silver paint 105 (Agar Scientific, Essex, United Kingdom) and the glass disc 106 was bonded to both the PZT and aluminium case. (Instead 107 of bonding the earth of the coaxial cable to the ring itself, 108 it was now bonded to the aluminum case). All other steps 109 remained the same. Table I shows the dimensions of the 110 different designs.

International audience; Hydroelectric power is a clean source of energy, providing up to 20% of the World's electricity. Nevertheless, hydroelectric power plants are plagued with a common problem: silt. The silt causes damage to turbine blades, which then require repairing or replacing. In this study, we investigated the possibility to filter micron-sized particles from water using ultrasound. We designed a custom-made flow chamber and performed flow simulations and experiments to evaluate its efficacy. We used a 195-kHz ultrasound transducer operating in continuous-wave mode with acoustic output powers up to 12 W. Our acoustic simulations showed that it should be possible to force a 200-µm particle over 2 cm in flow, using an acoustic pressure of 12 MPa. Our flow simulations showed, that the fluid flow is not drastically decreased with the flow chamber, which was validated by the experimental measurements. The flow was not reduced when the ultrasound was activated. The acoustic filtering was effective between acoustic powers of 2.6 and 6.4 W, where the particle concentration in the clean output was statistically significantly lower than the null experiments.

International audience; Therapeutic ultrasound has been in use for over 70 years but has primarily been a thermal modality. Sonoporation, the use of ultrasound and stable gas microbubbles in the size range of 2-10 µm to form transient pores in cell membranes, has been of great interest in the past 15 years. This technique could be used to improve the delivery of current drugs in very localised regions. There are several phenomena behind sonoporation that all occur non-exclusively: push, pull, jetting, inertial cavitation, shear and, translation. Pre-clinical work has shown that sonoporation can be used to reduce primary tumour burden and inhibit metastatic development. Our clinical trial showed that ultrasound in combination with microbubbles and chemotherapy can effectively double the number of chemotherapy cycles patients can undergo, meaning that the patients were healthier for a longer period of time. Nevertheless, sonoporation is still in its infancy and there is vast room for improvement in both the areas of microbubbles and ultrasound.

Clinical diagnostic ultrasound has been known as one of the safest imaging modalities available, yet very little is known about the cellular response to such acoustic conditions. With the increased interest in therapeutic ultrasound it is becoming ever more important to understand the effects of ultrasound on cells.

This paper presents the first study that uses the GEometry ANd Tracking 4 (GEANT4) toolkit to do quantitative comparisons with other modeling results related to the production of terrestrial gamma ray flashes and high-energy particle emission from thunderstorms. We will study the relativistic runaway electron avalanche (RREA) and the relativistic feedback process, as well as the production of bremsstrahlung photons from runaway electrons. The Monte Carlo simulations take into account the effects of electron ionization, electron by electron (Møller), and electron by positron (Bhabha) scattering as well as the bremsstrahlung process and pair production, in the 250 eV to 100 GeV energy range. Our results indicate that the multiplication of electrons during the development of RREAs and under the influence of feedback are consistent with previous estimates. This is important to validate GEANT4 as a tool to model RREAs and feedback in homogeneous electric fields. We also determine the ratio of bremsstrahlung photons to energetic electrons Nγ/Ne. We then show that the ratio has a dependence on the electric field, which can be expressed by the avalanche time τ(E) and the bremsstrahlung coefficient α(ε). In addition, we present comparisons of GEANT4 simulations performed with a “standard” and a “low-energy” physics list both validated in the 1 keV to 100 GeV energy range. This comparison shows that the choice of physics list used in GEANT4 simulations has a significant effect on the results. Key Points Testing the feedback mechanism with GEANT4 Validating the GEANT4 programming toolkit Study the ratio of bremsstrahlung photons to electrons at TGF source altitude

International audience; Single clouds of cavitation bubbles, driven by 254 kHz focused ultrasound at pressure amplitudes in the range of 0.48-1.22 MPa, have been observed via high-speed shadowgraphic imaging at 1 Â 10 6 frames per second. Clouds underwent repetitive growth, oscillation and collapse (GOC) cycles, with shock-waves emitted periodically at the instant of collapse during each cycle. The frequency of cloud collapse, and coincident shock-emission, was primarily dependent on the intensity of the focused ultrasound driving the activity. The lowest peak-to-peak pressure amplitude of 0.48 MPa generated shock-waves with an average period of 7.9 ± 0.5 ls, corresponding to a frequency of f 0 /2, half-harmonic to the fundamental driving. Increasing the intensity gave rise to GOC cycles and shock-emission periods of 11.8 ± 0.3, 15.8 ± 0.3, 19.8 ± 0.2 ls, at pressure amplitudes of 0.64, 0.92 and 1.22 MPa, corresponding to the higher-order subharmonics of f 0 /3, f 0 /4 and f 0 /5, respectively. Parallel passive acoustic detection, filtered for the fundamental driving, revealed features that correlated temporally to the shock-emissions observed via high-speed imaging, p(two-tailed) < 0.01 (r = 0.996, taken over all data). Subtracting the isolated acoustic shock profiles from the raw signal collected from the detector, demonstrated the removal of subharmonic spectral peaks, in the frequency domain. The larger cavitation clouds (>200 lm diameter, at maximum inflation), that developed under insonations of peak-to-peak pressure amplitudes >1.0 MPa, emitted shock-waves with two or more fronts suggesting non-uniform collapse of the cloud. The observations indicate that periodic shock-emissions from acoustically driven cavitation clouds provide a source for the cavitation subharmonic signal, and that shock structure may be used to study intra-cloud dynamics at sub-microsecond timescales.

National audience; In the current day and age, image guided and targeted drug delivery is becoming a necessity as it allowed a larger amount of therapeutic agent to be delivered to a precise location, allowing for tailored treatment to each and every patient, theoretically improving the treatment efficacy, whilst reducing systemic side effects. One of the most cost effective imaging modalities is ultrasound imaging. It is capable of deep tissue imaging in three dimensions in real time. In addition, it can be done bedside at any location, and has little to no known side effects. Sonoporation takes advantage of the behaviour of commercially available microbubbles, otherwise known as ultrasound contrast agents, under ultrasound sonication to form transient pores in cells, allowing for increased drug uptake. Pre-clinical and clinical trials have shown great promise. Nevertheless, in all instances, the therapeutic agent is delivered intravenously; hence there are still systemic side effects. Here we investigate the possibility of using drug-cored gas microbubbles (antibubbles) as an alternative to typical contrast agent. These antibubbles consist of a drug core, encapsulated air, encapsulated by a nano-particle stabilised shell. Our work here investigated the acoustic linear and non-linear behaviour of these antibubbles and compares them to commercial microbubbles. By adding the drug inside the bubble, we can theoretically force the drug into selected cells. Theoretical simulations were performed to evaluate the resonance frequency and radius time curves under sonication. Broadband acoustic attenuation measurements were performed to identify the resonant frequency and were compared to the size distribution. Ultra-high speed imaging was performed at high acoustic amplitudes to visualise the non-linear behaviour and to evaluate the gas content. The antibubbles were also imaged using a clinical scanner and several probes to evaluate the increase in contrast and non-linear acoustic backscatter. Our results showed that these antibubbles were acoustically active and highly non-linear, in a similar fashion to traditional contrast agents. These antibubbles may have potential as an ultrasound activated high-capacity drug carrier.

National audience; Ultrasound is one of the most cost-effective deep tissue clinical imaging modalities. Near all ultrasound transducers are fabricated from piezoelectric materials that require metal surface electrodes, making the transducers opaque. With the increasing need for multi-modal and compact imaging and therapeutic tools new transducers fabrication techniques need to be evaluated. In our work we evaluate several designs that allow a large optical window in combination with ultrasonic propagation collinear to the imaging path. Three types of transducers were made based on a stacked design, in two different sizes. The optical windows were 20-mm and 10-mm with outer diameters of 50-mm and 38-mm respectively. The devices were characterised for acoustic bandwidth and sensitivity using a pulse receive technique. The acoustic power was measured using a custom made radiation force balance. The beam profile was measured using a three-dimensional scanning chamber with a mobile needle-hydrophone. The transient response waveform of a burst wave was captured using the needle hydrophone, and an FFT was performed to get the power spectrum to determine the linearity of the ultrasound generation of the transducer. The frequency response showed that these transducers had a large FWHM bandwidth of 56%. The field scans showed that the acoustic propagation pattern was very similar to traditional ultrasound transducers, yet the different constructions affected the focal distance and sidelobes. In addition surface scans, indicated that in all transducers glass window acted like an oscillating diaphragm generating ultrasound. The acoustic power measurements indicated that these devices could exceed acoustic powers of 16 W. Traditional ultrasonic imaging only requires several milliwatts whereas therapeutic application only require several watts. These transducers indicate their potential for multimodal imaging and therapy for example combining endoscopy with ultrasound surgery, or simultaneous ultrasound and bioluminescence imaging.

International audience; PURPOSE:Adenocarcinoma of the pancreas remains one of the most lethal human cancers. The high mortality rates associated with this form of cancer are subsequent to late-stage clinical presentation and diagnosis, when surgery is rarely possible and of modest chemotherapeutic impact. Survival rates following diagnosis with advanced pancreatic cancer are very low; typical mortality rates of 50% are expected within 3 months of diagnosis. However, adjuvant chemotherapy improves the prognosis of patients even after palliative surgery, and successful newer neoadjuvant chemotherapeutical modalities have recently been reported. For patients whose tumours appear unresectable, chemotherapy remains the only option. During the past two decades, the nucleoside analogue gemcitabine has become the first-line chemotherapy for pancreatic adenocarcinoma. In this study, we aim to increase the delivery of gemcitabine to pancreatic tumours by exploring the effect of sonoporation for localised drug delivery of gemcitabine in an orthotopic xenograft mouse model of pancreatic cancer.EXPERIMENTAL DESIGN:An orthotopic xenograft mouse model of luciferase expressing MIA PaCa-2 cells was developed, exhibiting disease development similar to human pancreatic adenocarcinoma. Subsequently, two groups of mice were treated with gemcitabine alone and gemcitabine combined with sonoporation; saline-treated mice were used as a control group. A custom-made focused ultrasound transducer using clinically safe acoustic conditions in combination with SonoVue® ultrasound contrast agent was used to induce sonoporation in the localised region of the primary tumour only. Whole-body disease development was measured using bioluminescence imaging, and primary tumour development was measured using 3D ultrasound.RESULTS:Following just two treatments combining sonoporation and gemcitabine, primary tumour volumes were significantly lower than control groups. Additional therapy dramatically inhibited primary tumour growth throughout the course of the disease, with median survival increases of up to 10% demonstrated in comparison to the control groups.CONCLUSION:Combined sonoporation and gemcitabine therapy significantly impedes primary tumour development in an orthotopic xenograft model of human pancreatic cancer, suggesting additional clinical benefits for patients treated with gemcitabine in combination with sonoporation.

A time and polarization resolved reflective interferometry measurement on femtosecond laser heated gold is presented. We deduced the electron momentum damping frequency, the conduction electron density, and finally the electron temperature in the $0.6--5\phantom{\rule{0.28em}{0ex}}\mathrm{eV}$ range in out of equilibrium, solid density warm dense gold. This allows the experimental determination of the electron-electron collision frequency variation with the electron temperature in warm dense matter conditions. The comparison with several models shows the importance of properly taking into account the $d$-band electrons in noble metals.

International audience; We have probed, with time-resolved x-ray absorption near-edge spectroscopy (XANES), a femtosecond-laser-heated aluminum foil with fluences up to 1 J/cm2. The spectra reveal a loss of the short-range order in a few picoseconds. This time scale is compared with the electron-ion equilibration time, calculated with a two-temperature model. Hydrodynamic simulations shed light on complex features that affect the foil dynamics, including progressive density change from solid to liquid (∼10 ps). In this density range, quantum molecular dynamics simulations indicate that XANES is a relevant probe of the ionic temperature.

International audience; Microbubbles first developed as ultrasound contrast agents have been used to assist ultrasound for cellular drug and gene delivery. Their oscillation behavior during ultrasound exposure leads to transient membrane permeability of surrounding cells, facilitating targeted local delivery. The increased cell uptake of extracellular compounds by ultrasound in the presence of microbubbles is attributed to a phenomenon called sonoporation. In this review, we summarize current state of the art concerning microbubble-cell interactions and cellular effects leading to sonoporation and its application for gene delivery. Optimization of sonoporation protocol and composition of microbubbles for gene delivery are discussed.

International audience; Purpose: The purpose of this study was to investigate the ability and efficacy of inducing sonoporation in a clinical setting, using commercially available technology, to increase the patients’ quality of life and extend the low Eastern Cooperative Oncology Group performance grade; as a result increasing the overall survival in patients with pancreatic adenocarcinoma.Methods: Patients were treated using a customized configuration of a commercial clinical ultrasound scanner over a time period of 31.5 min following standard chemotherapy treatment with gemcitabine. SonoVue(R) ultrasound contrast agent was injected intravascularly during the treatment with the aim to induce sonoporation.Results: Using the authors’ custom acoustic settings, the authors’ patients were able to undergo an increased number of treatment cycles; from an average of 9 cycles, to an average of 16 cycles when comparing to a historical control group of 80 patients. In two out of five patients treated, the maximum tumor diameter was temporally decreased to 80 ± 5% and permanently to 70 ± 5% of their original size, while the other patients showed reduced growth. The authors also explain and characterize the settings and acoustic output obtained from a commercial clinical scanner used for combined ultrasound microbubble and chemotherapy treatment.Conclusions: It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available clinical ultrasound scanners to increase the number of treatment cycles, prolonging the quality of life in patients with pancreatic adenocarcinoma compared to chemotherapy alone.

International audience; Electron beam lithography (EBL) was used to fabricate microchannels to produce microbubbles with highly homogeneous size distributions. Using the EBL technique, microchannels can be prototyped at a fast and cost effective rate allowing for evaluation of various microbubble shell materials.

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