Hosing of a Long Relativistic Particle Bunch in Plasma.

Experimental results show that hosing of a long particle bunch in plasma can be induced by wakefields driven by a short, misaligned preceding bunch. Hosing develops in the plane of misalignment, self-modulation in the perpendicular plane, at frequencies close to the plasma electron frequency, and are reproducible. Development of hosing depends on misalignment direction, its growth on misalignment extent and on proton bunch charge. Results have the main characteristics of a theoretical model, are relevant to other plasma-based accelerators and represent the first characterization of hosing.

Acceleration of electrons in the plasma wakefield of a proton bunch.

High-energy particle accelerators have been crucial in providing a deeper understanding of fundamental particles and the forces that govern their interactions. To increase the energy of the particles or to reduce the size of the accelerator, new acceleration schemes need to be developed. Plasma wakefield acceleration1-5, in which the electrons in a plasma are excited, leading to strong electric fields (so called 'wakefields'), is one such promising acceleration technique. Experiments have shown that an intense laser pulse6-9 or electron bunch10,11 traversing a plasma can drive electric fields of tens of gigavolts per metre and above-well beyond those achieved in conventional radio-frequency accelerators (about 0.1 gigavolt per metre). However, the low stored energy of laser pulses and electron bunches means that multiple acceleration stages are needed to reach very high particle energies5,12. The use of proton bunches is compelling because they have the potential to drive wakefields and to accelerate electrons to high energy in a single acceleration stage13. Long, thin proton bunches can be used because they undergo a process called self-modulation14-16, a particle-plasma interaction that splits the bunch longitudinally into a series of high-density microbunches, which then act resonantly to create large wakefields. The Advanced Wakefield (AWAKE) experiment at CERN17-19 uses high-intensity proton bunches-in which each proton has an energy of 400 gigaelectronvolts, resulting in a total bunch energy of 19 kilojoules-to drive a wakefield in a ten-metre-long plasma. Electron bunches are then injected into this wakefield. Here we present measurements of electrons accelerated up to two gigaelectronvolts at the AWAKE experiment, in a demonstration of proton-driven plasma wakefield acceleration. Measurements were conducted under various plasma conditions and the acceleration was found to be consistent and reliable. The potential for this scheme to produce very high-energy electron bunches in a single accelerating stage20 means that our results are an important step towards the development of future high-energy particle accelerators21,22.

Controlled Growth of the Self-Modulation of a Relativistic Proton Bunch in Plasma.

A long, narrow, relativistic charged particle bunch propagating in plasma is subject to the self-modulation (SM) instability. We show that SM of a proton bunch can be seeded by the wakefields driven by a preceding electron bunch. SM timing reproducibility and control are at the level of a small fraction of the modulation period. With this seeding method, we independently control the amplitude of the seed wakefields with the charge of the electron bunch and the growth rate of SM with the charge of the proton bunch. Seeding leads to larger growth of the wakefields than in the instability case.

Hyperglycemia alters N-glycans on colon cancer cells through increased production of activated monosaccharides.

Diabetes Mellitus (DM) is both, correlated and a known risk factor for colorectal cancer (CRC). Besides favoring the incidence of CRC, DM also accelerates its progression, worsening its prognosis. Previously, hyperglycemia, the DM hallmark, has been shown to lead to aberrant glycosylation of CRC cells, heightening their malignancy both in vivo and in vitro. Here we use mass spectrometry to elucidate the composition and putative structures of N-glycans expressed by MC38 cultured in normoglycemic (LG) and hyperglycemic-like conditions (HG). N-glycans, 67, were identified in MC38 cells cultured in LG and HG. The cells grown in HG showed a greater abundance of N-glycans when compared to LNG cells, without changes in the proportion of sialylated, fucosylated and mannosylated N-glycans. Among the identified N-glycans, 16 were differentially expressed, mostly mannosylated and fucosylated, with a minority of them being sialylated. Metabolomics analysis indicates that the alterations observed in the N-glycosylation may be mostly due to increase of the activated monosaccharides pool, through an increased glucose entrance into the cells. The alterations found here corroborate data from the literature regarding the progression of CRC, advocating for development or repositioning of effective treatments against CRC in diabetic patients.

Transition between Instability and Seeded Self-Modulation of a Relativistic Particle Bunch in Plasma.

We use a relativistic ionization front to provide various initial transverse wakefield amplitudes for the self-modulation of a long proton bunch in plasma. We show experimentally that, with sufficient initial amplitude [≥(4.1±0.4) MV/m], the phase of the modulation along the bunch is reproducible from event to event, with 3%-7% (of 2π) rms variations all along the bunch. The phase is not reproducible for lower initial amplitudes. We observe the transition between these two regimes. Phase reproducibility is essential for deterministic external injection of particles to be accelerated.

Plasma Wakes Driven by Photon Bursts via Compton Scattering.

Photon bursts with a wavelength smaller than the plasma interparticle distance can drive plasma wakes via Compton scattering. We investigate this fundamental process analytically and numerically for different photon frequencies, photon flux, and plasma magnetization. Our results show that Langmuir and extraordinary modes are driven efficiently when the photon energy density lies above a certain threshold. The interaction of photon bursts with magnetized plasmas is of distinguished interest as the generated extraordinary modes can convert into pure electromagnetic waves at the plasma-vacuum boundary. This could possibly be a mechanism for the generation of radio waves in astrophysical scenarios in the presence of intense sources of high energy photons.

Proton Bunch Self-Modulation in Plasma with Density Gradient.

We study experimentally the effect of linear plasma density gradients on the self-modulation of a 400 GeV proton bunch. Results show that a positive or negative gradient increases or decreases the number of microbunches and the relative charge per microbunch observed after 10 m of plasma. The measured modulation frequency also increases or decreases. With the largest positive gradient we observe two frequencies in the modulation power spectrum. Results are consistent with changes in wakefields' phase velocity due to plasma density gradients adding to the slow wakefields' phase velocity during self-modulation growth predicted by linear theory.

Executive functions and memory in bipolar disorders I and II: new insights from meta-analytic results.

OBJECTIVE: To perform a systematic review and meta-analysis of executive functions (EF) and episodic memory in bipolar disorder (BD). METHODS: A literature search was conducted on three electronic databases. Results were combined using random-effects meta-analysis. RESULTS: A total of 126 studies (6424 patients with BDI, 702 with BDII, and 8276 controls) were included. BDI was associated with moderate to large impairments across all cognitive functions and BDII with small-to-medium impairments. Small significant differences were identified between BDI and BDII on all cognitive functions except inhibition. The Trail Making Test (TMT) (g = 0.74, 95% CI: 0.67-0.80), Hayling Test (g = 0.58, 95% CI: 0.34-0.81), Digit Span Total (g = 0.79, 95% CI: 0.57-1.01), and Category Fluency (g = 0.59, 95% CI: 0.45-0.72) tasks were most sensitive to cognitive impairment in BDI. The TMT (g = 0.65, 95% CI: 0.50-0.80) and Category Fluency (g = 0.56, 95% CI: 0.37-0.75) were also sensitive to cognitive alterations in patients with BDII. CONCLUSION: BD type I was associated with more severe and widespread impairments than BDII, which showed smaller impairments on all functions except inhibition, where impairments were larger. Education and (hypo)manic symptoms should be further investigated in future studies due to their possible influence on the neuropsychological profile of BD. The instruments identified in this review should be considered for inclusion in cognitive assessment batteries in BD.

Experimental Observation of Proton Bunch Modulation in a Plasma at Varying Plasma Densities.

We give direct experimental evidence for the observation of the full transverse self-modulation of a long, relativistic proton bunch propagating through a dense plasma. The bunch exits the plasma with a periodic density modulation resulting from radial wakefield effects. We show that the modulation is seeded by a relativistic ionization front created using an intense laser pulse copropagating with the proton bunch. The modulation extends over the length of the proton bunch following the seed point. By varying the plasma density over one order of magnitude, we show that the modulation frequency scales with the expected dependence on the plasma density, i.e., it is equal to the plasma frequency, as expected from theory.

Experimental Observation of Plasma Wakefield Growth Driven by the Seeded Self-Modulation of a Proton Bunch.

We measure the effects of transverse wakefields driven by a relativistic proton bunch in plasma with densities of 2.1×10^{14} and 7.7×10^{14} electrons/cm^{3}. We show that these wakefields periodically defocus the proton bunch itself, consistently with the development of the seeded self-modulation process. We show that the defocusing increases both along the bunch and along the plasma by using time resolved and time-integrated measurements of the proton bunch transverse distribution. We evaluate the transverse wakefield amplitudes and show that they exceed their seed value (<15 MV/m) and reach over 300 MV/m. All these results confirm the development of the seeded self-modulation process, a necessary condition for external injection of low energy and acceleration of electrons to multi-GeV energy levels.

Proton-driven plasma wakefield acceleration in AWAKE.

In this article, we briefly summarize the experiments performed during the first run of the Advanced Wakefield Experiment, AWAKE, at CERN (European Organization for Nuclear Research). The final goal of AWAKE Run 1 (2013-2018) was to demonstrate that 10-20 MeV electrons can be accelerated to GeV energies in a plasma wakefield driven by a highly relativistic self-modulated proton bunch. We describe the experiment, outline the measurement concept and present first results. Last, we outline our plans for the future. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.

A soluble inorganic pyrophosphatase from the cattle tick Rhipicephalus microplus capable of hydrolysing polyphosphates.

Polyphosphates have been found in all cell types examined to date and play diverse roles depending on the cell type. In eukaryotic organisms, polyphosphates have been investigated mainly in mammalian cells, and only a few studies have addressed arthropods. Pyrophosphatases have been shown to regulate polyphosphate metabolism. However, these studies were restricted to trypanosomatids. Here we focus on the tick Rhipicephalus microplus, a haematophagous ectoparasite that is highly harmful to cattle. We produced a recombinant R. microplus pyrophosphatase (rRmPPase) with the aim of investigating its kinetic parameters using polyphosphates as substrate. Molecular docking assays of RmPPase with polyphosphates were also carried out. The kinetic and Hill coefficient parameters indicated that rRmPPase has a greater affinity, higher catalytic efficiency and increased cooperativity for sodium phosphate glass type 15 (polyP15 ) than for sodium tripolyphosphate (polyP3 ). Through molecular docking, we found that polyP3 binds close to the Mg2+ atoms in the catalytic region of the protein, participating in their coordination network, whereas polyP15 interactions involve negatively charged phosphate groups and basic amino acid residues, such as Lys56, Arg58 and Lys193; polyP15 has a more favourable theoretical binding affinity than polyP3 , thus supporting the kinetic data. This study shows, for the first time in arthropods, a pyrophosphatase with polyphosphatase activity, suggesting its participation in polyphosphate metabolism.

[Multidisciplinary approach on subglottic pathology: a 5-year review]. / Manejo multidisciplinar de la patología subglótica: revisión a 5 años.

INTRODUCTION: Pediatric subglottic pathology still represents a challenge when it comes to choosing the right treatment. We present the management of patients followed in our center for this reason during the last 5 years. MATERIAL AND METHODS: Retrospective study of patients followed by glotosubglottic pathology (stenosis, cysts or granulomas) between 2011 and 2016 in a third level hospital. RESULTS: Twenty-seven patients were included in the review. Treatment options varied according to the nature, location and severity of the subglottic stenosis. Two patients with congenital subglottic stenosis were treated by laryngotracheoplasty. Seventeen patients with acquired subglottic stenosis were included: in one (5.9%) laryngotracheoplasty was performed, one (5.9%) received cricotracheal split, two of them (11.8%) underwent partial cricotracheal resection (PCTR) , seven patients (41.2%) underwent microsurgery, three (17.6%) received tracheal dilatation, and the last three (17.6%) were submitted to observation without needing further treatment. Five patients with post-intubation subglottic cysts received microsurgery. Of three patients diagnosed with post-intubation subglottic granuloma, two (66%) resolved spontaneously and one (33%) required microsurgery. CONCLUSIONS: Management of pediatric subglottic pathology remains a major challenge. Since the creation of the Airway Committee in our center, the improvement in the management of these patients has led to a multidisciplinary management, with the consequent impact on the clinical results.

OBJETIVOS: La patología del espacio subglótico en pacientes pediátricos sigue representando un reto a la hora de elegir el tratamiento idóneo. Presentamos el manejo de los pacientes seguidos en nuestro centro por este motivo durante los últimos 5 años. MATERIAL Y METODOS: Estudio retrospectivo de los pacientes seguidos por patología glotosubglótica (estenosis, quistes o granulomas) entre 2011 y 2016 en un centro de tercer nivel. RESULTADOS: Veintisiete pacientes fueron incluidos en la revisión. Las opciones de tratamiento variaron en función de la naturaleza, la localización y la gravedad de la afectación subglótica. Dos pacientes con estenosis subglótica congénita fueron tratados mediante laringotraqueoplastia. Se incluyeron 17 pacientes con estenosis subglótica adquirida: en uno (5,9%) se realizó laringotraqueoplastia, en uno (5,9%) split cricotiroideo, dos de ellos (11,8%) se intervinieron mediante resección cricotraqueal parcial (PCTR), siete pacientes (41,2%) se sometieron a microcirugía, tres (17,6%) recibieron dilatación traqueal y los tres últimos (17,6%) se sometieron a observación sin necesitar finalmente tratamiento. Cinco pacientes con quistes subglóticos postintubación recibieron microcirugía. De tres pacientes diagnosticados de granuloma subglótico postintubación, dos (66%) se resolvieron espontáneamente y uno (33%) requirió microcirugía. CONCLUSIONES: El manejo de la patología subglótica pediátrica sigue representando un gran desafío. Desde la creación del Comité de Vía Aérea en nuestro centro, la mejoría en la gestión de estos pacientes ha conducido a un manejo multidisciplinar de los mismos, con el consiguiente impacto en los resultados clínicos.

Mitigation of the Hose Instability in Plasma-Wakefield Accelerators.

Current models predict the hose instability to crucially limit the applicability of plasma-wakefield accelerators. By developing an analytical model which incorporates the evolution of the hose instability over long propagation distances, this work demonstrates that the inherent drive-beam energy loss, along with an initial beam-energy spread, detunes the betatron oscillations of beam electrons and thereby mitigates the instability. It is also shown that tapered plasma profiles can strongly reduce initial hosing seeds. Hence, we demonstrate that the propagation of a drive beam can be stabilized over long propagation distances, paving the way for the acceleration of high-quality electron beams in plasma-wakefield accelerators. We find excellent agreement between our models and particle-in-cell simulations.

High Orbital Angular Momentum Harmonic Generation.

We identify and explore a high orbital angular momentum (OAM) harmonics generation and amplification mechanism that manipulates the OAM independently of any other laser property, by preserving the initial laser wavelength, through stimulated Raman backscattering in a plasma. The high OAM harmonics spectra can extend at least up to the limiting value imposed by the paraxial approximation. We show with theory and particle-in-cell simulations that the orders of the OAM harmonics can be tuned according to a selection rule that depends on the initial OAM of the interacting waves. We illustrate the high OAM harmonics generation in a plasma using several examples including the generation of prime OAM harmonics. The process can also be realized in any nonlinear optical Kerr media supporting three-wave interactions.

Accuracy of genomic selection for age at puberty in a multi-breed population of tropically adapted beef cattle.

Genomic selection is becoming a standard tool in livestock breeding programs, particularly for traits that are hard to measure. Accuracy of genomic selection can be improved by increasing the quantity and quality of data and potentially by improving analytical methods. Adding genotypes and phenotypes from additional breeds or crosses often improves the accuracy of genomic predictions but requires specific methodology. A model was developed to incorporate breed composition estimated from genotypes into genomic selection models. This method was applied to age at puberty data in female beef cattle (as estimated from age at first observation of a corpus luteum) from a mix of Brahman and Tropical Composite beef cattle. In this dataset, the new model incorporating breed composition did not increase the accuracy of genomic selection. However, the breeding values exhibited slightly less bias (as assessed by deviation of regression of phenotype on genomic breeding values from the expected value of 1). Adding additional Brahman animals to the Tropical Composite analysis increased the accuracy of genomic predictions and did not affect the accuracy of the Brahman predictions.

Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

Growth and geographical variation in the use of cardiac imaging in Australia.

BACKGROUND AND AIM: Growth rates and regional differences in the use of cardiac imaging are potential metrics of quality of care. This study sought to define growth and regional variation in outpatient cardiac imaging in Australia. METHODS: Analyses are based on the rate of outpatient transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE) and stress echocardiography (SE) and single-photon emission computed tomography (SPECT) per 100 000 people in each geographic insurance region in Australia (Medicare local, ML). Numbers of tests from 2002 to 2013 were obtained from Medicare Australia Statistics, and the number of doctors was obtained from the Health Workforce data. Demographic data (total population, rural areas and quintiles of disadvantage) were obtained from census data. RESULTS: Over the past 11 years, TTE reimbursements/100 000 people increased from 1780 to 3497 (8.8% annualised growth), TOE from 33 to 61, SE from 181 to 947 and SPECT from 287 to 337. SE had the biggest increment, an average growth rate of 38.5%/year. The relationships between the use of each cardiac imaging techniques and demographic, medical and illness factors were analysed in outpatient tests reimbursed in 2012. For each additional medical practitioner per 1000 people, there was an increase in the rate of TTE (ß = 1.25 (95% confidence interval CI: 1.17-1.33), P < 0.001), and TOE use (ß = 1.13 (1.04-1.24), P = 0.005), independent of regional burden of cardiovascular disease and social determinants. For SPECT the largest independent correlate for testing was the percentage of women within the ML; each additional percentage increase resulted in doubling of the rate of testing (ß = 2.25 (1.72-2.94), P < 0.001). CONCLUSION: Variation in the use of TTE in Australia does not appear illness related and may be evidence of under- and overutilisation. An appropriate use process may contain this variation.

What is the evidence status of Appropriate Use Criteria (AUC)? Insight from a matching exercise with the guidelines for echocardiography.

There is interest in adapting the American Appropriate Use Criteria (AUC) for transthoracic echocardiography to Australian practice. We matched 90 of 98 AUC with the guidelines (53 appropriate, 12 sometimes appropriate, 25 rarely appropriate), but eight lacked any match. Among the matched criteria, 76 (82%) indications were concordant with the guidelines. A stronger evidence base would be desirable to settle these discrepancies before Australian adoption of AUC.