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The Advanced Wakefield Experiment (AWAKE) develops the first plasma wakefield accelerator with a high-energy proton bunch as driver. The 400 GeV bunch from CERN Super Proton Synchrotron (SPS) propagates through a 10 m long rubidium plasma, ionized by a 4TW laser pulse co-propagating with the proton bunch. The relativistic ionization front seeds a self-modulation process. The seeded self-modulation transforms the bunch into a train of micro-bunches resonantly driving wakefields. We measure the density modulation of the bunch, in time, with a streak camera with picosecond resolution. The observed effect corresponds to alternating focusing and defocusing fields. We present a procedure recovering the charge of the bunch from the experimental streak camera images containing the charge density. These studies are important to determine the charge per micro-bunch along the modulated proton bunch and to understand the wakefields driven by the modulated bunch.

Introduction Effective leadership and management (L&M) are essential to the success of health care organizations. Young medical leaders often find themselves ill-prepared to take on these new responsibilities, but rarely attend training in L&M skills. The aims of this study were to evaluate physician’s self-perceived competencies and training needs for L&M, to identify available regional L&M training, and to highlight opportunities, challenges and threats regarding physicians’ training in medical L&M in the French-speaking part of Switzerland. Methods We conducted a mixed methods study in three steps: (1) a survey on perceived L&M competencies and training needs (5 dimensions) to all physicians of a Swiss University Hospital (N = 2247); (2) a mapping of the Swiss French speaking L&M training programs through analysis of hospital websites and interviews; and (3) semi-structured interviews with L&M program coordinators about the programs’ strengths and weaknesses as well as the opportunities and challenges to include physicians in such training. We used analysis of variance to compare differences in perceived competences between physicians of different hierarchical status and used Cramer’s V to measure the association’s degree between physicians’ training needs and prior training in L&M and hierarchical status. We analysed semi-structured interviews using thematic analysis. Results Five-hundred thirty-two physicians responded (24%). Physicians perceived themselves as rather competent in most leadership dimensions. More experienced physicians reported a higher sense of competence in all dimensions of leadership (e.g. Working with others: F  = 15.55, p  < .001; Managing services: F  = 46.89, p  < .001). Three competencies did not vary according to the hierarchical status: emotional intelligence ( F  = 1.56, p = .20), time management ( F  = 0.47, p = .70) and communicating ( F  = 1.97, p = .12). There was a weak to moderate association between the responders’ self-perceived needs for training and their hierarchal status for all competencies (Cramer’s V ∈ [0.16;0.35]). Physicians expressed a strong desire to seek out training for all competencies, especially for knowing one’s leadership style (82%), managing teams (83%), and managing conflict (85%). Although existing local L&M training programs covered most relevant topics, only a forth of responders had attended any type of training. L&M program coordinators identified several facilitators and barriers to physician attendance on institutional (matching reality and training), relational (managing collective intelligence), and individual levels (beliefs and self-perceived identity). Conclusions French-speaking Swiss hospital physicians clearly express training needs for L&M skills although they only rarely attend such training programs. Reasons for non-attendance to such programs should be explored in order to understand physicians’ low participation rates in these trainings.

The anti-diabetic drug metformin is one of the most widely prescribed medicines in the world. Together with its degradation product guanylurea, it is a major pharmaceutical pollutant in wastewater treatment plants and surface waters. An operon comprising two genes of the ureohydrolase family in Pseudomonas and Aminobacter species has recently been implicated in metformin degradation. However, the corresponding proteins have not been characterized. Here we show that these genes encode a Ni 2+ -dependent enzyme that efficiently and specifically hydrolyzes metformin to guanylurea and dimethylamine. The active enzyme is a heteromeric complex of α- and β- subunits in which only the α-subunits contain the conserved His and Asp residues for the coordination of two Ni 2+ ions in the active site. A crystal structure of metformin hydrolase reveals an α 2 β 4 stoichiometry of the hexameric complex, which is unprecedented in the ureohydrolase family. By studying a closely related but more widely distributed enzyme, we find that the putative predecessor specifically hydrolyzes dimethylguanidine instead of metformin. Our findings establish the molecular basis for metformin hydrolysis to guanylurea as the primary pathway for metformin biodegradation and provide insight into the recent evolution of ureohydrolase family proteins in response to an anthropogenic compound. The diabetes drug metformin and its degradation product guanylurea are major pharmaceutical contaminants in waste and surface water. Here, a Ni2+-dependent enzyme that hydrolysed metformin to guanylurea and its evolutionary predecessor are presented.

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.

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 acceleration 1 – 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 pulse 6 – 9 or electron bunch 10 , 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 energies 5 , 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 stage 13 . Long, thin proton bunches can be used because they undergo a process called self-modulation 14 – 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 CERN 17 – 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 stage 20 means that our results are an important step towards the development of future high-energy particle accelerators 21 , 22 . Electron acceleration to very high energies is achieved in a single step by injecting electrons into a ‘wake’ of charge created in a 10-metre-long plasma by speeding long proton bunches.

Polyploidy, or whole-genome duplication, is a common speciation mechanism in plants. An important barrier to polyploid establishment is a lack of compatible mates. Because self-compatibility alleviates this problem, it has long been hypothesized that there should be an association between polyploidy and self-compatibility (SC), but empirical support for this prediction is mixed. Here, we investigate whether the molecular makeup of the Brassicaceae self-incompatibility (SI) system, and specifically dominance relationships among S-haplotypes mediated by small RNAs, could facilitate loss of SI in allopolyploid crucifers. We focus on the allotetraploid species Capsella bursa-pastoris, which formed ~300 kya by hybridization and whole-genome duplication involving progenitors from the lineages of Capsella orientalis and Capsella grandiflora. We conduct targeted long-read sequencing to assemble and analyze eight full-length S-locus haplotypes, representing both homeologous subgenomes of C. bursa-pastoris. We further analyze small RNA (sRNA) sequencing data from flower buds to identify candidate dominance modifiers. We find that C. orientalis-derived S-haplotypes of C. bursa-pastoris harbor truncated versions of the male SI specificity gene SCR and express a conserved sRNA-based candidate dominance modifier with a target in the C. grandiflora-derived S-haplotype. These results suggest that pollen-level dominance may have facilitated loss of SI in C. bursa-pastoris. Finally, we demonstrate that spontaneous somatic tetraploidization after a wide cross between C. orientalis and C. grandiflora can result in production of self-compatible tetraploid offspring. We discuss the implications of this finding on the mode of formation of this widespread weed.

Induction treatment with rabbit polyclonal antithymocyte globulins (ATGs) is frequent used in kidney transplant recipients with donorspecific HLA antibodies and shows acceptable outcomes. The two commonly used ATGs, Thymoglobulin and ATG-F have slightly different antigen profile and antibody concentrations. The two compounds have never been directly compared in a prospective trial in immunological high-risk recipients. Therefore we performed a prospective randomized controlled study comparing the two compounds in immunological high-risk kidney recipients in terms of safety and efficacy. Immunological high-risk kidney recipients, defined as the presence of HLA DSA but negative CDC-B and T-cell crossmatches were randomized 1:1 to receive ATG-F or Thymoglobulin. Maintenance immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and steroids. The per-protocol analysis included 35 patients. There was no immediate infusion reaction observed with both compounds. No PTLD or malignancy occurred during the follow-up in both groups. The incidence of viral and bacterial infections was similar in both groups (p = 0.62). The cumulative incidence of clinical and subclinical antibody mediated allograft rejection as well as T-cell mediated allograft rejection during the first year between ATG-F and Thymoglobulin was similar (35% versus 19%; p = 0.30 and 11% versus 18%; 0.54 respectively). The two-year graft function was similar with a median eGFR of 56 ml/min/1.73m2 (range 21-128) (ATG-F-group) and 51 ml/min/1.73m2 (range 22-132) (Thymo-group) (p = 0.69). We found no significant differences between the compared study drugs for induction treatment in immunological high-risk patients regarding safety and efficacy during follow-up with good allograft function at 2 years after transplantation.

The primary cilium emanates from the cell surface of growth-arrested cells and plays a central role in vertebrate development and tissue homeostasis. The mechanisms that control ciliogenesis have been extensively explored. However, the intersection between GPCR signaling and the ubiquitin pathway in the control of cilium stability are unknown. Here we observe that cAMP elevation promotes cilia resorption. At centriolar satellites, we identify a multimeric complex nucleated by PCM1 that includes two kinases, NEK10 and PKA, and the E3 ubiquitin ligase CHIP. We show that NEK10 is essential for ciliogenesis in mammals and for the development of medaka fish. PKA phosphorylation primes NEK10 for CHIP-mediated ubiquitination and proteolysis resulting in cilia resorption. Disarrangement of this control mechanism occurs in proliferative and genetic disorders. These findings unveil a pericentriolar kinase signalosome that efficiently links the cAMP cascade with the ubiquitin-proteasome system, thereby controlling essential aspects of ciliogenesis. The mechanisms that control ciliogenesis have been extensively explored however the signaling mechanisms that control cilium stability remain unclear. Here the authors show that GPCR signaling regulates cilia resorption via the ubiquitin-proteasome system.

A crucial step in the transition from outcrossing to self-fertilization is the loss of genetic self-incompatibility (SI). In the Brassicaceae, SI involves the interaction of female and male specificity components, encoded by the genes SRK and SCR at the self-incompatibility locus (S-locus). Theory predicts that S-linked mutations, and especially dominant mutations in SCR, are likely to contribute to loss of SI. However, few studies have investigated the contribution of dominant mutations to loss of SI in wild plant species. Here, we investigate the genetic basis of loss of SI in the self-fertilizing crucifer species Capsella orientalis, by combining genetic mapping, long-read sequencing of complete S-haplotypes, gene expression analyses and controlled crosses. We show that loss of SI in C. orientalis occurred < 2.6 Mya and maps as a dominant trait to the S-locus. We identify a fixed frameshift deletion in the male specificity gene SCR and confirm loss of male SI specificity. We further identify an S-linked small RNA that is predicted to cause dominance of self-compatibility. Our results agree with predictions on the contribution of dominant S-linked mutations to loss of SI, and thus provide new insights into the molecular basis of mating system transitions.

PurposeAquablation of the prostate using the AquaBeam™ system promises equivalent functional outcomes, reduced learning curve, and improved sexual function compared to transurethral prostate resection as shown in prospective randomized trials. This prospective cohort study aims to evaluate if published results can be transferred into the clinical routine in a non-selected patient collective.MethodsThis study includes all patients treated between September 2017 and June 2018 with Aquablation of the prostate. Patients have been evaluated prospectively for the perioperative course and early follow-up. Besides voiding parameter and symptom score, TRUS-volume change, ejaculatory function, and adverse events have been recorded.Results118 consecutive patients have been treated in the given time. Aquablation could be carried out successfully in all patients. IPSS, QoL, Qmax, and PVR improved significantly after the procedure and continued to improve during 3-month follow-up. Mean OR time was 20 min, TRUS volume decreased by 65%, and 73% of the patients retained antegrade ejaculation. Thirteen adverse events (> Clavien-Dindo I) occurred in 10 patients.ConclusionThe surgical ablation of the prostate using Aquablation achieved significant and immediate improvement of functional voiding parameters Qmax and PVR as well as symptomatic improvement of IPSS and QoL. Aquablation seems to be safe and effective with a low perioperative complication profile even in a non-selected group of patients.