Abstract
Readily available bright X-ray beams with narrow bandwidth and tunable energy promise to unlock novel developments in a wide range of applications. Among emerging alternatives to large-scale ...and costly present-day radiation sources which severely restrict the availability of such beams, compact laser-plasma-accelerator-driven inverse Compton scattering sources show great potential. However, these sources are currently limited to tens of percent bandwidths, unacceptably large for many applications. Here, we show conceptually that using active plasma lenses to tailor the electron bunch-photon interaction, tunable X-ray and gamma beams with percent-level bandwidths can be produced. The central X-ray energy is tunable by varying the focusing strength of the lens, without changing electron bunch properties, allowing for precision-tuning the X-ray beam energy. This method is a key development towards laser-plasma-accelerator-driven narrowband, precision tunable femtosecond photon sources, enabling a paradigm shift and proliferation of compact X-ray applications.
We report on a novel, noninvasive method applying Thomson scattering to measure the evolution of the electron beam energy inside a laser-plasma accelerator with high spatial resolution. The ...determination of the local electron energy enabled the in-situ detection of the acting acceleration fields without altering the final beam state. In this Letter we demonstrate that the accelerating fields evolve from (265±119) GV/m to (9±4) GV/m in a plasma density ramp. The presented data show excellent agreement with particle-in-cell simulations. This method provides new possibilities for detecting the dynamics of plasma-based accelerators and their optimization.
The FLASHForward experimental facility is a high-performance test-bed for precision plasma wakefield research, aiming to accelerate high-quality electron beams to GeV-levels in a few centimetres of ...ionized gas. The plasma is created by ionizing gas in a gas cell either by a high-voltage discharge or a high-intensity laser pulse. The electrons to be accelerated will either be injected internally from the plasma background or externally from the FLASH superconducting RF front end. In both cases, the wakefield will be driven by electron beams provided by the FLASH gun and linac modules operating with a 10 Hz macro-pulse structure, generating 1.25 GeV, 1 nC electron bunches at up to 3 MHz micro-pulse repetition rates. At full capacity, this FLASH bunch-train structure corresponds to 30 kW of average power, orders of magnitude higher than drivers available to other state-of-the-art LWFA and PWFA experiments. This high-power functionality means FLASHForward is the only plasma wakefield facility in the world with the immediate capability to develop, explore and benchmark high-average-power plasma wakefield research essential for next-generation facilities. The operational parameters and technical highlights of the experiment are discussed, as well as the scientific goals and high-average-power outlook. This article is part of the Theo Murphy meeting issue 'Directions in particle beam-driven plasma wakefield acceleration'.
Electron beams to be accelerated in beam-driven plasma wakes are commonly formed by a photocathode and externally injected into the wakefield of a preceding bunch. Alternatively, using the plasma ...itself as a cathode offers the possibility of generating ultrashort, low-emittance beams by trapping and accelerating electrons from the ambient plasma background. Here, we present a beam-driven plasma cathode realized via laser-triggered density-downramp injection, showing stable beam formation over more than a thousand consecutive events with an injection probability of 95%. The plasma cathode is highly tunable, resulting in the injection of electron bunches of tens of pC of charge, energies of up to 79 MeV, and relative energy spreads as low as a few percent. The stability of the injected beams was sufficiently high to experimentally determine their normalized emittance of9.3μmrms with a multishot method.
Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease ...could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a
dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2-STAT1 pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a
DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2 inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo-HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2 inhibition in selected patients.
AIM: To assess whether native and alien plant cover and richness respond similarly to flow regime, propagule pressure, climate and floodplain characteristics in highly dynamic braided river ...ecosystems. LOCATION: Canterbury, New Zealand. METHODS: A regional, multiscale survey was conducted across 19 braided river floodplains in multiple catchments. We measured alien and native cover and richness across gradients of flow regime (flow magnitude, variability and high/low‐flow events), propagule pressure (inferred from land cover), climate and local‐scale floodplain substrate and topography. Boosted regression trees were used to determine the relative and absolute importance of these variables on plant cover and richness. RESULTS: The floodplain ecosystems were highly invaded with 154 alien species and only 31 natives. Alien cover was higher in rivers with larger maximum flows, in plots with fine substrate texture, and at higher local river bed elevations. Alien richness increased as the variability of winter flows increased and followed a hump‐shaped relationship with river bed elevation. In contrast, native species richness and cover were both shaped primarily by climate and by land cover, higher in cooler and wetter areas with more adjacent native vegetation. MAIN CONCLUSIONS: Alien and native richness and cover were shaped by different variables, so managing the ecosystem (e.g. flow regime) to mitigate aliens would not necessarily promote natives. Promotion of natives will require considerations of propagule supply and whether extant native species are suited to low‐elevation climatic conditions. Aliens were associated with predictors that approximate disturbance processes. Increased flow variability in winter could lead to an increase in the number of aliens; conversely, flow stabilization is likely to allow problematic invaders to increase in cover locally.
Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif ...cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.
BACKGROUND
Pharmaceutical thrombosis prophylaxis (PTP) with low-molecular-weight heparin (LMWH) is highly effective in preventing venous thromboembolic events (VTEs) and fatal pulmonary embolism. ...Important risk factors for VTEs are surgery and immobilization, along with malignancy. Many studies involving gynaecological malignancies show no increased risk for bleeding complications with PTP. Little is known about the PTP-associated risk for bleeding complications with hysterectomy for benign disease, or about current VTE incidence in the less-invasive hysterectomy methods.
METHODS
Our observational prospective national 1-year cohort from 1 January to 31 December 2006 in 53 hospitals represented 79.4% (5297 of 6645) of hysterectomies performed for benign cause in Finland in 2006. We evaluated PTP use and VTE incidence. Operative and post-operative bleeding complications were analysed with logistic regression adjusted for confounders: age, BMI, experience of the gynaecological surgeon, hospital type, indication for hysterectomy, uterine weight, operative haemorrhage, concomitant surgery, adhesiolysis and antibiotic prophylaxis.
RESULTS
Hysterectomies were performed by three main approaches: 2345 vaginal hysterectomies (VHs, 44%), of which 1433 were for uterine prolapse and 912 for other indications, 1679 laparoscopic hysterectomies (LHs, 32%) and 1255 abdominal hysterectomies (AHs, 24%). PTP was given to 64.8% of patients (3420 of 5279) and was identified as LMWH in 3313 patients (97%); 107 left unidentified. By type of hysterectomy, PTP was given in VH for uterine prolapse to 73.2% of patients, VH for other indication to 51.6%, in LH to 59.4% and in AH to 71.9%. For all hysterectomies analysed together, PTP doubled the odds for post-operative haemorrhage or haematoma. By type of hysterectomy, PTP associated with post-operative haemorrhage or haematoma in VH for prolapse 2.7% of PTP given, versus 0.8% of no PTP; odds ratio (OR): 4.82, 95% confidence interval (CI): 1.38–16.83; and in AH (3.1% versus 1.4%; OR: 2.87, 95% CI: 1.03–7.98), and in AH also with post-operative transfusion (3.1% versus 1.4%; OR: 3.34, 95% CI: 1.41–7.88). For LH and VH for indications other than prolapse, the effect of PTP on post-operative haemorrhage was non-significant. For VH, the risk for post-operative haemorrhage fell with age. Operative mean haemorrhage with all hysterectomy types, and operative bleeding complications in AH and VH also fell with age. Obesity increased haemorrhage and operative bleeding complications for LH and VH, whereas post-operative bleeding complications were less for the obese in AH. VTEs were 6 of 5279 (0.1%): two PEs each occurred after AH and VH, and two deep venous thromboses after LH.
CONCLUSIONS
With a relatively wide PTP coverage (64.8%), VTEs were rare (0.1%). All affected had received PTP. Analysis of efficacy, meaning interpretation of how many VTEs or deaths were prevented, cannot be done from our observational study but related to safety in hysterectomy for benign disease, PTP associated with post-operative bleeding complications with AH and with VH for prolapse.
Trial registration number: ClinicalTrials.gov protocol (NCT00744172).
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