All-optical GeV electron bunch generation in a laser-plasma accelerator via truncated-channel injection.

We describe a simple scheme, truncated-channel injection, to inject electrons directly into the wakefield driven by a high-intensity laser pulse guided in an all-optical plasma channel. We use this approach to generate dark-current-free 1.2 GeV, 4.5% relative energy spread electron bunches with 120 TW laser pulses guided in a 110 mm-long hydrodynamic optical-field-ionized plasma channel. Our experiments and particle-in-cell simulations show that high-quality electron bunches were only obtained when the drive pulse was closely aligned with the channel axis, and was focused close to the density down ramp formed at the channel entrance. Start-to-end simulations of the channel formation, and electron injection and acceleration show that increasing the channel length to 410 mm would yield 3.65 GeV bunches, with a slice energy spread ∼5×10^{-4}

LRRK2 is a negative regulator of <em>Mycobacterium tuberculosis</em> phagosome maturation in macrophages

\ua9 2018 EMBO. Mutations in the leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson\u27s disease, chronic inflammation and mycobacterial infections. Although there is evidence supporting the idea that LRRK2 has an immune function, the cellular function of this kinase is still largely unknown. By using genetic, pharmacological and proteomics approaches, we show that LRRK2 kinase activity negatively regulates phagosome maturation via the recruitment of the Class III phosphatidylinositol-3 kinase complex and Rubicon to the phagosome in macrophages. Moreover, inhibition of LRRK2 kinase activity in mouse and human macrophages enhanced Mycobacterium tuberculosis phagosome maturation and mycobacterial control independently of autophagy. In vivo, LRRK2 deficiency in mice resulted in a significant decrease in M. tuberculosis burdens early during the infection. Collectively, our findings provide a molecular mechanism explaining genetic evidence linking LRRK2 to mycobacterial diseases and establish an LRRK2-dependent cellular pathway that controls M. tuberculosis replication by regulating phagosome maturation

Resonant excitation of plasma waves in a plasma channel

We demonstrate resonant excitation of a plasma wave by a train of short laser pulses guided in a preformed plasma channel, for parameters relevant to a plasma-modulated plasma accelerator (P-MoPA). We show experimentally that a train of N≈10 short pulses, of total energy ∼1J, can be guided through 110mm long plasma channels with on-axis densities in the range 1017-1018cm-3. The spectrum of the transmitted train is found to be strongly red shifted when the plasma period is tuned to the intratrain pulse spacing. Numerical simulations are found to be in excellent agreement with the measurements and indicate that the resonantly excited plasma waves have an amplitude in the range 3-10GVm-1, corresponding to an accelerator stage energy gain of order 1GeV

SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer

Pancreatic cancer has a devastating prognosis, with an overall 5-year survival rate of ~8%, restricted treatment options and characteristic molecular heterogeneity. SerpinB2 expression, particularly in the stromal compartment, is associated with reduced metastasis and prolonged survival in pancreatic ductal adenocarcinoma (PDAC) and our genomic analysis revealed that SERPINB2 is frequently deleted in PDAC. We show that SerpinB2 is required by stromal cells for normal collagen remodelling in vitro, regulating fibroblast interaction and engagement with collagen in the contracting matrix. In a pancreatic cancer allograft model, co-injection of PDAC cancer cells and SerpinB2(-/-) mouse embryonic fibroblasts (MEFs) resulted in increased tumour growth, aberrant remodelling of the extracellular matrix (ECM) and increased local invasion from the primary tumour. These tumours also displayed elevated proteolytic activity of the primary biochemical target of SerpinB2-urokinase plasminogen activator (uPA). In a large cohort of patients with resected PDAC, we show that increasing uPA mRNA expression was significantly associated with poorer survival following pancreatectomy. This study establishes a novel role for SerpinB2 in the stromal compartment in PDAC invasion through regulation of stromal remodelling and highlights the SerpinB2/uPA axis for further investigation as a potential therapeutic target in pancreatic cancer

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Resonant excitation of plasma waves in a plasma channel

We demonstrate resonant excitation of a plasma wave by a train of short laser pulses guided in a preformed plasma channel, for parameters relevant to a plasma-modulated plasma accelerator (P-MoPA). We show experimentally that a train of N≈10 short pulses, of total energy ∼1J, can be guided through 110mm long plasma channels with on-axis densities in the range 1017-1018cm-3. The spectrum of the transmitted train is found to be strongly red shifted when the plasma period is tuned to the intratrain pulse spacing. Numerical simulations are found to be in excellent agreement with the measurements and indicate that the resonantly excited plasma waves have an amplitude in the range 3-10GVm-1, corresponding to an accelerator stage energy gain of order 1GeV

Biosignals reflect pair-dynamics in collaborative work : EDA and ECG study of pair-programming in a classroom environment

Collaboration is a complex phenomenon, where intersubjective dynamics can greatly affect the productive outcome. Evaluation of collaboration is thus of great interest, and can potentially help achieve better outcomes and performance. However, quantitative measurement of collaboration is difficult, because much of the interaction occurs in the intersubjective space between collaborators. Manual observation and/or self-reports are subjective, laborious, and have a poor temporal resolution. The problem is compounded in natural settings where task-activity and response-compliance cannot be controlled. Physiological signals provide an objective mean to quantify intersubjective rapport (as synchrony), but require novel methods to support broad deployment outside the lab. We studied 28 student dyads during a self-directed classroom pair-programming exercise. Sympathetic and parasympathetic nervous system activation was measured during task performance using electrodermal activity and electrocardiography. Results suggest that (a) we can isolate cognitive processes (mental workload) from confounding environmental effects, and (b) electrodermal signals show role-specific but correlated affective response profiles. We demonstrate the potential for social physiological compliance to quantify pair-work in natural settings, with no experimental manipulation of participants required. Our objective approach has a high temporal resolution, is scalable, non-intrusive, and robust.Peer reviewe

CREB Inhibits AP-2α Expression to Regulate the Malignant Phenotype of Melanoma

The loss of AP-2alpha and increased activity of cAMP-responsive element binding (CREB) protein are two hallmarks of malignant progression of cutaneous melanoma. However, the molecular mechanism responsible for the loss of AP-2alpha during melanoma progression remains unknown.Herein, we demonstrate that both inhibition of PKA-dependent CREB phosphorylation, as well as silencing of CREB expression by shRNA, restored AP-2alpha protein expression in two metastatic melanoma cell lines. Moreover, rescue of CREB expression in CREB-silenced cell lines downregulates expression of AP-2alpha. Loss of AP-2alpha expression in metastatic melanoma occurs via a dual mechanism involving binding of CREB to the AP-2alpha promoter and CREB-induced overexpression of another oncogenic transcription factor, E2F-1. Upregulation of AP-2alpha expression following CREB silencing increases endogenous p21(Waf1) and decreases MCAM/MUC18, both known to be downstream target genes of AP-2alpha involved in melanoma progression.Since AP-2alpha regulates several genes associated with the metastatic potential of melanoma including c-KIT, VEGF, PAR-1, MCAM/MUC18, and p21(Waf1), our data identified CREB as a major regulator of the malignant melanoma phenotype