Design considerations for table-top, laser-based VUV and X-ray free electron lasers

A recent breakthrough in laser-plasma accelerators, based upon ultrashort high-intensity lasers, demonstrated the generation of quasi-monoenergetic GeV-electrons. With future Petawatt lasers ultra-high beam currents of ~100 kA in ~10 fs can be expected, allowing for drastic reduction in the undulator length of free-electron-lasers (FELs). We present a discussion of the key aspects of a table-top FEL design, including energy loss and chirps induced by space-charge and wakefields. These effects become important for an optimized table-top FEL operation. A first proof-of-principle VUV case is considered as well as a table-top X-ray-FEL which may open a brilliant light source also for new ways in clinical diagnostics.Comment: 6 pages, 4 figures; accepted for publication in Appl. Phys.

Improved limits on nuebar emission from mu+ decay

We investigated mu+ decays at rest produced at the ISIS beam stop target. Lepton flavor (LF) conservation has been tested by searching for \nueb via the detection reaction p(\nueb,e+)n. No \nueb signal from LF violating mu+ decays was identified. We extract upper limits of the branching ratio for the LF violating decay mu+ -> e+ \nueb \nu compared to the Standard Model (SM) mu+ -> e+ nue numub decay: BR < 0.9(1.7)x10^{-3} (90%CL) depending on the spectral distribution of \nueb characterized by the Michel parameter rho=0.75 (0.0). These results improve earlier limits by one order of magnitude and restrict extensions of the SM in which \nueb emission from mu+ decay is allowed with considerable strength. The decay \mupdeb as source for the \nueb signal observed in the LSND experiment can be excluded.Comment: 10 pages, including 1 figure, 1 tabl

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology

Detrended fluctuation analysis as a statistical tool to monitor the climate

Detrended fluctuation analysis is used to investigate power law relationship between the monthly averages of the maximum daily temperatures for different locations in the western US. On the map created by the power law exponents, we can distinguish different geographical regions with different power law exponents. When the power law exponents obtained from the detrended fluctuation analysis are plotted versus the standard deviation of the temperature fluctuations, we observe different data points belonging to the different climates, hence indicating that by observing the long-time trends in the fluctuations of temperature we can distinguish between different climates.Comment: 8 pages, 4 figures, submitted to JSTA

CLASH: z ~ 6 young galaxy candidate quintuply lensed by the frontier field cluster RXC J2248.7-4431

We present a quintuply lensed z ~ 6 candidate discovered in the field of the galaxy cluster RXC J2248.7-4431 (z ~ 0.348) targeted within the Cluster Lensing and Supernova survey with Hubble (CLASH) and selected in the deep HST Frontier Fields survey. Thanks to the CLASH 16-band HST imaging, we identify the quintuply lensed z ~ 6 candidate as an optical dropout in the inner region of the cluster, the brightest image having magAB=24.81+-0.02 in the f105w filter. We perform a detailed photometric analysis to verify its high-z and lensed nature. We get as photometric redshift z_phot ~ 5.9, and given the extended nature and NIR colours of the lensed images, we rule out low-z early type and galactic star contaminants. We perform a strong lensing analysis of the cluster, using 13 families of multiple lensed images identified in the HST images. Our final best model predicts the high-z quintuply lensed system with a position accuracy of 0.8''. The magnifications of the five images are between 2.2 and 8.3, which leads to a delensed UV luminosity of L_1600 ~ 0.5L*_1600 at z=6. We also estimate the UV slope from the observed NIR colours, finding a steep beta=-2.89+-0.38. We use singular and composite stellar population SEDs to fit the photometry of the hiz candidate, and we conclude that it is a young (age <300 Myr) galaxy with mass of M ~ 10^8Msol, subsolar metallicity (Z<0.2Zsol) and low dust content (AV ~ 0.2-0.4).Comment: 21 pages, 13 figures, 6 tables, submitted to MNRAS on 11 Aug 2013, accepted on 23 Nov 201

Towards Translational ImmunoPET/MR Imaging of Invasive Pulmonary Aspergillosis: The Humanised Monoclonal Antibody JF5 Detects Aspergillus Lung Infections In Vivo

This is the final published versionAvailable from Ivyspring International Publisher via the DOI in this recordInvasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of hematological malignancy and bone marrow transplant patients caused by the ubiquitous environmental fungus Aspergillus fumigatus. Current diagnostic tests for the disease lack sensitivity as well as specificity, and culture of the fungus from invasive lung biopsy, considered the gold standard for IPA detection, is slow and often not possible in critically ill patients. In a previous study, we reported the development of a novel non-invasive procedure for IPA diagnosis based on antibody-guided positron emission tomography and magnetic resonance imaging (immunoPET/MRI) using a [64Cu]DOTA-labeled mouse monoclonal antibody (mAb), mJF5, specific to Aspergillus. To enable translation of the tracer to the clinical setting, we report here the development of a humanised version of the antibody (hJF5), and pre-clinical imaging of lung infection using a [64Cu]NODAGA-hJF5 tracer. The humanised antibody tracer shows a significant increase in in vivo biodistribution in A. fumigatus infected lungs compared to its radiolabeled murine counterpart [64Cu]NODAGA-mJF5. Using reverse genetics of the pathogen, we show that the antibody binds to the antigenic determinant 1,5-galactofuranose (Galf) present in a diagnostic mannoprotein antigen released by the pathogen during invasive growth in the lung. The absence of the epitope Galf in mammalian carbohydrates, coupled with the enhanced imaging capabilities of the hJF5 antibody, means that the [64Cu]NODAGA-hJF5 tracer developed here represents an ideal candidate for the diagnosis of IPA and translation to the clinical setting.This work was supported by the European Union Seventh Framework Programme FP7/2007-2013 under Grant 602820, the Deutsche Forschungsgemeinschaft (Grant WI3777/1-2 to SW), and the Werner Siemens Foundation. We thank Sven Krappman for use of the A. fumigatustdTomato strain, and acknowledge the Imaging Centre Essen (IMCES) for assistance with optical imaging of lungs

Quantifying Cyanothece growth under DIC limitation.

The photoautotrophic, unicellular N2-fixer, Cyanothece, is a model organism that has been widely used to study photosynthesis regulation, the structure of photosystems, and the temporal segregation of carbon (C) and nitrogen (N) fixation in light and dark phases of the diel cycle. Here, we present a simple quantitative model and experimental data that together, suggest external dissolved inorganic carbon (DIC) concentration as a major limiting factor for Cyanothece growth, due to its high C-storage requirement. Using experimental data from a parallel laboratory study as a basis, we show that after the onset of the light period, DIC was rapidly consumed by photosynthesis, leading to a sharp drop in the rate of photosynthesis and C accumulation. In N2-fixing cultures, high rates of photosynthesis in the morning enabled rapid conversion of DIC to intracellular C storage, hastening DIC consumption to levels that limited further uptake. The N2-fixing condition allows only a small fraction of fixed C for cellular growth since a large fraction was reserved in storage to fuel night-time N2 fixation. Our model provides a framework for resolving DIC limitation in aquatic ecosystem simulations, where DIC as a growth-limiting factor has rarely been considered, and importantly emphasizes the effect of intracellular C allocation on growth rate that varies depending on the growth environment

Correlation of mRNA and protein levels: Cell type-specific gene expression of cluster designation antigens in the prostate

Background: Expression levels of mRNA and protein by cell types exhibit a range of correlations for different genes. In this study, we compared levels of mRNA abundance for several cluster designation (CD) genes determined by gene arrays using magnetic sorted and laser-capture microdissected human prostate cells with levels of expression of the respective CD proteins determined by immunohistochemical staining in the major cell types of the prostate - basal epithelial, luminal epithelial, stromal fibromuscular, and endothelial - and for prostate precursor/stem cells and prostate carcinoma cells. Immunohistochemical stains of prostate tissues from more than 50 patients were scored for informative CD antigen expression and compared with cell-type specific transcriptomes. Results: Concordance between gene and protein expression findings based on 'present' vs. 'absent' calls ranged from 46 to 68%. Correlation of expression levels was poor to moderate (Pearson correlations ranged from 0 to 0.63). Divergence between the two data types was most frequently seen for genes whose array signals exceeded background (> 50) but lacked immunoreactivity by immunostaining. This could be due to multiple factors, e.g. low levels of protein expression, technological sensitivities, sample processing, probe set definition or anatomical origin of tissue and actual biological differences between transcript and protein abundance. Conclusion: Agreement between these two very different methodologies has great implications for their respective use in both molecular studies and clinical trials employing molecular biomarkers.This work was supported by grant DK63630 and DK069690 from NIDDK. Additional funding came from grants CA85859, CA98699 and CA111244 from NCI, and PM50 GMO76547/Center for Systems Biology

Methylation patterns in serum DNA for early identification of disseminated breast cancer

BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent