Absolute energies and emission line shapes of the L x-ray transitions of lanthanide metals.

We use an array of transition-edge sensors, cryogenic microcalorimeters with 4 eV energy resolution, to measure L x-ray emission-line profiles of four elements of the lanthanide series: praseodymium, neodymium, terbium, and holmium. The spectrometer also surveys numerous x-ray standards in order to establish an absolute-energy calibration traceable to the international system of units for the energy range 4 keV to 10 keV. The new results include emission line profiles for 97 lines, each expressed as a sum of one or more Voigt functions; improved absolute energy uncertainty on 71 of these lines relative to existing reference data; a median uncertainty on the peak energy of 0.24 eV, four to ten times better than the median of prior work; and six lines that lack any measured values in existing reference tables. The 97 lines comprise nearly all of the most intense L lines from these elements under broad-band x-ray excitation. The work improves on previous measurements made with a similar cryogenic spectrometer by the use of sensors with better linearity in the absorbed energy and a gold x-ray absorbing layer that has a Gaussian energy-response function. It also employs a novel sample holder that enables rapid switching between science targets and calibration targets with excellent gain balancing. Most of the results for peak energy values shown here should be considered as replacements for the currently tabulated standard reference values, while the line shapes given here represent a significant expansion of the scope of available reference data.

Contemporary x-ray wavelength metrology and traceability.

We report recent advances in absolute x-ray wavelength metrology in the context of producing modern standard reference data. Primary x-ray wavelength standards are produced today using diffraction spectrometers using crystal optics arranged to be operated in dispersive and non-dispersive geometries, giving natural-line-width limited profiles with high resolution and accuracy. With current developments, measurement results can be made traceable to the Système internationale definition of the meter by using diffraction crystals that have absolute lattice-spacing provenance through x-ray-optical interferometry. Recent advances in goniometry, innovation of electronic x-ray area detectors, and new in situ alignment and measurement methods now permit robust measurement and quantification of previously-elusive systematic uncertainties. This capability supports infrastructures like the NIST Standard Reference Data programs and the International Initiative on X-ray Fundamental Parameters and their contributions to science and industry. Such data projects are further served by employing complementary wavelength-and energy-dispersive spectroscopic techniques. This combination can provide, among other things, new tabulations of less-intense x-ray lines that need to be identified in x-ray fluorescence investigation of uncharacterized analytes. After delineating the traceability chain for primary x-ray wavelength standards, and NIST efforts to produce standard reference data and materials in particular, this paper posits the new opportunities for x-ray reference data tabulation that modern methods now afford.

Validation of modelled imaging plates sensitivity to 1-100 keV x-rays and spatial resolution characterisation for diagnostics for the "PETawatt Aquitaine Laser".

Thanks to their high dynamic range and ability to withstand electromagnetic pulse, imaging plates (IPs) are commonly used as passive detectors in laser-plasma experiments. In the framework of the development of the diagnostics for the Petawatt Aquitaine Laser facility, we present an absolute calibration and spatial resolution study of five different available types of IP (namely, MS-SR-TR-MP-ND) performed by using laser-induced K-shell X-rays emitted by a solid silver target irradiated by the laser ECLIPSE at CEntre Lasers Intenses et Applications. In addition, IP sensitivity measurements were performed with a 160 kV X-ray generator at CEA DAM DIF, where the absolute response of IP SR and TR has been calibrated to X-rays in the energy range 8-75 keV with uncertainties of about 15%. Finally, the response functions have been modeled in Monte Carlo GEANT4 simulations in order to reproduce experimental data. Simulations enable extrapolation of the IP response functions to photon energies from 1 keV to 1 GeV, of interest, e.g., for laser-driven radiography.

Monte-Carlo simulation of noise in hard X-ray Transmission Crystal Spectrometers: identification of contributors to the background noise and shielding optimization.

Transmission crystal spectrometers (TCS) are used on many laser facilities to record hard X-ray spectra. During experiments, signal recorded on imaging plates is often degraded by a background noise. Monte-Carlo simulations made with the code GEANT4 show that this background noise is mainly generated by diffusion of MeV electrons and very hard X-rays. An experiment, carried out at LULI2000, confirmed that the use of magnets in front of the diagnostic, that bent the electron trajectories, reduces significantly this background. The new spectrometer SPECTIX (Spectromètre PETAL à Cristal en TransmIssion X), built for the LMJ/PETAL facility, will include this optimized shielding.

Measuring electron-positron annihilation radiation from laser plasma interactions.

We investigated various diagnostic techniques to measure the 511 keV annihilation radiations. These include step-wedge filters, transmission crystal spectroscopy, single-hit CCD detectors, and streaked scintillating detection. While none of the diagnostics recorded conclusive results, the step-wedge filter that is sensitive to the energy range between 100 keV and 700 keV shows a signal around 500 keV that is clearly departing from a pure Bremsstrahlung spectrum and that we ascribe to annihilation radiation.

K-line spectra from tungsten heated by an intense pulsed electron beam.

The plasma-filled rod-pinch diode (PFRP) is an intense source of x-rays ideal for radiography of dense objects. In the PRFP megavoltage electrons from a pulsed discharge concentrate at the pointed end of a 1 mm diameter tapered tungsten rod. Ionization of this plasma might increase the energy of tungsten's Kα(1) fluorescence line, at 59.3182 keV, enough for the difference to be observed by a high-resolution Cauchois transmission crystal spectrograph. When the PFRP's intense hard bremsstrahlung is suppressed by the proper shielding, such an instrument gives excellent fluorescence spectra, albeit with as yet insufficient resolution to see any effect of tungsten's ionization. Higher resolution is possible with various straightforward upgrades that are feasible thanks to the radiation's high intensity.

Hard x-ray transmission crystal spectrometer at the OMEGA-EP laser facility.

The transmission crystal spectrometer (TCS) is approved for taking data at the OMEGA-EP laser facility since 2009 and will be available for the OMEGA target chamber in 2010. TCS utilizes a Cauchois type cylindrically bent transmission crystal geometry with a source to crystal distance of 600 mm. Spectral images are recorded by image plates in four positions, one IP on the Rowland circle and three others at 200, 400, and 600 mm beyond the Rowland circle. An earlier version of TCS was used at LULI on experiments that determined the x-ray source size from spectral line broadening on one IP positioned behind the Rowland circle. TCS has recorded numerous backlighter spectra at EP for point projection radiography and for source size measurements. Hard x-ray source size can be determined from the source broadening of both K shell emission lines and from K absorption edges in the bremsstrahlung continuum, the latter being a new way to measure the spatial extent of the hard x-ray bremsstrahlung continuum.

Asymmetrically cut crystal pair as x-ray magnifier for imaging at high intensity laser facilities.

The potential of an x-ray magnifier prepared from a pair of asymmetrically cut crystals is studied to explore high energy x-ray imaging capabilities at high intensity laser facilities. OMEGA-EP and NIF when irradiating mid and high Z targets can be a source of high-energy x-rays whose production mechanisms and use as backlighters are a subject of active research. This paper studies the properties and potential of existing asymmetric cut crystal pairs from the National Institute of Standards and Technology (NIST) built in a new enclosure for imaging x-ray sources. The technique of the x-ray magnifier has been described previously. This new approach is aimed to find a design that could be used at laser facilities by magnifying the x-ray source into a screen far away from the target chamber center, with fixed magnification defined by the crystals' lattice spacing and the asymmetry angles. The magnified image is monochromatic and the imaging wavelength is set by crystal asymmetry and incidence angles. First laboratory results are presented and discussed.

Scaling studies with the dual crystal spectrometer at the OMEGA-EP laser facility.

The dual crystal spectrometer (DCS) is an approved diagnostic at the OMEGA and the OMEGA-EP laser facilities for the measurement of high energy x-rays in the 11-90 keV energy range, e.g., for verification of the x-ray spectrum of backlighter targets of point projection radiography experiments. DCS has two cylindrically bent transmission crystal channels with image plate detectors at distances behind the crystals close to the size of the respective Rowland circle diameters taking advantage of the focusing effect of the cylindrically bent geometry. DCS, with a source to crystal distance of 1.2 m, provides the required energy dispersion for simultaneous detection of x-rays in a low energy channel (11-45 keV) and a high-energy channel (19-90 keV). A scaling study is described for varied pulse length with unchanged laser conditions (energy, focusing). The study shows that the Kα line intensity is not strongly dependent on the length of the laser pulse.

Electronic temperatures, densities, and plasma x-ray emission of a 14.5 GHz electron-cyclotron resonance ion source.

We have performed a systematic study of the bremsstrahlung emission from the electrons in the plasma of a commercial 14.5 GHz electron-cyclotron resonance ion source. The electronic spectral temperature and the product of ionic and electronic densities of the plasma are measured by analyzing the bremsstrahlung spectra recorded for several rare gases (Ar, Kr, and Xe) as a function of the injected power. Within our uncertainty, we find an average temperature of approximately 48 keV above 100 W, with a weak dependency on the injected power and gas composition. Charge state distributions of extracted ion beams have been determined as well, providing a way to disentangle the ionic density from the electronic density. Moreover x-ray emission from highly charged argon ions in the plasma has been observed with a high-resolution mosaic-crystal spectrometer, demonstrating the feasibility for high-precision measurements of transition energies of highly charged ions, in particular, of the magnetic dipole (M1) transition of He-like of argon ions.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.

Over 100 distinct disease-associated mutations have been identified in the breast-ovarian cancer susceptibility gene BRCA1. Loss of the wild-type allele in > 90% of tumors from patients with inherited BRCA1 mutations indicates tumor suppressive function. The low incidence of somatic mutations suggests that BRCA1 inactivation in sporadic tumors occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability as well as potential transcriptional regulatory elements, a 117,143-bp DNA sequence encompassing BRCA1 was obtained by random sequencing of four cosmids identified from a human chromosome 17 specific library. The 24 exons of BRCA1 span an 81-kb region that has an unusually high density of Alu repetitive DNA (41.5%), but relatively low density (4.8%) of other repetitive sequences. BRCA1 intron lengths range in size from 403 bp to 9.2 kb and contain the intragenic microsatellite markers D17S1323, D17S1322, and D17S855, which localize to introns 12, 19, and 20, respectively. In addition to BRCA1, the contig contains two complete genes: Rho7, a member of the rho family of GTP binding proteins, and VAT1, an abundant membrane protein of cholinergic synaptic vesicles. Partial sequences of the 1A1-3B B-box protein pseudogene and IFP 35, an interferon induced leucine zipper protein, reside within the contig. An L21 ribosomal protein pseudogene is embedded in BRCA1 intron 13. The order of genes on the chromosome is: centromere-1FP 35-VAT1-Rho7-BRCA1-1A1-3B-telomere.

Human, canine and murine BRCA1 genes: sequence comparison among species.

Five to ten percent of breast cancer in the western world may be attributed to the inheritance of highly penetrant mutations in the breast and ovarian cancer susceptibility gene, BRCA1. The biological function of BRCA1 and factors affecting expressivity, such as gene-environment and gene-gene interactions, may be more effectively studied in appropriate animal models. We report the cloning and sequencing of the canine and murine BRCA1 genes and contrast the sequences with human BRCA1. The amino terminal 120 residues of the gene are > 80% identical among the three species. The C-terminus is also highly conserved, containing an 80 amino acid stretch that is over 80% identical. Motifs of likely functional significance are maintained, including the amino terminal RING finger motif (amino acids 24-64) and the granin consensus sequence (1214-1223). The distribution of missense mutations and neutral polymorphisms identified in BRCA1-linked breast cancer suggests that disease associated missense mutations occur at highly conserved residues whereas polymorphisms are in regions of lower conservation. Among eighteen missense mutations with unknown consequences, seven occur in amino acids that are identical across species. Four of these seven (E1219D, A1708E, P1749R and M1775R) are also within conserved domains. Taken together, these data predict regions of the gene which may be critical for normal function.

BRCA1 is secreted and exhibits properties of a granin.

Germline mutations in BRCA1 are responsible for most cases of inherited breast and ovarian cancer. However, the function of the BRCA1 protein has remained elusive. We now show that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. Interestingly, BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localize to secretory vesicles, are secreted by a regulated pathway, are post-translationally glycosylated and are responsive to hormones. As a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumour suppressor gene products.

Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.

Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2.

22 genes from chromosome 17q21: cloning, sequencing, and characterization of mutations in breast cancer families and tumors.

In our effort to identify BRCA1, 22 genes were cloned from a 1-Mb region of chromosome 17q21 defined by meiotic recombinants in families with inherited breast and/or ovarian cancer. Subsequent discovery of another meiotic recombinant narrowed the region to approximately 650 kb. Genes were cloned from fibroblast and ovarian cDNA libraries by direct screening with YACs and cosmids. The more than 400 cDNA clones so identified were mapped to cosmids, YACs, and P1 clones and to a chromosome 17 somatic panel informative for the BRCA1 region. Clones that mapped back to the region were hybridized to each other and consolidated into clusters reflecting 22 genes. Ten genes were known human genes, 5 were human homologs of known genes, and 7 were novel. Each gene was sequenced, compared to genes in the databases to find homologies, and analyzed for mutations in BRCA1-linked families and tumors. Eight mutations were found in tumors or families and not in controls. In the gene encoding alpha-N-acetylglucosaminidase, approximately 100 kb proximal to the 650-kb linked region, somatic nonsense, missense, and splice junction mutations occurred in 3 breast tumors, but not in these patients' germline DNA nor in controls. In an ets-related oncogene in the linked region, a missense mutation cosegregated with breast cancer in one family and was not observed in controls. In a human homolog of a yeast pre-mRNA splicing factor, 3 different mutations cosegregated with breast cancer in 3 families and were not observed in controls. In these and the other genes in the region, 36 polymorphic variants were observed in both cases and controls.

Inherited breast and ovarian cancer.

An estimated 5 to 10% of all breast and ovarian cancer is attributable to inherited mutations in two highly penetrant autosomal dominant susceptibility genes, BRCA1 and BRCA2. BRCA1 confers higher risk of ovarian cancer and BRCA2 much higher risk of male breast cancer. With the exception of missense mutations in the RING finger near the amino terminus of BRCA1, virtually all germline mutations in the gene cause the novel BRCA1 protein to be prematurely truncated. Approximately 90% of breast tumors in BRCA1 families, 50% of unselected breast tumors and 65-80% of unselected ovarian tumors have lost one allele of BRCA1 by somatic deletion. Very few tumors have detectable somatic point mutations in BRCA1. Inhibition of BRCA1 expression in mammary epithelial cell lines also suggests that BRCA1 may act as a tumor suppressor. The biological function of BRCA1 is still unknown, although identification of a patient homozygous for an inherited BRCA1 mutation suggests that the gene's function may be essential only to specific tissues. At least two other genes, P53 and the androgen receptor, are responsible for inherited predisposition to breast cancer in rare families. Several epidemiologic studies suggest that individuals carrying rare alleles at a minisatellite flanking the HRAS locus are at increased risk of cancer, including breast cancer. Finally, preliminary epidemiologic studies also suggest that individuals heterozygous for mutations in the ataxia telangiectasia gene may be at increased risk of breast cancer.

Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.

We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families with both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.