Diffraction of stochastic point sets : exactly solvable examples

Stochastic point sets are considered that display a diffraction spectrum of mixed type, with special emphasis on explicitly computable cases together with a unified approach of reasonable generality. Several pairs of autocorrelation and diffraction measures are discussed that show a duality structure that may be viewed as analogues of the Poisson summation formula for lattice Dirac combs

Diffraction of stochastic point sets: Exactly solvable examples

Stochastic point sets are considered that display a diffraction spectrum of mixed type, with special emphasis on explicitly computable cases together with a unified approach of reasonable generality. Several pairs of autocorrelation and diffraction measures are discussed that show a duality structure that may be viewed as analogues of the Poisson summation formula for lattice Dirac combs

Das Klimaschutz-Sofortprogramm

DAS KLIMASCHUTZ-SOFORTPROGRAMM Das Klimaschutz-Sofortprogramm / Aichinger, Wolfgang (Rights reserved) ( -

Influence of patient and tumor characteristics on therapy persistence with letrozole in postmenopausal women with advanced breast cancer: results of the prospective observational EvAluate-TM study

Background: Treatment of postmenopausal, hormone receptor-positive metastatic breast cancer (MBC) patients varies despite clear therapy guidelines, favoring endocrine treatment (ET). Aim of this study was to analyze persistence of palliative aromatase inhibitor (AI) monotherapy in MBC patients. Methods: EvAluate-TM is a prospective, multicenter, noninterventional study to evaluate treatment with letrozole in postmenopausal women with hormone receptor–positive breast cancer. To assess therapy persistence, defined as the time from therapy start to the end of the therapy (TTEOT), two pre-specified study visits took place after 6 and 12 months. Competing risk survival analyses were performed to identify patient and tumor characteristics that predict TTEOT. Results: Out of 200 patients, 66 patients terminated treatment prematurely, 26 (13%) of them due to causes other than disease progression. Persistence rate for reasons other than progression at 12 months was 77.7%. Persistence was lower in patients who reported any adverse event (AE) in the first 30 days of ET (89.5% with no AE and 56% with AE). Furthermore, patients had a lower persistence if they reported compliance problems in the past before letrozole treatment. Conclusions: Despite suffering from a life-threatening disease, AEs of an AI will result in a relevant number of treatment terminations that are not related to progression. Some subgroups of patients have very low persistence rates. Especially with regard to novel endocrine combination therapies, these data imply that some groups of patients will need special attention to guide them through the therapy process. Trial registration Clinical Trials Number: CFEM345DDE1

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Non-periodic Systems with Continuous Diffraction Measures

The present state of mathematical diffraction theory for systems with continuous spectral components is reviewed and extended. We begin with a discussion of various characteristic examples with singular or absolutely continuous diffraction, and then continue with a more general exposition of a systematic approach via stationary stochastic point processes. Here, the intensity measure of the Palm measure takes the role of the autocorrelation measure in the traditional approach. We furthermore introduce a 'Palm-type' measure for general complex-valued random measures that are stationary and ergodic, and relate its intensity measure to the autocorrelation measure

Characterisation of the nuclear transport of core histones: structural and functional analysis

Core-Histone sind kleine basischen Proteine, die die Nukleosomen im Chromatin eukaryonter Zellen bilden. In vitro Kernimportstudien zeigen, daß die vier Core-Histone H2A, H2B, H3 und H4 nicht durch freie Diffusion, sondern durch einen aktiven, rezeptorvermittelten Prozeß in den Zellkern importiert werden. Für diesen Vorgang sind Kernlokalisationssignale (NLS) erforderlich. Transfektionsstudien zeigen, daß Core-Histone wenigstens zwei Proteinabschnitte enthalten, die als NLS funktionieren können. Dabei wird jeweils zwischen einem in der Primärsequenz aus basischen Aminosäuren zusammengesetzten, N-terminalen Signal und einem hydrophoben Signalbereich unterschieden, der eine vollständige globuläre Domäne eines Core-Histons enthält. In vitro Kompetitionsstudien zeigen, daß die Core-Histone über einen anderen Mechanismus als Proteine mit klassischem NLS und auch anders als die H1-Linker-Histone in den Zellkern importiert werden. Rekonstitutionsstudien identifizierten Importin-beta, Importin5, Importin7 und Transportin als funktionelle Importrezeptoren für den Kernimport der Core-Histone

Subunits of the Heterotrimeric Transcription Factor NF-Y Are Imported into the Nucleus by Distinct Pathways Involving Importin β and Importin 13

The transcriptional activator NF-Y is a heterotrimeric complex composed of NF-YA, NF-YB, and NF-YC, which specifically binds the CCAAT consensus present in about 30% of eukaryotic promoters. All three subunits contain evolutionarily conserved core regions, which comprise a histone fold motif (HFM) in the case of NF-YB and NF-YC. Our results of in vitro binding studies and nuclear import assays reveal two different transport mechanisms for NF-Y subunits. While NF-YA is imported by an importin β-mediated pathway, the NF-YB/NF-YC heterodimer is translocated into the nucleus in an importin 13-dependent manner. We define a nonclassical nuclear localization signal (ncNLS) in NF-YA, and mutational analysis indicates that positively charged amino acid residues in the ncNLS are required for nuclear targeting of NF-YA. Importin β binding is restricted to the monomeric, uncomplexed NF-YA subunit. In contrast, the nuclear import of NF-YB and NF-YC requires dimer formation. Only the NF-YB/NF-YC dimer, but not the monomeric components, are recognized by importin 13 and are imported into the nucleus. Importin 13 competes with NF-YA for binding to the NF-YB/NF-YC dimer. Our data suggest that a distinct binding platform derived from the HFM of both subunits, NF-YB/NF-YC, mediates those interactions