Statistical Analysis of Data on Linker Histones/DNA Interactions

2000 Mathematics Subject Classification: 62P10, 92C40Linker histones (H1, H1o H5, subtypes and variants) play a pivotal role in formation of higher order chromatin structure and thus - as main regulators of the expression of genetic information kept in DNA. That is why the knowledge of the nature of linker histones/DNA interactions is of a greatest interest in understanding of such important issues as transcription regulation, cell division, and cancerogenesis. As DNA is a main "target" of most anticancer antibiotics, the analysis of competitive reactions between that drugs (in our case actinomycin D and netropsin) and linker histones for binding to certain sites in DNA gives hopeful information concerning the mode of such interactions. In this work we present statistical analysis of some experimental data concerning the influence of some anticancer antibiotics on linker histones/DNA interactions. First, it was investigated the formulated hypothesis of the dependence of H1/DNA interaction on actinomycin D concentration. Such a relation was expected knowing the different mode for binding of the both drugs to DNA double helix. The applied statistical analysis using chi-square test for independence showed that the concentration of Actinomycin D in reaction mixture had no essential effect on linker histone/DNA binding. On the contrary, the same analysis with the second antibiotic - netropsin showed that we could not reject the hypothesis of dependence. Some other statistical models are also proposed, applying chi-square test for homogeneity, test of Willcockson, Smirnov's test and others.This paper is supported by NESI - Bulgaria - Grant K - 1003/2000 Partialy supported by Pro-ENBIS GTC1 -2001-43031. This paper is supported by NESI - Bulgaria - Grant MM - 1101/2001

Characterization of exponential distribution via regression of one record value on two non-adjacent record values

We characterize the exponential distribution as the only one which satisfies a regression condition. This condition involves the regression function of a fixed record value given two other record values, one of them being previous and the other next to the fixed record value, and none of them are adjacent. In particular, it turns out that the underlying distribution is exponential if and only if given the first and last record values, the expected value of the median in a sample of record values equals the sample midrange.Comment: To appear in Metrik

Impaired Meningeal Lymphatic Vessel Development Worsens Stroke Outcome

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Space Charge at Nanoscale: Probing Injection and Dynamic Phenomena Under Dark/Light Configurations by Using KPFM and C-AFM

International audienc

Joint Criminal Enterprise

The concept of joint criminal enterprise (JCE) has been regarded as one of the most important modes of liability in ICL, which some scholars and practitioners have praised for ‘ensuring that individual culpability is not obscured in the fog of collective criminality and accountability evaded’. Indeed, ever since it was first articulated by the ICTY Appeals Chamber in the Tadić case, JCE liability has been widely applied in the case law of both the ICTY and the ICTR, and it was subsequently also adopted by the SCSL, the ECCC and the STL. Nowadays, it is well established that JCE is a form of co-perpetration, which applies in cases where a plurality of individuals share a common criminal purpose and coordinate efforts to commit its underlying crime

Parallel algorithms for downdating the least squares estimator of the regression model

Computationally efficient parallel algorithms for downdating the least squares estimator of the ordinary linear regression are proposed. The algorithms, which are based on the QR decomposition, are block versions of sequential Givens strategies and efficiently exploit the triangular structure of the data matrices. The first strategy utilizes only part of the orthogonal matrix which is derived from the QR decomposition of the initial data matrix. The rest of the orthogonal matrix is not updated or explicitly computed. A modification of the parallel algorithm, which explicitly computes the whole orthogonal matrix in the downdated QR decomposition, is also considered. An efficient distribution of the matrices over the processors is proposed. Furthermore, the new algorithms do not require any inter-processor communication. The theoretical complexities are derived and experimental results are presented and analyzed. The parallel strategies are scalable and highly efficient for large scale downdating least squares problems. A new parallel block-hyperbolic downdating strategy is developed. The algorithm is rich in BLAS-3 computations, involves negligible duplicated computations and requires insignificant inter-processor communication. It is found to outperform the previous downdating strategies and to be highly efficient for large scale problems. The experimental results confirm the derived theoretical complexities

Efficient algorithms for estimating the general linear model

Computationally efficient serial and parallel algorithms for estimating the general linear model are proposed. The sequential block-recursive algorithm is an adaptation of a known Givens strategy that has as a main component the Generalized QR decomposition. The proposed algorithm is based on orthogonal transformations and exploits the triangular structure of the Cholesky QRD factor of the variance–covariance matrix. Specifically, it computes the estimator of the general linear model by solving recursively a series of smaller and smaller generalized linear least squares problems. The new algorithm is found to outperform significantly the corresponding LAPACK routine. A parallel version of the new sequential algorithm which utilizes an efficient distribution of the matrices over the processors and has low inter-processor communication is developed. The theoretical computational complexity of the parallel algorithms is derived and analyzed. Experimental results are presented which confirm the theoretical analysis. The parallel strategy is found to be scalable and highly efficient for estimating large-scale general linear estimation problems