Fractal-like Distributions over the Rational Numbers in High-throughput Biological and Clinical Data

Recent developments in extracting and processing biological and clinical data are allowing quantitative approaches to studying living systems. High-throughput sequencing, expression profiles, proteomics, and electronic health records are some examples of such technologies. Extracting meaningful information from those technologies requires careful analysis of the large volumes of data they produce. In this note, we present a set of distributions that commonly appear in the analysis of such data. These distributions present some interesting features: they are discontinuous in the rational numbers, but continuous in the irrational numbers, and possess a certain self-similar (fractal-like) structure. The first set of examples which we present here are drawn from a high-throughput sequencing experiment. Here, the self-similar distributions appear as part of the evaluation of the error rate of the sequencing technology and the identification of tumorogenic genomic alterations. The other examples are obtained from risk factor evaluation and analysis of relative disease prevalence and co-mordbidity as these appear in electronic clinical data. The distributions are also relevant to identification of subclonal populations in tumors and the study of the evolution of infectious diseases, and more precisely the study of quasi-species and intrahost diversity of viral populations

The ansamycin antibiotic, rifamycin SV, inhibits BCL6 transcriptional repression and forms a complex with the BCL6-BTB/POZ domain

BCL6 is a transcriptional repressor that is over-expressed due to chromosomal translocations, or other abnormalities, in ~40% of diffuse large B-cell lymphoma. BCL6 interacts with co-repressor, SMRT, and this is essential for its role in lymphomas. Peptide or small molecule inhibitors, which prevent the association of SMRT with BCL6, inhibit transcriptional repression and cause apoptosis of lymphoma cells in vitro and in vivo. In order to discover compounds, which have the potential to be developed into BCL6 inhibitors, we screened a natural product library. The ansamycin antibiotic, rifamycin SV, inhibited BCL6 transcriptional repression and NMR spectroscopy confirmed a direct interaction between rifamycin SV and BCL6. To further determine the characteristics of compounds binding to BCL6-POZ we analyzed four other members of this family and showed that rifabutin, bound most strongly. An X-ray crystal structure of the rifabutin-BCL6 complex revealed that rifabutin occupies a partly non-polar pocket making interactions with tyrosine58, asparagine21 and arginine24 of the BCL6-POZ domain. Importantly these residues are also important for the interaction of BLC6 with SMRT. This work demonstrates a unique approach to developing a structure activity relationship for a compound that will form the basis of a therapeutically useful BCL6 inhibitor

Study of the a_0(980) meson via the radiative decay phi->eta pi^0 gamma with the KLOE detector

We have studied the phi->a_0(980) gamma process with the KLOE detector at the Frascati phi-factory DAPhNE by detecting the phi->eta pi^0 gamma decays in the final states with eta->gamma gamma and eta->pi^+ pi^- pi^0. We have measured the branching ratios for both final states: Br(phi->eta pi^0 gamma)=(7.01 +/- 0.10 +/- 0.20)x10^-5 and (7.12 +/- 0.13 +/- 0.22)x10^-5 respectively. We have also extracted the a_0(980) mass and its couplings to eta pi^0, K^+ K^-, and to the phi meson from the fit of the eta pi^0 invariant mass distributions using different phenomenological models.Comment: 17 pages, 6 figures, submitted to Physics Letters B. Corrected typos in eq.

Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma

PR domain containing 1 with zinc finger domain (PRDM1)/B lymphocyte–induced maturation protein 1 (BLIMP1) is a transcriptional repressor expressed in a subset of germinal center (GC) B cells and in all plasma cells, and required for terminal B cell differentiation. The BLIMP1 locus lies on chromosome 6q21-q22.1, a region frequently deleted in B cell lymphomas, suggesting that it may harbor a tumor suppressor gene. We report here that the BLIMP1 gene is inactivated by structural alterations in 24% (8 out of 34) activated B cell–like diffuse large cell lymphoma (ABC-DLBCL), but not in GC B cell–like (n = 0/37) or unclassified (n = 0/21) DLBCL. BLIMP1 alterations included gene truncations, nonsense mutations, frameshift deletions, and splice site mutations that generate aberrant transcripts encoding truncated BLIMP1 proteins. In all cases studied, both BLIMP1 alleles were inactivated by deletions or mutations. Furthermore, most non–GC type DLBCL cases (n = 20/26, 77%) lack BLIMP1 protein expression, despite the presence of BLIMP1 mRNA. These results indicate that a sizable fraction of ABC-DLBCL carry an inactive BLIMP1 gene, and suggest that the same gene is inactivated by epigenetic mechanisms in an additional large number of cases. These findings point to a role for BLIMP1 as a tumor suppressor gene, whose inactivation may contribute to lymphomagenesis by blocking post–GC differentiation of B cells toward plasma cells

A Study of the Radiative Ke3 Decay and Search for Direct Photon Emission with the KLOE Detector

We present a measurement of the ratio R = \Gamma(\keg;\Estar>30\mev,\qstar>20^\circ)$/$\Gamma(\kegf)$and a first measurement of the direct emission contribution in KL semileptonic decays. The measurement is done at the DAFNE phi-factory selecting phi->KL KS decays with the KLOE detector. We use 328 pb^{-1}$ of data corresponding to about 3.5 million Ke3(g) events and about 9000 radiative events. Our result is R=(924 +/- 23(stat) +/-16(syst)10^{-5} for the branching ratio and X=-2.3 +/- 1.3(stat) +/- 1.4(syst) for the parameter describing direct emission.Comment: 8 pages, 7 figure

Charged kaon lifetime at KLOE

Preliminary result on the charged kaon lifetime, obtained by the KLOE experiment operating at DA$\Phi$NE, the Frascati $\phi$-factory, is presentedComment: 3 pages, 3 figures, to appear in the proceedings of 42nd Rencontres de Moriond on Electroweak Interactions and Unified Theories, La Thuile, Aosta Valley, Italy, 10-17 Mar 200

Measurement of the K_L \to \pi\mu\nu form factor parameters with the KLOE detector

Using 328 pb^{-1}of data collected at DAFNE corresponding to $\sim$ 1.8 million $K_L\to \pi\mu\nu$ decays, we have measured the $K_{\mu 3}$ form factor parameters. The structure of the $K-\pi$ vector-current provides information about the dynamics of the strong interaction; its knowledge is necessary for evaluation of the phase-space integral required for measuring the CKM matrix element $V_{us}$ and for testing lepton universality in kaon decays. Using a new parametrization for the vector and scalar form factors, we find $\lambda_+$=\pt(25.7\pm 0.6),-3, and $\lambda_0$=\pt(14.0\pm 2.1),-3,. Our result for $\lambda_0$, together with recent lattice calculations of $f_\pi$, $f_K$ and $f(0)$, satisfies the Callan-Trieman relatio

Measurement of the absolute branching ratios for semileptonic K+/- decays with the KLOE detector

Using a sample of over 600 million phi->K+K- decays collected at the Dafne e+e- collider, we have measured with the KLOE detector the absolute branching ratios for the charged kaon semileptonic decays, K+/- -> p0 e nu (gamma) (Ke3) and K+/- -> p0 mu nu (gamma) (Kmu3). The results, BR(Ke3) = 0.04965 +/- 0.00038_{stat} +/- 0.00037_{syst} and BR(Kmu3) = 0.03233 +/- 0.00029_{stat} +/- 0.00026_{syst}, are inclusive of radiation. Accounting for correlations, we derive the ratio Kmu3/Ke3 = 0.6511+/-0.0064. Using the semileptonic form factors measured in the same experiment, we obtain V_{us}f_{+}(0) = 0.2141 +/- 0.0013.Comment: 13 pages, 3 figures, submitted to JHEP. v2: minor revisions required by JHEP, v3: final version published by JHEP (replacement of 2 incorrect affiliations)link: http://www.iop.org/EJ/abstract/1029-8479/2008/02/09

Determination of η→π+π−π0\eta\to\pi^+\pi^-\pi^0 Dalitz plot slopes and asymmetries with the KLOE detector

We have studied, with the KLOE detector at the DA$\Phi$NE $\Phi$-Factory, the dynamics of the decay $\eta\to\pi^+\pi^-\pi^0$ using $\eta$ mesons from the decay $\phi\to\eta\gamma$ for an integrated luminosity ${\mathcal L}$ = 450 pb$^{-1}$. From a fit to the Dalitz plot density distribution we obtain a precise measurement of the slope parameters. An alternative parametrization relates the $\pi^+\pi^-\pi^0$ slopes to that for $\eta\to 3\pi^0$ showing the consistency of KLOE results for both channels. We also obtain the best confirmation of the $C$-invariance in the $\eta\to\pi^+\pi^-\pi^0$ decay.Comment: 15 pages, 7 figure