Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD.

To understand how the nucleosome remodeling and deacetylase (NuRD) complex regulates enhancers and enhancer-promoter interactions, we have developed an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule trajectories. Unexpectedly, this has revealed that NuRD binds to chromatin for minutes, decompacts chromatin structure and increases enhancer dynamics. We also uncovered a rare fast-diffusing state of enhancers and found that NuRD restricts the time spent in this state.

Early Maladaptive Schemas Are Highly Indicative of Compulsive Sexual Behavior.

Unlike the consequences of compulsive sexual behavior (CSB) and the profile of people with CSB that were extensively studied, the cognitive distortions that might be responsible to the development and maintenance of CSB are less understood. In Study 1 ( = 68), we examined intercorrelations between CSB and early maladaptive schemas among a sample with clinical CSB (Sexaholic Anonymous; SAs). In Study 2 (sex offenders; = 103, and violence offenders; = 81), we examined the intercorrelations between CSB and early maladaptive schemas among a sample with a sexual deviance but non-clinical levels of CSB.

Compulsive sexual behavior and sexual offending: Differences in cognitive schemas, sensation seeking, and impulsivity.

Background And Aims: People from the community seeking treatment in frameworks such as Sexaholics Anonymous (SA) and sex offenders are preoccupied with sex, sexual fantasies, and behaviors. The rates of compulsive sexual behavior disorder (CSBD), however, are reported to be substantially lower among sex offenders than SAs. In this study, we examined differences between SAs and sex offenders in CSBD and in processes that might be at the core of CSBD - maladaptive schemas about the self and others, impulsivity, and sensation seeking.

Advances Using Single-Particle Trajectories to Reconstruct Chromatin Organization and Dynamics.

Chromatin organization remains complex and far from understood. In this article, we review recent statistical methods of extracting biophysical parameters from in vivo single-particle trajectories of loci to reconstruct chromatin reorganization in response to cellular stress such as DNA damage. We look at methods for analyzing both single locus and multiple loci tracked simultaneously and explain how to quantify and describe chromatin motion using a combination of extractable parameters.

Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers.

Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs). Folding hierarchy and internal organization of TADs is highly dynamic throughout cellular differentiation, and are correlated with gene activation and silencing. To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency Hi-C encounters within and between TADs into direct loci interactions using cross-links at a given base-pair resolution.

Statistics of randomly cross-linked polymer models to interpret chromatin conformation capture data.

Polymer models are used to describe chromatin, which can be folded at different spatial scales by binding molecules. By folding, chromatin generates loops of various sizes. We present here a statistical analysis of the randomly cross-linked (RCL) polymer model, where monomer pairs are connected randomly, generating a heterogeneous ensemble of chromatin conformations.

Two loci single particle trajectories analysis: constructing a first passage time statistics of local chromatin exploration.

Stochastic single particle trajectories are used to explore the local chromatin organization. We present here a statistical analysis of the first contact time distributions between two tagged loci recorded experimentally. First, we extract the association and dissociation times from data for various genomic distances between loci, and we show that the looping time occurs in confined nanometer regions.

Transient chromatin properties revealed by polymer models and stochastic simulations constructed from Chromosomal Capture data.

Chromatin organization can be probed by Chromosomal Capture (5C) data, from which the encounter probability (EP) between genomic sites is presented in a large matrix. This matrix is averaged over a large cell population, revealing diagonal blocks called Topological Associating Domains (TADs) that represent a sub-chromatin organization. To study the relation between chromatin organization and gene regulation, we introduce a computational procedure to construct a bead-spring polymer model based on the EP matrix.

Integrating in vitro sensitivity and dose-response slope is predictive of clinical response to ABL kinase inhibitors in chronic myeloid leukemia.

BCR-ABL mutations result in clinical resistance to ABL tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Although in vitro 50% inhibitory concentration (IC(50)) values for specific mutations have been suggested to guide TKI choice in the clinic, the quantitative relationship between IC(50) and clinical response has never been demonstrated. We used Hill's equation for in vitro response of Ba/F3 cells transduced with various BCR-ABL mutants to determine IC(50) and the slope of the dose-response curve.

Analyzing transformation of myelodysplastic syndrome to secondary acute myeloid leukemia using a large patient database.

One-third of patients with myelodysplastic syndrome (MDS) progress to secondary acute myeloid leukemia (sAML), with its concomitant poor prognosis. Recently, multiple mutations have been identified in association with MDS-to-sAMLtransition, but it is still unclear whether all these mutations are necessary for transformation. If multiple independent mutations are required for the transformation, sAML risk should increase with time from MDS diagnosis.