Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

Soliton approach to the noisy Burgers equation: Steepest descent method

The noisy Burgers equation in one spatial dimension is analyzed by means of the Martin-Siggia-Rose technique in functional form. In a canonical formulation the morphology and scaling behavior are accessed by mean of a principle of least action in the asymptotic non-perturbative weak noise limit. The ensuing coupled saddle point field equations for the local slope and noise fields, replacing the noisy Burgers equation, are solved yielding nonlinear localized soliton solutions and extended linear diffusive mode solutions, describing the morphology of a growing interface. The canonical formalism and the principle of least action also associate momentum, energy, and action with a soliton-diffusive mode configuration and thus provides a selection criterion for the noise-induced fluctuations. In a ``quantum mechanical'' representation of the path integral the noise fluctuations, corresponding to different paths in the path integral, are interpreted as ``quantum fluctuations'' and the growth morphology represented by a Landau-type quasi-particle gas of ``quantum solitons'' with gapless dispersion and ``quantum diffusive modes'' with a gap in the spectrum. Finally, the scaling properties are dicussed from a heuristic point of view in terms of a``quantum spectral representation'' for the slope correlations. The dynamic eponent z=3/2 is given by the gapless soliton dispersion law, whereas the roughness exponent zeta =1/2 follows from a regularity property of the form factor in the spectral representation. A heuristic expression for the scaling function is given by spectral representation and has a form similar to the probability distribution for Levy flights with index $z$.Comment: 30 pages, Revtex file, 14 figures, to be submitted to Phys. Rev.

Canonical phase space approach to the noisy Burgers equation: Probability distributions

We present a canonical phase space approach to stochastic systems described by Langevin equations driven by white noise. Mapping the associated Fokker-Planck equation to a Hamilton-Jacobi equation in the nonperturbative weak noise limit we invoke a {\em principle of least action} for the determination of the probability distributions. We apply the scheme to the noisy Burgers and KPZ equations and discuss the time-dependent and stationary probability distributions. In one dimension we derive the long-time skew distribution approaching the symmetric stationary Gaussian distribution. In the short-time region we discuss heuristically the nonlinear soliton contributions and derive an expression for the distribution in accordance with the directed polymer-replica and asymmetric exclusion model results. We also comment on the distribution in higher dimensions.Comment: 18 pages Revtex file, including 8 eps-figures, submitted to Phys. Rev.

Beyond Gross-Pitaevskii Mean Field Theory

A large number of effects related to the phenomenon of Bose-Einstein Condensation (BEC) can be understood in terms of lowest order mean field theory, whereby the entire system is assumed to be condensed, with thermal and quantum fluctuations completely ignored. Such a treatment leads to the Gross-Pitaevskii Equation (GPE) used extensively throughout this book. Although this theory works remarkably well for a broad range of experimental parameters, a more complete treatment is required for understanding various experiments, including experiments with solitons and vortices. Such treatments should include the dynamical coupling of the condensate to the thermal cloud, the effect of dimensionality, the role of quantum fluctuations, and should also describe the critical regime, including the process of condensate formation. The aim of this Chapter is to give a brief but insightful overview of various recent theories, which extend beyond the GPE. To keep the discussion brief, only the main notions and conclusions will be presented. This Chapter generalizes the presentation of Chapter 1, by explicitly maintaining fluctuations around the condensate order parameter. While the theoretical arguments outlined here are generic, the emphasis is on approaches suitable for describing single weakly-interacting atomic Bose gases in harmonic traps. Interesting effects arising when condensates are trapped in double-well potentials and optical lattices, as well as the cases of spinor condensates, and atomic-molecular coupling, along with the modified or alternative theories needed to describe them, will not be covered here.Comment: Review Article (19 Pages) - To appear in 'Emergent Nonlinear Phenomena in Bose-Einstein Condensates: Theory and Experiment', Edited by P.G. Kevrekidis, D.J. Frantzeskakis and R. Carretero-Gonzalez (Springer Verlag

A Platform-Independent Method for Detecting Errors in Metagenomic Sequencing Data: DRISEE

We provide a novel method, DRISEE (duplicate read inferred sequencing error estimation), to assess sequencing quality (alternatively referred to as “noise” or “error”) within and/or between sequencing samples. DRISEE provides positional error estimates that can be used to inform read trimming within a sample. It also provides global (whole sample) error estimates that can be used to identify samples with high or varying levels of sequencing error that may confound downstream analyses, particularly in the case of studies that utilize data from multiple sequencing samples. For shotgun metagenomic data, we believe that DRISEE provides estimates of sequencing error that are more accurate and less constrained by technical limitations than existing methods that rely on reference genomes or the use of scores (e.g. Phred). Here, DRISEE is applied to (non amplicon) data sets from both the 454 and Illumina platforms. The DRISEE error estimate is obtained by analyzing sets of artifactual duplicate reads (ADRs), a known by-product of both sequencing platforms. We present DRISEE as an open-source, platform-independent method to assess sequencing error in shotgun metagenomic data, and utilize it to discover previously uncharacterized error in de novo sequence data from the 454 and Illumina sequencing platforms

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Marine Tourism Development in the Arkhangelsk Region, Russian Arctic : Stakeholder’s Perspectives

Author's accepted version (postprint).This is an Accepted Manuscript of an article published by Springer in Springer Polar Sciences on (07/03/2020).Available online: https://link.springer.com/chapter/10.1007%2F978-3-030-28404-6_17acceptedVersio

JAK2 V617F Constitutive Activation Requires JH2 Residue F595: A Pseudokinase Domain Target for Specific Inhibitors

The JAK2 V617F mutation present in over 95% of Polycythemia Vera patients and in 50% of Essential Thrombocythemia and Primary Myelofibrosis patients renders the kinase constitutively active. In the absence of a three-dimensional structure for the full-length protein, the mechanism of activation of JAK2 V617F has remained elusive. In this study, we used functional mutagenesis to investigate the involvement of the JH2 αC helix in the constitutive activation of JAK2 V617F. We show that residue F595, located in the middle of the αC helix of JH2, is indispensable for the constitutive activity of JAK2 V617F. Mutation of F595 to Ala, Lys, Val or Ile significantly decreases the constitutive activity of JAK2 V617F, but F595W and F595Y are able to restore it, implying an aromaticity requirement at position 595. Substitution of F595 to Ala was also able to decrease the constitutive activity of two other JAK2 mutants, T875N and R683G, as well as JAK2 K539L, albeit to a lower extent. In contrast, the F595 mutants are activated by erythropoietin-bound EpoR. We also explored the relationship between the dimeric conformation of EpoR and several JAK2 mutants. Since residue F595 is crucial to the constitutive activation of JAK2 V617F but not to initiation of JAK2 activation by cytokines, we suggest that small molecules that target the region around this residue might specifically block oncogenic JAK2 and spare JAK2 wild-type

Bacterial diversity and community composition from seasurface to subseafloor

© The International Society for Microbial Ecology, 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in ISME Journal 10 (2016): 979–989, doi:10.1038/ismej.2015.175.We investigated compositional relationships between bacterial communities in the water column and those in deep-sea sediment at three environmentally distinct Pacific sites (two in the Equatorial Pacific and one in the North Pacific Gyre). Through pyrosequencing of the v4–v6 hypervariable regions of the 16S ribosomal RNA gene, we characterized 450 104 pyrotags representing 29 814 operational taxonomic units (OTUs, 97% similarity). Hierarchical clustering and non-metric multidimensional scaling partition the samples into four broad groups, regardless of geographic location: a photic-zone community, a subphotic community, a shallow sedimentary community and a subseafloor sedimentary community (greater than or equal to1.5 meters below seafloor). Abundance-weighted community compositions of water-column samples exhibit a similar trend with depth at all sites, with successive epipelagic, mesopelagic, bathypelagic and abyssopelagic communities. Taxonomic richness is generally highest in the water-column O2 minimum zone and lowest in the subseafloor sediment. OTUs represented by abundant tags in the subseafloor sediment are often present but represented by few tags in the water column, and represented by moderately abundant tags in the shallow sediment. In contrast, OTUs represented by abundant tags in the water are generally absent from the subseafloor sediment. These results are consistent with (i) dispersal of marine sedimentary bacteria via the ocean, and (ii) selection of the subseafloor sedimentary community from within the community present in shallow sediment.This study was funded by the Biological Oceanography Program of the US National Science Foundation (grant OCE-0752336) and by the NSF-funded Center for Dark Energy Biosphere Investigations (grant NSF-OCE-0939564)