Physical and Biogeochemical Studies in the Subtropical and Tropical Atlantic

Maria S. Merian Cruise Report MSM18/L2 Cruise No. 18, Leg 2 May 11 – June 19, 2011 Mindelo (Cape Verde Islands) – Mindelo (Cape Verde Islands

Measurement of the Top-Quark Mass with Dilepton Events Selected Using Neuroevolution at CDF

We report a measurement of the top-quark mass Mt in the dilepton decay channel tt̄→bl′+νl′b̄l-ν̄l. Events are selected with a neural network which has been directly optimized for statistical precision in top-quark mass using neuroevolution, a technique modeled on biological evolution. The top-quark mass is extracted from per-event probability densities that are formed by the convolution of leading order matrix elements and detector resolution functions. The joint probability is the product of the probability densities from 344 candidate events in 2.0fb-1 of pp̄ collisions collected with the CDF II detector, yielding a measurement of Mt=171.2±2.7(stat)±2.9(syst)GeV/c2

Recommendations of the LHC Dark Matter Working Group: Comparing LHC searches for heavy mediators of dark matter production in visible and invisible decay channels

Weakly-coupled TeV-scale particles may mediate the interactions between normal matter and dark matter. If so, the LHC would produce dark matter through these mediators, leading to the familiar "mono-X" search signatures, but the mediators would also produce signals without missing momentum via the same vertices involved in their production. This document from the LHC Dark Matter Working Group suggests how to compare searches for these two types of signals in case of vector and axial-vector mediators, based on a workshop that took place on September 19/20, 2016 and subsequent discussions. These suggestions include how to extend the spin-1 mediated simplified models already in widespread use to include lepton couplings. This document also provides analytic calculations of the relic density in the simplified models and reports an issue that arose when ATLAS and CMS first began to use preliminary numerical calculations of the dark matter relic density in these models.Comment: 19 pages, 4 figures; v2: author list and LaTeX problem fixe

Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

Structure and nucleic acid binding properties of KOW domains 4 and 6–7 of human transcription elongation factor DSIF

The human transcription elongation factor DSIF is highly conserved throughout all kingdoms of life and plays multiple roles during transcription. DSIF is a heterodimer, consisting of Spt4 and Spt5 that interacts with RNA polymerase II (RNAP II). DSIF binds to the elongation complex and induces promoter-proximal pausing of RNAP II. Human Spt5 consists of a NusG N-terminal (NGN) domain motif, which is followed by several KOW domains. We determined the solution structures of the human Spt5 KOW4 and the C-terminal domain by nuclear magnetic resonance spectroscopy. In addition to the typical KOW fold, the solution structure of KOW4 revealed an N-terminal four-stranded β-sheet, previously designated as the KOW3-KOW4 linker. In solution, the C-terminus of Spt5 consists of two β-barrel folds typical for KOW domains, designated KOW6 and KOW7. We also analysed the nucleic acid and RNAP II binding properties of the KOW domains. KOW4 variants interacted with nucleic acids, preferentially single stranded RNA, whereas no nucleic acid binding could be detected for KOW6-7. Weak binding of KOW4 to the RNAP II stalk, which is comprised of Rpb4/7, was also detected, consistent with transient interactions between Spt5 and these RNAP II subunits

Population Genomics: Whole-Genome Analysis of Polymorphism and Divergence in Drosophila simulans

The population genetic perspective is that the processes shaping genomic variation can be revealed only through simultaneous investigation of sequence polymorphism and divergence within and between closely related species. Here we present a population genetic analysis of Drosophila simulans based on whole-genome shotgun sequencing of multiple inbred lines and comparison of the resulting data to genome assemblies of the closely related species, D. melanogaster and D. yakuba. We discovered previously unknown, large-scale fluctuations of polymorphism and divergence along chromosome arms, and significantly less polymorphism and faster divergence on the X chromosome. We generated a comprehensive list of functional elements in the D. simulans genome influenced by adaptive evolution. Finally, we characterized genomic patterns of base composition for coding and noncoding sequence. These results suggest several new hypotheses regarding the genetic and biological mechanisms controlling polymorphism and divergence across the Drosophila genome, and provide a rich resource for the investigation of adaptive evolution and functional variation in D. simulans

RNF43 is frequently mutated in colorectal and endometrial cancers

We report somatic mutations of RNF43 in over 18% of colorectal adenocarcinomas and endometrial carcinomas. RNF43 encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling. Truncating mutations of RNF43 are more prevalent in microsatellite-unstable tumors and show mutual exclusivity with inactivating APC mutations in colorectal adenocarcinomas. These results indicate that RNF43 is one of the most commonly mutated genes in colorectal and endometrial cancers.National Human Genome Research Institute (U.S.) (Grant U54HG003067

CMS distributed computing workflow experience

The vast majority of the CMS Computing capacity, which is organized in a tiered hierarchy, is located away from CERN. The 7 Tier-1 sites archive the LHC proton-proton collision data that is initially processed at CERN. These sites provide access to all recorded and simulated data for the Tier-2 sites, via wide-area network (WAN) transfers. All central data processing workflows are executed at the Tier-1 level, which contain re-reconstruction and skimming workflows of collision data as well as reprocessing of simulated data to adapt to changing detector conditions. This paper describes the operation of the CMS processing infrastructure at the Tier-1 level. The Tier-1 workflows are described in detail. The operational optimization of resource usage is described. In particular, the variation of different workflows during the data taking period of 2010, their efficiencies and latencies as well as their impact on the delivery of physics results is discussed and lessons are drawn from this experience. The simulation of proton-proton collisions for the CMS experiment is primarily carried out at the second tier of the CMS computing infrastructure. Half of the Tier-2 sites of CMS are reserved for central Monte Carlo (MC) production while the other half is available for user analysis. This paper summarizes the large throughput of the MC production operation during the data taking period of 2010 and discusses the latencies and efficiencies of the various types of MC production workflows. We present the operational procedures to optimize the usage of available resources and we the operational model of CMS for including opportunistic resources, such as the larger Tier-3 sites, into the central production operation