An ultra-deep sequencing strategy to detect sub-clonal TP53 mutations in presentation chronic lymphocytic leukemia cases using multiple polymerases

Chronic lymphocytic leukaemia (CLL) is the most common clonal B-cell disorder characterized by clonal diversity, a relapsing and remitting course, and in its aggressive forms remains largely incurable. Current front-line regimes include agents such as fludarabine, which act primarily via the DNA damage response pathway. Key to this is the transcription factor p53. Mutations in the TP53 gene, altering p53 functionality, are associated with genetic instability, and are present in aggressive CLL. Furthermore, the emergence of clonal TP53 mutations in relapsed CLL, refractory to DNA-damaging therapy, suggests that accurate detection of sub-clonal TP53 mutations prior to and during treatment may be indicative of early relapse. In this study, we describe a novel deep sequencing workflow using multiple polymerases to generate sequencing libraries (MuPol-Seq), facilitating accurate detection of TP53 mutations at a frequency as low as 0.3%, in presentation CLL cases tested. As these mutations were mostly clustered within the regions of TP53 encoding DNA-binding domains, essential for DNA contact and structural architecture, they are likely to be of prognostic relevance in disease progression. The workflow described here has the potential to be implemented routinely to identify rare mutations across a range of diseases

J/psi production from proton-proton collisions at sqrt(s) = 200 GeV

J/psi production has been measured in proton-proton collisions at sqrt(s)= 200 GeV over a wide rapidity and transverse momentum range by the PHENIX experiment at RHIC. Distributions of the rapidity and transverse momentum, along with measurements of the mean transverse momentum and total production cross section are presented and compared to available theoretical calculations. The total J/psi cross section is 3.99 +/- 0.61(stat) +/- 0.58(sys) +/- 0.40(abs) micro barns. The mean transverse momentum is 1.80 +/- 0.23(stat) +/- 0.16(sys) GeV/c.Comment: 326 authors, 6 pages text, 4 figures, 1 table, RevTeX 4. To be submitted to PRL. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Centrality Dependence of Charm Production from Single Electrons in Au+Au Collisions at sqrt(s_NN) = 200 GeV

The PHENIX experiment has measured mid-rapidity transverse momentum spectra (0.4 < p_T < 4.0 GeV/c) of single electrons as a function of centrality in Au+Au collisions at sqrt(s_NN) = 200 GeV. Contributions to the raw spectra from photon conversions and Dalitz decays of light neutral mesons are measured by introducing a thin (1.7% X_0) converter into the PHENIX acceptance and are statistically removed. The subtracted ``non-photonic'' electron spectra are primarily due to the semi-leptonic decays of hadrons containing heavy quarks (charm and bottom). For all centralities, charm production is found to scale with the nuclear overlap function, T_AA. For minimum-bias collisions the charm cross section per binary collision is N_cc^bar/T_AA = 622 +/- 57 (stat.) +/- 160 (sys.) microbarns.Comment: 326 authors, 4 pages text, 3 figures, 1 table, RevTeX 4. To be submitted to Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Manufacturing and Supply Chain Flexibility: Building an Integrative Conceptual Model Through Systematic Literature Review and Bibliometric Analysis

The purpose of this study is twofold: first, to establish the current themes on the topic of manufacturing and supply chain flexibility (MSCF), assess their level of maturity in relation to each other, identify the emerging ones and reflect on how they can inform each other, and second, to develop a conceptual model of MSCF that links different themes connect and highlight future research opportunities. The study builds on a sample of 222 articles published from 1996 to 2018 in international, peer-reviewed journals. The analysis of the sample involves two complementary approaches: the co-word technique to identify the thematic clusters as well as their relative standing and a critical reflection on the papers to explain the intellectual content of these thematic clusters. The results of the co-word analysis show that MSCF is a dynamic topic with a rich and complex structure that comprises five thematic clusters. The value chain, capability and volatility clusters showed research topics that were taking a central role in the discussion on MSCF but were not mature yet. The SC purchasing practices and SC planning clusters involved work that was more focused and could be considered more mature. These clusters were then integrated in a framework that built on the competence–capability perspective and identified the major structural and infrastructural elements of MSCF as well as its antecedents and consequences. This paper proposes an integrative framework helping managers keep track the various decisions they need to make to increase flexibility from the viewpoint of the entire value chain