Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons

This is the peer reviewed version of the following article: Thomas, C. D., McParland, J. P. and Hanson, P. R. (2009), Divalent and Multivalent Activation in Phosphate Triesters: A Versatile Method for the Synthesis of Advanced Polyol Synthons. Eur. J. Org. Chem., 2009: 5487–5500. doi:10.1002/ejoc.200900560, which has been published in final form at http://doi.org/10.1002/ejoc.200900560. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The construction of mono- and bicyclic phosphate trimesters possessing divalent and multivalent activation and their subsequent use in the production of advanced polyol synthons is presented. The method highlights efforts to employ phosphate tethers as removable, functionally active tethers capable of multipositional activation and their subsequent role as leaving groups in selective cleavage reactions. The development of phosphate tethers represents an integrated platform for a new and versatile tether for natural product synthesis and sheds light on new approaches to the facile construction of small molecules

Systematic exploration of essential yeast gene function with temperature-sensitive mutants

Conditional temperature-sensitive (ts) mutations are valuable reagents for studying essential genes in the yeast Saccharomyces cerevisiae. We constructed 787 ts strains, covering 497 (~45%) of the 1,101 essential yeast genes, with ~30% of the genes represented by multiple alleles. All of the alleles are integrated into their native genomic locus in the S288C common reference strain and are linked to a kanMX selectable marker, allowing further genetic manipulation by synthetic genetic array (SGA)–based, high-throughput methods. We show two such manipulations: barcoding of 440 strains, which enables chemical-genetic suppression analysis, and the construction of arrays of strains carrying different fluorescent markers of subcellular structure, which enables quantitative analysis of phenotypes using high-content screening. Quantitative analysis of a GFP-tubulin marker identified roles for cohesin and condensin genes in spindle disassembly. This mutant collection should facilitate a wide range of systematic studies aimed at understanding the functions of essential genes

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Production of He-4 and (4) in Pb-Pb collisions at root(NN)-N-S=2.76 TeV at the LHC

Results on the production of He-4 and (4) nuclei in Pb-Pb collisions at root(NN)-N-S = 2.76 TeV in the rapidity range vertical bar y vertical bar <1, using the ALICE detector, are presented in this paper. The rapidity densities corresponding to 0-10% central events are found to be dN/dy4(He) = (0.8 +/- 0.4 (stat) +/- 0.3 (syst)) x 10(-6) and dN/dy4 = (1.1 +/- 0.4 (stat) +/- 0.2 (syst)) x 10(-6), respectively. This is in agreement with the statistical thermal model expectation assuming the same chemical freeze-out temperature (T-chem = 156 MeV) as for light hadrons. The measured ratio of (4)/He-4 is 1.4 +/- 0.8 (stat) +/- 0.5 (syst). (C) 2018 Published by Elsevier B.V.Peer reviewe

Investigation Of Chiral Symmetry Restoration Using Ξ\Xi(1820) Reconstruction From p-p, p-Pb, And Pb-Pb Collisions At ALICE

The Large Hadron Collider (LHC) at CERN, Geneva, Switzerland, stands at the forefront of our current understanding of high energy physics. Several important measurements, including assisting in the discovery of the Quark Gluon Plasma (QGP), have been made in recent years thanks to the efforts of the LHC. Further study of the properties of matter in these systems proves to be instrumental in our understanding of the universe and the physics used to describe it. Recent lattice quantum chromo dynamic (QCD) calculations seem to indicate the phenomenon of chiral symmetry restoration, which would result in changes in the masses of some hadron species under extreme conditions of pressure and temperature. These lattice QCD calculations highlight the idea of parity doubling, where the masses of negative parity particles decrease when the system approaches a pseudo-critical temperature and phase transition. Investigation into the modification of the affected particle's mass, width, and yield due to partial chiral symmetry restoration would prove instrumental to confirming some of the last remaining predictions of QCD. Measurements of the $\Xi$(1820)$^{-}$ and its antiparticle were performed with the ALICE detector in p-p, p-Pb, and Pb-Pb collisions at LHC energies $\sqrt{s}$ = 13 TeV for p-p and $\sqrt{s_{\mathrm{NN}}}$ = 5.02 TeV for p-Pb and Pb-Pb. The mass, width, and yield of $\Xi$(1820) are obtained and compared in various collision systems. The yield ratios of $\Xi$(1820) to $\Xi$(1530) and $\Xi$ are shown and discussed. Analysis into the $\Xi$(1820)$^{\mp}$ in p-p, p-Pb, and Pb-Pb collisions at LHC shows several signatures of chiral symmetry restoration. Most notably, a 2.38 $\sigma$ difference between the width of $\Xi$(1820)$^{\mp}$ signals from minimum bias p-p $\sqrt{s}$ = 13 TeV and central Pb-Pb $\sqrt{s_{NN}}$ = 5.02 TeV data is observed. While very impressive, more statistics are required to reach a conclusive statement

Development of a High-Propellant Throughput Small Spacecraft Electric Propulsion System (HT-SSEP) to Enable Lower Cost NASA Science Missions

Discusses progress at the NASA Glenn Research Center (GRC) in the development and demonstration of an integrated high-propellant throughput small spacecraft electric propulsion (HT-SSEP) system based on a Hall-effect thruster. A center-mounted cathode and an innovative magnetic circuit topology were implemented in the design of the Hall-effect thruster to achieve high-propellant throughput, high performance, and efficient packaging. To minimize technical risk, the HT-SSEP development approach sought to limit design features and materials to those with a clear path-to-flight. A propellant throughput capability of greater than 100 kilograms at a minimum thruster efficiency of 50 percent was targeted. The proof-of-concept NASA-H64M laboratory model (LM) thruster was designed, fabricated, and tested at GRC in fiscal year 2018. The thruster development leveraged heritage Hall-effect thruster design and manufacturing processes wherever appropriate. Recent NASA advances in Hall-effect thruster technology were also leveraged. A scalable discharge power supply (DPS) capable of powering the H64M-LM was developed, then demonstrated as part of an integrated system test. The DPS uses commercial off-the-shelf components with spaceflight equivalents. A keeper supply with DC ignitor was breadboarded, then demonstrated with a laboratory cathode. Finally, feed system trade studies were performed to ascertain what feed system architecture might be appropriate for an HT-SSEP system. This paper details the motivations for the project, the development approach, the chosen sub-system architectures, design considerations, and test results