66 research outputs found
Synthesis of cyclopropyl-substituted furans by Brønsted acid promoted cascade reactions
Chloroacetic acid promotes an efficient and diastereoselective intramolecular cascade reaction of electron-deficient ynenones to deliver products featuring a 2,3,5-trisubstituted furan bearing a fused cyclopropyl substituent at the 5-position. Synthetically relevant polycyclic building blocks featuring rings of various sizes and heteroatoms have been synthesized in high yield using this mild acid-catalyzed reaction
Modified Gravity and Cosmology
In this review we present a thoroughly comprehensive survey of recent work on
modified theories of gravity and their cosmological consequences. Amongst other
things, we cover General Relativity, Scalar-Tensor, Einstein-Aether, and
Bimetric theories, as well as TeVeS, f(R), general higher-order theories,
Horava-Lifschitz gravity, Galileons, Ghost Condensates, and models of extra
dimensions including Kaluza-Klein, Randall-Sundrum, DGP, and higher
co-dimension braneworlds. We also review attempts to construct a Parameterised
Post-Friedmannian formalism, that can be used to constrain deviations from
General Relativity in cosmology, and that is suitable for comparison with data
on the largest scales. These subjects have been intensively studied over the
past decade, largely motivated by rapid progress in the field of observational
cosmology that now allows, for the first time, precision tests of fundamental
physics on the scale of the observable Universe. The purpose of this review is
to provide a reference tool for researchers and students in cosmology and
gravitational physics, as well as a self-contained, comprehensive and
up-to-date introduction to the subject as a whole.Comment: 312 pages, 15 figure
Masitinib (AB1010), a Potent and Selective Tyrosine Kinase Inhibitor Targeting KIT
International audienceBackground: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole-type tyrosine kinase inhibitor that targets KIT. Methodology/Principal Findings: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC50) of 200 ± 40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC50 of 150 ± 80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. Conclusions: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicit
From Clock Synchronization to Dark Matter as a Relativistic Inertial Effect
Lecture at BOSS2011 on relativistic metrology, on clock synchronization,
relativistic dynamics and non-inertial frames in Minkowski spacetime, on
relativistic atomic physics, on ADM canonical tetrad gravity in asymptotically
Minkowskian spacetimes, on the York canonical basis identifying the inertial
(gauge) and tidal degrees of freedom of the gravitational field, on the
Post-Minkowskian linearization in 3-orthogonal gauges, on the Post-Newtonian
limit of matter Hamilton equations, on the possibility to interpret dark matter
as a relativistic inertial effect connected with relativistic metrology (i.e.
clock synchronization) in Einstein GR.Comment: 90 pages. Lecture at BOSS201
Synthesis of Cyclopropyl-Substituted Furans by Brønsted Acid Promoted Cascade Reactions
Synthesis of Cyclopropyl-Substituted Furans by Brønsted Acid Promoted Cascade Reactions
Genetic variants associated with longitudinal changes in brain structure across the lifespan
Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging
The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project
BACKGROUND: Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. METHODS: We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. RESULTS: Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia
Isothiourea-mediated one-pot synthesis of functionalized pyridines
This work was supported by the Royal Society, Syngenta/EPSRC, The Carnegie Trust for the Universities of Scotland and ERC.Publisher PDFPeer reviewe
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