Exploiting transient protein states for the design of small-molecule stabilizers of mutant p53

The destabilizing p53 cancer mutation Y220C creates an extended crevice on the surface of the protein that can be targeted by small-molecule stabilizers. Here, we identify different classes of small molecules that bind to this crevice and determine their binding modes by X-ray crystallography. These structures reveal two major conformational states of the pocket and a cryptic, transiently open hydrophobic subpocket that is modulated by Cys220. In one instance, specifically targeting this transient protein state by a pyrrole moiety resulted in a 40-fold increase in binding affinity. Molecular dynamics simulations showed that both open and closed states of this subsite were populated at comparable frequencies along the trajectories. Our data extend the framework for the design of high-affinity Y220C mutant binders for use in personalized anticancer therapy and, more generally, highlight the importance of implementing protein dynamics and hydration patterns in the drug-discovery process

Measurement of black carbon emissions from multiple engine and source types using laser-induced incandescence : sensitivity to laser fluence

A new regulatory standard for non-volatile particulate matter (nvPM) mass-based emissions from aircraft engines has been adopted by the International Civil Aviation Organisation. One of the instruments used for the regulatory nvPM mass emissions measurements in aircraft engine certification tests is the Artium Technologies LII 300, which is based on laser-induced incandescence. The LII 300 response has been shown in some cases to vary with the type of black carbon particle measured. Hence it is important to identify a suitable black carbon emission source for instrument calibration. In this study, the relationship between the nvPM emissions produced by different engine sources and the response of the LII 300 instrument utilising the auto-compensating laser-induced incandescence (AC-LII) method was investigated. Six different sources were used, including a turboshaft helicopter engine, a diesel generator, an intermediate pressure test rig of a single-sector combustor, an auxiliary power unit gas turbine engine, a medium-sized diesel engine, and a downsized turbocharged direct-injection gasoline engine. Optimum LII 300 laser fluence levels were determined for each source and operating condition evaluated. It was found that an optimised laser fluence can be valid for real-time measurements from a variety of sources, where the mass concentration was independent of laser fluence levels covering the typical operating ranges for the various sources. However, it is important to perform laser fluence sweeps to determine the optimum fluence range as differences were observed in the laser fluence required between sources and fuels. We discuss the measurement merits, variability, and best practices in the real-time quantification of nvPM mass concentration using the LII 300 instrument and compare that with other diagnostic techniques, namely absorption-based methods such as photoacoustic spectroscopy (using a photoacoustic extinctiometer, PAX, and a micro soot sensor, MSS) and thermal-optical analysis (TOA). Particle size distributions were also measured using a scanning mobility particle sizer (SMPS). Overall, the LII 300 provides robust and consistent results when compared with the other diagnostic techniques across multiple engine sources and fuels. The results from this study will inform the development of updated calibration protocols to ensure repeatable and reproducible measurements of nvPM mass emissions from aircraft engines using the LII 300

Dynamic Vortex Phases and Pinning in Superconductors with Twin Boundaries

We investigate the pinning and driven dynamics of vortices interacting with twin boundaries using large scale molecular dynamics simulations on samples with near one million pinning sites. For low applied driving forces, the vortex lattice orients itself parallel to the twin boundary and we observe the creation of a flux gradient and vortex free region near the edges of the twin boundary. For increasing drive, we find evidence for several distinct dynamical flow phases which we characterize by the density of defects in the vortex lattice, the microscopic vortex flow patterns, and orientation of the vortex lattice. We show that these different dynamical phases can be directly related to microscopically measurable voltage - current V(I) curves and voltage noise. By conducting a series of simulations for various twin boundary parameters we derive several vortex dynamic phase diagrams.Comment: 5 figures, to appear in Phys. Rev.

Population genomics of a predatory mammal reveals patterns of decline and impacts of exposure to toxic toads

Mammal declines across northern Australia are one of the major biodiversity loss events occurring globally. There has been no regional assessment of the implications of these species declines for genomic diversity. To address this, we conducted a species-wide assessment of genomic diversity in the northern quoll (Dasyurus hallucatus), an Endangered marsupial carnivore. We used next generation sequencing methods to genotype 10,191 single nucleotide polymorphisms (SNPs) in 352 individuals from across a 3220-km length of the continent, investigating patterns of population genomic structure and diversity, and identifying loci showing signals of putative selection. We found strong heterogeneity in the distribution of genomic diversity across the continent, characterized by (i) biogeographical barriers driving hierarchical population structure through long-term isolation, and (ii) severe reductions in diversity resulting from population declines, exacerbated by the spread of introduced toxic cane toads (Rhinella marina). These results warn of a large ongoing loss of genomic diversity and associated adaptive capacity as mammals decline across northern Australia. Encouragingly, populations of the northern quoll established on toad-free islands by translocations appear to have maintained most of the initial genomic diversity after 16 years. By mapping patterns of genomic diversity within and among populations, and investigating these patterns in the context of population declines, we can provide conservation managers with data critical to informed decision-making. This includes the identification of populations that are candidates for genetic management, the importance of remnant island and insurance/translocated populations for the conservation of genetic diversity, and the characterization of putative evolutionarily significant units

Measurement of the Mass Splittings between the bbˉχb,J(1P)b\bar{b}\chi_{b,J}(1P) States

We present new measurements of photon energies and branching fractions for the radiative transitions: Upsilon(2S)->gamma+chi_b(J=0,1,2). The masses of the chi_b states are determined from the measured radiative photon energies. The ratio of mass splittings between the chi_b substates, r==(M[J=2]-M[J=1])/(M[J=1]-M[J=0]) with M the chi_b mass, provides information on the nature of the bbbar confining potential. We find r(1P)=0.54+/-0.02+/-0.02. This value is in conflict with the previous world average, but more consistent with the theoretical expectation that r(1P)<r(2P); i.e., that this mass splittings ratio is smaller for the chi_b(1P) triplet than for the chi_b(2P) triplet.Comment: 11 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Radiative Decay Modes of the D0D^{0} Meson

Using data recorded by the CLEO-II detector at CESR we have searched for four radiative decay modes of the $D^0$ meson: $D^0\to\phi\gamma$, $D^0\to\omega\gamma$, $D^0\to\bar{K}^{*}\gamma$, and $D^0\to\rho^0\gamma$. We obtain 90% CL upper limits on the branching ratios of these modes of $1.9\times 10^{-4}$, $2.4\times 10^{-4}$, $7.6\times 10^{-4}$ and $2.4\times 10^{-4}$ respectively.Comment: 15 page postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio

Observation of a new chi_b state in radiative transitions to Upsilon(1S) and Upsilon(2S) at ATLAS

The chi_b(nP) quarkonium states are produced in proton-proton collisions at the Large Hadron Collider (LHC) at sqrt(s) = 7 TeV and recorded by the ATLAS detector. Using a data sample corresponding to an integrated luminosity of 4.4 fb^-1, these states are reconstructed through their radiative decays to Upsilon(1S,2S) with Upsilon->mu+mu-. In addition to the mass peaks corresponding to the decay modes chi_b(1P,2P)->Upsilon(1S)gamma, a new structure centered at a mass of 10.530+/-0.005 (stat.)+/-0.009 (syst.) GeV is also observed, in both the Upsilon(1S)gamma and Upsilon(2S)gamma decay modes. This is interpreted as the chi_b(3P) system.Comment: 5 pages plus author list (18 pages total), 2 figures, 1 table, corrected author list, matches final version in Physical Review Letter

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of the inclusive isolated prompt photon cross-section in pp collisions at sqrt(s)= 7 TeV using 35 pb-1 of ATLAS data

A measurement of the differential cross-section for the inclusive production of isolated prompt photons in pp collisions at a center-of-mass energy sqrt(s) = 7 TeV is presented. The measurement covers the pseudorapidity ranges |eta|<1.37 and 1.52<=|eta|<2.37 in the transverse energy range 45<=E_T<400GeV. The results are based on an integrated luminosity of 35 pb-1, collected with the ATLAS detector at the LHC. The yields of the signal photons are measured using a data-driven technique, based on the observed distribution of the hadronic energy in a narrow cone around the photon candidate and the photon selection criteria. The results are compared with next-to-leading order perturbative QCD calculations and found to be in good agreement over four orders of magnitude in cross-section.Comment: 7 pages plus author list (18 pages total), 2 figures, 4 tables, final version published in Physics Letters