Molecular Density Functional Theory for water with liquid-gas coexistence and correct pressure

The solvation of hydrophobic solutes in water is special because liquid and gas are almost at coexistence. In the common hypernetted chain approximation to integral equations, or equivalently in the homogenous reference fluid of molecular density functional theory, coexistence is not taken into account. Hydration structures and energies of nanometer-scale hydrophobic solutes are thus incorrect. In this article, we propose a bridge functional that corrects this thermodynamic inconsistency by introducing a metastable gas phase for the homogeneous solvent. We show how this can be done by a third order expansion of the functional around the bulk liquid density that imposes the right pressure and the correct second order derivatives. Although this theory is not limited to water, we apply it to study hydrophobic solvation in water at room temperature and pressure and compare the results to all-atom simulations. With this correction, molecular density functional theory gives, at a modest computational cost, quantitative hydration free energies and structures of small molecular solutes like n-alkanes, and of hard sphere solutes whose radii range from angstroms to nanometers. The macroscopic liquid-gas surface tension predicted by the theory is comparable to experiments. This theory gives an alternative to the empirical hard sphere bridge correction used so far by several authors.Comment: 18 pages, 6 figure

Molecular Density Functional Theory of Water describing Hydrophobicity at Short and Long Length Scales

We present an extension of our recently introduced molecular density functional theory of water [G. Jeanmairet et al., J. Phys. Chem. Lett. 4, 619, 2013] to the solvation of hydrophobic solutes of various sizes, going from angstroms to nanometers. The theory is based on the quadratic expansion of the excess free energy in terms of two classical density fields, the particle density and the multipolar polarization density. Its implementation requires as input a molecular model of water and three measurable bulk properties, namely the structure factor and the k-dependent longitudinal and transverse dielectric susceptibilities. The fine three-dimensional water structure around small hydrophobic molecules is found to be well reproduced. In contrast the computed solvation free-energies appear overestimated and do not exhibit the correct qualitative behavior when the hydrophobic solute is grown in size. These shortcomings are corrected, in the spirit of the Lum-Chandler-Weeks theory, by complementing the functional with a truncated hard-sphere functional acting beyond quadratic order in density. It makes the resulting functional compatible with the Van-der-Waals theory of liquid-vapor coexistence at long range. Compared to available molecular simulations, the approach yields reasonable solvation structure and free energy of hard or soft spheres of increasing size, with a correct qualitative transition from a volume-driven to a surface-driven regime at the nanometer scale.Comment: 24 pages, 8 figure

Rituximab therapy for refractory interstitial lung disease related to antisynthetase syndrome

SummaryObjectiveTo report our experience using rituximab as therapy for refractory antisynthetase syndrome (ASS)-associated interstitial lung disease.MethodsWe retrospectively evaluated the medical records of 7 ASS patients with refractory interstitial lung disease, which had previously failed to respond to prednisone and/or other cytotoxic drugs. All 7 patients received rituximab therapy, i.e.: 1 g at days 0 and 14 and at 6-month follow-up. Data on pulmonary symptoms, pulmonary function tests and high resolution computed tomography (HRCT) scan of the lungs were collected: 1) before rituximab initiation; and 2) at 6-month and one-year follow-up after the first infusion of rituximab.ResultsAt one-year follow-up, ASS patients had resolution (n = 2) or improvement of pulmonary clinical manifestations. Patients also exhibited significant improvement of interstitial lung disease parameters: 1) on pulmonary function tests: FVC (p = 0.03) and DLCO (p = 2 × 10−5); 2) and HRCT-scan of the lungs. Due to clinical resolution/improvement of interstitial lung disease, the median daily dose of oral prednisone could be reduced in these 7 ASS patients at one-year follow-up, compared with baseline (20 mg/day vs. 9 mg/day; p = 0.015).ConclusionOur findings suggest that rituximab may be a helpful therapy for refractory interstitial lung disease in patients with ASS

Generalized Heisenberg algebras and k-generalized Fibonacci numbers

It is shown how some of the recent results of de Souza et al. [1] can be generalized to describe Hamiltonians whose eigenvalues are given as k-generalized Fibonacci numbers. Here k is an arbitrary integer and the cases considered by de Souza et al. corespond to k=2.Comment: 8 page

Service Platform for Converged Interactive Broadband Broadcast and Cellular Wireless

A converged broadcast and telecommunication service platform is presented that is able to create, deliver, and manage interactive, multimedia content and services for consumption on three different terminal types. The motivations of service providers for designing converged interactive multimedia services, which are crafted for their individual requirements, are investigated. The overall design of the system is presented with particular emphasis placed on the operational features of each of the sub-systems, the flows of media and metadata through the sub-systems and the formats and protocols required for inter-communication between them. The key features of tools required for creating converged interactive multimedia content for a range of different end-user terminal types are examined. Finally possible enhancements to this system are discussed. This study is of particular interest to those organizations currently conducting trials and commercial launches of DVB-H services because it provides them with an insight of the various additional functions required in the service provisioning platforms to provide fully interactive services to a range of different mobile terminal types

In vivo E2F reporting reveals efficacious schedules of MEK1/2–CDK4/6 targeting and mTOR–s6 resistance mechanisms

Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance. SIGnIFICAnCE: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens

The High-Metallicity Explosion Environment of the Relativistic Supernova 2009bb

We investigate the environment of the nearby (d ~ 40Mpc) broad-lined Type Ic supernova SN 2009bb. This event was observed to produce a relativistic outflow likely powered by a central accreting compact object. While such a phenomenon was previously observed only in long-duration gamma-ray bursts (LGRBs), no LGRB was detected in association with SN 2009bb. Using an optical spectrum of the SN 2009bb explosion site, we determine a variety of ISM properties for the host environment, including metallicity, young stellar population age, and star formation rate. We compare the SN explosion site properties to observations of LGRB and broad-lined SN Ic host environments on optical emission line ratio diagnostic diagrams. Based on these analyses, we find that the SN 2009bb explosion site has a very high metallicity of ~2x solar, in agreement with other broad-lined SN Ic host environments and at odds with the low-redshift LGRB host environments and recently proposed maximum metallicity limits for relativistic explosions. We consider the implications of these findings and the impact that SN 2009bb's unusual explosive properties and environment have on our understanding of the key physical ingredient that enables some SNe to produce a relativistic outflow.Comment: 7 pages, 4 figures, 1 table; accepted for publication in ApJ Letters (replaced to include missing figure

Star formation in the early universe: beyond the tip of the iceberg

We present late-time Hubble Space Telescope imaging of the fields of six Swift GRBs lying at 5.0<z<9.5. Our data includes very deep observations of the field of the most distant spectroscopically confirmed burst, GRB 090423, at z=8.2. Using the precise positions afforded by their afterglows we can place stringent limits on the luminosities of their host galaxies. In one case, that of GRB 060522 at z=5.11, there is a marginal excess of flux close to the GRB position which may be a detection of a host at a magnitude J(AB)=28.5. None of the others are significantly detected meaning that all the hosts lie below L\star at their respective redshifts, with star formation rates SFR<4Mo/yr in all cases. Indeed, stacking the five fields with WFC3-IR data we conclude a mean SFR<0.17Mo/yr per galaxy. These results support the proposition that the bulk of star formation, and hence integrated UV luminosity, at high redshifts arises in galaxies below the detection limits of deep-field observations. Making the reasonable assumption that GRB rate is proportional to UV luminosity at early times allows us to compare our limits with expectations based on galaxy luminosity functions derived from the Hubble Ultra-Deep Field (HUDF) and other deep fields. We infer that a luminosity function which is evolving rapidly towards steeper faint-end slope (alpha) and decreasing characteristic luminosity (L\star), as suggested by some other studies, is consistent with our observations, whereas a non-evolving LF shape is ruled out at >90% confidence. Although it is not yet possible to make stronger statements, in the future, with larger samples and a fuller understanding of the conditions required for GRB production, studies like this hold great potential for probing the nature of star formation, the shape of the galaxy luminosity function, and the supply of ionizing photons in the early universe.Comment: ApJ in press. 14 pages, 6 figures. (small updates from version 1