Selection by AZT and Rapid Replacement in the Absence of Drugs of HIV Type 1 Resistant to Multiple Nucleoside Analogs

We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness

School Choice and Competition

The literature suggests that competition among schools might increase quality. However, not much empirical evidence is present as only a few countries allow competition at a large scale. One exception is the Netherlands. Free parental choice is the leading principle of the Dutch education system since the beginning of the 20th century. Based on panel data for the Netherlands we show that there is a relation between competition and student achievement in upper secondary education, but that it is negative. In addition, private schools have higher quality levels

A Modular Toolkit for Distributed Interactions

We discuss the design, architecture, and implementation of a toolkit which supports some theories for distributed interactions. The main design principles of our architecture are flexibility and modularity. Our main goal is to provide an easily extensible workbench to encompass current algorithms and incorporate future developments of the theories. With the help of some examples, we illustrate the main features of our toolkit.Comment: In Proceedings PLACES 2010, arXiv:1110.385

Electric field and exciton structure in CdSe nanocrystals

Quantum Stark effect in semiconductor nanocrystals is theoretically investigated, using the effective mass formalism within a $4\times 4$ Baldereschi-Lipari Hamiltonian model for the hole states. General expressions are reported for the hole eigenfunctions at zero electric field. Electron and hole single particle energies as functions of the electric field ($\mathbf{E}_{QD}$) are reported. Stark shift and binding energy of the excitonic levels are obtained by full diagonalization of the correlated electron-hole Hamiltonian in presence of the external field. Particularly, the structure of the lower excitonic states and their symmetry properties in CdSe nanocrystals are studied. It is found that the dependence of the exciton binding energy upon the applied field is strongly reduced for small quantum dot radius. Optical selection rules for absorption and luminescence are obtained. The electric-field induced quenching of the optical spectra as a function of $\mathbf{E}_{QD}$ is studied in terms of the exciton dipole matrix element. It is predicted that photoluminescence spectra present anomalous field dependence of the emission lines. These results agree in magnitude with experimental observation and with the main features of photoluminescence experiments in nanostructures.Comment: 9 pages, 7 figures, 1 tabl

Interplay of Mott Transition and Ferromagnetism in the Orbitally Degenerate Hubbard Model

A slave boson representation for the degenerate Hubbard model is introduced. The location of the metal to insulator transition that occurs at commensurate densities is shown to depend weakly on the band degeneracy M. The relative weights of the Hubbard sub-bands depend strongly on M, as well as the magnetic properties. It is also shown that a sizable Hund's rule coupling is required in order to have a ferromagnetic instability appearing. The metal to insulator transition driven by an increase in temperature is a strong function of it.Comment: 5 pages, revtex, 5 postscript figures, submitted to Phys. Rev.

Proteomic analysis of FOXP proteins reveals interactions between cortical transcription factors associated with neurodevelopmental disorders

FOXP transcription factors play important roles in neurodevelopment, but little is known about how their transcriptional activity is regulated. FOXP proteins cooperatively regulate gene expression by forming homo- and hetero-dimers with each other. Physical as

Summer CO2 evasion from streams and rivers in the Kolyma River basin, north-east Siberia

Inland water systems are generally supersaturated in carbon dioxide (CO2) and are increasingly recognized as playing an important role in the global carbon cycle. The Arctic may be particularly important in this respect, given the abundance of inland waters and carbon contained in Arctic soils; however, a lack of trace gas measurements from small streams in the Arctic currently limits this understanding.We investigated the spatial variability of CO2 evasion during the summer low-flow period from streams and rivers in the northern portion of the Kolyma River basin in north-eastern Siberia. To this end, partial pressure of carbon dioxide (pCO2) and gas exchange velocities (k) were measured at a diverse set of streams and rivers to calculate CO2 evasion fluxes. We combined these CO2 evasion estimates with satellite remote sensing and geographic information system techniques to calculate total areal CO2 emissions. Our results show that small streams are substantial sources of atmospheric CO2 owing to high pCO2 and k, despite being a small portion of total inland water surface area. In contrast, large rivers were generally near equilibrium with atmospheric CO2. Extrapolating our findings across the Panteleikha-Ambolikha sub-watersheds demonstrated that small streams play a major role in CO2 evasion, accounting for 86% of the total summer CO2 emissions from inland waters within these two sub-watersheds. Further expansion of these regional CO2 emission estimates across time and space will be critical to accurately quantify and understand the role of Arctic streams and rivers in the global carbon budget

The formation of planetary disks and winds: an ultraviolet view

Planetary systems are angular momentum reservoirs generated during star formation. This accretion process produces very powerful engines able to drive the optical jets and the molecular outflows. A fraction of the engine energy is released into heating thus the temperature of the engine ranges from the 3000K of the inner disk material to the 10MK in the areas where magnetic reconnection occurs. There are important unsolved problems concerning the nature of the engine, its evolution and the impact of the engine in the chemical evolution of the inner disk. Of special relevance is the understanding of the shear layer between the stellar photosphere and the disk; this layer controls a significant fraction of the magnetic field building up and the subsequent dissipative processes ougth to be studied in the UV. This contribution focus on describing the connections between 1 Myr old suns and the Sun and the requirements for new UV instrumentation to address their evolution during this period. Two types of observations are shown to be needed: monitoring programmes and high resolution imaging down to, at least, milliarsecond scales.Comment: Accepted for publication in Astrophysics and Space Science 9 figure

Local fluctuations in quantum critical metals

We show that spatially local, yet low-energy, fluctuations can play an essential role in the physics of strongly correlated electron systems tuned to a quantum critical point. A detailed microscopic analysis of the Kondo lattice model is carried out within an extended dynamical mean-field approach. The correlation functions for the lattice model are calculated through a self-consistent Bose-Fermi Kondo problem, in which a local moment is coupled both to a fermionic bath and to a bosonic bath (a fluctuating magnetic field). A renormalization-group treatment of this impurity problem--perturbative in $\epsilon=1-\gamma$, where $\gamma$ is an exponent characterizing the spectrum of the bosonic bath--shows that competition between the two couplings can drive the local-moment fluctuations critical. As a result, two distinct types of quantum critical point emerge in the Kondo lattice, one being of the usual spin-density-wave type, the other ``locally critical.'' Near the locally critical point, the dynamical spin susceptibility exhibits $\omega/T$ scaling with a fractional exponent. While the spin-density-wave critical point is Gaussian, the locally critical point is an interacting fixed point at which long-wavelength and spatially local critical modes coexist. A Ginzburg-Landau description for the locally critical point is discussed. It is argued that these results are robust, that local criticality provides a natural description of the quantum critical behavior seen in a number of heavy-fermion metals, and that this picture may also be relevant to other strongly correlated metals.Comment: 20 pages, 12 figures; typos in figure 3 and in the main text corrected, version as publishe

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors