Noninfectious retrovirus particles drive the APOBEC3/Rfv3 dependent neutralizing antibody response.

Members of the APOBEC3 family of deoxycytidine deaminases counteract a broad range of retroviruses in vitro through an indirect mechanism that requires virion incorporation and inhibition of reverse transcription and/or hypermutation of minus strand transcripts in the next target cell. The selective advantage to the host of this indirect restriction mechanism remains unclear, but valuable insights may be gained by studying APOBEC3 function in vivo. Apobec3 was previously shown to encode Rfv3, a classical resistance gene that controls the recovery of mice from pathogenic Friend retrovirus (FV) infection by promoting a more potent neutralizing antibody (NAb) response. The underlying mechanism does not involve a direct effect of Apobec3 on B cell function. Here we show that while Apobec3 decreased titers of infectious virus during acute FV infection, plasma viral RNA loads were maintained, indicating substantial release of noninfectious particles in vivo. The lack of plasma virion infectivity was associated with a significant post-entry block during early reverse transcription rather than G-to-A hypermutation. The Apobec3-dependent NAb response correlated with IgG binding titers against native, but not detergent-lysed virions. These findings indicate that innate Apobec3 restriction promotes NAb responses by maintaining high concentrations of virions with native B cell epitopes, but in the context of low virion infectivity. Finally, Apobec3 restriction was found to be saturable in vivo, since increasing FV inoculum doses resulted in decreased Apobec3 inhibition. By analogy, maximizing the release of noninfectious particles by modulating APOBEC3 expression may improve humoral immunity against pathogenic human retroviral infections

The effects of dyad reading and text difficulty on third-graders’ reading achievement

This study replicated, with modifications, previous research of dyad reading using texts at various levels of difficulty (Morgan, 1997). The current project measured the effects of using above–grade-level texts on reading achievement and sought to determine the influences of dyad reading on both lead and assisted readers. Results indicate that weaker readers, using texts at two, three, and four grade levels above their instructional levels with the assistance of lead readers, outscored both proficient and less proficient students in the control group across multiple measures of reading achievement. However, the gains made by assisted readers were not significantly different relative to the various text levels. When all assessments were considered, assisted readers reading texts two grade levels above their instructional levels showed the most robust gains in oral reading fluency and comprehension. Lead readers also benefited from dyad reading and continued their respective reading developmental trajectories across measures

A Single Nucleotide Polymorphism in Tetherin Promotes Retrovirus Restriction In Vivo

Tetherin is a membrane protein of unusual topology expressed from rodents to humans that accumulates enveloped virus particles on the surface of infected cells. However, whether this ‘tethering’ activity promotes or restricts retroviral spread during acute retrovirus infection in vivo is controversial. We report here the identification of a single nucleotide polymorphism in the Tetherin gene of NZW/LacJ (NZW) mice that mutated the canonical ATG start site to GTG. Translation of NZW Tetherin from downstream ATGs deleted a conserved dual-tyrosine endosomal sorting motif, resulting in higher cell surface expression and more potent inhibition of Friend retrovirus release compared to C57BL/6 (B6) Tetherin in vitro. Analysis of (B6×NZW)F1 hybrid mice revealed that increased Tetherin cell surface expression in NZW mice is a recessive trait in vivo. Using a classical genetic backcrossing approach, NZW Tetherin expression strongly correlated with decreased Friend retrovirus replication and pathogenesis. However, the protective effect of NZW Tetherin was not observed in the context of B6 Apobec3/Rfv3 resistance. These findings identify the first functional Tetherin polymorphism within a mammalian host, demonstrate that Tetherin cell surface expression is a key parameter for retroviral restriction, and suggest the existence of a restriction factor hierarchy to counteract pathogenic retrovirus infections in vivo

Shape-based peak identification for ChIP-Seq

We present a new algorithm for the identification of bound regions from ChIP-seq experiments. Our method for identifying statistically significant peaks from read coverage is inspired by the notion of persistence in topological data analysis and provides a non-parametric approach that is robust to noise in experiments. Specifically, our method reduces the peak calling problem to the study of tree-based statistics derived from the data. We demonstrate the accuracy of our method on existing datasets, and we show that it can discover previously missed regions and can more clearly discriminate between multiple binding events. The software T-PIC (Tree shape Peak Identification for ChIP-Seq) is available at http://math.berkeley.edu/~vhower/tpic.htmlComment: 12 pages, 6 figure

The dynamics of quantum phases in a spinor condensate

We discuss the quantum phases and their diffusion dynamics in a spinor-1 atomic Bose-Einstein condensate. For ferromagnetic interactions, we obtain the exact ground state distribution of the phases associated with the total atom number ($N$), the total magnetization (${\cal M}$), and the alignment (or hypercharge) ($Y$) of the system. The mean field ground state is stable against fluctuations of atom numbers in each of the spin components, and the phases associated with the order parameter for each spin components diffuse while dynamically recover the two broken continuous symmetries [U(1) and SO(2)] when $N$ and ${\cal M}$ are conserved as in current experiments. We discuss the implications to the quantum dynamics due to an external (homogeneous) magnetic field. We also comment on the case of a spinor-1 condensate with anti-ferromagnetic interactions.Comment: 5 figures, an extended version of cond-mat/030117

All Optical Formation of an Atomic Bose-Einstein Condensate

We have created a Bose-Einstein condensate of 87Rb atoms directly in an optical trap. We employ a quasi-electrostatic dipole force trap formed by two crossed CO_2 laser beams. Loading directly from a sub-doppler laser-cooled cloud of atoms results in initial phase space densities of ~1/200. Evaporatively cooling through the BEC transition is achieved by lowering the power in the trapping beams over ~ 2 s. The resulting condensates are F=1 spinors with 3.5 x 10^4 atoms distributed between the m_F = (-1,0,1) states.Comment: 4 pages, 4 figures, to appear in Phys. Rev. Let

On the single mode approximation in spinor-1 atomic condensate

We investigate the validity conditions of the single mode approximation (SMA) in spinor-1 atomic condensate when effects due to residual magnetic fields are negligible. For atomic interactions of the ferromagnetic type, the SMA is shown to be exact, with a mode function different from what is commonly used. However, the quantitative deviation is small under current experimental conditions (for $^{87}$Rb atoms). For anti-ferromagnetic interactions, we find that the SMA becomes invalid in general. The differences among the mean field mode functions for the three spin components are shown to depend strongly on the system magnetization. Our results can be important for studies of beyond mean field quantum correlations, such as fragmentation, spin squeezing, and multi-partite entanglement.Comment: Revised, newly found analytic proof adde

Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis

Human African trypanosomiasis (HAT), or sleeping sickness, results from infection with the protozoan parasites <i>Trypanosoma brucei</i> (<i>T.b.</i>) <i>gambiense</i> or <i>T.b.rhodesiense</i> and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS) to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal) is the only currently available treatment for CNS-stage <i>T.b.rhodesiense</i> infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-͎-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties <i>in vitro</i> and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy

Near Resonant Spatial Images of Confined Bose-Einstein Condensates in the '4D' Magnetic Bottle

We present quantitative measurements of the spatial density profile of Bose-Einstein condensates of sodium atoms confined in a new '4D' magnetic bottle. The condensates are imaged in transmission with near resonant laser light. We demonstrate that the Thomas-Fermi surface of a condensate can be determined to better than 1%. More generally, we obtain excellent agreement with mean-field theory. We conclude that precision measurements of atomic scattering lengths and interactions between phase separated cold atoms in a harmonic trap can be measured with high precision using this method.Comment: 15 pages, 3 figures. Submitted 10/30/97, accepted for publication in Phys. Rev. A Rapid Com

Metalevel algorithms for variant satisfiability

Variant satisfiability is a theory-generic algorithm to decide quantifier-free satisfiability in an initial algebra when its corresponding theory has the finite variant property and its constructors satisfy a compactness condition. This paper: (i) gives a precise definition of several meta-level sub-algorithms needed for variant satisfiability; (ii) proves them correct; and (iii) presents a reflective implementation in Maude 2.7 of variant satisfiability using these sub-algorithms.NSF CNS 13-19109Ope