Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization

Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation

A bivalent live-attenuated influenza vaccine for the control and prevention of H3N8 and H3N2 canine influenza viruses

Canine influenza viruses (CIVs) cause a contagious respiratory disease in dogs. CIV subtypes include H3N8, which originated from the transfer of H3N8 equine influenza virus (EIV) to dogs; and the H3N2, which is an avian-origin virus adapted to infect dogs. Only inactivated influenza vaccines (IIVs) are currently available against the different CIV subtypes. However, the efficacy of these CIV IIVs is not optimal and improved vaccines are necessary for the efficient prevention of disease caused by CIVs in dogs. Since live-attenuated influenza vaccines (LAIVs) induce better immunogenicity and protection efficacy than IIVs, we have combined our previously described H3N8 and H3N2 CIV LAIVs to create a bivalent vaccine against both CIV subtypes. Our findings show that, in a mouse model of infection, the bivalent CIV LAIV is safe and able to induce, upon a single intranasal immunization, better protection than that induced by a bivalent CIV IIV against subsequent challenge with H3N8 or H3N2 CIVs. These protection results also correlated with the ability of the bivalent CIV LAIV to induce better humoral immune responses. This is the first description of a bivalent LAIV for the control and prevention of H3N8 and H3N2 CIV infections in dogs

High modulus invert analog glass compositions containing beryllia

Glass compositions having a Young's modulus of at least 15 million psi and a specific modulus of at least 110 million inches consisting essentially of, in mols, 10-45% SiO2, 2-15% Li2O, 3-34% BeO, 12-36% of at least one bivalent oxide selected from the group consisting of CaO, ZnO, MgO and CuO, 10-39% of at least one trivalent oxide selected from the group consisting of Al2O3, B2O3, La2O3, Y2O3 and the mixed rare earth oxides, the total number of said bivalent and trivalent oxides being at least three, and up to 10% of a tetravalent oxide selected from the group consisting of ZrO2, TiO2 and CeO2

Certified Universal Gathering in R2R^2 for Oblivious Mobile Robots

We present a unified formal framework for expressing mobile robots models, protocols, and proofs, and devise a protocol design/proof methodology dedicated to mobile robots that takes advantage of this formal framework. As a case study, we present the first formally certified protocol for oblivious mobile robots evolving in a two-dimensional Euclidean space. In more details, we provide a new algorithm for the problem of universal gathering mobile oblivious robots (that is, starting from any initial configuration that is not bivalent, using any number of robots, the robots reach in a finite number of steps the same position, not known beforehand) without relying on a common orientation nor chirality. We give very strong guaranties on the correctness of our algorithm by proving formally that it is correct, using the COQ proof assistant. This result demonstrates both the effectiveness of the approach to obtain new algorithms that use as few assumptions as necessary, and its manageability since the amount of developed code remains human readable.Comment: arXiv admin note: substantial text overlap with arXiv:1506.0160

Extended ergativity in Bumthang

This paper addresses ergativity in Bumthang. In 2016, Donohue & Donohue reported on the variable use of the ergative case marker in Bumthang transitive clauses. They identified a number of largely pragmatic, semantic, and informational structural contexts that license the use of the ergative case on the subjects. Given the nature of the factors involved we examined similar conditions for arguments of monovalent verbs, not a typical context for receiving ergative case if structural conditions were uniquely determining case, but which would likely also be sensitive to these same factors. We find that there are some contexts in which the sole argument of an monovalent verb can bear ergative case, drawing on some of the same features, but not identical to those relevant for transitive verbs. In particular, the notion of agentivity is of paramount importance for licensing ergative case arguments of monovalent verbs, and we discuss the set of factors that need to coincide for this to happen

Asymmetric switch costs in numeral naming and number word reading: Implications for models of bilingual language production

One approach used to gain insight into the processes underlying bilingual language comprehension and production examines the costs that arise from switching languages. For unbalanced bilinguals, asymmetric switch costs are reported in speech production, where the switch cost for Ll is larger than the switch cost for L2, whereas, symmetric switch costs are reported in language comprehension tasks, where the cost of switching is the same for L1 and L2. Presently, it is unclear why asymmetric switch costs are observed in speech production, but not in language comprehension. Three experiments are reported that simultaneously examine methodological explanations of task related differences in the switch cost asymmetry and the predictions of three accounts of the switch cost asymmetry in speech production. The results of these experiments suggest that (1) the type of language task (comprehension vs. production) determines whether an asymmetric switch cost is observed and (2) at least some of the switch cost asymmetry arises within the language system

Preparation of heterocyclic block copolymer from perfluoroalkylene oxide alpha, omega-diamidoximes

Diamidoxime monomers are intermolecularly and thermally condensed to form a heat and chemical resistant polymer containing 1,2,4-oxadiazole linkages with identical bivalent organic radicals or any combination of bivalent organic radicals selected from the group consisting of -(CX(sub 2))p-, wherein P ranges from 2 to 8 when X is fluorine and 2 to 18 when X is hydrogen, chlorine, nitro or aryl; arylene; and an oligometric or polymeric radical prepared by reacting a dicarboxylic acid halide with a fluorinated epoxide and having the formula: (CFY(OCF(sub 2)CFY)sub m)O(CX(sub 2))(sub p)O(CFYCF(sub 2)O)(sub n)CFY wherein Y is flourine or tryifluoromethyl, X is nitro, aryl, hydrogen, chlorine or fluorine, preferably the latter, p ranges from 1 to 18 and m+n ranges from 2 to 7

A Complexity-Based Hierarchy for Multiprocessor Synchronization

For many years, Herlihy's elegant computability based Consensus Hierarchy has been our best explanation of the relative power of various types of multiprocessor synchronization objects when used in deterministic algorithms. However, key to this hierarchy is treating synchronization instructions as distinct objects, an approach that is far from the real-world, where multiprocessor programs apply synchronization instructions to collections of arbitrary memory locations. We were surprised to realize that, when considering instructions applied to memory locations, the computability based hierarchy collapses. This leaves open the question of how to better capture the power of various synchronization instructions. In this paper, we provide an approach to answering this question. We present a hierarchy of synchronization instructions, classified by their space complexity in solving obstruction-free consensus. Our hierarchy provides a classification of combinations of known instructions that seems to fit with our intuition of how useful some are in practice, while questioning the effectiveness of others. We prove an essentially tight characterization of the power of buffered read and write instructions.Interestingly, we show a similar result for multi-location atomic assignments