Sequence analysis reveals extensive polymorphism and evidence of deletions within the E2 glycoprotein gene of several strains of murine hepatitis virus.

Direct RNA sequence analysis of the E2 gene of wild-type MHV-4 and of neutralization resistant, neuroattenuated variants has identified a polymorphic region with respect to deletions. These variants had large deletions of 142 to 159 amino acids mapping to a localized region in the amino-terminal domain of the peplomer glycoprotein. The nucleotide sequence of the E2 gene for wild-type strain MHV-4 was found to be very similar to that of MHV-JHM but had an insertion of 423 nucleotides resulting in the addition of a stretch of 141 unique amino acids in the amino-terminal domain of E2. We propose that deletions reflect a major source of heterogeneity in the E2 protein of MHV

Discrete elastic model for stretching-induced flagellar polymorphs

Force-induced reversible transformations between coiled and normal polymorphs of bacterial flagella have been observed in recent optical-tweezer experiment. We introduce a discrete elastic rod model with two competing helical states governed by a fluctuating spin-like variable that represents the underlying conformational states of flagellin monomers. Using hybrid Brownian dynamics Monte-Carlo simulations, we show that a helix undergoes shape transitions dominated by domain wall nucleation and motion in response to externally applied uniaxial tension. A scaling argument for the critical force is presented in good agreement with experimental and simulation results. Stretching rate-dependent elasticity including a buckling instability are found, also consistent with the experiment

Strategic polymorphism requires just two combinators!

In previous work, we introduced the notion of functional strategies: first-class generic functions that can traverse terms of any type while mixing uniform and type-specific behaviour. Functional strategies transpose the notion of term rewriting strategies (with coverage of traversal) to the functional programming paradigm. Meanwhile, a number of Haskell-based models and combinator suites were proposed to support generic programming with functional strategies. In the present paper, we provide a compact and matured reconstruction of functional strategies. We capture strategic polymorphism by just two primitive combinators. This is done without commitment to a specific functional language. We analyse the design space for implementational models of functional strategies. For completeness, we also provide an operational reference model for implementing functional strategies (in Haskell). We demonstrate the generality of our approach by reconstructing representative fragments of the Strafunski library for functional strategies.Comment: A preliminary version of this paper was presented at IFL 2002, and included in the informal preproceedings of the worksho

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT

The Sketch of a Polymorphic Symphony

In previous work, we have introduced functional strategies, that is, first-class generic functions that can traverse into terms of any type while mixing uniform and type-specific behaviour. In the present paper, we give a detailed description of one particular Haskell-based model of functional strategies. This model is characterised as follows. Firstly, we employ first-class polymorphism as a form of second-order polymorphism as for the mere types of functional strategies. Secondly, we use an encoding scheme of run-time type case for mixing uniform and type-specific behaviour. Thirdly, we base all traversal on a fundamental combinator for folding over constructor applications. Using this model, we capture common strategic traversal schemes in a highly parameterised style. We study two original forms of parameterisation. Firstly, we design parameters for the specific control-flow, data-flow and traversal characteristics of more concrete traversal schemes. Secondly, we use overloading to postpone commitment to a specific type scheme of traversal. The resulting portfolio of traversal schemes can be regarded as a challenging benchmark for setups for typed generic programming. The way we develop the model and the suite of traversal schemes, it becomes clear that parameterised + typed strategic programming is best viewed as a potent combination of certain bits of parametric, intensional, polytypic, and ad-hoc polymorphism

Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins

Major histocompatibility complex class I molecules (MHC I) present peptides to cytotoxic T-cells at the surface of almost all nucleated cells. The function of MHC I molecules is to select high affinity peptides from a large intracellular pool and they are assisted in this process by co-factor molecules, notably tapasin. In contrast to mammals, MHC homozygous chickens express a single MHC I gene locus, termed BF2, which is hypothesised to have co-evolved with the highly polymorphic tapasin within stable haplotypes. The BF2 molecules of the B15 and B19 haplotypes have recently been shown to differ in their interactions with tapasin and in their peptide selection properties. This study investigated whether these observations might be explained by differences in the protein plasticity that is encoded into the MHC I structure by primary sequence polymorphisms. Furthermore, we aimed to demonstrate the utility of a complimentary modelling approach to the understanding of complex experimental data. Combining mechanistic molecular dynamics simulations and the primary sequence based technique of statistical coupling analysis, we show how two of the eight polymorphisms between BF2*15:01 and BF2*19:01 facilitate differences in plasticity. We show that BF2*15:01 is intrinsically more plastic than BF2*19:01, exploring more conformations in the absence of peptide. We identify a protein sector of contiguous residues connecting the membrane bound ?3 domain and the heavy chain peptide binding site. This sector contains two of the eight polymorphic residues. One is residue 22 in the peptide binding domain and the other 220 is in the ?3 domain, a putative tapasin binding site. These observations are in correspondence with the experimentally observed functional differences of these molecules and suggest a mechanism for how modulation of MHC I plasticity by tapasin catalyses peptide selection allosterically

The TLR4 D299G and T399I SNPs Are Constitutively Active to Up-Regulate Expression of Trif-Dependent Genes

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