129,269 research outputs found
p22phox C242T Single-Nucleotide Polymorphism Inhibits Inflammatory Oxidative Damage to Endothelial Cells and Vessels.
BACKGROUND: The NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism, C242T of the p22(phox) subunit of NADPH oxidase, has been reported to be negatively associated with coronary heart disease and may predict disease prevalence. However, the underlying mechanisms remain unknown. METHODS AND RESULTS: With the use of computer molecular modeling, we discovered that C242T single-nucleotide polymorphism causes significant structural changes in the extracellular loop of p22(phox) and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22(phox) significantly reduced Nox2 expression but had no significant effect on basal endothelial O2 (.-) production or the expression of Nox1 and Nox4. When cells were stimulated with tumor necrosis factor-α (or high glucose), C242T p22(phox) significantly inhibited tumor necrosis factor-α-induced Nox2 maturation, O2 (.-) production, mitogen-activated protein kinases and nuclear factor κB activation, and inflammation (all P<0.05). These C242T effects were further confirmed using p22(phox) short-hairpin RNA-engineered HeLa cells and Nox2(-/-) coronary microvascular endothelial cells. Clinical significance was investigated by using saphenous vein segments from non-coronary heart disease subjects after phlebotomies. TT (C242T) allele was common (prevalence of ≈22%) and, in comparison with CC, veins bearing TT allele had significantly lower levels of Nox2 expression and O2 (.-) generation in response to high-glucose challenge. CONCLUSIONS: C242T single-nucleotide polymorphism causes p22(phox) structural changes that inhibit endothelial Nox2 activation and oxidative response to tumor necrosis factor-α or high-glucose stimulation. C242T single-nucleotide polymorphism may represent a natural protective mechanism against inflammatory cardiovascular diseases
Structural Subtyping as Parametric Polymorphism
Structural subtyping and parametric polymorphism provide similar flexibility
and reusability to programmers. For example, both features enable the
programmer to provide a wider record as an argument to a function that expects
a narrower one. However, the means by which they do so differs substantially,
and the precise details of the relationship between them exists, at best, as
folklore in literature.
In this paper, we systematically study the relative expressive power of
structural subtyping and parametric polymorphism. We focus our investigation on
establishing the extent to which parametric polymorphism, in the form of row
and presence polymorphism, can encode structural subtyping for variant and
record types. We base our study on various Church-style -calculi
extended with records and variants, different forms of structural subtyping,
and row and presence polymorphism.
We characterise expressiveness by exhibiting compositional translations
between calculi. For each translation we prove a type preservation and
operational correspondence result. We also prove a number of non-existence
results. By imposing restrictions on both source and target types, we reveal
further subtleties in the expressiveness landscape, the restrictions enabling
otherwise impossible translations to be defined. More specifically, we prove
that full subtyping cannot be encoded via polymorphism, but we show that
several restricted forms of subtyping can be encoded via particular forms of
polymorphism.Comment: 47 pages, accepted by OOPSLA 202
High-Pressure High-Temperature Exploration of Phase Boundaries Using Raman Spectroscopy
Metastability of states can provide interesting properties that may not be readily accessible in a material’s ground state. Many materials show high levels of polymorphism, indicating a rich energy landscape and a potential for metastable states. Melt crystallization techniques provide a potential route to these states. We use a resistively heated diamond anvil cell (DAC) with fine control of a system’s pressure and temperature to explore these systems. Raman spectroscopy is used to track subtle structural changes across phase boundaries. Organic systems, such as glycine and aspirin, were our initial interest due to their high polymorphism and reported low melting temperatures; however, complications with these systems ultimately showed that they are not ideal candidates for this technique. Metallic systems with allowed Raman modes are better samples for this method. We successfully map the phase stability of β-tin under high pressure and temperature conditions using Raman spectroscopy
From isomorphism to polymorphism: connecting interzeolite transformations to structural and graph similarity
Zeolites are nanoporous crystalline materials with abundant industrial
applications. Despite sustained research, only 235 different zeolite frameworks
have been realized out of millions of hypothetical ones predicted by
computational enumeration. Structure-property relationships in zeolite
synthesis are very complex and only marginally understood. Here, we apply
structure and graph-based unsupervised machine learning to gain insight on
zeolite frameworks and how they relate to experimentally observed polymorphism
and phase transformations. We begin by describing zeolite structures using the
Smooth Overlap of Atomic Positions method, which clusters crystals with similar
cages and density in a way consistent with traditional hand-selected composite
building units. To also account for topological differences, zeolite crystals
are represented as multigraphs and compared by isomorphism tests. We find that
fourteen different pairs and one trio of known frameworks are graph isomorphic.
Based on experimental interzeolite conversions and occurrence of competing
phases, we propose that the availability of kinetic-controlled transformations
between metastable zeolite frameworks is related to their similarity in the
graph space. When this description is applied to enumerated structures, over
3,400 hypothetical structures are found to be isomorphic to known frameworks,
and thus might be realized from their experimental counterparts. Using a
continuous similarity metric, the space of known zeolites shows additional
overlaps with experimentally observed phase transformations. Hence, graph-based
similarity approaches suggest a venue for realizing novel zeolites from
existing ones by providing a relationship between pairwise structure similarity
and experimental transformations.Comment: 11 pages, 6 figure
Structural Polymorphism of the Cytoskeleton: A Model of Linker-Assisted Filament Aggregation
The phase behavior of charged rods in the presence of inter-rod linkers is
studied theoretically as a model for the equilibrium behavior underlying the
organization of actin filaments by linker proteins in the cytoskeleton. The
presence of linkers in the solution modifies the effective inter-rod
interaction and can lead to inter-filament attraction. Depending on the
system's composition and physical properties such as linker binding energies,
filaments will either orient perpendicular or parallel to each other, leading
to network-like or bundled structures. We show that such a system can have one
of three generic phase diagrams, one dominated by bundles, another by networks,
and the third containing both bundle and network-like phases. The first two
diagrams can be found over a wide range of interaction energies, while the
third occurs only for a narrow range. These results provide theoretical
understanding of the classification of linker proteins as bundling proteins or
crosslinking proteins. In addition, they suggest possible mechanisms by which
the cell may control cytoskeletal morphology.Comment: 17 pages, 3 figure
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