Structure-preserving Functions Research Articles

Modulation of Titin-Based Stiffness in Hypertrophic Cardiomyopathy via Protein Kinase D

The giant protein titin performs structure-preserving functions in the sarcomere and is important for the passive stiffness (Fpassive) of cardiomyocytes. Protein kinase D (PKD) enzymes play crucial roles in regulating myocardial contraction, hypertrophy, and remodeling. PKD phosphorylates myofilament proteins, but it is not known whether the giant protein titin is also a PKD substrate. Here, we aimed to determine whether PKD phosphorylates titin and thereby modulates cardiomyocyte Fpassive in normal and failing myocardium. The phosphorylation of titin was assessed in cardiomyocyte-specific PKD knock-out mice (cKO) and human hearts using immunoblotting with a phosphoserine/threonine and a phosphosite-specific titin antibody. PKD-dependent site-specific titin phosphorylation in vivo was quantified by mass spectrometry using stable isotope labeling by amino acids in cell culture (SILAC) of SILAC-labeled mouse heart protein lysates that were mixed with lysates isolated from hearts of either wild-type control (WT) or cKO mice. Fpassive of single permeabilized cardiomyocytes was recorded before and after PKD and HSP27 administration. All-titin phosphorylation was reduced in cKO compared to WT hearts. Multiple conserved PKD-dependent phosphosites were identified within the Z-disk, A-band and M-band regions of titin by quantitative mass spectrometry, and many PKD-dependent phosphosites detected in the elastic titin I-band region were significantly decreased in cKO. Analysis of titin site-specific phosphorylation showed unaltered or upregulated phosphorylation in cKO compared to matched WT hearts. Fpassive was elevated in cKO compared to WT cardiomyocytes and PKD administration lowered Fpassive of WT and cKO cardiomyocytes. Cardiomyocytes from hypertrophic cardiomyopathy (HCM) patients showed higher Fpassive compared to control hearts and significantly lower Fpassive after PKD treatment. In addition, we found higher phosphorylation at CaMKII-dependent titin sites in HCM compared to control hearts. Expression and phosphorylation of HSP27, a substrate of PKD, were elevated in HCM hearts, which was associated with increased PKD expression and phosphorylation. The relocalization of HSP27 in HCM away from the sarcomeric Z-disk and I-band suggested that HSP27 failed to exert its protective action on titin extensibility. This protection could, however, be restored by administration of HSP27, which significantly reduced Fpassive in HCM cardiomyocytes. These findings establish a previously unknown role for PKDin regulating diastolic passive properties of healthy and diseased hearts.

Specifying concurrent programs in separation logic: morphisms and simulations

In addition to pre- and postconditions, program specifications in recent separation logics for concurrency have employed an algebraic structure of resources —a form of state transition systems—to describe the state-based program invariants that must be preserved, and to record the permissible atomic changes to program state. In this paper we introduce a novel notion of resource morphism , i.e. structure-preserving function on resources, and show how to effectively integrate it into separation logic, using an associated notion of morphism-specific simulation . We apply morphisms and simulations to programs verified under one resource, to compositionally adapt them to operate under another resource, thus facilitating proof reuse.

From Ancient to Modern Computing: A History of Information Hiding

This article proposes a methodological approach to the historiography of computing in terms of information hiding--that is, the introduction of levels of abstraction (LoAs) between the human being and the computing machine. This approach applies the LoAs, in terms of the epistemological levelism proposed within the philosophy of information, to the transition from ancient to modern computing. In particular, the black-box metaphor and von Neumann's architectures are discussed. Also, the authors propose a formal LoAs method as a mathematical counterpart. Information itself is then treated as structure-preserving functions so that a LoA can distinguish what kind of information gets hidden when human beings interact with computing machines.

The Minimal Levels of Abstraction in the History of Modern Computing

From the advent of general purpose, Turing-complete machines, the relation between operators, programmers and users with computers can be observed as interconnected informational organisms (inforgs), henceforth analysed with the method of levels of abstraction (LoAs), risen within the philosophy of information (PI). In this paper, the epistemological levellism proposed by L. Floridi in the PI to deal with LoAs will be formalised in constructive terms using category theory, so that information itself is treated as structure-preserving functions instead of Cartesian products. The milestones in the history of modern computing are then analysed through constructive levellism to show how the growth of system complexity lead to more and more information hiding.

An Aspectual Analysis of BA

The ba construction has been widely discussed in theliterature; however, so far no analysis provides a satisfactoryaccount for all of the distributional properties of ba. Thispaper considers the ba construction from an aspectual point ofview. I argue that the ba predicate describes a bounded event.Whether an event is bounded in Chinese may depend on situationtype only, or it may depend on both situation type and the aspecta situation is presented in. As for the ba NP, it is specific inthe sense of Liu (1990). I further argue that the two properties-- boundedness and specificity -- are related. There is adependency between the ba argument denotations and the eventdescribed by the predicate, and this dependency can becharacterized in terms of a structure-preserving function -- ahomomorphism. The relation preserved is the 'all of' relation. Onthis view boundedness and specificity are simply differentmanifestations of the same property that is inherent in themeaning of a ba predicate. The ba construction is thus shown tobe an example of how aspectual considerations constrain both thepredicate and an NP argument in Chinese.