Duality between decomposition and gluing: a theoretical biology via adjoint functors

Two ideas in theoretical biology, ‘decomposition into functions’ and ‘gluing functions’, are formalized as endofunctors on the category of directed graphs. We prove that they constitute an adjunction. The invariant structures of the adjunction are obtained. They imply two biologically significant conditions: the existence of cycles in finite graphs and anticipatory diagrams.     

Synthesis and structure-activity relationship of novel RXR antagonists: orally active anti-diabetic and anti-obesity agents

A series of diazepinylbenzoic acid derivatives were synthesized and tested in the inhibition assay of the transactivation of RXR. Oral treatment of cyano derivatives (16f) was found to show anti-diabetic and anti-obesity effects in KK-A(y) mice.     

Synthesis and structure-activity relationship of RXR antagonists based on the diazepinylbenzoic acid structure

Synthesis and structure-activity relationship of RXR antagonists employing a diazepinylbenzoic acid scaffold are described. Of those antagonists, sulfonamide derivatives (6v and 6w) reveal a high antagonistic activity and good pharmacokinetic properties.     

Novel scaffold for cathepsin K inhibitors

Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11-20.     

Fluctuation-driven flocking movement in three dimensions and scale-free correlation

Recent advances in the study of flocking behavior have permitted more sophisticated analyses than previously possible. The concepts of "topological distances" and "scale-free correlations" are important developments that have contributed to this improvement. These concepts require us to reconsider the notion of a neighborhood when applied to theoretical models. Previous work has assumed that individuals interact with neighbors within a certain radius (called the "metric distance"). However, other work has shown that, assuming topological interactions, starlings interact on average with the six or seven nearest neighbors within a flock. Accounting for this observation, we previously proposed a metric-topological interaction model in two dimensions. The goal of our model was to unite these two interaction components, the metric distance and the topological distance, into one rule. In our previous study, we demonstrated that the metric-topological interaction model could explain a real bird flocking phenomenon called scale-free correlation, which was first reported by Cavagna et al. In this study, we extended our model to three dimensions while also accounting for variations in speed. This three-dimensional metric-topological interaction model displayed scale-free correlation for velocity and orientation. Finally, we introduced an additional new feature of the model, namely, that a flock can store and release its fluctuations.     

Abstract heterarchy: time/state-scale re-entrant form

A heterarchy is a dynamical hierarchical system inheriting logical inconsistencies between levels. Because of these inconsistencies, it is very difficult to formalize a heterarchy as a dynamical system. Here, the essence of a heterarchy is proposed as a pair of the property of self-reference and the property of a frame problem interacting with each other. The coupling of them embodies a one-ity inheriting logical inconsistency. The property of self-reference and a frame problem are defined in terms of logical operations, and are replaced by two kinds of dynamical system, temporal dynamics and state-scale dynamics derived from the same "liar statement". A modified tent map serving as the temporal dynamics is twisted and coupled with a tent map serving as the state-scale dynamics, and this results in a discontinuous self-similar map as a dynamical system. This reveals that the state-scale and temporal dynamics attribute to the system, and shows both robust and emergent behaviors.     

Heterarchy in biological systems: a logic-based dynamical model of abstract biological network derived from time-state-scale re-entrant form

Heterarchical structure is important for understanding robustness and evolvability in a wide variety of levels of biological systems. Although many studies emphasize the heterarchical nature of biological systems, only a few computational representations of heterarchy have been created thus far. We propose here the time-state-scale re-entrant form to address the self-referential property derived from setting heterarchical structure. In this paper, we apply the time-state-scale re-entrant form to abstract self-referential modeling for a functional manifestation of biological network presented by [Tsuda, I., Tadaki, K., 1997. A logic-based dynamical theory for a genesis of biological threshold. BioSystems 42, 45-64]. The numerical results of this system show different intermittent phase transitions and power-law distribution of time spent in activating functional manifestation. The Hierarchically separated time-scales obtained from spectrum analysis imply that the reactions at different levels simultaneously appear in a dynamical system. The results verify the mutual inter-relationship between heterarchical structure in biological systems and the self-referential property of computational heterarchical systems.     

Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.     

Bmx Tyrosine Kinase Has a Redundant Function Downstream of Angiopoietin and Vascular Endothelial Growth Factor Receptors in Arterial Endothelium

The Bmx gene, a member of the Tec tyrosine kinase gene family, is known to be expressed in subsets of hematopoietic and endothelial cells. In this study, mice were generated in which the first coding exon of the Bmx gene was replaced with the lacZ reporter gene by a knock-in strategy. The homozygous mice lacking Bmx activity were fertile and had a normal life span without an obvious phenotype. Staining of their tissues using beta-galactosidase substrate to assess the sites of Bmx expression revealed strong signals in the endothelial cells of large arteries and in the endocardium starting between days 10.5 and 12.5 of embryogenesis and continuing in adult mice, while the venular endothelium showed a weak signal only in the superior and inferior venae cavae. Of the five known endothelial receptor tyrosine kinases tested, activated Tie-2 induced tyrosyl phosphorylation of the Bmx protein and both Tie-2 and vascular endothelial growth factor receptor 1 (VEGFR-1) stimulated Bmx tyrosine kinase activity. Thus, the Bmx tyrosine kinase has a redundant role in arterial endothelial signal transduction downstream of the Tie-2 and VEGFR-1 growth factor receptors.     

Interaction of tumor cells and immune system in the metastatic process

The metastatic process is rather complicated and relatively inefficient. Millions of tumor cells are constantly shedding from the primary tumor into the blood stream, but very few of them are able to form metastatic tumors in the different organs or tissues of the host. It is widely accepted that metastatic cells have to possess a complex array of various properties that allow them to complete the metastatic cascade. The realization of the metastatic potential largely depends on the ability of tumor cells to evade host defense mechanisms. The potential role of specific and nonspecific immune mechanisms in the control of metastatic spread and growth is the subject of the present review. A better understanding of the mechanisms of antimetastatic defense is of prime importance for development of efficient immunotherapeutic methods for the treatment and eradication of disseminated tumor metastases.