Regulatory mechanisms of mitogen-activated kinase signaling

MAP kinases (MAPKs) are evolutionarily conserved regulators that mediate signal transduction and play essential roles in various physiological processes. There are three main families of MAPKs in mammals, whose functions are regulated by activators, inactivators, substrates and scaffolds, which together form delicate signaling cascades in response to different extracellular or intracellular stimulation. MAPK signaling is tightly regulated so that optimal biological activities are achieved and health is maintained. However, how the specificity of the signaling flow along each cascade is achieved is still relatively unclear. In this review, we summarize recent advances in understanding the regulation of MAPK cascades and the roles of MAP kinases and their regulators in development and in immune responses. Received 11 January 2007; received after revision 31 May 2007; accepted 5 July 2007     

Mechanistic artefact explanation

One thing about technical artefacts that needs to be explained is how their physical make-up, or structure, enables them to fulfil the behaviour associated with their function, or, more colloquially, how they work. In this paper I develop an account of such explanations based on the familiar notion of mechanistic explanation. To accomplish this, I (1) outline two explanatory strategies that provide two different types of insight into an artefact’s functioning, and (2) show how human action inevitably plays a role in artefact explanation. I then use my own account to criticize other recent work on mechanistic explanation and conclude with some general implications for the philosophy of explanation.     

The Janus kinase family of protein tyrosine kinases and their role in signaling

In the early 1990s, the search for protein kinases led to the discovery of a novel family of non-receptor tyrosine kinases, the Janus kinases or JAKs. These proteins were unusual because they contained two kinase homology domains and no other known signaling modules. It soon became clear that these were not ‘just another’ type of kinase. Their ability to complement mutant cells insensitive to interferons and to be activated by a variety of cytokines demonstrated their central signaling function. Now, as we approach the end of the decade, it is evident from biochemical studies to knockout mice that JAKs play non-redundant functions in development, differentiation, and host defense mechanisms. Here, recent progress is reviewed, with particular emphasis on structure-function studies aimed at revealing how this family of tyrosine kinases is regulated.     

Protein kinase C and phospholipase D: intimate interactions in intracellular signaling

Diacylglycerol (DAG) was discovered as a potent lipid second messenger with protein kinase C (PKC) as its major cellular target more than 25 years ago. There is increasing evidence of significant complexity within lipid signaling, and the classical DAG-PKC model no longer stands alone but is part of a larger bioactive lipid universe involving glycerolipids and sphingolipids. Multiple layers of regulation exist among PKC- and DAG-metabolizing enzymes such as phosphatidylcholine (PC)-specific phospholipase D, and cross-talk exists between the glycerolipid and sphingolipid pathways, with PKC at the center. Currently, there is intense interest in the question of whether DAG derived from PC can function as a lipid second messenger and regulate PKC analogous to DAG derived from phosphatidylinositol-4,5-bisphosphate (PIP₂). To address these issues and incorporate DAG-PKC and other signaling pathways into an expanded view of cell biology, it will be necessary to go beyond the classical approaches and concepts.Received 29 November 2004; received after revision 18 January 2005; accepted 4 March 2005This work is dedicated to the memory of Dr. Yasutomi Nishizuka, the discoverer of protein kinase C, who was both a gentleman and a scientist.     

Three principles of unity in Newton

I discuss three principles of unity available in Newton’s physics, appealing to space and time, causal interaction, and law-constitution respectively. I compare these three approaches with respect to aggregation (how a collection of entities can compose a whole) and multiplicity (how the world as a whole can contain a multiplicity of genuine unities), outlining the problems faced by the first two approaches and arguing that the third looks a promising candidate for further philosophical investigation.     

A Nylon Reograd Rotor embodying new principles

Zusammenfassung Der verbesserte, neu konzipierte Reograd-Rotor eignet sich für die präparative Zentrifugierung von Makromolekülen und Viren.     

Mechanisms, principles, and Lorentz's cautious realism

I show that Albert Einstein's distinction between principle and constructive theories was predated by Hendrik A. Lorentz's equivalent distinction between mechanism- and principle-theories. I further argue that Lorentz's views toward realism similarly prefigure what Arthur Fine identified as Einstein's “motivational realism.”     

Ethical principles and guidelines for experiments on animals

Swiss Academy of Medical Sciences and Swiss Academy of Sciences

Ethical principles and guidelines for experiments on animals     

Ethical principles and guidelines for experiments on animals

Editorial Note The following Ethical principles and guidelines for scientific experiments on animals are reprinted here with the kind permission of the Commission appointed to formulate the guidelines and both Swiss Academies represented on the Commission. They form the basis on which Editors and referees judge whether studies involving experimentation on animals can be considered for our journal. Authors are asked to adhere strictly to these rules.EXPERIENTIA fully endorses article 5.7 wherein Scientific journals are urged not to accept the results of such experiments [i.e. those which contravene the ethical principles and the present guidelines] for publication.     

A biogenetic proposal for the simaroubaceous bitter principles

Zusammenfassung Ein biogenetischer Vorschlag für Simaruba-Bitterstoffe, welcher ihre chemische Struktur, Stereochemie und ihre Entstehung in der Pflanze erklärt, wird vorgelegt.

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Citrus Bitter Principles I.     

Integrin signaling in atherosclerosis

Atherosclerosis, a chronic lipid-driven inflammatory disease affecting large arteries, represents the primary cause of cardiovascular disease in the world. The local remodeling of the vessel intima during atherosclerosis involves the modulation of vascular cell phenotype, alteration of cell migration and proliferation, and propagation of local extracellular matrix remodeling. All of these responses represent targets of the integrin family of cell adhesion receptors. As such, alterations in integrin signaling affect multiple aspects of atherosclerosis, from the earliest induction of inflammation to the development of advanced fibrotic plaques. Integrin signaling has been shown to regulate endothelial phenotype, facilitate leukocyte homing, affect leukocyte function, and drive smooth muscle fibroproliferative remodeling. In addition, integrin signaling in platelets contributes to the thrombotic complications that typically drive the clinical manifestation of cardiovascular disease. In this review, we examine the current literature on integrin regulation of atherosclerotic plaque development and the suitability of integrins as potential therapeutic targets to limit cardiovascular disease and its complications.     

Flow signaling and atherosclerosis

Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be athero-protective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow. The ability of ECs to differentially respond to the two types of flow provides an opportunity to identify molecular events that lead to endothelial dysfunction and atherosclerosis. In this review, we will focus on various molecular events, which are differentially regulated by these two flow types. We will discuss how various kinases, ER stress, inflammasome, SUMOylation, and DNA methylation play roles in the differential flow response, endothelial dysfunction, and atherosclerosis. We will also discuss the interplay among the molecular events and how they coordinately regulate flow-dependent signaling and cellular responses. It is hoped that clear understanding of the way how the two flow types beget each unique phenotype in ECs will lead us to possible points of intervention against endothelial dysfunction and cardiovascular diseases.