Kinetic and structural evidence of the alkenal/one reductase specificity of human ζ-crystallin

Human ζ-crystallin is a Zn²⁺-lacking medium-chain dehydrogenase/reductase (MDR) included in the quinone oxidoreductase (QOR) family because of its activity with quinones. In the present work a novel enzymatic activity was characterized: the double bond α,β-hydrogenation of medium-chain 2-alkenals and 3-alkenones. The enzyme is especially active with lipid peroxidation products such as 4-hydroxyhexenal, and a role in their detoxification is discussed. This specificity is novel in the QOR family, and it is similar to that described in the distantly related alkenal/one reductase family. Moreover, we report the X-ray structure of ζ-crystallin, which represents the first structure solved for a tetrameric Zn²⁺-lacking MDR, and which allowed the identification of the active-site lining residues. Docking simulations suggest a role for Tyr53 and Tyr59 in catalysis. The kinetics of Tyr53Phe and Tyr59Phe mutants support the implication of Tyr53 in binding/catalysis of alkenal/one substrates, while Tyr59 is involved in the recognition of 4-OH-alkenals.     

Relaxin family peptide systems and the central nervous system

Since its discovery in the 1920s, relaxin has enjoyed a reputation as a peptide hormone of pregnancy. However, relaxin and other relaxin family peptides are now associated with numerous non-reproductive physiologies and disease states. The new millennium bought with it the sequence of the human genome and subsequently new directions for relaxin research. In 2002, the ancestral relaxin gene RLN3 was identified from genome databases. The relaxin-3 peptide is highly expressed in a small region of the brain and in species from teleost to primates and has both conserved sequence and sites of expression. Combined with the discovery of the relaxin family peptide receptors, interest in the role of the relaxin family peptides in the central nervous system has been reignited. This review explores the relaxin family peptides that are expressed in or act upon the brain, the receptors that mediate their actions, and what is currently known of their functions.     

Identification of an emerin–β-catenin complex in the heart important for intercalated disc architecture and β-catenin localisation

How mutations in the protein emerin lead to the cardiomyopathy associated with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is unclear. We identified emerin at the adherens junction of the intercalated disc, where it co-localised with the catenin family of proteins. Emerin bound to wild type β-catenin both in vivo and in vitro. Mutating the GSK3β phosphorylation sites on β-catenin abolished this binding. Wild type but not mutant forms of emerin associated with X-EDMD were able to reduce β-catenin protein levels. Cardiomyocytes from emerin-null mice hearts exhibited erroneous β-catenin distribution and intercalated disc architecture. Treatment of wild type cardiomyocytes with phenylephrine, which inactivates GSK3β, redistributed emerin and β-catenin. Emerin was identified as a direct target of GSK3β activity since exogenous expression of GSK3β reduced emerin levels at the nuclear envelope. We propose that perturbation to or total loss of the emerin–β-catenin complex compromises both intercalated disc function and β-catenin signalling in cardiomyocytes.     

The Advantages of Obscurity: Charles Darwin's Negative Inference from the Histories of Domestic Breeds

In The Origin of Species, Charles Darwin famously accounted for the lack of fossil evidence in support of species evolution on the grounds that the fossil record is naturally incomplete. This essay examines a similar argument that Darwin applied to his analogy between natural and artificial selection: the scarcity of data about the historical backgrounds of domestic breeds was the natural by-product of an extremely gradual change process. The point was to enhance the ability of the artificial selection analogy to suggest that nature's species had undergone a similar transformation. Darwin did not depend on this negative inference alone, however, for in his writings he included whatever information he could find about the actual histories of particular breeds. A comparison with Darwin's treatment of the fossil record suggests the reasonableness of this combined use of opposite kinds of evidence to establish a single point. The comparison also suggests the unique qualities of negative inference as applied to the breeding analogy.     

Physical,Human and Divine attraction in the life and thought of George Cheyne

This paper is a study of the mental environment of the Newtonian conception of attraction in the case of George Cheyne, M.D. (1671–1743), physician of the early 18th century and author of a number of popular medical works. It traces the growth of his notions of a spiritual attraction between God and his creatures and between the creatures themselves, and the relation of these ideas both to his use of the Newtonian model of short-range attraction, and to his conception of the creatures as reflections of the divine essence. The paper contends that the development of these aspects of Cheyne's thought harmonizes with the changing pattern of his life, and that this harmony is expressed by his general technique of reasoning by analogy between the various spheres of experience.