Heritable changeability: Epimutation and the legacy of negative definition in epigenetic concepts

Epigenetic concepts are fundamentally shaped by a legacy of negative definition, often understood by what they are not. Yet the function and implication of negative definition for scientific discourse has thus far received scant attention. Using the term epimutation as exemplar, we analyze the paradoxical like-but-unlike structure of a term that must simultaneously connect with but depart from genetic concepts. We assess the historical forces structuring the use of epimutation and like terms such as paramutation. This analysis highlights the positive characteristics defining epimutation: the regularity, oxymoronic temporality, and materiality of stable processes. Integrating historical work, ethnographic observation, and insights from philosophical practice-oriented conceptual analysis, we detail the distinctive epistemic goals the epimutation concept fulfils in medicine, plant biology and toxicology. Epimutation and allied epigenetic terms have succeeded by being mutation-like and recognizable, yet have failed to consolidate for exactly the same reason: they are tied simultaneously by likeness and opposition to nouns that describe things that are assumed to persist unchanged over space and time. Moreover, negative definition casts the genetic-epigenetic relationship as an either/or binary, overshadowing continuities and connections. This analysis is intended to assist practitioners and observers of genetics and epigenetics in recognizing and moving beyond the conceptual legacies of negative definition.     

Polyreactivity increases the apparent affinity of anti-HIV antibodies by heteroligation

During immune responses, antibodies are selected for their ability to bind to foreign antigens with high affinity, in part by their ability to undergo homotypic bivalent binding. However, this type of binding is not always possible. For example, the small number of gp140 glycoprotein spikes displayed on the surface of the human immunodeficiency virus (HIV) disfavours homotypic bivalent antibody binding. Here we show that during the human antibody response to HIV, somatic mutations that increase antibody affinity also increase breadth and neutralizing potency. Surprisingly, the responding naive and memory B cells produce polyreactive antibodies, which are capable of bivalent heteroligation between one high-affinity anti-HIV-gp140 combining site and a second low-affinity site on another molecular structure on HIV. Although cross-reactivity to self-antigens or polyreactivity is strongly selected against during B-cell development, it is a common serologic feature of certain infections in humans, including HIV, Epstein-Barr virus and hepatitis C virus. Seventy-five per cent of the 134 monoclonal anti-HIV-gp140 antibodies cloned from six patients with high titres of neutralizing antibodies are polyreactive. Despite the low affinity of the polyreactive combining site, heteroligation demonstrably increases the apparent affinity of polyreactive antibodies to HIV.     

Crystal structure of the ligand-free G-protein-coupled receptor opsin

In the G-protein-coupled receptor (GPCR) rhodopsin, the inactivating ligand 11-cis-retinal is bound in the seven-transmembrane helix (TM) bundle and is cis/trans isomerized by light to form active metarhodopsin II. With metarhodopsin II decay, all-trans-retinal is released, and opsin is reloaded with new 11-cis-retinal. Here we present the crystal structure of ligand-free native opsin from bovine retinal rod cells at 2.9 ?ngstr?m (A) resolution. Compared to rhodopsin, opsin shows prominent structural changes in the conserved E(D)RY and NPxxY(x)(5,6)F regions and in TM5-TM7. At the cytoplasmic side, TM6 is tilted outwards by 6-7 A, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, some of which were attributed to an active GPCR state, reorganize the empty retinal-binding pocket to disclose two openings that may serve the entry and exit of retinal. The opsin structure sheds new light on ligand binding to GPCRs and on GPCR activation.     

Improper ferroelectricity in perovskite oxide artificial superlattices

Ferroelectric thin films and superlattices are currently the subject of intensive research because of the interest they raise for technological applications and also because their properties are of fundamental scientific importance. Ferroelectric superlattices allow the tuning of the ferroelectric properties while maintaining perfect crystal structure and a coherent strain, even throughout relatively thick samples. This tuning is achieved in practice by adjusting both the strain, to enhance the polarization, and the composition, to interpolate between the properties of the combined compounds. Here we show that superlattices with very short periods possess a new form of interface coupling, based on rotational distortions, which gives rise to 'improper' ferroelectricity. These observations suggest an approach, based on interface engineering, to produce artificial materials with unique properties. By considering ferroelectric/paraelectric PbTiO3/SrTiO3 multilayers, we first show from first principles that the ground-state of the system is not purely ferroelectric but also primarily involves antiferrodistortive rotations of the oxygen atoms in a way compatible with improper ferroelectricity. We then demonstrate experimentally that, in contrast to pure PbTiO3 and SrTiO3 compounds, the multilayer system indeed behaves like a prototypical improper ferroelectric and exhibits a very large dielectric constant of epsilon(r) approximately 600, which is also fairly temperature-independent. This behaviour, of practical interest for technological applications, is distinct from that of normal ferroelectrics, for which the dielectric constant is typically large but strongly evolves around the phase transition temperature and also differs from that of previously known improper ferroelectrics that exhibit a temperature-independent but small dielectric constant only.     

A STUDY OF SEAM STRENGTH AND EXTENSIBILITY FOR PRESSURE GARMENTS

Pressure garments are functional garments designed for medical purposes and arc normally used under prolonged stress. The stress across seams is related to the size of the wearer and the fit and the garment, the more close fitting a garment, the greater stress is put on the seam. Since pressure garments are subjected to appreciable stress during wear, seams with the required strength and extensiblity are particular important. The seam type, stitch type, stitch density and thread strength are the main factors determining the strength and extensibility of a seam. In this paper, investigation of seam strength and extensibility are made on four types of seams which have been used for making pressure garments. Five different types of stitch densities and two sizes of sewing thread are used on each type of scam to be tested. The seaming conditions of the selected fabric are also examined.     

A structural view of nuclear hormone receptor: endocrine disruptor interactions

Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system by interfering with hormone biosynthesis, metabolism, or action. The molecular mechanisms of EDCs involve different pathways including interactions with nuclear hormone receptors (NHRs) which are primary targets of a large variety of environmental contaminants. Here, based on the crystal structures currently available in the Protein Data Bank, we review recent studies showing the many ways in which EDCs interact with NHRs and impact their signaling pathways. Like the estrogenic chemical diethylstilbestrol, some EDCs mimic the natural hormones through conserved protein–ligand contacts, while others, such as organotins, employ radically different binding mechanisms. Such structure-based knowledge, in addition to providing a better understanding of EDC activities, can be used to predict the endocrine-disrupting potential of environmental pollutants and may have applications in drug discovery.     

Caudal movements in western fence lizards ( Sceloporus occidentalis ) prior to attempted prey capture

Many snakes employ tail movements to attract prey, but this behavior is rare in lizards. Use of caudal movements to distract prey, however, is rare in all squamates. Recently, caudal movements in a Sceloporus occidentalis individual immediately prior to attempted prey capture were documented. We supplement this sole documentation of caudal movements in S. occidentalis with additional field observations. Additionally, video footage of the behavior was recorded on 2 occasions. From these additional observations, we hypothesize that this behavior might serve to distract prey.