History, Sociology, Modernity : How Connect?

Special Issue on 'The State of Scottish History: Past, Present and Future'Peer reviewedPublisher PD

Functional States of the Genome-Scale Escherichia Coli Transcriptional Regulatory System

A transcriptional regulatory network (TRN) constitutes the collection of regulatory rules that link environmental cues to the transcription state of a cell's genome. We recently proposed a matrix formalism that quantitatively represents a system of such rules (a transcriptional regulatory system [TRS]) and allows systemic characterization of TRS properties. The matrix formalism not only allows the computation of the transcription state of the genome but also the fundamental characterization of the input-output mapping that it represents. Furthermore, a key advantage of this “pseudo-stoichiometric” matrix formalism is its ability to easily integrate with existing stoichiometric matrix representations of signaling and metabolic networks. Here we demonstrate for the first time how this matrix formalism is extendable to large-scale systems by applying it to the genome-scale Escherichia coli TRS. We analyze the fundamental subspaces of the regulatory network matrix (R) to describe intrinsic properties of the TRS. We further use Monte Carlo sampling to evaluate the E. coli transcription state across a subset of all possible environments, comparing our results to published gene expression data as validation. Finally, we present novel in silico findings for the E. coli TRS, including (1) a gene expression correlation matrix delineating functional motifs; (2) sets of gene ontologies for which regulatory rules governing gene transcription are poorly understood and which may direct further experimental characterization; and (3) the appearance of a distributed TRN structure, which is in stark contrast to the more hierarchical organization of metabolic networks

From Large Zones to Small Terranes to Detailed Reconstruction of an Early to Middle Ordovician Arc–Backarc System Preserved Along the Iapetus Suture Zone: A Legacy of Hank Williams

The Annieopsquotch accretionary tract (AAT) comprises a thrust stack of Lower to Middle Ordovician arc and backarc terranes that were accreted to the composite Laurentian margin of Iapetus during the Middle to Late Ordovician. Geological relationships suggest that the constituent terranes of the AAT initially formed outboard of the composite Laurentian margin in an extensional arc that underwent multiple rifting episodes prior to its accretion. The initiation of AAT magmatism led to the development of Tremadocian to Floian supra-subduction zone ophiolites (481 to 477 Ma) with organized ridges indicated by the presence of well-developed sheeted dyke complexes. This spreading centre propagated through a fragment of Laurentian crust and separated it from the composite Laurentian margin. This Laurentian crust fragment then formed the basement to subsequent Floian to Darriwilian AAT arc magmatism. The Floian arc (473 to 468 Ma) underwent extensive rifting indicated by organized spreading in the Lloyds River backarc basin, which was floored by juvenile backarc ophiolitic crust (472 Ma). The establishment of the Darriwilian arc (467 to 462 Ma) was in part coeval with yet another stage of rifting. Darriwilian magmatism is characterised by significant along-strike variability, ranging from continental to primitive calc-alkaline arc to tholeiitic backarc-like magmatism. The diversity of Darriwilian magmatism can be attributed to fragmentation and magmatic reworking of Laurenian-derived basement along strike in the same arc undergoing disorganized spreading. The development of the AAT is interpreted to be similar to that of the modern Izu – Bonin – Mariana arc in the western Pacific.SOMMAIRELa bande d’accrétion d’Annieopsquotch (AAT) est constituée d’un empilement de chevauchements de l’Ordovicien précoce à moyen, et de terranes d’arc et d’arrière-arc qui se sont accrétés à la marge composite laurentienne japétienne à l’Ordovicien moyen à tardif.  Les faits géologiques relevés portent à penser que les terranes constitutifs de l’AAT se sont constitués à l’extérieur de la marge laurentienne dans un arc d’extension qui a subi de multiples épisodes de rifting avant son accrétion.  L’initiation du magmatisme de l’AAT a mené au développement de zones d’ophiolites de supra-subduction du Trémadocien au Floien (481 Ma à 477 Ma), avec des crêtes ordonnées mises en évidence par la présence de complexes de tapis de dikes bien développés.  Ce centre d’extension s’est propagé à travers un fragment de la croûte laurentienne, et l’a ultimement séparé de la marge composite laurentienne.  Et, du Floien au Darriwilien, ce fragment de croûte laurentienne a servi de substratum au magmatisme d’arc de l’AAT.  Au Floien (473 Ma à 468 Ma), cette zone d’arc a subi un important rifting, comme l’indique la distension ordonnée du bassin d’arrière-arc de Lloyds River, lequel a servi de semelle à une croûte ophiolitique d’arrière-arc (472 Ma).  La mise en place de l’arc au Darriwilien (467 Ma à 462 Ma) a coexisté pour un temps avec un autre épisode de rifting.  Le magmatisme darriwilien est caractérisé par une variabilité de composition importante parallèlement à sa direction, passant d’une composition d’arc continental à celle d’arrière-arc primitif calco-alcalin jusqu’à une composition de magmatisme de type tholéiitique d’arrière-arc.  La diversité du magmatisme darriwilien peut être attribuée à la fragmentation et au remaniement magmatique de la croûte d’origine laurentienne parallèlement à la direction d’un même arc subissant une distension désordonnée.  Nous proposons que le développement de l’AAT a été similaire à celui de l’arc moderne Izy–Bonin–Marianne du Pacifique occidental

Long-Range Periodic Patterns in Microbial Genomes Indicate Significant Multi-Scale Chromosomal Organization

Genome organization can be studied through analysis of chromosome position-dependent patterns in sequence-derived parameters. A comprehensive analysis of such patterns in prokaryotic sequences and genome-scale functional data has yet to be performed. We detected spatial patterns in sequence-derived parameters for 163 chromosomes occurring in 135 bacterial and 16 archaeal organisms using wavelet analysis. Pattern strength was found to correlate with organism-specific features such as genome size, overall GC content, and the occurrence of known motility and chromosomal binding proteins. Given additional functional data for Escherichia coli, we found significant correlations among chromosome position dependent patterns in numerous properties, some of which are consistent with previously experimentally identified chromosome macrodomains. These results demonstrate that the large-scale organization of most sequenced genomes is significantly nonrandom, and, moreover, that this organization is likely linked to genome size, nucleotide composition, and information transfer processes. Constraints on genome evolution and design are thus not solely dependent upon information content, but also upon an intricate multi-parameter, multi-length-scale organization of the chromosome

Matrix Formalism to Describe Functional States of Transcriptional Regulatory Systems

Complex regulatory networks control the transcription state of a genome. These transcriptional regulatory networks (TRNs) have been mathematically described using a Boolean formalism, in which the state of a gene is represented as either transcribed or not transcribed in response to regulatory signals. The Boolean formalism results in a series of regulatory rules for the individual genes of a TRN that in turn can be used to link environmental cues to the transcription state of a genome, thereby forming a complete transcriptional regulatory system (TRS). Herein, we develop a formalism that represents such a set of regulatory rules in a matrix form. Matrix formalism allows for the systemic characterization of the properties of a TRS and facilitates the computation of the transcriptional state of the genome under any given set of environmental conditions. Additionally, it provides a means to incorporate mechanistic detail of a TRS as it becomes available. In this study, the regulatory network matrix, R, for a prototypic TRS is characterized and the fundamental subspaces of this matrix are described. We illustrate how the matrix representation of a TRS coupled with its environment (R*) allows for a sampling of all possible expression states of a given network, and furthermore, how the fundamental subspaces of the matrix provide a way to study key TRS features and may assist in experimental design

Cognitive and disease-modifying effects of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia

School related factors and 1yr change in physical activity amongst 9-11 year old English schoolchildren.

BACKGROUND: Activity levels are known to decline with age and there is growing evidence of associations between the school environment and physical activity. In this study we investigated how objectively measured one-year changes in physical activity may be associated with school-related factors in 9- to 10-year-old British children. METHODS: Data were analysed from 839 children attending 89 schools in the SPEEDY (Sport, Physical Activity, and Eating behaviours: Environmental Determinants in Young People) study. Outcomes variables were one year changes in objectively measured sedentary, moderate, and vigorous physical activity, with baseline measures taken when the children were 9-10 years old. School characteristics hypothesised to be associated with change in physical activity were identified from questionnaires, grounds audits, and computer mapping. Associations were examined using simple and multivariable multilevel regression models for both school (9 am - 3 pm) and travel (8-9 am and 3-4 pm) time. RESULTS: Significant associations during school time included the length of the morning break which was found to be supportive of moderate (β coefficient: 0.68 [p: 0.003]) and vigorous (β coefficient: 0.52 [p: 0.002]) activities and helps to prevent adverse changes in sedentary time (β coefficient: -2.52 [p: 0.001]). During travel time, positive associations were found between the presence of safe places to cross roads around the school and changes in moderate (β coefficient: 0.83 [p:0.022]) and vigorous (β coefficient: 0.56 [p:0.001]) activity, as well as sedentary time (β coefficient: -1.61 [p:0.005]). CONCLUSION: This study suggests that having longer morning school breaks and providing road safety features such as cycling infrastructure, a crossing guard, and safe places for children to cross the road may have a role to play in supporting the maintenance of moderate and vigorous activity behaviours, and preventing the development of sedentary behaviours in children.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Curvaton reheating: an application to braneworld inflation

The curvaton was introduced recently as a distinct inflationary mechanism for generating adiabatic density perturbations. Implicit in that scenario is that the curvaton offers a new mechanism for reheating after inflation, as it is a form of energy density not diluted by the inflationary expansion. We consider curvaton reheating in the context of a braneworld inflation model, {\em steep inflation}, which features a novel use of the braneworld to give a new mechanism for ending inflation. The original steep inflation model featured reheating by gravitational particle production, but the inefficiency of that process brings observational difficulties. We demonstrate here that the phenomenology of steep inflation is much improved by curvaton reheating.Comment: 8 pages RevTeX4 file with two figures incorporated. Improved referencing, matches PRD accepted versio

A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell lineage tracing in multiple mouse models to show that Piezo2 is expressed in a subset of murine EE and EC cells, and it is distributed near serotonin vesicles by superresolution microscopy. Mechanical stimulation of a subset of isolated EE cells leads to a rapid inward ionic current, which is diminished by Piezo2 knockdown and channel inhibitors. In these mechanosensitive EE cells force leads to Piezo2-dependent intracellular Ca(2+) increase in isolated cells as well as in EE cells within intestinal organoids, and Piezo2-dependent mechanosensitive serotonin release in EC cells. Conditional knockout of intestinal epithelial Piezo2 results in a significant decrease in mechanically stimulated epithelial secretion. This study shows that a subset of primary EE and EC cells is mechanosensitive, uncovers Piezo2 as their primary mechanotransducer, defines the molecular mechanism of their mechanotransduction and mechanosensitive serotonin release, and establishes the role of epithelial Piezo2 mechanosensitive ion channels in regulation of intestinal physiology