Reciprocal regulation of A-to-I RNA editing and the vertebrate nervous system

The fine control of molecules mediating communication in the nervous system is key to adjusting neuronal signaling during development and in maintaining the stability of established networks in the face of altered sensory input. To prevent the culmination of pathological recurrent network excitation or debilitating periods of quiescence, adaptive alterations occur in the signaling molecules and ion channels that control membrane excitability and synaptic transmission. However, rather than encoding (and thus "hardwiring") modified gene copies, the nervous systems of metazoa have opted for expanding on post-transcriptional pre-mRNA splicing by altering key encoded amino acids using a conserved mechanism of A-to-I RNA editing: the enzymatic deamination of adenosine to inosine. Inosine exhibits similar base-pairing properties to guanosine with respect to tRNA codon recognition, replication by polymerases, and RNA secondary structure (i.e.,: forming-capacity). In addition to recoding within the open reading frame, adenosine deamination also occurs with high frequency throughout the non-coding transcriptome, where it affects multiple aspects of RNA metabolism and gene expression. Here, we describe the recoding function of key RNA editing targets in the mammalian central nervous system and their potential to be regulated. We will then discuss how interactions of A-to-I editing with gene expression and alternative splicing could play a wider role in regulating the neuronal transcriptome. Finally, we will highlight the increasing complexity of this multifaceted control hub by summarizing new findings from high-throughput studies. © 2013 Penn, Balik and Greger

Evidence-Based Design: Theoretical and Practical Reflections of an Emerging Approach in Office Architecture

Evidence-based design is a practice that has emerged only relatively recently, inspired by a growing popularity of evidence-based approaches in other professions such as medicine. It has received greatest attention in design for the health sector, but has received less in office architecture, although this would seem not only to be beneficial for clients, but increasingly important in a changing business environment. This paper outlines the history and origins of evidence-based practice, its influence in the health sector, as well as some of the reasons why it has been found more difficult to apply in office architecture. Based on these theoretical reflections, data and experiences from several research case studies in diverse workplace environments are presented following a three part argument: firstly we show how organisational behaviours may change as a result of an organisation moving into a new building; secondly we argue that not all effects of space on organisations are consistent. Examples of both consistent and inconsistent results are presented, giving possible reasons for differences in outcomes. Thirdly, practical implications of evidence-based design are made and difficulties for evidence-based practice, for example the problem of investment of time, are reflected on. The paper concludes that organisations may be distinguished according to both their spatial and transpatial structure (referring to a concept initially introduced by Hillier and Hanson in their study of societies). This means that evidence-based design in office architecture needs to recognise that it deals with a multiplicity of possible organisational forms, with specific clients requiring case-dependent research and evidence gathering. In this evidence-based design practice differs markedly from evidence-based medicine. Finally, we suggest a framework for systematic review inclusion criteria in the development of Evidence-Based Design as a field of practice. We argue that it is only through the development of an approach tailored to the specific nature of design practice and organisational function that research evidence can properly be brought to bear. Keywords: Architecture; Design Practice; Evidence-Based Design; Workplace; Research; Case Study.</p

On the Roman-Byzantine adoption of the stirrup once more:A new find from seventh-century Aphrodisias in Caria

Archaeological evidence and the text of the Strategikon show that it was only in the late sixth century AD that the Roman-Byzantine military adopted the stirrup. It is now widely argued that the Avars, who settled in the Carpathian basin in the sixth century, played a key role in introducing iron stirrups to the Roman-Byzantine world. However, the evidence to support this assertion is limited. Although hundreds of stirrups have been found in Avar graves in the Carpathian basin, very few stirrups of sixth- or seventh-century date are known from the Roman-Byzantine empire - no more than seven - and only two of these are of definitively Avar type. The text of the Strategikon, sometimes argued to support this Avar source, can be interpreted differently, as indeed can the archaeological evidence. While the debate about the Roman-Byzantine adoption of the stirrup has focused mostly on finds from the Balkans, two early stirrups are known from Asia Minor, from Pergamon and Sardis. This paper presents a third, previously unpublished stirrup, from a seventh-century deposit at Aphrodisias in Caria; this is the first stirrup found in Asia Minor from a datable context. Here we present this find and its context, and use it to reconsider the model of solely Avar stirrup transmission that has dominated scholarship to date. So varied are the early stirrups that multiple sources of influence, Avar and other, and even a degree of experimentation, seem more likely to underpin the Roman-Byzantine adoption of this technology

Postsecondary and Vocational Education Programs and the Otherwise Qualified Provision of Section 504 of the Rehabilitation Act of 1973

While the Rehabilitation Act defines a handicapped individual,\u27\u27 neither the language of section 504 nor its legislative history sheds much light on the exact meaning of the term \u27\u27otherwise qualified handicapped individual.\u27\u27 This article will argue that the definition of this term must be broad enough to include severely handicapped persons, the primary group that Congress intended to benefit and protect in enacting section 504. Focussing on the area of postsecondary education, this article will argue that the interpretation developed in the Department of Health, Education and Welfare (HEW) Regulation most effectively fulfills the purposes which Congress intended in enacting section 504. The article examines who is a qualified handicapped student entitled to non- . discriminatory admission to and participation in college, university, and vocational programs. The article also examines the challenges to affirmative duties placed upon schools which admit handicapped applicants

Activity-mediated AMPA receptor remodeling, driven by alternative splicing in the ligand-binding domain

The AMPA-type glutamate receptor (AMPAR) subunit composition shapes synaptic transmission and varies throughout development and in response to different input patterns. Here, we show that chronic activity deprivation gives rise to synaptic AMPAR responses with enhanced fidelity. Extrasynaptic AMPARs exhibited changes in kinetics and pharmacology associated with splicing of the alternative flip/flop exons. AMPAR mRNA indeed exhibited reprogramming of the flip/flop exons for GluA1 and GluA2 subunits in response to activity, selectively in the CA1 subfield. However, the functional changes did not directly correlate with the mRNA expression profiles but result from altered assembly of GluA1/GluA2 subunit splice variants, uncovering an additional regulatory role for flip/flop splicing in excitatory signaling. Our results suggest that activity-dependent AMPAR remodeling underlies changes in short-term synaptic plasticity and provides a mechanism for neuronal homeostasis

Prospectus, December 7, 1977

BR-R-R-R-R: YES, WINTER IS HERE..; but warmth is on the way!!; Newspapers from your town at LRC; Parkland Events; Snow policy; Money to burn: Wide screen TV an \u27egregious toy\u27; Letters to the editors; Tape delay unit could be built for much less; Snow? What snow?; Winter divertissement: Party tonight, concert given Sunday; Pre-register or...; Mr. C receives early present; Kuhn\u27s \u27Sister Celebration\u27 is for women as alternative: creative religious celebration; Of trees and trim: Tell do\u27s and don\u27ts: safe Christmas; VA payment increase is part of GI Bill Improvement Act; Fun night next Friday; Corbin answeres all your questions about animals; Poet\u27s Corner: Old Wisdom , Purple Cow ; Classifieds; Liquid protein diet works, but results may be killer; Women\u27s delegates appear-Foundation; Officiating confuses coaches, players: Cobras win one, lose one in wild week; Two tie in Bouncing Bob\u27s opening Basketball Bonanzahttps://spark.parkland.edu/prospectus_1977/1001/thumbnail.jp

Activity-regulated RNA editing in select neuronal subfields in hippocampus

RNA editing by adensosine deaminases is a widespread mechanism to alter genetic information in metazoa. In addition to modifications in non-coding regions, editing contributes to diversification of protein function, in analogy to alternative splicing. However, although splicing programs respond to external signals, facilitating fine tuning and homeostasis of cellular functions, a similar regulation has not been described for RNA editing. Here, we show that the AMPA receptor R/G editing site is dynamically regulated in the hippocampus in response to activity. These changes are bi-directional, reversible and correlate with levels of the editase Adar2. This regulation is observed in the CA1 hippocampal subfield but not in CA3 and is thus subfield/celltype-specific. Moreover, alternative splicing of the flip/flop cassette downstream of the R/G site is closely linked to the editing state, which is regulated by Ca(2+). Our data show that A-to-I RNA editing has the capacity to tune protein function in response to external stimuli

The London childcare market

This report investigates the London Childcare Market. It was written for the London Development Agency by a team comprised of Roger Tym & Partners, Laing Buisson and the University of East London. 2. The LDA is concerned that there may be market failures operating in London which cause problems in the provision of childcare services. The hypothesis is that if these failures were corrected, then childcare in London might be more available and affordable. If this were the case, goes the logic, then parents would be able to return to the labour market, raising output and lifting more children out of poverty. 3. This report concentrates on paid for (formal) childcare provided for early years (0-5 years) children by OFSTED-registered establishments and individuals. In less detail, we also cover childcare for children aged 5, 6 and 7 years provided in OFSTED registered childcare settings such as out of school clubs and by OFSTED registered individuals such as childminders

The genomic diversification of grapevine clones.

BACKGROUND:Vegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better appreciate clone diversity and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03. RESULTS:Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than in genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and because methylated cytosines often spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones. CONCLUSIONS:These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clones accumulate putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions or some mechanism by which mutations are less frequent in coding than noncoding regions of the genome