A promoter-level mammalian expression atlas

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

A markov chain Monte Carlo method for estimating population mixing using Y-chromosome markers: Mixing of the Han people in China

We present a new approach for estimating mixing between populations based on non-recombining markers, specifically Y-chromosome microsatellites. A Markov chain Monte Carlo (MCMC) Bayesian statistical approach is used to calculate the posterior probability

Weight loss intervention for young adults using mobile technology: design and rationale of a randomized controlled trial - Cell Phone Intervention for You (CITY).

BACKGROUND: The obesity epidemic has spread to young adults, leading to significant public health implications later in adulthood. Intervention in early adulthood may be an effective public health strategy for reducing the long-term health impact of the epidemic. Few weight loss trials have been conducted in young adults. It is unclear what weight loss strategies are beneficial in this population. PURPOSE: To describe the design and rationale of the NHLBI-sponsored Cell Phone Intervention for You (CITY) study, which is a single center, randomized three-arm trial that compares the impact on weight loss of 1) a behavioral intervention that is delivered almost entirely via cell phone technology (Cell Phone group); and 2) a behavioral intervention delivered mainly through monthly personal coaching calls enhanced by self-monitoring via cell phone (Personal Coaching group), each compared to 3) a usual care, advice-only control condition. METHODS: A total of 365 community-dwelling overweight/obese adults aged 18-35 years were randomized to receive one of these three interventions for 24 months in parallel group design. Study personnel assessing outcomes were blinded to group assignment. The primary outcome is weight change at 24 [corrected] months. We hypothesize that each active intervention will cause more weight loss than the usual care condition. Study completion is anticipated in 2014. CONCLUSIONS: If effective, implementation of the CITY interventions could mitigate the alarming rates of obesity in young adults through promotion of weight loss. ClinicalTrial.gov: NCT01092364.

State power matters: power, the state and political struggle in the post-war American novel

This article is concerned with resituating the state at the centre of the analytical stage and, concomitantly, with drawing attention to the dangers of losing sight of the state as a locus of power. It seeks to uncover the relationship between two related lines of critical inquiry: Marxist and Foucauldian theories of the state; and the attempts by three postwar American novelist (Ken Kesey, William Burroughs and E.L. Doctorow) to determine the nature and extent of this power and to consider under what conditions political struggle might be possible. It argues that such a move is needed because recent critical analysis has been too preoccupied by corporeal micropolitics and global macropolitics, and that the postwar American novel can help us in this move because it is centrally concerned with the repressive potentiality of the US state. It maintains that the resuscitation of Marxist state theories in early 1970s and a debate between Poulantzas and Foucault is intriguingly foreshadowed and even critiqued by these novels. Consequently, it concludes that these novels constitute an unrecognized pre-history of what would become one of the key intellectual debates of the late twentieth century: an engagement between Marxist and post-structuralist conceptions of the power and resistance.

Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis

We genotyped 2,861 cases of primary biliary cirrhosis (PBC) from the UK PBC Consortium and 8,514 UK population controls across 196,524 variants within 186 known autoimmune risk loci. We identified 3 loci newly associated with PBC (at P <5 × 10(-8)), increasing the number of known susceptibility loci to 25. The most associated variant at 19p12 is a low-frequency nonsynonymous SNP in TYK2, further implicating JAK-STAT and cytokine signaling in disease pathogenesis. An additional five loci contained nonsynonymous variants in high linkage disequilibrium (LD; r(2) > 0.8) with the most associated variant at the locus. We found multiple independent common, low-frequency and rare variant association signals at five loci. Of the 26 independent non-human leukocyte antigen (HLA) signals tagged on the Immunochip, 15 have SNPs in B-lymphoblastoid open chromatin regions in high LD (r(2) > 0.8) with the most associated variant. This study shows how data from dense fine-mapping arrays coupled with functional genomic data can be used to identify candidate causal variants for functional follow-up.

O terrível nascimento da beleza: a criação literária em diversos autores

De onde brota a inspiração para baladas de amor e canções de guerra, lendas e narrativas, tragédias e comédias? Ao longo de séculos, escritores e leitores interrogaram-se acerca do nascimento da beleza. Neste artigo, abordo essa questão intrigante, em quatro etapas: a) Examino algumas personificações criadas por Hesíodo, Homero, Luís de Camões e Federico García Lorca para descreverem a inspiração; b) Exploro as estratégias utilizadas por Samuel Coleridge, Salvador Dalí e William Burroughs, para penetrar no reino da fantasia, o inconsciente; c) Apresento as explicações científicas propostas por Sigmund Freud, Carl Jung e Robert Sperry para o impulso criativo; d) Para concluir, menciono as razões que levaram Fernando Pessoa, Eugénio de Andrade e Emily Dickinson a desconfiarem da musa inspiradora, preferindo o esforço que corrige a emoção e gera a obra de arte. Seguindo uma perspectiva comparada, o meu objectivo é mostrar diferentes formas de perceber a criatividade literária. Para tanto, recorro ao trabalho dos escritores e cientistas atrás mencionados e, naturalmente, à minha opinião.

Niagara Ship Canal [to accompany Bill H.R. no.432] (1858)

At head of Caption title: 35th Congress, 1st session. House of Representatives, Report no. 374.

Three adult cases of orbital hidrocystoma presenting with blepharoptosis

To report adult cases of superior orbital apocrine hidrocystoma. Retrospective case series of three patients with superior orbital apocrine hidrocystoma and blepharoptosis with review of the clinical aspects of each of the cases. All three cases presented with blepharoptosis. Two of the cases had occult hidrocystoma, and one was visibly subcutaneous at presentation. Although rare and more common along the eyelid margin, apocrine hidrocystomas may occur in the orbit leading to secondary blepharoptosis and should be included within the differential diagnosis of orbital cysts. Physicians should therefore be aware of this possibility.

Reduction of Soil Erosion on Forest Roads

Results of onsite erosion control work from across the United States provide estimates of the amount of erosion reduction on forest roads from various treatments. Supplementary information includes the effects of slope gradient, soil characteristics, and ground cover. Estimates of sediment travel below fillslopes can be made, together with the combined effect of erosion control treatments of the running surface, road cut, and ditch.

Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions

The intermediate stage of hepatocellular carcinoma (HCC) comprises a highly heterogeneous patient population and therefore poses unique challenges for therapeutic management, different from the early and advanced stages. Patients classified as having intermediate HCC by the Barcelona Clinic Liver Cancer (BCLC) staging system present with varying tumor burden and liver function. Transarterial chemoembolization (TACE) is currently recommended as the standard of care in this setting, but there is considerable variation in the clinical benefit patients derive from this treatment.In April 2012, a panel of experts convened to discuss unresolved issues surrounding the application of current guidelines when managing patients with intermediate HCC. The meeting explored the applicability of a subclassification system for intermediate HCC patients to tailor therapeutic interventions based on the evidence available to date and expert opinion. The present report summarizes the proposal of the expert panel: four substages of intermediate HCC patients, B1 to B4.

Differences of pathophysiology in experimental meningitis caused by three strains of Streptococcus pneumoniae

Differences in cytochemical and pathophysiologic abnormalities in experimental meningitis caused by pneumococcal strains A, B, and C were determined. Strain C produced the most severe abnormalities of cerebrospinal fluid (CSF) concentrations of lactate (P less than .01), protein (P less than .02), and glucose (P less than .01), CSF white blood cell count (P less than .04), cerebral blood flow (P less than .02), and clinical signs (P less than .05). Brain edema occurred only with strains A anc C, with no association with disease severity; intracranial hypertension was also independent of disease severity. Strain B, not C, achieved the highest bacterial titers in the CSF (P less than .005). The widely different abilities of strains of Streptococcus pneumoniae to induce intracranial abnormalities suggest that virulence determinants affect not only evasion of defense during colonization and invasion, as shown in other models, but also determine the course of disease once infection has been established. Differences of cell-wall metabolism among pneumococcal strains may play a role in this latter phase of the development of meningitis.

Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Hsf1 and Hsp90 orchestrate temperature-dependent global transcriptional remodelling and chromatin architecture in Candida albicans

We thank Karim Gharbi and Urmi Trivedi for their assistance with RNA sequencing, carried out in the GenePool genomics facility (University of Edinburgh). We also thank Susan Fairley and Eduardo De Paiva Alves (Centre for Genome Enabled Biology and Medicine, University of Aberdeen) for help with the initial bioinformatics analysis. We thank Aaron Mitchell for kindly providing the ALS3 mutant, Julian Naglik for the gift of TR146 cells, and Jon Richardson for technical assistance. We thank the Genomics and Bioinformatics core of the Faculty of Health Sciences for Next Generation Sequencing and Bioinformatics support, the Information and Communication Technology Office at the University of Macau for providing access to a High Performance Computer and Jacky Chan and William Pang for their expert support on the High Performance Computer. Finally, we thank Amanda Veri for generating CaLC2928. M.D.L. is supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust 096072), R.A.F. by a Wellcome Trust-Massachusetts Institute of Technology (MIT) Postdoctoral Fellowship, L.E.C. by a Canada Research Chair in Microbial Genomics and Infectious Disease and by Canadian Institutes of Health Research Grants MOP-119520 and MOP-86452, A.J. P.B. was supported by the UK Biotechnology and Biological Sciences Research Council (BB/F00513X/1) and by the European Research Council (ERC-2009-AdG-249793-STRIFE), KHW is supported by the Science and Technology Development Fund of Macau S.A.R (FDCT) (085/2014/A2) and the Research and Development Administrative Office of the University of Macau (SRG2014-00003-FHS) and R.T.W. by the Burroughs Wellcome fund and NIH R15AO094406. Data availability RNA-sequencing data sets are available at ArrayExpress (www.ebi.ac.uk) under accession code E-MTAB-4075. ChIP-seq data sets are available at the NCBI SRA database (http://www.ncbi.nlm.nih.gov) under accession code SRP071687. The authors declare that all other data supporting the findings of this study are available within the article and its supplementary information files, or from the corresponding author upon request.

Capping and methylation of mRNA by purified recombinant VP4 protein of bluetongue virus

The core of bluetongue virus (BTV) is a multienzyme complex composed of two major proteins (VP7 and VP3) and three minor proteins (VP1, VP4, and VP6) in addition to the viral genome. The core is transcriptionally active and produces capped mRNA from which all BTV proteins are translated, but the relative role of each core component in the overall reaction process remains unclear. Previously we showed that the 76-kDa VP4 protein possesses guanylyltransferase activity, a necessary part of the RNA capping reaction. Here, through the use of highly purified (>95%) VP4 and synthetic core-like particles containing VP4, we have investigated the extent to which this protein is also responsible for other activities associated with cap formation. We show that VP4 catalyzes the conversion of unmethylated GpppG or in vitro-produced uncapped BTV RNA transcripts to m7GpppGm in the presence of S-adenosyl-l-methionine. Analysis of the methylated products of the reaction by HPLC identified both methyltransferase type 1 and type 2 activities associated with VP4, demonstrating that the complete BTV capping reaction is associated with this one protein.

Ireland and Northern Ireland, 1705 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: A mapp of the kingdom of Ireland : newly corrected & improv'd by actual observations : divided into its provinces, counties, & baronies, and supply'd with many market towns & other places of note omitted in former mapps ... : together with plans of the citys and fortified towns, as allso a short description of the kingdom by Henry Pratt ; to this map is added a large index of the measur'd distances of ev'ry town from Dublin, of the burroughs, barracks, and post towns with many other improuements and emendations ; I. Harris, sculp. It was published by H. Pratt in 1708. Scale [ca. 1:385,000]. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Irish Grid (Transverse Mercator 1965 (TM-65)) coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, cities and other human settlements, major roads, territorial and administrative boundaries, shoreline features, and more. Relief shown pictorially. Includes also text, index, 16 ancillary town maps, and inset: The sea coasts of Great Britain and Ireland.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.