The upgrading of fire safety in historic buildings

There is a seemingly continual erosion of our cultural heritage due to fires in historic buildings. Some of these fires result in partial loss of the asset, some result in total loss – in all cases irreplaceable historic fabric is destroyed. Accurate recording for fires in historic buildings is problematic, but such data as has been collated indicates that the level of loss is high. One of the key factors in achieving robust fire safety in historic buildings is the upgrading of physical fire protection measures. It has been suggested that we should assume a fire event is probable, and together with a context in which outside help might be some time in arriving, such measures are considered crucial in containing the fire and raising the alarm as quickly as possible. This article considers passive and active fire protection measures, using case study material to provide illustrative examples. Where it might be expected that conservation requirements, aiming to avoid negative impact to character and significance, might hinder disruptive physical interventions to improve fire protection, in fact a great deal can be achieved. Such a pragmatic approach is arguably necessary for the safety and preservation of built heritage, when the alternative might otherwise be yet another burnt-out shell

Citrobacter rodentium Subverts ATP Flux and Cholesterol Homeostasis in Intestinal Epithelial Cells In Vivo.

The intestinal epithelial cells (IECs) that line the gut form a robust line of defense against ingested pathogens. We investigated the impact of infection with the enteric pathogen Citrobacter rodentium on mouse IEC metabolism using global proteomic and targeted metabolomics and lipidomics. The major signatures of the infection were upregulation of the sugar transporter Sglt4, aerobic glycolysis, and production of phosphocreatine, which mobilizes cytosolic energy. In contrast, biogenesis of mitochondrial cardiolipins, essential for ATP production, was inhibited, which coincided with increased levels of mucosal O2 and a reduction in colon-associated anaerobic commensals. In addition, IECs responded to infection by activating Srebp2 and the cholesterol biosynthetic pathway. Unexpectedly, infected IECs also upregulated the cholesterol efflux proteins AbcA1, AbcG8, and ApoA1, resulting in higher levels of fecal cholesterol and a bloom of Proteobacteria. These results suggest that C. rodentium manipulates host metabolism to evade innate immune responses and establish a favorable gut ecosystem

Critical Dimensions in Architectural Photography: Contributions to Architectural Knowledge

This paper illustrates and explores three critical dimensions of photography in architecture, each of which informs the production of images, texts, and other artifacts which establish what might be called a building’s media footprint. The paper’s broad goal is to question the extent to which these critical dimensions are relevant to architectural decision-making processes. Acknowledging that such dimensions as the ones examined here rarely predict an architect’s specific design decisions in a transparent manner, the paper discusses not only the decisions made by architects during the process of designing buildings, but the decisions made by critics, visitors, and members of the general public as they engage in activities such as visiting buildings, writing about them and, particularly, photographing them. First, the text discusses the potential of buildings to operate as mechanisms for producing images, in the sense originated by Beatriz Colomina. The question is developed through the analysis of the space of photography – mapping of points of view, directions of view, and fields of view of defined photographic collections. Secondly, it considers photography’s complicity in the canonization of buildings, and specifically, the extent to which photography is responsible for distinguishing between major and minor architectural works. Finally, the essay examines the erosion over time of photography’s historical power to frame when confronted with contemporary technologies of virtual reality and photo realistically rendered digital models. Each of these critical dimensions, or concepts, develops a specific aspect of how photographic information about buildings is organized, structured, and disseminated, and is thus only part of the larger project of architectural epistemology, which inquires into this wider field. This will be done through an examination of the Mies van der Rohe-designed Commons Building at ITT in Chicago and the evolution of its relationship with architectural photography and photographic representation – both on its own terms and through the prism of the Rem Koolhaas-designed McCormick Tribune Student Center, which adds to and incorporates the Commons Building. Until the end of the twentieth century, the Commons Building on the campus of the Illinois Institute of Technology was generally considered one of Mies van der Rohe’s lesser works. Reportedly neglected by its own architect during the design process, and frequently marginalized in academic discussions of the campus, when mentioned at all the building was often cited as an unrefined prototype of Crown Hall. This discourse took a new direction when in 1998, Rem Koolhaas/OMA won a design competition for a student center on the IIT campus: uniquely among the competition entries, Koolhaas’s design incorporated the Commons Building within a new context – what ultimately became the McCormick Tribune Campus Center (MTCC). When critics concluded that the incorporation of the Commons Building into the larger whole could compromise its integrity as an exemplar of Mies’s work, the building became the object of renewed interest and controversy. The two projects considered here show a clear evolution in architecture’s relationship with the photographic image. Specifically, the history of the Commons Building can be traced through photographs: during and shortly following its construction, the building was photographed as part of Mies’s own attention to publicity; it was documented as part of historical analyses; and over time it was visited and photographed by casual and amateur photographers. Following the competition results, photographs of the Commons Building were strategically deployed by both proponents and critics of Koolhaas’s design. Contemporary photographs of the building appear in architectural and campus guidebooks and on websites such as Flickr.com. Examining the ways in which photographs of the Commons Building appear in these various contexts allows discussion of the critical dimensions identified above and permits us to trace the evolution of the mutually reinforcing relationship between architecture and photography

АССОЦИАЦИЯ СОЧЕТАНИЯ АБЕРРАЦИЙ ЧИСЛА КОПИЙ ГЕНОВ WNT-СИГНАЛИНГА И АМПЛИФИКАЦИЙ ГЕНОВ СТВОЛОВОСТИ В ОПУХОЛИ МОЛОЧНОЙ ЖЕЛЕЗЫ С МЕТАСТАЗИРОВАНИЕМ

We studied the association between the presence of 2 or more stemness gene amplifications as well as copy number aberrations (CNAs) of WNT signaling genes in residual breast tumor and metastasis. WNT pathway genes associated with metastasis were identified.Material and Methods. The study included 30 patients with breast cancer, who had 2 or more stemness gene amplifications in the residual tumor after neoadjuvant chemotherapy. Fifteen of the thirty patients developed hematogenous metastases; they constituted a group with metastases, the remaining 15 patients entered the second group without metastases. The tumor DNA was examined using a CytoScanHD Array microarray (Affymetrix, USA).Results. By subtracting amplification and deletion frequencies in 852 cytobands between groups with metastases and without metastases, 21 cytobands were identified with the largest difference in deletion and amplification frequencies. They contain 19/150 of WNT genes (12 activators: SKP1, WNT8A, MAPK9, CCND3, FZD9, WNT8B, CCND1, PLCB2, PRKCB, FZD2, WNT3, WNT9B and 7 negative regulators: GSK3B, APC, CSNK2B, SFRP5, BTRC, TCF7L2, CSNK2A2). A point system was developed: when amplifying WNT-signaling activators or deletion of negative regulators, one point was added to the total score, and vice versa when deleting WNT-signaling activators or amplification of negative regulators, one point was taken from the total amount. It was shown that 93% (14/15) of patients with metastases had a total score higher than 0, while 93% (14/15) of patients without metastases had a total score of zero or less than zero. The differences between the groups were statistically significant according to the two-sided Fisher test with a high level of confidence probability (p=0.000003) and the log-rank test (p=0.00004) when assessing non-metastatic survival by the Kaplan-Mayer method.Conclusion. Nineteen WNT signaling genes were identified. Copy number aberrations of these genes in combination with stemness gene amplifications in residual tumors were associated with metastasis. A new highly effective prognostic factor for breast cancer was identified. Введение. Изучена ассоциация с гематогенным метастазированием наличия 2 и более амплификаций генов стволовости и CNA (Copy Number Aberration) локусов генов WNT-сигнального пути в остаточной резидуальной опухоли молочной железы. Идентифицированы гены WNT-pathway, ассоциированные с метастазированием.Материал и методы. В исследование были включены 30 больных раком молочной железы, в резидуальной опухоли которых после неоадъювантной химиотерапии были 2 и более амплификации генов стволовости. У 15 из 30 больных развились гематогенные метастазы, они составили группу с метастазами, во вторую группу без метастазов вошли остальные 15 пациентов. ДНК опухоли была исследована при помощи микроматрицы CytoScanHD Array (Affymetrix, USA).Результаты. Путем вычитания частот амплификаций и делеций по 852 цитобендам между группами с метастазами и без метастазов был установлен 21 цитобенд с наибольшей разницей частот делеций и амплификаций. В них находятся 19 из 150 генов WNT (14 активаторов: SKP1, WNT8A, MAPK9, CCND3, FZD9, WNT8B, CCND1, PLCB2, PRKCB, FZD2, WNT3, WNT9B и 7 негативных регуляторов: GSK3B, APC, CSNK2B, SFRP5, BTRC, TCF7L2, CSNK2A2). Была разработана балльная система, при амплификации активаторов WNT-сигналинга или делеции негативных регуляторов к общей сумме баллов прибавлялся один балл, и, наоборот, при делеции активаторов WNT-сигналинга или амплификации негативных регуляторов от общей суммы отнимался один балл. Показано, что 93 % (14/15) больных с метастазами имеют суммарный балл больше 0, в то время как 93 % (14/15) больных без метастазов имеют суммарный балл, равный нулю или меньше нуля. Различия между группами статистически значимы по двустороннему критерию Фишера с высоким уровнем доверительной вероятности (р=0,000003) и по лог-ранговому тесту (р=0,00004) при оценке безметастатической выживаемости по методу Каплана – Майера.Заключение. Были идентифицированы 19 генов WNT-сигналинга, CNA которых в резидуальной опухоли, совместно с амплификациями генов стволовости ассоциированы с метастазированием и могут использоваться в качестве прогностического фактора.

The case for open science: rare diseases.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally

Locations and patterns of meiotic recombination in two-generation pedigrees

<p>Abstract</p> <p>Background</p> <p>Meiotic crossovers are the major mechanism by which haplotypes are shuffled to generate genetic diversity. Previously available methods for the genome-wide, high-resolution identification of meiotic crossover sites are limited by the laborious nature of the assay (as in sperm typing).</p> <p>Methods</p> <p>Several methods have been introduced to identify crossovers using high density single nucleotide polymorphism (SNP) array technologies, although programs are not widely available to implement such analyses.</p> <p>Results</p> <p>Here we present a two-generation "reverse pedigree analysis" method (analyzing the genotypes of two children relative to each parent) and a web-accessible tool to determine and visualize inheritance differences among siblings and crossover locations on each parental gamete. This approach is complementary to existing methods and uses informative markers which provide high resolution for locating meiotic crossover sites. We introduce a segmentation algorithm to identify crossover sites, and used a synthetic data set to determine that the segmentation algorithm specificity was 92% and sensitivity was 89%. The use of reverse pedigrees allows the inference of crossover locations on the X chromosome in a maternal gamete through analysis of two sons and their father. We further analyzed genotypes from eight multiplex autism families, observing a 1.462 maternal to paternal recombination ratio and no significant differences between affected and unaffected children. Meiotic recombination results from pediSNP can also be used to identify haplotypes that are shared by probands within a pedigree, as we demonstrated with a multiplex autism family.</p> <p>Conclusion</p> <p>Using "reverse pedigrees" and defining unique sets of genotype markers within pedigree data, we introduce a method that identifies inherited allelic differences and meiotic crossovers. We implemented the method in the pediSNP software program, and we applied it to several data sets. This approach uses data from two generations to identify crossover sites, facilitating studies of recombination in disease. pediSNP is available online at <url>http://pevsnerlab.kennedykrieger.org/pediSNP</url>.</p

Visualization of Shared Genomic Regions and Meiotic Recombination in High-Density SNP Data

A fundamental goal of single nucleotide polymorphism (SNP) genotyping is to determine the sharing of alleles between individuals across genomic loci. Such analyses have diverse applications in defining the relatedness of individuals (including unexpected relationships in nominally unrelated individuals, or consanguinity within pedigrees), analyzing meiotic crossovers, and identifying a broad range of chromosomal anomalies such as hemizygous deletions and uniparental disomy, and analyzing population structure.We present SNPduo, a command-line and web accessible tool for analyzing and visualizing the relatedness of any two individuals using identity by state. Using identity by state does not require prior knowledge of allele frequencies or pedigree information, and is more computationally tractable and is less affected by population stratification than calculating identity by descent probabilities. The web implementation visualizes shared genomic regions, and generates UCSC viewable tracks. The command-line version requires pedigree information for compatibility with existing software and determining specified relationships even though pedigrees are not required for IBS calculation, generates no visual output, is written in portable C++, and is well-suited to analyzing large datasets. We demonstrate how the SNPduo web tool identifies meiotic crossover positions in siblings, and confirm our findings by visualizing meiotic recombination in synthetic three-generation pedigrees. We applied SNPduo to 210 nominally unrelated Phase I / II HapMap samples and, consistent with previous findings, identified six undeclared pairs of related individuals. We further analyzed identity by state in 2,883 individuals from multiplex families with autism and identified a series of anomalies including related parents, an individual with mosaic loss of chromosome 18, an individual with maternal heterodisomy of chromosome 16, and unexplained replicate samples.SNPduo provides the ability to explore and visualize SNP data to characterize the relatedness between individuals. It is compatible with, but distinct from, other established analysis software such as PLINK, and performs favorably in benchmarking studies for the analyses of genetic relatedness

A blot on the landscape? Civic memory and municipal public parks in early twentieth century Manchester

This paper examines the decision to locate the façade of Manchester’s old Town Hall in a public park (Heaton Park) in 1912. It argues that, in so doing, the city’s Parks and Cemeteries committee was attempting to refine the didactic space of the park as a site of civic memory. The early Victorian urban parks had sought to educate their visitors through their museums, art galleries and exhibition spaces, glasshouses and carefully-planned and planted walkways. The insertion into this environment of part of a former civic building was intended to remind the visitors of their civic history and to warn surrounding districts of the expansionist tendencies of the city of Manchester. The failure to identify the façade or to connect it to its surroundings meant that its meaning was ultimately lost to many parks visitors and it remained in place as a civic folly. Public parks presented the municipal authorities with an opportunity to highlight the provision of recreation and leisure facilities, but also an occasion to re-invent the municipal tradition. However, as this paper shows, such gestures were often futile in the complex and contested space of the public park