Notes on the Useful Arts — Technological Progress as a Basis for Modern Architecture

It is a commonplace that Modern Architecture is a product of the Industrial Revolution, as practically all representatives of the Modern Movement refer, in some way or another, to technology and regard it as the foundation of their architecture. According to established historiography it is not only inspired by avantgarde art, but also draws on 19th century engineering and the “anonymous ethos” of modern mass-society—it is architecture for the “Machine Age”.A closer look reveals that art and technology have both accompanied humankind from the beginning and share the same root—creative imagination. With the Industrial Revolution, however, technology has not only opened up unprecedented new possibilities, but has also divorced itself from art, leading to technology—i.e., handicrafts, engineering, and industry—on the one hand being considered artless, and art on other hand—i.e., poetry, music and the visual arts—useless

Deep phenotyping: symptom annotation made simple with SAMS.

Precision medicine needs precise phenotypes. The Human Phenotype Ontology (HPO) uses clinical signs instead of diagnoses and has become the standard annotation for patients\u27 phenotypes when describing single gene disorders. Use of the HPO beyond human genetics is however still limited. With SAMS (Symptom Annotation Made Simple), we want to bring sign-based phenotyping to routine clinical care, to hospital patients as well as to outpatients. Our web-based application provides access to three widely used annotation systems: HPO, OMIM, Orphanet. Whilst data can be stored in our database, phenotypes can also be imported and exported as Global Alliance for Genomics and Health (GA4GH) Phenopackets without using the database. The web interface can easily be integrated into local databases, e.g. clinical information systems. SAMS offers users to share their data with others, empowering patients to record their own signs and symptoms (or those of their children) and thus provide their doctors with additional information. We think that our approach will lead to better characterised patients which is not only helpful for finding disease mutations but also to better understand the pathophysiology of diseases and to recruit patients for studies and clinical trials. SAMS is freely available at https://www.genecascade.org/SAMS/

MutationDistiller: user-driven identification of pathogenic DNA variants

MutationDistiller is a freely available online tool for user-driven analyses of Whole Exome Sequencing data. It offers a user-friendly interface aimed at clinicians and researchers, who are not necessarily bioinformaticians. MutationDistiller combines Mutation- Taster’s pathogenicity predictions with a phenotypebased approach. Phenotypic information is not limited to symptoms included in the Human Phenotype Ontology (HPO), but may also comprise clinical diagnoses and the suspected mode of inheritance. The search can be restricted to lists of candidate genes (e.g. virtual gene panels) and by tissue-specific gene expression. The inclusion of GeneOntology (GO) and metabolic pathways facilitates the discovery of hitherto unknown disease genes. In a novel approach, we trained MutationDistiller’s HPO-based prioritization on authentic genotype–phenotype sets obtained from ClinVar and found it to match or outcompete current prioritization tools in terms of accuracy. In the output, the program provides a list of potential disease mutations ordered by the likelihood of the affected genes to cause the phenotype. MutationDistiller provides links to gene-related information from various resources. It has been extensively tested by clinicians and their suggestions have been valued in many iterative cycles of revisions. The tool, a comprehensive documentation and examples are freely available at https://www.mutationdistiller.org

FABIAN-variant: predicting the effects of DNA variants on transcription factor binding.

While great advances in predicting the effects of coding variants have been made, the assessment of non-coding variants remains challenging. This is especially problematic for variants within promoter regions which can lead to over-expression of a gene or reduce or even abolish its expression. The binding of transcription factors to the DNA can be predicted using position weight matrices (PWMs). More recently, transcription factor flexible models (TFFMs) have been introduced and shown to be more accurate than PWMs. TFFMs are based on hidden Markov models and can account for complex positional dependencies. Our new web-based application FABIAN-variant uses 1224 TFFMs and 3790 PWMs to predict whether and to which degree DNA variants affect the binding of 1387 different human transcription factors. For each variant and transcription factor, the software combines the results of different models for a final prediction of the resulting binding-affinity change. The software is written in C++ for speed but variants can be entered through a web interface. Alternatively, a VCF file can be uploaded to assess variants identified by high-throughput sequencing. The search can be restricted to variants in the vicinity of candidate genes. FABIAN-variant is available freely at https://www.genecascade.org/fabian/

GeneDistiller—Distilling Candidate Genes from Linkage Intervals

Background: Linkage studies often yield intervals containing several hundred positional candidate genes. Different manual or automatic approaches exist for the determination of the gene most likely to cause the disease. While the manual search is very flexible and takes advantage of the researchers ’ background knowledge and intuition, it may be very cumbersome to collect and study the relevant data. Automatic solutions on the other hand usually focus on certain models, remain ‘‘black boxes’ ’ and do not offer the same degree of flexibility. Methodology: We have developed a web-based application that combines the advantages of both approaches. Information from various data sources such as gene-phenotype associations, gene expression patterns and protein-protein interactions was integrated into a central database. Researchers can select which information for the genes within a candidate interval or for single genes shall be displayed. Genes can also interactively be filtered, sorted and prioritised according to criteria derived from the background knowledge and preconception of the disease under scrutiny. Conclusions: GeneDistiller provides knowledge-driven, fully interactive and intuitive access to multiple data sources. It displays maximum relevant information, while saving the user from drowning in the flood of data. A typical query takes less than two seconds, thus allowing an interactive and explorative approach to the hunt for the candidate gene

AutozygosityMapper: Identification of disease-mutations in consanguineous families

With the shift from SNP arrays to high-throughput sequencing, most researchers studying diseases in consanguineous families do not rely on linkage analysis any longer, but simply search for deleterious variants which are homozygous in all patients. AutozygosityMapper allows the fast and convenient identification of disease mutations in patients from consanguineous pedigrees by focussing on homozygous segments shared by all patients. Users can upload multi-sample VCF files, including WGS data, without any pre-processing. Genome-wide runs of homozygosity and the underlying genotypes are presented in graphical interfaces. AutozygosityMapper extends the functions of its predecessor. HomozygosityMapper, to the search for autozygous regions, in which all patients share the same homozygous genotype. We provide export of VCF files containing only the variants found in homozygous regions, this usually reduces the number of variants by two orders of magnitude. These regions can also directly be analysed with our disease mutation identification tool MutationDistiller. The application comes with simple and intuitive graphical interfaces for data upload, analysis, and results. We kept the structure of HomozygosityMapper so that previous users will find it easy to switch. With AutozygosityMapper, we provide a fast web-based way to identify disease mutations in consanguineous families. AutozygosityMapper is freely available at https://www.genecascade. org/AutozygosityMapper/

GLS loss of function causes autosomal recessive spastic ataxia and optic atrophy.

We describe a consanguineous family in which two brothers were affected by childhood onset spastic ataxia with optic atrophy and loss of motor and language skills. Through a combination of homozygosity mapping and whole-genome sequencing, we identified a homozygous copy number variant in GLS as the cause. The duplication leads to complete knockout of GLS expression. GLS encodes the brain- and kidney-specific enzyme glutaminase, which hydrolyzes glutamine for the production of glutamate, the most abundant central nervous system neurotransmitter. This is the first report implicating GLS loss of function in human disease

"Festive Customs" and "Everyday Beauty". The Agenda and Self-Conception of the Nordic Life Reform Movement

In the second half of the 19th century, a wave of modernization, industrialization and urbanization swept the Nordic countries, catapulting what had until then been lagging and primarily rural countries into modernity. These major upheavals, however, also plunged the Nordic countries into a profound social and cultural crisis resulting from their consciousness of their own backwardness vis-a-vis the countries on the European continent, as well as the recognition that a nostalgic nationalism recalling a mythical past had become obsolete in the industrial age. In response to this crisis, a life reform movement emerged that was based on Arts and Crafts movements as well as various artistic and literary reform movements and-equally absorbing rural traditions and progressive social ideas-tried to establish a new national everyday culture. In this article, the two key terms coined by Ellen Key, "Festive Customs" ("festvanor") and "Everyday Beauty" ("vardagsskonhet")-the programmatic core of the Nordic life reform movement-are analysed and illustrated in various typical manifestations. It also examines to what extent the Nordic life reform movement with these two key concepts as its core agenda found expression in arts and crafts, in painting as well as in the architecture of the late nineteenth and early twentieth century and contributed to the progress of social and cultural renewal

The Construction Kit and the Assembly Line — Walter Gropius’ Concepts for Rationalizing Architecture

With the breakthrough of modernism, various efforts are undertaken to rationalize architecture and building processes using industrial principles. Few architects explore these as intensively as Walter Gropius, the founder of the Bauhaus. Even before World War One, and increasingly in the interwar years, Gropius and a number of colleagues undertake various experiments which manifest in a series of projects, essays, model houses and Siedlungen. These aim at conceptually different goals, i.e. they follow two different categories of industrial logic: first, a flexible construction kit and, second, an assembly line serial production. This article traces the genesis of these two concepts and analyses their characteristics using these early manifestations. Compared to existing literature, this article takes into account hitherto neglected primary sources as well as technological and construction history aspects—allowing for a distinction based not only on theoretical, but also technological and structural characteristics. This article shows that Gropius succeeds in formulating and exploring the two principles in theory and practice as well as drawing conclusions by the end of the 1920s. With them, he contributed significantly to the rationalization of architecture, and his principles have been picked up and developed further by numerous architects since then