Fast, linked, and open – the future of taxonomic publishing for plants: launching the journal PhytoKeys

The paper describes the focus, scope and the rationale of PhytoKeys, a newly established, peer-reviewed, open-access journal in plant systematics. PhytoKeys is launched to respond to four main challenges of our time: (1) Appearance of electronic publications as amendments or even alternatives to paper publications; (2) Open Access (OA) as a new publishing model; (3) Linkage of electronic registers, indices and aggregators that summarize information on biological species through taxonomic names or their persistent identifiers (Globally Unique Identifiers or GUIDs; currently Life Science Identifiers or LSIDs); (4) Web 2.0 technologies that permit the semantic markup of, and semantic enhancements to, published biological texts. The journal will pursue cutting-edge technologies in publication and dissemination of biodiversity information while strictly following the requirements of the current International Code of Botanical Nomenclature (ICBN)

Neuorientierung der Arbeitsmarktpolitik : Die Neuausrichtung der arbeitsmarktpolitischen Instrumente aus dem Jahr 2009 im Blickpunkt: Mehr Flexibilität und größere Handlungsspielräume für die Vermittler?

"This paper deals with the strategic reorientation concerning the instruments of active labor market policy in Germany which came into force at January 1st 2009. The main objective of this reform was to streamline the portfolio of existing instruments and make it more transparent and clearly structured. Moreover, caseworkers in local job offices are to be granted more discretion and flexibility than prior to the reforms. The authors address the question whether the implementation of more discretionary power was successful, and which of the implementation's characteristics prove to be crucial for attaining this goal. To this purpose, expert interviews with caseworkers, their superior officers (team leaders) and members of the board were conducted in 14 local job offices. The study is based on the methodological concept of the socalled 'scientific source text' ('wissenschaftlicher Quellentext') which was used to analyze and interpret the interviews. Empirically, the authors find that the reform did not induce fundamental changes concerning the instruments of active labor market policy while the special budget for the support of job search activities ('Vermittlungsbudget') according to § 45 SGB III can be regarded as an innovation. Caseworkers especially stress the conflict between compliance to the rules and the considerable autonomy involved in the everyday practice of street-level bureaucrats. Rules aimed at structuring discretional leeway in the local job offices (so-called 'Ermessenslenkende Weisungen') help define the relative concept of discretion, because they include instructions already valid before the reforms. Finally, it is remarkable to note that § 16f SGB II does not play an important role after the reform." (Author's abstract, IAB-Doku) ((en))Arbeitsmarktpolitik, Reformpolitik - Erfolgskontrolle, arbeitsmarktpolitische Maßnahme, Arbeitsvermittler, Handlungsspielraum, Aktivierung, berufliche Reintegration, Arbeitslose, Arbeitsvermittlung, Budget, Sozialgesetzbuch II, Sozialgesetzbuch III, freie Förderung, Politikumsetzung

Bromodomains as therapeutic targets

Acetylation of lysine residues is a post-translational modification with broad relevance to cellular signalling and disease biology. Enzymes that ‘write’ (histone acetyltransferases, HATs) and ‘erase’ (histone deacetylases, HDACs) acetylation sites are an area of extensive research in current drug development, but very few potent inhibitors that modulate the ‘reading process’ mediated by acetyl lysines have been described. The principal readers of ɛ-N-acetyl lysine (Kac) marks are bromodomains (BRDs), which are a diverse family of evolutionary conserved protein-interaction modules. The conserved BRD fold contains a deep, largely hydrophobic acetyl lysine binding site, which represents an attractive pocket for the development of small, pharmaceutically active molecules. Proteins that contain BRDs have been implicated in the development of a large variety of diseases. Recently, two highly potent and selective inhibitors that target BRDs of the BET (bromodomains and extra-terminal) family provided compelling data supporting targeting of these BRDs in inflammation and in an aggressive type of squamous cell carcinoma. It is likely that BRDs will emerge alongside HATs and HDACs as interesting targets for drug development for the large number of diseases that are caused by aberrant acetylation of lysine residues

Structural basis of fumarate hydratase deficiency

Fumarate hydratase catalyzes the stereospecific hydration across the olefinic double bond in fumarate leading to L-malate. The enzyme is expressed in mitochondrial and cytosolic compartments, and participates in the Krebs cycle in mitochondria, as well as in regulation of cytosolic fumarate levels. Fumarate hydratase deficiency is an autosomal recessive trait presenting as metabolic disorder with severe encephalopathy, seizures and poor neurological outcome. Heterozygous mutations are associated with a predisposition to cutaneous and uterine leiomyomas and to renal cancer. The crystal structure of human fumarate hydratase shows that mutations can be grouped into two distinct classes either affecting structural integrity of the core enzyme architecture, or are localized around the enzyme active site

Assessing cellular efficacy of bromodomain inhibitors using fluorescence recovery after photobleaching

BACKGROUND: Acetylation of lysine residues in histone tails plays an important role in the regulation of gene transcription. Bromdomains are the readers of acetylated histone marks, and, consequently, bromodomain-containing proteins have a variety of chromatin-related functions. Moreover, they are increasingly being recognised as important mediators of a wide range of diseases. The first potent and selective bromodomain inhibitors are beginning to be described, but the diverse or unknown functions of bromodomain-containing proteins present challenges to systematically demonstrating cellular efficacy and selectivity for these inhibitors. Here we assess the viability of fluorescence recovery after photobleaching (FRAP) assays as a target agnostic method for the direct visualisation of an on-target effect of bromodomain inhibitors in living cells. RESULTS: Mutation of a conserved asparagine crucial for binding to acetylated lysines in the bromodomains of BRD3, BRD4 and TRIM24 all resulted in reduction of FRAP recovery times, indicating loss of or significantly reduced binding to acetylated chromatin, as did the addition of known inhibitors. Significant differences between wild type and bromodomain mutants for ATAD2, BAZ2A, BRD1, BRD7, GCN5L2, SMARCA2 and ZMYND11 required the addition of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) to amplify the binding contribution of the bromodomain. Under these conditions, known inhibitors decreased FRAP recovery times back to mutant control levels. Mutation of the bromodomain did not alter FRAP recovery times for full-length CREBBP, even in the presence of SAHA, indicating that other domains are primarily responsible for anchoring CREBBP to chromatin. However, FRAP assays with multimerised CREBBP bromodomains resulted in a good assay to assess the efficacy of bromodomain inhibitors to this target. The bromodomain and extraterminal protein inhibitor PFI-1 was inactive against other bromodomain targets, demonstrating the specificity of the method. CONCLUSIONS: Viable FRAP assays were established for 11 representative bromodomain-containing proteins that broadly cover the bromodomain phylogenetic tree. Addition of SAHA can overcome weak binding to chromatin, and the use of tandem bromodomain constructs can eliminate masking effects of other chromatin binding domains. Together, these results demonstrate that FRAP assays offer a potentially pan-bromodomain method for generating cell-based assays, allowing the testing of compounds with respect to cell permeability, on-target efficacy and selectivity

A Gene for Universal Congenital Alopecia Maps to Chromosome 8p21-22

SummaryComplete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development

The scientific impact of the Structural Genomics Consortium: a protein family and ligand-centered approach to medically-relevant human proteins

As many of the structural genomics centers have ended their first phase of operation, it is a good point to evaluate the scientific impact of this endeavour. The Structural Genomics Consortium (SGC), operating from three centers across the Atlantic, investigates human proteins involved in disease processes and proteins from Plasmodium falciparum and related organisms. We present here some of the scientific output of the Oxford node of the SGC, where the target areas include protein kinases, phosphatases, oxidoreductases and other metabolic enzymes, as well as signal transduction proteins. The SGC has aimed to achieve extensive coverage of human gene families with a focus on protein–ligand interactions. The methods employed for effective protein expression, crystallization and structure determination by X-ray crystallography are summarized. In addition to the cumulative impact of accelerated delivery of protein structures, we demonstrate how family coverage, generic screening methodology, and the availability of abundant purified protein samples, allow a level of discovery that is difficult to achieve otherwise. The contribution of NMR to structure determination and protein characterization is discussed. To make this information available to a wide scientific audience, a new tool for disseminating annotated structural information was created that also represents an interactive platform allowing for a continuous update of the annotation by the scientific community