Nanorotors and self-assembling macromolecular machines: The torque ring of the bacterial flagellar motor

The bacterial flagellar motor (BFM) is a self-assembling rotary nanomachine. It converts a flux of cations into the mechanical rotation of long filaments that propel bacteria through viscous media. The BFM contains a torque-generating ring that is complete with molecular machinery known as the switch complex that allows it to reverse directions. With four billion years of optimization, the BFM probably offers the pinnacle of sophisticated nanorotor design. Moreover as one of the best-characterized large biomolecular complexes, it offers the potential for convergence between nanotechnology and biology, which requires an atomic level understanding of BFM structure and function. This review focuses on current molecular models of the reversible BFM and the strategies used to derive them

The Dermatan Sulfate Proteoglycan Decorin Modulates α2β1 Integrin and the Vimentin Intermediate Filament System during Collagen Synthesis.

Decorin, a small leucine-rich proteoglycan harboring a dermatan sulfate chain at its N-terminus, is involved in regulating matrix organization and cell signaling. Loss of the dermatan sulfate of decorin leads to an Ehlers-Danlos syndrome characterized by delayed wound healing. Decorin-null (Dcn(-/-)) mice display a phenotype similar to that of EDS patients. The fibrillar collagen phenotype of Dcn(-/-) mice could be rescued in vitro by decorin but not with decorin lacking the glycosaminoglycan chain. We utilized a 3D cell culture model to investigate the impact of the altered extracellular matrix on Dcn(-/-) fibroblasts. Using 2D gel electrophoresis followed by mass spectrometry, we identified vimentin as one of the proteins that was differentially upregulated by the presence of decorin. We discovered that a decorin-deficient matrix leads to abnormal nuclear morphology in the Dcn(-/-) fibroblasts. This phenotype could be rescued by the decorin proteoglycan but less efficiently by the decorin protein core. Decorin treatment led to a significant reduction of the α2β1 integrin at day 6 in Dcn(-/-) fibroblasts, whereas the protein core had no effect on β1. Interestingly, only the decorin core induced mRNA synthesis, phosphorylation and de novo synthesis of vimentin indicating that the proteoglycan decorin in the extracellular matrix stabilizes the vimentin intermediate filament system. We could support these results in vivo, because the dermis of wild-type mice have more vimentin and less β1 integrin compared to Dcn(-/-). Furthermore, the α2β1 null fibroblasts also showed a reduced amount of vimentin compared to wild-type. These data show for the first time that decorin has an impact on the biology of α2β1 integrin and the vimentin intermediate filament system. Moreover, our findings provide a mechanistic explanation for the reported defects in wound healing associated with the Dcn(-/-) phenotype

Achieving consensus in the measurement of psychological adjustment to cleft lip and/or palate at age 8 years+

Background: Consensus regarding optimal outcome measurement has been identified as one of the most important, yet most challenging developments for the future of cleft lip and/or palate (CL/P) services. In 2011, a process began to adopt a shared conceptual framework and to identify a set of core outcome measures for the comprehensive assessment of psychological adjustment. Objectives: The aim of the current article is to outline the collaborative process used to achieve consensus in the academic and clinical measurement of psychological adjustment to CL/P from the age of 8 years onward. Results: A conceptual framework and corresponding parent- and self-reported outcome measures for use at ages 8, 10, 12, 15, 18, 20, and 25 years have been agreed upon by clinicians, researchers, and patient and parent representatives. All measures have been evaluated according to their psychometric properties, clinical utility, ability to produce meaningful longitudinal data, and a range of pragmatic considerations. Conclusions: Although the collaborative process has been challenging and has required ongoing dedication from multiple stakeholders, consistency in data collection over time will allow for key research questions in CL/P to be addressed, both in the United Kingdom (UK) and internationally. The process has also demonstrated the clinical utility of the measures and the potential for the gradual integration of the measures into clinical practice. UK progress has sparked global interest, and the adaptation of the framework and its corresponding measures for worldwide use is now a prominent focus

Vorwort und Editorial

Auch wenn (berufs-)bildungspolitische Diskussionen um Gleichwertigkeit, Durchlässigkeit, Anerkennung und aktuell um Verberuflichung des Akademischen und Akademisierung des Beruflichen eine Annäherung allgemeiner und beruflicher Bildung vermuten lassen, ist die Frage nach dem Verhältnis dieser beiden Bildungen nicht eindeutig gelöst. Vielmehr stehen nach wie vor unterschiedliche Positionen nebeneinander. Im folgenden Beitrag geht es weniger um die Frage danach, was beide Bildungen eint, trennt und wie sie miteinander verbunden werden können. Vielmehr soll sich der Frage angenähert werden, von welchen übergreifenden historischen bildungstheoretischen und -politischen Gedanken und Ereignissen beide Bereiche betroffen waren und sind, und wie diese die Verhältnisfrage tangiert und entschieden haben. Unter drei historisch widersprüchlichen Aspekten, von denen sowohl die allgemeine als auch die berufliche Bildung betroffen sind, wird thematisiert, wie diese Widersprüche intern, also im Verhältnis zwischen Allgemeinbildung und Berufsbildung als Idee und allgemeiner und beruflicher Bildung als soziale Realität historisch gelöst wurden. Zu diesen übergreifenden Widersprüchen gehören: Bildung für alle und die soziale Portionierung von Bildung, Allseitigkeit von Bildung und Halbbildung und allgemeine Nützlichkeit von Bildung und Ökonomisierung. Die Frage, die mit diesem Beitrag angestoßen werden soll, ist, wie über Bildung übergreifend nachgedacht werden kann, damit allgemeine und berufliche Bildung nicht mehr gegeneinander ausgespielt werden und ohne Ungleichwertigkeiten ineinanderfließen, sich abgrenzen und ergänzen können

Tangible Data Souvenirs as a Bridge between a Physical Museum Visit and Online Digital Experience

This paper presents the design, implementation, use and evaluation of a tangible data souvenir for an interactive museum exhibition. We define a data souvenir as the materialisation of the personal visiting experience: a data souvenir is dynamically created on the basis of data recorded throughout the visit and therefore captures and represents the experience as lived. The souvenir provides visitors with a memento of their visit and acts as a gateway to further online content. A step further is to enable visitors to contribute, in other words the data souvenir can become a means to collect visitor-generated content. We discuss the rationale behind the use of a data souvenir, the design process and resulting artefacts, and the implementation of both the data souvenir and online content system. Finally we examine the installation of the data souvenirs as part of a long-lasting exhibition: the use of this souvenir by visitors has been logged over seven months and issues around the gathering of user-generated content in such a way are discussed. Keywords: Tangible interaction; data souvenir; museums; user-generated content

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The N–Terminal Tail of hERG Contains an Amphipathic α–Helix That Regulates Channel Deactivation

The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013)

The Two-Component Signal Transduction System CopRS of Corynebacterium glutamicum Is Required for Adaptation to Copper-Excess Stress

Copper is an essential cofactor for many enzymes but at high concentrations it is toxic for the cell. Copper ion concentrations ≥50 µM inhibited growth of Corynebacterium glutamicum. The transcriptional response to 20 µM Cu2+ was studied using DNA microarrays and revealed 20 genes that showed a ≥ 3-fold increased mRNA level, including cg3281-cg3289. Several genes in this genomic region code for proteins presumably involved in the adaption to copper-induced stress, e. g. a multicopper oxidase (CopO) and a copper-transport ATPase (CopB). In addition, this region includes the copRS genes (previously named cgtRS9) which encode a two-component signal transduction system composed of the histidine kinase CopS and the response regulator CopR. Deletion of the copRS genes increased the sensitivity of C. glutamicum towards copper ions, but not to other heavy metal ions. Using comparative transcriptome analysis of the ΔcopRS mutant and the wild type in combination with electrophoretic mobility shift assays and reporter gene studies the CopR regulon and the DNA-binding motif of CopR were identified. Evidence was obtained that CopR binds only to the intergenic region between cg3285 (copR) and cg3286 in the genome of C. glutamicum and activates expression of the divergently oriented gene clusters cg3285-cg3281 and cg3286-cg3289. Altogether, our data suggest that CopRS is the key regulatory system in C. glutamicum for the extracytoplasmic sensing of elevated copper ion concentrations and for induction of a set of genes capable of diminishing copper stress

The Pseudomonas aeruginosa Chemotaxis Methyltransferase CheR1 Impacts on Bacterial Surface Sampling

The characterization of factors contributing to the formation and development of surface-associated bacterial communities known as biofilms has become an area of intense interest since biofilms have a major impact on human health, the environment and industry. Various studies have demonstrated that motility, including swimming, swarming and twitching, seems to play an important role in the surface colonization and establishment of structured biofilms. Thereby, the impact of chemotaxis on biofilm formation has been less intensively studied. Pseudomonas aeruginosa has a very complex chemosensory system with two Che systems implicated in flagella-mediated motility. In this study, we demonstrate that the chemotaxis protein CheR1 is a methyltransferase that binds S-adenosylmethionine and transfers a methyl group from this methyl donor to the chemoreceptor PctA, an activity which can be stimulated by the attractant serine but not by glutamine. We furthermore demonstrate that CheR1 does not only play a role in flagella-mediated chemotaxis but that its activity is essential for the formation and maintenance of bacterial biofilm structures. We propose a model in which motility and chemotaxis impact on initial attachment processes, dispersion and reattachment and increase the efficiency and frequency of surface sampling in P. aeruginosa