Strategies for Site‐Specific Labeling of Receptor Proteins on the Surfaces of Living Cells by Using Genetically Encoded Peptide Tags

Fluorescence microscopy imaging enables receptor proteins to be investigated within their biological context. A key challenge is to site-specifically incorporate reporter moieties into proteins without interfering with biological functions or cellular networks. Small peptide tags offer the opportunity to combine inducible labeling with small tag sizes that avoid receptor perturbation. Herein, we review the current state of live-cell labeling of peptide-tagged cell-surface proteins. Considering their importance as targets in medicinal chemistry, we focus on membrane receptors such as G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). We discuss peptide tags that i) are subject to enzyme-mediated modification reactions, ii) guide the complementation of reporter proteins, iii) form coiled-coil complexes, and iv) interact with metal complexes. Given our own contributions in the field, we place emphasis on peptide-templated labeling chemistry.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Leipzig School of Natural SciencesPeer Reviewe

Ligand-binding and -scavenging of the chemerin receptor GPR1

Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: as a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other. Graphic abstractDeutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Universität Leipzig (1039)Peer Reviewe

Defining robustness protocols: a method to include and evaluate robustness in clinical plans.

This is the final version of the article. It first appeared from IOP Publishing via http://dx.doi.org/10.1088/0031-9155/60/7/2671We aim to define a site-specific robustness protocol to be used during the clinical plan evaluation process. Plan robustness of 16 skull base IMPT plans to systematic range and random set-up errors have been retrospectively and systematically analysed. This was determined by calculating the error-bar dose distribution (ebDD) for all the plans and by defining some metrics used to define protocols aiding the plan assessment. Additionally, an example of how to clinically use the defined robustness database is given whereby a plan with sub-optimal brainstem robustness was identified. The advantage of using different beam arrangements to improve the plan robustness was analysed. Using the ebDD it was found range errors had a smaller effect on dose distribution than the corresponding set-up error in a single fraction, and that organs at risk were most robust to the range errors, whereas the target was more robust to set-up errors. A database was created to aid planners in terms of plan robustness aims in these volumes. This resulted in the definition of site-specific robustness protocols. The use of robustness constraints allowed for the identification of a specific patient that may have benefited from a treatment of greater individuality. A new beam arrangement showed to be preferential when balancing conformality and robustness for this case. The ebDD and error-bar volume histogram proved effective in analysing plan robustness. The process of retrospective analysis could be used to establish site-specific robustness planning protocols in proton therapy. These protocols allow the planner to determine plans that, although delivering a dosimetrically adequate dose distribution, have resulted in sub-optimal robustness to these uncertainties. For these cases the use of different beam start conditions may improve the plan robustness to set-up and range uncertainties.This work was partly funded by an MRC Doctoral Training Grant

Hybrid Cultures in Medieval Europe

Kulturen sind keine monolithischen Blöcke. Sie sind hybrid, setzen sich also aus Elementen verschiedenster Herkunft zusammen und bringen aus ihnen Neues hervor. Das DFG-Schwerpunktprogramm "Integration und Desintegration der Kulturen im europäischen Mittelalter" hat sich zum Ziel gesetzt, die Geschichte Europas im Mittelalter vom permanenten Kontakt und Austausch her zu denken und die sich daraus ergebenden Prozesse kultureller Innovationen zu analysieren. Auf einer "International Spring School" im April 2008 präsentierte sich das Schwerpunktprogramm einer breiten wissenschaftlichen Öffentlichkeit. Der Band vereint die dort gehaltenen Vorträge und Workshops. Das Phänomen der Hybridität von Kulturen und die Differenzen der mittelalterlichen Welt zwischen Island und der Levante, zwischen Skandinavien und Nordafrika werden aus den Blickwinkeln verschiedener Disziplinen (Byzantinistik, Skandinavistik, Mediävistik, Germanistik, Kunstgeschichte, Orientalistik, Judaistik, Osteuropäische Geschichte) und Wissenschaftsnationen (Ungarn, Italien, Niederlande, Russland, Frankreich, Israel, Griechenland, USA, Island, Deutschland) beleuchtet

Common characteristics of open source software development and applicability for drug discovery: a systematic review

<p>Abstract</p> <p>Background</p> <p>Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery.</p> <p>Methods</p> <p>A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project.</p> <p>Results</p> <p>Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined.</p> <p>Conclusions</p> <p>We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.</p

Mittelalter im Labor

Mit diesem Band präsentiert das Schwerpunktprogramm 1173 der Deutschen Forschungsgemeinschaft „Integration und Desintegration der Kulturen im europäischen Mittelalter“ erste Ergebnisse seiner Arbeit. Von Anfang an war ihm die Aufgabe gestellt, das mittelalterliche Europa in transkultureller Perspektive und auf Wegen einer transdisziplinären Wissenschaft zu erforschen und zu begreifen. Immer ging es darum, die disziplinär verfassten Einzelwissenschaften durch transdisziplinäre Arbeit zu ergänzen. Das wissenschaftliche Anliegen des Programms ist es, das europäische Mittelalter von seinen geografischen Rändern und seinen kulturellen Differenzen her zu erforschen und zu beschreiben. Der holistischen Frage nach der Einheit Europas wird die innere Vielfalt als gegenständlicher Ausgangspunkt entgegengesetzt. Europa wird nicht als abgeschlossenes, kohärentes Gebilde verstanden, sondern als ein Kontinent, dessen permanente Austausch- und Wechselbeziehungen zwischen den verschiedenen Regionen und Kulturen überhaupt erst zur Ausbildung seiner charakteristischen Merkmale geführt haben

Brain imaging of the cortex in ADHD: a coordinated analysis of large-scale clinical and population-based samples

Objective: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. Methods: Cortical thickness and surface area (based on the Desikan–Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). Results: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen’s d=−0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. Conclusions: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis

Shared genetic risk between eating disorder- and substance-use-related phenotypes:Evidence from genome-wide association studies

First published: 16 February 202

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe