New pathogen-specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection

PublishedArticleThe specific and rapid detection of Enterobacteriaceae, the most frequent cause of gram-negative bacterial infections in humans, remains a major challenge. We developed a non-invasive method to rapidly detect systemic Yersinia enterocolitica infections using immunoPET (antibody-targeted positron emission tomography) with [64Cu]NODAGA-labeled Yersinia-specific polyclonal antibodies targeting the outer membrane protein YadA. In contrast to the tracer [18F]FDG, [64Cu]NODAGA-YadA uptake co-localized in a dose dependent manner with bacterial lesions of Yersinia-infected mice, as detected by magnetic resonance (MR) imaging. This was accompanied by elevated uptake of [64Cu]NODAGA-YadA in infected tissues, in ex vivo biodistribution studies, whereas reduced uptake was observed following blocking with unlabeled anti-YadA antibody. We show, for the first time, a bacteria-specific, antibody-based, in vivo imaging method for the diagnosis of a Gram-negative enterobacterial infection as a proof of concept, which may provide new insights into pathogen-host interactions.The research leading to these results has received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement n°602820, from the European Social Fund Baden-Württemberg (to SEA), and from the Deutsche Forschungsgemeinschaft (grant WI 3777/1-2; to SW)

The Anglo-Saxon migration and the formation of the early English gene pool

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2,3,4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6

Author Correction: The Anglo-Saxon migration and the formation of the early English gene pool.

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The Anglo-Saxon migration and the formation of the early English gene pool.

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2-4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans-including 278 individuals from England-alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6

A Model-Driven Approach for Conducting Simulation Experiments

With the increasing complexity of simulation studies, and thus increasing complexity of simulation experiments, there is a high demand for better support for them to be conducted. Recently, model-driven approaches have been explored for facilitating the specification, execution, and reproducibility of simulation experiments. However, a more general approach that is suited for a variety of modeling and simulation areas, experiment types, and tools, which also allows for further automation, is still missing. Therefore, we present a novel model-driven engineering (MDE) framework for simulation studies that extends the state-of-the-art of conducting simulation experiments in the following ways: (a) Providing a structured representation of the various ingredients of simulation experiments in the form of meta models and collecting them in a repository improves knowledge sharing across application domains and simulation approaches. (b) Specifying simulation experiments in the quasi-standardized form of the meta models (e.g., via a GUI) and, subsequently, performing the automatic generation of experiment specifications in a language of choice increases both the productivity and quality of complex simulation experiments. (c) Automatic code transformation between specification languages via the meta models enables the reusability of simulation experiments. (d) Integrating the framework using a command-line interface allows for further automation of subprocesses within a simulation study. We demonstrate the advantages and practicality of our approach using real simulation studies from three different fields of simulation (stochastic discrete-event simulation of a cell signaling pathway, virtual prototyping of a neurostimulator, and finite element analysis of electric fields) and various experiment types (global sensitivity analysis, time course analysis, and convergence testing). The proposed framework can be the starting point for further automation of simulation experiments and, therefore, can assist in conducting simulation studies in a more systematic and effective manner. For example, based on this MDE framework, approaches for automatically selecting and parametrizing experimentation methods, or for planning follow-up activities depending on the context of the simulation study, could be developed

The Positron Emission Tomography Tracer 3'-Deoxy-3'-[18F]Fluorothymidine ([18F]FLT) Is Not Suitable to Detect Tissue Proliferation Induced by Systemic Yersinia enterocolitica Infection in Mice.

Most frequently, gram-negative bacterial infections in humans are caused by Enterobacteriaceae and remain a major challenge in medical diagnostics. We non-invasively imaged moderate and severe systemic Yersinia enterocolitica infections in mice using the positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT), which is a marker of proliferation, and compared the in vivo results to the ex vivo biodistributions, bacterial loads, and histologies of the corresponding organs. Y. enterocolitica infection is detectable with histology using H&E staining and immunohistochemistry for Ki 67. [18F]FLT revealed only background uptake in the spleen, which is the main manifestation site of systemic Y. enterocolitica-infected mice. The uptake was independent of the infection dose. Antibody-based thymidine kinase 1 (Tk-1) staining confirmed the negative [18F]FLT-PET data. Histological alterations of spleen tissue, observed via Ki 67-antibody-based staining, can not be detected by [18F]FLT-PET in this model. Thus, the proliferation marker [18F]FLT is not a suitable tracer for the diagnosis of systemic Y. enterocolitica infection in the C57BL/6 animal model of yersiniosis

The Structure of the Protonated Serine Octamer

The amino acid serine has long been known to form a protonated "magic-number" cluster containing eight monomer units that shows an unusually high abundance in mass spectra and has a remarkable homochiral preference. Despite many experimental and theoretical studies, there is no consensus on a Ser(8)H(+) structure that is in agreement with all experimental observations. Here, we present the structure of Ser(8)H(+) determined by a combination of infrared spectroscopy and ab initio molecular dynamics simulations. The three-dimensional structure that we determine is similar to 25 kcal mol(-1) more stable than the previous most stable published structure and explains both the homochiral preference and the experimentally observed facile replacement of two serine units.115sciescopu

PET imaging of the proliferation in <i>Ye</i>-infected mice and the histological findings.

<p>(A) Coronal [¹⁸F]FLT-PET and fused PET and MR images from PBS-treated (n = 3), low- (n = 7) and high dose- (n = 8) infected mice 3 days <i>p</i>.<i>i</i>. The arrows indicate the positions of the spleens, which showed no increased uptake of [¹⁸F]FLT in <i>Ye</i> infected animals compared to PBS-treated controls. (B) Immunohistochemical stainings of spleen tissue sections from the PBS-treated, low dose-, and high dose-infected mice 3 days <i>p</i>.<i>i</i>. Sections were stained for H&E, Ki 67 and Tk-1.The encircled areas indicate germinal centers. A: abscess, RP: red pulp, WP: white pulp. Data are representative of 6 analyzed mice.</p