Genetische Instabilität bei myeloischen Neoplasien

Die systemische Mastozytose (SM) reiht sich seit der jüngsten World Health Organisation (WHO) Klassifikation von 2016 als eine eigenständige Entität in die Gruppen der myeloischen Neoplasien ein. Die SM ist selten und aufgrund ihrer klinischen Heterogenität schwer zu diagnostizieren, zu klassifizieren und zu charakterisieren. Unabhängig von der Aggressivität der Erkrankung (indolent vs. fortgeschritten) kann bei >80 % der SM-Patienten eine aktivierende Punktmutation im KIT Gen an Stelle D816 detektiert werden. Diese Mutationen (am häufigsten KIT D816V) definieren den Phänotyp der SM, haben aber keinerlei prognostische Relevanz. In den letzten Jahren konnten molekulare Marker (z.B. Mutationen in SRSF2, ASXL1 und RUNX1) und klinische Parameter (z.B. Splenomegalie, erhöhte alkalische Phosphatase) identifiziert werden, die bei der SM mit einer schlechten Prognose assoziiert sind. Die Inzidenz und Bedeutung zytogenetischer Veränderungen bei SM-Patienten ist bisher nicht bekannt. Ziel der vorliegenden Arbeit war es, zytogenetische Aberrationen bei Patienten mit SM prognostisch einzuordnen, deren Einfluss auf Laborparameter und Überleben zu untersuchen und das Progressionsverhalten der Patienten mit aberrantem Karyotyp zu bestimmen. Um den klonalen Ursprung von Patienten mit SM und einer assoziierten hämatologischen Neoplasie (AHN) mit aberrantem Karyotyp zu untersuchen, sollte der Zusammenhang von Zytogenetik und Molekulargenetik bei multimutierten Patienten erforscht werden. In diesem Kontext sollte außerdem das Vorkommen klonaler Hierarchien geprüft werden. Im Rahmen unseres Registers für „Erkrankungen der Eosinophilen und Mastzellen“ konnten 109 Patienten mit SM (indolente SM, n= 26, 24 %; fortgeschrittene SM, n=83, 76 %) identifiziert werden, bei denen initial und/oder im Verlauf ihrer Erkrankung zytogenetische Analysen durchgeführt wurden. Alle Patienten mit indolenter SM hatten einen normalen Karyotyp während 19 % (16/83) der Patienten mit fortgeschrittener SM einen aberranten Karyotyp aufwiesen. Bei 15/16 (94 %) der Patienten wurde neben der SM eine AHN diagnostiziert. Analog zu anderen myeloischen Neoplasien, z.B. den myelodysplastischen Syndromen oder der akuten myeloischen Leukämie (AML), wurden die aberranten Karyotypen entweder in eine „prognostisch günstige“ (6/16) oder eine „prognostisch ungünstige“ (10/16) Risikogruppe eingeteilt. Patienten mit einem prognostisch günstigen Karyotyp lebten (unabhängig vom Mutationsstatus) länger (P<0,0001) und transformierten seltener in eine AML oder eine Mastzellleukämie als Patienten mit einem prognostisch ungünstigem Karyotyp (1/6, 17 % vs. 7/10, 70 %). Untersuchungen zur klonalen Architektur wurden an Kolonien von sechs SM-AHN Patienten durchgeführt. Während die KIT D816V Mutation zusammen mit Zusatzaberrationen wie SRSF2, ASXL1 und RUNX1 in derselben Zelle gefunden wurde, konnte die zytogenetische Veränderung nicht gemeinsam mit der KIT Mutation detektiert werden. In der vorliegenden Arbeit konnte erstmals der Stellenwert zytogenetischer Aberrationen bei Patienten mit SM-AHN gezeigt werden. Die gewonnenen Erkenntnisse identifizieren definierte chromosomale Veränderungen als prognostischen Marker für ein schlechtes Überleben, sind von hoher klinischer Relevanz und ermöglichen eine Änderung der Therapiestrategie

Morphology‐Dependent Influences on the Performance of Battery Cells with a Hierarchically Structured Positive Electrode**

The rising demand for high-performing batteries requires new technological concepts. To facilitate fast charge and discharge, hierarchically structured electrodes offer short diffusion paths in the active material. However, there are still gaps in understanding the influences on the cell performance of such electrodes. Here, we employed a cell model to demonstrate that the morphology of the hierarchically structured electrode determines which electrochemical processes dictate the cell performance. The potentially limiting processes include electronic conductivity within the porous secondary particles, solid diffusion within the primary particles, and ionic transport in the electrolyte surrounding the secondary particles. Mitigating these limits requires an electronic conductivity in the active material of at least 10−4 S m−1 and a primary particle radius below 100 nm. Our insights enable a goal-oriented tailoring of hierarchically structured electrodes for high-power applications

Host-pathogen systems biology: logical modelling of hepatocyte growth factor and Helicobacter pylori induced c-Met signal transduction

<p>Abstract</p> <p>Background</p> <p>The hepatocyte growth factor (HGF) stimulates mitogenesis, motogenesis, and morphogenesis in a wide range of tissues, including epithelial cells, on binding to the receptor tyrosine kinase c-Met. Abnormal c-Met signalling contributes to tumour genesis, in particular to the development of invasive and metastatic phenotypes. The human microbial pathogen <it>Helicobacter pylori </it>can induce chronic gastritis, peptic ulceration and more rarely, gastric adenocarcinoma. The <it>H. pylori </it>effector protein cytotoxin associated gene A (CagA), which is translocated via a type IV secretion system (T4SS) into epithelial cells, intracellularly modulates the c-Met receptor and promotes cellular processes leading to cell scattering, which could contribute to the invasiveness of tumour cells. Using a logical modelling framework, the presented work aims at analysing the c-Met signal transduction network and how it is interfered by <it>H. pylori </it>infection, which might be of importance for tumour development.</p> <p>Results</p> <p>A logical model of HGF and <it>H. pylori </it>induced c-Met signal transduction is presented in this work. The formalism of logical interaction hypergraphs (LIH) was used to construct the network model. The molecular interactions included in the model were all assembled manually based on a careful meta-analysis of published experimental results. Our model reveals the differences and commonalities of the response of the network upon HGF and <it>H. pylori </it>induced c-Met signalling. As another important result, using the formalism of minimal intervention sets, phospholipase Cγ1 (PLCγ1) was identified as knockout target for repressing the activation of the extracellular signal regulated kinase 1/2 (ERK1/2), a signalling molecule directly linked to cell scattering in <it>H. pylori </it>infected cells. The model predicted only an effect on ERK1/2 for the <it>H. pylori </it>stimulus, but not for HGF treatment. This result could be confirmed experimentally in MDCK cells using a specific pharmacological inhibitor against PLCγ1. The <it>in silico </it>predictions for the knockout of two other network components were also verified experimentally.</p> <p>Conclusion</p> <p>This work represents one of the first approaches in the direction of host-pathogen systems biology aiming at deciphering signalling changes brought about by pathogenic bacteria. The suitability of our network model is demonstrated by an <it>in silico </it>prediction of a relevant target against pathogen infection.</p

Morphology-Dependent Influences on the Performance of Battery Cells with a Hierarchically Structured Positive Electrode

The rising demand for high-performing batteries requires new technological concepts. To facilitate fast charge and discharge, hierarchically structured electrodes offer short diffusion paths in the active material. However, there are still gaps in understanding the influences on the cell performance of such electrodes. Here, we employed a cell model to demonstrate that the morphology of the hierarchically structured electrode determines which electrochemical processes dictate the cell performance. The potentially limiting processes include electronic conductivity within the porous secondary particles, solid diffusion within the primary particles, and ionic transport in the electrolyte surrounding the secondary particles. Our insights enable a goal-oriented tailoring of hierarchically structured electrodes for high-power applications

Importance of cortactin for efficient epithelial NF-ĸB activation by Helicobacter pylori, Salmonella enterica and Pseudomonas aeruginosa, but not Campylobacter spp.

Transcription factors of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF-ĸB) family control important signaling pathways in the regulation of the host innate immune system. Various bacterial pathogens in the human gastrointestinal tract induce NF-ĸB activity and provoke pro-inflammatory signaling events in infected epithelial cells. NF-ĸB activation requires the phosphorylation-dependent proteolysis of inhibitor of ĸB (IĸB) molecules including the NF-ĸB precursors through ubiquitin-mediated proteolysis. The canonical NF-ĸB pathway merges on IĸB kinases (IKKs), which are required for signal transduction. Using CRISPR-Cas9 technology, secreted embryonic alkaline phosphatase (SEAP) reporter assays and cytokine enzyme-linked immunosorbent assay (ELISA), we demonstrate that the actin-binding protein cortactin is involved in NF-ĸB activation and subsequent interleukin-8 (IL-8) production upon infection by Helicobacter pylori, Salmonella enterica and Pseudomonas aeruginosa. Our data indicate that cortactin is needed to efficiently activate the c-Sarcoma (Src) kinase, which can positively stimulate NF-ĸB during infection. In contrast, cortactin is not involved in activation of NF-ĸB and IL-8 expression upon infection with Campylobacter species C. jejuni, C. coli or C. consisus, suggesting that Campylobacter species pluralis (spp.) induce a different signaling pathway upstream of cortactin to trigger the innate immune response

LIME : Software for 3-D visualization, interpretation, and communication of virtual geoscience models

Parts of LIME have been developed to address research requirements in projects funded by the Research Council of Norway (RCN) through the Petromaks and Petromaks 2 programs. The following grants are acknowledged: 153264 (VOG [Virtual Outcrop Geology]; with Statoil ASA), 163316 (Carbonate Reservoir Geomodels [IRIS (International Research Institute of Stavanger)]), 176132 (Paleokarst Reservoirs [Uni Research CIPR]), 193059 (EUSA; with FORCE Sedimentology and Stratigraphy Group), 234152 (Trias North [University of Oslo]; with Deutsche Erdoel AG, Edison, Lundin, Statoil, and Tullow), 234111 (VOM2MPS [Uni Research CIPR]; with FORCE Sedimentology and Stratigraphy Group), as well as SkatteFUNN (RCN) project 266740. In addition, the SAFARI project consortium (http://safaridb.com) is thanked for its continued support. The OSG and wxWidgets communities are acknowledged for ongoing commitment to providing mature and powerful software libraries. All authors thank colleagues past and present for studies culminating in the presented figures: Kristine Smaadal and Aleksandra Sima (Figs. 1 and 4); Colm Pierce (Fig. 2A); Eivind Bastesen, Roy Gabrielsen and Haakon Fossen (Fig. 3); Christian Haug Eide (Fig. 7); Ivar Grunnaleite and Gunnar Sælen (Fig. 8); and Magda Chmielewska (Fig. 9). Isabelle Lecomte contributed to discussions on geospatial-geophysical data fusion. Bowei Tong and Joris Vanbiervliet are acknowledged for internal discussions during article revision. The lead author thanks Uni Research for providing a base funding grant to refine some of the presented features. Finally, authors Buckley and Dewez are grateful to Institut Carnot BRGM for the RADIOGEOM mobility grant supporting the writing of this paper. Corbin Kling and one anonymous reviewer helped improve the final manuscript.Peer reviewedPublisher PD

Old name, new face: a systematic analysis of flexor digitorum superficialis muscle with "chiasma antebrachii"

he gross anatomy of the forearm flexors, particularly that of the flexor digitorum superficialis (FDS) muscle, has been described and graphically illustrated in several anatomical books and atlases starting in the middle of the century before last. However, in anatomical dissection studies as well as in clinical-anatomical courses training muscle-specific targeted injections due to movement disorders such as dystonia or spasticity, it has become apparent that there is a need for a closer investigation of the complex construction of the FDS muscle. To this end, we studied the structure of the muscle bellies and tendons of FDS on 46 human body donates that have been used either in our dissection or clinical-anatomical training courses. With this, we demonstrate here the topographical configuration of the individual muscle belly for each of digits 2 through 5 and the exact paths of their tendons until their passing through the carpal tunnel. Furthermore, we demonstrate the presence of a chiasm of the FDS tendons for the digits 2 and 3, approximately 3-4 cm proximal of the carpal tunnel. Thus, we introduce herewith the terminology “chiasma antebrachii”. These findings were confirmed in situ by imaging of fixed human body donates via MRI and corroborated by MRI and ultrasound imaging in two volunteers. Taken together, the present findings enable an updated understanding of the complex organization of the heads, bellies, and tendons of FDS that is relevant not only for anatomical teaching but also clinical interventions

Clec12a Is an Inhibitory Receptor for Uric Acid Crystals that Regulates Inflammation in Response to Cell Death

SummaryRecognition of cell death by the innate immune system triggers inflammatory responses. However, how these reactions are regulated is not well understood. Here, we identify the inhibitory C-type lectin receptor Clec12a as a specific receptor for dead cells. Both human and mouse Clec12a could physically sense uric acid crystals (monosodium urate, MSU), which are key danger signals for cell-death-induced immunity. Clec12a inhibited inflammatory responses to MSU in vitro, and Clec12a-deficient mice exhibited hyperinflammatory responses after being challenged with MSU or necrotic cells and after radiation-induced thymocyte killing in vivo. Thus, we identified a negative regulatory MSU receptor that controls noninfectious inflammation in response to cell death that has implications for autoimmunity and inflammatory disease