Epithelial calcineurin controls microbiota-dependent intestinal tumor development.

Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and selectively activated in intestinal tumors as a result of impaired stratification of the tumor-associated microbiota and toll-like receptor signaling. Epithelial calcineurin supports the survival and proliferation of cancer stem cells in an NFAT-dependent manner and promotes the development of intestinal tumors in mice. Moreover, somatic mutations that have been identified in human CRC are associated with constitutive activation of calcineurin, whereas nuclear translocation of NFAT is associated with increased death from CRC. These findings highlight an epithelial cell-intrinsic pathway that integrates signals derived from the commensal microbiota to promote intestinal tumor development.This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grants ZE814/5-1 (S.Z.), BA2863/5-1 (J.F.B.) and CH279/5-1 (T.C.), the European Research Council (ERC) starting grant 336528 (S.Z.), a Postdoctoral Fellowship Award from the Crohn's and Colitis Foundation of America (S.Z.), the European Commission (Marie Curie International Reintegration grant 256363; S.Z.), the DFG Excellence Cluster 'Inflammation at Interfaces' (S.Z. and J.F.B.), the DFG Excellence Cluster 'Center for Regenerative Therapies' (S.Z.); the US National Institutes of Health grants DK044319 (R.S.B.), DK051362 (R.S.B.), DK053056 (R.S.B.) and DK088199 (R.S.B.), the Harvard Digestive Diseases Center (HDDC) grant DK0034854 (R.S.B.), and the AIRC grant IG-14233 (M.E.B.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nm.407

Expression of PROKR1 and PROKR2 in Human Enteric Neural Precursor Cells and Identification of Sequence Variants Suggest a Role in HSCR

Background The enteric nervous system (ENS) is entirely derived from neural crest and its normal development is regulated by specific molecular pathways. Failure in complete ENS formation results in aganglionic gut conditions such as Hirschsprung's disease (HSCR). Recently, PROKR1 expression has been demonstrated in mouse enteric neural crest derived cells and Prok-1 was shown to work coordinately with GDNF in the development of the ENS. Principal Findings In the present report, ENS progenitors were isolated and characterized from the ganglionic gut from children diagnosed with and without HSCR, and the expression of prokineticin receptors was examined. Immunocytochemical analysis of neurosphere-forming cells demonstrated that both PROKR1 and PROKR2 were present in human enteric neural crest cells. In addition, we also performed a mutational analysis of PROKR1, PROKR2, PROK1 and PROK2 genes in a cohort of HSCR patients, evaluating them for the first time as susceptibility genes for the disease. Several missense variants were detected, most of them affecting highly conserved amino acid residues of the protein and located in functional domains of both receptors, which suggests a possible deleterious effect in their biological function. Conclusions Our results suggest that not only PROKR1, but also PROKR2 might mediate a complementary signalling to the RET/GFRα1/GDNF pathway supporting proliferation/survival and differentiation of precursor cells during ENS development. These findings, together with the detection of sequence variants in PROKR1, PROK1 and PROKR2 genes associated to HSCR and, in some cases in combination with RET or GDNF mutations, provide the first evidence to consider them as susceptibility genes for HSCR.This work was supported by Fondo de Investigación Sanitaria, Spain (PI070080, PI1001290 and PI071315 for the E-Rare project), Consejería de Innovación Ciencia y Empresa de la Junta de Andalucía (CTS 2590) and Consejería de Salud de la Junta de Andalucía (PI0249-2008). The CIBER de Enfermedades Raras is an initiative of the ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Oberflächenuntersuchungen mit Vakuum-UV-Strahlung

PTB-Mitteilungen. Band 124 (2014), Heft 4, Seite 29 - 32. ISSN 0030-834

An X-ray gas monitor for free-electron lasers

A novel X-ray gas monitor (XGM) has been developed which allows the measurement of absolute photon pulse energy and photon beam position at all existing and upcoming free-electron lasers (FELs) over a broad spectral range covering vacuum ultraviolet (VUV), extreme ultraviolet (EUV) and soft and hard X-rays. The XGM covers a wide dynamic range from spontaneous undulator radiation to FEL radiation and provides a temporal resolution of better than 200 ns. The XGM consists of two X-ray gas-monitor detectors (XGMDs) and two huge-aperture open electron multipliers (HAMPs). The HAMP enhances the detection efficiency of the XGM for low-intensity radiation down to 10$^5$ photons per pulse and for FEL radiation in the hard X-ray spectral range, while the XGMD operates in higher-intensity regimes. The relative standard uncertainty for measurements of the absolute photon pulse energy is well below 10%, and down to 1% for measurements of relative pulse-to-pulse intensity on pulses with more than 10$^{10}$ photons per pulse. The accuracy of beam-position monitoring in the vertical and horizontal directions is of the order of 10 µm

Identifying surface reaction intermediates with photoemission tomography

The determination of reaction pathways and the identification of reaction intermediates are key issues in chemistry. Surface reactions are particularly challenging, since many methods of analytical chemistry are inapplicable at surfaces. Recently, atomic force microscopy has been employed to identify surface reaction intermediates. While providing an excellent insight into the molecular backbone structure, atomic force microscopy is less conclusive about the molecular periphery, where adsorbates tend to react with the substrate. Here we show that photoemission tomography is extremely sensitive to the character of the frontier orbitals. Specifically, hydrogen abstraction at the molecular periphery is easily detected, and the precise nature of the reaction intermediates can be determined. This is illustrated with the thermally induced reaction of dibromo-bianthracene to graphene which is shown to proceed via a fully hydrogenated bisanthene intermediate. We anticipate that photoemission tomography will become a powerful companion to other techniques in the study of surface reaction pathways

Metrologie mit Synchrotronstrahlung, Teil II (Auszug aus: PTB-Mitteilungen 2014, Band 124, Heft 4. ISSN 0030-834X)

PTB-Mitteilungen. Band 124 (2014), Heft 4. ISSN 0030-834X1.: Scholze, Frank, Christian Laubis, Annett Barboutis, Christian Buchholz, Andreas Fischer, Jana Puls und Christian Stadelhoff: Radiometrie für die EUV-Lithographie. doi: 10.7795/310.20140401 http://dx.doi.org/10.7795/210.20140401 2.: Scholze, Frank, Anton Haase, Michael Krumrey, Victor Soltwisch und Jan Wernecke: Streuverfahren an nanostrukturierten Oberflächen. doi: 10.7795/310.20140402 http://dx.doi.org/10.7795/310.20140402 3.: Krumrey, Michael, Raul Garcia-Diez, Christian Gollwitzer und Stefanie Langner: Größenbestimmung von Nanopartikeln mit Röntgenkleinwinkelstreuung. doi: 10.7795/310.20140403 http://dx.doi.org/10.7795/310.20140403 4.: Müller, Matthias, Martin Gerlach, Ina Holfelder, Philipp Hönicke, Janin Lubeck, Andreas Nutsch, Beatrix Pollakowski, Cornelia Streeck, Rainer Unterumsberger, Jan Weser und Burkhard Beckhoff: Röntgenspektrometrie mit Synchrotronstrahlung. doi: 10.7795/310.20140404 http://dx.doi.org/10.7795/210.20140404 5.: Hermann, Peter, Arne Hoehl, Andrea Hornemann, Bernd Kästner, Ralph Müller, Burkhard Beckhoff und Gerhard Ulm: Mikro- und Nano-Spektroskopie und Detektorcharakterisierung im IR- und THz-Bereich an der Metrology Light Source. doi: 10.7795/310.20140405 http://dx.doi.org/10.7795/310.20140405 6.: Kolbe, Michael, Erik Darlatt, Rolf Fliegauf, Hendrik Kaser, Alexander Gottwald und Mathias Richter: Oberflächenuntersuchungen mit Vakuum-UV-Strahlung. doi: 10.7795/310.20140406 http://dx.doi.org/10.7795/310.2014040

Research update for articles published in EJCI in 2008

Eur J Clin Invest 2010; 40 (9): 770-78