Deletion of CD39 on natural killer cells attenuates hepatic ischemia/reperfusion injury in mice

Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion. CONCLUSION: We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.

MET inhibition in tumor cells by PHA665752 impairs homologous recombination repair of DNA double strand breaks

Abnormal activation of cellular DNA repair pathways by deregulated signaling of receptor tyrosine kinase systems has broad implications for both cancer biology and treatment. Recent studies suggest a potential link between DNA repair and aberrant activation of the hepatocyte growth factor receptor Mesenchymal-Epithelial Transition (MET), an oncogene that is overexpressed in numerous types of human tumors and considered a prime target in clinical oncology. Using the homologous recombination (HR) direct-repeat direct-repeat green fluorescent protein ((DR)-GFP) system, we show that MET inhibition in tumor cells with deregulated MET activity by the small molecule PHA665752 significantly impairs in a dose-dependent manner HR. Using cells that express MET-mutated variants that respond differentially to PHA665752, we confirm that the observed HR inhibition is indeed MET-dependent. Furthermore, our data also suggest that decline in HR-dependent DNA repair activity is not a secondary effect due to cell cycle alterations caused by PHA665752. Mechanistically, we show that MET inhibition affects the formation of the RAD51-BRCA2 complex, which is crucial for error-free HR repair of double strand DNA lesions, presumably via downregulation and impaired translocation of RAD51 into the nucleus. Taken together, these findings assist to further support the role of MET in the cellular DNA damage response and highlight the potential future benefit of MET inhibitors for the sensitization of tumor cells to DNA damaging agents.

How does socio economic position link to health behaviour? Sociological pathways and perspectives for health promotion

Socio economic inequalities in adult health behaviour are consistently observed. Despite a well-documented pattern, social determinants of variations in health behaviour have not been sufficiently clarified. This article therefore presents sociological pathways to explain the existing inequalities in health behaviour. At a micro level, control beliefs have been part of several behavioural theories. We suggest that these beliefs might bridge the gap between sociology and psychology by emphasising their roots in fundamental socio-economic environments. At a meso level, social networks and support have not been explicitly considered as behavioural determinants. This contribution states that these social factors influence health behaviour while being unequally distributed across society. At a macro level, characteristics of the neighbourhood environment influence health behaviour of its residents above and beyond their individual background. Providing further opportunity for policy makers, it is shown that peer and school context equalise inequalities in risky behaviour in adolescence. As a conclusion, factors such as control expectations, social networks, neighbourhood characteristics, and school context should be included as strategies to improve health behaviour in socially disadvantaged people.

Internationaler Zivilprozess 2011, Zusammenspiel des revLugÜ mit dem revSchKG und der schweizerischen ZPO, mit Beiträgen von Prof. Dr. Jürgen Brönnimann, Prof. Dr. Felix Dasser, Prof. Dr. Alexander R. Markus, Prof. Dr. Rodrigo Rodriguez, Prof. Dr. Daniel Staehelin, Prof. Dr. Walter A. Stoffel

Am 10. September 2010 fand in Bern die erste Schweizerische Tagung für Zivilverfahrensrecht des Instituts für Internationales Privatrecht und Verfahrensrecht der Universität Bern statt. Die Tagung mit dem Titel "Internationaler Zivilprozess 2011" befasste sich mit dem Zusammenspiel der am 1.1.2011 in Kraft tretenden neuen oder revidierten Erlasse (ZPO, revLugÜ, und revSchKG) im Rahmen des internationalen Zivilprozesses. Der Tagungsband enthält auf den Tagungsvorträgen basierende Beiträge namhafter Autoren zu aktuellen und praxisrelevanten Themen des neuen internationalen Zivilprozesses, namentlich zum neuen Arrestrecht, zur Behandlung von Zustellungsmängeln unter dem revLugÜ, zum Zahlungsbefehl im Lichte der revLugÜ-Zuständigkeiten, zur vollstreckbaren öffentliche Urkunde sowie zur Rechtshängigkeit und zur Streitgenossenschaft im internationalen Verhältnis. Der Tagungsband "Internationaler Zivilprozess 2011" eröffnet eine neue Schriftenreihe zum Internationalen Privatrecht und Verfahrensrecht.

The link between visual exploration and neuronal activity: A multi-modal study combining eye tracking, functional magnetic resonance imaging and transcranial magnetic stimulation

In the present multi-modal study we aimed to investigate the role of visual exploration in relation to the neuronal activity and performance during visuospatial processing. To this end, event related functional magnetic resonance imaging er-fMRI was combined with simultaneous eye tracking recording and transcranial magnetic stimulation (TMS). Two groups of twenty healthy subjects each performed an angle discrimination task with different levels of difficulty during er-fMRI. The number of fixations as a measure of visual exploration effort was chosen to predict blood oxygen level-dependent (BOLD) signal changes using the general linear model (GLM). Without TMS, a positive linear relationship between the visual exploration effort and the BOLD signal was found in a bilateral fronto-parietal cortical network, indicating that these regions reflect the increased number of fixations and the higher brain activity due to higher task demands. Furthermore, the relationship found between the number of fixations and the performance demonstrates the relevance of visual exploration for visuospatial task solving. In the TMS group, offline theta bursts TMS (TBS) was applied over the right posterior parietal cortex (PPC) before the fMRI experiment started. Compared to controls, TBS led to a reduced correlation between visual exploration and BOLD signal change in regions of the fronto-parietal network of the right hemisphere, indicating a disruption of the network. In contrast, an increased correlation was found in regions of the left hemisphere, suggesting an intent to compensate functionality of the disturbed areas. TBS led to fewer fixations and faster response time while keeping accuracy at the same level, indicating that subjects explored more than actually needed.

Hot Clones, Maintaining a Link Between Software Clones Across Repositories

Code duplication is common in current programming-practice: programmers search for snippets of code, incorporate them into their projects and then modify them to their needs. In today's practice, no automated scheme is in place to inform both parties of any distant changes of the code. As code snippets continues to evolve both on the side of the user and on the side of the author, both may wish to benefit from remote bug fixes or refinements --- authors may be interested in the actual usage of their code snippets, and researchers could gather information on clone usage. We propose maintaining a link between software clones across repositories and outline how the links can be created and maintained.

A novel allele of FILAMENTOUS FLOWER reveals new insights on the link between inflorescence and floral meristem organization and flower morphogenesis

Background The Arabidopsis FILAMENTOUS FLOWER (FIL) gene encodes a YABBY (YAB) family putative transcription factor that has been implicated in specifying abaxial cell identities and thus regulating organ polarity of lateral organs. In contrast to double mutants of fil and other YAB genes, fil single mutants display mainly floral and inflorescence morphological defects that do not reflect merely a loss of abaxial identity. Recently, FIL and other YABs have been shown to regulate meristem organization in a non-cell-autonomous manner. In a screen for new mutations affecting floral organ morphology and development, we have identified a novel allele of FIL, fil-9 and characterized its floral and meristem phenotypes. Results The fil-9 mutation results in highly variable disruptions in floral organ numbers and size, partial homeotic transformations, and in defective inflorescence organization. Examination of meristems indicates that both fil-9 inflorescence and floral meristems are enlarged as a result of an increase in cell number, and deformed. Furthermore, primordia emergence from these meristems is disrupted such that several primordia arise simultaneously instead of sequentially. Many of the organs produced by the inflorescence meristems are filamentous, yet they are not considered by the plant as flowers. The severity of both floral organs and meristem phenotypes is increased acropetally and in higher growth temperature. Conclusions Detailed analysis following the development of fil-9 inflorescence and flowers throughout flower development enabled the drawing of a causal link between multiple traits of fil-9 phenotypes. The study reinforces the suggested role of FIL in meristem organization. The loss of spatial and temporal organization of fil-9 inflorescence and floral meristems presumably leads to disrupted cell allocation to developing floral organs and to a blurring of organ whorl boundaries. This disruption is reflected in morphological and organ identity aberrations of fil-9 floral organs and in the production of filamentous organs that are not perceived as flowers. Here, we show the role of FIL in reproductive meristem development and emphasize the potential of using fil mutants to study mersitem organization and the related effects on flower morphogenesis.

The homeobox gene HLXB9 is upregulated in a morphological subset of poorly differentiated hepatocellular carcinoma

The prognostic outcome for hepatocellular carcinoma (HCC) remains poor. Disease progression is accompanied by dedifferentiation of the carcinoma, a process that is not well understood. The aim of this study was to get more insight into the molecular characteristics of dedifferentiated carcinomas using high throughput techniques. Microarray-based global gene expression analysis was performed on five poorly differentiated HCC cell lines compared with non-neoplastic hepatic controls and a set of three cholangiolar carcinoma (CC) cell lines. The gene with the highest upregulation was HLXB9. HLXB9 is a gene of the homeobox genfamily important for the development of the pancreas. RT-PCR confirmed the upregulation of HLXB9 in surgical specimens of carcinoma tissue, suggesting its biological significance. Interestingly, HLXB9 upregulation was primary observed in poorly differentiated HCC with a pseudoglandular pattern compared with a solid pattern HCC or in moderate or well-differentiated HCC. Additional the expression of translated HLXB9, the protein HB9 (NCBI: NP_001158727), was analyzed by western blotting. Expression of HB9 was only detected in the cytoplasm but not in the nuclei of the HCC cells. For validation CC were also investigated. Again, we found an upregulation of HLXB9 in CC cells accompanied by an expression of HB9 in the cytoplasms of these tumor cells, respectively. In conclusion, homeobox HLXB9 is upregulated in poorly differentiated HCC with a pseudoglandular pattern. The translated HB9 protein is found in the cytoplasm of these HCC and CC. We therefore assume HLXB9 as a possible link in the understanding of the development of HCC and CC, respectively.

Vorsorglicher Rechtsschutz. Vorsorgliche Massnahmen im internationalen Kontext, offene Fragen im neuen Arrestrecht und Sicherungsmassnahmen der ZPO, mit Beiträgen von Dr. Isabelle Chabloz, Dr. Richard Gassmann, PD Dr. Pascal Grolimund, Dr. Jürg Roth, Prof. Dr. Daniel Staehelin

Am 9. September 2011 führte das Institut für Verfahrensrecht und Internationales Privatrecht (CIVPRO) der Universität Bern in bewährter Zusammenarbeit mit der schweizerischen SchKG-Vereinigung die zweite Schweizer Tagung für Internationales Zivilverfahrensrecht durch. Im Mittelpunkt der Tagung standen vorsorgliche Massnahmen im internationalen Kontext vor dem Hintergrund der neuesten Entwicklungen, namentlich (aber nicht nur) des neuen Lugano-Übereinkommens. Der Tagungsband enthält die auf den Vorträgen basierenden, überarbeiteten und erweiterten Beiträge namhafter Autorinnen und Autoren zum vorsorglichen Rechtsschutz im neuen IZPR (Pascal Grolimund). Besondere Aufmerksamkeit gilt dem neuen Arrestrecht sowohl im als auch ausserhalb des Anwendungsbereichs des Lugano-Übereinkommens (Richard Gassmann und Jürg Roth). Ebenso enthält der Band Beiträge zu den Sicherungsmassnahmen in der Realvollstreckung (Daniel Staehelin) sowie zur Anerkennung ausländischer vorsorglicher Massnahmen (Isabelle Chabloz).