Cycles and the cohomology of arithmetic subgroups of the exceptional group G2G_2

Das Hauptaugenmerk meiner Dissertation ist die geometrische Konstruktion von (Ko-) Homologieklassen für arithmetische Untergruppen von halbeinfachen, über \Q definierten, \Q-anisotropen algebraischen Gruppen {\bf G}. Ich untersuche im speziellen eine \Q-Gruppe ${\bf G}$, in der der nicht kompakte Faktor der Gruppe der reellen Punkte ${\bf G}(\R)$, die reelle zerfallende exzeptionelle Lie Gruppe vom Typ $G_2$ ist. All dies basiert auf dem allgemeinen Ansatz Zykel zu konstruieren (wie von J. Millson und M.S. Raghunathan initiiert und von J. Rohlfs und J. Schwermer weitergeführt). Ich kombiniere diese Ergebnisse und erhalte damit eine neue Formel für die Schnittzahl von zwei Zykeln die einander nicht transversal schneiden. Im Falle der Gruppe $G_2$ sind Beiträge der Zykeln zur Homologie in folgendem Sinn "Vollständig": als erstes gibt es in "jedem" kohomologischen Grad einen nicht trivialen Zykel, der einer unitären Darstellungen mit nicht-verschwindender Kohomologie entspricht und zweitens benutzten wir jeden auftretenden Typ von reduktiven Untergruppen von ${\bf G}$ um Zykel zu konstruieren. Weiters gebe ich zwei hinreichende Kriterien an Zykel an, die zeigen das die Poincar\'e duale Klasse zu dem Zykel durch eine Differentialform, die nicht invariant unter ${\bf G}(\R)$ ist, gegeben ist.The main focus of my doctoral thesis is the geometric construction of (co)homology classes of arithmetic subgroups of semisimple \Q-anisotropic algebraic groups ${\bf G}$ defined over \Q. In particular, I discuss a \Q-group ${\bf G}$ in which the non compact factor of the group of real points ${\bf G}(\R)$ is the real split exceptional Lie group of type $G_2$. All that is based on the general approach of constructing cycles (as initiated by J. Millson and M.S. Raghunathan and pursued by J. Rohlfs and J. Schwermer). Combining their results I get a new formula for the intersection number of two cycles which intersect each other non-transversally. In the case of the group $G_2$, the description of the contribution of cycles to the homology is "complete" in the following sense: first, we found in "every" cohomological degree a non trivial cycle which corresponds to a unitary representation of $G_2$ with non-zero cohomology and second, we found at least one group of every possible type of reductive subgroups of ${\bf G}$, to get a cycle. Further, I give two sufficient criteria on cycles, which imply that the Poincar\'e dual class to the cycle is represented by a differential form which is not invariant under the action of ${\bf G}(\R)$

Heat-shock mediated overexpression of HNF1β mutations has differential effects on gene expression in the Xenopus pronephric kidney.

The transcription factor HNF1B, encoded by the TCF2 gene, plays an important role in the organogenesis of vertebrates. In humans, heterozygous mutations of HNF1B are associated with several diseases, such as pancreatic β-cell dysfunction leading to maturity-onset diabetes of the young (MODY5), defective kidney development, disturbed liver function, pancreas atrophy, and malformations of the genital tract. The African claw frog Xenopus laevis is an excellent model to study the processes involved in embryogenesis and organogenesis, as it can be manipulated easily with a series of methods. In the present study, we overexpressed HNF1β mutants in the developing Xenopus embryo to assess their roles during organogenesis, particularly in the developing pronephric kidney. Towards this goal, we developed a heat-shock inducible binary Cre/loxP system with activator and effector strains. Heat-shock activation of the mutant HNF1B variants P328L329del and A263insGG resulted in malformations of various organs and the affected larvae developed large edemas. Defects in the pronephros were primarily confined to malformed proximal tubules. Furthermore, the expression of the proximal tubule marker genes tmem27 and slc3a1, both involved in amino acid transport, was affected. Both P328L329del and A263insGG downregulated expression of slc3a1. In addition, P328L329del reduced tmem27 expression while A263insGG overexpression decreased expression of the chloride channel clcnk and the transcription factor pax2. Overexpression of two mutant HNF1B derivatives resulted in distinct phenotypes reflected by either a reduction or an enlargement of pronephros size. The expression of selected pronephric marker genes was differentially affected upon overexpression of HNF1B mutations. Based on our findings, we postulate that HNF1B mutations influence gene regulation upon overexpression in specific and distinct manners. Furthermore, our study demonstrates that the newly established Cre/loxP system for Xenopus embryos is an attractive alternative to examine the gene regulatory potential of transcription factors in developing pronephric kidney as exemplified here for HNF1B

Lack of Intestinal Epithelial Atg7 Affects Paneth Cell Granule Formation but Does Not Compromise Immune Homeostasis in the Gut

Genetic polymorphisms of autophagy-related genes have been associated with an increased risk to develop inflammatory bowel disease (IBD). Autophagy is an elementary process participating in several cellular events such as cellular clearance and nonapoptotic programmed cell death. Furthermore, autophagy may be involved in intestinal immune homeostasis due to its participation in the digestion of intracellular pathogens and in antigen presentation. In the present study, the role of autophagy in the intestinal epithelial layer was investigated. The intestinal epithelium is essential to maintain gut homeostasis, and defects within this barrier have been associated with the pathogenesis of IBD. Therefore, mice with intestinal epithelial deletion of Atg7 were generated and investigated in different mouse models. Knockout mice showed reduced size of granules and decreased levels of lysozyme in Paneth cells. However, this was dispensable for gut immune homeostasis and had no effect on susceptibility in mouse models of experimentally induced colitis

Double conditional human embryonic kidney cell line based on FLP and ΦC31 mediated transgene integration

<p>Abstract</p> <p>Background</p> <p>FLP recombinase mediated integration into a pre-integrated FRT site is routinely used to generate highly reproducible stable transgenic cell lines. In this study, we broaden the system of site specific integration by introducing ΦC31 integrase mediated integration into attP sites.</p> <p>Results</p> <p>We generated a HEK293 host cell line with a single copy FRT as well as an attP site allowing site specific integration of two distinct transgenes. To achieve conditional control, we used the tetracycline and Shld1 inducible systems. By introducing fluorescent reporters we show that integration and induction of two transgenes are completely independent. We applied this new technique to investigate the effect of HNF4α on proliferation of HEK293 cells by introducing HNF4α into each integration site. We obtained in two independent cell lines highly reproducible results that prove the usefulness of this novel HEK-attP/FRT cell line.</p> <p>Conclusions</p> <p>In this study we have established and applied a HEK-attP/FRT cell line that allows site specific integration of two conditional transgenes using the FLP recombinase as well as the ΦC31 integrase.</p

N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy

Background &amp; Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC

A global reference database of crowdsourced cropland data collected using the Geo-Wiki platform

A global reference data set on cropland was collected through a crowdsourcing campaign using the Geo-Wiki crowdsourcing tool. The campaign lasted three weeks, with over 80 participants from around the world reviewing almost 36,000 sample units, focussing on cropland identification. For quality assessment purposes, two additional data sets are provided. The first is a control set of 1,793 sample locations validated by students trained in satellite image interpretation. This data set was used to assess the quality of the crowd as the campaign progressed. The second data set contains 60 expert validations for additional evaluation of the quality of the contributions. All data sets are split into two parts: the first part shows all areas classified as cropland and the second part shows cropland average per location and user. After further processing, the data presented here might be suitable to validate and compare medium and high resolution cropland maps generated using remote sensing. These could also be used to train classification algorithms for developing new maps of land cover and cropland extent

VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer

Inflammation drives expression of VEGFR2, which is expressed on and drives growth of tumor cells in colitis-associated cancer