IST Austria Thesis

Chemokines organize immune cell trafficking by inducing either directed (tactic) or random (kinetic) migration and by activating integrins in order to support surface adhesion (haptic). Beyond that the same chemokines can establish clearly defined functional areas in secondary lymphoid organs. Until now it is unclear how chemokines can fulfill such diverse functions. One decisive prerequisite to explain these capacities is to know how chemokines are presented in tissue. In theory chemokines could occur either soluble or immobilized, and could be distributed either homogenously or as a concentration gradient. To dissect if and how the presenting mode of chemokines influences immune cells, I tested the response of dendritic cells (DCs) to differentially displayed chemokines. DCs are antigen presenting cells that reside in the periphery and migrate into draining lymph nodes (LNs) once exposed to inflammatory stimuli to activate naïve T cells. DCs are guided to and within the LN by the chemokine receptor CCR7, which has two ligands, the chemokines CCL19 and CCL21. Both CCR7 ligands are expressed by fibroblastic reticular cells in the LN, but differ in their ability to bind to heparan sulfate residues. CCL21 has a highly charged C-terminal extension, which mediates binding to anionic surfaces, whereas CCL19 is lacking such residues and likely distributes as a soluble molecule. This study shows that surface-bound CCL21 causes random, haptokinetic DC motility, which is confined to the chemokine coated area by insideout activation of β2 integrins that mediate cell binding to the surface. CCL19 on the other hand forms concentration gradients which trigger directional, chemotactic movement, but no surface adhesion. In addition DCs can actively manipulate this system by recruiting and activating serine proteases on their surfaces, which create - by proteolytically removing the adhesive C-terminus - a solubilized variant of CCL21 that functionally resembles CCL19. By generating a CCL21 concentration gradient DCs establish a positive feedback loop to recruit further DCs from the periphery to the CCL21 coated region. In addition DCs can sense chemotactic gradients as well as immobilized haptokinetic fields at the same time and integrate these signals. The result is chemotactically biased haptokinesis - directional migration confined to a chemokine coated track or area - which could explain the dynamic but spatially tightly controlled swarming leukocyte locomotion patterns that have been observed in lymphatic organs by intravital microscopists. The finding that DCs can approach soluble cues in a non-adhesive manner while they attach to surfaces coated with immobilized cues raises the question how these cells transmit intracellular forces to the environment, especially in the non-adherent migration mode. In order to migrate, cells have to generate and transmit force to the extracellular substrate. Force transmission is the prerequisite to procure an expansion of the leading edge and a forward motion of the whole cell body. In the current conceptions actin polymerization at the leading edge is coupled to extracellular ligands via the integrin family of transmembrane receptors, which allows the transmission of intracellular force. Against the paradigm of force transmission during migration, leukocytes, like DCs, are able to migrate in threedimensional environments without using integrin transmembrane receptors (Lämmermann et al., 2008). This reflects the biological function of leukocytes, as they can invade almost all tissues, whereby their migration has to be independent from the extracellular environment. How the cells can achieve this is unclear. For this study I examined DC migration in a defined threedimensional environment and highlighted actin-dynamics with the probe Lifeact-GFP. The result was that chemotactic DCs can switch between integrin-dependent and integrin- independent locomotion and can thereby adapt to the adhesive properties of their environment. If the cells are able to couple their actin cytoskeleton to the substrate, actin polymerization is entirely converted into protrusion. Without coupling the actin cortex undergoes slippage and retrograde actin flow can be observed. But retrograde actin flow can be completely compensated by higher actin polymerization rate keeping the migration velocity and the shape of the cells unaltered. Mesenchymal cells like fibroblast cannot balance the loss of adhesive interaction, cannot protrude into open space and, therefore, strictly depend on integrinmediated force coupling. This leukocyte specific phenomenon of “adaptive force transmission” endows these cells with the unique ability to transit and invade almost every type of tissue

Extraction of Knowledge-Rich Contexts in Russian – A Study in the Automotive Domain

Proceedings of the 18th Nordic Conference of Computational Linguistics NODALIDA 2011. Editors: Bolette Sandford Pedersen, Gunta Nešpore and Inguna Skadiņa. NEALT Proceedings Series, Vol. 11 (2011), 311-314. © 2011 The editors and contributors. Published by Northern European Association for Language Technology (NEALT) http://omilia.uio.no/nealt . Electronically published at Tartu University Library (Estonia) http://hdl.handle.net/10062/1695

Vergleich individueller CAD/CAM-basierter Implantate aus Hydroxylapatit und Titan zur Kranioplastie - eine randomisierte klinische Multizenterstudie

Abstract Objective Cranioplasty is routinely performed in neurosurgery. One of its underestimated problems is the high postoperative complication rate of up to 40%. Due to the lack of good prospective studies and the low number of patients (5–20 each year) receiving alloplastic materials, decisions in favor or against a certain material are based on subjective empirical or eco-nomic reasons. The main goal of this first prospective, randomized multicenter study in Germany of custom-made titanium and hydroxyapatite (HA) implants was to compare lo-cal and systemic infections related to the implant within the first six months after implanta-tion. Secondary objectives included comparing reoperation rates, the complication rate, clinical and neurological outcome, and health-related quality of life. Methods The study included patient screening and randomization 6–8 weeks before operation, pre-, intra and postoperative documentation until discharge, and postoperative follow-ups after one and six months. Approval for the study was obtained from the local ethics committee. The study design was published on www.clinicaltrials.gov. Results A total of 52 patients were included in the study. The rate of local, implant associated wound infection in the HA group was 2 out of 26 (7.7%) patients and 5 out of 24 (20.8%) patients in the titanium group (p=0.407 n.s.). Systemic inflammation within six months after operation affected none of the patients in the HA group and 4 out of 24 (37.5%) pa-tients in the titanium group (p=0.107 n.s.). In both groups, 7 patients had to be reoperated after the six-month follow-up (26.9% in the HA group and 29.2% in the titanium group; n.s.). Re-surgery with explantation was necessary in 3 patients in each group (11.5% in the HA group and 12.5% in the titanium group; n.s.). The results demonstrated a significantly higher number of epidural hematomas in the HA group compared to none in the titanium group. Altogether, 46 AE were measured in 27 patients (54%). An improvement of the neurologi-cal outcome after six months was experienced by 43% of the patients in the HA group and 26.3% in the titanium group (p=0.709 n.s.). Conclusion The study emphasizes that cranioplasty is a high-risk intervention. Compared to tita-nium, HA shows a benefit in the infection rate and the neurological outcome, but has at the same time a higher postoperative risk for epidural hematoma. Depending on the individual conditions both materials have their place in future therapy of cranioplasty

Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case

IgG4-related lung disease is commonly associated with autoimmune pancreatitis. Recently, isolated IgG4-related interstitial lung disease (ILD) without other organ involvement has newly been reported in two cases with clinical features of nonspecific interstitial pneumonitis (NSIP). We report the first case of an isolated IgG4-related ILD in a 78-year-old man with dry cough and dyspnea, whose clinical findings proved to be different from NSIP. Serum IgG4 levels were increased. Chest CT scan revealed bilateral consolidations especially in the lower lobes, enlarged mediastinal and hilar lymph nodes and pleural effusions. Video-assisted thoracoscopic (VATS) lung biopsy revealed a pattern similar to usual interstitial pneumonia (UIP) and an abundant IgG4-positive plasma cell infiltration. He was effectively treated by steroid therapy. Increasing recognition of IgG4 related diseases has led to a growing number of new entities. The novel concept of isolated IgG4-related ILD as a pulmonary manifestation of a systemic IgG4-related disorder should be taken into account as a possible differential diagnosis of ILD and mass-forming lesions, even when no other organ manifestation is clinically apparent at the time of diagnosis. Lung specific diagnostic criteria and algorithms are required to enhance diagnostic accuracy in cases of possible IgG4-related ILD

Werte in der Rezeptions- und Wirkungsforschung. Exploration des Forschungsfeldes

Die Rezeptions- und Wirkungsforschung unterliegt seit jeher expliziten und impliziten normativen Rahmungen, die sich je nach historischer Phase u.a. am passiven Mediennutzer oder aktiven und kreativen Rezipienten orientieren. Allerdings wurden die Werte und Normen dieses Forschungsfeldes bisher kaum systematisch analysiert. Um dies zu leisten, wird eine Literaturanalyse nationaler und internationaler Zeitschriftenbeiträge zu Werten und Normen in der Rezeptions- und Wirkungsforschung von 1993 bis 2011 durchgeführt. Die Ergebnisse zeigen, dass die Rezeptions- und Wirkungsforschung vielfältige normative Bezüge zu Wirkungsphänomenen im Kontext der Forschung zur Kinder- und Jugendmediennutzung, zur Konstruktion kultureller Werte und Normen, zu (gesellschafts-)politischen Themen und zu neuen, interaktiven Medien herstellt. Sie veranschaulichen aber auch, dass eine definitorische und theoretische Auseinandersetzung mit den Konstrukten „Werte“ und „Normen“ in der Regel bisher kaum stattfindet.EnglishArne Freya Zillich/Kathrin Friederike Müller/ Christina Schumann / Stephanie Geise: Values in Reception and Impact Research. Exploration of this Field of Research Reception and impact studies have always been characterized by explicit and implicit normative assumptions which postulate – depending on the historical phase – a passive audience or an active, creative recipient. However, the values and norms of this research field have not been analyzed systematically so far. In order to accomplish this, a literature review of national and international journal articles on values and norms in audience and reception studies from 1993 until 2011 was conducted. The results show that reception and impact studies address multiple normative references to media effects in the context of research on children’s and adolescents’ media use, on the construction of cultural values and norms, on (socio-) political issues and on new, interactive media. They also illustrate that a definitional and theoretical deba- te on the constructs “values” and “norms” hardly exists to date.

SemEval-2018 Task 7: Semantic Relation Extraction and Classification in Scientific Papers

International audienceThis paper describes the first task on semantic relation extraction and classification in scientific paper abstracts at SemEval 2018. The challenge focuses on domain-specific semantic relations and includes three different sub-tasks. The subtasks were designed so as to compare and quantify the effect of different pre-processing steps on the relation classification results. We expect the task to be relevant for a broad range of researchers working on extracting specialized knowledge from domain corpora, for example but not limited to scientific or bio-medical information extraction. The task attracted a total of 32 participants, with 158 submissions across different scenarios

EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory

Correction: Volume: 80 Issue: 8 DOI: 10.1007/s00018-023-04835-3 Article Number: 201 Published: AUG 2023Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression.Peer reviewe

DELight: a Direct search Experiment for Light dark matter with superfluid helium

To reach ultra-low detection thresholds necessary to probe unprecedentedly low Dark Matter masses, target material alternatives and novel detector designs are essential. One such target material is superfluid $^4$He which has the potential to probe so far uncharted light Dark Matter parameter space at sub-GeV masses. The new ``Direct search Experiment for Light dark matter'', DELight, will be using superfluid helium as active target, instrumented with magnetic micro-calorimeters. It is being designed to reach sensitivity to masses well below 100\,MeV in Dark Matter-nucleus scattering interactions.Comment: IDM2022 proceedings submitted to SciPos

FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration

Background: Forkhead-Box-Protein P3 (FoxP3) is a transcription factor and marker of regulatory T cells, converting naive T cells into Tregs that can downregulate the effector function of other T cells. We previously detected the expression of FoxP3 in retinal pigment epithelial (RPE) cells, forming the outer blood-retina barrier of the immune privileged eye. Methods: We investigated the expression, subcellular localization, and phosphorylation of FoxP3 in RPE cells in vivo and in vitro after treatment with various stressors including age, retinal laser burn, autoimmune inflammation, exposure to cigarette smoke, in addition of IL-1 beta and mechanical cell monolayer destruction. Eye tissue from humans, mouse models of retinal degeneration and rats, and ARPE-19, a human RPE cell line for in vitro experiments, underwent immunohistochemical, immunofluorescence staining, and PCR or immunoblot analysis to determine the intracellular localization and phosphorylation of FoxP3. Cytokine expression of stressed cultured RPE cells was investigated by multiplex bead analysis. Depletion of the FoxP3 gene was performed with CRISPR/Cas9 editing. Results: RPE in vivo displayed increased nuclear FoxP3-expression with increases in age and inflammation, long-term exposure of mice to cigarette smoke, or after laser burn injury. The human RPE cell line ARPE-19 constitutively expressed nuclear FoxP3 under non-confluent culture conditions, representing a regulatory phenotype under chronic stress. Confluently grown cells expressed cytosolic FoxP3 that was translocated to the nucleus after treatment with IL-1 beta to imitate activated macrophages or after mechanical destruction of the monolayer. Moreover, with depletion of FoxP3, but not of a control gene, by CRISPR/Cas9 gene editing decreased stress resistance of RPE cells. Conclusion: Our data suggest that FoxP3 is upregulated by age and under cellular stress and might be important for RPE function