Case Retrieval Nets as a Model for Building Flexible Information Systems

Im Rahmen dieser Arbeit wird das Modell der Case Retrieval Netze vorgestellt, das ein Speichermodell für die Phase des Retrievals beim fallbasierten Schliessen darstellt. Dieses Modell lehnt sich an Assoziativspeicher an, insbesondere wird das Retrieval als Rekonstruktion des Falles betrachtet anstatt als eine Suche im traditionellen Sinne. Zwei der wesentlichen Vorteile des Modells sind Effizienz und Flexibilität: Effizienz beschreibt dabei die Fähigkeit, mit grossen Fallbasen umzugehen und dennoch schnell ein Resultat des Retrievals liefern zu können. Im Rahmen dieser Arbeit wird dieser Aspekt formal untersucht, das Hauptaugenmerk ist aber eher pragmatisch motiviert insofern als der Retrieval-Prozess so schnell sein sollte, dass der Benutzer möglichst keine Wartezeiten in Kauf nehmen muss. Flexibilität betrifft andererseits die allgemeine Anwendbarkeit des Modells in Bezug auf veränderte Aufgabenstellungen, auf alternative Formen der Fallrepräsentation usw. Hierfür wird das Konzept der Informationsvervollständigung diskutiert, welches insbesondere für die Beschreibung von interaktiven Entscheidungsunterstützungssystemen geeignet ist. Traditionelle Problemlöseverfahren, wie etwa Klassifikation oder Diagnose, können als Spezialfälle von Informationsvervollständigung aufgefasst werden. Das formale Modell der Case Retrieval Netze wird im Detail erläutert und dessen Eigenschaften untersucht. Anschliessend werden einige möglich Erweiterungen beschrieben. Neben diesen theoretischen Aspekten bilden Anwendungen, die mit Hilfe des Case Retrieval Netz Modells erstellt wurden, einen weiteren Schwerpunkt. Diese lassen sich in zwei grosse Richtungen einordnen: intelligente Verkaufsunterstützung für Zwecke des E-Commerce sowie Wissensmanagement auf Basis textueller Dokumente, wobei für letzteres der Aspekt der Wiederbenutzung von Problemlösewissen essentiell ist. Für jedes dieser Gebiete wird eine Anwendung im Detail beschrieben, weitere dienen der Illustration und werden nur kurz erläutert. Zuvor wird allgemein beschrieben, welche Aspekte bei Entwurf und Implementierung eines Informationssystems zu beachten sind, welches das Modell der Case Retrieval Netze nutzt.In this thesis, a specific memory structure is presented that has been developed for the retrieval task in Case-Based Reasoning systems, namely Case Retrieval Nets (CRNs). This model borrows from associative memories in that it suggests to interpret case retrieval as a process of re-constructing a stored case rather than searching for it in the traditional sense. Tow major advantages of this model are efficiency and flexibility: Efficiency, on the one hand, is concerned with the ability to handle large case bases and still deliver retrieval results reasonably fast. In this thesis, a formal investigation of efficiency is included but the main focus is set on a more pragmatic view in the sense that retrieval should, in the ideal case, be fast enough such that for the users of a related system no delay will be noticeable. Flexibility, on the other hand, is related to the general applicability of a case memory depending on the type of task to perform, the representation of cases etc. For this, the concept of information completion is discussed which allows to capture the interactive nature of problem solving methods in particular when they are applied within a decision support system environment. As discussed, information completion, thus, covers more specific problem solving types, such as classification and diagnosis. The formal model of CRNs is presented in detail and its properties are investigated. After that, some possible extensions are described. Besides these more theoretical aspects, a further focus is set on applications that have been developed on the basis of the CRN model. Roughly speaking, two areas of applications can be recognized: electronic commerce applications for which Case-Based Reasoning may provide intelligent sales support, and knowledge management based on textual documents where the reuse of problem solving knowledge plays a crucial role. For each of these areas, a single application is described in full detail and further case studies are listed for illustration purposes. Prior to the details of the applications, a more general framework is presented describing the general design and implementation of an information system that makes uses of the model of CRNs

The ratio of SRPK1/SRPK1a regulates erythroid differentiation in K562 leukaemic cells

AbstractSRPK1, the prototype of the serine/arginine family of kinases, has been implicated in the regulation of multiple cellular processes such as pre-mRNA splicing, chromatin structure, nuclear import and germ cell development. SRPK1a is a much less studied isoform of SRPK1 that contains an extended N-terminal domain and so far has only been detected in human testis. In the present study we show that SRPK1 is the predominant isoform in K562 cells, with the ratio of the two isoforms being critical in determining cell fate. Stable overexpression of SRPK1a induces erythroid differentiation of K562 cells. The induction of globin synthesis was accompanied by a marked decrease in proliferation and a significantly reduced clonogenic potential. Small interfering RNA-mediated down-regulation of SRPK1 in K562 cells results similarly in a decrease in proliferative capacity and induction of globin synthesis. A decreased SRPK1/SRPK1a ratio is also observed upon hemin/DMSO-induced differentiation of K562 cells as well as in normal human erythroid progenitor cells. Mass spectrometric analysis of SRPK1a-associated proteins identified multiple classes of RNA-binding proteins including RNA helicases, heterogeneous nuclear ribonucleoproteins, ribosomal proteins, and mRNA-associated proteins. Several of the SRPK1a-copurifying proteins have been previously identified in ribosomal and pre-ribosomal complexes, thereby suggesting that SRPK1a may play an important role in linking ribosomal assembly and/or function to erythroid differentiation in human leukaemic cells

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design

A Prospective Study to Validate the Functional Assessment of Cancer Therapy (FACT) for Epidermal Growth Factor Receptor Inhibitor (EGFRI)-induced Dermatologic Toxicities FACT-EGFRI 18 Questionnaire: SWOG S1013

Background Papulopustular rash is a common class effect of epidermal growth factor receptor inhibitors (EGFRI) that can affect patients’ health-related quality of life and cause disruptions to treatment. SWOG S1013 (NCT01416688) is a multi-center study designed to validate the Functional Assessment of Cancer Therapy EGFRI 18 (FACT-EGFRI 18) using 7-items from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to assess EGFRI-induced skin-related toxicities and their impact on functional status. Methods Patients with a diagnosis of colorectal or lung cancer to receive EGFRI therapies for at least 6 weeks were enrolled. Patient self-assessments using the FACT-EGFRI 18 were completed prior to undergoing CTCAE assessment by trained clinicians at baseline, weekly × 6, and then monthly × 3. The psychometric properties of the FACT-EGFRI 14 (skin toxicity items only) and 18 (plus 2 nail and 2 hair items) were established based on criterion validity, known groups validity, internal consistency reliability, and responsiveness to change. Results Of the 146 registered patients, 124 were evaluable. High Cronbach’s alpha (\u3e 0.70) for both FACT-EGFRI 14 and FACT-EGFRI 18 scores across assessment times were observed. Although agreement (i.e. criterion validity) between individual and summary scales of the FACT-EGFRI 18 for assessing skin toxicity was good, agreement with the clinician-reported CTCAE was only fair. The minimal important difference was determined to be 3 points. The results also demonstrated responsiveness to symptom change. Discussion Based on the results of this multi-center validation study, the FACT-EGFRI 18 patient-reported outcome instrument provided data from the patient’s perspective yielding unique information as well as complementing clinician-rated CTCAE grades, especially for the symptoms of pain, pruritus, and paronychia. Conclusions Good to excellent psychometric properties for the FACT-EGFRI 18 were demonstrated, supporting further use of this patient-reported outcomes measure. Additional validation with a more diverse group of patients should be conducted

Spatial structure of In0.25Ga0.75As/GaAs/GaP quantum dots on the atomic scale

This article may be downloaded for personal use only. Any other use requires prior permission of the author and AIP Publishing. This article appeared in Appl. Phys. Lett. 102, 123102 (2013) and may be found at https://doi.org/10.1063/1.4798520.In0.25Ga0.75As/GaAs quantum dots grown by metalorganic vapor-phase epitaxy in a GaP matrix have been investigated on the atomic scale using cross-sectional scanning tunneling microscopy. The quantum dots have a truncated pyramidal shape with a reversed cone stoichiometry profile. All deposited indium is found within the quantum dots and the occasionally observed quantum rings, while the wetting layer has a GaAsP composition without any indium inside. This indicates an intense lateral material transfer during growth.DFG, 43659573, SFB 787: Halbleiter - Nanophotonik: Materialien, Modelle, Bauelement

The MOSAiC ice floe: Sediment-laden survivor from the Siberian shelf

In September 2019, the research icebreaker Polarstern started the largest multidisciplinary Arctic expedition to date, the MOSAiC (Multidisciplinary drifting Observatory for the Study of Arctic Climate) drift experiment. Being moored to an ice floe for a whole year, thus including the winter season, the declared goal of the expedition is to better understand and quantify relevant processes within the atmosphere-ice-ocean system that impact the sea ice mass and energy budget, ultimately leading to much improved climate models. Satellite observations, atmospheric reanalysis data, and readings from a nearby meteorological station indicate that the interplay of high ice export in late winter and exceptionally high air temperatures resulted in the longest ice-free summer period since reliable instrumental records began. We show, using a Lagrangian tracking tool and a thermodynamic sea ice model, that the MOSAiC floe carrying the Central Observatory (CO) formed in a polynya event north of the New Siberian Islands at the beginning of December 2018. The results further indicate that sea ice in the vicinity of the CO ( \u3c 40 km distance) was younger and 36 % thinner than the surrounding ice with potential consequences for ice dynamics and momentum and heat transfer between ocean and atmosphere. Sea ice surveys carried out on various reference floes in autumn 2019 verify this gradient in ice thickness, and sediments discovered in ice cores (so-called dirty sea ice) around the CO confirm contact with shallow waters in an early phase of growth, consistent with the tracking analysis. Since less and less ice from the Siberian shelves survives its first summer (Krumpen et al., 2019), the MOSAiC experiment provides the unique opportunity to study the role of sea ice as a transport medium for gases, macronutrients, iron, organic matter, sediments and pollutants from shelf areas to the central Arctic Ocean and beyond. Compared to data for the past 26 years, the sea ice encountered at the end of September 2019 can already be classified as exceptionally thin, and further predicted changes towards a seasonally ice-free ocean will likely cut off the long-range transport of ice-rafted materials by the Transpolar Drift in the future. A reduced long-range transport of sea ice would have strong implications for the redistribution of biogeochemical matter in the central Arctic Ocean, with consequences for the balance of climate-relevant trace gases, primary production and biodiversity in the Arctic Ocean

Molecular and functional profiling identifies therapeutically targetable vulnerabilities in plasmablastic lymphoma

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients

The MOSAiC ice floe: sediment-laden survivor from the Siberian shelf

In September 2019, the research icebreaker Polarstern started the largest multidisciplinary Arctic expedition to date, the MOSAiC (Multidisciplinary drifting Observatory for the Study of Arctic Climate) drift experiment. Being moored to an ice floe for a whole year, thus including the winter season, the declared goal of the expedition is to better understand and quantify relevant processes within the atmosphere–ice–ocean system that impact the sea ice mass and energy budget, ultimately leading to much improved climate models. Satellite observations, atmospheric reanalysis data, and readings from a nearby meteorological station indicate that the interplay of high ice export in late winter and exceptionally high air temperatures resulted in the longest ice-free summer period since reliable instrumental records began. We show, using a Lagrangian tracking tool and a thermodynamic sea ice model, that the MOSAiC floe carrying the Central Observatory (CO) formed in a polynya event north of the New Siberian Islands at the beginning of December 2018. The results further indicate that sea ice in the vicinity of the CO (<40 km distance) was younger and 36 % thinner than the surrounding ice with potential consequences for ice dynamics and momentum and heat transfer between ocean and atmosphere. Sea ice surveys carried out on various reference floes in autumn 2019 verify this gradient in ice thickness, and sediments discovered in ice cores (so-called dirty sea ice) around the CO confirm contact with shallow waters in an early phase of growth, consistent with the tracking analysis. Since less and less ice from the Siberian shelves survives its first summer (Krumpen et al., 2019), the MOSAiC experiment provides the unique opportunity to study the role of sea ice as a transport medium for gases, macronutrients, iron, organic matter, sediments and pollutants from shelf areas to the central Arctic Ocean and beyond. Compared to data for the past 26 years, the sea ice encountered at the end of September 2019 can already be classified as exceptionally thin, and further predicted changes towards a seasonally ice-free ocean will likely cut off the long-range transport of ice-rafted materials by the Transpolar Drift in the future. A reduced long-range transport of sea ice would have strong implications for the redistribution of biogeochemical matter in the central Arctic Ocean, with consequences for the balance of climate-relevant trace gases, primary production and biodiversity in the Arctic Ocean

HCV genotypes are differently prone to the development of resistance to linear and macrocyclic protease inhibitors

Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs)

Transgenic Expression of Soluble Human CD5 Enhances Experimentally-Induced Autoimmune and Anti-Tumoral Immune Responses

CD5 is a lymphoid-specific transmembrane glycoprotein constitutively expressed on thymocytes and mature T and B1a lymphocytes. Current data support the view that CD5 is a negative regulator of antigen-specific receptor-mediated signaling in these cells, and that this would likely be achieved through interaction with CD5 ligand/s (CD5L) of still undefined nature expressed on immune or accessory cells. To determine the functional consequence of loss of CD5/CD5L interaction in vivo, a new transgenic mouse line was generated (shCD5EμTg), expressing a circulating soluble form of human CD5 (shCD5) as a decoy to impair membrane-bound CD5 function. These shCD5EμTg mice showed an enhanced response to autologous antigens, as deduced from the presentation of more severe forms of experimentally inducible autoimmune disease (collagen-induced arthritis, CIA; and experimental autoimmune encephalitis, EAE), as well as an increased anti-tumoral response in non-orthotopic cancer models (B16 melanoma). This enhancement of the immune response was in agreement with the finding of significantly reduced proportions of spleen and lymph node Treg cells (CD4+CD25+FoxP3+), and of peritoneal IL-10-producing and CD5+ B cells, as well as an increased proportion of spleen NKT cells in shCD5EμTg mice. Similar changes in lymphocyte subpopulations were observed in wild-type mice following repeated administration of exogenous recombinant shCD5 protein. These data reveal the relevant role played by CD5/CD5L interactions on the homeostasis of some functionally relevant lymphocyte subpopulations and the modulation of immune responses to autologous antigens