Implementierung und Erweiterung der Sprache ALCP

Diese Dokumentation beschreibt die Implementierung und Erweiterung der Sprache ALCP. ALCP ist eine von [Heinsohn 94a] entwickelte Erweiterung der terminologischen Wissensrepräsentationssprache ALC um eine probabilistische Komponente, so daß auch unsicheres Wissen repräsentiert und für Inferenzen verwendet werden kann. Nach einer Einführung in die grundlegenden Bereiche der Wahrscheinlichkeitstheorie und der Wissensrepräsentation erfolgt eine kurze Beschreibung der Sprache ALCP. Anschließend werden die bei der Implementierung verwendeten Konzepte vorgestellt und die benutzten Datenstrukturen und Algorithmen werden beschrieben und erläutert. Der praktische Aspekt der Verwendung der Sprache ALCP wird durch eine Beschreibung der verwendbaren Funktionen, eine Bedienungsanleitung und eine Beispielsitzung abgedeckt. Desweiteren wird die Mächtigkeit der Sprache ALCP anhand einiger Beispiele veranschaulicht

The MultiHttpServer : a parallel pull engine

Internet agents require fast, concurrent access to many web pages. This service should be stable, central, and easy to access independently from the actual implementation language. This paper describes the MultiHttpServer (MHS), a parallel pull engine implemented in Java with a TCP/IP interface for communication with other programs. A second TCP/IP interface provides information for administration purposes. A simple config-file allows application-oriented tuning of the MultiHttpServer. An optional JAVA-Servlet can remotely start up the MultiHttpServer on demand. The focus of this report is on a user oriented description of functionality and usage of the system. Sample clients in several languages are discussed

PRESTK : situation-aware presentation of messages and infotainment content for drivers

The amount of in-car information systems has dramatically increased over the last few years. These potentially mutually independent information systems presenting information to the driver increase the risk of driver distraction. In a first step, orchestrating these information systems using techniques from scheduling and presentation planning avoid conflicts when competing for scarce resources such as screen space. In a second step, the cognitive capacity of the driver as another scarce resource has to be considered. For the first step, an algorithm fulfilling the requirements of this situation is presented and evaluated. For the second step, I define the concept of System Situation Awareness (SSA) as an extension of Endsley’s Situation Awareness (SA) model. I claim that not only the driver needs to know what is happening in his environment, but also the system, e.g., the car. In order to achieve SSA, two paths of research have to be followed: (1) Assessment of cognitive load of the driver in an unobtrusive way. I propose to estimate this value using a model based on environmental data. (2) Developing model of cognitive complexity induced by messages presented by the system. Three experiments support the claims I make in my conceptual contribution to this field. A prototypical implementation of the situation-aware presentation management toolkit PRESTK is presented and shown in two demonstrators.In den letzten Jahren hat die Menge der informationsanzeigenden Systeme im Auto drastisch zugenommen. Da sie potenziell unabhängig voneinander ablaufen, erhöhen sie die Gefahr, die Aufmerksamkeit des Fahrers abzulenken. Konflikte entstehen, wenn zwei oder mehr Systeme zeitgleich auf limitierte Ressourcen wie z. B. den Bildschirmplatz zugreifen. Ein erster Schritt, diese Konflikte zu vermeiden, ist die Orchestrierung dieser Systeme mittels Techniken aus dem Bereich Scheduling und Präsentationsplanung. In einem zweiten Schritt sollte die kognitive Kapazität des Fahrers als ebenfalls limitierte Ressource berücksichtigt werden. Der Algorithmus, den ich zu Schritt 1 vorstelle und evaluiere, erfüllt alle diese Anforderungen. Zu Schritt 2 definiere ich das Konzept System Situation Awareness (SSA), basierend auf Endsley’s Konzept der Situation Awareness (SA). Dadurch wird erreicht, dass nicht nur der Fahrer sich seiner Umgebung bewusst ist, sondern auch das System (d.h. das Auto). Zu diesem Zweck m¨ussen zwei Bereiche untersucht werden: (1) Die kognitive Belastbarkeit des Fahrers unaufdringlich ermitteln. Dazu schlage ich ein Modell vor, das auf Umgebungsinformationen basiert. (2) Ein weiteres Modell soll die Komplexität der präsentierten Informationen bestimmen. Drei Experimente stützen die Behauptungen in meinem konzeptuellen Beitrag. Ein Prototyp des situationsbewussten Präsentationsmanagement-Toolkits PresTK wird vorgestellt und in zwei Demonstratoren gezeigt

Common miRNA patterns of Alzheimer’s disease and Parkinson’s disease and their putative impact on commensal gut microbiota

With the rise of Next-Generation-Sequencing (NGS) methods, Micro-RNAs (miRNAs) have achieved an important position in the research landscape and have been found to present valuable diagnostic tools in various diseases such as multiple sclerosis or lung cancer. There is also emerging evidence that miRNAs play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). Apparently, these diseases come along with changes in miRNA expression patterns which led to attempts from researchers to use these small RNA species from several body fluids for a better diagnosis and in order to observe disease progression. Additionally, it became evident that microbial commensals might play an important role for pathology development and were shown to have a significantly different composition in patients suffering from neurodegeneration compared with healthy controls. As it could recently be shown that secreted miRNAs are able to enter microbial organisms, it is conceivable that the host’s miRNA might affect the gut microbial ecosystem. As such, miRNAs may inherit a central role in shaping the “diseased microbiome” and thereby mutually act on the characteristics of these neurodegenerative diseases. We have therefore 1) compiled a list of miRNAs known to be associated with AD and/or PD, 2) performed an in silico target screen for binding sites of these miRNA on human gut metagenome sequences and 3) evaluated the hit list for interesting matches potentially relevant to the etiology of AD and or PD. The examination of protein identifiers connected to bacterial secretion system, lipopolysaccharide biosynthesis and biofilm formation revealed an overlap of 37 bacterial proteins that were targeted by human miRNAs. The identified links of miRNAs to the biological processes of bacteria connected to AD and PD have yet to be validated via in vivo experiments. However, our results show a promising new approach for understanding aspects of these neurodegenerative diseases in light of the regulation of the microbiome

Automated real-time text messaging as a means for rapidly identifying acute stroke patients for clinical trials

Background Recruiting stroke patients into acute treatment trials is challenging because of the urgency of clinical diagnosis, treatment, and trial inclusion. Automated alerts that identify emergency patients promptly may improve trial performance. The main purposes of this project were to develop an automated real-time text messaging system to immediately inform physicians of patients with suspected stroke and to test its feasibility in the emergency setting. Methods An electronic standardized stroke algorithm (SSA) was implemented in the clinical information system (CIS) and linked to a remote data capture system. Within 10 minutes following the documentation and storage of basic information to CIS, a text message was triggered for patients with suspected stroke and sent to a dedicated trial physician. Each text message provided anonymized information on the exact department and unit, date and time of admission, age, sex, and National Institute of Health Stroke Scale (NIHSS) of the patient. All necessary information needed to generate a text message was already available – routine processes in the emergency department were not affected by the automated real-time text messaging system. The system was tested for three 4-week periods. Feasibility was analyzed based on the number of patients correctly identified by the SSA and the door-to-message time. Results In total, 513 text messages were generated for patients with suspected stroke (median age 74 years (19–106); 50.3% female; median NIHSS 4 (0–41)), representing 96.6% of all cases. For 48.3% of these text messages, basic documentation was completed within less than 1 hour and a text message was sent within 60 minutes after patient admission. Conclusions The system proved to be stable in generating text messages using IT-based CIS to identify acute stroke trial patients. The system operated on information which is documented routinely and did not result in a higher workload. Delays between patient admission and the text message were caused by delayed completion of basic documentation. To use the automated real-time text messaging system to immediately identify emergency patients suitable for acute stroke trials, further development needs to focus on eliminating delays in documentation for the SSA in the emergency department

Lithium inhibits tryptophan catabolism via the inflammation‐induced kynurenine pathway in human microglia

Despite its decades' long therapeutic use in psychiatry, the biological mechanisms underlying lithium's mood-stabilizing effects have remained largely elusive. Here, we investigated the effect of lithium on tryptophan breakdown via the kynurenine pathway using immortalized human microglia cells, primary human microglia isolated from surgical specimens, and microglia-like cells differentiated from human induced pluripotent stem cells. Interferon (IFN)-gamma, but not lipopolysaccharide, was able to activate immortalized human microglia, inducing a robust increase in indoleamine-2,3-dioxygenase (IDO1) mRNA transcription, IDO1 protein expression, and activity. Further, chromatin immunoprecipitation verified enriched binding of both STAT1 and STAT3 to the IDO1 promoter. Lithium counteracted these effects, increasing inhibitory GSK3 beta(S9) phosphorylation and reducing STAT1(S727) and STAT3(Y705) phosphorylation levels in IFN-gamma treated cells. Studies in primary human microglia and hiPSC-derived microglia confirmed the anti-inflammatory effects of lithium, highlighting that IDO activity is reduced by GSK3 inhibitor SB-216763 and STAT inhibitor nifuroxazide via downregulation of P-STAT1(S727) and P-STAT3(Y705). Primary human microglia differed from immortalized human microglia and hiPSC derived microglia-like cells in their strong sensitivity to LPS, resulting in robust upregulation of IDO1 and anti-inflammatory cytokine IL-10. While lithium again decreased IDO1 activity in primary cells, it further increased release of IL-10 in response to LPS. Taken together, our study demonstrates that lithium inhibits the inflammatory kynurenine pathway in the microglia compartment of the human brain

Refining Humane Endpoints in Mouse Models of Disease by Systematic Review and Machine Learning-Based Endpoint Definition

Ideally, humane endpoints allow for early termination of experiments by minimizing an animal’s discomfort, distress and pain, while ensuring that scientific objectives are reached. Yet, lack of commonly agreed methodology and heterogeneity of cut-off values published in the literature remain a challenge to the accurate determination and application of humane endpoints. With the aim to synthesize and appraise existing humane endpoint definitions for commonly used physiological parameters, we conducted a systematic review of mouse studies of acute and chronic disease models, which used body weight, temperature and/or sickness scores for endpoint definition. In the second part of the study, we used previously published and unpublished data on weight, temperature and sickness scores from mouse models of sepsis and stroke and applied machine learning algorithms to assess the usefulness of this method for parameter selection and endpoint definition across models. Studies were searched for in two electronic databases (MEDLINE/Pubmed and Embase). Out of 110 retrieved full-text manuscripts, 34 studies were included. We found large intra- and inter-model variance in humane endpoint determination and application due to varying animal models, lack of standardized experimental protocols and heterogeneity of performance metrics (part 1). Machine learning models trained with physiological data and sickness severity score or modified DeSimoni neuroscore identified animals with a high risk of death at an early time point in both mouse models of stroke (male: 93.2% at 72h post-treatment; female: 93.0% at 48h post-treatment) and sepsis (96.2% at 24h post-treatment), thus demonstrating generalizability in endpoint determination across models (part 2)

A Semiquantitative Non-invasive Measurement of PcomA Patency in C57BL/6 Mice Explains Variance in Ischemic Brain Damage in Filament MCAo

Numerous studies on experimental ischemic stroke use the filament middle cerebral artery occlusion (fMCAo) model in C57BL/6 mice, but lesion sizes in this strain are highly variable. A known contributor is variation in the posterior communicating artery (PcomA) patency. We therefore aimed to provide a semiquantitative non-invasivein vivomethod to routinely assess PcomA patency. We included 43 male C57BL/6 mice from four independent studies using a transient 45 min fMCAo model. Edema-corrected lesion sizes were measured by magnetic resonance (MR) imaging 24 h after reperfusion. Time-of-flight MR angiography was performed 7 days before and 24 h after fMCAo. Scores of PcomA size measured 24 h after, but not scores measured 7 days before fMCAo were negatively correlated with lesion size. Variability in PcomA patency explained 30% of the variance in our cohort (p< 0.0001, coefficient of determinationr(2)= 0.3). In a simulation using parameters typical for experimental stroke research, the power to detect a true effect ofd= 1 between two groups increased by 15% when an according covariate was included in the statistical model. We have demonstrated thatin vivomeasurement of PcomA size is feasible and can lead to increased accuracy in assessing the effect of treatments

Effect of informed consent on patient characteristics in a stroke thrombolysis trial

Objective: To determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials. Methods: We analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups. Results: In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older (median 71 vs 66 years, p &lt; 0.0001) and had a higher frequency of arterial hypertension (58.2% vs 43.4%, p &lt; 0.0001). They showed higher scores on the NIH Stroke Scale (median 11 vs 5, p &lt; 0.0001) and more frequently aphasia (73.7% vs 20.0%, p &lt; 0.0001). The rate of proxy consent varied among countries (p &lt; 0.0001), ranging from 77.1% in Spain to 1.2% in Denmark. Conclusions: Patients recruited by proxy consent were older, had more severe strokes, and had higher prevalence of aphasia than those with capacity to give personal consent. Variations in the manner of consent across countries may influence trial results. Clinicaltrials.gov and Clinicaltrialsregister.eu identifiers: NCT01525290 (clinicaltrials.gov); 2011-005906-32 (clinicaltrialsregister.eu)

Common miRNA Patterns of Alzheimer’s Disease and Parkinson’s Disease and Their Putative Impact on Commensal Gut Microbiota

With the rise of Next-Generation-Sequencing (NGS) methods, Micro-RNAs (miRNAs) have achieved an important position in the research landscape and have been found to present valuable diagnostic tools in various diseases such as multiple sclerosis or lung cancer. There is also emerging evidence that miRNAs play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD) or Parkinson’s disease (PD). Apparently, these diseases come along with changes in miRNA expression patterns which led to attempts from researchers to use these small RNA species from several body fluids for a better diagnosis and in order to observe disease progression. Additionally, it became evident that microbial commensals might play an important role for pathology development and were shown to have a significantly different composition in patients suffering from neurodegeneration compared with healthy controls. As it could recently be shown that secreted miRNAs are able to enter microbial organisms, it is conceivable that the host’s miRNA might affect the gut microbial ecosystem. As such, miRNAs may inherit a central role in shaping the “diseased microbiome” and thereby mutually act on the characteristics of these neurodegenerative diseases. We have therefore (1) compiled a list of miRNAs known to be associated with AD and/or PD, (2) performed an in silico target screen for binding sites of these miRNA on human gut metagenome sequences and (3) evaluated the hit list for interesting matches potentially relevant to the etiology of AD and or PD. The examination of protein identifiers connected to bacterial secretion system, lipopolysaccharide biosynthesis and biofilm formation revealed an overlap of 37 bacterial proteins that were targeted by human miRNAs. The identified links of miRNAs to the biological processes of bacteria connected to AD and PD have yet to be validated via in vivo experiments. However, our results show a promising new approach for understanding aspects of these neurodegenerative diseases in light of the regulation of the microbiome