Ralf Mikut

Zebrafish embryos as models for embryotoxic and teratological effects of chemicals

The experimental virtues of the zebrafish embryo such as small size, development outside of the mother, cheap maintenance of the adult made the zebrafish an excellent model for phenotypic genetic and more recently also chemical screens. The availability of a genome sequence and several thousand mutants and transgenic lines together with gene arrays and a broad spectrum of techniques to manipulate gene functions add further to the experimental strength of this model. Pioneering studies suggest that chemicals can have in many cases very similar toxicological and teratological effects in zebrafish embryos and humans. In certain areas such as cardiotoxicity, the zebrafish appears to outplay the traditional rodent models of toxicity testing. Several pilot projects used zebrafish embryos to identify new chemical entities with specific biological functions. In combination with the establishment of transgenic sensor lines and the further development of existing and new automated imaging systems, the zebrafish embryos could therefore be used as cost-effective and ethically acceptable animal models for drug screening as well as toxicity testing.

Interpretability issues in data-based learning of fuzzy systems

This paper presents a method for an automatic and complete design of fuzzy systems from data. The main objective is to build fuzzy systems with a user-controllable trade-off between accuracy and interpretability. Whereas criteria for accuracy mostly follow straightforwardly from the application, definition of interpretability and its criteria are subject to controversial discussion. For this reason, a set of interpretability criteria is given which guide the design process. Consequently, interpretability is maintained by structural choices regarding the type of membership functions, rules, and inference mechanism, on the one hand, and by including interpretability criteria in the rule/rule base evaluation, on the other hand. An application in Instrumented Gait Analysis, to characterize a certain group of patients in comparison to healthy subjects, illustrates the proposed algorithm.

SOX2 gene amplification and protein overexpression are associated with better outcome in squamous cell lung cancer

The transcription factor SOX2 (3q26.3–q27) is a key regulator of foregut development and an embryonic stem cell factor cooperating during induction of pluripotency in terminally differentiated somatic cells. Recently, we found SOX2 to be amplified in a subset of squamous cell lung and esophageal cancers. The aim of this study was to explore the prognostic role of SOX2 in a large series of squamous cell carcinomas and adenocarcinomas of the lung. A total of 891 samples from two independent population-based cohorts were assessed by fluorescence in situ hybridization and immunohistochemistry. Furthermore, we assessed for associations between SOX2 amplification/upregulation and clinicopathological features. Similar results were found in the two cohorts. Within squamous cell carcinoma cases, 8% high-level as well as 68 and 65% low-level SOX2 amplifications occurred in the two cohorts, respectively. In adenocarcinomas, no high-level amplification was found and low-level amplification occurred in 6% of the two cohorts. Within squamous cell carcinomas of one cohort, SOX2 amplification was associated with lower tumor grade, while higher levels of SOX2 expression were related to younger age, smaller tumor size, and lower probability of angiolymphatic invasion and metastasis. High SOX2 expression levels proved to be a marker for prolonged overall survival among patients with squamous cell carcinomas. In conclusion, SOX2 amplification and upregulation are frequent events in squamous cell carcinomas of the lung and are associated with indicators of favorable prognosis.

Data mining tools

The development and application of data mining algorithms requires the use of powerful software tools. As the number of available tools continues to grow, the choice of the most suitable tool becomes increasingly difficult. This paper attempts to support the decision‐making process by discussing the historical development and presenting a range of existing state‐of‐the‐art data mining and related tools. Furthermore, we propose criteria for the tool categorization based on different user groups, data structures, data mining tasks and methods, visualization and interaction styles, import and export options for data and models, platforms, and license policies. These criteria are then used to classify data mining tools into nine different types. The typical characteristics of these types are explained and a selection of the most important tools is categorized. This paper is organized as follows: the first section Historical Development and State‐of‐the‐Art highlights the historical development of data mining software until present; the criteria to compare data mining software are explained in the second section Criteria for Comparing Data Mining Software. The last section Categorization of Data Mining Software into Different Types proposes a categorization of data mining software and introduces typical software tools for the different types.

SOX2 amplification is a common event in squamous cell carcinomas of different organ sites

Acquired chromosomal aberrations, including gene copy number alterations, are involved in the development and progression of human malignancies. SOX2, a transcription factor-coding gene located at 3q26.33, is known to be recurrently and specifically amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. In these organs, the SOX2 protein plays an important role in tumorigenesis and tumor survival. The aim of this study was to determine whether SOX2 amplification is also found in squamous cell carcinomas in other organs commonly affected by this tumor entity. In addition, we examined a large spectrum of lung cancer entities with neuroendocrine differentiation (ie, small cell cancers, large cell cancers, typical and atypical carcinoids) for SOX2 and TTF1 copy number gains to reveal potential molecular ties to squamous cell carcinomas or adenocarcinomas of the lung. Applying fluorescence in situ hybridization, we assessed squamous cell carcinomas of the cervix uteri (n = 47), the skin (n = 57), and the penis (n = 53) for SOX2 copy number alterations and detected amplifications in 28%, 28%, and 32% of tumors, respectively. Furthermore, we performed immunohistochemical SOX2 staining and found that SOX2 amplification is significantly associated with overexpression of the corresponding protein in squamous cell carcinomas (P < .001). Of the lung cancer entities with neuroendocrine differentiation, only small cell cancers and large cell cancers exhibited SOX2 or TTF1 amplifications at significant frequencies, indicating that at least a subset of these might be dedifferentiated forms of squamous cell carcinomas or adenocarcinomas of the lung. We conclude that SOX2 amplification and consequent SOX2 protein overexpression may represent important mechanisms of tumor initiation and progression in a considerable subset of squamous cell carcinomas.

A hydraulically driven multifunctional prosthetic hand

In this paper a new prosthetic hand is presented that closely approximates the grasping abilities of a human hand. A large variety of different objects can be grasped reliably and the movements of the hand appear to natural. This five-finger hand has 15 degrees of freedom driven by small sized flexible fluidic actuators. The drives are within the fingers allowing a very compact and lightweight hand. Also, a concept for the control of different grasp types is presented. The characteristics of the new hand are illustrated.

Identification of Nonvisual Photomotor Response Cells in the Vertebrate Hindbrain

Nonvisual photosensation enables animals to sense light without sight. However, the cellular and molecular mechanisms of nonvisual photobehaviors are poorly understood, especially in vertebrate animals. Here, we describe the photomotor response (PMR), a robust and reproducible series of motor behaviors in zebrafish that is elicited by visual wavelengths of light but does not require the eyes, pineal gland, or other canonical deep-brain photoreceptive organs. Unlike the relatively slow effects of canonical nonvisual pathways, motor circuits are strongly and quickly (seconds) recruited during the PMR behavior. We find that the hindbrain is both necessary and sufficient to drive these behaviors. Using in vivo calcium imaging, we identify a discrete set of neurons within the hindbrain whose responses to light mirror the PMR behavior. Pharmacological inhibition of the visual cycle blocks PMR behaviors, suggesting that opsin-based photoreceptors control this behavior. These data represent the first known light-sensing circuit in the vertebrate hindbrain.

Automated Processing of Zebrafish Imaging Data: A Survey

Due to the relative transparency of its embryos and larvae, the zebrafish is an ideal model organism for bioimaging approaches in vertebrates. Novel microscope technologies allow the imaging of developmental processes in unprecedented detail, and they enable the use of complex image-based read-outs for high-throughput/high-content screening. Such applications can easily generate Terabytes of image data, the handling and analysis of which becomes a major bottleneck in extracting the targeted information. Here, we describe the current state of the art in computational image analysis in the zebrafish system. We discuss the challenges encountered when handling high-content image data, especially with regard to data quality, annotation, and storage. We survey methods for preprocessing image data for further analysis, and describe selected examples of automated image analysis, including the tracking of cells during embryogenesis, heartbeat detection, identification of dead embryos, recognition of tissues and anatomical landmarks, and quantification of behavioral patterns of adult fish. We review recent examples for applications using such methods, such as the comprehensive analysis of cell lineages during early development, the generation of a three-dimensional brain atlas of zebrafish larvae, and high-throughput drug screens based on movement patterns. Finally, we identify future challenges for the zebrafish image analysis community, notably those concerning the compatibility of algorithms and data formats for the assembly of modular analysis pipelines.

A cognitive architecture for a humanoid robot: a first approach

Future life pictures humans having intelligent humanoid robotic systems taking part in their everyday life. Thus researchers strive to supply robots with an adequate artificial intelligence in order to achieve a natural and intuitive interaction between human being and robotic system. Within the German Humanoid Project we focus on learning and cooperating multimodal robotic systems. In this paper we present a first cognitive architecture for our humanoid robot: The architecture is a mixture of a hierarchical three-layered form on the one hand and a composition of behaviour-specific modules on the other hand. Perception, learning, planning of actions, motor control, and human-like communication play an important role in the robotic system and are embedded step by step in our architecture

Postacute management of patients with spinal cord injury due to metastatic tumour disease: survival and efficacy of rehabilitation

Study design: Retrospective study utilising clinical records and public administration databases.Objectives: This study was performed to analyse the clinical presentation and survival rate of individuals with spinal cord injury (SCI) due to spinal metastasis after primary treatment, and to evaluate the efficacy of rehabilitative efforts.Setting: Spinal Cord Injury Unit, University Hospital, Heidelberg.Methods: A total of 68 consecutive patients were included. Demographics, clinical data, tumour type, level and completeness of SCI, initial treatment, functional independence measure (FIM) and survival time were derived from hospital and public administration databases. Cox regression and fuzzy logic rule generation were used for statistical analysis.Results: Of the 68 patients, 66 patients died 11 months (median, interquartile range (IQR) 4–29 months) after the onset of neurological symptoms at an average age of 58 years. The functional independence measure (FIM) score describing the general clinical and functional status proved to be the most reliable prognostic factor of survival. Other more specific parameters (eg tumour type or level of lesion) did not have such an impact. In total, 51 patients completed the rehabilitation programme within 50 days (median, IQR 27–99 days). The FIM score improved from 62 at admission to 84 at discharge.Conclusion: The clinical and functional status is a valuable prognostic factor for survival. Since institutionalised rehabilitative efforts are effective, this group of patients should be accepted into such a program.