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Robicsek O.,Rambam Medical Center | Karry R.,Rambam Medical Center | Petit I.,University Paris Diderot | Muller F.-J.,Zentrum fur Integrative Psychiatrie | And 3 more authors.
Molecular Psychiatry | Year: 2013

One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons. iPSCs were differentiated into Pax6 +/Nestin + neural precursors and then further differentiated into β3-Tubulin +/tyrosine hydroxylase +/DAT + dopaminergic neurons. In addition, iPSCs were differentiated through embryonic bodies into β3-Tubulin +/Tbox brain1 + glutamatergic neurons. Schizophrenia-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial respiration and its sensitivity to dopamine-induced inhibition were impaired in schizophrenia- derived keratinocytes and iPSCs. Moreover, we observed dissipation of mitochondrial membrane potential (Δψ m) and perturbations in mitochondrial network structure and connectivity in dopaminergic along the differentiation process and in glutamatergic cells. Our data unravel perturbations in neural differentiation and mitochondrial function, which may be interconnected, and of relevance to dysfunctional neurodevelopmental processes in schizophrenia. © 2013 Macmillan Publishers Limited All rights reserved.

Williams R.,Sanford Burnham Institute for Medical Research | Schuldt B.,RWTH Aachen | Muller F.-J.,Zentrum fur Integrative Psychiatrie
BioEssays | Year: 2011

We have developed a first generation tool for the unbiased identification and characterization of human pluripotent stem cells, termed PluriTest. This assay utilizes all the information contained on a microarray and abandons the conventional stem cell marker concept. Stem cells are defined by the ability to replenish themselves and to differentiate into more mature cell types. As differentiation potential is a property that cannot be directly proven in the stem cell state, biologists have to rely on correlative measurements in stem cells associated with differentiation potential. Unfortunately, most, if not all, of those markers are only valid within narrow limits of specific experimental systems. Microarray technologies and recently next-generation sequencing have revolutionized how cellular phenotypes can be characterized on a systems-wide level. Here we discuss the challenges PluriTest and similar global assays need to address to fulfill their enormous potential for industrial, diagnostic and therapeutic applications. PluriTest is a first generation tool for the unbiased identification and characterization of human pluripotent stem cells which utilizes all the information contained on a microarray and abandons the conventional stem cell marker concept. © 2011 WILEY Periodicals, Inc.

Lenz M.,RWTH Aachen | Schuldt B.M.,RWTH Aachen | Muller F.-J.,Zentrum fur Integrative Psychiatrie | Schuppert A.,RWTH Aachen | Schuppert A.,Bayer AG
PLoS ONE | Year: 2013

Relating expression signatures from different sources such as cell lines, in vitro cultures from primary cells and biopsy material is an important task in drug development and translational medicine as well as for tracking of cell fate and disease progression. Especially the comparison of large scale gene expression changes to tissue or cell type specific signatures is of high interest for the tracking of cell fate in (trans-) differentiation experiments and for cancer research, which increasingly focuses on shared processes and the involvement of the microenvironment. These signature relation approaches require robust statistical methods to account for the high biological heterogeneity in clinical data and must cope with small sample sizes in lab experiments and common patterns of co-expression in ubiquitous cellular processes. We describe a novel method, called PhysioSpace, to position dynamics of time series data derived from cellular differentiation and disease progression in a genome-wide expression space. The PhysioSpace is defined by a compendium of publicly available gene expression signatures representing a large set of biological phenotypes. The mapping of gene expression changes onto the PhysioSpace leads to a robust ranking of physiologically relevant signatures, as rigorously evaluated via sample-label permutations. A spherical transformation of the data improves the performance, leading to stable results even in case of small sample sizes. Using PhysioSpace with clinical cancer datasets reveals that such data exhibits large heterogeneity in the number of significant signature associations. This behavior was closely associated with the classification endpoint and cancer type under consideration, indicating shared biological functionalities in disease associated processes. Even though the time series data of cell line differentiation exhibited responses in larger clusters covering several biologically related patterns, top scoring patterns were highly consistent with a priory known biological information and separated from the rest of response patterns. © 2013 Lenz et al.

Macarthur B.D.,University of Southampton | Sevilla A.,Mount Sinai School of Medicine | Lenz M.,RWTH Aachen | Muller F.-J.,Zentrum fur Integrative Psychiatrie | And 8 more authors.
Nature Cell Biology | Year: 2012

A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach that includes high-throughput single-cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability. © 2012 Macmillan Publishers Limited.

Reiff J.,Zentrum fur Integrative Psychiatrie
Movement disorders : official journal of the Movement Disorder Society | Year: 2011

Quality of life in Parkinson patients with subthreshold depression could be improved if the prevalence and symptom profile were better understood. Our study used standard DSM-IV and Judd criteria as well as motor, depression, and quality-of-life scales to investigate a sample of 110 nondemented Parkinson patients. This led to formation of nondepressed (48.2%), subthreshold depressed (25.5%), and depressed (26.4%) groups. Quality of life was seen to be significantly lower in subthreshold depressed patients than in the nondepressed, and there were differences in the frequency of depressive symptoms that partially overlapped with nonmotor symptoms of vegetative origin in Parkinson's disease (appetite, sleep disorders). Key measures of depression (diminished interest/pleasure) were more frequent in the depressed group compared with the subthreshold depressed, although the motor functions of these 2 groups did not differ significantly. The Beck Depression Inventory score ranging from 9 to 15 points differentiates subthreshold depressed from nondepressed and depressed patients best. Copyright © 2011 Movement Disorder Society.

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