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S Bahn

Publications and source records attributed to S Bahn.

At least 19 recordsLinked to original sources
PubMed2006

Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes.

Bipolar affective disorder is a severe psychiatric disorder with a strong genetic component but unknown pathophysiology. We used microarray technology to determine the expression of approximately 22,000 mRNA transcripts in post-mortem tissue from two brain regions in patients with bipolar disorder and matched healthy controls. Dorsolateral prefrontal cortex tissue from a cohort of 70 subjects and orbitofrontal cortex tissue from a separate cohort of 30 subjects was investigated. The final analysis included 30 bipolar and 31 control subjects for the dorsolateral prefrontal cortex and 10 bipolar and 11 control subjects for the orbitofrontal cortex. Differences between disease and control groups were identified using a rigorous statistical analysis with correction for confounding variables and multiple testing. In the orbitofrontal cortex, 393 differentially expressed transcripts were identified by microarray analysis and a representative subset was validated by quantitative real-time PCR. Pathway analysis revealed significant upregulation of genes involved in G-protein coupled receptor signalling and response to stimulus (in particular the immune response), while genes relating to the ubiquitin cycle and intracellular transport showed coordinated downregulation in bipolar disorder. Additionally, several genes involved in synaptic function were significantly downregulated in bipolar disorder. No significant changes in gene expression were observed in the dorsolateral prefrontal cortex using microarray analysis or quantitative real-time PCR. Our findings implicate the orbitofrontal cortex as a region prominently involved in bipolar disorder and indicate that diverse processes are affected. Overall, our results suggest that dysregulation of the ubiquitin pathway and synaptic function may be central to the disease process.

Adult↗
PubMed2005

Psychiatry in Europe.

Explore the source record for details and available documents.

Cross-Cultural Comparison↗
PubMed2004

Protein profiling of human postmortem brain using 2-dimensional fluorescence difference gel electrophoresis (2-D DIGE).

Two-dimensional gel electrophoresis (2-D GE) is a key tool for comparative proteomics research. With its ability to separate complex protein mixtures with high resolution, 2-D GE is a technique commonly employed for protein profiling studies. Significant improvements have been made in 2-D GE technology with the development of two-dimensional fluorescence difference gel electrophoresis (2-D DIGE), where proteins are first labelled with one of three spectrally resolvable fluorescent cyanine dyes before being separated over first and second dimensions according to their charge and size, respectively. When used in conjunction with automated analysis packages, this multiplexing approach can accurately and reproducibly quantify protein expression for control and experimental groups. Differentially expressed proteins can be subsequently identified by mass spectrometric methods. Here, we describe the successful application and optimisation of 2-D DIGE technology for human postmortem brain studies. This technology, especially when coupled with other functional genomics approaches, such as transcriptomics and metabolomics studies, will enhance our current understanding of human disease and lead to new therapeutic and diagnostic possibilities.

Brain Chemistry↗
PubMed2004

Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress.

The etiology and pathophysiology of schizophrenia remain unknown. A parallel transcriptomics, proteomics and metabolomics approach was employed on human brain tissue to explore the molecular disease signatures. Almost half the altered proteins identified by proteomics were associated with mitochondrial function and oxidative stress responses. This was mirrored by transcriptional and metabolite perturbations. Cluster analysis of transcriptional alterations showed that genes related to energy metabolism and oxidative stress differentiated almost 90% of schizophrenia patients from controls, while confounding drug effects could be ruled out. We propose that oxidative stress and the ensuing cellular adaptations are linked to the schizophrenia disease process and hope that this new disease concept may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Brain↗
PubMed2004

Functional genomics and proteomics: application in neurosciences.

The sequencing of the complete genome for many organisms, including man, has opened the door to the systematic understanding of how complex structures such as the brain integrate and function, not only in health but also in disease. This blueprint, however, means that the piecemeal analysis regimes of the past are being rapidly superseded by new methods that analyse not just tens of genes or proteins at any one time, but thousands, if not the entire repertoire of a cell population or tissue under investigation. Using the most appropriate method of analysis to maximise the available data therefore becomes vital if a complete picture is to be obtained of how a system or individual cell is affected by a treatment or disease. This review examines what methods are currently available for the large scale analysis of gene and protein expression, and what are their limitations.

Brain↗
PubMed2001

Indexing-based differential display--studies on post-mortem Alzheimer's brains.

In this study we demonstrate for the first time that a novel indexing-based differential display technique generates valid and reproducible results when applied to human post-mortem tissue. We studied expression profiles in prefrontal cortex tissue derived from Alzheimer's disease (AD) and control brains, respectively, and found robust changes in several expressed genes, some of which have a known association with the disease process in AD. These included the dramatic reduction of calcineurin (known to be involved in tau phosphorylation) and GAP-43 (associated with synapse remodelling). Differential display results were confirmed by semi-quantitative RT-PCR on a larger number of brains.

Aged↗
PubMed2001

Gene expression profiling in the post-mortem human brain--no cause for dismay.

Global expression profiling techniques such as microarray technology promise to revolutionize biology. Soon it will be possible to investigate alterations at the transcript level of the entire human genome. There is great hope that these techniques will at last shed light on the pathological processes involved in complex neuropsychiatric disorders such as schizophrenia. These scientific advances in turn have re-kindled a great interest and demand for post-mortem brain tissue. Good quality post-mortem tissue undoubtedly is the fundamental prerequisite to investigate complex brain disorders with molecular profiling techniques. In this review we show that post-mortem brain tissue can yield good quality mRNA and intact protein antigens which allow the successful application of traditional molecular biology methods as well as novel profiling techniques. We also consider the use of laser-capture microdissection on post-mortem tissue. This recently developed technique allows the experimenter to explore the molecular basis of cellular function at the single cell level. The combination of laser-capture microdissection with high throughput profiling techniques offers opportunities to obtain precise genetic fingerprints of individual neurons allowing comparisons of normal and pathological states.

Autopsy↗
PubMed2000

Analysis of vertebrate SCL loci identifies conserved enhancers.

The SCL gene encodes a highly conserved bHLH transcription factor with a pivotal role in hemopoiesis and vasculogenesis. We have sequenced and analyzed 320 kb of genomic DNA composing the SCL loci from human, mouse, and chicken. Long-range sequence comparisons demonstrated multiple peaks of human/mouse homology, a subset of which corresponded precisely with known SCL enhancers. Comparisons between mammalian and chicken sequences identified some, but not all, SCL enhancers. Moreover, one peak of human/mouse homology (+23 region), which did not correspond to a known enhancer, showed significant homology to an analogous region of the chicken SCL locus. A transgenic Xenopus reporter assay was established and demonstrated that the +23 region contained a new neural enhancer. This combination of long-range comparative sequence analysis with a high-throughput transgenic bioassay provides a powerful strategy for identifying and characterizing developmentally important enhancers.

Amino Acid Sequence↗
PubMed1999

Distinct 5' SCL enhancers direct transcription to developing brain, spinal cord, and endothelium: neural expression is mediated by GATA factor binding sites.

The SCL gene encodes a basic helix-loop-helix transcription factor with a pivotal role in the development of endothelium and of all hematopoietic lineages. SCL is also expressed in the central nervous system, although its expression pattern has not been examined in detail and its function in neural development is unknown. In this article we present the first analysis of SCL transcriptional regulation in vivo. We have identified three spatially distinct regulatory modules, each of which was both necessary and sufficient to direct reporter gene expression in vivo to three different regions within the normal SCL expression domain, namely, developing endothelium, midbrain, and hindbrain/spinal cord. In addition we have demonstrated that GATA factor binding sites are essential for neural expression of the SCL constructs. The midbrain element was particularly powerful and axonal lacZ expression revealed the details of axonal projections, thus implicating SCL in the development of occulomotor, pupillary, or retinotectal pathways. The neural expression pattern of the SCL gene was highly conserved in mouse, chicken, and zebrafish embryos and the 5' region of the chicken SCL locus exhibited a striking degree of functional conservation in transgenic mice. These data suggest that SCL performs critical functions in neural development. The regulatory elements identified here provide important tools for analyzing these functions.

Animals↗
PubMed1999

The intrinsic specification of gamma-aminobutyric acid type A receptor alpha6 subunit gene expression in cerebellar granule cells.

The patterns of gamma-aminobutyric acid type A (GABAA) receptor subunit gene expression in the brain are complex. For example, mouse hippocampal dentate granule cells express many subunit genes, whereas adult cerebellar granule cells, which may share differentiation mechanisms, have a smaller compliment and uniquely express the alpha6 subunit gene. To see how the alpha6 expression component arises, i.e. if intrinsically or environmentally specified, we used a mouse line (Deltaalpha6lacZ) with a beta-galactosidase reporter inserted into the alpha6 gene. Precursor cells from postnatal day 1 Deltaalpha6lacZ cerebellum were transplanted to the adult hippocampus and cerebellum of wild-type mice; 4 weeks after transplantation, Deltaalpha6lacZ cells expressed alpha6-lacZ in the hippocampus, amygdala and cerebellum. Thus, different adult environments support both the development and maintenance of alpha6 gene expression from cerebellar granule cell precursors. Establishing alpha6 gene expression is not likely to require specific patterns of neurotransmitter innervation or other factors present only in the developing brain; instead, alpha6 expression can be timed and maintained autonomously.

Amygdala↗
PubMed1998

The T-cell oncogenic protein HOX11 activates Aldh1 expression in NIH 3T3 cells but represses its expression in mouse spleen development.

Hox11 is a homeobox gene essential for spleen formation in mice, since atrophy of the anlage of a developing spleen occurs in early embryonic development in Hox11 null mice. HOX11 is also expressed in a subset of T-cell acute leukemias after specific chromosomal translocations. Since the protein has a homeodomain and can activate transcription, it probably exerts at least some of its effects in vivo by regulation of target genes. Representational difference analysis has been used to isolate cDNA clones corresponding to mRNA species activated following stable expression of HOX11 in NIH 3T3 cells. The gene encoding the retinoic acid-synthesizing enzyme aldehyde dehydrogenase 1 (Aldh1), initially called Hdg-1, was found to be ectopically activated by HOX11 in this system. Study of Aldh1 gene expression during spleen development showed that the presence of Aldh1 mRNA inversely correlated with Hox11. Hox11 null mouse embryos have elevated Aldh1 mRNA in spleen primordia prior to atrophy, while Aldh1 seems to be repressed by Hox11 during organogenesis of the spleens of wild-type mice. This result suggests that expression of Aldh1 protein is negatively regulated by Hox11 and that abnormal expression of Aldh1 in Hox11 null mice may cause loss of splenic precursor cells by aberrant retinoic acid metabolism.

3T3 Cells↗
PubMed1997

Directing gene expression to cerebellar granule cells using gamma-aminobutyric acid type A receptor alpha6 subunit transgenes.

Expression of the gamma-aminobutyric acid type A receptor alpha6 subunit gene is restricted to differentiated granule cells of the cerebellum and cochlear nucleus. The mechanisms underlying this limited expression are unknown. Here we have characterized the expression of a series of alpha6-based transgenes in adult mouse brain. A DNA fragment containing a 1-kb portion upstream of the start site(s), together with exons 1-8, can direct high-level cerebellar granule cell-specific reporter gene expression. Thus powerful granule cell-specific determinants reside within the 5' half of the alpha6 subunit gene body. This intron-containing transgene appears to lack the cochlear nucleus regulatory elements. It therefore provides a cassette to deliver gene products solely to adult cerebellar granule cells.

Animals↗
PubMed1997

Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression.

Cerebellar granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact alpha6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse alpha6 subunit gene was disrupted by homologous recombination. In alpha6 -/- granule cells, the delta subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with delta subunit-specific antibodies. The delta subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the delta subunit. These results provide genetic evidence for a specific association between the alpha6 and delta subunits. Because in alpha6 -/- neurons the remaining alpha1, beta2/3, and gamma2 subunits cannot rescue the delta subunit, certain potential subunit combinations may not be found in wild-type cells.

Animals↗
PubMed1996

The cerebellum: a model system for studying GABAA receptor diversity.

The basic unsolved questions concerning GABAA receptors are: "How many receptor subtypes exist?", "What subtypes are used by which types of neuron and where are they located on the cell?", and "What are the functions of the different subtypes?" As described in this Review, the cerebellum is an ideal vertebrate brain region for investigating these issues.

Animals↗
PubMed1996

Conservation of gamma-aminobutyric acid type A receptor alpha 6 subunit gene expression in cerebellar granule cells.

The gamma-aminobutyric acid type A receptor cDNAs encoding the alpha 6 subunit homologues from chicken and goldfish have been cloned and sequenced. These proteins exhibit 83 and 75% identity, respectively, to the rat alpha 6 polypeptide. In situ hybridization has demonstrated that, as in mammals, the avian and teleost fish alpha 6 subunit genes are predominantly expressed in cerebellar granule cells. Correspondingly, flunitrazepam-non-displaceable binding of [3H]Ro 15-4513 (a benzodiazepine partial inverse agonist), which is a major characteristic of gamma-aminobutyric acid type-A receptors that contain the alpha 6 polypeptide, is also mainly found for cerebellar granule cells of fish and chick. The conservation of this expression pattern suggests that gamma-aminobutyric acid type A receptors possessing the alpha 6 subunit are of fundamental importance for cerebellar function and that the corresponding gene regulatory elements, e.g., granule cell-specific enhancers, have also been conserved.

Amino Acid Sequence↗
PubMed1996

Characterization of a cerebellar granule cell-specific gene encoding the gamma-aminobutyric acid type A receptor alpha 6 subunit.

The alpha 6 subunit of gamma-aminobutyric type A receptors is a marker for cerebellar granule cells and is an attractive candidate to study cell-specific gene expression in the brain. The mouse alpha 6 subunit gene has nine exons and spans approximately 14 kb. The largest intron (intron 8) is approximately 7 kb. For a minority of mRNAs, a missplice of the first exon was identified that disrupts the signal peptide and most likely results in the production of nonfunctional protein. The gene is transcribed from a TATA-less promoter that uses multiple start sites. Using transgenic mice, it was found that the proximal 0.5 kb of the rat alpha 6 gene upstream region confers expression on a beta-galactosidase reporter gene. One founder gave rise to a line with cerebellar granule cell-specific expression, although expression varied with lobule region. Other founders had ectopic but neuron-specific expression, with beta-galactosidase found in cerebellar Purkinje cells, neocortex, thalamus, hippocampus, caudate-putamen, and inferior colliculi. Thus, we have defined a region containing the basal promoter of the alpha 6 subunit gene and that confers neuron-specific expression.

Alternative Splicing↗
PubMed1994

Maxillary odontogenic myxoma. A case report.

The odontogenic myxoma, a slow-growing, benign but often recurrent tumor, is unpredictable. The case presented here demonstrates the difficulty of choosing an appropriate treatment plan.

Adult↗