Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates... more
Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation m...
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Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional... more
Genomic copy number variants (CNVs) have been implicated in multiple psychiatric disorders, but not much is known about their influence on anxiety disorders specifically. Using next-generation sequencing (NGS) and two additional array-based genotyping approaches, we detected CNVs in a mouse model consisting of two inbred mouse lines showing high (HAB) and low (LAB) anxiety-related behavior, respectively. An influence of CNVs on gene expression in the central (CeA) and basolateral (BLA) amygdala, paraventricular nucleus (PVN), and cingulate cortex (Cg) was shown by a two-proportion Z-test (p = 1.6 x 10-31), with a positive correlation in the CeA (p = 0.0062), PVN (p = 0.0046) and Cg (p = 0.0114), indicating a contribution of CNVs to the genetic predisposition to trait anxiety in the specific context of HAB/LAB mice. In order to confirm anxiety-relevant CNVs and corresponding genes in a second mouse model, we further examined CD-1 outbred mice. We revealed the distribution of CNVs by ...
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Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels... more
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was
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Photosynthetic microbial mats are complex, stratified ecosystems in which high rates of primary production create a demand for nitrogen, met partially by N₂ fixation. Dinitrogenase reductase (nifH) genes and transcripts from Cyanobacteria... more
Photosynthetic microbial mats are complex, stratified ecosystems in which high rates of primary production create a demand for nitrogen, met partially by N₂ fixation. Dinitrogenase reductase (nifH) genes and transcripts from Cyanobacteria and heterotrophic bacteria (for example, Deltaproteobacteria) were detected in these mats, yet their contribution to N2 fixation is poorly understood. We used a combined approach of manipulation experiments with inhibitors, nifH sequencing and single-cell isotope analysis to investigate the active diazotrophic community in intertidal microbial mats at Laguna Ojo de Liebre near Guerrero Negro, Mexico. Acetylene reduction assays with specific metabolic inhibitors suggested that both sulfate reducers and members of the Cyanobacteria contributed to N₂ fixation, whereas (15)N₂ tracer experiments at the bulk level only supported a contribution of Cyanobacteria. Cyanobacterial and nifH Cluster III (including deltaproteobacterial sulfate reducers) sequence...
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Past studies of hydrogen cycling in hypersaline microbial mats have shown an active nighttime cycle, with production largely from Cyanobacteria and consumption from sulfate-reducing bacteria (SRB). However, the mechanisms and magnitude of... more
Past studies of hydrogen cycling in hypersaline microbial mats have shown an active nighttime cycle, with production largely from Cyanobacteria and consumption from sulfate-reducing bacteria (SRB). However, the mechanisms and magnitude of hydrogen cycling have not been extensively studied. Two mats types near Guerrero Negro, Mexico-permanently submerged Microcoleus microbial mat (GN-S), and intertidal Lyngbya microbial mat (GN-I)-were used in microcosm diel manipulation experiments with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), molybdate, ammonium addition, and physical disruption to understand the processes responsible for hydrogen cycling between mat microbes. Across microcosms, H2 production occurred under dark anoxic conditions with simultaneous production of a suite of organic acids. H2 production was not significantly affected by inhibition of nitrogen fixation, but rather appears to result from constitutive fermentation of photosynthetic storage products by oxygenic pho...
High spatial-resolution secondaryion microprobespectrometry, synchrotron radiation Fourier-transform infraredspectroscopy and polyacrylamide gel analysis demonstrate the intimateassociation of proteins with spheroidal aggregates of... more
High spatial-resolution secondaryion microprobespectrometry, synchrotron radiation Fourier-transform infraredspectroscopy and polyacrylamide gel analysis demonstrate the intimateassociation of proteins with spheroidal aggregates of biogenic zincsulfide nanocrystals, an example of extracellular biomineralization.Experiments involving synthetic ZnS nanoparticles and representativeamino acids indicate a driving role for cysteine in rapid nanoparticleaggregation. These findings suggest that microbially-derivedextracellular proteins can limit dispersal of nanoparticulatemetal-bearing phases, such as the
Research Interests: Biofilms, Science, Secondary Ion Mass Spectrometry, Nanoparticles, Transmission Electron Microscopy, and 16 moreMultidisciplinary, Synchrotron Radiation, Sulfides, Bacteria, Protein Aggregation, Nitrogen, Zinc, Amino Acids, Infrared, Chemical Precipitation, Fourier transform, Particle Size, Fourier transform infrared spectroscopy, Zinc Compounds, High Spatial Resolution, and Oxidation-Reduction
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To examine phylogenetic identity and metabolic activity of individual cells in complex microbial communi- ties, we developed a method which combines rRNA-based in situ hybridization with stable isotope imaging based on nanometer-scale... more
To examine phylogenetic identity and metabolic activity of individual cells in complex microbial communi- ties, we developed a method which combines rRNA-based in situ hybridization with stable isotope imaging based on nanometer-scale secondary-ion mass spectrometry (NanoSIMS). Fluorine or bromine atoms were introduced into cells via 16S rRNA-targeted probes, which enabled phylogenetic identification of individual cells by NanoSIMS imaging. To overcome
Research Interests: Biofilms, Microbial Ecology, Fluorescence Microscopy, Secondary Ion Mass Spectrometry, Multidisciplinary, and 19 moreIn Situ Hybridization, Humans, Carbon Isotopes, Escherichia coli, Stable Isotope, Vibrio cholerae, Applied, Applied Environmental Microbiology, Male, Bacteria, Nitrogen, Nitrogen Isotopes, Single Cell, Fluorine, Fluorescent in situ hybridization, Adult, Mouth, Isotope Labeling, and Bromine
A method for wideband measurement and for post-processing of mobile radio channel impulse responses which include unambiguous information about the directions-of-arrival in the azimuth is introduced. Based on this method, measurement... more
A method for wideband measurement and for post-processing of mobile radio channel impulse responses which include unambiguous information about the directions-of-arrival in the azimuth is introduced. Based on this method, measurement results for outdoor macrocellular environments are presented. These results are essential for assessing, developing, evaluating and optimizing adaptive directional antenna concepts for future mobile radio systems and for extending
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In the past years, there has been growing awareness about childhood onset multiple sclerosis (MS) and the relevance of psychosocial aspects such as cognitive disturbances, fatigue and depression in this population. We describe a case of a... more
In the past years, there has been growing awareness about childhood onset multiple sclerosis (MS) and the relevance of psychosocial aspects such as cognitive disturbances, fatigue and depression in this population. We describe a case of a 16-year-old patient with relapsing-remitting multiple sclerosis (RRMS) who presented at our clinic with severe fatigue symptoms and who underwent repeated neuropsychological examinations. A sudden significant slowing indicated a new relapse while neurological examination did not. This case highlights the high sensitivity and clinical relevance of neuropsychological testing in patients with juvenile MS even in the context of treatment decisions.
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A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to... more
A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.
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An extension of Rohling's (1984) single-parameter technique for processing Constant False Alarm Rate (CFAR) based on the ordered statistics of the reference cells, is described. The present version of the technique maintains a CFAR... more
An extension of Rohling's (1984) single-parameter technique for processing Constant False Alarm Rate (CFAR) based on the ordered statistics of the reference cells, is described. The present version of the technique maintains a CFAR for two-parameter distributions where the mean power and skewness of the system are variable. It is shown that the method is more robust than the single-parameter technique but has higher CFAR loss.
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Research Interests: Genetics, Brazil, Morocco, Adolescent, Human, and 20 morePortugal, Humans, Genetic Testing, Mutation, Algeria, Haplotypes, Female, Male, Young Adult, Proteins, Pedigree, Clinical Sciences, Middle Aged, Spectrum, Agenesis of the Corpus Callosum, Family Health, Genotype, Adult, Large Scale, and Base Sequence
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Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies... more
Although gene expression profiles in peripheral blood in major depression are not likely to identify genes directly involved in the pathomechanism of affective disorders, they may serve as biomarkers for this disorder. As previous studies using baseline gene expression profiles have provided mixed results, our approach was to use an in vivo dexamethasone challenge test and to compare glucocorticoid receptor (GR)-mediated changes in gene expression between depressed patients and healthy controls. Whole genome gene expression data (baseline and following GR-stimulation with 1.5 mg dexamethasone p.o.) from two independent cohorts were analyzed to identify gene expression pattern that would predict case and control status using a training (N=18 cases/18 controls) and a test cohort (N=11/13). Dexamethasone led to reproducible regulation of 2670 genes in controls and 1151 transcripts in cases. Several genes, including FKBP5 and DUSP1, previously associated with the pathophysiology of majo...
Research Interests: Depression, RNA, Neuropsychopharmacology, Adolescent, Fatigue, and 23 moreGene expression, Dexamethasone, Humans, Random Forest, Burnout, Male, Young Adult, Psychoneuroendocrinology, Aged, Middle Aged, Major Depression, Adult, Molecular Marker, Reproducibility of Results, Adrenocorticotropic Hormone, Occupations, Glucocorticoids, Affective Disorder, Gene Expression Regulation, Gene expression profiling, Cohort Studies, Aerobic Exercise, and Gene Expression Data
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Page 1. Experimental determination of the sources of otolith carbon and associated isotopic fractionation Christopher T. Solomon, Peter K. Weber, Joseph J. Cech, Jr., B. Lynn Ingram, Mark E. Conrad, Madhav V. Machavaram, Asya R. Pogodina,... more
Page 1. Experimental determination of the sources of otolith carbon and associated isotopic fractionation Christopher T. Solomon, Peter K. Weber, Joseph J. Cech, Jr., B. Lynn Ingram, Mark E. Conrad, Madhav V. Machavaram, Asya R. Pogodina, and Rebecca L. Franklin ...
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... Lipophilicity in Molecular Modeling Bernard Testa,1'2 Pierre-Alain Carrupt,1 Patrick Gaillard,1 Frédéric Billois,1 and Peter Weber1 Received ... In V. Pliska, B. Testa, and H. van de Waterbeemd (eds.), Lipophil-icity in Drug... more
... Lipophilicity in Molecular Modeling Bernard Testa,1'2 Pierre-Alain Carrupt,1 Patrick Gaillard,1 Frédéric Billois,1 and Peter Weber1 Received ... In V. Pliska, B. Testa, and H. van de Waterbeemd (eds.), Lipophil-icity in Drug Research, VCH Publishers, Weinheim, 1996, in press. 16. ...