Showing papers by "Humboldt University of Berlin published in 2003"

Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Abstract: Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)—which encodes a vital negative regulatory molecule of the immune system—as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1?kb 3′ region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Synthesis of Serotonin by a Second Tryptophan Hydroxylase Isoform

Abstract: The neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] is causally involved in multiple central nervous facets of mood control and in regulating sleep, anxiety, alcoholism, drug abuse, food intake, and sexual behavior ([1][1]). In peripheral tissues, 5-HT regulates vascular tone, gut motility,

Genome divergence in two Prochlorococcus ecotypes reflects oceanic niche differentiation

Abstract: The marine unicellular cyanobacterium Prochlorococcus is the smallest-known oxygen-evolving autotroph1. It numerically dominates the phytoplankton in the tropical and subtropical oceans2,3, and is responsible for a significant fraction of global photosynthesis. Here we compare the genomes of two Prochlorococcus strains that span the largest evolutionary distance within the Prochlorococcus lineage4 and that have different minimum, maximum and optimal light intensities for growth5. The high-light-adapted ecotype has the smallest genome (1,657,990 base pairs, 1,716 genes) of any known oxygenic phototroph, whereas the genome of its low-light-adapted counterpart is significantly larger, at 2,410,873 base pairs (2,275 genes). The comparative architectures of these two strains reveal dynamic genomes that are constantly changing in response to myriad selection pressures. Although the two strains have 1,350 genes in common, a significant number are not shared, and these have been differentially retained from the common ancestor, or acquired through duplication or lateral transfer. Some of these genes have obvious roles in determining the relative fitness of the ecotypes in response to key environmental variables, and hence in regulating their distribution and abundance in the oceans.

Gene expression-based classification of malignant gliomas correlates better with survival than histological classification.

Abstract: In modern clinical neuro-oncology, histopathological diagnosis affects therapeutic decisions and prognostic estimation more than any other variable. Among high-grade gliomas, histologically classic glioblastomas and anaplastic oligodendrogliomas follow markedly different clinical courses. Unfortunately, many malignant gliomas are diagnostically challenging; these nonclassic lesions are difficult to classify by histological features, generating considerable interobserver variability and limited diagnostic reproducibility. The resulting tentative pathological diagnoses create significant clinical confusion. We investigated whether gene expression profiling, coupled with class prediction methodology, could be used to classify high-grade gliomas in a manner more objective, explicit, and consistent than standard pathology. Microarray analysis was used to determine the expression of ∼12,000 genes in a set of 50 gliomas, 28 glioblastomas and 22 anaplastic oligodendrogliomas. Supervised learning approaches were used to build a two-class prediction model based on a subset of 14 glioblastomas and 7 anaplastic oligodendrogliomas with classic histology. A 20-feature k -nearest neighbor model correctly classified 18 of the 21 classic cases in leave-one-out cross-validation when compared with pathological diagnoses. This model was then used to predict the classification of clinically common, histologically nonclassic samples. When tumors were classified according to pathology, the survival of patients with nonclassic glioblastoma and nonclassic anaplastic oligodendroglioma was not significantly different ( P = 0.19). However, class distinctions according to the model were significantly associated with survival outcome ( P = 0.05). This class prediction model was capable of classifying high-grade, nonclassic glial tumors objectively and reproducibly. Moreover, the model provided a more accurate predictor of prognosis in these nonclassic lesions than did pathological classification. These data suggest that class prediction models, based on defined molecular profiles, classify diagnostically challenging malignant gliomas in a manner that better correlates with clinical outcome than does standard pathology.

Scenario Reduction Algorithms in Stochastic Programming

Abstract: We consider convex stochastic programs with an (approximate) initial probability distribution P having finite support supp P, i.e., finitely many scenarios. The behaviour of such stochastic programs is stable with respect to perturbations of P measured in terms of a Fortet-Mourier probability metric. The problem of optimal scenario reduction consists in determining a probability measure that is supported by a subset of supp P of prescribed cardinality and is closest to P in terms of such a probability metric. Two new versions of forward and backward type algorithms are presented for computing such optimally reduced probability measures approximately. Compared to earlier versions, the computational performance (accuracy, running time) of the new algorithms has been improved considerably. Numerical experience is reported for different instances of scenario trees with computable optimal lower bounds. The test examples also include a ternary scenario tree representing the weekly electrical load process in a power management model.

Scenario Reduction in Stochastic Programming

Abstract: Given a convex stochastic programming problem with a discrete initial probability distribution, the problem of optimal scenario reduction is stated as follows: Determine a scenario subset of prescribed cardinality and a probability measure based on this set that is the closest to the initial distribution in terms of a natural (or canonical) probability metric. Arguments from stability analysis indicate that Fortet-Mourier type probability metrics may serve as such canonical metrics. Efficient algorithms are developed that determine optimal reduced measures approximately. Numerical experience is reported for reductions of electrical load scenario trees for power management under uncertainty. For instance, it turns out that after 50% reduction of the scenario tree the optimal reduced tree still has about 90% relative accuracy.

Electronic structure and electrical properties of interfaces between metals and π-conjugated molecular films

Abstract: The field of organic thin films and devices is progressing at an extremely rapid pace. Organic–metal and organic–organic interfaces play crucial roles in charge injection into, and transport through, these devices. Their electronic structure, chemical properties, and electrical behavior must be fully characterized and understood if the engineering and control of organic devices are to reach the levels obtained for inorganic semiconductor devices. This article provides an extensive, although admittedly nonexhaustive, review of experimental work done in our group on the electronic structure and electrical properties of interfaces between films of π-conjugated molecular films and metals. It introduces several mechanisms currently believed to affect the formation of metal–organic interface barriers. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 41: 2529–2548, 2003

Beyond the Visible—Imaging the Human Brain with Light:

Abstract: Optical approaches to investigate cerebral function and metabolism have long been applied in invasive studies. From the neuron cultured in vitro to the exposed cortex in the human during neurosurgical procedures, high spatial resolution can be reached and several processes such as membrane potential, cell swelling, metabolism of mitochondrial chromophores, and vascular response can be monitored, depending on the respective preparation. The authors focus on an extension of optical methods to the noninvasive application in the human. Starting with the pioneering work of Jobsis 25 years ago, near-infrared spectroscopy (NIRS) has been used to investigate functional activation of the human cerebral cortex. Recently, several groups have started to use imaging systems that allow the generation of images of a larger area of the subject's head and, thereby, the production of maps of cortical oxygenation changes. Such images have a much lower spatial resolution compared with the invasively obtained optical images. The noninvasive NIRS images, however, can be obtained in undemanding set-ups that can be easily combined with other functional methods, in particular EEG. Moreover, NIRS is applicable to bedside use. The authors briefly review some of the abundant literature on intrinsic optical signals and the NIRS imaging studies of the past few years. The weaknesses and strengths of the approach are critically discussed. The authors conclude that NIRS imaging has two major advantages: it can address issues concerning neurovascular coupling in the human adult and can extend functional imaging approaches to the investigation of the diseased brain.

Scenario reduction and scenario tree construction for power management problems

Abstract: Portfolio and risk management problems of power utilities may be modeled by multistage stochastic programs. These models use a set of scenarios and corresponding probabilities to model the multivariate random data process (electrical load, stream flows to hydro units, and fuel and electricity prices). For most practical problems the optimization problem that contains all possible scenarios is too large. Due to computational complexity and to time limitations this program is often approximated by a model involving a (much) smaller number of scenarios. The proposed reduction algorithms determine a subset of the initial scenario set and assign new probabilities to the preserved scenarios. The scenario tree construction algorithms successively reduce the number of nodes of a fan of individual scenarios by modifying the tree structure and by bundling similar scenarios. Numerical experience is reported for constructing scenario trees for the load and spot market prices entering a stochastic portfolio management model of a German utility.

A nomenclature for restriction enzymes, DNA methyltransferases, homing endonucleases and their genes

Abstract: A nomenclature is described for restriction endonucleases, DNA methyltransferases, homing endonucleases and related genes and gene products. It provides explicit categories for the many different Type II enzymes now identified and provides a system for naming the putative genes found by sequence analysis of microbial genomes.

The roles of APC and Axin derived from experimental and theoretical analysis of the Wnt pathway.

Abstract: Wnt signaling plays an important role in both oncogenesis and development. Activation of the Wnt pathway results in stabilization of the transcriptional coactivator β-catenin. Recent studies have demonstrated that axin, which coordinates β-catenin degradation, is itself degraded. Although the key molecules required for transducing a Wnt signal have been identified, a quantitative understanding of this pathway has been lacking. We have developed a mathematical model for the canonical Wnt pathway that describes the interactions among the core components: Wnt, Frizzled, Dishevelled, GSK3β, APC, axin, β-catenin, and TCF. Using a system of differential equations, the model incorporates the kinetics of protein–protein interactions, protein synthesis/degradation, and phosphorylation/dephosphorylation. We initially defined a reference state of kinetic, thermodynamic, and flux data from experiments using Xenopus extracts. Predictions based on the analysis of the reference state were used iteratively to develop a more refined model from which we analyzed the effects of prolonged and transient Wnt stimulation on β-catenin and axin turnover. We predict several unusual features of the Wnt pathway, some of which we tested experimentally. An insight from our model, which we confirmed experimentally, is that the two scaffold proteins axin and APC promote the formation of degradation complexes in very different ways. We can also explain the importance of axin degradation in amplifying and sharpening the Wnt signal, and we show that the dependence of axin degradation on APC is an essential part of an unappreciated regulatory loop that prevents the accumulation of β-catenin at decreased APC concentrations. By applying control analysis to our mathematical model, we demonstrate the modular design, sensitivity, and robustness of the Wnt pathway and derive an explicit expression for tumor suppression and oncogenicity.

Highly Emissive Colloidal CdSe/CdS Heterostructures of Mixed Dimensionality

Abstract: We demonstrate that efficient shape control may be achieved in the shell of colloidally grown semiconductor nanocrystals (independent of the core), allowing the combination of a 0-D spherical CdSe core with a 1-D rodlike CdS shell. Besides exhibiting linearly polarized emission with a room-temperature quantum efficiency above 70%, these mixed-dimensionality colloidal heterostructures display large, length-dependent Stokes shifts as well as giant extinction coefficients approaching 107cm-1 M-1.

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification

Abstract: Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) This cell surface enzyme generates inorganic pyrophosphate (PP(i)), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification

A universal model for spike-frequency adaptation

Abstract: Spike-frequency adaptation is a prominent feature of neural dynamics. Among other mechanisms, various ionic currents modulating spike generation cause this type of neural adaptation. Prominent examples are voltage-gated potassium currents (M-type currents), the interplay of calcium currents and intracellular calcium dynamics with calcium-gated potassium channels (AHP-type currents), and the slow recovery from inactivation of the fast sodium current. While recent modeling studies have focused on the effects of specific adaptation currents, we derive a universal model for the firing-frequency dynamics of an adapting neuron that is independent of the specific adaptation process and spike generator. The model is completely defined by the neuron's onset f-I curve, the steady-state f-I curve, and the time constant of adaptation. For a specific neuron, these parameters can be easily determined from electrophysiological measurements without any pharmacological manipulations. At the same time, the simplicity of the model allows one to analyze mathematically how adaptation influences signal processing on the single-neuron level. In particular, we elucidate the specific nature of high-pass filter properties caused by spike-frequency adaptation. The model is limited to firing frequencies higher than the reciprocal adaptation time constant and to moderate fluctuations of the adaptation and the input current. As an extension of the model, we introduce a framework for combining an arbitrary spike generator with a generalized adaptation current.

Genome sequence of the cyanobacterium Prochlorococcus marinus SS120, a nearly minimal oxyphototrophic genome

Abstract: Prochlorococcus marinus, the dominant photosynthetic organism in the ocean, is found in two main ecological forms: high-light-adapted genotypes in the upper part of the water column and low-light-adapted genotypes at the bottom of the illuminated layer. P. marinus SS120, the complete genome sequence reported here, is an extremely low-light-adapted form. The genome of P. marinus SS120 is composed of a single circular chromosome of 1,751,080 bp with an average G+C content of 36.4%. It contains 1,884 predicted protein-coding genes with an average size of 825 bp, a single rRNA operon, and 40 tRNA genes. Together with the 1.66-Mbp genome of P. marinus MED4, the genome of P. marinus SS120 is one of the two smallest genomes of a photosynthetic organism known to date. It lacks many genes that are involved in photosynthesis, DNA repair, solute uptake, intermediary metabolism, motility, phototaxis, and other functions that are conserved among other cyanobacteria. Systems of signal transduction and environmental stress response show a particularly drastic reduction in the number of components, even taking into account the small size of the SS120 genome. In contrast, housekeeping genes, which encode enzymes of amino acid, nucleotide, cofactor, and cell wall biosynthesis, are all present. Because of its remarkable compactness, the genome of P. marinus SS120 might approximate the minimal gene complement of a photosynthetic organism.

Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFTs) formed of tau-based paired helical filaments (PHFs) and extracellular β-amyloid plaques. The degree of Alzheimer dementia correlates with the severity of PHFs and NFTs. As an intraneuronal accumulation of oxidatively damaged proteins has been found in the brains of patients with AD, a dysfunction of the proteasomal system, which degrades damaged proteins, has been assumed to cause protein aggregation and therefore neurodegeneration in AD. In this study, we revealed that such proteasome dysfunction in AD brain results from the inhibitory binding of PHF-tau to proteasomes. We analysed the proteasome activity in brains from patients with AD and age-matched controls, and observed a significant decrease to 56% of the control level in the straight gyrus of patients with AD. This loss of activity was not associated with a decrease in the proteasome protein. PHF-tau co-precipitated during proteasome immunoprecipitation and proteasome subunits could be co-isolated during isolation of PHFs from AD brain. Furthermore, the proteasome activity in human brains strongly correlated with the amount of co-precipitated PHF-tau during immunoprecipitation of proteasome. Incubation of isolated proteasomes with PHF-tau isolated from AD brain, and with PHFs after in vitro assembly from human recombinant tau protein, resulted in a distinct inhibition of proteasome activity by PHF-tau. As this inhibition of proteasome activity was sufficient to induce neuronal degeneration and death, we suggest that PHF-tau is able directly to induce neuronal damage in the AD brain.

Association Between Adiponectin and Mediators of Inflammation in Obese Women

Abstract: Low plasma levels of the anti-inflammatory factor adiponectin characterize obesity and insulin resistance. To elucidate the relationship between plasma levels of adiponectin, adiponectin gene expression in adipose tissue, and markers of inflammation, we obtained blood samples, anthropometric measures, and subcutaneous adipose tissue samples from 65 postmenopausal healthy women. Adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects and inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression (partial r = 0.38, P < 0.05). Furthermore, the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables (partial r = -0.32, P < 0.05), whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables. In conclusion, our data suggest a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and demonstrate that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk.

The Petri net markup language: concepts, technology, and tools

Abstract: The Petri Net Markup Language (PNML) is an XML-based interchange format for Petri nets. In order to support different versions of Petri nets and, in particular, future versions of Petri nets, PNML allows the definition of Petri net types. Due to this flexibility, PNML is a starting point for a standard interchange format for Petri nets. This paper discusses the design principles, the basic concepts, and the underlying XML technology of PNML. The main purpose of this paper is to disseminate the ideas of PNML and to stimulate discussion on and contributions to a standard Petri net interchange format.

Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis, before and after successful therapy with infliximab: Evaluation of a new scoring system

Abstract: Objective To evaluate a magnetic resonance imaging (MRI) scoring system for the assessment of spinal inflammation in patients with ankylosing spondylitis (AS) who participated in a randomized, placebo-controlled trial of infliximab, and to examine whether infliximab is also effective for the reduction of MRI-proven spinal inflammation. Methods Twenty patients with AS (9 women and 11 men, mean age 40.9 years) were examined at baseline and after 3 months. Nine patients had received infusions of infliximab (5 mg/kg body weight) at weeks 0, 2, and 6, and 11 patients had received placebo. Three MRI sequences and 2 scoring systems were used. Chronic lesions were evaluated by T1-weighted turbo spin-echo (TSE) sequences and were assigned a chronicity score. Active lesions were evaluated either by repetition of T1-weighted TSE sequences after infusion of gadolinium–diethylenetriaminepentaacetic acid (Gd-DTPA) or by short tau inversion recovery (STIR) sequences, and were assigned an activity score. The 40 images were evaluated twice by 2 readers who were blinded to the names of the patients and the dates of the examinations, and were analyzed in relation to the clinical results. Results Active spinal lesions were detected in 15 of 20 patients (75%); the frequency as determined by STIR was equal in the 2 groups. At baseline, the total MRI scores determined using Gd-DTPA, STIR, and T1 were 112.5, 156, and 253.5, respectively. The interrater variance and intrarater variance were, respectively, 6.4 and 7.7 for the active lesion score as determined by Gd-DTPA, 15.7 and 5.3 for the active lesion score as determined by STIR sequence, and 167.3 and 75.5 for the chronic lesion score as determined by T1 sequence. Based on the means of the scores assigned by the 2 readers, the active lesion score as determined by Gd-DTPA improved by 40% in the infliximab group compared with 6% in the placebo group, the active lesion score as determined by STIR improved by 60% in the infliximab group but deteriorated by 21% in the placebo group, and the chronic lesion score as determined by T1 improved by 7% in the infliximab group but worsened by 35% in the placebo group. Five patients in the infliximab group and 2 in the placebo group were clinical responders. The acute MRI changes correlated with clinical improvement as assessed by the Bath Ankylosing Spondylitis Disease Activity Index. Conclusion This novel MRI scoring system performed well in assessing acute inflammation by using STIR and post–Gd-DTPA sequences. In correlation with clinical improvement in patients with active AS who were treated with infliximab, significant regression of spinal inflammation was shown by using the MRI activity scores.

Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial.

Abstract: Objective To evaluate the safety of anakinra (a recombinant human interleukin-1 receptor antagonist) in a large population of patients with rheumatoid arthritis (RA), typical of those seen in clinical practice. Methods A total of 1,414 patients were randomly assigned to treatment with 100 mg of anakinra or placebo, administered daily by subcutaneous injection. Background medications included disease-modifying antirheumatic drugs, corticosteroids, and nonsteroidal antiinflammatory drugs, alone or in combination. The primary end point was safety, which was evaluated by adverse events (including infections), discontinuation from study due to adverse events, and death. Results Safety was evaluated in 1,399 patients (1,116 in the anakinra group and 283 in the placebo group; 15 patients were randomized but did not receive any study drug) during the initial 6-month, double-blind, placebo-controlled phase of this long-term safety study. Baseline demographics, disease characteristics, and concomitant medications were similar between the 2 groups. The study group included patients with numerous comorbid conditions and a wide range of RA disease activity. Serious adverse events occurred at a similar rate in the anakinra group and the placebo group (7.7% and 7.8%, respectively). Serious infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the placebo group). The rate of withdrawal due to adverse events was 13.4% in the anakinra group and 9.2% in the placebo group. Conclusion Results from this large, placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA, including those with comorbid conditions and those using multiple combinations of concomitant therapies. Although the frequency of serious infection was slightly higher in the anakinra group, no infection was attributed to opportunistic microorganisms or resulted in death.

Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans.

Abstract: Remodeling of the cytoskeleton is central to the modulation of cell shape and migration. Filamin A, encoded by the gene FLNA, is a widely expressed protein that regulates re-organization of the actin cytoskeleton by interacting with integrins, transmembrane receptor complexes and second messengers. We identified localized mutations in FLNA that conserve the reading frame and lead to a broad range of congenital malformations, affecting craniofacial structures, skeleton, brain, viscera and urogenital tract, in four X-linked human disorders: otopalatodigital syndrome types 1 (OPD1; OMIM 311300) and 2 (OPD2; OMIM 304120), frontometaphyseal dysplasia (FMD; OMIM 305620) and Melnick-Needles syndrome (MNS; OMIM 309350). Several mutations are recurrent, and all are clustered into four regions of the gene: the actin-binding domain and rod domain repeats 3, 10 and 14/15. Our findings contrast with previous observations that loss of function of FLNA is embryonic lethal in males but manifests in females as a localized neuronal migration disorder, called periventricular nodular heterotopia (PVNH; refs. 3-6). The patterns of mutation, X-chromosome inactivation and phenotypic manifestations in the newly described mutations indicate that they have gain-of-function effects, implicating filamin A in signaling pathways that mediate organogenesis in multiple systems during embryonic development.