Showing papers by "University of Kiel published in 2005"

SWAT2000: current capabilities and research opportunities in applied watershed modelling

Abstract: SWAT (Soil and Water Assessment Tool) is a conceptual, continuous time model that was developed in the early 1990s to assist water resource managers in assessing the impact of management and climate on water supplies and non-point source pollution in watersheds and large river basins. SWAT is the continuation of over 30 years of model development within the US Department of Agriculture's Agricultural Research Service and was developed to ‘scale up’ past field-scale models to large river basins. Model components include weather, hydrology, erosion/sedimentation, plant growth, nutrients, pesticides, agricultural management, stream routing and pond/reservoir routing. The latest version, SWAT2000, has several significant enhancements that include: bacteria transport routines; urban routines; Green and Ampt infiltration equation; improved weather generator; ability to read in daily solar radiation, relative humidity, wind speed and potential ET; Muskingum channel routing; and modified dormancy calculations for tropical areas. A complete set of model documentation for equations and algorithms, a user manual describing model inputs and outputs, and an ArcView interface manual are now complete for SWAT2000. The model has been recoded into Fortran 90 with a complete data dictionary, dynamic allocation of arrays and modular subroutines. Current research is focusing on bacteria, riparian zones, pothole topography, forest growth, channel downcutting and widening, and input uncertainty analysis. The model SWAT is meanwhile used in many countries all over the world. Recent developments in European Environmental Policy, such as the adoption of the European Water Framework directive in December 2000, demand tools for integrative river basin management. The model SWAT is applicable for this purpose. It is a flexible model that can be used under a wide range of different environmental conditions, as this special issue will show. The papers compiled here are the result of the first International SWAT Conference held in August 2001 in Rauischholzhausen, Germany. More than 50 participants from 14 countries discussed their modelling experiences with the model development team from the USA. Nineteen selected papers with issues reaching from the newest developments, the evaluation of river basin management, interdisciplinary approaches for river basin management, the impact of land use change, methodical aspects and models derived from SWAT are published in this special issue. Copyright © 2005 John Wiley & Sons, Ltd.

The DNA sequence of the human X chromosome

Abstract: The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.

Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up

Abstract: Deep brain stimulation (DBS) is associated with significant improvement of motor complications in patients with severe Parkinson's disease after some 6-12 months of treatment. Long-term results in a large number of patients have been reported only from a single study centre. We report 69 Parkinson's disease patients treated with bilateral DBS of the subthalamic nucleus (STN, n = 49) or globus pallidus internus (GPi, n = 20) included in a multicentre study. Patients were assessed preoperatively and at 1 year and 3-4 years after surgery. The primary outcome measure was the change in the 'off' medication score of the Unified Parkinson's Disease Rating Scale motor part (UPDRS-III) at 3-4 years. Stimulation of the STN or GPi induced a significant improvement (50 and 39%; P < 0.0001) of the 'off' medication UPDRS-III score at 3-4 years with respect to baseline. Stimulation improved cardinal features and activities of daily living (ADL) (P < 0.0001 and P < 0.02 for STN and GPi, respectively) and prolonged the 'on' time spent with good mobility without dyskinesias (P < 0.00001). Daily dosage of levodopa was significantly reduced (35%) in the STN-treated group only (P < 0.001). Comparison of the improvement induced by stimulation at 1 year with 3-4 years showed a significant worsening in the 'on' medication motor states of the UPDRS-III, ADL and gait in both STN and GPi groups, and speech and postural stability in the STN-treated group. Adverse events (AEs) included cognitive decline, speech difficulty, instability, gait disorders and depression. These were more common in patients treated with DBS of the STN. No patient abandoned treatment as a result of these side effects. This experience, which represents the first multicentre study assessing the long-term efficacy of either STN or GPi stimulation, shows a significant and substantial clinically important therapeutic benefit for at least 3-4 years in a large cohort of patients with severe Parkinson's disease.

Reduced Paneth cell α-defensins in ileal Crohn's disease

Abstract: The pathogenesis of Crohn′s disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human α-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC α-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC α-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of α-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of α-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Natalizumab induction and maintenance therapy for Crohn's disease.

Abstract: BackgroundNatalizumab, a humanized monoclonal antibody against α4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue. MethodsWe conducted two controlled trials to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease. In the first trial, 905 patients were randomly assigned to receive 300 mg of natalizumab or placebo at weeks 0, 4, and 8. The primary outcome was response, defined by a decrease in the Crohn's Disease Activity Index (CDAI) score of at least 70 points, at week 10. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive 300 mg of natalizumab or placebo every four weeks through week 56. The primary outcome was a sustained response through week 36. A secondary outcome in both trials was disease remission (a CDAI score of less than 150). ResultsIn the first trial, the natalizumab and placebo groups had similar rates of response (56 percent and 49 percent, respective...

The genome of the protist parasite Entamoeba histolytica

Abstract: Entamoeba histolytica is an intestinal parasite and the causative agent of amoebiasis, which is a significant source of morbidity and mortality in developing countries. Here we present the genome of E. histolytica, which reveals a variety of metabolic adaptations shared with two other amitochondrial protist pathogens: Giardia lamblia and Trichomonas vaginalis. These adaptations include reduction or elimination of most mitochondrial metabolic pathways and the use of oxidative stress enzymes generally associated with anaerobic prokaryotes. Phylogenomic analysis identifies evidence for lateral gene transfer of bacterial genes into the E. histolytica genome, the effects of which centre on expanding aspects of E. histolytica's metabolic repertoire. The presence of these genes and the potential for novel metabolic pathways in E. histolytica may allow for the development of new chemotherapeutic agents. The genome encodes a large number of novel receptor kinases and contains expansions of a variety of gene families, including those associated with virulence. Additional genome features include an abundance of tandemly repeated transfer-RNA-containing arrays, which may have a structural function in the genome. Analysis of the genome provides new insights into the workings and genome evolution of a major human pathogen.

How does transcranial DC stimulation of the primary motor cortex alter regional neuronal activity in the human brain

Abstract: Transcranial direct current stimulation (tDCS) of the primary motor hand area (M1) can produce lasting polarity-specific effects on corticospinal excitability and motor learning in humans. In 16 healthy volunteers, O positron emission tomography (PET) of regional cerebral blood flow (rCBF) at rest and during finger movements was used to map lasting changes in regional synaptic activity following 10 min of tDCS (+/-1 mA). Bipolar tDCS was given through electrodes placed over the left M1 and right frontopolar cortex. Eight subjects received anodal or cathodal tDCS of the left M1, respectively. When compared to sham tDCS, anodal and cathodal tDCS induced widespread increases and decreases in rCBF in cortical and subcortical areas. These changes in rCBF were of the same magnitude as task-related rCBF changes during finger movements and remained stable throughout the 50-min period of PET scanning. Relative increases in rCBF after real tDCS compared to sham tDCS were found in the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions irrespective of polarity. With the exception of some posterior and ventral areas, anodal tDCS increased rCBF in many cortical and subcortical regions compared to cathodal tDCS. Only the left dorsal premotor cortex demonstrated an increase in movement related activity after cathodal tDCS, however, modest compared with the relatively strong movement-independent effects of tDCS. Otherwise, movement related activity was unaffected by tDCS. Our results indicate that tDCS is an effective means of provoking sustained and widespread changes in regional neuronal activity. The extensive spatial and temporal effects of tDCS need to be taken into account when tDCS is used to modify brain function.

Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection

Abstract: Human healthy skin is continuously exposed to bacteria, but is particularly resistant to the common gut bacterium Escherichia coli. We show here that keratinocytes secrete, as the main E. coli-killing compound, the S100 protein psoriasin in vitro and in vivo in a site-dependent way. In vivo treatment of human skin with antibodies to psoriasin inhibited its E. coli-killing properties. Psoriasin was induced in keratinocytes in vitro and in vivo by E. coli, indicating that its focal expression in skin may derive from local microbial induction. Zn(2+)-saturated psoriasin showed diminished antimicrobial activity, suggesting that Zn(2+) sequestration could be a possible antimicrobial mechanism. Thus, psoriasin may be key to the resistance of skin against E. coli.

ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation.

Abstract: E-cadherin controls a wide array of cellular behaviors, including cell-cell adhesion, differentiation, and tissue development. We show here that E-cadherin is cleaved specifically by ADAM (a disintegrin and metalloprotease) 10 in its ectodomain. Analysis of ADAM10-deficient fibroblasts, inhibitor studies, and RNA interference-mediated down-regulation of ADAM10 demonstrated that ADAM10 is responsible not only for the constitutive shedding but also for the regulated shedding of this adhesion molecule in fibroblasts and keratinocytes. ADAM10-mediated E-cadherin shedding affects epithelial cell-cell adhesion as well as cell migration. Furthermore, the shedding of E-cadherin by ADAM10 modulates the beta-catenin subcellular localization and downstream signaling. ADAM10 overexpression in epithelial cells increased the expression of the beta-catenin downstream gene cyclin D1 dose-dependently and enhanced cell proliferation. In ADAM10-deficient mouse embryos, the C-terminal E-cadherin fragment is not generated, and the full-length protein accumulates, highlighting the in vivo relevance for ADAM10 in E-cadherin shedding. Our data strongly suggest that this protease constitutes a major regulatory element for the multiple functions of E-cadherin under physiological as well as pathological conditions.

Maturation of autophagic vacuoles in Mammalian cells.

Abstract: The autophagic process was first described in mammalian cells several decades ago. After their formation as double-membraned vacuoles containing cytoplasmic material, autophagic vacuoles or autophagosomes undergo a stepwise maturation including fusion with both endosomal and lysosomal vesicles. However, the molecular mechanisms regulating these fusion steps have begun to emerge only recently. The list of newly discovered molecules that regulate the maturation of autophagosomes to degradative autolysosomes includes the AAA ATPase SKD1, the small GTP binding protein Rab7, and possibly also the Alzheimer-linked presenilin 1. This review combines previous data on the endo/lysosomal fusion steps during autophagic vacuole maturation with recent findings on the molecules regulating these fusion steps. Interestingly, autophagic vacuole maturation appears to be blocked in certain human diseases including neuronal ceroid lipofuscinosis and Danon disease. This suggests that autophagy has important housekeeping or pr...

Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.

Abstract: Now that more than two decades have passed since the first reports of intraductal papillary-mucinous neoplasms (IPMNs), it has become clear that IPMN consists of a spectrum of neoplasms with both morphological and immunohistochemical variations. At a meeting of international experts on pancreatic precursor lesions held in 2003, it was agreed that a consensus classification of IPMN subtypes should be established to enable a more detailed analysis of the clinicopathological significance of the variations. Based on our experience and on information from the literature, we selected representative histological examples of IPMNs and defined a consensus nomenclature and criteria for classifying variants as distinctive IPMN subtypes including gastric type, intestinal type, pancreatobiliary type, and oncocytic type. These definitions can be used for further analyses of the clinicopathological significance of the variations of IPMN.

The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption.

Abstract: Period (Per) genes are involved in regulation of the circadian clock and are thought to modulate several brain functions. We demonstrate that Per2Brdm1 mutant mice, which have a deletion in the PAS domain of the Per2 protein, show alterations in the glutamatergic system. Lowered expression of the glutamate transporter Eaat1 is observed in these animals, leading to reduced uptake of glutamate by astrocytes. As a consequence, glutamate levels increase in the extracellular space of Per2Brdm1 mutant mouse brains. This is accompanied by increased alcohol intake in these animals. In humans, variations of the PER2 gene are associated with regulation of alcohol consumption. Acamprosate, a drug used to prevent craving and relapse in alcoholic patients is thought to act by dampening a hyper-glutamatergic state. This drug reduced augmented glutamate levels and normalized increased alcohol consumption in Per2Brdm1 mutant mice. Collectively, these data establish glutamate as a link between dysfunction of the circadian clock gene Per2 and enhanced alcohol intake.

The apoptosis/autophagy paradox: autophagic vacuolization before apoptotic death

Abstract: Autophagic cell death is morphologically characterized by an accumulation of autophagic vacuoles. Here, we show that inactivation of LAMP2 by RNA interference or by homologous recombination leads to autophagic vacuolization in nutrient-depleted cells. Cells that lack LAMP2 expression showed an enhanced accumulation of vacuoles carrying the marker LC3, yet a decreased colocalization of LC3 and lysosomes, suggesting that the fusion between autophagic vacuoles and lysosomes was inhibited. While a fraction of mitochondria from starved LAMP2-expressing cells colocalized with lysosomal markers, within autophagolysosomes, no such colocalization was found on removal of LAMP2 from the experimental system. Of note, LAMP1 depletion had no such effects and did not aggravate the phenotype induced by LAMP2-specific small interfering RNA. Serum and amino acid-starved LAMP2-negative cells exhibited an accumulation of autophagic vacuoles and then succumbed to cell death with hallmarks of apoptosis such as loss of the mitochondrial transmembrane potential, caspase activation and chromatin condensation. While caspase inhibition retarded cell death, it had no protective effect on mitochondria. Stabilization of mitochondria by overexpression of Bcl-2 or the mitochondrion-targeted cytomegalovirus protein vMIA, however, blocked all signs of apoptosis. Neither caspase inhibition nor mitochondrial stabilization antagonized autophagic vacuolization in LAMP2-deficient cells. Altogether, these data indicate that accumulation of autophagic vacuoles can precede apoptotic cell death. These findings argue against the clear-cut distinction between type 1 (apoptotic) and type 2 (autophagic) cell death.

ADAM10 cleavage of N‐cadherin and regulation of cell–cell adhesion and β‐catenin nuclear signalling

Abstract: Cadherins are critically involved in tissue development and tissue homeostasis. We demonstrate here that neuronal cadherin (N-cadherin) is cleaved specifically by the disintegrin and metalloproteinase ADAM10 in its ectodomain. ADAM10 is not only responsible for the constitutive, but also for the regulated, shedding of this adhesion molecule in fibroblasts and neuronal cells directly regulating the overall levels of N-cadherin expression at the cell surface. The ADAM10-induced N-cadherin cleavage resulted in changes in the adhesive behaviour of cells and also in a dramatic redistribution of β-catenin from the cell surface to the cytoplasmic pool, thereby influencing the expression of β-catenin target genes. Our data therefore demonstrate a crucial role of ADAM10 in the regulation of cell–cell adhesion and on β-catenin signalling, leading to the conclusion that this protease constitutes a central switch in the signalling pathway from N-cadherin at the cell surface to β-catenin/LEF-1-regulated gene expression in the nucleus.

Tissue Distribution of Quercetin in Rats and Pigs

Abstract: Quercetin is a dietary polyphenolic compound with potentially beneficial effects on health. Claims that quercetin has biological effects are based mainly on in vitro studies with quercetin aglycone. However, quercetin is rapidly metabolized, and we have little knowledge of its availability to tissues. To assess the long-term tissue distribution of quercetin, 2 groups of rats were given a 0.1 or 1% quercetin diet [∼50 or 500 mg/kg body weight (wt)] for 11 wk. In addition, a 3-d study was done with pigs fed a diet containing 500 mg quercetin/kg body wt. Tissue concentrations of quercetin and quercetin metabolites were analyzed with an optimized extraction method. Quercetin and quercetin metabolites were widely distributed in rat tissues, with the highest concentrations in lungs (3.98 and 15.3 nmol/g tissue for the 0.1 and 1% quercetin diet, respectively) and the lowest in brain, white fat, and spleen. In the short-term pig study, liver (5.87 nmol/g tissue) and kidney (2.51 nmol/g tissue) contained high concentrations of quercetin and quercetin metabolites, whereas brain, heart, and spleen had low concentrations. These studies have for the first time identified target tissues of quercetin, which may help to understand its mechanisms of action in vivo. © 2005 American Society for Nutritional Sciences.

Coevolutionary dynamics: from finite to infinite populations.

Abstract: Traditionally, frequency dependent evolutionary dynamics is described by deterministic replicator dynamics assuming implicitly infinite population sizes. Only recently have stochastic processes been introduced to study evolutionary dynamics in finite populations. However, the relationship between deterministic and stochastic approaches remained unclear. Here we solve this problem by explicitly considering large populations. In particular, we identify different microscopic stochastic processes that lead to the standard or the adjusted replicator dynamics. Moreover, differences on the individual level can lead to qualitatively different dynamics in asymmetric conflicts and, depending on the population size, can even invert the direction of the evolutionary process.

Climatic controls on central African hydrology during the past 20,000 years

Abstract: Past hydrological changes in Africa have been linked to various climatic processes, depending on region and timescale. Long-term precipitation changes in the regions of northern and southern Africa influenced by the monsoons are thought to have been governed by precessional variations in summer insolation(1,2). Conversely, short-term precipitation changes in the northern African tropics have been linked to North Atlantic sea surface temperature anomalies, affecting the northward extension of the Intertropical Convergence Zone and its associated rainbelt(3,4). Our knowledge of large-scale hydrological changes in equatorial Africa and their forcing factors is, however, limited(5). Here we analyse the isotopic composition of terrigenous plant lipids, extracted from a marine sediment core close to the Congo River mouth, in order to reconstruct past central African rainfall variations and compare this record to sea surface temperature changes in the South Atlantic Ocean. We find that central African precipitation during the past 20,000 years was mainly controlled by the difference in sea surface temperatures between the tropics and subtropics of the South Atlantic Ocean, whereas we find no evidence that changes in the position of the Intertropical Convergence Zone had a significant influence on the overall moisture availability in central Africa. We conclude that changes in ocean circulation, and hence sea surface temperature patterns, were important in modulating atmospheric moisture transport onto the central African continent.

Sarcoidosis is associated with a truncating splice site mutation in BTNL2.

Abstract: Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; P(TDT) = 3 x 10(-6), P(case-control) = 1.1 x 10(-8); replication P(TDT) = 0.0018, P(case-control) = 1.8 x 10(-6)) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G --> A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.

Li6ALa2Ta2O12 (A = Sr, Ba): Novel Garnet‐Like Oxides for Fast Lithium Ion Conduction

Abstract: Oxides with the nominal chemical formula Li6ALa2Ta2O12 (A = Sr, Ba) have been prepared via a solid-state reaction in air using high purity La2O3, LiOH·H2O, Sr(NO3)2, Ba(NO3)2, and Ta2O5 and are characterized by powder X-ray diffraction (XRD) in order to identify the phase formation and AC impedance to determine the lithium ion conductivity. The powder XRD data of Li6ALa2Ta2O12 show that they are isostructural with the parent garnet-like compound Li5La3Ta2O12. The cubic lattice parameter was found to increase with increasing ionic size of the alkaline earth ions (Li6SrLa2Ta2O12: 12.808(2) A; Li6BaLa2Ta2O12: 12.946(3) A). AC impedance results show that both the strontium and barium members exhibit mainly a bulk contribution with a rather small grain-boundary contribution. The ionic conductivity increases with increasing ionic radius of the alkaline earth elements. The barium compound, Li6BaLa2Ta2O12, shows the highest ionic conductivity, 4.0×10–5 S cm–1 at 22 °C with an activation energy of 0.40 eV, which is comparable to other lithium ion conductors, especially with the presently employed solid electrolyte lithium phosphorus oxynitride (Lipon) for all-solid-state lithium ion batteries. DC electrical measurements using lithium-ion-blocking and reversible electrodes revealed that the electronic conductivity is very small, and a high electrochemical stability (&n62; 6 V/Li) was exhibited at room temperature. Interestingly, Li6ALa2Ta2O12 was found to be chemically stable with molten metallic lithium.