Showing papers by "University of Cologne published in 2006"

Archaea predominate among ammonia-oxidizing prokaryotes in soils

Abstract: Ammonia oxidation is the first step in nitrification, a key process in the global nitrogen cycle that results in the formation of nitrate through microbial activity. The increase in nitrate availability in soils is important for plant nutrition, but it also has considerable impact on groundwater pollution owing to leaching. Here we show that archaeal ammonia oxidizers are more abundant in soils than their well-known bacterial counterparts. We investigated the abundance of the gene encoding a subunit of the key enzyme ammonia monooxygenase (amoA) in 12 pristine and agricultural soils of three climatic zones. amoA gene copies of Crenarchaeota (Archaea) were up to 3,000-fold more abundant than bacterial amoA genes. High amounts of crenarchaeota-specific lipids, including crenarchaeol, correlated with the abundance of archaeal amoA gene copies. Furthermore, reverse transcription quantitative PCR studies and complementary DNA analysis using novel cloning-independent pyrosequencing technology demonstrated the activity of the archaea in situ and supported the numerical dominance of archaeal over bacterial ammonia oxidizers. Our results indicate that crenarchaeota may be the most abundant ammonia-oxidizing organisms in soil ecosystems on Earth.

CD4+ count-guided interruption of antiretroviral treatment.

Abstract: Methods We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease. Results A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P = 0.007) and 1.7 (95% CI, 1.1 to 2.5; P = 0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1). Conclusions Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352.)

Daptomycin versus Standard Therapy for Bacteremia and Endocarditis Caused by Staphylococcus aureus

Abstract: Background Alternative therapies for Staphylococcus aureus bacteremia and endocarditis are needed. Methods We randomly assigned 124 patients with S. aureus bacteremia with or without endocarditis to receive 6 mg of daptomycin intravenously per kilogram of body weight daily and 122 to receive initial low-dose gentamicin plus either an antistaphylococcal penicillin or vancomycin. The primary efficacy end point was treatment success 42 days after the end of therapy. Results Forty-two days after the end of therapy in the modified intention-to-treat analysis, a successful outcome was documented for 53 of 120 patients who received daptomycin as compared with 48 of 115 patients who received standard therapy (44.2 percent vs. 41.7 percent; absolute difference, 2.4 percent; 95 percent confidence interval, −10.2 to 15.1 percent). Our results met prespecified criteria for the noninferiority of daptomycin. The success rates were similar in subgroups of patients with complicated bacteremia, right-sided endocarditis, a...

Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase.

Abstract: Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.

Ferroelectricity in spiral magnets

Abstract: It was recently observed that the ferroelectrics showing the strongest sensitivity to an applied magnetic field are spiral magnets. We present a phenomenological theory of inhomogeneous ferroelectric magnets, which describes their thermodynamics and magnetic field behavior, e.g., dielectric susceptibility anomalies at magnetic transitions and sudden flops of electric polarization in an applied magnetic field. We show that electric polarization can also be induced at domain walls and that magnetic vortices carry electric charge.

The Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey

Abstract: The Boston University-Five College Radio Astronomy Observatory Galactic Ring Survey is a new survey of Galactic 13CO J = 1 → 0 emission. The survey used the SEQUOIA multipixel array on the Five College Radio Astronomy Observatory 14 m telescope to cover a longitude range of l = 18°-557 and a latitude range of |b| 40°. At the velocity resolution of 0.21 km s-1, the typical rms sensitivity is σ(T) ~ 0.13 K. The survey comprises a total of 1,993,522 spectra. We show integrated intensity images (zeroth moment maps), channel maps, position-velocity diagrams, and an average spectrum of the completed survey data set. We also discuss the telescope and instrumental parameters, the observing modes, the data reduction processes, and the emission and noise characteristics of the data set. The Galactic Ring Survey data are available to the community online or in DVD form by request.

Introducing MASC: a movie for the assessment of social cognition.

Abstract: In the present study we introduce a sensitive video-based test for the evaluation of subtle mindreading difficulties: the Movie for the Assessment of Social Cognition (MASC). This new mindreading tool involves watching a short film and answering questions referring to the actors' mental states. A group of adults with Asperger syndrome (n = 19) and well-matched control subjects (n = 20) were administered the MASC and three other mindreading tools as part of a broader neuropsychological testing session. Compared to control subjects, Asperger individuals exhibited marked and selective difficulties in social cognition. A Receiver Operating Characteristic (ROC) analysis for the mindreading tests identified the MASC as discriminating the diagnostic groups most accurately. Issues pertaining to the multidimensionality of the social cognition construct are discussed.

Climate-controlled Holocene occupation in the Sahara: motor of Africa's evolution.

Abstract: Radiocarbon data from 150 archaeological excavations in the now hyper-arid Eastern Sahara of Egypt, Sudan, Libya, and Chad reveal close links between climatic variations and prehistoric occupation during the past 12,000 years. Synoptic multiple-indicator views for major time slices demonstrate the transition from initial settlement after the sudden onset of humid conditions at 8500 B.C.E. to the exodus resulting from gradual desiccation since 5300 B.C.E. Southward shifting of the desert margin helped trigger the emergence of pharaonic civilization along the Nile, influenced the spread of pastoralism throughout the continent, and affects sub-Saharan Africa to the present day.

Dynamics of Social Capital and Their Performance Implications: Lessons from Biotechnology Start-ups

Abstract: Based on comparative longitudinal case analyses of six new biotechnology firms, this paper explores how the configuration, management, and evolution of entrepreneurial firms' social capital affect

Longer-term effects of cardiac resynchronization therapy on mortality in heart failure [the CArdiac REsynchronization-Heart Failure (CARE-HF) trial extension phase].

Abstract: Aims The CArdiac REsynchronization-Heart Failure study randomized patients with left ventricular ejection fraction � 35%, markers of cardiac dyssynchrony, and persistent moderate or severe symptoms of heart failure despite pharmacological therapy, to implantation of a cardiac resynchronization therapy (CRT) device or not. The main study observed substantial benefits on morbidity and mortality during a mean follow-up of 29.4 months [median 29.6, interquartile range (IQR) 23.6–34.6]. Prior to study closure, an extension phase lasting a further 8 months (allowing time for data analysis and presentation) was declared during which cross-over was discouraged. Methods and results This was an extension of the already reported open-label randomized trial described above. The primary outcome of the extension phase was all-cause mortality from the time of randomization to completion of the extension phase. The secondary outcome was mode of death. The mean follow-up was 37.4 months (median 37.6, IQR 31.5–42.5, range 26.1–52.6 months). There were 154 deaths (38.1%) in 404 patients assigned to medical therapy and 101 deaths (24.7%) in 409 patients assigned to CRT (hazard ratio 0.60, 95% CI 0.47–0.77, P , 0.0001) without evidence of heterogeneity in pre-specified subgroups. A reduction in the risk of death due to heart failure (64 vs. 38 deaths; hazard ratio 0.55, 95% CI 0.37–0.82, P ¼ 0.003) and sudden death was observed (55 vs. 32; hazard ratio 0.54, 95% CI 0.35–0.84, P ¼ 0.005). Conclusion The benefits of CRT observed in the main trial persist or increase with longer follow-up. Reduction in mortality was due to fewer deaths both from worsening heart failure and from sudden death.

CUPSAT: prediction of protein stability upon point mutations

Abstract: CUPSAT (Cologne University Protein Stability Analysis Tool) is a web tool to analyse and predict protein stability changes upon point mutations (single amino acid mutations). This program uses structural environment specific atom potentials and torsion angle potentials to predict ΔΔG, the difference in free energy of unfolding between wild-type and mutant proteins. It requires the protein structure in Protein Data Bank format and the location of the residue to be mutated. The output consists information about mutation site, its structural features (solvent accessibility, secondary structure and torsion angles), and comprehensive information about changes in protein stability for 19 possible substitutions of a specific amino acid mutation. Additionally, it also analyses the ability of the mutated amino acids to adapt the observed torsion angles. Results were tested on 1538 mutations from thermal denaturation and 1603 mutations from chemical denaturation experiments. Several validation tests (split-sample, jack-knife and k-fold) were carried out to ensure the reliability, accuracy and transferability of the prediction method that gives >80% prediction accuracy for most of these validation tests. Thus, the program serves as a valuable tool for the analysis of protein design and stability. The tool is accessible from the link http://cupsat.uni-koeln.de.

The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4

Abstract: The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.

Recombinant Human Erythropoietins and Cancer Patients: Updated Meta-Analysis of 57 Studies Including 9353 Patients

Abstract: This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

Infrared dark clouds: precursors to star clusters

Abstract: Infrared dark clouds (IRDCs) are dense molecular clouds seen as extinction features against the bright mid-infrared Galactic background. Millimeter continuum maps toward 38 IRDCs reveal extended cold dust emission to be associated with each of the IRDCs. IRDCs range in morphology from filamentary to compact and have masses of 120 to 16,000 M?, with a median mass of ~940 M?. Each IRDC contains at least one compact (?0.5 pc) dust core and most show multiple cores. We find 140 cold millimeter cores unassociated with MSX 8 ?m emission. The core masses range from 10 to 2100 M?, with a median mass of ~120 M?. The slope of the IRDC core mass spectrum (? ~ 2.1 ? 0.4) is similar to that of the stellar IMF. Assuming that each core will form a single star, the majority of the cores will form OB stars. IRDC cores have similar sizes, masses, and densities as hot cores associated with individual, young high-mass stars, but they are much colder. We therefore suggest that IRDC represent an earlier evolutionary phase in high-mass star formation. In addition, because IRDCs contain many compact cores and have the same sizes and masses as molecular clumps associated with young clusters, we suggest that IRDCs are the cold precursors to star clusters. Indeed, an estimate of the star formation rate within molecular clumps with similar properties to IRDCs (~2 M? yr-1) is comparable to the global star formation rate in the Galaxy, supporting the idea that all stars may form in such clumps.

The imprint of the geographical, evolutionary and ecological context on species–area relationships

Abstract: Species–area relationships (SAR) are fundamental in the understanding of biodiversity patterns and of critical importance for predicting species extinction risk worldwide. Despite the enormous attention given to SAR in the form of many individual analyses, little attempt has been made to synthesize these studies. We conducted a quantitative meta-analysis of 794 SAR, comprising a wide span of organisms, habitats and locations. We identified factors reflecting both pattern-based and dynamic approaches to SAR and tested whether these factors leave significant imprints on the slope and strength of SAR. Our analysis revealed that SAR are significantly affected by variables characterizing the sampling scheme, the spatial scale, and the types of organisms or habitats involved. We found that steeper SAR are generated at lower latitudes and by larger organisms. SAR varied significantly between nested and independent sampling schemes and between major ecosystem types, but not generally between the terrestrial and the aquatic realm. Both the fit and the slope of the SAR were scale-dependent. We conclude that factors dynamically regulating species richness at different spatial scales strongly affect the shape of SAR. We highlight important consequences of this systematic variation in SAR for ecological theory, conservation management and extinction risk predictions.

Transcription Analysis of Arabidopsis Membrane Transporters and Hormone Pathways during Developmental and Induced Leaf Senescence

Abstract: A comparative transcriptome analysis for successive stages of Arabidopsis (Arabidopsis thaliana) developmental leaf senescence (NS), darkening-induced senescence of individual leaves attached to the plant (DIS), and senescence in dark-incubated detached leaves (DET) revealed many novel senescence-associated genes with distinct expression profiles. The three senescence processes share a high number of regulated genes, although the overall number of regulated genes during DIS and DET is about 2 times lower than during NS. Consequently, the number of NS-specific genes is much higher than the number of DIS- or DET-specific genes. The expression profiles of transporters (TPs), receptor-like kinases, autophagy genes, and hormone pathways were analyzed in detail. The Arabidopsis TPs and other integral membrane proteins were systematically reclassified based on the Transporter Classification system. Coordinate activation or inactivation of several genes is observed in some TP families in all three or only in individual senescence types, indicating differences in the genetic programs for remobilization of catabolites. Characteristic senescence type-specific differences were also apparent in the expression profiles of (putative) signaling kinases. For eight hormones, the expression of biosynthesis, metabolism, signaling, and (partially) response genes was investigated. In most pathways, novel senescence-associated genes were identified. The expression profiles of hormone homeostasis and signaling genes reveal additional players in the senescence regulatory network.

Role of Managerial Incentives and Discretion in Hedge Fund Performance

Abstract: Using a comprehensive hedge fund database, we examine the role of managerial incentives and discretion in hedge fund performance. Hedge funds with greater managerial incentives, proxied by the delta of the option-like incentive fee contracts, higher levels of managerial ownership, and the inclusion of high-water mark provisions in the incentive contracts, are associated with superior performance. The incentive fee percentage rate by itself does not explain performance. We also find that funds with a higher degree of managerial discretion, proxied by longer lockup, notice, and redemption periods, deliver superior performance. These results are robust to using alternative performance measures and controlling for different data-related biases.

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.

Abstract: Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.

Salicylic Acid–Independent ENHANCED DISEASE SUSCEPTIBILITY1 Signaling in Arabidopsis Immunity and Cell Death Is Regulated by the Monooxygenase FMO1 and the Nudix Hydrolase NUDT7

Abstract: Arabidopsis thaliana ENHANCED DISEASE SUSCEPTIBILITY1 (EDS1) controls defense activation and programmed cell death conditioned by intracellular Toll-related immune receptors that recognize specific pathogen effectors. EDS1 is also needed for basal resistance to invasive pathogens by restricting the progression of disease. In both responses, EDS1, assisted by its interacting partner, PHYTOALEXIN-DEFICIENT4 (PAD4), regulates accumulation of the phenolic defense molecule salicylic acid (SA) and other as yet unidentified signal intermediates. An Arabidopsis whole genome microarray experiment was designed to identify genes whose expression depends on EDS1 and PAD4, irrespective of local SA accumulation, and potential candidates of an SA-independent branch of EDS1 defense were found. We define two new immune regulators through analysis of corresponding Arabidopsis loss-of-function insertion mutants. FLAVIN-DEPENDENT MONOOXYGENASE1 (FMO1) positively regulates the EDS1 pathway, and one member (NUDT7) of a family of cytosolic Nudix hydrolases exerts negative control of EDS1 signaling. Analysis of fmo1 and nudt7 mutants alone or in combination with sid2-1, a mutation that severely depletes pathogen-induced SA production, points to SA-independent functions of FMO1 and NUDT7 in EDS1-conditioned disease resistance and cell death. We find instead that SA antagonizes initiation of cell death and stunting of growth in nudt7 mutants.

Recent developments of the chemistry development kit (CDK) - an open-source java library for chemo- and bioinformatics

Abstract: The Chemistry Development Kit (CDK) provides methods for common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc. Implemented in Java, it is used both for server-side computational services, possibly equipped with a web interface, as well as for applications and client-side applets. This article introduces the CDK's new QSAR capabilities and the recently introduced interface to statistical software.

Mutations in the Tight-Junction Gene Claudin 19 (CLDN19) Are Associated with Renal Magnesium Wasting, Renal Failure, and Severe Ocular Involvement

Abstract: Claudins are major components of tight junctions and contribute to the epithelial-barrier function by restricting free diffusion of solutes through the paracellular pathway We have mapped a new locus for recessive renal magnesium loss on chromosome 1p342 and have identified mutations in CLDN19, a member of the claudin multigene family, in patients affected by hypomagnesemia, renal failure, and severe ocular abnormalities CLDN19 encodes the tight-junction protein claudin-19, and we demonstrate high expression of CLDN19 in renal tubules and the retina The identified mutations interfere severely with either cell-membrane trafficking or the assembly of the claudin-19 protein The identification of CLDN19 mutations in patients with chronic renal failure and severe visual impairment supports the fundamental role of claudin-19 for normal renal tubular function and undisturbed organization and development of the retina

BMP-4 is required for hepatic specification of mouse embryonic stem cell–derived definitive endoderm

Abstract: When differentiated in the presence of activin A in serum-free conditions, mouse embryonic stem cells efficiently generate an endoderm progenitor population defined by the coexpression of either Brachyury, Foxa2 and c-Kit, or c-Kit and Cxcr4. Specification of these progenitors with bone morphogenetic protein-4 in combination with basic fibroblast growth factor and activin A results in the development of hepatic populations highly enriched (45-70%) for cells that express the alpha-fetoprotein and albumin proteins. These cells also express transcripts of Afp, Alb1, Tat, Cps1, Cyp7a1 and Cyp3a11; they secrete albumin, store glycogen, show ultrastructural characteristics of mature hepatocytes, and are able to integrate into and proliferate in injured livers in vivo and mature into hepatocytes expressing dipeptidyl peptidase IV or fumarylacetoacetate hydrolase. Together, these findings establish a developmental pathway in embryonic stem cell differentiation cultures that leads to efficient generation of cells with an immature hepatocytic phenotype.