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Showing papers by "University of Marburg published in 2008"


Journal ArticleDOI
Christopher G. Goetz1, Barbara C. Tilley2, Stephanie R. Shaftman2, Glenn T. Stebbins1, Stanley Fahn3, Pablo Martinez-Martin, Werner Poewe4, Cristina Sampaio5, Matthew B. Stern6, Richard Dodel7, Bruno Dubois8, Robert G. Holloway9, Joseph Jankovic10, Jaime Kulisevsky11, Anthony E. Lang12, Andrew J. Lees13, Sue Leurgans1, Peter A. LeWitt14, David L. Nyenhuis15, C. Warren Olanow16, Olivier Rascol17, Anette Schrag13, Jeanne A. Teresi3, Jacobus J. van Hilten18, Nancy R. LaPelle19, Pinky Agarwal, Saima Athar, Yvette Bordelan, Helen Bronte-Stewart, Richard Camicioli, Kelvin L. Chou, Wendy Cole, Arif Dalvi, Holly Delgado, Alan Diamond, Jeremy P.R. Dick, John E. Duda, Rodger J. Elble, Carol Evans, V. G. H. Evidente, Hubert H. Fernandez, Susan H. Fox, Joseph H. Friedman, Robin D. Fross, David A. Gallagher, Deborah A. Hall, Neal Hermanowicz, Vanessa K. Hinson, Stacy Horn, Howard I. Hurtig, Un Jung Kang, Galit Kleiner-Fisman, Olga Klepitskaya, Katie Kompoliti, Eugene C. Lai, Maureen L. Leehey, Iracema Leroi, Kelly E. Lyons, Terry McClain, Steven W. Metzer, Janis M. Miyasaki, John C. Morgan, Martha Nance, Joanne Nemeth, Rajesh Pahwa, Sotirios A. Parashos, Jay S. Schneider, Kapil D. Sethi, Lisa M. Shulman, Andrew Siderowf, Monty Silverdale, Tanya Simuni, Mark Stacy, Robert Malcolm Stewart, Kelly L. Sullivan, David M. Swope, Pettaruse M. Wadia, Richard Walker, Ruth H. Walker, William J. Weiner, Jill Wiener, Jayne R. Wilkinson, Joanna M. Wojcieszek, Summer C. Wolfrath, Frederick Wooten, Allen Wu, Theresa A. Zesiewicz, Richard M. Zweig 
TL;DR: The combined clinimetric results of this study support the validity of the MDS‐UPDRS for rating PD.
Abstract: We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.

4,589 citations


Journal ArticleDOI
TL;DR: In methanogens with cytochromes, the first and last steps in methanogenesis from CO2 are coupled chemiosmotically, whereas in methenogens without cyto Chromes, these steps are energetically coupled by a cytoplasmic enzyme complex that mediates flavin-based electron bifurcation.
Abstract: Most methanogenic archaea can reduce CO(2) with H(2) to methane, and it is generally assumed that the reactions and mechanisms of energy conservation that are involved are largely the same in all methanogens. However, this does not take into account the fact that methanogens with cytochromes have considerably higher growth yields and threshold concentrations for H(2) than methanogens without cytochromes. These and other differences can be explained by the proposal outlined in this Review that in methanogens with cytochromes, the first and last steps in methanogenesis from CO(2) are coupled chemiosmotically, whereas in methanogens without cytochromes, these steps are energetically coupled by a cytoplasmic enzyme complex that mediates flavin-based electron bifurcation.

1,620 citations


Journal ArticleDOI
08 Dec 2008-Polymer
TL;DR: The importance of electrospinning for biomedical applications like tissue engineering drug release, wound dressing, enzyme immobilization etc. is highlighted in this paper, where the focus is also on the types of materials that have been electrospun.

1,608 citations


Journal ArticleDOI
TL;DR: This critical review gives a short overview of the widespread use of gold nanoparticles in biology, identifying four classes of applications in which gold nanoparticle have been used so far: labelling, delivering, heating, and sensing.
Abstract: This critical review gives a short overview of the widespread use of gold nanoparticles in biology. We have identified four classes of applications in which gold nanoparticles have been used so far: labelling, delivering, heating, and sensing. For each of these applications the underlying mechanisms and concepts, the specific features of the gold nanoparticles needed for this application, as well as several examples are described (142 references).

1,558 citations


Journal ArticleDOI
24 Apr 2008-Nature
TL;DR: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products.
Abstract: Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.

1,248 citations


Journal ArticleDOI
TL;DR: Since keratins also exhibit characteristic expression patterns in human tumors, several of them have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping.
Abstract: The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family.

1,186 citations


Journal ArticleDOI
13 Mar 2008-Neuron
TL;DR: A type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala is identified.

850 citations


Journal ArticleDOI
TL;DR: This work proposes a suitable extension of label ranking that incorporates the calibrated scenario and substantially extends the expressive power of existing approaches and suggests a conceptually novel technique for extending the common learning by pairwise comparison approach to the multilabel scenario, a setting previously not being amenable to the pairwise decomposition technique.
Abstract: Label ranking studies the problem of learning a mapping from instances to rankings over a predefined set of labels. Hitherto existing approaches to label ranking implicitly operate on an underlying (utility) scale which is not calibrated in the sense that it lacks a natural zero point. We propose a suitable extension of label ranking that incorporates the calibrated scenario and substantially extends the expressive power of these approaches. In particular, our extension suggests a conceptually novel technique for extending the common learning by pairwise comparison approach to the multilabel scenario, a setting previously not being amenable to the pairwise decomposition technique. The key idea of the approach is to introduce an artificial calibration label that, in each example, separates the relevant from the irrelevant labels. We show that this technique can be viewed as a combination of pairwise preference learning and the conventional relevance classification technique, where a separate classifier is trained to predict whether a label is relevant or not. Empirical results in the area of text categorization, image classification and gene analysis underscore the merits of the calibrated model in comparison to state-of-the-art multilabel learning methods.

825 citations


Journal ArticleDOI
TL;DR: Iron-sulfur (Fe/S) proteins are involved in a wide variety of cellular processes such as enzymatic reactions, respiration, cofactor biosynthesis, ribosome biogenesis, regulation of gene expression, and DNA-RNA metabolism.
Abstract: Iron-sulfur (Fe/S) proteins are involved in a wide variety of cellular processes such as enzymatic reactions, respiration, cofactor biosynthesis, ribosome biogenesis, regulation of gene expression, and DNA-RNA metabolism. Assembly of Fe/S clusters, small inorganic cofactors, is assisted by complex proteinaceous machineries, which use cysteine as a source of sulfur, combine it with iron to synthesize an Fe/S cluster on scaffold proteins, and finally incorporate the cluster into recipient apoproteins. In eukaryotes, such as yeast and human cells, more than 20 components are known that facilitate the maturation of Fe/S proteins in mitochondria, cytosol, and nucleus. These biogenesis components also perform crucial roles in other cellular pathways, e.g., in the regulation of iron homeostasis or the modification of tRNA. Numerous diseases including several neurodegenerative and hematological disorders have been associated with defects in Fe/S protein biogenesis, underlining the central importance of this proce...

580 citations


Journal ArticleDOI
TL;DR: This work shows that a simple (weighted) voting strategy minimizes risk with respect to the well-known Spearman rank correlation and compares RPC to existing label ranking methods, which are based on scoring individual labels instead of comparing pairs of labels.

538 citations


Journal ArticleDOI
25 Jul 2008-Science
TL;DR: A crystal structure of [Fe]-hydrogenase is presented, showing a mononuclear iron coordinated by the sulfur of cysteine 176, two carbon monoxide molecules, and the sp2-hybridized nitrogen of a 2-pyridinol compound with back-bonding properties similar to those of cyanide.
Abstract: Biological formation and consumption of molecular hydrogen (H2) are catalyzed by hydrogenases, of which three phylogenetically unrelated types are known: [NiFe]-hydrogenases, [FeFe]-hydrogenases, and [Fe]-hydrogenase. We present a crystal structure of [Fe]-hydrogenase at 1.75 angstrom resolution, showing a mononuclear iron coordinated by the sulfur of cysteine 176, two carbon monoxide (CO) molecules, and the sp2-hybridized nitrogen of a 2-pyridinol compound with back-bonding properties similar to those of cyanide. The three-dimensional arrangement of the ligands is similar to that of thiolate, CO, and cyanide ligated to the low-spin iron in binuclear [NiFe]- and [FeFe]-hydrogenases, although the enzymes have evolved independently and the CO and cyanide ligands are not found in any other metalloenzyme. The related iron ligation pattern of hydrogenases exemplifies convergent evolution and presumably plays an essential role in H2 activation. This finding may stimulate the ongoing synthesis of catalysts that could substitute for platinum in applications such as fuel cells.

Journal ArticleDOI
TL;DR: The genome sequence of C. kluyveri was reported, which revealed new insights into the metabolic capabilities of this well studied organism and suggested that the two enzymes, which are isolated together in a macromolecular complex, form a carboxysome-like structure.
Abstract: Clostridium kluyveri is unique among the clostridia; it grows anaerobically on ethanol and acetate as sole energy sources. Fermentation products are butyrate, caproate, and H2. We report here the genome sequence of C. kluyveri, which revealed new insights into the metabolic capabilities of this well studied organism. A membrane-bound energy-converting NADH:ferredoxin oxidoreductase (RnfCDGEAB) and a cytoplasmic butyryl-CoA dehydrogenase complex (Bcd/EtfAB) coupling the reduction of crotonyl-CoA to butyryl-CoA with the reduction of ferredoxin represent a new energy-conserving module in anaerobes. The genes for NAD-dependent ethanol dehydrogenase and NAD(P)-dependent acetaldehyde dehydrogenase are located next to genes for microcompartment proteins, suggesting that the two enzymes, which are isolated together in a macromolecular complex, form a carboxysome-like structure. Unique for a strict anaerobe, C. kluyveri harbors three sets of genes predicted to encode for polyketide/nonribosomal peptide synthetase hybrides and one set for a nonribosomal peptide synthetase. The latter is predicted to catalyze the synthesis of a new siderophore, which is formed under iron-deficient growth conditions.


Journal ArticleDOI
TL;DR: The eye position of human observers is measured while they inspect photographs of common natural scenes to suggest that early saliency has only an indirect effect on attention, acting through recognized objects.
Abstract: Humans move their eyes while looking at scenes and pictures. Eye movements correlate with shifts in attention and are thought to be a consequence of optimal resource allocation for high-level tasks such as visual recognition. Models of attention, such as “saliency maps,” are often built on the assumption that “early” features (color, contrast, orientation, motion, and so forth) drive attention directly. We explore an alternative hypothesis: Observers attend to “interesting” objects. To test this hypothesis, we measure the eye position of human observers while they inspect photographs of common natural scenes. Our observers perform different tasks: artistic evaluation, analysis of content, and search. Immediately after each presentation, our observers are asked to name objects they saw. Weighted with recall frequency, these objects predict fixations in individual images better than early saliency, irrespective of task. Also, saliency combined with object positions predicts which objects are frequently named. This suggests that early saliency has only an indirect effect on attention, acting through recognized objects. Consequently, rather than treating attention as mere preprocessing step for object recognition, models of both need to be integrated.

Journal ArticleDOI
TL;DR: An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP and recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for Patients with other solid tumours as primary disease.

Journal ArticleDOI
03 Mar 2008-Small
TL;DR: The amphiphilic polymer described here is based on a poly(maleic anhydride) backbone which involves a third kind of building block: functional organic molecules and provides additional functionality in the particle surface.
Abstract: Inorganic colloidal nanoparticles, such as quantum dots or Au nanoparticles, have been extensively investigated for two decades in physics as well as in chemistry. Applications in a variety of fields such as optics, electronics, and biology are envisaged and important proof-of-concept studies have been reported. In particular, with regard to biologically motivated applications, colloidal stability is a key requirement. Apart from nanoparticles stabilized with small ligand molecules, lipids, [6–8] and surface silanization, amphiphilic polymers have been also used by several groups to disperse originally hydrophobic nanoparticles in aqueous solution. This class of amphiphilic particle coatings not only enables the phase transfer of the nanoparticles from organic solvents to aqueous solution, but also serves as a versatile platform for chemical modification and bioconjugation of the particles because biological molecules can be covalently linked to the polymer surface. Because the stability of the amphiphilic coating around the nanoparticle solely depends on the hydrophobic interaction, this procedure is very general and does, for example, not depend on the material of the inorganic nanoparticle core, as it is the case for ligand exchange protocols. Because of the numerous contact points mediated by hydrophobic interaction, the attachment of the polymer to the particle surface is highly stable and can be improved further by crosslinking of the polymer shell. Nowadays quantum dots coated with amphiphilic polymers and with various biological molecules attached to their surface are commercially available (e.g., Invitrogen). The amphiphilic polymers that have been used so far for coating hydrophobic inorganic nanoparticles consist of hydrophobic side chains for the linkage to the nanoparticle surface and a hydrophilic backbone that provides water solubility through charged groups (in general -COO ) and also acts as an anchor for the attachment of biological molecules with bioconjugate chemistry. In this report, we introduce an amphiphilic polymer which involves a third kind of building block: functional organic molecules. The functional organic molecules are linked to the hydrophobic side chains in a similar way as the hydrophilic backbone and provide additional functionality in the particle surface (Figure 1). The amphiphilic polymer described here is based on a poly(maleic anhydride) backbone. Reaction of a fraction of the anhydride rings with alkylamines leads to the formation of the hydrophobic side chains that are needed for intercalation with the hydrophobic surfactant layer on the nanoparticle surface. Another fraction of the anhydride rings is used to link functional organic molecules to the backbone. Like the alkylamines, organic molecules bearing amino-groups can be directly linked to the anhydride rings by reaction of the anhydride with the amino group. In this way alkylamines and organic molecules with amino terminations can be linked to the polymer backbone in a one-pot reaction. The resulting amphiphilic polymer is then wrapped around hydrophobic capped nanoparticles and the organic solvent is replaced by aqueous solution according to our previously published procedure. By linking some of the remaining anhydride rings with diamine linkers, the polymer molecules around each nanoparticle are interconnected and, thus, the shell is crosslinked. Upon phase transfer to aqueous solution, the remaining anhydride rings open to yield negatively charged carboxyl groups, which provide electrostatic repulsion resulting in a stable dispersion of the nanoparticles. Apart from negatively charged carboxyl groups, the polymer surface of the nanoparticles also contains embedded functional organic molecules. The strategy reported here has several advantageous features: 1) The maleic anhydride moieties react spontaneously with high yield with both amino-modified hydrophobic side-chains (such as alkylamines) and functional organic molecules with amino terminal groups. 2) No additional reagents are needed for the coupling. In comparison, [*] R. A. Sperling, M. Zanella, Prof. W. J. Parak Fachbereich Physik, Philipps Universit#t Marburg Renthof 7, 35037 Marburg (Germany) E-mail: Wolfgang.Parak@physik.uni-marburg.de C.-A. J. Lin, R. A. Sperling, P.-Y. Li, M. Zanella, Prof. W. J. Parak Center for NanoScience Ludwig-Maximilians-Universit#t M8nchen Munich (Germany) C.-A. J. Lin, T.-Y. Yang, W. H. Chang Department of Biomedical Engineering Chung Yuan Christian University Taiwan (ROC) C.-A. J. Lin, J. K. Li, W. H. Chang R&D Center for Membrane Technology Center for Nano Bioengineering Chung Yuan Christian University Taiwan (ROC) [] These authors contributed equally to this work. [] Present address: Institute of Biotechnology, National Cheng Kung University, Taiwan (ROC)

Journal ArticleDOI
TL;DR: The finding that routine prehospital initiation of high-bolus dose tirofiban improved ST-segment resolution and clinical outcome after PCI, emphasises that further platelet aggregation inhibition besides high-dose clopidogrel is mandated in patients with STEMI undergoing PCI.

Journal ArticleDOI
TL;DR: Fredoxin reduction with NADH in cell extracts from Clostridium kluyveri is catalyzed by the butyryl-CoA dehydrogenase/Etf complex and the implications of this finding for the energy metabolism of butyrate-forming anaerobes are discussed in the accompanying paper.
Abstract: Cell extracts of butyrate-forming clostridia have been shown to catalyze acetyl-coenzyme A (acetyl-CoA)- and ferredoxin-dependent formation of H2 from NADH. It has been proposed that these bacteria contain an NADH:ferredoxin oxidoreductase which is allosterically regulated by acetyl-CoA. We report here that ferredoxin reduction with NADH in cell extracts from Clostridium kluyveri is catalyzed by the butyryl-CoA dehydrogenase/Etf complex and that the acetyl-CoA dependence previously observed is due to the fact that the cell extracts catalyze the reduction of acetyl-CoA with NADH via crotonyl-CoA to butyryl-CoA. The cytoplasmic butyryl-CoA dehydrogenase complex was purified and is shown to couple the endergonic reduction of ferredoxin (E0' = -410 mV) with NADH (E0' = -320 mV) to the exergonic reduction of crotonyl-CoA to butyryl-CoA (E0' = -10 mV) with NADH. The stoichiometry of the fully coupled reaction is extrapolated to be as follows: 2 NADH + 1 oxidized ferredoxin + 1 crotonyl-CoA = 2 NAD+ + 1 ferredoxin reduced by two electrons + 1 butyryl-CoA. The implications of this finding for the energy metabolism of butyrate-forming anaerobes are discussed in the accompanying paper.

Journal ArticleDOI
TL;DR: Energy conservation in chemotrophic organisms is generally coupled to redox reactions in catabolic pathways, and in the oxidative part or branch, “energy-rich” compounds are formed and ATP is generated via substrate-level phosphorylation.
Abstract: Energy conservation in chemotrophic organisms is generally coupled to redox reactions in catabolic pathways. In the oxidative part or branch, “energy-rich” compounds are formed, from which ATP is generated via substrate-level phosphorylation (SLP). In the reductive branch the electron carriers

Journal ArticleDOI
14 Aug 2008-Neuron
TL;DR: Taken together, the results establish TRPC3 as a new type of postsynaptic channel that mediates mGluR-dependent synaptic transmission in cerebellar Purkinje cells and is crucial for motor coordination.

Journal ArticleDOI
TL;DR: A genome-wide association study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing ~500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders.
Abstract: A genome-wide association (GWA) study with pooled DNA in adult attention-deficit/hyperactivity disorder (ADHD) employing ~500K SNP markers identifies novel risk genes and reveals remarkable overlap with findings from recent GWA scans in substance use disorders. Comparison with results from our previously reported high-resolution linkage scan in extended pedigrees confirms several chromosomal loci, including 16q23.1-24.3 which also reached genome-wide significance in a recent meta-analysis of seven linkage studies (Zhou et al. in Am J Med Genet Part B, 2008). The findings provide additional support for a common effect of genes coding for cell adhesion molecules (e.g., CDH13, ASTN2) and regulators of synaptic plasticity (e.g., CTNNA2, KALRN) despite the complex multifactorial etiologies of adult ADHD and addiction vulnerability.

Journal ArticleDOI
TL;DR: It is concluded that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-à-vis the origins of PDAC.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is believed to arise through a multistep model comprised of putative precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). Recent genetically engineered mouse models of PDAC demonstrate a comparable morphologic spectrum of murine PanIN (mPanIN) lesions. The histogenesis of PanIN and PDAC in both mice and men remains controversial. The most faithful genetic models activate an oncogenic KrasG12D knockin allele within the pdx1- or ptf1a/p48-expression domain of the entire pancreatic anlage during development, thus obscuring the putative cell(s)-of-origin from which subsequent mPanIN lesions arise. In our study, activation of this knockin KrasG12D allele in the Elastase- and Mist1-expressing mature acinar compartment of adult mice resulted in the spontaneous induction of mPanIN lesions of all histological grades, although invasive carcinomas per se were not seen. We observed no requirement for concomitant chronic exocrine injury in the induction of mPanIN lesions from the mature acinar cell compartment. The acinar cell derivation of the mPanINs was established through lineage tracing in reporter mice, and by microdissection of lesional tissue demonstrating Cre-mediated recombination events. In contrast to the uniformly penetrant mPanIN phenotype observed following developmental activation of KrasG12D in the Pdx1-expressing progenitor cells, the Pdx1-expressing population in the mature pancreas (predominantly islet β cells) appears to be relatively resistant to the effects of oncogenic Kras. We conclude that in the appropriate genetic context, the differentiated acinar cell compartment in adult mice retains its susceptibility for spontaneous transformation into mPanIN lesions, a finding with potential relevance vis-a-vis the origins of PDAC.

Journal ArticleDOI
TL;DR: The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.
Abstract: Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.


Journal ArticleDOI
TL;DR: The ground state structure of the complete sensory module of Cph1 phytochrome from the cyanobacterium Synechocystis 6803 is reported, and it is shown that the PHY domain, previously considered unique to phY, is structurally a member of the GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) family.
Abstract: Phytochromes are red/far-red photochromic biliprotein photoreceptors, which in plants regulate seed germination, stem extension, flowering time, and many other light effects. However, the structure/functional basis of the phytochrome photoswitch is still unclear. Here, we report the ground state structure of the complete sensory module of Cph1 phytochrome from the cyanobacterium Synechocystis 6803. Although the phycocyanobilin (PCB) chromophore is attached to Cys-259 as expected, paralleling the situation in plant phytochromes but contrasting to that in bacteriophytochromes, the ZZZssa conformation does not correspond to that expected from Raman spectroscopy. We show that the PHY domain, previously considered unique to phytochromes, is structurally a member of the GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) family. Indeed, the tandem-GAF dumbbell revealed for phytochrome sensory modules is remarkably similar to the regulatory domains of cyclic nucleotide (cNMP) phosphodiesterases and adenylyl cyclases. A unique feature of the phytochrome structure is a long, tongue-like protrusion from the PHY domain that seals the chromophore pocket and stabilizes the photoactivated far-red-absorbing state (Pfr). The tongue carries a conserved PRxSF motif, from which an arginine finger points into the chromophore pocket close to ring D forming a salt bridge with a conserved aspartate residue. The structure that we present provides a framework for light-driven signal transmission in phytochromes.

Journal ArticleDOI
C. Alt1, Katarzyna Grebieszkow2, I. K. Yoo3, W. Peryt2, E. Gladysz4, V. Eckardt5, B. Lungwitz1, Z. Fodor6, N. Schmitz5, J. Sziklai7, J. Bartke4, P. Chung8, Kreso Kadija, V. Friese9, Ferenc Sikler7, P. Csato7, M. Slodkowski2, Zbigniew Wlodarczyk, M. Vassiliou10, Helena Bialkowska, C. Strabel1, Andras Laszlo7, G. L. Melkumov11, V. I. Kolesnikov11, Maciej Rybczyński, Christoph Blume1, J. G. Cramer12, Apostolos Panagiotou10, J. Pluta2, M. Szuba2, G. Stefanek, D. Barna7, M. van Leeuwen, D. Vranic9, I. Kraus9, O. Chvala13, Gunther Roland14, C. Höhne15, J. Gál7, S. Hegyi7, M. Makariev, Andre Mischke, Andreas Petridis10, G. Pálla7, M. Botje, M. K. Mitrovski1, Mrowczynski7, Panagiota Foka9, P. Dinkelaker1, B. Baatar11, Marek Kowalski4, S. Kniege1, P. Christakoglou10, Leander Litov, R. Bramm9, Peter Levai7, E. Skrzypczak16, Thorsten Sven Kollegger1, M. Gazdzicki7, E. Kornas4, Branislav Sitar17, Tatjana Susa, Tome Anticic, D. Flierl1, R. Lacey8, Andrzej Rybicki4, Latchezar Betev18, H. Ströbele1, Miroslav Pikna17, V. Genchev19, Jozsef Molnar7, I. Szentpetery7, M. Mateev, F. Pühlhofer15, P. Szymanski, Alexander Malakhov11, V. Trubnikov, Michal Kreps17, Rainer Arno Ernst Renfordt1, J. Zimányi7, D. J. Prindle12, Predrag Buncic18, T. R. Schuster1, V. Cerny17, A. Karev5, Bożena Boimska, M. Kliemant1, D. P. Kikola2, Dezso Varga7, P. Seyboth5, R. Stock1, V. Nicolic, Gabor Istvan Veres7, Gyorgy Vesztergombi7, J. Bracinik17, D. Panayotov, A. Sandoval9, A. Wetzler1, Christof Roland14 
TL;DR: In this paper, results on charged pion and kaon production in central Pb+Pb collisions at 20A and 30A GeV are presented and compared to data at lower and higher energies.
Abstract: Results on charged pion and kaon production in central Pb+Pb collisions at 20A and 30A GeV are presented and compared to data at lower and higher energies. Around 30A GeV a rapid change of the energy dependence for the yields of pions and kaons as well as for the shape of the transverse mass spectra is observed. The change is compatible with the prediction that the threshold for production of a state of deconfined matter at the early stage of the collisions is located at low CERN Super Proton Synchroton energies.

Journal ArticleDOI
TL;DR: It is shown that adaptive mutations D701N in PB2 and N319K in NP enhance binding of these proteins to importin α1 in mammalian cells, demonstrating that adaptation of the viral polymerase to the nuclear import machinery plays an important role in interspecies transmission of influenza virus.
Abstract: We have previously reported that mutations in the polymerase proteins PB1, PB2, PA, and the nucleocapsid protein NP resulting in enhanced transcription and replication activities in mammalian cells are responsible for the conversion of the avian influenza virus SC35 (H7N7) into the mouse-adapted variant SC35M. We show now that adaptive mutations D701N in PB2 and N319K in NP enhance binding of these proteins to importin α1 in mammalian cells. Enhanced binding was paralleled by transient nuclear accumulation and cytoplasmic depletion of importin α1 as well as increased transport of PB2 and NP into the nucleus of mammalian cells. In avian cells, enhancement of importin α1 binding and increased nuclear transport were not observed. These findings demonstrate that adaptation of the viral polymerase to the nuclear import machinery plays an important role in interspecies transmission of influenza virus.

Journal ArticleDOI
TL;DR: It is shown that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist‐independent activation of Gq/11‐coupled receptors, which subsequently signal to TRPC channels in a G protein‐ and phospholipase C‐dependent manner.
Abstract: Despite the central physiological function of the myogenic response, the underlying signalling pathways and the identity of mechanosensors in vascular smooth muscle (VSM) are still elusive. In contrast to present thinking, we show that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist-independent activation of Gq/11-coupled receptors, which subsequently signal to TRPC channels in a G protein- and phospholipase C-dependent manner. Mechanically activated receptors adopt an active conformation, allowing for productive G protein coupling and recruitment of β-arrestin. Agonist-independent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT1 angiotensin II receptor density in mechanically unresponsive rat aortic A7r5 cells resulted in mechanosensitivity. Myogenic tone of cerebral and renal arteries is profoundly diminished by the inverse angiotensin II AT1 receptor agonist losartan independently of angiotensin II (AII) secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signalling-2. These findings suggest that Gq/11-coupled receptors function as sensors of membrane stretch in VSM cells.

Journal ArticleDOI
Udo Kelle1
TL;DR: A taxonomy of mixed-methods designs has been proposed in this paper, but there is a lack of agreement regarding basic concepts and definitions, as is bemoaned by many experts in this field.
Abstract: Despite ongoing ‘paradigm wars’ between the methodological traditions of qualitative and quantitative research, ‘mixed methods’ represents nowadays a rapidly developing field of social science methodology. In such discussions it is often emphasized that the use of methods should be predominantly influenced by substantive research questions, and not only by methodological and epistemological considerations. As all methods have specific limitations as well as particular strengths, many discussants propose that qualitative and quantitative methods should be combined in order to compensate for their mutual and overlapping weaknesses. However, although a variety of proposals have been made for a taxonomy of mixed-methods designs, there is yet a lack of agreement regarding basic concepts and definitions, as is bemoaned by many experts in this field. This lack of common ground is due to the fact that crucial questions regarding the relations between research domains and methods have been not sufficiently discuss...

Journal ArticleDOI
TL;DR: The results show that the bonding situations in L(2)C compounds 1-8 can be interpreted in terms of donor-acceptor interactions between closed-shell ligands L and a carbon atom which has two lone-pair orbitals L-->C<--L, and particularly for the carbodiphosphoranes 1-3, which are classified as divalent carbon(0) compounds.
Abstract: Quantum-chemical calculations with DFT (BP86) and ab initio methods [MP2, SCS-MP2, CCSD(T)] have been carried out for the molecules C(PH(3))(2) (1), C(PMe(3))(2) (2), C(PPh(3))(2) (3), C(PPh(3))(CO) (4), C(CO)(2) (5), C(NHC(H))(2) (6), C(NHC(Me))(2) (7) (Me(2)N)(2)C=C=C(NMe(2))(2) (8), and NHC (9), where NHC=N-heterocyclic carbene and NHC(Me)=N-methyl-substituted NHC. The electronic structure in 1-9 was analyzed with charge- and energy-partitioning methods. The results show that the bonding situations in L(2)C compounds 1-8 can be interpreted in terms of donor-acceptor interactions between closed-shell ligands L and a carbon atom which has two lone-pair orbitals L-->C C((1)D) donor-acceptor bonds are roughly twice as strong as the respective L-->BH(3) bond.