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Periplasmic Sud protein encoded by the Wolinella succinogenes catalyses the transfer of bound polysulfide-sulfur to the active site of the membrane bound polysulfide reductase. The homodimeric protein consists of 131 residues per monomer, each with one cysteine residue in the active site. Polysulfide-sulfur is covalently bound to the catalytic Cys residues of the Sud protein. In order to understand the structure-function relationship of this protein, the features of its solution structure determined by heteronuclear multidimensional NMR techniques are reported here. The first step of structure determination leads to resonance assignments using 15N/13C/2H- and 15N/13C-labeled protein. The sequential backbone and side chain resonance assignments have been successfully completed. Structure calculations were carried out using the ARIA program package. The structure is based on 2688 NOE-derived distance restraints, 68 backbone hydrogen bond restraints derived from 34 slow-exchanging backbone amide protons and 334 torsion angle restraints obtained from the TALOS program as well as 158 residual dipolar coupling restraints for the refinement of relative vector orientations. The three-dimensional structure of the Sud protein was determined with an averaged rootmean- square deviation of 0.72 Å and 1.28 Å for the backbone and heavy atoms, respectively, excluding the terminal residues. Without the poorly defined segment between residues 90-94 the average r.m.s.d. value drops down to 0.6 Å and 1.14 Å. The ensemble refined with residual dipolar coupling (rdc) restraints shows good convergence. The r.m.s.d. value for the backbone heavy atoms, excluding residues 90- 94, drops down from 0.97 to 0.66 for the rdc-refined ensemble. The relative orientation of the two monomers in the protein structures refined with residual dipolar coupling restraints are also different from those without residual dipolar coupling restraints. The structure determination of the dimeric protein has been hampered by the high molecular mass (30 kDa), severe peak degeneracy, and by the small number of experimental intermonomer NOEs (relative orientation problem of two monomers). For the resonance assignments of aliphatic side chain, many resonances were ambiguously assigned because of severe overlap of signals. The Sud dimer protein contains 17 Lys, 14 Leu and one His tag for each monomer. It complicated the resonance assignments. The conventional 3D 15N-separated TOCSY HSQC experiment failed because of the large molecular weight which results in line broadening and hence made the resonance assignments of side chains more difficult. The determined structure contains a five-stranded parallel ß-sheet enclosing a hydrophobic core, a two-stranded anti-parallel ß-sheet and seven a-helices. The dimer structure is stabilized predominantly by hydrophobic residues. Sud catalyses the transfer of the polysulfide-sulfur to cyanide, similar to rhodanese encoded by Azotobacter vinelandii (Bordo et al., 2000). The two proteins are similar in the active site environment primarily owing to the main-chain conformation of the active-site loop with the cysteine residue and with respect to the surrounding positively charged residues. The active-site loop (residues 89-95) in the Sud protein appears to be flexible, reflected by few assigned proton resonances of residues 90-94 in the active site. Despite their similarity in function and their similar structure in active site, the amino acid sequences and the folds of the two proteins are remarkably different. The negatively charged polysulfide interacts with positively charged R46, R67, and R94 and hence may be stabilized in structure. The mutation of one of the three arginines that are also conserved in rhodanese from A. vinelandii leads to a loss of sulfur-transfer activity. The polysulfide chain extends from inside of Sud protein to outside, where Sud may form contacts with polysulfide reductase. These contacts provide the possible polysulfide-sulfur transfer from Sud protein to the active site of polysulfide reductase.
The genus Parandes Muir, 1925 (Cixiinae, Andini) is recorded from China for the first time with two new species, Parandes circinatus Wang & Chen sp. nov. and Parandes fuscus Wang & Chen sp. nov. Color images for the adults of the two new species and line drawings for the genitalia are provided. A key is presented to separate all species within the genus.
Background Although current molecular clock methods offer greater flexibility in modelling historical evolutionary events, calibration of the clock with dates from the fossil record is still problematic for many groups. Here we implement several new approaches in molecular dating to estimate evolutionary ages of Lacertidae, an Old World family of lizards with a poor fossil record and uncertain phylogeny. Four different models of rate variation are tested in a new program for Bayesian phylogenetic analysis called TreeTime, based on a combination of mitochondrial and nuclear gene sequences. We incorporate paleontological uncertainty into divergence estimates by expressing multiple calibration dates as a range of probabilistic distributions. We also test the reliability of our proposed calibrations by exploring effects of individual priors on posterior estimates. Results According to the most reliable model, as indicated by Bayes factor comparison, modern lacertids arose shortly after the K/T transition and entered Africa about 45 million years ago, with the majority of their African radiation occurring in the Eocene and Oligocene. Our findings indicate much earlier origins for these clades than previously reported, and we discuss our results in light of paleogeographic trends during the Cenozoic. Conclusions This study represents the first attempt to estimate evolutionary ages of a specific group of reptiles exhibiting uncertain phylogenetic relationships, molecular rate variation and a poor fossil record. Our results emphasize the sensitivity of molecular divergence dates to fossil calibrations, and support the use of combined molecular data sets and multiple, well-spaced dates from the fossil record as minimum node constraints. The bioinformatics program used here, TreeTime, is publicly available, and we recommend its use for molecular dating of taxa faced with similar challenges.
Borrelia burgdorferi sensu lato (Bbsl), the causative agent of Lyme disease, establishes an initial infection in the host’s skin following a tick bite, and then disseminates to distant organs, leading to multisystem manifestations. Tick-to-vertebrate host transmission requires that Bbsl survives during blood feeding. Complement is an important innate host defense in blood and interstitial fluid. Bbsl produces a polymorphic surface protein, CspA, that binds to a complement regulator, Factor H (FH) to block complement activation in vitro. However, the role that CspA plays in the Bbsl enzootic cycle remains unclear. In this study, we demonstrated that different CspA variants promote spirochete binding to FH to inactivate complement and promote serum resistance in a host-specific manner. Utilizing a tick-to-mouse transmission model, we observed that a cspA-knockout B. burgdorferi is eliminated from nymphal ticks in the first 24 hours of feeding and is unable to be transmitted to naïve mice. Conversely, ectopically producing CspA derived from B. burgdorferi or B. afzelii, but not B. garinii in a cspA-knockout strain restored spirochete survival in fed nymphs and tick-to-mouse transmission. Furthermore, a CspA point mutant, CspA-L246D that was defective in FH-binding, failed to survive in fed nymphs and at the inoculation site or bloodstream in mice. We also allowed those spirochete-infected nymphs to feed on C3-/- mice that lacked functional complement. The cspA-knockout B. burgdorferi or this mutant strain complemented with cspA variants or cspA-L246D was found at similar levels as wild type B. burgdorferi in the fed nymphs and mouse tissues. These novel findings suggest that the FH-binding activity of CspA protects spirochetes from complement-mediated killing in fed nymphal ticks, which ultimately allows Bbsl transmission to mammalian hosts.
Global investment in biomedical research has grown significantly over the last decades, reaching approximately a quarter of a trillion US dollars in 2010. However, not all of this investment is distributed evenly by gender. It follows, arguably, that scarce research resources may not be optimally invested (by either not supporting the best science or by failing to investigate topics that benefit women and men equitably). Women across the world tend to be significantly underrepresented in research both as researchers and research participants, receive less research funding, and appear less frequently than men as authors on research publications. There is also some evidence that women are relatively disadvantaged as the beneficiaries of research, in terms of its health, societal and economic impacts. Historical gender biases may have created a path dependency that means that the research system and the impacts of research are biased towards male researchers and male beneficiaries, making it inherently difficult (though not impossible) to eliminate gender bias. In this commentary, we – a group of scholars and practitioners from Africa, America, Asia and Europe – argue that gender-sensitive research impact assessment could become a force for good in moving science policy and practice towards gender equity. Research impact assessment is the multidisciplinary field of scientific inquiry that examines the research process to maximise scientific, societal and economic returns on investment in research. It encompasses many theoretical and methodological approaches that can be used to investigate gender bias and recommend actions for change to maximise research impact. We offer a set of recommendations to research funders, research institutions and research evaluators who conduct impact assessment on how to include and strengthen analysis of gender equity in research impact assessment and issue a global call for action.
Bayessche Methoden zur Schätzung von Stammbäumen mit Verzweigungszeitpunkten aus molekularen Daten
(2009)
Ein großes Ziel der Evolutionsbiologie ist es, die Stammesgeschichte der Arten zu rekonstruieren. Historisch verwendeten Systematiker hierfür morphologische und anatomische Merkmale. Mit dem stetigen Zuwachs an verfügbaren Sequenzdaten werden heute verstärkt Methoden entwickelt und eingesetzt, welche die Rekonstruktion auf Basis von molekularen Daten ermöglichen. Im Fokus der aktuellen Forschung steht die Anwendung und Weiterentwicklung Bayesscher Methoden. Diese Methoden besitzen große Popularität, da sie in Verbindung mit Markov-Ketten-Monte-Carlo-Verfahren eingesetzt werden können, um einen Stammbaum zu vorgegebenen Spezies zu schätzen und dessen Variabilität zu bestimmen. Im Rahmen dieser Dissertation wurde die erweiterbare Software TreeTime entwickelt. TreeTime bietet Schnittstellen für die Einbindung von molekularen Evolutions- und Ratenänderungsmodellen und stellt neu entwickelte Methoden bereit, um Stammbäume mit Verzweigungszeitpunkten zu rekonstruieren. In TreeTime werden die molekularen Daten und die zeitlichen Informationen, wie z.B. Fossilfunde, in einem Bayes-Verfahren simultan berücksichtigt, um die Zeitpunkte der Artaufspaltungen genauer zu datieren. Für die Anwendung Bayesscher Methoden in der Rekonstruktion von Stammbäumen wird ein stochastisches Modell benötigt, das die Evolution der molekularen Sequenzen entlang den Kanten eines Stammbaums beschreibt. Der Mutationsprozess der Sequenzen wird durch ein molekulares Evolutionsmodell definiert. Die Verwendung der klassischen molekularen Evolutionsmodelle impliziert die Annahme einer konstanten Evolutionsgeschwindigkeit der Sequenzen im Stammbaum. Diese Annahme wird als Hypothese der molekularen Uhr bezeichnet und bildet die Grundlage zum Schätzen der Verzweigungszeiten des Stammbaums. Der Verzweigungszeitpunkt, an dem sich zwei Spezies im Stammbaum aufspalten, spiegelt sich in der Ähnlichkeit der zugehörigen molekularen Sequenzen. Je älter dieser Verzweigungszeitpunkt ist, desto größer ist die Anzahl der unterschiedlichen Positionen in den Sequenzen. Häufig ist jedoch die Annahme der molekularen Uhr verletzt, so dass in gewissen Teilbereichen eines Stammbaums eine erhöhte Evolutionsgeschwindigkeit nachweisbar ist. Falls die Verletzung konstanter Evolutionsgeschwindigkeiten nicht ausgeschlossen werden kann, sollten schwankende Mutationsraten in der Modellierung explizit berücksichtigt werden. Hierfür wurden verschiedene Ratenänderungsmodelle vorgeschlagen. Bisher sind nur wenige dieser Ratenänderungsmodelle in Softwarepaketen verfügbar und ihre Eigenschaften sind nicht ausreichend erforscht. Das Ziel dieser Arbeit ist die Entwicklung und Bereitstellung von Bayesschen Modellen und Methoden zum Schätzen von Stammbäumen mit Verzweigungszeitpunkten. Die Methoden sollten auch bei unterschiedlichen Evolutionsgeschwindigkeiten im Stammbaum anwendbar sein. Vorgestellt wird ein neues Ratenänderungsmodell, eine neue Möglichkeit der Angabe von flexiblen Beschränkungen für die Topologie des Stammbaums sowie die Nutzung dieser Beschränkungen für die zeitliche Kalibrierung. Das neue Raten Änderungsmodell sowie die topologischen und zeitlichen Beschränkungen werden in einen modularen Softwareentwurf eingebettet. Durch den erweiterbaren Entwurf können bestehende und zukünftige molekulare Evolutionsmodelle und Ratenänderungsmodelle in die Software eingebunden und verwendet werden. Die vorgestellten Modelle und Methoden werden gemäß dem Softwareentwurf in das neu entwickelte Programm TreeTime aufgenommen und effzient implementiert. Zusätzlich werden bereits vorhandene Modelle programmiert und eingebunden, die nicht in anderen Softwarepaketen verfügbar sind. Des Weiteren wird eine neue Methode entwickelt und angewendet, um die Passgenauigkeit eines Modells für die Apriori-Verteilung auf der Menge der Baumtopologien zu beurteilen. Diese Methode wird zur Auswahl geeigneter Modelle benutzt, indem eine Auswertung der beobachteten Baumtopologien der Datenbank TreeBASE durchgeführt wird. Anschließend wird die Software TreeTime in einer Simulationsstudie eingesetzt, um die Eigenschaften der implementierten Ratenänderungsmodelle zu vergleichen. Die Software wird für die Rekonstruktion des Stammbaums zu 38 Spezies aus der Familie der Eidechsen (Lacertidae) verwendet. Da die zugehörigen molekularen Daten von der Hypothese der molekularen Uhr abweichen, werden unterschiedliche Ratenänderungsmodelle bei der Rekonstruktion verwendet und abschließend bewertet. ........
BACKGROUND & AIMS: Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents.
METHODS: We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents.
RESULTS: Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P = .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P = .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI.
CONCLUSIONS: In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).
Camellia sinensis is one of the major crops grown in Taiwan and has been widely cultivated around the island. Tea leaves are prone to various fungal infections, and leaf spot is considered one of the major diseases in Taiwan tea fields. As part of a survey on fungal species causing leaf spots on tea leaves in Taiwan, 19 fungal strains morphologically similar to the genus Diaporthe were collected. ITS (internal transcribed spacer), tef1-α (translation elongation factor 1-α), tub2 (beta-tubulin), and cal (calmodulin) gene regions were used to construct phylogenetic trees and determine the evolutionary relationships among the collected strains. In total, six Diaporthe species, including one new species, Diaporthe hsinchuensis, were identified as linked with leaf spot of C. sinensis in Taiwan based on both phenotypic characters and phylogeny. These species were further characterized in terms of their pathogenicity, temperature, and pH requirements under laboratory conditions. Diaporthe tulliensis, D. passiflorae, and D. perseae were isolated from C. sinensis for the first time. Furthermore, pathogenicity tests revealed that, with wound inoculation, only D. hongkongensis was pathogenic on tea leaves. This investigation delivers the first assessment of Diaporthe taxa related to leaf spots on tea in Taiwan.
Pathogens possess the ability to adapt and survive in some host species but not in others–an ecological trait known as host tropism. Transmitted through ticks and carried mainly by mammals and birds, the Lyme disease (LD) bacterium is a well-suited model to study such tropism. Three main causative agents of LD, Borrelia burgdorferi, B. afzelii, and B. garinii, vary in host ranges through mechanisms eluding characterization. By feeding ticks infected with different Borrelia species, utilizing feeding chambers and live mice and quail, we found species-level differences in bacterial transmission. These differences localize on the tick blood meal, and specifically complement, a defense in vertebrate blood, and a polymorphic bacterial protein, CspA, which inactivates complement by binding to a host complement inhibitor, Factor H (FH). CspA selectively confers bacterial transmission to vertebrates that produce FH capable of allele-specific recognition. CspA is the only member of the Pfam54 gene family to exhibit host-specific FH-binding. Phylogenetic analyses revealed convergent evolution as the driver of such uniqueness, and that FH-binding likely emerged during the last glacial maximum. Our results identify a determinant of host tropism in Lyme disease infection, thus defining an evolutionary mechanism that shapes host-pathogen associations.
Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.