2,488 research outputs found

    Engineering of a bifunctional anti-Kv10.1 antibody for cancer therapy

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    Lunar rocks as meteoroid detectors

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    About 5000 microcraters on seven lunar rocks recovered during the Apollo 12 mission have been systematically studied using a stereomicroscope. Based on comparisons with laboratory cratering experiments, at least 95 percent of all millimeter sized craters observed were formed by impacts in which the impact velocity exceeded 10 km/s. The dynamics of particle motion near the moon and the distribution of microcraters on the rocks require an extralunar origin for these impacting particles. The microcrater population on at least one side of all rocks studied was in equilibrium for millimeter sized craters; i.e., statistically, craters a few millimeters in diameter and smaller were being removed by the superposition of new craters at the same rate new craters were being formed. The population of craters on such a surface is directly related to the total population of particles impacting that surface. Crater size distribution data together with an experimentally determined relationship between the crater size and the physical parameters of the impacting particle, yield the mass distribution of interplanetary dust at 1 AU

    Fatigue reliability and post-fracture residual capacity of a two-girder steel bridge

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    2016 Fall.Includes bibliographical references.Due to the immense and always increasing traffic volume, bridges are permanently subjected to repetitive loadings. These high numbers of cyclic loads can cause the initiation of fatigue cracks. If these flaws remain undetected they may become through-thickness cracks and further propagate, if left unrepaired, until they eventually lead to fracture of the entire member. The criticality of a full member fracture is not well defined nor agreed upon. Previous failure cases have demonstrated the ability of two-girder steel bridges to withstand full girder fracture of one of the two girders without structural collapse. Other cases, however, have shown the criticality of a complete girder failure on complete system collapse. Due to uncertainties in bridge redundancy and the ability to develop alternative load path, the American Association of State Highway and Transportation Officials (AASHTO) attempts to prevent fracture or collapse by classifying bridges with respect to their redundancy into fracture critical bridges (FCB) and decreasing their inspection periods. However, this leads to higher construction and maintenance costs for the owners of FCBs. Clearly, the level of uncertainty in bridge performance when one of its two girders suffer complete fracture should be represented in a probabilistic manner to evaluate the probability of fatigue crack growth and system collapse. To that end, thesis uses probabilistic analysis to assess the crack propagation behavior in a girder of a two-girder steel bridge by conducting finite element Monte Carlo simulations. The simulations account for the scatter in the load and the resistance by treating those uncertainties as random variables with predefined statistical distributions. Additionally, the post fracture redundancy is evaluated by comparing the resulting equivalent plastic strain to the failure strain of steel. The results show that the bridge provides sufficient redundancy to redistribute the load after full depth fracture a FC member. Furthermore, the results of the probabilistic analyses provide a basis for choosing the inspection intervals for FCBs

    What comparative genomics tells us about the evolution of the eukaryotic recombination machinery

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    The growing number of completely deciphered genomic sequences provides an enormous reservoir of data, which can be used for addressing questions related to functional and evolutionary biology. The wealth of this approach is documented by the fast growing numbers of recent publications in the field of evolutionary biology based on comparative genomics. Many proteins of the recombination machinery are conserved between plants, fungi and animals but some of them also show remarkable differences regarding their presence, copy number or molecular structure. For example, the protein responsible for double strand break (DSB) induction during meiosis, SPO11, which is related to the subunit A of the archaebacterial topoisomerase VI, is coded by a single gene in animals and fungi. In contrast, plants harbour three distantly related homologues, which seem to have non-redundant functions either in meiosis or in somatic cells and are indispensable for viability. Moreover, plants possess a homologue of the subunit B of the archaebacterial topoisomerase VI, not present in other eukaryotes. We also summarise the recent progress in the usage of genomic data to analyse the evolution of other DNA recombination factors. Finally, several recent studies report on a strong conservation of a reasonable number of intron positions between plants, animals and fungi. This kind of study provides a basis for comparative genomic analyses across kingdoms and demonstrates the existence of ancient introns, a topic of intensive debate

    The RecQ gene family in plants

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    structure and function. They are 30–50 DNA helicases resolving different recombinogenic DNA structures. The RecQ helicases are key factors in a number of DNA repair and recombination pathways involved in the maintenance of genome integrity. In eukaryotes the number of RecQ genes and the structure of RecQ proteins vary strongly between organisms. Therefore, they have been named RecQ-like genes. Knockouts of several RecQ-like genes cause severe diseases in animals or harmful cellular phenotypes in yeast. Until now the largest number of RecQ-like genes per organism has been found in plants. Arabidopsis and rice possess seven different RecQ-like genes each. In the almost completely sequenced genome of the moss Physcomitrella patens at least five RecQ-like genes are present. One of the major present and future research aims is to define putative plant-specific functions and to assign their roles in DNA repair and recombination pathways in relation to RecQ genes from other eukaryotes. Regarding their intron positions, the structures of six RecQ-like genes of dicots and monocots are virtually identical indicating a conservation over a time scale of 150 million years. In contrast to other eukaryotes one gene (RecQsim) exists exclusively in plants. It possesses an interrupted helicase domain but nevertheless seems to have maintained the RecQ function. Owing to a recent gene duplication besides the AtRecQl4A gene an additional RecQ-like gene (AtRecQl4B) exists in the Brassicaceae only. Genetic studies indicate that a AtRecQl4A knockout results in sensitivity to mutagens as well as an hyperrecombination phenotype. Since AtRecQl4B was still present, both genes must have non-redundant roles. Analysis of plant RecQ-like genes will not only increase the knowledge on DNA repair and recombination, but also on the evolution and radiation of protein families

    Biochemical Characterization of an Exonuclease from Arabidopsis thaliana Reveals Similarities to the DNA Exonuclease of the Human Werner Syndrome Protein

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    The human Werner syndrome protein (hWRN-p) possessing DNA helicase and exonuclease activities is essential for genome stability. Plants have no homologue of this bifunctional protein, but surprisingly the Arabidopsis genome contains a small open reading frame (ORF) (AtWRNexo) with homology to the exonuclease domain of hWRN-p. Expression of this ORF in Escherichia coli revealed an exonuclease activity for AtWRNexo-p with similarities but also some significant differences to hWRN-p. The protein digests recessed strands of DNA duplexes in the 3\u27 -> 5\u27 direction but hardly single-stranded DNA or blunt-ended duplexes. In contrast to the Werner exonuclease, AtWRNexo-p is also able to digest 3\u27-protruding strands. DNA with recessed 3\u27-PO4 and 3\u27-OH termini is degraded to a similar extent. AtWRNexo-p hydrolyzes the 3\u27-recessed strand termini of duplexes containing mismatched bases. AtWRNexo-p needs the divalent cation Mg2+^{2+} for activity, which can be replaced by Mn2+^{2+}. Apurinic sites, cholesterol adducts, and oxidative DNA damage (such as 8-oxoadenine and 8-oxoguanine) inhibit or block the enzyme. Other DNA modifications, including uracil, hypoxanthine and ethenoadenine, did not inhibit AtWRNexo-p. A mutation of a conserved residue within the exonuclease domain (E135A) completely abolished the exonucleolytic activity. Our results indicate that a type of WRN-like exonuclease activity seems to be a common feature of the DNA metabolism of animals and plants

    Two closely related RecQ-helicases have antagonistic roles in homologous recombination and DNA repair in Arabidopsis thaliana

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    RecQ helicases are involved in the processing of DNA structures arising during replication, recombination, and repair throughout all kingdoms of life. Mutations of different RecQ homologues are responsible for severe human diseases, such as Blooms (BLM) or Werner (WRN) syndrome. The loss of RecQ function is often accompanied by hyperrecombination caused by a lack of crossover suppression. In the Arabidopsis genome seven different RecQ genes are present. Two of them (AtRECQ4A and 4B) arose because of a recent duplication and are still nearly 70% identical on a protein level. Knockout of these genes leads to antagonistic phenotypes: the RECQ4A mutant shows sensitivity to DNA-damaging agents, enhanced homologous recombination (HR) and lethality in a mus81 background. Moreover, mutation of RECQ4A partially suppresses the lethal phenotype of an AtTOP3alpha mutant, a phenomenon that had previously been demonstrated for RecQ homologues of unicellular eukaryotes only. Together, these facts strongly suggest that in plants RECQ4A is functionally equivalent to SGS1 of Saccharomyces cerevisiae and the mammalian BLM protein. In stark contrast, mutants of the closely related RECQ4B are not mutagen-sensitive, not viable in a mus81 background, and unable to suppress the induced lethality caused by loss of TOP3. Moreover, they are strongly impaired in HR. Thus, AtRECQ4B is specifically required to promote but not to suppress crossovers, a role in which it differs from all eukaryotic RecQ homologues known

    The Dynamics of Behavioral Responses During a Crisis

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    This paper investigates the dynamics of behavioral changes during a crisis. We study this in the context of the first year of the Covid-19 pandemic, where behavioral responses were important in mitigating the costs of the pandemic. To identify behavioral responses to unanticipated and transient health risk shocks, we combine high-frequency cellphone mobility data with detailed incidence data in Germany. Using an event-study design on local outbreaks, we find that county-level mobility immediately and significantly decreased by about 2.5% in response to an outbreak independent of non-pharmaceutical interventions. We also find that the reproduction rate decreased by about 17% in response to a local outbreak. Both behavioral responses are quite persistent even after the relative health risk has dissipated. By the time of the second wave, the behavioral response to a second or third shock is small or negligible. Our results demonstrate the importance of (1) integrating behavioral persistence in models used to study behavior and policies that change behavior, (2) the effectiveness of policies that provide high-frequency localized information on health risks, and (3) the potential persistence of behavioral changes after the Covid-19 pandemic has passed

    Local bifurcations in differential equations with state-dependent delay

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    This is the author accepted manuscript. The final version is available from AIP Publishing via the DOI in this record.A common task when analysing dynamical systems is the determination of normal forms near local bifurcations of equilibria. As most of these normal forms have been classified and analysed, finding which particular class of normal form one encounters in a numerical bifurcation study guides follow-up computations. This paper builds on normal form algorithms for equilibria of delay differential equations with constant delay that were developed and implemented in DDE-Biftool recently. We show how one can extend these methods to delay-differential equations with state-dependent delay (sd-DDEs). Since higher degrees of regularity of local center manifolds are still open for sd-DDEs, we give an independent (still only partial) argument which phenomena from the truncated normal must persist in the full sd-DDE. In particular, we show that all invariant manifolds with a sufficient degree of normal hyperbolicity predicted by the normal form exist also in the full sd-DDEJ.S. gratefully acknowledges the financial support of the EPSRC via grants EP/N023544/1 and EP/N014391/1. J.S. has also received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement number 643073
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