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  • 1
    Publikationsdatum: 2015-09-22
    Beschreibung: The phenomenon of male sterility in interspecies hybrids has been observed for over a century, however, few genes influencing this recurrent phenotype have been identified. Genetic investigations have been primarily limited to a small number of model organisms, thus limiting our understanding of the underlying molecular basis of this well-documented "rule of speciation." We utilized two interspecies hybrid cat breeds in a genome-wide association study employing the Illumina 63 K single-nucleotide polymorphism array. Collectively, we identified eight autosomal genes/gene regions underlying associations with hybrid male sterility (HMS) involved in the function of the blood-testis barrier, gamete structural development, and transcriptional regulation. We also identified several candidate hybrid sterility regions on the X chromosome, with most residing in close proximity to complex duplicated regions. Differential gene expression analyses revealed significant chromosome-wide upregulation of X chromosome transcripts in testes of sterile hybrids, which were enriched for genes involved in chromatin regulation of gene expression. Our expression results parallel those reported in Mus hybrids, supporting the "Large X-Effect" in mammalian HMS and the potential epigenetic basis for this phenomenon. These results support the value of the interspecies feline model as a powerful tool for comparison to rodent models of HMS, demonstrating unique aspects and potential commonalities that underpin mammalian reproductive isolation.
    Print ISSN: 0737-4038
    Digitale ISSN: 1537-1719
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 2
  • 3
    Publikationsdatum: 2015-09-27
    Beschreibung: We present early results from the JCMT (James Clerk Maxwell Telescope) Plane Survey (JPS), which has surveyed the northern inner Galactic plane between longitudes  = 7° and  = 63° in the 850-μm continuum with SCUBA-2 (Submm Common-User Bolometer Array 2), as part of the JCMT Legacy Survey programme. Data from the  = 30° survey region, which contains the massive-star-forming regions W43 and G29.96, are analysed after approximately 40 per cent of the observations had been completed. The pixel-to-pixel noise is found to be 19 mJy beam –1 after a smooth over the beam area, and the projected equivalent noise levels in the final survey are expected to be around 10 mJy beam –1 . An initial extraction of compact sources was performed using the FellWalker method, resulting in the detection of 1029 sources above a 5 surface-brightness threshold. The completeness limits in these data are estimated to be around 0.2 Jy beam –1 (peak flux density) and 0.8 Jy (integrated flux density) and are therefore probably already dominated by source confusion in this relatively crowded section of the survey. The flux densities of extracted compact sources are consistent with those of matching detections in the shallower APEX (Atacama Pathfinder Experiment) Telescope Large Area Survey of the Galaxy (ATLASGAL) survey. We analyse the virial and evolutionary state of the detected clumps in the W43 star-forming complex and find that they appear younger than the Galactic-plane average.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 4
    Publikationsdatum: 2015-05-02
    Beschreibung: We present a Radio Recombination Line (RRL) survey of the Galactic plane from the H i Parkes All-sky Survey and associated Zone of Avoidance survey, which mapped the region l  = 196°–0°–52° and | b | ≤ 5° at 1.4 GHz and 14.4 arcmin resolution. We combine three RRLs, H168α, H167α, and H166α to derive fully sampled maps of the diffuse ionized emission along the inner Galactic plane. The velocity information, at a resolution of 20 km s –1 , allows us to study the spatial distribution of the ionized gas and compare it with that of the molecular gas, as traced by CO. The longitude–velocity diagram shows that the RRL emission is mostly associated with CO gas from the molecular ring and is concentrated within the inner 30° of longitude. A map of the free–free emission in this region of the Galaxy is derived from the line-integrated RRL emission, assuming an electron temperature gradient with Galactocentric radius of 496 ± 100 K kpc –1 . Based on the thermal continuum map, we extracted a catalogue of 317 compact (15 arcmin) sources, with flux densities, sizes, and velocities. We report the first RRL observations of the southern ionized lobe in the Galactic Centre. The line profiles and velocities suggest that this degree-scale structure is in rotation. We also present new evidence of diffuse ionized gas in the 3-kpc arm. Helium and carbon RRLs are detected in this survey. The He line is mostly observed towards H ii regions, whereas the C line is also detected further away from the source of ionization. These data represent the first observations of diffuse C RRLs in the Galactic plane at a frequency of 1.4 GHz.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 5
    Publikationsdatum: 2015-05-12
    Beschreibung: Motivation: Proteins underlay the functioning of a cell and the wiring of proteins in protein–protein interaction network (PIN) relates to their biological functions. Proteins with similar wiring in the PIN ( topology around them) have been shown to have similar functions. This property has been successfully exploited for predicting protein functions. Topological similarity is also used to guide network alignment algorithms that find similarly wired proteins between PINs of different species; these similarities are used to transfer annotation across PINs, e.g. from model organisms to human. To refine these functional predictions and annotation transfers, we need to gain insight into the variability of the topology-function relationships. For example, a function may be significantly associated with specific topologies, while another function may be weakly associated with several different topologies. Also, the topology-function relationships may differ between different species. Results: To improve our understanding of topology-function relationships and of their conservation among species, we develop a statistical framework that is built upon canonical correlation analysis. Using the graphlet degrees to represent the wiring around proteins in PINs and gene ontology (GO) annotations to describe their functions, our framework: (i) characterizes statistically significant topology-function relationships in a given species, and (ii) uncovers the functions that have conserved topology in PINs of different species, which we term topologically orthologous functions. We apply our framework to PINs of yeast and human, identifying seven biological process and two cellular component GO terms to be topologically orthologous for the two organisms. Availability and implementation: http://bio-nets.doc.ic.ac.uk/goCCA.zip Contact: natasha@imperial.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Digitale ISSN: 1460-2059
    Thema: Biologie , Informatik , Medizin
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 6
    Publikationsdatum: 2015-01-24
    Beschreibung: Delivery of siRNA is a key hurdle to realizing the therapeutic promise of RNAi. By targeting internalizing cell surface antigens, antibody–siRNA complexes provide a possible solution. However, initial reports of antibody–siRNA complexes relied on non-specific charged interactions and have not been broadly applicable. To assess and improve this delivery method, we built on an industrial platform of therapeutic antibodies called THIOMABs, engineered to enable precise covalent coupling of siRNAs. We report that such coupling generates monomeric antibody–siRNA conjugates (ARCs) that retain antibody and siRNA activities. To broadly assess this technology, we generated a battery of THIOMABs against seven targets that use multiple internalization routes, enabling systematic manipulation of multiple parameters that impact delivery. We identify ARCs that induce targeted silencing in vitro and extend tests to target prostate carcinoma cells following systemic administration in mouse models. However, optimal silencing was restricted to specific conditions and only observed using a subset of ARCs. Trafficking studies point to ARC entrapment in endocytic compartments as a limiting factor, independent of the route of antigen internalization. Our broad characterization of multiple parameters using therapeutic-grade conjugate technology provides a thorough assessment of this delivery technology, highlighting both examples of success as well as remaining challenges.
    Print ISSN: 0305-1048
    Digitale ISSN: 1362-4962
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 7
    Publikationsdatum: 2015-12-28
    Beschreibung: Porphyromonads play an important role in human periodontal disease and recently have been shown to be highly prevalent in canine mouths. Porphyromonas cangingivalis is the most prevalent canine oral bacterial species in both plaque from healthy gingiva and plaque from dogs with early periodontitis. The ability of P. cangingivalis to flourish in the different environmental conditions characterized by these two states suggests a degree of metabolic flexibility. To characterize the genes responsible for this, the genomes of 32 isolates (including 18 newly sequenced and assembled) from 18 Porphyromonad species from dogs, humans, and other mammals were compared. Phylogenetic trees inferred using core genes largely matched previous findings; however, comparative genomic analysis identified several genes and pathways relating to heme synthesis that were present in P. cangingivalis but not in other Porphyromonads. Porphyromonas cangingivalis has a complete protoporphyrin IX synthesis pathway potentially allowing it to synthesize its own heme unlike pathogenic Porphyromonads such as Porphyromonas gingivalis that acquire heme predominantly from blood. Other pathway differences such as the ability to synthesize siroheme and vitamin B12 point to enhanced metabolic flexibility for P. cangingivalis , which may underlie its prevalence in the canine oral cavity.
    Digitale ISSN: 1759-6653
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 8
    Publikationsdatum: 2015-05-30
    Beschreibung: Studies of antagonistic coevolution between hosts and parasites typically focus on resistance and infectivity traits. However, coevolution could also have genome-wide effects on the hosts due to pleiotropy, epistasis, or selection for evolvability. Here, we investigate these effects in the bacterium Pseudomonas fluorescens SBW25 during approximately 400 generations of evolution in the presence or absence of bacteriophage (coevolution or evolution treatments, respectively). Coevolution resulted in variable phage resistance, lower competitive fitness in the absence of phages, and greater genome-wide divergence both from the ancestor and between replicates, in part due to the evolution of increased mutation rates. Hosts from coevolution and evolution treatments had different suites of mutations. A high proportion of mutations observed in coevolved hosts were associated with a known phage target binding site, the lipopolysaccharide (LPS), and correlated with altered LPS length and phage resistance. Mutations in evolved bacteria were correlated with higher fitness in the absence of phages. However, the benefits of these growth-promoting mutations were completely lost when these bacteria were subsequently coevolved with phages, indicating that they were not beneficial in the presence of resistance mutations (consistent with negative epistasis). Our results show that in addition to affecting genome-wide evolution in loci not obviously linked to parasite resistance, coevolution can also constrain the acquisition of mutations beneficial for growth in the abiotic environment.
    Print ISSN: 0737-4038
    Digitale ISSN: 1537-1719
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 9
    Publikationsdatum: 2015-06-24
    Beschreibung: Massive early-type galaxies (ETGs) commonly have gas discs which are kinematically misaligned with the stellar component. These discs feel a torque from the stars and the angular momentum vectors are expected to align quickly. We present results on the evolution of a misaligned gas disc in a cosmological simulation of a massive ETG from the feedback in realistic environments project. This galaxy experiences a merger which, together with a strong galactic wind, removes most of the original gas disc. The galaxy subsequently reforms a gas disc through accretion of cold gas, but it is initially 120° misaligned with the stellar rotation axis. This misalignment persists for about 2 Gyr before the gas–star misalignment angle drops below 20°. The time it takes for the gaseous and stellar components to align is much longer than previously thought, because the gas disc is accreting a significant amount of mass for about 1.5 Gyr after the merger, during which the angular momentum change induced by accreted gas dominates over that induced by stellar torques. Once the gas accretion rate has decreased sufficiently, the gas disc decouples from the surrounding halo gas and realigns with the stellar component in about six dynamical times. During the late evolution of the misaligned gas disc, the centre aligns faster than the outskirts, resulting in a warped disc. We discuss the observational consequences of the long survival of our misaligned gas disc and how our results can be used to calibrate merger rate estimates from observed gas misalignments.
    Print ISSN: 0035-8711
    Digitale ISSN: 1365-2966
    Thema: Physik
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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  • 10
    Publikationsdatum: 2015-07-18
    Beschreibung: Divergence in gene regulation is hypothesized to underlie much of phenotypic evolution, but the role of natural selection in shaping the molecular phenotype of gene expression continues to be debated. To resolve the mode of gene expression, evolution requires accessible theoretical predictions for the effect of selection over long timescales. Evolutionary quantitative genetic models of phenotypic evolution can provide such predictions, yet those predictions depend on the underlying hypotheses about the distributions of mutational and selective effects that are notoriously difficult to disentangle. Here, we draw on diverse genomic data sets including expression profiles of natural genetic variation and mutation accumulation lines, empirical estimates of genomic mutation rates, and inferences of genetic architecture to differentiate contrasting hypotheses for the roles of stabilizing selection and mutation in shaping natural expression variation. Our analysis suggests that gene expression evolves in a domain of phenotype space well fit by the House-of-Cards (HC) model. Although the strength of selection inferred is sensitive to the number of loci controlling gene expression, the model is not. The consistency of these results across evolutionary time from budding yeast through fruit fly implies that this model is general and that mutational effects on gene expression are relatively large. Empirical estimates of the genetic architecture of gene expression traits imply that selection provides modest constraints on gene expression levels for most genes, but that the potential for regulatory evolution is high. Our prediction using data from laboratory environments should encourage the collection of additional data sets allowing for more nuanced parameterizations of HC models for gene expression.
    Print ISSN: 0737-4038
    Digitale ISSN: 1537-1719
    Thema: Biologie
    Publiziert von Oxford University Press
    Standort Signatur Erwartet Verfügbarkeit
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