130 research outputs found
Chemical Optimization of Selective Pseudomonas aeruginosa LasB Elastase Inhibitors and Their Impact on LasB-Mediated Activation of IL-1β in Cellular and Animal Infection Models
LasB elastase is a broad-spectrum exoprotease and a key virulence factor of Pseudomonas aeruginosa, a major pathogen causing lung damage and inflammation in acute and chronic respiratory infections. Here, we describe the chemical optimization of specific LasB inhibitors with druglike properties and investigate their impact in cellular and animal models of P. aeruginosa infection. Competitive inhibition of LasB was demonstrated through structural and kinetic studies. In vitro LasB inhibition was confirmed with respect to several host target proteins, namely, elastin, IgG, and pro-IL-1 beta. Furthermore, inhibition of LasBmediated IL-1 beta activation was demonstrated in macrophage and mouse lung infection models. In mice, intravenous administration of inhibitors also resulted in reduced bacterial numbers at 24 h. These highly potent, selective, and soluble LasB inhibitors constitute valuable tools to study the proinflammatory impact of LasB in P. aeruginosa infections and, most importantly, show clear potential for the clinical development of a novel therapy for life-threatening respiratory infections caused by this opportunistic pathogen
Planetary population synthesis
In stellar astrophysics, the technique of population synthesis has been
successfully used for several decades. For planets, it is in contrast still a
young method which only became important in recent years because of the rapid
increase of the number of known extrasolar planets, and the associated growth
of statistical observational constraints. With planetary population synthesis,
the theory of planet formation and evolution can be put to the test against
these constraints. In this review of planetary population synthesis, we first
briefly list key observational constraints. Then, the work flow in the method
and its two main components are presented, namely global end-to-end models that
predict planetary system properties directly from protoplanetary disk
properties and probability distributions for these initial conditions. An
overview of various population synthesis models in the literature is given. The
sub-models for the physical processes considered in global models are
described: the evolution of the protoplanetary disk, the planets' accretion of
solids and gas, orbital migration, and N-body interactions among concurrently
growing protoplanets. Next, typical population synthesis results are
illustrated in the form of new syntheses obtained with the latest generation of
the Bern model. Planetary formation tracks, the distribution of planets in the
mass-distance and radius-distance plane, the planetary mass function, and the
distributions of planetary radii, semimajor axes, and luminosities are shown,
linked to underlying physical processes, and compared with their observational
counterparts. We finish by highlighting the most important predictions made by
population synthesis models and discuss the lessons learned from these
predictions - both those later observationally confirmed and those rejected.Comment: 47 pages, 12 figures. Invited review accepted for publication in the
'Handbook of Exoplanets', planet formation section, section editor: Ralph
Pudritz, Springer reference works, Juan Antonio Belmonte and Hans Deeg, Ed
Design and Performance of a Novel Low Energy Multi-Species Beamline for the ALPHA Antihydrogen Experiment
The ALPHA Collaboration, based at the CERN Antiproton Decelerator, has
recently implemented a novel beamline for low-energy ( 100 eV)
positron and antiproton transport between cylindrical Penning traps that have
strong axial magnetic fields. Here, we describe how a combination of
semianalytical and numerical calculations were used to optimise the layout and
design of this beamline. Using experimental measurements taken during the
initial commissioning of the instrument, we evaluate its performance and
validate the models used for its development. By combining data from a range of
sources, we show that the beamline has a high transfer efficiency, and estimate
that the percentage of particles captured in the experiments from each bunch is
(78 3)% for up to antiprotons, and (71 5)% for bunches of
up to positrons.Comment: 15 pages, 15 figure
The Drosophila melanogaster Genetic Reference Panel
A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics
Connecting Planetary Composition with Formation
The rapid advances in observations of the different populations of
exoplanets, the characterization of their host stars and the links to the
properties of their planetary systems, the detailed studies of protoplanetary
disks, and the experimental study of the interiors and composition of the
massive planets in our solar system provide a firm basis for the next big
question in planet formation theory. How do the elemental and chemical
compositions of planets connect with their formation? The answer to this
requires that the various pieces of planet formation theory be linked together
in an end-to-end picture that is capable of addressing these large data sets.
In this review, we discuss the critical elements of such a picture and how they
affect the chemical and elemental make up of forming planets. Important issues
here include the initial state of forming and evolving disks, chemical and dust
processes within them, the migration of planets and the importance of planet
traps, the nature of angular momentum transport processes involving turbulence
and/or MHD disk winds, planet formation theory, and advanced treatments of disk
astrochemistry. All of these issues affect, and are affected by the chemistry
of disks which is driven by X-ray ionization of the host stars. We discuss how
these processes lead to a coherent end-to-end model and how this may address
the basic question.Comment: Invited review, accepted for publication in the 'Handbook of
Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018). 46 pages, 10
figure
The Experiences of Late-diagnosed Women with Autism Spectrum Conditions: An Investigation of the Female Autism Phenotype
Structural variants exhibit widespread allelic heterogeneity and shape variation in complex traits
This work is licensed under a Creative Commons Attribution 4.0 International License.It has been hypothesized that individually-rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits. Here we identified more than 20,000 euchromatic SVs from 14 Drosophila melanogaster genome assemblies, of which ~40% are invisible to high specificity short-read genotyping approaches. SVs are common, with 31.5% of diploid individuals harboring a SV in genes larger than 5kb, and 24% harboring multiple SVs in genes larger than 10kb. SV minor allele frequencies are rarer than amino acid polymorphisms, suggesting that SVs are more deleterious. We show that a number of functionally important genes harbor previously hidden structural variants likely to affect complex phenotypes. Furthermore, SVs are overrepresented in candidate genes associated with quantitative trait loci mapped using the Drosophila Synthetic Population Resource. We conclude that SVs are ubiquitous, frequently constitute a heterogeneous allelic series, and can act as rare alleles of large effect
Direct discovery of the inner exoplanet in the HD206893 system. Evidence for deuterium burning in a planetary-mass companion
Long term precise radial velocity (RV) monitoring of the nearby star
HD206893, as well as anomalies in the system proper motion, have suggested the
presence of an additional, inner companion in the system. Here we describe the
results of a multi-epoch search for the companion responsible for this RV drift
and proper motion anomaly using the VLTI/GRAVITY instrument. Utilizing
information from ongoing precision RV measurements with the HARPS spectrograph,
as well as Gaia host star astrometry, we report a high significance detection
of the companion HD206893c over three epochs, with clear evidence for Keplerian
orbital motion. Our astrometry with 50-100 arcsec precision afforded
by GRAVITY allows us to derive a dynamical mass of 12.7 M and an orbital separation of 3.53 au for HD206893c. Our
fits to the orbits of both companions in the system utilize both Gaia
astrometry and RVs to also provide a precise dynamical estimate of the
previously uncertain mass of the B component, and therefore derive an age of
Myr. We find that theoretical atmospheric/evolutionary models
incorporating deuterium burning for HD206893c, parameterized by cloudy
atmospheres provide a good simultaneous fit to the luminosity of both HD206893B
and c. In addition to utilizing long-term RV information, this effort is an
early example of a direct imaging discovery of a bona fide exoplanet that was
guided in part with Gaia astrometry. Utilizing Gaia astrometry is expected to
be one of the primary techniques going forward to identify and characterize
additional directly imaged planets. Lastly, this discovery is another example
of the power of optical interferometry to directly detect and characterize
extrasolar planets where they form at ice-line orbital separations of 2-4\,au.Comment: Accepted to A&
A model species for agricultural pest genomics: the genome of the Colorado potato beetle, Leptinotarsa decemlineata (Coleoptera: Chrysomelidae)
The Colorado potato beetle is one of the most challenging agricultural pests to manage. It has shown a spectacular ability to adapt to a variety of solanaceaeous plants and variable climates during its global invasion, and, notably, to rapidly evolve insecticide resistance. To examine evidence of rapid evolutionary change, and to understand the genetic basis of herbivory and insecticide resistance, we tested for structural and functional genomic changes relative to other arthropod species using genome sequencing, transcriptomics, and community annotation. Two factors that might facilitate rapid evolutionary change include transposable elements, which comprise at least 17% of the genome and are rapidly evolving compared to other Coleoptera, and high levels of nucleotide diversity in rapidly growing pest populations. Adaptations to plant feeding are evident in gene expansions and differential expression of digestive enzymes in gut tissues, as well as expansions of gustatory receptors for bitter tasting. Surprisingly, the suite of genes involved in insecticide resistance is similar to other beetles. Finally, duplications in the RNAi pathway might explain why Leptinotarsa decemlineata has high sensitivity to dsRNA. The L. decemlineata genome provides opportunities to investigate a broad range of phenotypes and to develop sustainable methods to control this widely successful pest
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