408 research outputs found
Coupled dark matter-dark energy in light of near Universe observations
Cosmological analysis based on currently available observations are unable to
rule out a sizeable coupling among the dark energy and dark matter fluids. We
explore a variety of coupled dark matter-dark energy models, which satisfy
cosmic microwave background constraints, in light of low redshift and near
universe observations. We illustrate the phenomenology of different classes of
dark coupling models, paying particular attention in distinguishing between
effects that appear only on the expansion history and those that appear in the
growth of structure. We find that while a broad class of dark coupling models
are effectively models where general relativity (GR) is modified --and thus can
be probed by a combination of tests for the expansion history and the growth of
structure--, there is a class of dark coupling models where gravity is still
GR, but the growth of perturbations is, in principle modified. While this
effect is small in the specific models we have considered, one should bear in
mind that an inconsistency between reconstructed expansion history and growth
may not uniquely indicate deviations from GR. Our low redshift constraints
arise from cosmic velocities, redshift space distortions and dark matter
abundance in galaxy voids. We find that current data constrain the
dimensionless coupling to be |xi|<0.2, but prospects from forthcoming data are
for a significant improvement. Future, precise measurements of the Hubble
constant, combined with high-precision constraints on the growth of structure,
could provide the key to rule out dark coupling models which survive other
tests. We shall exploit as well weak equivalence principle violation arguments,
which have the potential to highly disfavour a broad family of coupled models.Comment: 34 pages, 6 figures; changes to match published versio
Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling
It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity is not observed in all patients treated with the anticancer drug irinotecan, and it has been suggested that this variability is a result of differences in the types and levels of gut bacterial β-glucuronidases (GUS). GUS enzymes promote drug toxicity by hydrolyzing the inactive drug-glucuronide conjugate back to the active drug, which damages the GI epithelium. Proteomics-based identification of the exact GUS enzymes responsible for drug reactivation from the complexity of the human microbiota has not been accomplished, however. Here, we discover the specific bacterial GUS enzymes that generate SN-38, the active and toxic metabolite of irinotecan, from human fecal samples using a unique activity-based protein profiling (ABPP) platform. We identify and quantify gut bacterial GUS enzymes from human feces with an ABPP-enabled proteomics pipeline and then integrate this information with ex vivo kinetics to pinpoint the specific GUS enzymes responsible for SN-38 reactivation. Furthermore, the same approach also reveals the molecular basis for differential gut bacterial GUS inhibition observed between human fecal samples. Taken together, this work provides an unprecedented technical and bioinformatics pipeline to discover the microbial enzymes responsible for specific reactions from the complexity of human feces. Identifying such microbial enzymes may lead to precision biomarkers and novel drug targets to advance the promise of personalized medicine.Bio-organic SynthesisMedical Biochemistr
Spallation reactions. A successful interplay between modeling and applications
The spallation reactions are a type of nuclear reaction which occur in space
by interaction of the cosmic rays with interstellar bodies. The first
spallation reactions induced with an accelerator took place in 1947 at the
Berkeley cyclotron (University of California) with 200 MeV deuterons and 400
MeV alpha beams. They highlighted the multiple emission of neutrons and charged
particles and the production of a large number of residual nuclei far different
from the target nuclei. The same year R. Serber describes the reaction in two
steps: a first and fast one with high-energy particle emission leading to an
excited remnant nucleus, and a second one, much slower, the de-excitation of
the remnant. In 2010 IAEA organized a worskhop to present the results of the
most widely used spallation codes within a benchmark of spallation models. If
one of the goals was to understand the deficiencies, if any, in each code, one
remarkable outcome points out the overall high-quality level of some models and
so the great improvements achieved since Serber. Particle transport codes can
then rely on such spallation models to treat the reactions between a light
particle and an atomic nucleus with energies spanning from few tens of MeV up
to some GeV. An overview of the spallation reactions modeling is presented in
order to point out the incomparable contribution of models based on basic
physics to numerous applications where such reactions occur. Validations or
benchmarks, which are necessary steps in the improvement process, are also
addressed, as well as the potential future domains of development. Spallation
reactions modeling is a representative case of continuous studies aiming at
understanding a reaction mechanism and which end up in a powerful tool.Comment: 59 pages, 54 figures, Revie
Extremal Bundles on Calabi-Yau Threefolds
We study constructions of stable holomorphic vector bundles on Calabi–Yau threefolds, especially those with exact anomaly cancellation which we call extremal. By going through the known databases we find that such examples are rare in general and can be ruled out for the spectral cover construction for all elliptic threefolds. We then introduce a general Hartshorne–Serre construction and use it to find extremal bundles of general ranks and study their stability, as well as computing their Chern numbers. Based on both existing and our new constructions, we revisit the DRY conjecture for the existence of stable sheaves on Calabi–threefolds, and provide theoretical and numerical evidence for its correctness. Our construction can be easily generalized to bundles with no extremal conditions imposed
Species and biotype distribution of thermotolerant Campylobacters in animal reservoirs in Southern Chile
Sedimentary cycles in a Mesoproterozoic aeolian erg-margin succession: Mangabeira Formation, Espinhaço Supergroup, Brazil
Aeolian systems were abundant and widespread in the early Proterozoic, post-2.2 Ga. However, the majority of aeolian successions of such great age are intensely deformed and are preserved only in a fragmentary state meaning that, hitherto, few attempts have been made to apply a sequence stratigraphic approach to determine mechanisms of aeolian construction, accumulation and preservation in such systems. The Mangabeira Formation is a well preserved Mesoproterozoic erg successions covering part of the São Francisco Craton, northeastern Brazil. The lower unit of the Mangabeira Formation (~ 500 m thick) comprises aeolian deposits of dune, interdune, and sand-sheet origin, as well as some of waterlain origin. These deposits are organized into vertically stacked depositional cycles, each 6 to 20 m thick, and characterized by aeolian sandsheet and waterlain deposits succeeded by aeolian dune and interdune deposits indicative of a drying-upward trend. Aeolian cross-strata exhibit a mean dip direction to the north. Each of these cycles likely arose in response to climatic oscillation from relatively humid to arid conditions, possibly related to orbital forcing. The lower unit of the Mangabeira Formation comprises up to 14 erg sequences. The accumulation and preservation of each was determined by the relative rate of water-table rise and the availability of sand for aeolian transport, both of which changed through time, resulting in the preservation of a succession of repeated drying-upward cycles
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Energetic particle influence on the Earth's atmosphere
This manuscript gives an up-to-date and comprehensive overview of the effects of energetic particle precipitation (EPP) onto the whole atmosphere, from the lower thermosphere/mesosphere through the stratosphere and troposphere, to the surface. The paper summarizes the different sources and energies of particles, principally
galactic cosmic rays (GCRs), solar energetic particles (SEPs) and energetic electron precipitation (EEP). All the proposed mechanisms by which EPP can affect the atmosphere
are discussed, including chemical changes in the upper atmosphere and lower thermosphere, chemistry-dynamics feedbacks, the global electric circuit and cloud formation. The role of energetic particles in Earth’s atmosphere is a multi-disciplinary problem that requires expertise from a range of scientific backgrounds. To assist with this synergy, summary tables are provided, which are intended to evaluate the level of current knowledge of the effects of energetic particles on processes in the entire atmosphere
A selective ATP-binding cassette subfamily G member 2 efflux inhibitor revealed via high-throughput flow cytometry
Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)-driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented
Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.Bio-organic Synthesi
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