245 research outputs found
Duality Invariant Actions and Generalised Geometry
We construct the non-linear realisation of the semi-direct product of E(11)
and its first fundamental representation at lowest order and appropriate to
spacetime dimensions four to seven. This leads to a non-linear realisation of
the duality groups and introduces fields that depend on a generalised space
which possess a generalised vielbein. We focus on the part of the generalised
space on which the duality groups alone act and construct an invariant action.Comment: 59 pages (typos fixed and added comments
Identification of novel subgroup a variants with enhanced receptor binding and replicative capacity in primary isolates of anaemogenic strains of feline leukaemia virus
<b>BACKGROUND:</b>
The development of anaemia in feline leukaemia virus (FeLV)-infected cats is associated with the emergence of a novel viral subgroup, FeLV-C. FeLV-C arises from the subgroup that is transmitted, FeLV-A, through alterations in the amino acid sequence of the receptor binding domain (RBD) of the envelope glycoprotein that result in a shift in the receptor usage and the cell tropism of the virus. The factors that influence the transition from subgroup A to subgroup C remain unclear, one possibility is that a selective pressure in the host drives the acquisition of mutations in the RBD, creating A/C intermediates with enhanced abilities to interact with the FeLV-C receptor, FLVCR. In order to understand further the emergence of FeLV-C in the infected cat, we examined primary isolates of FeLV-C for evidence of FeLV-A variants that bore mutations consistent with a gradual evolution from FeLV-A to FeLV-C.<p></p>
<b>RESULTS:</b>
Within each isolate of FeLV-C, we identified variants that were ostensibly subgroup A by nucleic acid sequence comparisons, but which bore mutations in the RBD. One such mutation, N91D, was present in multiple isolates and when engineered into a molecular clone of the prototypic FeLV-A (Glasgow-1), enhanced replication was noted in feline cells. Expression of the N91D Env on murine leukaemia virus (MLV) pseudotypes enhanced viral entry mediated by the FeLV-A receptor THTR1 while soluble FeLV-A Env bearing the N91D mutation bound more efficiently to mouse or guinea pig cells bearing the FeLV-A and -C receptors. Long-term in vitro culture of variants bearing the N91D substitution in the presence of anti-FeLV gp70 antibodies did not result in the emergence of FeLV-C variants, suggesting that additional selective pressures in the infected cat may drive the subsequent evolution from subgroup A to subgroup C.<p></p>
<b>CONCLUSIONS:</b>
Our data support a model in which variants of FeLV-A, bearing subtle differences in the RBD of Env, may be predisposed towards enhanced replication in vivo and subsequent conversion to FeLV-C. The selection pressures in vivo that drive the emergence of FeLV-C in a proportion of infected cats remain to be established
Identification and functional characterisation of CRK12:CYC9, a novel cyclin-dependent kinase (CDK)-cyclin complex in Trypanosoma brucei
The protozoan parasite, Trypanosoma brucei, is spread by the tsetse fly and causes trypanosomiasis in humans and animals. Both the life cycle and cell cycle of the parasite are complex. Trypanosomes have eleven cdc2-related kinases (CRKs) and ten cyclins, an unusually large number for a single celled organism. To date, relatively little is known about the function of many of the CRKs and cyclins, and only CRK3 has previously been shown to be cyclin-dependent in vivo. Here we report the identification of a previously uncharacterised CRK:cyclin complex between CRK12 and the putative transcriptional cyclin, CYC9. CRK12:CYC9 interact to form an active protein kinase complex in procyclic and bloodstream T. brucei. Both CRK12 and CYC9 are essential for the proliferation of bloodstream trypanosomes in vitro, and we show that CRK12 is also essential for survival of T. brucei in a mouse model, providing genetic validation of CRK12:CYC9 as a novel drug target for trypanosomiasis. Further, functional characterisation of CRK12 and CYC9 using RNA interference reveals roles for these proteins in endocytosis and cytokinesis, respectively
Planet Populations as a Function of Stellar Properties
Exoplanets around different types of stars provide a window into the diverse
environments in which planets form. This chapter describes the observed
relations between exoplanet populations and stellar properties and how they
connect to planet formation in protoplanetary disks. Giant planets occur more
frequently around more metal-rich and more massive stars. These findings
support the core accretion theory of planet formation, in which the cores of
giant planets form more rapidly in more metal-rich and more massive
protoplanetary disks. Smaller planets, those with sizes roughly between Earth
and Neptune, exhibit different scaling relations with stellar properties. These
planets are found around stars with a wide range of metallicities and occur
more frequently around lower mass stars. This indicates that planet formation
takes place in a wide range of environments, yet it is not clear why planets
form more efficiently around low mass stars. Going forward, exoplanet surveys
targeting M dwarfs will characterize the exoplanet population around the lowest
mass stars. In combination with ongoing stellar characterization, this will
help us understand the formation of planets in a large range of environments.Comment: Accepted for Publication in the Handbook of Exoplanet
Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters
Recent progress in studies of globular clusters has shown that they are not
simple stellar populations, being rather made of multiple generations. Evidence
stems both from photometry and spectroscopy. A new paradigm is then arising for
the formation of massive star clusters, which includes several episodes of star
formation. While this provides an explanation for several features of globular
clusters, including the second parameter problem, it also opens new
perspectives about the relation between globular clusters and the halo of our
Galaxy, and by extension of all populations with a high specific frequency of
globular clusters, such as, e.g., giant elliptical galaxies. We review progress
in this area, focusing on the most recent studies. Several points remain to be
properly understood, in particular those concerning the nature of the polluters
producing the abundance pattern in the clusters and the typical timescale, the
range of cluster masses where this phenomenon is active, and the relation
between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review
Optimal assignment methods for ligand-based virtual screening
<p>Abstract</p> <p>Background</p> <p>Ligand-based virtual screening experiments are an important task in the early drug discovery stage. An ambitious aim in each experiment is to disclose active structures based on new scaffolds. To perform these "scaffold-hoppings" for individual problems and targets, a plethora of different similarity methods based on diverse techniques were published in the last years. The optimal assignment approach on molecular graphs, a successful method in the field of quantitative structure-activity relationships, has not been tested as a ligand-based virtual screening method so far.</p> <p>Results</p> <p>We evaluated two already published and two new optimal assignment methods on various data sets. To emphasize the "scaffold-hopping" ability, we used the information of chemotype clustering analyses in our evaluation metrics. Comparisons with literature results show an improved early recognition performance and comparable results over the complete data set. A new method based on two different assignment steps shows an increased "scaffold-hopping" behavior together with a good early recognition performance.</p> <p>Conclusion</p> <p>The presented methods show a good combination of chemotype discovery and enrichment of active structures. Additionally, the optimal assignment on molecular graphs has the advantage to investigate and interpret the mappings, allowing precise modifications of internal parameters of the similarity measure for specific targets. All methods have low computation times which make them applicable to screen large data sets.</p
Use of Cis-[18F]Fluoro-Proline for Assessment of Exercise-Related Collagen Synthesis in Musculoskeletal Connective Tissue
Protein turnover in collagen rich tissue is influenced by exercise, but can only with difficulty be studied in vivo due to use of invasive procedure. The present study was done to investigate the possibility of applying the PET-tracer, cis-[18F]fluoro-proline (cis-Fpro), for non-invasive assessment of collagen synthesis in rat musculoskeletal tissues at rest and following short-term (3 days) treadmill running. Musculoskeletal collagen synthesis was studied in rats at rest and 24 h post-exercise. At each session, rats were PET scanned at two time points following injection of cis-FPro: (60 and 240 min p.i). SUV were calculated for Achilles tendon, calf muscle and tibial bone. The PET-derived results were compared to mRNA expression of collagen type I and III. Tibial bone had the highest SUV that increased significantly (p<0.001) from the early (60 min) to the late (240 min) PET scan, while SUV in tendon and muscle decreased (p<0.001). Exercise had no influence on SUV, which was contradicted by an increased gene expression of collagen type I and III in muscle and tendon. The clearly, visible uptake of cis-Fpro in the collagen-rich musculoskeletal tissues is promising for multi-tissue studies in vivo. The tissue-specific differences with the highest basal uptake in bone are in accordance with earlier studies relying on tissue incorporation of isotopic-labelled proline. A possible explanation of the failure to demonstrate enhanced collagen synthesis following exercise, despite augmented collagen type I and III transcription, is that SUV calculations are not sensitive enough to detect minor changes in collagen synthesis. Further studies including kinetic compartment modeling must be performed to establish whether cis-Fpro can be used for non-invasive in-vivo assessment of exercise-induced changes in musculoskeletal collagen synthesis
Autoacetylation of the Ralstonia solanacearum Effector PopP2 Targets a Lysine Residue Essential for RRS1-R-Mediated Immunity in Arabidopsis
Type III effector proteins from bacterial pathogens manipulate components of host immunity to suppress defence responses and promote pathogen development. In plants, host proteins targeted by some effectors called avirulence proteins are surveyed by plant disease resistance proteins referred to as “guards”. The Ralstonia solanacearum effector protein PopP2 triggers immunity in Arabidopsis following its perception by the RRS1-R resistance protein. Here, we show that PopP2 interacts with RRS1-R in the nucleus of living plant cells. PopP2 belongs to the YopJ-like family of cysteine proteases, which share a conserved catalytic triad that includes a highly conserved cysteine residue. The catalytic cysteine mutant PopP2-C321A is impaired in its avirulence activity although it is still able to interact with RRS1-R. In addition, PopP2 prevents proteasomal degradation of RRS1-R, independent of the presence of an integral PopP2 catalytic core. A liquid chromatography/tandem mass spectrometry analysis showed that PopP2 displays acetyl-transferase activity leading to its autoacetylation on a particular lysine residue, which is well conserved among all members of the YopJ family. These data suggest that this lysine residue may correspond to a key binding site for acetyl-coenzyme A required for protein activity. Indeed, mutation of this lysine in PopP2 abolishes RRS1-R-mediated immunity. In agreement with the guard hypothesis, our results favour the idea that activation of the plant immune response by RRS1-R depends not only on the physical interaction between the two proteins but also on its perception of PopP2 enzymatic activity
The Cyst Nematode SPRYSEC Protein RBP-1 Elicits Gpa2- and RanGAP2-Dependent Plant Cell Death
Plant NB-LRR proteins confer robust protection against microbes and metazoan
parasites by recognizing pathogen-derived avirulence (Avr) proteins that are
delivered to the host cytoplasm. Microbial Avr proteins usually function as
virulence factors in compatible interactions; however, little is known about the
types of metazoan proteins recognized by NB-LRR proteins and their relationship
with virulence. In this report, we demonstrate that the secreted protein RBP-1
from the potato cyst nematode Globodera pallida elicits defense
responses, including cell death typical of a hypersensitive response (HR),
through the NB-LRR protein Gpa2. Gp-Rbp-1 variants from
G. pallida populations both virulent and avirulent to
Gpa2 demonstrated a high degree of polymorphism, with
positive selection detected at numerous sites. All Gp-RBP-1
protein variants from an avirulent population were recognized by Gpa2, whereas
virulent populations possessed Gp-RBP-1 protein variants both
recognized and non-recognized by Gpa2. Recognition of Gp-RBP-1
by Gpa2 correlated to a single amino acid polymorphism at position 187 in the
Gp-RBP-1 SPRY domain. Gp-RBP-1 expressed
from Potato virus X elicited Gpa2-mediated defenses that required Ran
GTPase-activating protein 2 (RanGAP2), a protein known to interact with the Gpa2
N terminus. Tethering RanGAP2 and Gp-RBP-1 variants via fusion
proteins resulted in an enhancement of Gpa2-mediated responses. However,
activation of Gpa2 was still dependent on the recognition specificity conferred
by amino acid 187 and the Gpa2 LRR domain. These results suggest a two-tiered
process wherein RanGAP2 mediates an initial interaction with pathogen-delivered
Gp-RBP-1 proteins but where the Gpa2 LRR determines which
of these interactions will be productive
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