556 research outputs found
The Trypanosome Rab-Related Proteins RabX1 and RabX2 Play No Role in IntraCellular Trafficking but May Be Involved in Fly Infectivity
BACKGROUND: Rab GTPases constitute the largest subgroup of the Ras superfamily and are primarily involved in vesicle targeting. The full extent of Rab family function is unexplored. Several divergent Rab-like proteins are known but few have been characterized. In Trypanosoma brucei there are sixteen Rab genes, but RabX1, RabX2 and RabX3 are divergent within canonical sequence regions. Where known, trypanosome Rab functions are broadly conserved when orthologous relationships may be robustly established, but specific functions for RabX1, X2 and X3 have yet to be determined. RabX1 and RabX2 originated via tandem duplication and subcellular localization places RabX1 at the endoplasmic reticulum, while RabX2 is at the Golgi complex, suggesting distinct functions. We wished to determine whether RabX1 and RabX2 are involved in vesicle transport or other cellular processes. METHODOLOGY/PRINCIPAL FINDINGS: Using comparative genomics we find that RabX1 and RabX2 are restricted to trypanosomatids. Gene knockout indicates that RabX1 and RabX2 are non-essential. Simultaneous RNAi knockdown of both RabX1 and RabX2, while partial, was also non-lethal and may suggest non-redundant function, consistent with the distinct locations of the proteins. Analysis of the knockout cell lines unexpectedly failed to uncover a defect in exocytosis, endocytosis or in the morphology or location of multiple markers for the endomembrane system, suggesting that neither RabX1 nor RabX2 has a major role in intracellular transport. However, it was apparent that RabX1 and RabX2 knockout cells displayed somewhat enhanced survival within flies. CONCLUSIONS/SIGNIFICANCE: RabX1 and RabX2, two members of the trypanosome Rab subfamily, were shown to have no major detectable role in intracellular transport, despite the localization of each gene product to highly specific endomembrane compartments. These data extend the functional scope of Rab proteins in trypanosomes to include non-canonical roles in differentiation-associated processes in protozoa
The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapyâinduced gastrointestinal toxicity
Online 28 Aug 2018Chemotherapyâinduced gastrointestinal toxicity (CIGT) occurs in up to 80% of all patients undergoing cancer treatment, and leads to symptoms such as diarrhoea, abdominal bleeding and pain. There is currently limited understanding of how to predict an individual patient's risk of CIGT. It is believed the gut microbiome and its interactions with the host's innate immune system plays a key role in the development of this toxicity and potentially other toxicities, however comprehensive bioinformatics modelling has not been rigorously performed. The innate immune system is strongly influenced by the microbial environment and viceâversa. Ways this may occur include the immune system controlling composition and compartmentalisation of the microbiome, the microbiome affecting development of antigenâpresenting cells, and finally, the NLRP6 inflammasome orchestrating the colonic hostâmicrobiome interface. This evidence calls into question the role of preâtreatment risk factors in the development of gastrointestinal toxicity after chemotherapy. This review aims to examine evidence of a bidirectional interaction between the gut microbiome and innate immunity, and how these interactions occur in CIGT. In the future, knowledge of these interactions may lead to improved personalised cancer medicine, predictive risk stratification methods and the development of targeted interventions to reduce, or even prevent, CIGT severity.Kate R. Secombe, Janet K. Coller, Rachel J. Gibson, Hannah R. Wardill and Joanne M. Bowe
Characterisation of data resources for in silico modelling: benchmark datasets for ADME properties.
Introduction: The cost of in vivo and in vitro screening of ADME properties of compounds has motivated efforts to develop a range of in silico models. At the heart of the development of any computational model are the data; high quality data are essential for developing robust and accurate models. The characteristics of a dataset, such as its availability, size, format and type of chemical identifiers used, influence the modelability of the data. Areas covered: This review explores the usefulness of publicly available ADME datasets for researchers to use in the development of predictive models. More than 140 ADME datasets were collated from publicly available resources and the modelability of 31selected datasets were assessed using specific criteria derived in this study. Expert opinion: Publicly available datasets differ significantly in information content and presentation. From a modelling perspective, datasets should be of adequate size, available in a user-friendly format with all chemical structures associated with one or more chemical identifiers suitable for automated processing (e.g. CAS number, SMILES string or InChIKey). Recommendations for assessing dataset suitability for modelling and publishing data in an appropriate format are discussed
Discovery of a first-in-class small molecule antagonist against the adrenomedullin-2 receptor: structureâactivity relationships and optimization
Class B G-protein-coupled receptors (GPCRs) remain an underexploited target for drug development. The calcitonin receptor (CTR) family is particularly challenging, as its receptors are heteromers comprising two distinct components: the calcitonin receptor-like receptor (CLR) or calcitonin receptor (CTR) together with one of three accessory proteins known as receptor activity-modifying proteins (RAMPs). CLR/RAMP1 forms a CGRP receptor, CLR/RAMP2 forms an adrenomedullin-1 (AM1) receptor, and CLR/RAMP3 forms an adrenomedullin-2 (AM2) receptor. The CTR/RAMP complexes form three distinct amylin receptors. While the selective blockade of AM2 receptors would be therapeutically valuable, inhibition of AM1 receptors would cause clinically unacceptable increased blood pressure. We report here a systematic study of structureâactivity relationships that has led to the development of first-in-class AM2 receptor antagonists. These compounds exhibit therapeutically valuable properties with 1000-fold selectivity over the AM1 receptor. These results highlight the therapeutic potential of AM2 antagonists
Geographies of responsibility
Issues of space, place and politics run deep. There is a long history of the entanglement of the conceptualisation of space and place with the framing of political positions. The injunction to think space relationally is a very general one and, as this collection indicates, can lead in many directions. The particular avenue to be explored in this paper concerns the relationship between identity and responsibility, and the potential georaphies of both
First Measurement of Z/gamma* Production in Compton Scattering of Quasi-real Photons
We report the first observation of Z/gamma* production in Compton scattering
of quasi-real photons. This is a subprocess of the reaction e+e- to
e+e-Z/gamma*, where one of the final state electrons is undetected.
Approximately 55 pb-1 of data collected in the year 1997 at an e+e-
centre-of-mass energy of 183 GeV with the OPAL detector at LEP have been
analysed. The Z/gamma* from Compton scattering has been detected in the
hadronic decay channel. Within well defined kinematic bounds, we measure the
product of cross-section and Z/gamma* branching ratio to hadrons to be
(0.9+-0.3+-0.1) pb for events with a hadronic mass larger than 60 GeV,
dominated by (e)eZ production. In the hadronic mass region between 5 GeV and 60
GeV, dominated by (e)egamma* production, this product is found to be
(4.1+-1.6+-0.6) pb. Our results agree with the predictions of two Monte Carlo
event generators, grc4f and PYTHIA.Comment: 18 pages, LaTeX, 5 eps figures included, submitted to Physics Letters
Search for Higgs Bosons in e+e- Collisions at 183 GeV
The data collected by the OPAL experiment at sqrts=183 GeV were used to
search for Higgs bosons which are predicted by the Standard Model and various
extensions, such as general models with two Higgs field doublets and the
Minimal Supersymmetric Standard Model (MSSM). The data correspond to an
integrated luminosity of approximately 54pb-1. None of the searches for neutral
and charged Higgs bosons have revealed an excess of events beyond the expected
background. This negative outcome, in combination with similar results from
searches at lower energies, leads to new limits for the Higgs boson masses and
other model parameters. In particular, the 95% confidence level lower limit for
the mass of the Standard Model Higgs boson is 88.3 GeV. Charged Higgs bosons
can be excluded for masses up to 59.5 GeV. In the MSSM, mh > 70.5 GeV and mA >
72.0 GeV are obtained for tan{beta}>1, no and maximal scalar top mixing and
soft SUSY-breaking masses of 1 TeV. The range 0.8 < tanb < 1.9 is excluded for
minimal scalar top mixing and m{top} < 175 GeV. More general scans of the MSSM
parameter space are also considered.Comment: 49 pages. LaTeX, including 33 eps figures, submitted to European
Physical Journal
A Measurement of the Product Branching Ratio f(b->Lambda_b).BR(Lambda_b->Lambda X) in Z0 Decays
The product branching ratio, f(b->Lambda_b).BR(Lambda_b->Lambda X), where
Lambda_b denotes any weakly-decaying b-baryon, has been measured using the OPAL
detector at LEP. Lambda_b are selected by the presence of energetic Lambda
particles in bottom events tagged by the presence of displaced secondary
vertices. A fit to the momenta of the Lambda particles separates signal from B
meson and fragmentation backgrounds. The measured product branching ratio is
f(b->Lambda_b).BR(Lambda_b->Lambda X) = (2.67+-0.38(stat)+0.67-0.60(sys))%
Combined with a previous OPAL measurement, one obtains
f(b->Lambda_b).BR(Lambda_b->Lambda X) = (3.50+-0.32(stat)+-0.35(sys))%.Comment: 16 pages, LaTeX, 3 eps figs included, submitted to the European
Physical Journal
Measurement of the Michel Parameters in Leptonic Tau Decays
The Michel parameters of the leptonic tau decays are measured using the OPAL
detector at LEP. The Michel parameters are extracted from the energy spectra of
the charged decay leptons and from their energy-energy correlations. A new
method involving a global likelihood fit of Monte Carlo generated events with
complete detector simulation and background treatment has been applied to the
data recorded at center-of-mass energies close to sqrt(s) = M(Z) corresponding
to an integrated luminosity of 155 pb-1 during the years 1990 to 1995. If e-mu
universality is assumed and inferring the tau polarization from neutral current
data, the measured Michel parameters are extracted. Limits on non-standard
coupling constants and on the masses of new gauge bosons are obtained. The
results are in agreement with the V-A prediction of the Standard Model.Comment: 32 pages, LaTeX, 9 eps figures included, submitted to the European
Physical Journal
Measurement of (anti)deuteron and (anti)proton production in DIS at HERA
The first observation of (anti)deuterons in deep inelastic scattering at HERA
has been made with the ZEUS detector at a centre-of-mass energy of 300--318 GeV
using an integrated luminosity of 120 pb-1. The measurement was performed in
the central rapidity region for transverse momentum per unit of mass in the
range 0.3<p_T/M<0.7. The particle rates have been extracted and interpreted in
terms of the coalescence model. The (anti)deuteron production yield is smaller
than the (anti)proton yield by approximately three orders of magnitude,
consistent with the world measurements.Comment: 26 pages, 9 figures, 5 tables, submitted to Nucl. Phys.
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