725 research outputs found
Computational Analysis of T Cell Receptor Repertoire and Structure
The human adaptive immune system has evolved to provide a sophisticated response to a vast body of pathogenic microbes and toxic substances. The primary mediators of this response are T and B lymphocytes. Antigenic peptides presented at the surface of infected cells by major histocompatibility complex (MHC) molecules are recognised by T cell receptors (TCRs) with exceptional specificity. This specificity arises from the enormous diversity in TCR sequence and structure generated through an imprecise process of somatic gene recombination that takes place during T cell development. Quantification of the TCR repertoire through the analysis of data produced by high-throughput RNA sequencing allows for a characterisation of the immune response to disease over time and between patients, and the development of methods for diagnosis and therapeutic design. The latest version of the software package Decombinator extracts and quantifies the TCR repertoire with improved accuracy and compatibility with complementary experimental protocols and external computational tools. The software has been extended for analysis of fragmented short-read
data from single cells, comparing favourably with two alternative tools. The development of cell-based therapeutics and vaccines is incomplete without an understanding of molecular level interactions. The breadth of TCR diversity and cross-reactivity presents a barrier for comprehensive structural resolution of the repertoire by traditional means. Computational modelling of TCR structures and TCR-pMHC complexes provides an efficient alternative. Four generalpurpose protein-protein docking platforms were compared in their ability to accurately model TCR-pMHC complexes. Each platform was evaluated against an expanded benchmark of docking test cases and in the context of varying additional information about the binding interface.
Continual innovation in structural modelling techniques sets the stage for novel automated tools for TCR design. A prototype platform has been developed, integrating structural modelling and an optimisation routine, to engineer desirable features into TCR and TCR-pMHC complex models
Nonlinear internal wave penetration via parametric subharmonic instability
We present the results of a laboratory experimental study of an internal wave field generated by harmonic, spatially periodic boundary forcing from above of a density stratification comprising a strongly stratified, thin upper layer sitting atop a weakly stratified, deep lower layer. In linear regimes, the energy flux associated with relatively high frequency internal waves excited in the upper layer is prevented from entering the lower layer by virtue of evanescent decay of the wave field. In the experiments, however, we find that the development of parametric subharmonic instability in the upper layer transfers energy from the forced primary wave into a pair of subharmonic daughter waves, each capable of penetrating the weakly stratified lower layer. We find that around 10% of the primary wave energy flux penetrates into the lower layer via this nonlinear wave-wave interaction for the regime we study.ONLITUR ((No. ANR-2011-BS04-006-01)National Science Foundation (U.S.) (No. OCE-1357434
The molecular basis of antigenic variation among A(H9N2) avian influenza viruses
Avian influenza A(H9N2) viruses are an increasing threat to global poultry production and, through zoonotic infection,
to human health where they are considered viruses with pandemic potential. Vaccination of poultry is a key element
of disease control in endemic countries, but vaccine effectiveness is persistently challenged by the emergence of
antigenic variants. Here we employed a combination of techniques to investigate the genetic basis of H9N2 antigenic
variability and evaluate the role of different molecular mechanisms of immune escape. We systematically tested the
influence of published H9N2 monoclonal antibody escape mutants on chicken antisera binding, determining that
many have no significant effect. Substitutions introducing additional glycosylation sites were a notable exception,
though these are relatively rare among circulating viruses. To identify substitutions responsible for antigenic variation
in circulating viruses, we performed an integrated meta-analysis of all published H9 haemagglutinin sequences and
antigenic data. We validated this statistical analysis experimentally and allocated several new residues to H9N2
antigenic sites, providing molecular markers that will help explain vaccine breakdown in the field and inform vaccine
selection decisions. We find evidence for the importance of alternative mechanisms of immune escape, beyond simple
modulation of epitope structure, with substitutions increasing glycosylation or receptor-binding avidity, exhibiting the
largest impacts on chicken antisera binding. Of these, meta-analysis indicates avidity regulation to be more relevant to
the evolution of circulating viruses, suggesting that a specific focus on avidity regulation is required to fully understand
the molecular basis of immune escape by influenza, and potentially other viruses
Weak gravitational lensing in the standard Cold Dark Matter model, using an algorithm for three-dimensional shear
We investigate the effects of weak gravitational lensing in the standard Cold
Dark Matter cosmology, using an algorithm which evaluates the shear in three
dimensions. The algorithm has the advantage of variable softening for the
particles, and our method allows the appropriate angular diameter distances to
be applied to every evaluation location within each three-dimensional
simulation box. We investigate the importance of shear in the distance-redshift
relation, and find it to be very small. We also establish clearly defined
values for the smoothness parameter in the relation, finding its value to be at
least 0.88 at all redshifts in our simulations. From our results, obtained by
linking the simulation boxes back to source redshifts of 4, we are able to
observe the formation of structure in terms of the computed shear, and also
note that the major contributions to the shear come from a very broad range of
redshifts. We show the probability distributions for the magnification, source
ellipticity and convergence, and also describe the relationships amongst these
quantities for a range of source redshifts. We find a broad range of
magnifications and ellipticities; for sources at a redshift of 4, 97{1/2}% of
all lines of sight show magnifications up to 1.3 and ellipticities up to 0.195.
There is clear evidence that the magnification is not linear in the
convergence, as might be expected for weak lensing, but contains contributions
from higher order terms in both the convergence and the shear.Comment: 14 pages, LaTeX, 15 figures include
Measuring the three-dimensional shear from simulation data, with applications to weak gravitational lensing
We have developed a new three-dimensional algorithm, based on the standard
PM method, for computing deflections due to weak gravitational lensing. We
compare the results of this method with those of the two-dimensional planar
approach, and rigorously outline the conditions under which the two approaches
are equivalent. Our new algorithm uses a Fast Fourier Transform convolution
method for speed, and has a variable softening feature to provide a realistic
interpretation of the large-scale structure in a simulation. The output values
of the code are compared with those from the Ewald summation method, which we
describe and develop in detail. With an optimal choice of the high frequency
filtering in the Fourier convolution, the maximum errors, when using only a
single particle, are about 7 per cent, with an rms error less than 2 per cent.
For ensembles of particles, used in typical -body simulations, the rms
errors are typically 0.3 per cent. We describe how the output from the
algorithm can be used to generate distributions of magnification, source
ellipticity, shear and convergence for large-scale structure.Comment: 22 pages, latex, 11 figure
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