564 research outputs found
The case for absolute ligand discrimination : modeling information processing and decision by immune T cells
Some cells have to take decision based on the quality of surroundings
ligands, almost irrespective of their quantity, a problem we name "absolute
discrimination". An example of absolute discrimination is recognition of
not-self by immune T Cells. We show how the problem of absolute discrimination
can be solved by a process called "adaptive sorting". We review several
implementations of adaptive sorting, as well as its generic properties such as
antagonism. We show how kinetic proofreading with negative feedback implements
an approximate version of adaptive sorting in the immune context. Finally, we
revisit the decision problem at the cell population level, showing how
phenotypic variability and feedbacks between population and single cells are
crucial for proper decision
Quantitative Immunology for Physicists
The adaptive immune system is a dynamical, self-organized multiscale system
that protects vertebrates from both pathogens and internal irregularities, such
as tumours. For these reason it fascinates physicists, yet the multitude of
different cells, molecules and sub-systems is often also petrifying. Despite
this complexity, as experiments on different scales of the adaptive immune
system become more quantitative, many physicists have made both theoretical and
experimental contributions that help predict the behaviour of ensembles of
cells and molecules that participate in an immune response. Here we review some
recent contributions with an emphasis on quantitative questions and
methodologies. We also provide a more general methods section that presents
some of the wide array of theoretical tools used in the field.Comment: 78 page revie
Ron Germain: Towards a grand unified theory
As data floods in, Germain works overtime to decipher which immunological information matters and how it can be applied to saving lives
T Cells Integrate Local and Global Cues to Discriminate between Structurally Similar Antigens
International audienceT lymphocytes' ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines
There and (slowly) back again: Entropy-driven hysteresis in a model of DNA overstretching
When pulled along its axis, double-stranded DNA elongates abruptly at a force
of about 65 pN. Two physical pictures have been developed to describe this
overstretched state. The first proposes that strong forces induce a phase
transition to a molten state consisting of unhybridized single strands. The
second picture instead introduces an elongated hybridized phase, called S-DNA,
structurally and thermodynamically distinct from standard B-DNA. Little
thermodynamic evidence exists to discriminate directly between these competing
pictures. Here we show that within a microscopic model of DNA we can
distinguish between the dynamics associated with each. In experiment,
considerable hysteresis in a cycle of stretching and shortening develops as
temperature is increased. Since there are few possible causes of hysteresis in
a system whose extent is appreciable in only one dimension, such behavior
offers a discriminating test of the two pictures of overstretching. Most
experiments are performed upon nicked DNA, permitting the detachment
(`unpeeling') of strands. We show that the long-wavelength progression of the
unpeeled front generates hysteresis, the character of which agrees with
experiment only if we assume the existence of S-DNA. We also show that internal
melting (distinct from unpeeling) can generate hysteresis, the degree of which
is strongly dependent upon the nonextensive loop entropy of single-stranded
DNA.Comment: 18 pages, 10 figure
DNA as a programmable viscoelastic nanoelement
The two strands of a DNA molecule with a repetitive sequence can pair into
many different basepairing patterns. For perfectly periodic sequences, early
bulk experiments of Poerschke indicate the existence of a sliding process,
permitting the rapid transition between different relative strand positions
[Biophys. Chem. 2 (1974) 83]. Here, we use a detailed theoretical model to
study the basepairing dynamics of periodic and nearly periodic DNA. As
suggested by Poerschke, DNA sliding is mediated by basepairing defects (bulge
loops), which can diffuse along the DNA. Moreover, a shear force f on opposite
ends of the two strands yields a characteristic dynamic response: An outward
average sliding velocity v~1/N is induced in a double strand of length N,
provided f is larger than a threshold f_c. Conversely, if the strands are
initially misaligned, they realign even against an external force less than
f_c. These dynamics effectively result in a viscoelastic behavior of DNA under
shear forces, with properties that are programmable through the choice of the
DNA sequence. We find that a small number of mutations in periodic sequences
does not prevent DNA sliding, but introduces a time delay in the dynamic
response. We clarify the mechanism for the time delay and describe it
quantitatively within a phenomenological model. Based on our findings, we
suggest new dynamical roles for DNA in artificial nanoscale devices. The
basepairing dynamics described here is also relevant for the extension of
repetitive sequences inside genomic DNA.Comment: 10 pages, 7 figures; final version to appear in Biophysical Journa
Discerning Aggregation in Homogeneous Ensembles: A General Description of Photon Counting Spectroscopy in Diffusing Systems
In order to discern aggregation in solutions, we present a quantum mechanical
analog of the photon statistics from fluorescent molecules diffusing through a
focused beam. A generating functional is developed to fully describe the
experimental physical system as well as the statistics. Histograms of the
measured time delay between photon counts are fit by an analytical solution
describing the static as well as diffusing regimes. To determine empirical
fitting parameters, fluorescence correlation spectroscopy is used in parallel
to the photon counting. For expedient analysis, we find that the distribution's
deviation from a single Poisson shows a difference between two single fluor
moments or a double fluor aggregate of the same total intensities. Initial
studies were performed on fixed-state aggregates limited to dimerization.
However preliminary results on reactive species suggest that the method can be
used to characterize any aggregating system.Comment: 30 pages, 5 figure
Towards a Rigorous Assessment of Systems Biology Models: The DREAM3 Challenges
Background: Systems biology has embraced computational modeling in response to the quantitative nature and increasing scale of contemporary data sets. The onslaught of data is accelerating as molecular profiling technology evolves. The Dialogue for Reverse Engineering Assessments and Methods (DREAM) is a community effort to catalyze discussion about the design, application, and assessment of systems biology models through annual reverse-engineering challenges. Methodology and Principal Findings: We describe our assessments of the four challenges associated with the third DREAM conference which came to be known as the DREAM3 challenges: signaling cascade identification, signaling response prediction, gene expression prediction, and the DREAM3 in silico network challenge. The challenges, based on anonymized data sets, tested participants in network inference and prediction of measurements. Forty teams submitted 413 predicted networks and measurement test sets. Overall, a handful of best-performer teams were identified, while a majority of teams made predictions that were equivalent to random. Counterintuitively, combining the predictions of multiple teams (including the weaker teams) can in some cases improve predictive power beyond that of any single method. Conclusions: DREAM provides valuable feedback to practitioners of systems biology modeling. Lessons learned from the predictions of the community provide much-needed context for interpreting claims of efficacy of algorithms described in the scientific literature
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