Showing papers by "Mehran Kardar published in 2013"

The Effects of Somatic Hypermutation on Neutralization and Binding in the PGT121 Family of Broadly Neutralizing HIV Antibodies

Abstract: Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121–134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121–134 but were still capable of neutralizing roughly 40–80% of PGT121–134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121–134. Such antibodies with lower levels of SHM may be more amenable to elicitation through vaccination while still providing noteworthy coverage. Binding characterization indicated a preference of inferred intermediates for native Env binding over monomeric gp120, suggesting that the PGT121–134 lineage may have been selected for binding to native Env at some point during maturation. Analysis of glycan-dependent neutralization for inferred intermediates identified additional adjacent glycans that comprise the epitope and suggests changes in glycan dependency or recognition over the course of affinity maturation for this lineage. Finally, patterns of neutralization of inferred bnAb intermediates suggest hypotheses as to how SHM may lead to potent and broad HIV neutralization and provide important clues for immunogen design.

Spin models inferred from patient-derived viral sequence data faithfully describe HIV fitness landscapes.

Abstract: Mutational escape from vaccine-induced immune responses has thwarted the development of a successful vaccine against AIDS, whose causative agent is HIV, a highly mutable virus. Knowing the virus' fitness as a function of its proteomic sequence can enable rational design of potent vaccines, as this information can focus vaccine-induced immune responses to target mutational vulnerabilities of the virus. Spin models have been proposed as a means to infer intrinsic fitness landscapes of HIV proteins from patient-derived viral protein sequences. These sequences are the product of nonequilibrium viral evolution driven by patient-specific immune responses and are subject to phylogenetic constraints. How can such sequence data allow inference of intrinsic fitness landscapes? We combined computer simulations and variational theory \'a la Feynman to show that, in most circumstances, spin models inferred from patient-derived viral sequences reflect the correct rank order of the fitness of mutant viral strains. Our findings are relevant for diverse viruses.

Quorum sensing allows T cells to discriminate between self and nonself

Abstract: T cells orchestrate pathogen-specific adaptive immune responses by identifying peptides derived from pathogenic proteins that are displayed on the surface of infected cells. Host cells also display peptide fragments from the host’s own proteins. Incorrectly identifying peptides derived from the body’s own proteome as pathogenic can result in autoimmune disease. To minimize autoreactivity, immature T cells that respond to self-peptides are deleted in the thymus by a process called negative selection. However, negative selection is imperfect, and autoreactive T cells exist in healthy individuals. To understand how autoimmunity is yet avoided, without loss of responsiveness to pathogens, we have developed a model of T-cell training and response. Our model shows that T cells reliably respond to infection and avoid autoimmunity because collective decisions made by the T-cell population, rather than the responses of individual T cells, determine biological outcomes. The theory is qualitatively consistent with experimental data and yields a criterion for thymic selection to be adequate for suppressing autoimmunity.

Scattering approach to the dynamical Casimir effect

Abstract: We develop a unified scattering approach to dynamical Casimir problems which can be applied to both accelerating boundaries and dispersive objects in relative motion. A general (trace) formula is derived for the radiation from accelerating boundaries. Applications are provided for objects with different shapes in various dimensions, and undergoing rotational or linear motion. Within this framework, photon generation is discussed in the context of a modulated optical mirror. For dispersive objects, we find general results solely in terms of the scattering matrix. Specifically, we discuss the vacuum friction on a rotating object, and the friction on an atom moving parallel to a surface.

Quantum Cherenkov radiation and noncontact friction

Abstract: We present a number of arguments to demonstrate that a quantum analog of the Cherenkov effect occurs when two nondispersive half spaces are in relative motion We show that they experience friction beyond a threshold velocity which, in their center-of-mass frame, is the phase speed of light within their medium, and the loss in mechanical energy is radiated through the medium before getting fully absorbed in the form of heat By deriving various correlation functions inside and outside the two half spaces, we explicitly compute this radiation and discuss its dependence on the reference frame

Conformal field theory of critical Casimir interactions in 2D

Abstract: Thermal fluctuations of a critical system induce long-ranged Casimir forces between objects that couple to the underlying field. For two-dimensional (2D) conformal field theories (CFT) we derive an exact result for the Casimir interaction between two objects of arbitrary shape, in terms of 1) the free energy of a circular ring whose radii are determined by the mutual capacitance of two conductors with the objects' shape; and 2) a purely geometric energy that is proportional to the conformal charge of the CFT, but otherwise super-universal in that it depends only on the shapes and is independent of boundary conditions and other details.

Interplay of roughness/modulation and curvature for surface interactions at proximity

Abstract: Employing the proximity approximation, we show that roughness or surface modulations change the distance dependence of (power-law) interactions between curved objects at proximity. The modified scaling law is simply related to the order of the first non-vanishing coefficient of the Taylor expansion of the distribution of separations between the surfaces. The latter can in principle be estimated by scanning measurements, or computed for well characterized modulations, and then used to predict short-distance scaling behavior in disparate experiments. For example, we predict that the radiative heat transfer between a rough sphere and a plate approaches a constant with decreasing separation. Similar saturation is expected for the Casimir force between dielectric or metallic surfaces with appropriate modulations over distinct length scales.

Linear response relations in fluctuational electrodynamics

Abstract: Near field radiative heat transfer and vacuum friction are just two instances of topics of technological and fundamental interest studied via the formalism of fluctuational electrodynamics. From the perspective of experiment and simulations, it is hard to precisely control and probe such nonequilibrium situations. Fluctuations in equilibrium are easier to measure, and typically can be related to nonequilibrium response functions by Green-Kubo relations. We consider a collection of arbitrary objects in vacuum, perturbed by changing the temperature or velocity of one object. Developing a method for computation of higher order correlation functions in fluctuational electrodynamics, we explicitly compare linear response and equilibrium fluctuations. We obtain a Green-Kubo relation for the radiative heat transfer, as well as a closed formula for the vacuum friction in arbitrary geometries in the framework of scattering theory. We comment on the signature of the radiative heat conductivity in equilibrium fluctuations.

Quantum Cherenkov radiation and noncontact friction

Abstract: We present a number of arguments to demonstrate that a quantum analog of the Cherenkov effect occurs when two nondispersive half spaces are in relative motion. We show that they experience friction beyond a threshold velocity which, in their center-of-mass frame, is the phase speed of light within their medium, and the loss in mechanical energy is radiated through the medium before getting fully absorbed in the form of heat. By deriving various correlation functions inside and outside the two half spaces, we explicitly compute this radiation and discuss its dependence on the reference frame.

Interplay of roughness/modulation and curvature at proximity

Abstract: We show that roughness or surface modulations change the distance dependence of (power-law) interactions between curved objects at proximity. The modified scaling law is then simply related to the order of the first non-vanishing coefficient of the Taylor expansion of the distribution of separations between the surfaces. The latter can in principle be estimated by scanning measurements, or computed for well characterized modulations, and then used to predict short-distance scaling behavior in disparate experiments. For example, we predict that the radiative heat transfer between a rough sphere and a plate approaches a constant with decreasing separation. Similar saturation is expected for the Casimir force between dielectric or metallic surfaces with appropriate modulations over distinct length scales.

Small distance expansion for radiative heat transfer between curved objects

Abstract: We develop a small distance expansion for the radiative heat transfer between gently curved objects, in terms of the ratio of distance to radius of curvature. A gradient expansion allows us to go beyond the lowest-order proximity transfer approximation. The range of validity of such expansion depends on temperature as well as material properties. Generally, the expansion converges faster for the derivative of the transfer than for the transfer itself, which we use by introducing a near-field adjusted plot. For the case of a sphere and a plate, the logarithmic correction to the leading term has a very small prefactor for all materials investigated.

Linear response relations in fluctuational electrodynamics

Abstract: Near field radiative heat transfer and vacuum friction are just two instances of topics of technological and fundamental interest studied via the formalism of fluctuational electrodynamics. From the perspective of experiment and simulations, it is hard to precisely control and probe such nonequilibrium situations. Fluctuations in equilibrium are easier to measure, and typically can be related to nonequilibrium response functions by Green-Kubo relations. We consider a collection of arbitrary objects in vacuum, perturbed by changing the temperature or velocity of one object. Developing a method for computation of higher order correlation functions in fluctuational electrodynamics, we explicitly compare linear response and equilibrium fluctuations. We obtain a Green-Kubo relation for the radiative heat transfer, as well as a closed formula for the vacuum friction in arbitrary geometries in the framework of scattering theory. We comment on the signature of the radiative heat conductivity in equilibrium fluctuations.

Conformal Field Theory of Critical Casimir Interactions in 2D

Abstract: Thermal fluctuations of a critical system induce long-ranged Casimir forces between objects that couple to the underlying field. For two dimensional (2D) conformal field theories (CFT) we derive an exact result for the Casimir interaction between two objects of arbitrary shape, in terms of (1) the free energy of a circular ring whose radii are determined by the mutual capacitance of two conductors with the objects' shape; and (2) a purely geometric energy that is proportional to conformal charge of the CFT, but otherwise super-universal in that it depends only on the shapes and is independent of boundary conditions and other details.

Statistical Physics of T-Cell Development and Pathogen Specificity

Abstract: In addition to an innate immune system that battles pathogens in a nonspecific fashion, higher organisms, such as humans, possess an adaptive immune system to combat diverse (and evolving) microbial pathogens. Remarkably, the adaptive immune system mounts pathogen-specific responses, which can be recalled upon reinfection with the same pathogen. It is difficult to see how the adaptive immune system can be preprogrammed to respond specifically to a vast and unknown set of pathogens. Although major advances have been made in understanding pertinent molecular and cellular phenomena, the precise principles that govern many aspects of an immune response are largely unknown. We discuss complementary approaches from statistical mechanics and cell biology that can shed light on how key components of the adaptive immune system, T cells, develop to enable pathogen-specific responses against many diverse pathogens. The mechanistic understanding that emerges has implications for how host genetics may influence the de...