Guy Hed

Cluster analysis of human autoantibody reactivities in health and in type 1 diabetes mellitus: a bio-informatic approach to immune complexity

Informatic methodologies are being applied successfully to analyze the complexity of the genome. But beyond the genome, the immune system reflects the state of the body in health and disease. Traditionally, immunologists have reduced the immune system, where possible, to one-to-one relationships between particular antigens and particular antibodies or T-cell clones. Autoimmune diseases, caused by an immune attack against a body component, are usually investigated by following the response to single self-antigens. In this study, we apply informatics to analyze patterns of autoantibodies rather than single species of autoantibodies. This study was designed not to replace traditional approaches to immune diagnosis, but to test whether meaningful patterns of autoantibodies might exist. Using an unbiased solid-phase ELISA antibody test, we detected serum IgG and IgM antibodies in the sera of 20 healthy persons and 20 persons with type 1 diabetes mellitus binding to an array of 87 different antigens, mostly self-antigens. The healthy subjects manifested autoantibodies to a variety of self-antigens, many known to be associated with autoimmune diseases. We investigated the patterns of these autoantibodies using a coupled two-way clustering algorithm developed for analyzing data from gene arrays. We now report that the reactivity patterns of autoantibodies to particular subsets of self-antigens exhibited non-trivial structure, which significantly discriminated between healthy persons and persons with type 1 diabetes. The results show that despite the wide prevalence of autoantibodies, the patterns of reactivity to defined subsets of self-antigens can provide information about the state of the body.

Initiation and Dynamics of Hemifusion in Lipid Bilayers

One approach to the understanding of fusion in cells and model membranes involves stalk formation and expansion of the hemifusion diaphragm. We predict theoretically the initiation of hemifusion by stalk expansion and the dynamics of mesoscopic hemifusion diaphragm expansion in the light of recent experiments and theory that suggested that hemifusion is driven by intramembrane tension far from the fusion zone. Our predictions include a square-root scaling of the hemifusion zone size on time as well as an estimate of the minimal tension for initiation of hemifusion. Whereas a minimal amount of pressure is evidently needed for stalk formation, it is not necessarily required for stalk expansion. The energy required for tension-induced fusion is much smaller than that required for pressure-driven fusion.

Lack of Ultrametricity in the Low-Temperature Phase of Three-Dimensional Ising Spin Glasses

We study the low-temperature spin-glass phases of the Sherrington-Kirkpatrick (SK) model and of the 3-dimensional short-range Ising spin-glass (3DISG). By using clustering to focus on the relevant parts of phase space and reduce finite size effects, we found that for the SK model ultrametricity becomes clearer as the system size increases, while for the short-range case our results indicate the opposite, i.e., lack of ultrametricity. Another method, which does not rely on clustering, indicates that the mean-field solution works for the SK model but does not apply in detail to the 3DISG, for which stochastic stability is also violated.

Attractive Instability of Oppositely Charged Membranes Induced by Charge Density Fluctuations

We predict the conditions under which two oppositely charged membranes show a dynamic, attractive instability. Two layers with unequal charges of opposite sign can repel or be stable when in close proximity. However, dynamic charge density fluctuations can induce an attractive instability and thus facilitate fusion. We predict the dominant instability modes and time scales and show how these are controlled by the relative charge and membrane viscosities. These dynamic instabilities may be the precursors of membrane fusion in systems where artificial vesicles are engulfed by biological cells of opposite charge.

The immunity of polymer-microemulsion networks

Abstract.The concept of network immunity, i.e., the robustness of the network connectivity after a random deletion of edges or vertices, has been investigated in biological or communication networks. We apply this concept to a self-assembling, physical network of microemulsion droplets connected by telechelic polymers, where more than one polymer can connect a pair of droplets. The gel phase of this system has higher immunity if it is more likely to survive (i.e., maintain a macroscopic, connected component) when some of the polymers are randomly degraded. We consider the distribution p(σ) of the number of polymers between a pair of droplets, and show that gel immunity decreases as the variance of p(σ) increases. Repulsive interactions between the polymers decrease the variance, while attractive interactions increase the variance, and may result in a bimodal p(σ).

State hierarchy induced by correlated spin domains in short-range spin glasses

We generate equilibrium configurations for the three- and four-dimensional Ising spin glass with Gaussian distributed couplings at temperatures well below the transition temperature Tc . These states are analyzed by a recently proposed method using clustering. The analysis reveals a hierarchical state space structure. At each level of the hierarchy states are labeled by the orientations of a set of correlated macroscopic spin domains. Our picture of the low temperature phase of short-range spin glasses is that of a state hierarchy induced by correlated spin domains ~SHICS!. The complexity of the low temperature phase is manifest in the fact that the composition of such a spin domain ~i.e., its constituent spins !, as well as its identifying label, are defined and determined by the ‘‘location’’ in the state hierarchy at which it appears. Mapping out the phase space structure by means of the orientations assumed by these domains enhances our ability to investigate the overlap distribution, which we find to be nontrivial. Evidence is also presented that these states may have a nonultrametric structure.

Temperature Integration: An efficient procedure for calculation of free energy differences

We propose a method, Temperature Integration, which allows an efficient calculation of free energy differences between two systems of interest, with the same degrees of freedom, which may have rough energy landscapes. The method is based on calculating, for each single system, the difference between the values of lnZ at two temperatures, using a Parallel Tempering procedure. If our two systems of interest have the same phase space volume, they have the same values of lnZ at high-T, and we can obtain the free energy difference between them, using the two single-system calculations described above. If the phase space volume of a system is known, our method can be used to calculate its absolute (versus relative) free energy as well. We apply our method and demonstrate its efficiency on a “toy model” of hard rods on a 1-dimensional ring.

New extrapolation of overlap distribution in spin glasses

We study in d = 3 dimensions the short-range Ising spin glass with Jij = ±1 couplings and periodic boundary conditions at T = 0. We show that the overlap distribution is non-trivial in the limit of large system size.

Nontrivial link overlap distribution in three-dimensional Ising spin glasses

We investigate the distributions of the link overlap,

Spin domains generate hierarchical ground state structure in J = +/-1 spin glasses.

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