Biomedical subjects

Yisroel Brumer

Publications and source records attributed to Yisroel Brumer.

6 recordsLinked to original sources

PubMed2006

Genetic instability and the quasispecies model.

Genetic instability is a defining characteristic of cancers. Microsatellite instability (MIN) leads to by elevated point mutation rates, whereas chromosomal instability (CIN) refers to increased rates of losing or gaining whole chromosomes or parts of chromosomes during cell division. CIN and MIN are, in general, mutually exclusive. The quasispecies model is a very successful theoretical framework for the study of evolution at high mutation rates. It predicts the existence of an experimentally verified error catastrophe. This catastrophe occurs when the mutation rates exceed a threshold value, the error threshold, above which replicative infidelity is incompatible with cell survival. We analyse the semiconservative quasispecies model of both MIN and CIN tumors. We consider the role of post-methylation DNA repair in tumor cells and demonstrate that DNA repair is fundamental to the nature of the error catastrophe in both types of tumors. We find that CIN introduces a plateau in the maximum viable mutation rate for a repair-free model, which does not exist in the case of MIN. This provides a plausible explanation for the mutual exclusivity of CIN and MIN.

Chromosomal Instability↗

PubMed2005

Selective advantage for conservative viruses.

In this article we study the full semiconservative treatment of a model for the coevolution of a virus and an adaptive immune system. Regions of viability are calculated for both conservatively and semiconservatively replicating viruses interacting with a realistic semiconservatively replicating immune system. The conservative virus is found to have a selective advantage in the form of an ability to survive in regions with a wider range of mutation rates than its semiconservative counterpart, as well as an increased replication rate where both species can survive. This may help explain the existence of a rich range of viruses with conservatively replicating genomes, a trait that is found nowhere else in nature.

Adaptation, Physiological↗

PubMed2004

Importance of DNA repair in tumor suppression.

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. On a specific single fitness peak landscape, the repair-free semiconservative system is shown to mimic a conservative system exactly. We postulate that inactivation of post-methylation repair mechanisms is fundamental to the progression of a tumor cell and hence these mechanisms act as a method for the prevention and destruction of cancerous genomes.

Animals↗

PubMed2004

Host-parasite coevolution and optimal mutation rates for semiconservative quasispecies.

In this paper, we extend a model of host-parasite coevolution to incorporate the semiconservative nature of DNA replication for both the host and the parasite. We find that the optimal mutation rate for the semiconservative and conservative hosts converge for realistic genome lengths, thus maintaining the admirable agreement between theory and experiment found previously for the conservative model and justifying the conservative approximation in some cases. We demonstrate that, while the optimal mutation rate for a conservative and semiconservative parasite interacting with a given immune system is similar to that of a conservative parasite, the properties away from this optimum differ significantly. We suspect that this difference, coupled with the requirement that a parasite optimize survival in a range of viable hosts, may help explain why semiconservative viruses are known to have significantly lower mutation rates than their conservative counterparts.

Adaptation, Physiological↗

PubMed2004

Mean-field theory, mode-coupling theory, and the onset temperature in supercooled liquids.

We consider the relationship between the temperature at which averaged energy landscape properties change sharply (T(o)) and the breakdown of mean-field treatments of the dynamics of supercooled liquids. First, we show that the solution of the wave vector dependent mode-coupling equations undergoes an ergodic-nonergodic transition consistently close to T(o). Generalizing the landscape concept to include hard-sphere systems, we show that the property of inherent structures that changes near T(o) is governed more fundamentally by packing and free volume than potential energy. Lastly, we study the finite-size random orthogonal model (ROM), and show that the onset of noticeable corrections to mean-field behavior occurs at T(o). These results highlight connections between the energy landscape and mode-coupling approach to supercooled liquids, and identify which features of the relaxation of supercooled liquids are properly captured by mode-coupling theory.

Journal Article↗

PubMed2003

Electrostatic self-assembly of macroscopic crystals using contact electrification.

Self-assembly of components larger than molecules into ordered arrays is an efficient way of preparing microstructured materials with interesting mechanical and optical properties. Although crystallization of identical particles or particles of different sizes or shapes can be readily achieved, the repertoire of methods to assemble binary lattices of particles of the same sizes but with different properties is very limited. This paper describes electrostatic self-assembly of two types of macroscopic components of identical dimensions using interactions that are generated by contact electrification. The systems we have examined comprise two kinds of objects (usually spheres) made of different polymeric materials that charge with opposite electrical polarities when agitated on flat, metallic surfaces. The interplay of repulsive interactions between like-charged objects and attractive interactions between unlike-charged ones results in the self-assembly of these objects into highly ordered, closed arrays. Remarkably, some of the assemblies that form are not electroneutral-that is, they possess a net charge. We suggest that the stability of these unusual structures can be explained by accounting for the interactions between electric dipoles that the particles in the aggregates induce in their neighbours.

Caprolactam↗