Telomeres, non-coding terminal structures of DNA strands, consist of repetitive long tandem repeats of a specific length. An absence of an enzyme, telomerase, in certain cellular structures requires an alternative telomerase-independent pathway for telomeric sequence length regulation. Besides linear telomeres other configurations such as telomeric circles and telomeric loops were experimentally observed. They are suspected to play an important role in a universal mechanism for stabilization of the ends of linear DNA that possibly dates back to pre-telomerase ages. We propose a mathematical model that captures biophysical interactions of various telomeric structures on a short time scale and that is able to reproduce experimental measurements in mtDNA of yeast. Moreover, the model opens up a couple of interesting mathematical problems such as validity of a quasi-steady state approximation and dynamic properties of discrete coagulation-fragmentation systems. We also identify and estimate key factors influencing the length distribution of telomeric circles, loops and strand invasions using numerical simulations.
Stability plays an important role in engineering, for it limits the load carrying capacity of all kinds of structures. Many failure mechanisms in advanced engineering materials are stability-related, such as localized deformation zones occurring in fiber-reinforced composites and cellular materials, used in aerospace and packaging applications. Moreover, modern biomedical applications, such as vascular stents, orthodontic wire etc., are based on shape memory alloys (SMA’s) that exploit the displacive phase transformations in these solids, which are macroscopic manifestations of lattice-level instabilities.
The presentation starts with the introduction of the concepts of stability and bifurcation for conservative elastic systems with a particular emphasis on solids with periodic microstructures. The concept of Bloch wave analysis is introduced, which allows one to find the lowest load instability mode of an infinite, perfect structure, based solely on unit cell considerations. The relation between instability at the microscopic level and macroscopic properties of the solid is studied for several types of applications involving different scales: composites (fiber-reinforced), cellular solids (hexagonal honeycomb) and finally SMA's, where temperature- or stress-induced instabilities at the atomic level have macroscopic manifestations visible to the naked eye.
Atherosclerosis is the leading cause of death, both above and below age 65, in the United States and all Western countries. Its earliest prelesion events appear to be the transmural (across the wall)-pressure (DP)-driven advection of large molecules such as low-density lipoprotein (LDL) cholesterol from the blood into the inner wall layers across the monolayer of endothelial cells that tile the blood-wall interface. This transport occurs through the junctions around rare (~one cell every few thousand) endothelial cells whose junctions are wide enough to allow large molecules to pass. These LDL molecules can bind to extracellular matrix (ECM) in the wall’s thin subendothelial intima (SI) layer and accumulate there. On the other hand, the overall transmural water flow can dilute the local intima LDL concentration, thereby slowing its kinetics of binding to ECM, and flushes unbound lipid from the wall. An understanding of the nature of this water flow is clearly critical.
We have found that rat aortic endothelial cells express the ubiquitous membrane water-channel protein aquaporin-1 (AQP), and that blocking its water channel or knocking down its expression significantly reduces the apparent hydraulic conductivity Lp of the endothelium and, consequently of the entire wall. This decrease has an unexpected and strong DP -dependence. We present a fluid mechanics theory based on the premise that DP compacts the SI, which, as we show, lowers its Lp. The theory shows that blocking or knocking down AQP flow changes the critical DP at which this compaction occurs and explains our observed dependence of Lp on DP. Such compaction may affect lipid transport and accumulation in vivo. However, AQP’s sharp water selectivity gives rise to an oncotic paradox: the SI should quickly become hypotonic and shut down this AQP flow. The mass transfer problem resolve this paradox. The importance of aquaporin-based, rather than simply junctional water transport is that transport via protein channels allows for the possibility of active control of vessel Lp by up- or down-regulation of protein expression. We show that rat aortic endothelial cells significantly change their AQP numbers in response to chronic hypertension (high blood pressure), which may help explain the as yet poorly-understood fact that hypertension correlates with atherosclerosis. We also consider lowering AQP numbers as a strategy to affect disease progression.