לוח שנה משולב

A theory of cortical function is proposed, based on a family of recurrent neural circuits, called ORGaNICs (Oscillatory Recurrent GAted Neural Integrator Circuits). The theory is applied to working memory and motor control. Working memory is a cognitive process for temporarily maintaining and manipulating information. Most empirical neuroscience research on working memory has measured sustained activity during delayed-response tasks, and most models of working memory are designed to explain sustained activity. But this focus on sustained activity (i.e., maintenance) ignores manipulation, and there are a variety of experimental results that are difficult to reconcile with sustained activity. ORGaNICs can be used to explain the complex dynamics of activity, and ORGaNICs can be use to manipulate (as well as maintain) information during a working memory task. The theory provides a means for reading out information from the dynamically varying responses at any point in time, in spite of the complex dynamics. When applied to motor systems, ORGaNICs can be used to convert spatial patterns of premotor activity to temporal profiles of motor activity: different spatial patterns of premotor activity evoke different temporal response dynamics. ORGaNICs offer a novel conceptual framework; Rethinking cortical computation in these terms should have widespread implications, motivating a variety of experiments.

Much of our understanding of the biological mechanisms that underlie cellular functions, such as migration, differentiation and force sensing has been garnered from studying cells cultured on two-dimensional (2D) substrates. In the recent years there has been intense interest and effort to understand cell mechanics in three-dimensional (3D) cultures, which more closely resemble the in vivo microenvironment. However, a major challenge unique to 3D settings is the dynamic feedback between cells and their surroundings. In many 3D matrices, cells remodel and reorient local extracellular microenvironment, which in turn alters the active mechanics and in many cases, the cell phenotype. Most models for matrices to date do not account for such positive feedback. Such models, validated by experiments, can provide a quantitative framework to study how injury related factors (in pathological conditions such as fibrosis and cancer metastasis) alter extracellular matrix (ECM) mechanics. They can also be used to analyze tissue morphology in complex 3D environments such as during morphogenesis and organogenesis, and guide such processes in engineered 3D tissues. In this talk, I will present discrete network simulations to study how cells remodel matrices and how this remodeling can lead to force transmission over large distances in cells. I will also discuss an active tissue model to quantitatively study the influence of mechanical constraints and matrix stiffness on contractility and stability of micropatterned tissues.

Site-specific installation of paramagnetic lanthanide ions in proteins is a powerful method in delineating the structures, dynamics and interactions of proteins by NMR and EPR. Since most proteins do not have a paramagnetic center, efforts towards site-specific labeling of proteins with paramagnetic ions have thus been made via thiol chemistry, click chemistry, and molecular biology. The formation of disulfide bond between a protein and the paramagnetic tag is mostly applied in protein modifications, whereas the disulfide bond tether succumbs to low stability in reducing conditions or high pH. We have been focusing on development of paramagnetic tagging proteins in formation of a stable thioether bond for analysis of proteins in vitro and in cells using NMR and EPR. A number of stable paramagnetic tags have been designed and the performance of the respective protein conjugates has been evaluated in vitro and in cells by high resolution NMR spectroscopy. Using these high-performance paramagnetic tags, we were able to determine the 3D structure of a protein in live cells and 3D structure of unstable and short-lived thioester intermediate of Sortase A with pseudocontact shifts (PCSs) as structural restraints.