Molecular Systems Biology of ErbB1 Signaling: Bridging the Gap through Multiscale Modeling and High-Performance Computing

The complexity in intracellular signaling mechanisms relevant for the conquest of many diseases resides at different levels of organization with scales ranging from the subatomic realm relevant to catalytic functions of enzymes to the mesoscopic realm relevant to the cooperative association of molecular assemblies and membrane processes. Consequently, the challenge of representing and quantifying functional or dysfunctional modules within the networks remains due to the current limitations in our understanding of mesoscopic biology, i.e., how the components assemble into functional molecular ensembles. A multiscale approach is necessary to treat a hierarchy of interactions ranging from molecular (nm, ns) to signaling (μm, ms) length and time scales, which necessitates the development and application of specialized modeling tools. Complementary to multiscale experimentation (encompassing structural biology, mechanistic enzymology, cell biology, and single molecule studies) multiscale modeling offers a powerful and quantitative alternative for the study of functional intracellular signaling modules. Here, we describe the application of a multiscale approach to signaling mediated by the ErbB1 receptor which constitutes a network hub for the cell’s proliferative, migratory, and survival programs. Through our multiscale model, we mechanistically describe how point-mutations in the ErbB1 receptor can profoundly alter signaling characteristics leading to the onset of oncogenic transformations. Specifically, we describe how the point mutations induce cascading fragility mechanisms at the molecular scale as well as at the scale of the signaling network to preferentially activate the survival factor Akt. We provide a quantitative explanation for how the hallmark of preferential Akt activation in cell-lines harboring the constitutively active mutant ErbB1 receptors causes these cell-lines to be addicted to ErbB1-mediated generation of survival signals. Consequently, inhibition of ErbB1 activity leads to a remarkable therapeutic response in the addicted cell lines

ME-EM 2007 Annual Report

Table of Contents Research Expansion Research Groups Faculty & Staff Students Alumni Resources Graduates Publicationshttps://digitalcommons.mtu.edu/mechanical-annualreports/1011/thumbnail.jp

Quantum Communication, Sensing and Measurement in Space

The main theme of the conclusions drawn for classical communication systems operating at optical or higher frequencies is that there is a well‐understood performance gain in photon efficiency (bits/photon) and spectral efficiency (bits/s/Hz) by pursuing coherent‐state transmitters (classical ideal laser light) coupled with novel quantum receiver systems operating near the Holevo limit (e.g., joint detection receivers). However, recent research indicates that these receivers will require nonlinear and nonclassical optical processes and components at the receiver. Consequently, the implementation complexity of Holevo‐capacityapproaching receivers is not yet fully ascertained. Nonetheless, because the potential gain is significant (e.g., the projected photon efficiency and data rate of MIT Lincoln Laboratory's Lunar Lasercom Demonstration (LLCD) could be achieved with a factor‐of‐20 reduction in the modulation bandwidth requirement), focused research activities on ground‐receiver architectures that approach the Holevo limit in space‐communication links would be beneficial. The potential gains resulting from quantum‐enhanced sensing systems in space applications have not been laid out as concretely as some of the other areas addressed in our study. In particular, while the study period has produced several interesting high‐risk and high‐payoff avenues of research, more detailed seedlinglevel investigations are required to fully delineate the potential return relative to the state‐of‐the‐art. Two prominent examples are (1) improvements to pointing, acquisition and tracking systems (e.g., for optical communication systems) by way of quantum measurements, and (2) possible weak‐valued measurement techniques to attain high‐accuracy sensing systems for in situ or remote‐sensing instruments. While these concepts are technically sound and have very promising bench‐top demonstrations in a lab environment, they are not mature enough to realistically evaluate their performance in a space‐based application. Therefore, it is recommended that future work follow small focused efforts towards incorporating practical constraints imposed by a space environment. The space platform has been well recognized as a nearly ideal environment for some of the most precise tests of fundamental physics, and the ensuing potential of scientific advances enabled by quantum technologies is evident in our report. For example, an exciting concept that has emerged for gravity‐wave detection is that the intermediate frequency band spanning 0.01 to 10 Hz—which is inaccessible from the ground—could be accessed at unprecedented sensitivity with a space‐based interferometer that uses shorter arms relative to state‐of‐the‐art to keep the diffraction losses low, and employs frequency‐dependent squeezed light to surpass the standard quantum limit sensitivity. This offers the potential to open up a new window into the universe, revealing the behavior of compact astrophysical objects and pulsars. As another set of examples, research accomplishments in the atomic and optics fields in recent years have ushered in a number of novel clocks and sensors that can achieve unprecedented measurement precisions. These emerging technologies promise new possibilities in fundamental physics, examples of which are tests of relativistic gravity theory, universality of free fall, frame‐dragging precession, the gravitational inverse‐square law at micron scale, and new ways of gravitational wave detection with atomic inertial sensors. While the relevant technologies and their discovery potentials have been well demonstrated on the ground, there exists a large gap to space‐based systems. To bridge this gap and to advance fundamental‐physics exploration in space, focused investments that further mature promising technologies, such as space‐based atomic clocks and quantum sensors based on atom‐wave interferometers, are recommended. Bringing a group of experts from diverse technical backgrounds together in a productive interactive environment spurred some unanticipated innovative concepts. One promising concept is the possibility of utilizing a space‐based interferometer as a frequency reference for terrestrial precision measurements. Space‐based gravitational wave detectors depend on extraordinarily low noise in the separation between spacecraft, resulting in an ultra‐stable frequency reference that is several orders of magnitude better than the state of the art of frequency references using terrestrial technology. The next steps in developing this promising new concept are simulations and measurement of atmospheric effects that may limit performance due to non‐reciprocal phase fluctuations. In summary, this report covers a broad spectrum of possible new opportunities in space science, as well as enhancements in the performance of communication and sensing technologies, based on observing, manipulating and exploiting the quantum‐mechanical nature of our universe. In our study we identified a range of exciting new opportunities to capture the revolutionary capabilities resulting from quantum enhancements. We believe that pursuing these opportunities has the potential to positively impact the NASA mission in both the near term and in the long term. In this report we lay out the research and development paths that we believe are necessary to realize these opportunities and capitalize on the gains quantum technologies can offer

Engineering Division

The objectives of the Engineering Division are to provide an association for those having an interest in library and information science as they apply to engineering and the physical sciences and to promote the use of materials and knowledge for the benefit of libraries and other educational organizations