Integrated Calendar

Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per-gene basis. Analysis of large-scale melanoma exome data by this approach discovered 6 novel melanoma genes, 3 of which harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations we defined and provided new oncogenic insights in BRAF- and NRAS-driven melanoma and a subset without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provides unequivocal genomic evidence for a direct mutagenic role of UV in melanoma pathogenesis.

Proteomic technologies, next-generation sequencing and RNAi screens are providing increasingly detailed descriptions of the molecular changes that occur in diseases. However, it is difficult to assemble these data into a coherent picture that could lead to new therapeutic insights for several reasons. Despite their power, each of these methods still only captures a small fraction of the cellular response. Moreover, when different assays are applied to the same problem, they often provide apparently conflicting answers. We have developed powerful new approaches to integrate these data to identify small, functionally coherent networks that underlie cellular behavior. I will show that these methods suggest novel therapeutic strategies for the brain tumor glioblastoma multiforme.

Vigorous research in nanoscience and nanotechnology is expected to lead to exciting new applications, but considering that the first person to envision science at the nano scale was one of the greatest theoretical physicists of the last century, one should wonder whether we can expect to see any new physics emerging from this activity as well. I will attempt to answer this question by reviewing some exciting developments in the field of nanomechanics, emphasizing my particular interests, ranging from classical nonlinear dynamics, through mesoscopic physics of phonons, to the ultimate limit of QEM (quantum electromechanics).

Abstract.
Selenocysteine is the 21st encoded amino acid, found in several selenoproteins, most of which are redox selenoenzymes. Its resemblance to cysteine enabled its use for protein chemical synthesis and mechanistic studies. As they belong to the same group of elements in the periodic table, sulfur and selenium share many features including similar size, electronegativity and major oxidation states. However they differ in other properties, for example, selenium compounds are easier to oxidize and show greater electrophilic character. The selenium atom is also more polarizable than sulfur, so selenols are softer nucleophiles than thiols. Because selenols are substantially more acidic (ΔpKa ~3), selenocysteine is ionized at physiological pH, further enhancing its reactivity relative to cysteine. These properties make selenocysteine a valuable building block for constructing peptides and proteins with novel properties and as a tool for protein synthesis and folding studies. For example, native chemical ligation at selenocysteine followed by selective deselenization will enable chemical synthesis of proteins without protecting groups on cysteine residues. Additionally, targeted insertion of a non-native diselenide cross-link into a cysteine-rich protein can be exploited to direct the early stages of oxidative folding so as to avoid accumulation of unproductive intermediates that limit folding efficiency. This novel strategy could facilitate the production of many difficult-to-fold peptides and proteins. Results from

60 years ago, Hodgkin and Huxley published their seminal papers which described the kinetics of voltage-gated ionic currents in the squid giant axon and used these measurements to produce the fundamental model of action potential generation. Their findings have become the basis for our understanding of neuronal excitability and information processing and are central to computational models of neuronal function. However, it turns out that the precise activation and inactivation characteristics of voltage-gated sodium channels in the CNS can vary widely, not only depending on the brain region, cell type and molecular subunit, but also as a function of the location of channels within the neuron and their relationship to the local membrane cytoskeleton. These differences in current properties can have a profound functional impact. I will discuss our data on transient and persistent sodium currents in the various compartments of the cortical pyramidal neuron, collected in brain slices using whole-cell current and on-cell single channel recordings and imaging of sodium-sensitive fluorescent dyes.