Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design

<p>Abstract</p> <p>Background</p> <p>Empirical scoring functions have proven useful in protein structure modeling. Most such scoring functions depend on protein side chain conformations. However, backbone-only scoring functions do not require computationally intensive structure optimization and so are well suited to protein design, which requires fast score evaluation. Furthermore, scoring functions that account for the distinctive relative position and orientation preferences of residue pairs are expected to be more accurate than those that depend only on the separation distance.</p> <p>Results</p> <p>Residue pair scoring functions for fixed backbone protein design were derived using only backbone geometry. Unlike previous studies that used spherical harmonics to fit 2D angular distributions, Gaussian Mixture Models were used to fit the full 3D (position only) and 6D (position and orientation) distributions of residue pairs. The performance of the 1D (residue separation only), 3D, and 6D scoring functions were compared by their ability to identify correct threading solutions for a non-redundant benchmark set of protein backbone structures. The threading accuracy was found to steadily increase with increasing dimension, with the 6D scoring function achieving the highest accuracy. Furthermore, the 3D and 6D scoring functions were shown to outperform side chain-dependent empirical potentials from three other studies. Next, two computational methods that take advantage of the speed and pairwise form of these new backbone-only scoring functions were investigated. The first is a procedure that exploits available sequence data by averaging scores over threading solutions for homologs. This was evaluated by applying it to the challenging problem of identifying interacting transmembrane alpha-helices and found to further improve prediction accuracy. The second is a protein design method for determining the optimal sequence for a backbone structure by applying Belief Propagation optimization using the 6D scoring functions. The sensitivity of this method to backbone structure perturbations was compared with that of fixed-backbone all-atom modeling by determining the similarities between optimal sequences for two different backbone structures within the same protein family. The results showed that the design method using 6D scoring functions was more robust to small variations in backbone structure than the all-atom design method.</p> <p>Conclusions</p> <p>Backbone-only residue pair scoring functions that account for all six relative degrees of freedom are the most accurate and including the scores of homologs further improves the accuracy in threading applications. The 6D scoring function outperformed several side chain-dependent potentials while avoiding time-consuming and error prone side chain structure prediction. These scoring functions are particularly useful as an initial filter in protein design problems before applying all-atom modeling.</p

Custom Integrated Circuits

Contains reports on six research projects.U.S. Air Force - Office of Scientific Research (Grant AFOSR-86-0164)U.S. Navy - Office of Naval Research (Contract N00014-80-C-0622)National Science Foundation (Grant ECS-83-10941

Identification of Methylated Genes Associated with Aggressive Bladder Cancer

Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation bead-array in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment

German Romantics

Scherzo from Piano Sonata in F Minor by Johannes Brahms (1833 -1897) Performed by David Fraley Faculty Mentor: Prof. Edward Francis The Scherzo is the third movement of Brahms’ massive five-movement sonata. It is written in triple meter and ternary form (ABA). The A section is called the scherzo, and the B section is called the trio. The scherzo is playful and whirling, a devilish waltz. After the tumultuous sweep of the scherzo, the trio provides welcome relief with stately major chords. Brahms’ music is often categorized by these sharp contrasts. Sometimes Brahms likes to emphasize similarities between each of the hands -- listen for the octave echoes between the right and left hand. After the trio ends, Brahms introduces a transitional section of music, which reintroduces the scherzo . Notice the return of the boisterous waltz and the way it transforms the major key of the trio back into the minor key of the scherzo. Selige Nacht by Joseph Marx (1882-1964), Poetry by Otto Erich Harleben (1864-1905) Performed by Jessica Ragsdale Faculty Mentor: Prof. Ida Nicolosi Written by Joseph Marx around 1913, Selige Nacht is a quintessential German Lied of the late German Romantic style. Otto Erich Hartleben’s poem uses imagery from nature, a common theme in Romantic poetry, to describe the poet’s peaceful night in bed with a lover. Joseph Marx uses chromaticism and polyrhythm to heighten the expressivity of the poem and embraces the impressionistic techniques that are characteristic of the late Romantic style. The accompaniment plays in triplets while the vocal line stays in duplet eighth notes. This creates a cross-rhythm that keeps the vocal line floating above the rolling piano texture. The piece centers around the key of A-flat but never really settles fully into the key, and there are no full cadences, leaving the listener in suspense and dependent on the vocal line to give direction and closure to the piece. Nachtgang by Richard Strauss (1864-1949), Poetry by Otto Julius Bierbaum (1865-1910) Performed by Andrew Leidenthal Faculty Mentor: Dr. Keith Coclough Richard Strauss was a late Romantic composer who was mostly known for his Lieder and opera. Emerging from the shadow of the romantic genius of Brahms, Mahler, and Wagner, Strauss\u27s compositional style emphasized pluralism, combining contemporary styles with traditional technique. This allowed him to compose a wide range of eclectic works over the course of eight centuries. Strauss was indifferent to the philosophic intentions in music which Wagner and Mahler exemplified, instead choosing to set texts of modern poets. His philosophy was to shine light on the paradoxes and inconsistencies of everyday life. In Nachtgang, Strauss turns a casual evening stroll into a highly emotional and spiritual encounter

Synthesis of (+)-Dynemicin A and Analogs of Wide Structural Variability: Establishment of the Absolute Configuration of Natural Dynemicin A.

Background: Dynemicin A is an exceedingly potent antitumor antibiotic derived from microbial fermentation that cleaves double-stranded B-form DNA in vitro in the presence of activating factors such as NADPH or glutathione. Because of the structural complexity, high reactivity, and scarcity of natural dynemicin A, it has not been feasible to modify the structure to any significant extent. Previous studies have not determined the absolute configuration of the natural product. Results: A multistep route for the preparation of enantiomerically pure, synthetic dynemicin A was developed. The absolute configuration of natural dynernicin was determined by comparing the synthetic drug with dynemicin A derived from fermentation. The route that was developed is highly convergent, as the result of a late-stage coupling reaction that combines two complex synthetic fragments, and has been shown to provide access to non-natural dynemicins of wide structural variability by modifications of these fragments. In this way, several nonnatural dynemicins, unavailable by any other means, were synthesized and shown to have DNA-cleaving activity in the presence of glutathione or NADPH. Conclusions: Enantiomerically pure dynernicin A is now available by laboratory synthesis. The natural, (+)-enantiomer of dynemicin A is shown to possess the 2S, 3S, 4S, 7R, 8R configuration. A wide variety of heretofore unavailable, active analogs of dynemicin A have been prepared and are found to produce subtle variations in sequence specificity of DNA cleavage compared to the natural product and, of potentially greater significance, display variations in the efficiency of DNA cleavage as a function of the activating agent.Chemistry and Chemical Biolog

DEVELOPMENT AND F-CLASS INDUSTRIAL GAS TURBINE ENGINE TESTING OF SMART COMPONENTS WITH DIRECT WRITE EMBEDDED SENSORS AND HIGH TEMPERATURE WIRELESS TELEMETRY

ABSTRACT The potential for savings provided to worldwide operators of industrial gas turbines, by transitioning from the current standard of interval-based maintenance to condition-based maintenance may be in the tens of millions of dollars per year. Knowledge of the historical and current condition of lifelimiting components will enable more efficient use of industrial gas turbine resources via increased operational flexibility, with less risk of unplanned outages as a result of off-parameter operations. To date, it has been impossible to apply true condition-based maintenance to industrial gas turbines because the extremely harsh operating conditions in the heart of a gas turbine preclude using the necessary advanced sensor systems to monitor the machine&apos;s condition continuously. The U. Wireless, Smart Turbine Components. The target was to develop a potentially industrychanging technology to build smart, self-aware engine components that incorporate embedded, harsh-environmentcapable sensors and high temperature capable wireless telemetry systems for continuously monitoring component condition in both the compressor and turbine sections. The approach involves several difficult engineering challenges, including the need to embed sensors on complex shapes, such as turbine blades, embedding wireless telemetry systems in regions with temperatures that preclude the use of conventional silicon-based electronics, protecting both sensors and wireless devices from the extreme temperatures and environments of an operating gas turbine, and successfully transmitting the senso