Domain-based small molecule binding site annotation

BACKGROUND: Accurate small molecule binding site information for a protein can facilitate studies in drug docking, drug discovery and function prediction, but small molecule binding site protein sequence annotation is sparse. The Small Molecule Interaction Database (SMID), a database of protein domain-small molecule interactions, was created using structural data from the Protein Data Bank (PDB). More importantly it provides a means to predict small molecule binding sites on proteins with a known or unknown structure and unlike prior approaches, removes large numbers of false positive hits arising from transitive alignment errors, non-biologically significant small molecules and crystallographic conditions that overpredict ion binding sites. DESCRIPTION: Using a set of co-crystallized protein-small molecule structures as a starting point, SMID interactions were generated by identifying protein domains that bind to small molecules, using NCBI's Reverse Position Specific BLAST (RPS-BLAST) algorithm. SMID records are available for viewing at . The SMID-BLAST tool provides accurate transitive annotation of small-molecule binding sites for proteins not found in the PDB. Given a protein sequence, SMID-BLAST identifies domains using RPS-BLAST and then lists potential small molecule ligands based on SMID records, as well as their aligned binding sites. A heuristic ligand score is calculated based on E-value, ligand residue identity and domain entropy to assign a level of confidence to hits found. SMID-BLAST predictions were validated against a set of 793 experimental small molecule interactions from the PDB, of which 472 (60%) of predicted interactions identically matched the experimental small molecule and of these, 344 had greater than 80% of the binding site residues correctly identified. Further, we estimate that 45% of predictions which were not observed in the PDB validation set may be true positives. CONCLUSION: By focusing on protein domain-small molecule interactions, SMID is able to cluster similar interactions and detect subtle binding patterns that would not otherwise be obvious. Using SMID-BLAST, small molecule targets can be predicted for any protein sequence, with the only limitation being that the small molecule must exist in the PDB. Validation results and specific examples within illustrate that SMID-BLAST has a high degree of accuracy in terms of predicting both the small molecule ligand and binding site residue positions for a query protein

Chapter 11: City-Wide Collaborations for Urban Climate Education

Although cities cover only 2 percent of the Earth's surface, more than 50 percent of the world's people live in urban environments, collectively consuming 75 percent of the Earth's resources. Because of their population densities, reliance on infrastructure, and role as centers of industry, cities will be greatly impacted by, and will play a large role in, the reduction or exacerbation of climate change. However, although urban dwellers are becoming more aware of the need to reduce their carbon usage and to implement adaptation strategies, education efforts on these strategies have not been comprehensive. To meet the needs of an informed and engaged urban population, a more systemic, multiplatform and coordinated approach is necessary. The Climate and Urban Systems Partnership (CUSP) is designed to explore and address this challenge. Spanning four cities-Philadelphia, New York, Pittsburgh, and Washington, DC-the project is a partnership between the Franklin Institute, the Columbia University Center for Climate Systems Research, the University of Pittsburgh Learning Research and Development Center, Carnegie Museum of Natural History, New York Hall of Science, and the Marian Koshland Science Museum of the National Academy of Sciences. The partnership is developing a comprehensive, interdisciplinary network to educate urban residents about climate science and the urban impacts of climate change

Temperature dependence of magnetic anisotropy in Mn-substituted cobalt ferrite

The temperature variation of magnetic anisotropy and coercive field of magnetoelastic manganese-substituted cobaltferrites (CoMnxFe2−xO4 with 0⩽x⩽0.6) was investigated. Major magnetic hysteresis loops were measured for each sample at temperatures over the range 10–400 K, using a superconducting quantum interference device magnetometer. The high-field regimes of the hysteresis loops were modeled using the law of approach to saturation equation, based on the assumption that at sufficiently high field only rotational processes remain, with an additional forced magnetization term that was linear with applied field. The cubic anisotropy constant K1 was calculated from the fitting of the data to the theoretical equation. It was found that anisotropy increases substantially with decreasing temperature from 400 to 150 K, and decreases with increasing Mn content. Below 150 K, it appears that even under a maximum applied field of 5 T, the anisotropy of CoFe2O4 and CoMn0.2Fe1.8O4 is so high as to prevent complete approach to saturation, thereby making the use of the law of approach questionable in these cases

Aircraft Conceptual Design Using Vehicle Sketch Pad

Vehicle Sketch Pad (VSP) is a parametric geometry modeling tool that is intended for use in the conceptual design of aircraft. The intent of this software is to rapidly model aircraft configurations without expending the expertise and time that is typically required for modeling with traditional Computer Aided Design (CAD) packages. VSP accomplishes this by using parametrically defined components, such as a wing that is defined by span, area, sweep, taper ratio, thickness to cord, and so on. During this phase of frequent design builds, changes to the model can be rapidly visualized along with the internal volumetric layout. Using this geometry-based approach, parameters such as wetted areas and cord lengths can be easily extracted for rapid external performance analyses, such as a parasite drag buildup. At the completion of the conceptual design phase, VSP can export its geometry to higher fidelity tools. This geometry tool was developed by NASA and is freely available to U.S. companies and universities. It has become integral to conceptual design in the Aeronautics Systems Analysis Branch (ASAB) here at NASA Langley Research Center and is currently being used at over 100 universities, aerospace companies, and other government agencies. This paper focuses on the use of VSP in recent NASA conceptual design studies to facilitate geometry-centered design methodology. Such a process is shown to promote greater levels of creativity, more rapid assessment of critical design issues, and improved ability to quickly interact with higher order analyses. A number of VSP vehicle model examples are compared to CAD-based conceptual design, from a designer perspective; comparisons are also made of the time and expertise required to build the geometry representations as well

Investigation of Exoskeletal Engine Propulsion System Concept

An innovative approach to gas turbine design involves mounting compressor and turbine blades to an outer rotating shell. Designated the exoskeletal engine, compression (preferable to tension for high-temperature ceramic materials, generally) becomes the dominant blade force. Exoskeletal engine feasibility lies in the structural and mechanical design (as opposed to cycle or aerothermodynamic design), so this study focused on the development and assessment of a structural-mechanical exoskeletal concept using the Rolls-Royce AE3007 regional airliner all-axial turbofan as a baseline. The effort was further limited to the definition of an exoskeletal high-pressure spool concept, where the major structural and thermal challenges are represented. The mass of the high-pressure spool was calculated and compared with the mass of AE3007 engine components. It was found that the exoskeletal engine rotating components can be significantly lighter than the rotating components of a conventional engine. However, bearing technology development is required, since the mass of existing bearing systems would exceed rotating machinery mass savings. It is recommended that once bearing technology is sufficiently advanced, a "clean sheet" preliminary design of an exoskeletal system be accomplished to better quantify the potential for the exoskeletal concept to deliver benefits in mass, structural efficiency, and cycle design flexibility

Active Learning Pipeline for Brain Mapping in a High Performance Computing Environment

This paper describes a scalable active learning pipeline prototype for large-scale brain mapping that leverages high performance computing power. It enables high-throughput evaluation of algorithm results, which, after human review, are used for iterative machine learning model training. Image processing and machine learning are performed in a batch layer. Benchmark testing of image processing using pMATLAB shows that a 100$\times$ increase in throughput (10,000%) can be achieved while total processing time only increases by 9% on Xeon-G6 CPUs and by 22% on Xeon-E5 CPUs, indicating robust scalability. The images and algorithm results are provided through a serving layer to a browser-based user interface for interactive review. This pipeline has the potential to greatly reduce the manual annotation burden and improve the overall performance of machine learning-based brain mapping.Comment: 6 pages, 5 figures, submitted to IEEE HPEC 2020 proceeding

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care

Prospectus, November 25, 1987

https://spark.parkland.edu/prospectus_1987/1026/thumbnail.jp