Development of Computer-Aided Molecular Design Methods for Bioengineering Applications

Computer-aided molecular design (CAMD) offers a methodology for rational product design. The CAMD procedure consists of pre-design, design and post-design phases. CAMD was used to address two bioengineering problems: design of excipients for lyophilized protein formulations and design of ionic liquids for use in bioseparations. Protein stability remains a major concern during protein drug development. Lyophilization, or freeze-drying, is often sought to improve chemical stability. However, lyophilization can result in protein aggregation. Excipients, or additives, are included to stabilize proteins in lyophilized formulations. CAMD was used to rationally select or design excipients for lyophilized protein formulations. The use of solvents to aid separation is common in chemical processes. Ionic liquids offer a class of molecules with tunable properties that can be altered to find optimal solvents for a given application. CAMD was used to design ionic liquids for extractive distillation and in situ extractive fermentation processes. The pre-design phase involves experimental data gathering and problem formulation. When available, data was obtained from literature sources. For excipient design, data of percent protein monomer remaining post-lyophilization was measured for a variety of protein-excipient combinations. In problem formulation, the objective was to minimize the difference between the properties of the designed molecule and the target property values. Problem formulations resulted in either mixed-integer linear programs (MILPs) or mixed-integer non-linear programs (MINLPs). The design phase consists of the forward problem and the reverse problem. In the forward problem, linear quantitative structure-property relationships (QSPRs) were developed using connectivity indices. Chiral connectivity indices were used for excipient property models to improve fit and incorporate three-dimensional structural information. Descriptor selection methods were employed to find models that minimized Mallow's Cp statistic, obtaining models with good fit while avoiding overfitting. Cross-validation was performed to access predictive capabilities. Model development was also performed to develop group contribution models and non-linear QSPRs. A UNIFAC model was developed to predict the thermodynamic properties of ionic liquids. In the reverse problem of the design phase, molecules were proposed with optimal property values. Deterministic methods were used to design ionic liquids entrainers for azeotropic distillation. Tabu search, a stochastic optimization method, was applied to both ionic liquid and excipient design to provide novel molecular candidates. Tabu search was also compared to a genetic algorithm for CAMD applications. Tuning was performed using a test case to determine parameter values for both methods. After tuning, both stochastic methods were used with design cases to provide optimal excipient stabilizers for lyophilized protein formulations. Results suggested that the genetic algorithm provided a faster time to solution while the tabu search provides quality solutions more consistently. The post-design phase provides solution analysis and verification. Process simulation was used to evaluate the energy requirements of azeotropic separations using designed ionic liquids. Results demonstrated that less energy was required than processes using conventional entrainers or ionic liquids that were not optimally designed. Molecular simulation was used to guide protein formulation design and may prove to be a useful tool in post-design verification. Finally, prediction intervals were used for properties predicted from linear QSPRs to quantify the prediction error in the CAMD solutions. Overlapping prediction intervals indicate solutions with statistically similar property values. Prediction interval analysis showed that tabu search returns many results with statistically similar property values in the design of carbohydrate glass formers for lyophilized protein formulations. The best solutions from tabu search and the genetic algorithm were shown to be statistically similar for all design cases considered. Overall the CAMD method developed here provides a comprehensive framework for the design of novel molecules for bioengineering approaches

Advances in functional neuroimaging in dementias and potential pitfalls

Neuroimaging is continuously advancing at a rapid rate and has progressed from excluding relatively uncommon secondary causes (stroke, tumor) to assisting with early diagnosis and subtype of dementia. Structural imaging has given way to functional, metabolic and receptor imaging

Competitive Lending with Partial Knowledge of Loan Repayment

We study a competitive credit market in which lenders with partial knowledge of loan repayment use one of three decision criteria – maximization of expected utility, maximin, or minimax regret – to make lending decisions. Lenders allocate endowments between loans and a safe asset, while borrowers demand loans to undertake investments. Borrowers may incompletely repay their loans when investment productivity turns out to be low ex post. We characterize market equilibrium, the contracted repayment rate being the price variable that equilibrates loan supply and demand. Supposing that a public Authority wants to maximize the net social return to borrowing, we study two interventions in the credit market to achieve this objective. One intervention manipulates the return on the safe asset and the other guarantees a minimum loan return to lenders. In a simple scenario, we find that manipulation of the return on the safe asset can be an effective way to achieve the socially desired outcome if lender beliefs about the return to lending are not too pessimistic relative to the beliefs of the Authority. Contrariwise, guaranteeing a minimum loan return can be effective if lender beliefs are not too optimistic relative to the beliefs of the Authority.

Intelligent Scanner

In today\u27s world, too much of teachers’ time is occupied with tedious work, such as grading homework and entering grades. These menial tasks distract teachers from their true purpose—teaching. The purpose of this project was to conduct a needs analysis for a tool to reduce the time spent on these tasks. We gathered and evaluated requirements for such a tool. The target user for this tool ranged from elementary to high school teachers. The main goal was to make it widely available for teachers, especially those in the public school system. We found that there was a large variability between different public schools, such as in technology literacy and school funding. This made it somewhat difficult to create a universal solution; however, there were commonalities that we could leverage

Describing Chaos: Willem de Kooning's Collage Painting Asheville and its Relationship to Traditions of Description and Illusionism in Western Art

Any study of Willem de Kooning is inevitably speculative. As an artist he was more concerned that the viewer "never know" and in provoking questions rather than presenting answers. The diverse and disjointed de Kooning literature bears witness to his success in this regard and to the opaque nature of his achievement. Recognizing the obdurate character of de Kooning's work, this essay, rather then directly pursuing meaning, has instead tried to address the question of how de Kooning's interest in eluding definition manifested itself in one of his most important collage paintings, Asheville of 1948. The first part of the thesis reconstructs the collage painting process of Asheville presenting it as a descriptive enterprise in which de Kooning consciously pursued the more chaotic "unknowable" aspects of his visual life by illusionistically recording fragments of objects and momentary glimpses of events. Recognizing de Kooning's interest in depicting fragmented phenomena as the underlying source for the visual chaos of Asheville illuminates the painting's relationship to long established traditions of description and illusion in Western art exemplified by the letter rack paintings of 19th century American art and 17th century Dutch art. Finally, as the contentious debate over meaning in Dutch painting illustrate, descriptive works of art, because of the ambivalent way they engage disordered aspects of visual experience, are particularly difficult to interpret. In his conscious allegiance to older descriptive and illusionistic traditions in Asheville de Kooning had found an especially effective way to obscure meaning

Do Gamma-Ray Burst Sources Repeat?

The demonstration of repeated gamma-ray bursts from an individual source would severely constrain burst source models. Recent reports (Quashnock and Lamb 1993; Wang and Lingenfelter 1993) of evidence for repetition in the first BATSE burst catalog have generated renewed interest in this issue. Here, we analyze the angular distribution of 585 bursts of the second BATSE catalog (Meegan et al. 1994). We search for evidence of burst recurrence using the nearest and farthest neighbor statistic and the two-point angular correlation function. We find the data to be consistent with the hypothesis that burst sources do not repeat; however, a repeater fraction of up to about 20% of the observed bursts cannot be excluded.Comment: ApJ Letters, in press, 13 pages, including three embedded figures. uuencoded Unix-compressed PostScrip

Investigation of Water Quality in the Ashepoo-Combahee-Edisto (ACE) Basin NERR: A GIS Approach

2010 South Carolina Water Resource Conference. Informing strategic water planning to address natural resource, community and economic challenges

Assessment of commercially available computerized neurocognitive testing in the adolescent concussed athlete: A retrospective analysis.

Background: Clinicians frequently use computer-based neurocognitive assessments to aid in the diagnosis and management of Sport Related Concussion (SRC). With practitioners using varied Neuro-Cognitive Assessment Tools (NCAT), questions arise concerning among NCAT and how these differences may affect patient care. The purpose of the current study is to offer a comparative analysis of two widely accepted, commercially available computer-based neurocognitive testing modalities in the adolescent concussed athlete. Hypothesis: There will be a difference between the C3 Logix® vs ImPACT® scoring in the IRPT and RTP Study Design: Retrospective chart review. Methods: In order to identify patients that were diagnosed with SRC, the records of patients reporting to a Sports Medicine practice were reviewed from a period of 18 months. All patients were assessed with either the ImPACT® or C3 Logix NCAT®. The date of the injury (DOI) as well as the patient’s symptom level (IVAL), time to initiation of the return to play protocol (IRTP), and time to the return to play (RTP) were recorded. Results: Two hundred and twenty-two records (222) were identified. There was no difference in the symptom score (P = 0.22) at the IEVAL between C3 Logix® (31.5±27.0) and ImPACT® (23.2±21.9), in the IRTP (P = 0.22) between the C3 Logix® (6.2±4.3 days) and ImPACT® (5.1±4.3 days) or RTP (P = 0.46) between C3 Logix (12.1±4.9 days) and ImPACT (15.6±19.8 days). Weak to moderate correlations were found between symptom scores, IRTP, and RTP. Conclusions: Clinicians made similar recommendations, independent of the NCAT used, as when to initiate the return to play protocol and when the patient could ultimately return to play. Clinical Relevance: The particular NCAT utilized by clinician was not a primary factor in the clinical judgement towards the management of the patient with SRC