Beyond BLASTing : ribonucleoprotein evolution via structural prediction and ancestral sequence reconstruction

Primary homology in DNA and protein sequence has long been used to infer a relationship between similar sequences. However gene sequence, and thus protein sequence, can change over time. In evolutionary biology that time can be millions of years and related sequences may become unrecognisable via primary homology. This is demonstrated most effectively in chapter 4a (figure 10). Conversely the number of possible folds that proteins can adopt is limited by the attractions between residues and therefore the number of possible folds is not infinite. This means that folds may arise via convergence between evolutionarily unrelated DNA sequences. This thesis aims to look at a process to will wring more information from the primary protein sequence than is usually used and finds other factors that can support or refute the placement of a protein sequence within the family in question. Two quite different proteins; the Major Vault Protein whose monomers make up the enigmatic vault particle and the argonaute family of proteins (AGO and PIWI) that appear to have a major hand in quelling parasitic nucleic acid and control of endogenous gene expression, are used to demonstrate the flexibility of the workflow. Principally the method relies on prediction of three-dimensional structure. This requires at least a partially solved crystal structure but once one exists this method should be suitable for any protein. Whole genome sequencing is now a routine practice but annotation of the resultant sequence lags behind for lack of skilled personnel. Automated pipeline data does a good job in annotating close homologs but more effort is needed for correct annotation of the exponentially growing data bank of uncharacterised (and wrongly characterised) proteins. Lastly, in deference to budding biologists the world over, I have tried to find free stable software that can be used on an ordinary personal computer and by a researcher with minimal computer literacy to help with this task

Homogenization of two fluid flow in porous media

The macroscopic behavior of air and water in porous media is often approximated using Richards’ equation for the fluid saturation and pressure. This equation is parametrized by the hydraulic conductivity and water release curve. In this paper, we use homogenization to derive a general model for saturation and pressure in porous media based on an underlying periodic porous structure. Under an appropriate set of assumptions, i.e., constant gas pressure, this model is shown to reduce to the simpler form of Richards’ equation. The starting point for this derivation is the Cahn-Hilliard phase field equation coupled with Stokes equations for fluid flow. This approach allows us, for the first time, to rigorously derive the water release curve and hydraulic conductivities through a series of cell problems. The method captures the hysteresis in the water release curve and ties the macroscopic properties of the porous media to the underlying geometrical and material properties

Formulation of consumables management models. Volume 2: Mission planning processor user guide

A user guide for the MPP (Mission Planning Processor) is presented. The MPP is used in the evaluation of particular missions, with appropriate display and storage of related consumables data. Design goals are accomplished by the use of an on-line/demand mode computer terminal Cathode Ray Tube Display. The process is such that the user merely adds specific mission/flight functions to a skeleton flight and/or alters the skeleton. The skeleton flight includes operational aspects from prelaunch through ground support equipment connect after rollout as required to place the STS (Space Transportation System) in a parking orbit, maintain the spacecraft and crew for the stated on-orbit period and return

All That Sprawl, Y’all: An Analysis of Development on Steinwehr Avenue and York Street in Gettysburg, Pennsylvania, from 1971 to 2014

The advent of the automobile transformed the American landscape in the 20th century. In conjunction with the increasing importance of the automobile, numerous post-WW II government programs such as the Interstate Highway System encouraged suburban sprawl. Towns and cities adjacent to tourist attractions, known as gateway communities, face unique problems caused by sprawl. Gettysburg, Pennsylvania, is an example of a gateway community as it includes the Gettysburg National Military Park. Two study sites, portions of Steinwehr Avenue and York Street, were studied to analyze the effects of sprawl in Gettysburg. The sites were analyzed using ArcGIS, data compiled from historic phonebooks, and discussions with local business owners. Development along York Street exemplifies an auto-centric culture with many regional and national chain establishments set back from the road. Steinwehr Avenue represents a walkable community comprising on-street parking, sidewalks, and local “mom-and-pop” establishments. Trends associated with categories of businesses varied between the two sites and revealed different development patterns. We predict that that York Street will continue to sprawl while Steinwehr Avenue development will be limited due to its close proximity to the battlefield

Pharmacogenomics of anticoagulants: steps toward personal dosage

Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application

Pharmacogenomics of anticoagulants: steps toward personal dosage

Warfarin and other coumarin anticoagulants are widely used clinically, but currently dosing is determined individually on the basis of patient response. There is increasing evidence that genetic factors, together with several non-genetic patient-specific factors, are important determinants of stable dose requirement for these compounds. Genotype for CYP2C9, which encodes the main cytochrome P450 enzyme that metabolizes warfarin, and VKORC1, the gene encoding the warfarin target vitamin K epoxide reductase, together account for approximately 30% of the variability in dose requirement. The past two years have seen several advances in the area of genetic factors affecting coumarin anticoagulant response. In particular, prospective studies have taken place to analyze whether earlier small retrospective studies can be confirmed, and the question of whether genes other than CYP2C9 and VKORC1 are important in determining dose requirement has been examined. So far, no strong evidence that other genes contribute to dose requirement has been found, apart from a minor but novel role for another cytochrome P450 gene, CYP4F2. A recently published whole genome association study confirms that the main genes important in warfarin response are CYP2C9 and VKORC1. Clinical trials comparing genotype-guided and conventional warfarin initiation have suggested that genotyping may be of value, but larger studies are still needed to show clear clinical benefit. Current knowledge of genetic factors affecting other coumarin anticoagulants is more limited and this area requires further study, as does the impact of ethnic variation in genes relevant to coumarin responses. Here we review recent advances in the area of coumarin anticoagulant genetics and its potential clinical application