Accurate estimation of homologue-specific DNA concentration-ratios in cancer samples allows long-range haplotyping

Interpretation of allelic copy measurements at polymorphic markers in cancer samples presents distinctive challenges and opportunities. Due to frequent gross chromosomal alterations occurring in cancer (aneuploidy), many genomic regions are present at homologous-allele imbalance. Within such regions, the unequal contribution of alleles at heterozygous markers allows for direct phasing of the haplotype derived from each individual parent. In addition, genome-wide estimates of homologue specific copy- ratios (HSCRs) are important for interpretation of the cancer genome in terms of fixed integral copy-numbers. We describe HAPSEG, a probabilistic method to interpret bi- allelic marker data in cancer samples. HAPSEG operates by partitioning the genome into segments of distinct copy number and modeling the four distinct genotypes in each segment. We describe general methods for fitting these models to data which are suit- able for both SNP microarrays and massively parallel sequencing data. In addition, we demonstrate a specially tailored error-model for interpretation of systematic variations arising in microarray platforms. The ability to directly determine haplotypes from cancer samples represents an opportunity to expand reference panels of phased chromosomes, which may have general interest in various population genetic applications. In addition, this property may be exploited to interrogate the relationship between germline risk and cancer phenotype with greater sensitivity than is possible using unphased genotype. Finally, we exploit the statistical dependency of phased genotypes to enable the fitting of more elaborate sample-level error-model parameters, allowing more accurate estimation of HSCRs in cancer samples

Effect of Corn Price on Profitability of Control Vs Phytase Enhanced Diet of Hogs

Economic Simulation model (SIMETAR) was used to investigate the effect of future corn price on profitability of control and phytase enhanced diet of hogs. The completed simulation model was used to estimate probability distribution for control vs lower excretion diet profitability under different corn prices. Data used was collected from recent field trials in Oklahoma that tested the effect of phytase enhanced diets on reducing phosphorus emission. The results showed that as the market price of corn increases control diet will be more profitable than phytase enhanced diet, given the cost of other remaining feed ingredient is constant for both the diets.profitability, SIMETAR, control diet, phytase enhanced diet, swine, Production Economics,

Analysis of alterations in the human cancer genome

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011.Cataloged from PDF version of thesis.Includes bibliographical references.Aneuploidy, an abnormal complement of chromosomes, is present in approximately 90% of human malignancies. Despite over 100 years of research, many questions remain regarding the contribution of aneuploidy to the cancer phenotype. In this thesis, we develop computational methods to infer the presence and specific patterns of aneuploidy across thousands of primary cancer tissue specimens. We then combine these inferences with clinical and genomic features of the cancer samples to refine our understanding of both the clinical implications of aneuploidy, and how it evolves in various human cancers. We identified a signature of chromosomal instability from specific genes whose expression was consistently correlated with aneuploidy in several cancer types, and which was predictive of poor clinical outcome multiple cancer types. Current genomic characterization techniques measure somatic alterations in a cancer sample in units of genomes (DNA mass). The meaning of such measurements is highly dependent on the tumors purity and its overall ploidy; they are hence complicated to interpret and compare across samples. Ideally, copy-number should be measured in copies-per-cancer-cell. Such measurements are straightforward to interpret and, for alterations that are fixed in the cancer cell population, are simple integer values. We develop two computational methods to infer tumor purity and malignant cell ploidy directly from allelic analysis of DNA. First we describe HAPSEG, a probabilistic method to interpret bi-allelic marker data in cancer samples in order to produce genome-wide estimates of homologue specific copy-ratios. Second, we describe ABSOLUTE, a method that infers purity, ploidy, and absolute copy-numbers from the estimates produced by HAPSEG. In addition, ABSOLUTE can analyze point mutations to detect subclonal heterogeneity and somatic homozygosity. We used ABSOLUTE to analyze ovarian cancer data and discovered that 54% of somatic point mutations were, in fact, subclonal. In contrast, mutations occurring in key tumor suppressor genes, TP53 and NF1 were predominantly clonal and homozygous. Analysis of absolute allelic copy-number profiles from 3,155 cancer specimens revealed that genome-doubling events are common in human cancer, and likely occur in already aneuploid cells in many cancer types. By correlating genome-doubling status with mutation data, we found that homozygous mutations in NF1 occurred predominantly in non-doubled samples. This finding suggests that genome doubling influences the pathways of tumor progression, with recessive inactivation being less common after genome doubling.by Scott L. Carter.Ph.D

Integral group actions on symmetric spaces and discrete duality symmetries of supergravity theories

For $G(\mathbb{R})$ a split, simply connected, semisimple Lie group of rank $n$ and $K$ the maximal compact subgroup of $G$, we give a method for computing Iwasawa coordinates of $G/K$ using the Chevalley generators and the Steinberg presentation. When $G/K$ is a scalar coset for a supergravity theory in dimensions $\geq 3$, we determine the action of the integral form $G(\mathbb{Z})$ on $G/K$. We give explicit results for the action of the discrete $U$--duality groups $SL_2(\mathbb{Z})$ and $E_7(\mathbb{Z})$ on the scalar cosets $SL_2(\mathbb{R})/SO_2(\mathbb{R})$ and $E_{7(+7)}(\mathbb{R})/[SU(8,\mathbb{R})/\{\pm Id\}]$ for type IIB supergravity in ten dimensions and 11--dimensional supergravity in $D=4$ dimensions, respectively. For the former, we use this to determine the discrete U--duality transformations on the scalar sector in the Borel gauge and we describe the discrete symmetries of the dyonic charge lattice. We determine the spectrum--generating symmetry group for fundamental BPS solitons of type IIB supergravity in $D=10$ dimensions at the classical level and we propose an analog of this symmetry at the quantum level. We indicate how our methods can be used to study the orbits of discrete U--duality groups in general

Einstein Cluster Alignments Revisited

We have examined whether the major axes of rich galaxy clusters tend to point toward their nearest neighboring cluster. We have used the data of Ulmer, McMillan, and Kowalski, who used position angles based on X-ray morphology. We also studied a subset of this sample with updated positions and distances from the MX Northern Abell Cluster Survey (for rich clusters ($R \geq 1$) with well known redshifts). A Kolmogorov-Smirnov (KS) test showed no significant signal for nonrandom angles on any scale $\leq 100h^{-1}$Mpc. However, refining the null hypothesis with the Wilcoxon rank-sum test, we found a high confidence signal for alignment. Confidence levels increase to a high of 99.997% as only near neighbors which are very close are considered. We conclude there is a strong alignment signal in the data, consistent with gravitational instability acting on Gaussian perturbations.Comment: Minor revisions. To be published in Ap

The Ecological Significance of Emerging Deltas in Regulated Rivers

Sedimentary deltas forming in the world’s regulated rivers are a glaring gap in our knowledge of dammed riverine ecosystems. Basic ecological information is needed to inform the current debate about whether deltas should be retained and managed to gain ecosystem services lost under reservoirs or whether they should be partially removed to improve flow conveyance and to resupply sediment-starved reaches below dams. An examination of nine deltas on the heavily regulated upper and middle Missouri River showed the following: The sizes, dynamics, and biotic communities vary widely across deltas; riparian forest has established on portions of most deltas; the current delta area is over 1000 square kilometers, exceeding forest area in remnant unimpounded reaches and offering considerable land area for restoration actions; and small adjustments to reservoir operations could improve the restoration potential of deltas. Ecological studies are urgently needed to determine the future role that deltas could play in river ecosystem restoration

A Co-moving Coordinate System for Relativistic Hydrodynamics

The equations of relativistic hydrodynamics are transformed so that steps forward in time preserves local simultaneity. In these variables, the space-time coordinates of neighboring points on the mesh are simultaneous according to co-moving observers. Aside from the time step varying as a function of the location on the mesh, the local velocity gradient and the local density then evolve according to non-relativistic equations of motion. Analytic solutions are found for two one-dimensional cases with constant speed of sound. One solution has a Gaussian density profile when mapped into the new coordinates. That solution is analyzed for the effects of longitudinal acceleration in relativistic heavy ion collisions at RHIC, especially in regards to two-particle correlation measurements of the longitudinal size

Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells.

Candida albicans is the most common cause of hematogenously disseminated and oropharyngeal candidiasis. Both of these diseases are characterized by fungal invasion of host cells. Previously, we have found that C. albicans hyphae invade endothelial cells and oral epithelial cells in vitro by inducing their own endocytosis. Therefore, we set out to identify the fungal surface protein and host cell receptors that mediate this process. We found that the C. albicans Als3 is required for the organism to be endocytosed by human umbilical vein endothelial cells and two different human oral epithelial lines. Affinity purification experiments with wild-type and an als3delta/als3delta mutant strain of C. albicans demonstrated that Als3 was required for C. albicans to bind to multiple host cell surface proteins, including N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. Furthermore, latex beads coated with the recombinant N-terminal portion of Als3 were endocytosed by Chinese hamster ovary cells expressing human N-cadherin or E-cadherin, whereas control beads coated with bovine serum albumin were not. Molecular modeling of the interactions of the N-terminal region of Als3 with the ectodomains of N-cadherin and E-cadherin indicated that the binding parameters of Als3 to either cadherin are similar to those of cadherin-cadherin binding. Therefore, Als3 is a fungal invasin that mimics host cell cadherins and induces endocytosis by binding to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells. These results uncover the first known fungal invasin and provide evidence that C. albicans Als3 is a molecular mimic of human cadherins