1,186 research outputs found
From Strings to Graphs: Personalized Repeat-Aware Algorithms for Improved Long Read Structural Variant Detection
No full textSomatic structural variants have the ability to cause disease and drive disease progression. The identification of novel somatic structural variants in cancers is often based on the alignment of sequencing reads to a standard reference genome that while effective can be limited. Recent technological advancements have allowed for the use of personalized reference data, such as fully phased diploid assemblies of individuals, in the detection of novel somatic structural variants. In this thesis I present methods and analysis approaches that aim to show how personalized approaches to structural variant detection can help mitigate and reduce some of the current limitations of reference based detection methodsIn Chapter 2 I present a novel approach to quantifying the rate of retrotransposition in addition
to two pipelines to detect rare somatic retrotransposon insertions from long read sequencing data.
These approaches were designed to address limitations in previous rate estimates and allow for the
detection of rare somatic retrotransposon insertions with as little as one supporting read using a
personalized approach with a phased diploid assembly. I subsequently applied these methods to an
analysis of treated cancer samples to assess the efects of the treatment on retrotransposition rate.
In Chapter 3 I describe a phenomenon I term alignment ambiguity, where long read aligners may
represent a single insertion event diferently across multiple reads spanning the insertion, with insertion
calls for the same event possibly placed hundreds to thousands of bases away from each other.
I present a toolkit called somrit designed to address this alignment ambiguity, through the use of
local realignment guided by a consensus sequence. I subsequently show how somrit can be applied
to the detection of rare retrotransposon insertions, demonstrating how it has increased sensitivity
compared to existing approaches for the detection of rare events, and how local realignment can be
used to reduce false positive translocation calls tied to repeat-induced alignment errors.
Lastly in Chapter 4 I discuss challenges faced by current approaches to detect chromosomal translocations,
noting that current methods may generate many false positive calls tied to misalignments when using a read to linear reference alignments. I present SomvarG, a method that aligns reads to a
personalized sequence graph that contains paths for known variants to detect translocations. I then
show how SomvarG can generate sequence graphs that contain known variation not found in the linear
reference genome and how SomvarG can use these graphs to detect chromosomal translocations
with far fewer false positive calls and in less time.Ph.D
DNA fusion gene vaccination mobilizes effective anti-leukemic cytotoxic T lymphocytes from a tolerized repertoire
No full textThe majority of known human tumor-associated antigens derive from non-mutated self proteins. T cell tolerance, essential to prevent autoimmunity, must therefore be cautiously circumvented to generate cytotoxic T cell responses against these targets. Our strategy uses DNA fusion vaccines to activate high levels of peptide-specific CTL. Key foreign sequences from tetanus toxin activate tolerance-breaking CD4+ T cell help. Candidate MHC class Ibinding tumor peptide sequences are fused to the C terminus for optimal processing and presentation. To model performance against a leukemia-associated antigen in a tolerized setting, we constructed a fusion vaccine encoding an immunodominant CTL epitopederived from Friend murine leukemia virus gag protein (FMuLVgag) and vaccinated tolerant FMuLVgag-transgenic (gag-Tg) mice. Vaccination with the construct induced epitopespecificIFN-c-producing CD8+ T cells in normal and gag-Tg mice. The frequency and avidity of activated cells were reduced in gag-Tg mice, and no autoimmune injury resulted. However, these CD8+ T cells did exhibit gag-specific cytotoxicity in vitro and in vivo. Also, epitope-specific CTL killed FBL-3 leukemia cells expressing endogenous FMuLVgag antigen and protected against leukemia challenge in vivo. These results demonstrate a simple strategy to engage anti-microbial T cell help to activate epitope-specific polyclonal CD8+ T cell responses from a residual tolerized repertoire
Kanter Revisited: Gender, Power and (In)visibility
No full textThis paper revisits Kanter's (1977) seminal work Men and Women of the Corporation, rereading her account of numerical advantage and disadvantage through a poststructuralist lens which exposes hidden dimensions of gendered power. This lens is captured in the ‘(In)visibility Vortex’ (Lewis and Simpson, 2010) which highlights struggles and tensions around the norm through processes of preservation and concealment within the norm as well as dynamics of revealing, exposure and disappearance as features of the margins. The study draws on developments in feminist theorizing, specially around visibility, invisibility and power, to facilitate this rereading. In so doing, the author demonstrate that while Kanter retreated from explanations based on the gendering of organizations or from recognition of gendered power, these dynamics can be identified in her text. The authors suggest that rereading classic texts can surface dimensions of organizations that have contemporary significance and can inform future research
Spaces of contestation: the everyday experiences of ten African migrants in Cape Town
No full textIncludes bibliographical references.Xenophobia in South Africa is so overt that it has take a covert form. The 'xenocide' events that took place in 2008 were called xenophobic acts. It is the recurrent denialism of xenophobia on an everyday basis that this project has explored through the narrative accounts of ten African migrants in Cape Town. The lived everyday experiences of ten African migrants have brought forward the central argument of this thesis. From the data, it is evident that as a reponse to everyday pressures of prejudices and xenophobia in social and physical spaces, African migrants have developed mutable, unsettled and vagrant identities in order to cope with everyday low level violence. This argument emerged as four key stressors have been identified as the components of a more substantial explanation of xenophobia in South Africa. The four key components are: the enforcement of identity (national and group), the demarcation of spaces of belonging, the experiences of economic insecurity, and lastly a 'culture of violence' in South Africa. This thesis argues that these four stressors are the result of an on-going active process of xenophobic attitudes
"From Sit Ins to Sell Outs", circa 1960
No full textThis document has two articles; one is titled "From Sit-Ins to Sell-Outs. A Call to Action NOW" by Atmore T. Simpson, and the other article is titled "The Truth About the Atlanta Sit-downs and the Role of Martin Luther King" by C.B Williams. Simpson discusses the sell-out by the Black middle-class leadership in Atlanta, comparing it to the betrayal of Judas in the Bible. It criticizes the repeated betrayals by Black leadership and traces this pattern before to the time of Booker T. Washington. The recent sell-out involved an agreement between Black leaders and white merchants to reopen segregated lunch counters and eliminate boycotts and demonstrations. The article urges Black individuals to assert their determination, boycott downtown stores, support genuine leaders, and continue the struggle for freedom. It also highlights the discontent among students and the role of the Reverend Martin Luther King Jr. 1 page
Player agency in interactive narrative: audience, actor & author
No full textThe question motivating this review paper is, how can
computer-based interactive narrative be used as a constructivist learn-
ing activity? The paper proposes that player agency can be used to
link interactive narrative to learner agency in constructivist theory,
and to classify approaches to interactive narrative. The traditional
question driving research in interactive narrative is, ‘how can an in-
teractive narrative deal with a high degree of player agency, while
maintaining a coherent and well-formed narrative?’ This question
derives from an Aristotelian approach to interactive narrative that,
as the question shows, is inherently antagonistic to player agency.
Within this approach, player agency must be restricted and manip-
ulated to maintain the narrative. Two alternative approaches based
on Brecht’s Epic Theatre and Boal’s Theatre of the Oppressed are
reviewed. If a Boalian approach to interactive narrative is taken the
conflict between narrative and player agency dissolves. The question
that emerges from this approach is quite different from the traditional
question above, and presents a more useful approach to applying in-
teractive narrative as a constructivist learning activity
Imitative sequel writing: divine breathings, second part of the Pilgrim's Progress, and the case of T. S. (aka Thomas Sherman)
No full textDuring the period between 1640 and 1700, over forty works were produced by authors identifying themselves as ���T. S.��� In the field of early modern literary studies, one T. S. has been particularly important to scholars because of this author���s imitative version of John Bunyan���s popular allegory titled The Second Part of the Pilgrim���s Progress (1682). This work by T. S., who has become known as Thomas Sherman, achieves minor success and prompts Bunyan to write his own authentic sequel. My research has uncovered an attribution history that identifies four additional texts���Divine Breathings (circa 1671); Youth���s Tragedy (1671); Youth���s Comedy (1680); Divine Breathings, the Second Part (1680)���and credits all of them to a Thomas Sherman. Of the five works attributed to this author, the most impressive printing history belongs to the earliest offering, Divine Breathings, or a Pious Soul Thirsting after Christ in a Hundred Pathetical Meditations, which appears in over 60 printings from 1671 to 1883 in England, Scotland, and North America. My research scrutinizes this attribution history and raises questions about identifying this T. S. as Thomas Sherman. Based on internal and external evidence, I argue that T. S. is not the author of Divine Breathings but establishes his authorial identity as an imitative writer who actively participates in the genre of Protestant meditational literature by providing sequels (i.e., Divine Breathings ���the Second Part and Second Part of the Pilgrim���s Progress)
The outcome of juvenile court intervention on truancy among middle school students, 2005
No full textThis study investigated the outcome of juvenile court intervention on truancy among middle school students. Truancy, the unauthorized non-attendance of school has been a major problem for many schools across the United States and abroad. Research supports that truancy can be linked to substance use, low academic achievement, poor school performance and violence (Cho, Hallfors, Iriani, Khatapoush, & Saxe, 2002). These factors indicate the desperate need for changes in laws and programs that affect truancy and many states have begun developing such programs. The purpose of this study is to examine the impact of juvenile court intervention on truancy among middle school students. The sample population was taken from Joseph Emerson Brown Middle School (grades 6-8) located in Atlanta, Georgia and consisted of 30 student attendance records from the 2002 - 2003 and 2003 - 2004 school years. These students had been petitioned to juvenile court for truancy. Student attendance records prior to court intervention were compared with attendance records following court intervention, and a demographic questionnaire was developed and utilized. The data was analyzed using the One Sample T-test and descriptive statistics. A pre and posttest model was also used to determine the change in truancy. It was hypothesized that juvenile court intervention, the independent variable, would decrease truancy, the dependent variable, among middle school students ages 11-13. Findings from this study inferred that juvenile court intervention does not reduce truancy rates among students petitioned to appear in court. Because the study was not longitudinal, the researcher was unable to determine the long-term effects of juvenile court intervention on truancy. This study will aid education administrators in deciding whether to continue to utilize juvenile court as an intervention for truant students or to seek other measures to reduce absenteeism
Efficient de novo assembly of large genomes using compressed data structures
No full textDe novo genome sequence assembly is important both to generate new sequence assemblies for previously uncharacterized genomes and to identify the genome sequence of individuals in a reference-unbiased way. We present memory efficient data structures and algorithms for assembly using the FM-index derived from the compressed Burrows-Wheeler transform, and a new assembler based on these called SGA (String Graph Assembler). We describe algorithms to error-correct, assemble, and scaffold large sets of sequence data. SGA uses the overlap-based string graph model of assembly, unlike most de novo assemblers that rely on de Bruijn graphs, and is simply parallelizable. We demonstrate the error correction and assembly performance of SGA on 1.2 billion sequence reads from a human genome, which we are able to assemble using 54 GB of memory. The resulting contigs are highly accurate and contiguous, while covering 95% of the reference genome (excluding contigs <200 bp in length). Because of the low memory requirements and parallelization without requiring inter-process communication, SGA provides the first practical assembler to our knowledge for a mammalian-sized genome on a low-end computing cluster.</jats:p
Efficient construction of an assembly string graph using the FM-index
No full textAbstract
Motivation: Sequence assembly is a difficult problem whose importance has grown again recently as the cost of sequencing has dramatically dropped. Most new sequence assembly software has started by building a de Bruijn graph, avoiding the overlap-based methods used previously because of the computational cost and complexity of these with very large numbers of short reads. Here, we show how to use suffix array-based methods that have formed the basis of recent very fast sequence mapping algorithms to find overlaps and generate assembly string graphs asymptotically faster than previously described algorithms.
Results: Standard overlap assembly methods have time complexity O(N2), where N is the sum of the lengths of the reads. We use the Ferragina–Manzini index (FM-index) derived from the Burrows–Wheeler transform to find overlaps of length at least τ among a set of reads. As well as an approach that finds all overlaps then implements transitive reduction to produce a string graph, we show how to output directly only the irreducible overlaps, significantly shrinking memory requirements and reducing compute time to O(N), independent of depth. Overlap-based assembly methods naturally handle mixed length read sets, including capillary reads or long reads promised by the third generation sequencing technologies. The algorithms we present here pave the way for overlap-based assembly approaches to be developed that scale to whole vertebrate genome de novo assembly.
Contact: [email protected]</jats:p
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