420 research outputs found
Categorizing the Unintended Side Effects of Genetic Transformation
From the Washington University Senior Honors Thesis Abstracts (WUSHTA), 2017. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Sciences; Lindsey Paunovich, Editor; Helen Human, Programs Manager and Assistant Dean in the College of Arts and Sciences Mentor: Michael R. Bren
Iterative Machine Learning of a Cis-Regulatory Grammar
Gene regulation allows for the quantitative control of gene expression. Gene regulation is a complex process encoded through cis-regulatory sequences, short DNA sequences containing clusters of transcription factor binding sites. Each binding site can occur millions of times in multicellular genomes, and seemingly similar collections of binding sites can have very different activities. A leading model to explain these degeneracies is that cis-regulatory sequences follow a “grammar” defined by the number, identity, strength, arrangement, and/or context of the underlying binding sites. Understanding cis-regulatory grammar requires high-throughput technology, quantitative measurements, and computational modeling. This thesis describes an iterative machine learning approach to study cis-regulatory grammar using mouse photoreceptors as a model system. First, I characterized sequence features associated with enhancer and silencer activity in sequences bound by the transcription factor CRX. I showed that both enhancers and silencers are highly occupied by CRX compared to inactive sequences, and enhancers are uniquely enriched for a diverse but degenerate collection of eight motifs. I demonstrated that this information captures a majority of the available signal in genomic sequences and developed an information content metric that summarizes the effects of motif number and diversity. Second, I developed an active machine learning framework that iteratively samples informative perturbations to address the limitations of training quantitative models on genomic sequences alone. I showed that this approach, when complemented with human decision-making, effectively guides machine learning models towards a biologically relevant representation of cis-regulatory grammar. I also highlighted how perturbations selected with active learning are more informative than other perturbations generated by the same procedure. The final machine learning model can capture global and local context-dependencies of transcription factor binding motifs. Using this model, I found that the same motifs can produce the same activity in multiple arrangements. Thus, active machine learning is an effective way to sample perturbations that improve quantitative models of cis-regulatory grammar. Collectively, these results provide an iterative framework to design and sample perturbations that reveal the complexities of cis-regulatory grammar underlying gene regulation
Transcription factor interactions explain the context-dependent activity of CRX binding sites
The effects of transcription factor binding sites (TFBSs) on the activity of a cis-regulatory element (CRE) depend on the local sequence context. In rod photoreceptors, binding sites for the transcription factor (TF) Cone-rod homeobox (CRX) occur in both enhancers and silencers, but the sequence context that determines whether CRX binding sites contribute to activation or repression of transcription is not understood. To investigate the context-dependent activity of CRX sites, we fit neural network-based models to the activities of synthetic CREs composed of photoreceptor TFBSs. The models revealed that CRX binding sites consistently make positive, independent contributions to CRE activity, while negative homotypic interactions between sites cause CREs composed of multiple CRX sites to function as silencers. The effects of negative homotypic interactions can be overcome by the presence of other TFBSs that either interact cooperatively with CRX sites or make independent positive contributions to activity. The context-dependent activity of CRX sites is thus determined by the balance between positive heterotypic interactions, independent contributions of TFBSs, and negative homotypic interactions. Our findings explain observed patterns of activity among genomic CRX-bound enhancers and silencers, and suggest that enhancers may require diverse TFBSs to overcome negative homotypic interactions between TFBSs
Pathogenic variants in CRX have distinct cis-regulatory effects on enhancers and silencers in photoreceptors
Dozens of variants in the gene for the homeodomain transcription factor (TF) cone-rod homeobox
Energy Release During Disk Accretion onto a Rapidly Rotating Neutron Star
The energy release L_s on the surface of a neutron star (NS) with a weak
magnetic field and the energy release L_d in the surrounding accretion disk
depend on two independent parameters that determine its state (for example,
mass M and cyclic rotation frequency f) and is proportional to the accretion
rate. We derive simple approximation formulas illustrating the dependence of
the efficiency of energy release in an extended disk and in a boundary layer
near the NS surface on the frequency and sense of rotation for various NS
equations of state. Such formulas are obtained for the quadrupole moment of a
NS, for a gap between its surface and a marginally stable orbit, for the
rotation frequency in an equatorial Keplerian orbit and in the marginally
stable circular orbit, and for the rate of NS spinup via disk accretion. In the
case of NS and disk counterrotation, the energy release during accretion can
reach . The sense of NS rotation is a factor that strongly
affects the observed ratio of nuclear energy release during bursts to
gravitational energy release between bursts in X-ray bursters. The possible
existence of binary systems with NS and disk counterrotation in the Galaxy is
discussed. Based on the static criterion for stability, we present a method of
constructing the dependence of gravitational mass M on Kerr rotation parameter
j and on total baryon mass (rest mass) m for a rigidly rotating neutron star.
We show that all global NS characteristics can be expressed in terms of the
function M(j, m) and its derivatives.Comment: 42 pages, 12 figures, to appear in Astronomy Letters, 2000, v.26,
p.69
Marjolin's ulcers: theories, prognostic factors and their peculiarities in spina bifida patients
<p>Abstract</p> <p>Background</p> <p>Due to improved care, more and more children born with spina bifida in rural Kenya are surviving into adulthood. This improved survival has led to significant challenges in their lifestyles, especially the need to ensure pressure ulcer prevention and treatment. Malignant degeneration of pressure ulcers in spina bifida patients is very rare. The author describes the clinical presentation of two pressure ulcer carcinomas that are at variance from classical descriptions.</p> <p>Materials and methods</p> <p>An internet/Medline/PubMed search of English literature for theories on Marjolin's ulcer evolution and prognostic features of Marjolin's ulcers was performed.</p> <p>A chart review of two young adults with spina bifida who had presented to the author's hospital between 2004 and August 2010 with chronic pressure ulcers found to be Marjolin's ulcers on histo-pathological examination was performed, and the clinical features are reported.</p> <p>Results</p> <p>The two ulcers appeared clinically benign: one was a deep ulcer, while the other was shallow; both had normal, benign-appearing edges, and a foul smelling discharge. The two ulcers were surrounded by induration and multiple communicating sinuses, with no evidence of chronic osteomyelitis. The internet search revealed a total of nine theories on Marjolin's ulcer development, as well as seven clinical and four histological prognostic features.</p> <p>Discussion</p> <p>The multifactorial theory, a coalescence of a number of proposed theories, best explains the evolution of Marjolin's ulcers. Poor prognostic features include pressure ulcer carcinomas, lesions and location in the lower limbs/trunks, all present in the two patients making their prognosis dim: this is despite the surgical margins being clear of tumor. Benign appearance, induration and presence of multiple communicating sinuses are features that have not been previously described as presenting features of pressure ulcers carcinomas.</p> <p>Conclusion</p> <p>There is need for spina bifida patients and their guardians/caretakers to receive a close follow-up throughout life; health education focused on pressure ulcer prevention as well as early treatment of pressure ulcers when they occur, will avert the development of Marjolin's ulcers, and save lives.</p
Extraordinary Molecular Evolution in the PRDM9 Fertility Gene
Recent work indicates that allelic incompatibility in the mouse PRDM9 (Meisetz) gene can cause hybrid male sterility, contributing to genetic isolation and potentially speciation. The only phenotype of mouse PRDM9 knockouts is a meiosis I block that causes sterility in both sexes. The PRDM9 gene encodes a protein with histone H3(K4) trimethyltransferase activity, a KRAB domain, and a DNA-binding domain consisting of multiple tandem C2H2 zinc finger (ZF) domains. We have analyzed human coding polymorphism and interspecies evolutionary changes in the PRDM9 gene. The ZF domains of PRDM9 are evolving very rapidly, with compelling evidence of positive selection in primates. Positively selected amino acids are predominantly those known to make nucleotide specific contacts in C2H2 zinc fingers. These results suggest that PRDM9 is subject to recurrent selection to change DNA-binding specificity. The human PRDM9 protein is highly polymorphic in its ZF domains and nearly all polymorphisms affect the same nucleotide contact residues that are subject to positive selection. ZF domain nucleotide sequences are strongly homogenized within species, indicating that interfinger recombination contributes to their evolution. PRDM9 has previously been assumed to be a transcription factor required to induce meiosis specific genes, a role that is inconsistent with its molecular evolution. We suggest instead that PRDM9 is involved in some aspect of centromere segregation conflict and that rapidly evolving centromeric DNA drives changes in PRDM9 DNA-binding domains
Adaptive Evolution in Zinc Finger Transcription Factors
The majority of human genes are conserved among mammals, but some gene families have undergone extensive expansion in particular lineages. Here, we present an evolutionary analysis of one such gene family, the poly–zinc-finger (poly-ZF) genes. The human genome encodes approximately 700 members of the poly-ZF family of putative transcriptional repressors, many of which have associated KRAB, SCAN, or BTB domains. Analysis of the gene family across the tree of life indicates that the gene family arose from a small ancestral group of eukaryotic zinc-finger transcription factors through many repeated gene duplications accompanied by functional divergence. The ancestral gene family has probably expanded independently in several lineages, including mammals and some fishes. Investigation of adaptive evolution among recent paralogs using dN/dS analysis indicates that a major component of the selective pressure acting on these genes has been positive selection to change their DNA-binding specificity. These results suggest that the poly-ZF genes are a major source of new transcriptional repression activity in humans and other primates
Specific and individuated death reflection fosters identity integration
Identity integration is the process wherein a person assimilates multiple or conflicting identities (e.g., beliefs, values, needs) into a coherent, unified self-concept. Three experiments examined whether contemplating mortality in a specific and individuated manner (i.e., via the death reflection manipulation) facilitated outcomes indicative of identity integration. Participants in the death reflection condition (vs. control conditions) considered positive and negative life experiences as equally important in shaping their current identity (Experiment 1), regarded self-serving values and other-serving values as equally important life principles (Experiment 2), and were equally motivated to pursue growth-oriented and security-oriented needs (Experiment 3). Death reflection motivates individuals to integrate conflicting aspects of their identity into a coherent self-concept. Given that identity integration is associated with higher well-being, the findings have implications for understanding the psychological benefits of existential contemplation
Measurement of the average time-integrated mixing probability of b-flavored hadrons produced at the Tevatron
We have measured the number of like-sign (LS) and opposite-sign (OS) lepton
pairs arising from double semileptonic decays of and -hadrons,
pair-produced at the Fermilab Tevatron collider. The data samples were
collected with the Collider Detector at Fermilab (CDF) during the 1992-1995
collider run by triggering on the existence of and candidates
in an event. The observed ratio of LS to OS dileptons leads to a measurement of
the average time-integrated mixing probability of all produced -flavored
hadrons which decay weakly, (stat.)
(syst.), that is significantly larger than the world average .Comment: 47 pages, 10 figures, 15 tables Submitted to Phys. Rev.
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