VictorJuiz/thesis huggingface dataset:
Regulatory controls of microRNA genes beyond the mature microRNAs [electronic resource]

MicroRNA (miRNA) genes, which encode an abundant class of ~22-nucleotide (nt), evolutionarily conserved small RNAs, control a fundamental layer of genetic programs at the post-transcriptional level. However, little is known about how the activity of miRNA genes is regulated and how the regulatory information controlling their activity is encoded. Interestingly, mature miRNAs can often be classified into large families consisting of members with identical seeds (nucleotides 2 through 8 of the mature miRNAs) and highly homologous ~22-nt mature miRNA sequences, but with divergent sequences and structural elements beyond their mature miRNAs. Here we investigated whether members of a miRNA gene family that encode identical or nearly identical mature miRNAs are functionally interchangeable in vivo and if not, why? We compare the activities of the mir-181 gene family in promoting double positive T cell development and show that miRNA genes that encode identical to nearly identical mature miRNAs can have distinct activities. The differences in activity between mir-181a-1 and mir-181c are largely determined by their unique primary/precursor-miRNA (pri/pre-miRNA) loop nucleotides, and the differences in activity between mir-181a-1 and mir-181b-1 are determined by both the pri/pre-miRNA loop and stem. Furthermore, the organization of mir-181a-1/b-1 in a cluster is important for its full activity. We also show that mir-181 family members can differentially regulate target genes quantitatively, and that some target genes can be upregulated. Taken together, we have demonstrated that regulatory information encoded in a miRNA gene beyond the mature miRNA plays a critical role in controlling the activity of the miRNA gene, suggesting that miRNA family members could have evolved different functions through their divergent miRNA gene sequences and structural elements beyond their mature miRNAs. Although, proteins may have evolved to recognize the structural and sequence elements of the pri/pre-miRNAs, we suggest that the regulatory information encoded in the structured pri/pre-miRNA may be directly interpreted through target and pri/pre-miRNA interactions.

Keywords: Microbiology and Immunology.
Advisor: Chen Chang-Zheng primary advisor. Thesis advisor
Blau Helen M. advisor. Thesis advisor
Fire Andrew Zachary advisor. Thesis advisor
Sarnow P. (Peter) advisor. Thesis advisor
Relating time series in data to spatial variation in the reservoir using wavelets [electronic resource]

An important issue in reservoir parameter estimation is to develop methods that are computationally efficient and reliable. Furthermore, in history matching, one of the challenges in the use of gradient-based Newton algorithms such as Gauss-Newton and Levenberg-Marquardt in solving the inverse problem is the huge cost associated with the computation of sensitivity matrix. Although the Newton type of algorithm gives faster convergence than most other gradient-based inverse solution algorithms, its use is limited to small and medium-scale problems in which the sensitivity coefficients are easily and quickly computed. Modelers often use less efficient algorithms such as conjugate-gradient and quasi-Newton to model large-scale problems because these algorithms avoid the direct computation of sensitivity coefficients. To find a direction of descent, such algorithms often use less precise curvature information that would be contained in the gradient of the objective function. Using a sensitivity matrix gives more detailed information about the curvature of the function; however this comes with a significant computational cost for large-scale problems. We present a multiresolution wavelet approach to estimate the spatial distribution of reservoir parameters, by performing the nonlinear least squares regression in the wavelet domains of both time and space. Wavelet transforms have the ability to reveal important events in time signals or spatial images. Thus we transformed both the model space and the time series pressure data into spatial wavelet and time wavelet domains and used a thresholding to select a subset of wavelet coefficients from each of the transformed domains. These subsets were used subsequently in nonlinear regression to estimate the appropriate description of reservoir parameters. The appropriate subset is not only smaller; the problem is also reduced to the consideration of only the important components of the measured data and only the part of the reservoir description that depends on them. Furthermore, the approach developed in this research improves parameter estimation by reducing the dimension of the inverse problem without significant loss in accuracy. We transformed the inverse problem into reduced wavelet spaces and subsequently coupled the transformation with adjoint sensitivity formulation to reduce the cost associated with computing sensitivity coefficients. The improved adjoint sensitivity formulation presented in this work exploits the reduction in observation (data) space to enforce a reduction in the adjoint linear system of equations thus leading to a reduction in the memory and time required to compute sensitivities. We were able to achieve up to 20 times reduction in computational requirements in some example cases.

Keywords: Energy Resources Engineering
Advisor: Horne Roland N. primary advisor. Thesis advisor
Durlofsky Louis advisor. Thesis advisor
Gerritsen Margot (Margot G.) advisor. Thesis advisor
Replacing the "teacher-proof" curriculum with the "curriculum-proof" teacher [electronic resource] : toward a more systematic way for mathematics teachers to interact with their textbooks

This research examines when and how secondary mathematics teachers adapt textbook curricula within "typical" cycles of planning and teaching over the course of a school year. The curriculum use of four middle and high school teachers was examined before (September) and after (December, March) engagement in a form of professional development called the Mathematics Curriculum Assessment and Adaptation (MCAA) process. Classroom materials were collected from teachers at three distinct points in the school year, at which time teachers were observed and interviewed about their planning and teaching practices. Overall, the number of textbook materials teachers used as-is dropped dramatically while the number of materials they adapted increased. This finding was true regardless of teaching experience, teaching context, textbook used or content taught, and was reflected in changes in teachers' commentaries about their planning and teaching and changes in classroom practice. Furthermore, the types of adaptations teachers made to their curricula were more reflective of the MCAA process in March than they were in the beginning of the school year. This dissertation research sits within the broader domain of understanding how mathematics teachers use curriculum and raises new questions about how, when and why teachers make changes to textbook materials.

Keywords: Education.
Advisor: Murata Aki primary advisor. Thesis advisor
Boaler Jo
Borko Hilda advisor. Thesis advisor
Stipek Deborah J.
Reproduction and early life of the Humboldt squid [electronic resource]

Dosidicus gigas, the Humboldt squid, is endemic to the eastern Pacific, and its range has been expanding poleward in recent years. It is a voracious predator of small fish and invertebrates and prominent prey for large fish and mammals, including humans. Very little is known about Humboldt squid reproduction, development, and early life stages. To study the behavior, including dispersal capabilities, of paralarval D. gigas, I analyzed video of animals swimming in the laboratory, and determined that paralarvae are active swimmers that engage in hop-and-sink behavior. Control of the mantle aperture allows them to engage in slow swimming, in which water is leaked through the mantle aperture, and fast jetting, in which the mantle aperture is tightly closed and all water is expelled through the siphon--as is typical of adult jetting. A theoretical model of squid swimming was built to study the importance of aperture control during the jet cycle. This model predicts that active reduction of the aperture during jetting increases hydrodynamic efficiency, and that squid of large sizes can constrain the risk of embolism by increasing aperture size and decreasing jet frequency to values comparable to empirical measurements. Connectivity among populations of D. gigas throughout the range of this species was assessed with a population genetic approach, in which D. gigas was compared to the co-occurring squid Sthenoteuthis oualaniensis. In D. gigas, only two weakly differentiated populations were evident, with a biogeographic break at 5-6° N. I uncovered four deeply divergent clades in S. oualaniensis, including one which aligns with previous descriptions in the literature of Sthenoteuthis sp. nov. Breaks between clades of S. oualaniensis also occurred at 5-6° N. Range overlap between these two species occurs in the eastern tropical Pacific (ETP), a region both are believed to use as spawning grounds. I looked for paralarvae of D. gigas and S. oualaniensis in surface and subsurface net tows taken in the ETP from 1998 to 2006, and found that abundance was much greater in surface than subsurface tows. I then used a Generalized Linear Model approach to assess the importance of in situ oceanographic variables as predictors of paralarval incidence. Sea surface temperature was found to be a strong predictor of incidence in both surface and subsurface tows, with the probability of paralarval capture rising monotonically from near zero at 15 °C to 0.9 at 30 °C. The apparent lack of paralarvae at surface temperatures below 15 °C raises a question of whether D. gigas can spawn in the temperate and even subpolar waters of its expanded range. I conducted in vitro fertilization studies and found the optimal temperature range for successful laboratory development of D. gigas is 15-25° C.

Keywords: Biological Sciences.
Advisor: Gilly William primary advisor. Thesis advisor
Denny Mark W.
Somero George N. advisor. Thesis advisor
A robust platform for high-throughput genomics in microorganisms [electronic resource]

Accurate, large-scale gene annotation is a major challenge in biology. Traditionally, gene function can be assigned by observing the phenotype of a null mutant under various conditions. This principle has engendered the creation of genome-wide deletion collections in which each gene in a genome is knocked out or disrupted. Phenotype can then be assayed for each gene knockout individually. Parallelization of phenotypic assays via the introduction of molecular barcodes has proved invaluable for interrogating genome-wide collections of mutants in many conditions. This approach has been most visibly successful in the case of the budding yeast Saccharomyces cerevisiae, but it has the potential to bring insight to the genomes of many more microorganisms. The strategy of creating the genome-wide mutant collections that permit parallel phenotypic analysis has not been broadly applied beyond S. cerevisiae due primarily to technical limitations. In this dissertation, we describe a universal approach to rapidly generate comparable tagged, mutant collections. This approach combines DNA tag technology with transposon mutagenesis, and thereby can be generalized to any microorganism amenable to transposon mutagenesis. We created a universal collection of tags whose utility can extend to any application requiring sample tracking or multiplexing. We describe the validation of this tag resource as well as its use in the transposon mutagenesis of two different microorganisms, the bacteria Shewanella oneidensis MR-1 and the yeast Candida albicans. We then describe the expansion of this method to generate a genome-wide tagged transposon mutant collection in C. albicans. We used this collection to identify i) haploinsufficient genes in different nutrient conditions, and ii) mechanisms of drug-induced haploinsufficiency in C. albicans, and illustrated how these data can be used as a resource for genome annotation and hypothesis generation. Moreover, these studies illustrate why direct study of C. albicans is necessary, because relying solely on similarities between its traditional model organism, S. cerevisiae, would result in exclusion of C. albicans-specific genes and processes that are involved in its pathogenesis and may prove to be novel therapeutic targets.

Keywords: Genetics
Advisor: Davis Ronald W. (Ronald Wayne)
Nislow Corey
Pringle John
Sherlock Gavin advisor. Thesis advisor
The role of endocytosis in neuronal migration [electronic resource]

Disruptions in neuronal migration have been implicated in a variety of human mental disorders, including epilepsy, autism, and schizophrenia. Despite the critical role of migration during nervous system development, the basic physical and cytoskeletal mechanisms of coordinated neuronal movement have not yet been fully characterized. A migrating neuron moves with morphologically distinct steps: a single leading process extends ahead of a stationary cell soma, followed by the formation of a cytoplasmic dilation ahead of the nucleus, subsequent movement of the nucleus into the dilation, and retraction of the cell rear. The temporal and spatial regulation of adhesion is important for the proper progression of these steps. I investigated the role of endocytosis in regulating adhesion during neuronal migration. Using genetic and pharmacological methods to disrupt endocytosis either in vitro or in vivo leads to altered neuronal migration. Introducing dominant negative clathrin or dynamin into the developing cortex delays radial migration in vivo. Pharmacologically inhibiting clathrin or dynamin reduces the velocity of anterior subventricular zone (SVZa) neurons migrating in a three-dimensional matrix in vitro. Components of clathrin endocytic machinery are localized to the dilation region of a migrating neuron at points of matrix attachment. The absence of adhesion molecules at the cell rear led us to the hypothesis that endocytosis weakens adhesions in the dilation to allow the cell rear to move forward during migration. In support of this hypothesis, exposing SVZa explants to pharmacological inhibitors of either clathrin or dynamin prevents migration out of explants, and neurons that have migrated out have altered morphology and adhesion molecule distribution. Neurons exposed to a dynamin inhibitor tend to have "tails" of membrane at the rear, and these tails contain adhesion molecules. The presence of adhesion molecules at the rear of migrating neurons exposed to a dynamin inhibitor supports the idea that endocytosis plays a role in regulating adhesion disassembly. Endocytosis likely plays a critical role in general neuronal migration regardless of the specific neuronal subtype, migration mode, or substrate.

Advisor: McConnell Susan K. primary advisor. Thesis advisor
Clandinin Thomas R. (Thomas Robert)
Shen Kang
The role of glycoprotein H in Varicella-zoster virus pathogenesis [electronic resource]

Glycoprotein H (gH) plays an essential role in virus binding, entry and fusion of the Herpesviridae. Varicella-zoster virus (VZV) is an important human pathogen that causes varicella (chicken pox) and herpes zoster (shingles). VZV gH function has not be analyzed in depth. gH function was demonstrated to be important for VZV pathogenesis in skin xenografts in vivo by administration of anti-gH mAb 206, a conformation dependent neutralizing antibody. Antibody administration prevented infection in 42% of skin xenografts, and reduced virus replication and lesion formation in the remaining skin xenografts. Antibody binding to gH altered gH localization following endocytosis, preventing gH trafficking to the trans-Golgi network for virus secondary envelopment. Antibody binding to gH within the virus envelope resulted in internalization of virus particles, possibly for targeted degradation. Deletion of ORF 37, which encodes gH, demonstrated that gH was essential for VZV pathogenesis. Mutational analysis demonstrated that the N-terminus of the protein formed a structural epitope required for efficient VZV pathogenesis in vivo. Several neutralizing anti-gH antibodies target this epitope. A region of the C-terminus was required for VZV pathogenesis, and for efficient virus-induced cell-cell fusion. Predicted [alpha]-helices that might act as heptad repeats or fusion peptides were also required for gH function and VZV pathogenesis. Cysteine residues were important for gH maturation and transport, and possibly for correct expression of gH on the cell surface. Altogether, these studies demonstrate the importance of structural and functional domains for gH-dependent fusion and VZV pathogenesis.

Keywords: Microbiology and Immunology
Advisor: Arvin Ann M. primary advisor. Thesis advisor
Glenn Jeffrey S.
Greenberg Harry B. advisor. Thesis advisor
Kirkegaard Karla advisor. Thesis advisor
The role of natural killer cells and activating receptors on natural killer cells in transplantation [electronic resource]

Natural killer (NK) cells are an important component of the innate immune system. NK cells have cytotoxic and cytokine-producing abilities, and are known for their anti-tumor and anti-viral roles. On the other hand, the role of NK cells in solid organ transplantation is not clear. Our studies and others have shown that NK cells infiltrate allografts and NK cell depletion prevents graft rejection. We further described that NK cell depletion prevents tolerance induction in a rat liver transplant model of spontaneous tolerance. NK cell functions are determined by a balance of signals transmitted through their inhibitory and activating receptors. We showed that distinct NK activating receptors - NKp46, NKp30 and NKG2D, mediate NK cell interactions with dendritic cells (DC) and hepatoma tumor cells in vitro, presenting a way to perturb NK-DC interactions while retaining tumor responsiveness. Finally, initial experiments with NKG2D knockout mice showed that NKG2D deficiency combined with costimulation blockade prolongs allograft survival, suggesting that NKG2D inhibition may improve future costimulation blockade therapies. Importantly, current immunosuppressive drugs used to control graft rejection have differential effects on NK cell function. Thus understanding the interactions NK cells have with the graft and other immune cells in the context of transplantation is essential for improving transplantation therapeutics.

Advisor: Krams Sheri Michele primary advisor. Thesis advisor
Jones Patricia P. advisor. Thesis advisor
Negrin Robert S. advisor. Thesis advisor
Parham Peter
The role of processing complexity in word order variation and change [electronic resource]

All normal humans have the same basic cognitive capacity for language. Nevertheless, the world's languages differ in the kind and number of grammatical options they give their speakers to express themselves with. Sometimes, a language's grammatical constructions may differ in how easy they are for comprehenders to process or how readily speakers will choose them. It has been observed that languages which allow more difficult constructions also tend to allow easier ones, and when a language only allows one option, it tends to allow the easiest to process. This correlation is intuitive: languages tend to give their speakers options that they find easy to use. However, the causal process that underlies it is not well understood. How did the world's languages come to have this convenient property? In this dissertation, I discuss a family of evolutionary models of language change in which processing-efficient variants tend to be selected more frequently, and hence over time have the potential to displace less efficient variants, pushing them out of the language. I begin by showing that a psycholinguistic theory, dependency length minimization, accounts for word ordering preferences in data taken from Old and Middle English just as it does in Present Day English. I then discuss computer simulations of a model of language change which implements this bias, predicting observed word order changes in English. Finally, I present experimental studies of online comprehension in Japanese which not only display evidence for the dependency length bias, but also suggest that comprehenders encode it as part of their knowledge about language, using it to help understand the sentences they receive from their peers.

Keywords: Linguistics.
Advisor: Wasow Thomas primary advisor. Thesis advisor
Anttila Arto advisor. Thesis advisor
Jurafsky Dan
Levy Roger advisor. Thesis advisor
The role of solvent in protein folding in vivo [electronic resource]

How a protein folds from an unstructured heteropolymer into a unique native structure is an important unanswered question in the field of molecular biophysics. In recent years, there have been a number of experiments and computer simulations that have provided insight into the mechanism by which folding occurs. Most of these experiments and simulations measure the dynamics of proteins in infinite dilution. However, bulk solvent is different from the cellular environment in which proteins truly fold. In vivo, protein dynamics occur in the context of the crowded cellular milieu as well as in confined spaces such as the chaperonin cavity, the proteosome, the ribosome exit tunnel, the translocon, etc. When considering these factors it is reasonable to assume that proteins may experience different microenvironments when folding in vivo than in bulk, and these differences may constitute a significant piece of the folding puzzle. Here we show via molecular dynamics simulation, that the presence of solvent when confining a mini- protein affects the probability and mechanism of folding. In a separate study, we use computer simulation to calculate the physical properties of water confined to the ribosome exit tunnel. We find that this solvent is quite different from bulk water, possessing a highly heterogeneous free energy landscape containing extensive water structure, areas of reduced solvent entropy. Finally we show that the foldase activity of GroEL cavity mutants is highly correlated with the hydrophilicy of the inner cavity.

Advisor: Pande Vijay primary advisor. Thesis advisor
Kasson Peter M.
Frydman Judith advisor. Thesis advisor
Levitt Michael
The role of teacher language background in the scoring of science responses from English learner students [electronic resource]

This dissertation explored differences among bilingual and monolingual teacher's scoring and interpretations of English learner (EL) students' responses to open-ended science items. Scores were analyzed using a split plot analysis of variance and interpretations were used to gather qualitative information about what teachers focused on as they read the responses. Analyses of scoring data collected for this study revealed that teacher language background was not significantly related to scores for EL or non-EL student groups. This suggests that teachers, regardless of their language background, interpreted the rubric and student responses similarly when they assigned scores. The presence of language features in certain student responses was, however, associated with scoring. The presence of language features appeared to matter for incorrect responses, particularly for EL students, and not correct responses. In the interpretations, teachers wrote along three characteristics: content focus, use of qualifiers, and noticing student language. Of the three characteristics, noticing student language revealed the most differences among teachers of the different language background groups. These findings, however, warrant further studies since the monolingual population used in this study was geographically unique and their everyday exposure to a second language is not typical for most monolinguals.

Keywords: Education.
Advisor: Shavelson Richard J.
Valdés Guadalupe primary advisor. Thesis advisor
Brown Bryan Anthony advisor. Thesis advisor
Solano Flores Guillermo advisor. Thesis advisor