Dans ce travail, nous étudions de manière approfondie les lois $\al$-stables (lois à variance infinie). Dans le premier chapitre, nous rappelons les différentes propriétés des lois $\al$-stables univariées (stabilité, calcul des moments, simulation). Nous introduisons ensuite les lois symétriques $\al$-stables (\SaS) multivariées. Après avoir parlé de la mesure spectrale et de son intérêt pour caractériser l'indépendance, nous nous concentrons sur les mesures de dépendance. Constatant que le coefficient de covariation, largement utilisé actuellement, admet certaines limites, nous construisons dans le deuxième chapitre une nouvelle mesure de dépendance, appelée coefficient de covariation symétrique. Ce dernier nous permet, entre autres, de découvrir quelques spécificités des vecteurs \SaS. En effet, contrairement aux vecteurs gaussiens, on peut obtenir pour certains vecteurs \SaS\ à la fois une dépendance positive et une dépendance négative. Après avoir conclu le chapitre par l'étude de la loi asymptotique de l'estimateur du coefficient de covariation, nous abordons, dans le troisième chapitre, les processus autorégressifs à innovations stables. Nous présentons les différentes méthodes d'identification de l'ordre d'un processus AR: autocorrélation partielle (Brockwell et Davis) et statistiques quadratiques asymptotiquement invariantes basées sur les rangs (Garel et Hallin). De nombreuses simulations, effectuées en Matlab et Fortran, nous permettent de comparer ces méthodes et de constater l'importance du rôle joué par les statistiques de rang dans ce domaine. Pour finir, un problème de test séquentiel, développé dans le cadre d'un contrat industriel, nous permet d'introduire la notion de niveau de confiance après décision.

Influenza A is a negative stranded RNA virus with a segmented genome. Once the virus infects a cell it must replicate its full length viral genomic RNA (vRNA) through a positive sense complementary intermediate RNA (cRNA) as well as transcribe viral messenger RNA (mRNA) using the vRNA as a template. The regulation of whether the viral polymerase replicates the genome by synthesizing cRNA, or produces mRNA in order to make viral protein involves, the viral nucleoprotein (NP). We tried to find the sequence residues of NP that directly interact with the viral polymerase. We mutated to alanine several residues on NP that are surface exposed on recently solved crystal structures as well as those thought to be oriented toward the viral polymerase complex in cryo-EM studies. As a first screen, we tested these mutants in a mini-genome assay where the NP stimulation of the viral polymerase can be studied in transfected cells. Through this screen we found that the NP mutants that hindered its ability to stimulate polymerase activity the most were located in a loop between two alpha helixes in the head domain of NP located at residues 203 to 209. Specifically, the NP single mutants of R204, W207, and R208 were inactive in the mini-genome assay. Using RT-PCR we found that the cRNA to vRNA step of replication is severely inhibited by these mutations. Immunoprecipitation using transfected cells showed that the NP mutants lost the ability to bind all three polymerase subunits. This indicates that this loss of polymerase binding may be the reason the NP mutant fails to stimulate polymerase activity. To make sure that this loss of polymerase stimulation was not due to altering other functions of NP we made sure that the protein had proper cellular localization, oligomerization, and RNA binding abilities. Using immuniflourescence we found that mutant NP localized to the nucleus just like wild type. In order to test RNA binding and oligomerization we tested NP purified from a baculovirus expressing system. Using fluorescence polarization we found that NP binds single stranded RNA with similar affinity to wild type. Using gel filtration we found that mutant NP forms oligomers just like wild type. Using covariation analysis of how different positions in an amino acid alignment change relative to each other we predicted possible binding sites between NP and the three polymerase subunits PA, PB1 and PB2. Due to more complete crystal structure data we focused on the PA-NP interaction and found that covariation aided in finding binding sequence residues on PA but not NP. Another outcome of developing the covariation method was developing a program to view broad primary structure changes in large sequence alignments. This method has been informative in evaluating how amino acid positions in influenza have changed over time, as well as what defines specific residues as belonging to human or avian viruses. / text

RNA molecules form complex higher-order structures which are essential to perform their biological activities. The accurate prediction of an RNA secondary structure and other higher-order structural constraints will significantly enhance the understanding of RNA molecules and help interpret their functions. Covariation analysis is the predominant computational method to accurately predict the base pairs in the secondary structure of RNAs. I developed a novel and powerful covariation method, Phylogenetic Events Count (PEC) method, to determine the positional covariation. The application of the PEC method onto a bacterial 16S rRNA sequence alignment proves that it is more sensitive and accurate than other mutual information based method in the identification of base-pairs and other structural constraints of the RNA structure. The analysis also discoveries a new type of structural constraint – neighbor effect, between sets of nucleotides that are in proximity in the three dimensional RNA structure with weaker but significant covariation with one another. Utilizing these covariation methods, a proposed secondary structure model of an entire HIV-1 genome RNA is evaluated. The results reveal that vast majority of the predicted base pairs in the proposed HIV-1 secondary structure model do not have covariation, thus lack the support from comparative analysis. Generating the most accurate multiple sequence alignment is fundamental and essential of performing high-quality comparative analysis. The rapid determination of nucleic acid sequences dramatically increases the number of available sequences. Thus developing the accurate and rapid alignment program for these RNA sequences has become a vital and challenging task to decipher the maximum amount of information from the data. A template-based RNA sequence alignment system, CRWAlign-2, is developed to accurately align new sequences to an existing reference sequence alignment based on primary and secondary structural similarity. A comparison of CRWAlign-2 with eight alternative widely-used alignment programs reveals that CRWAlign-2 outperforms other programs in aligning new sequences with higher accuracy. In addition to aligning sequences accurately, CRWAlign-2 also creates secondary structure models for each sequence to be aligned, which provides very useful information for the comparative analysis of RNA sequences and structures. The CRWAlign-2 program also provides opportunities for multiple areas including the identification of chimeric 16S rRNA sequences generated in microbiome sequencing projects. / text

In line with Schwarz’s (2008) suggestion of extending Situational CrisisCommunication Theory (SCCT) with Kelley’s covariation principle, the presentresearch aims to further examine the applicability of integrating a covariation-basedapproach to crisis responsibility assessment into the SCCT framework. Specifically, acontent analysis was conducted to verify the basic assumptions for applying acovariation-based approach in crisis communication context. A follow-upexperimental study was exercised to test the effect of consensus information – themissing variable in SCCT – on crisis responsibility attributions. The researchsuggested that a covariation-based approach of crisis responsiblilty assessment couldbe legitimately applied in the SCCT framework, and that crisis responsibilityassessment in the SCCT framework could be improved, at least in some particularsituations, by more consistently and systematically taking into account the threeinformation dimensions in covariation principle as integrated information patternsrather than separately considering the effect of one single information dimensionalone.Keywords:

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Esta pesquisa teve por objetivo analisar as contribuiÃÃes de metodologia desenvolvida, com suporte de tecnologias digitais, para o desenvolvimento do conceito de covariaÃÃo presente nas estruturas multiplicativas. Para isso, foram realizadas anÃlises das situaÃÃes presentes no campo conceitual multiplicativo, verificando a ocorrÃncia, ou nÃo, da covariaÃÃo. O desenvolvimento das atividades foi fundamentado em estudos relacionados Ãs contribuiÃÃes das mÃltiplas representaÃÃes para a aprendizagem e da abordagem seres-humanos-com-mÃdias. Utilizou-se, como metodologia, a pesquisa de intervenÃÃo. A investigaÃÃo foi realizada em uma Escola Municipal de Tempo Integral, localizada no municÃpio de Fortaleza - CearÃ, com estudantes de uma das turmas do 6 ano do Ensino Fundamental. A turma de alunos foi dividida em: Grupo Controle (GC), com 15 alunos e Grupo Experimental (GE), com 12 alunos. A investigaÃÃo foi dividida em trÃs etapas: prÃ-teste, intervenÃÃo e pÃs-teste. Todos os alunos, dos dois grupos, participaram do prÃ-teste e do pÃs-teste, aplicados individualmente e sem uso do computador. Tendo sido aplicados para diagnosticar os conhecimentos dos alunos em relaÃÃo à compreensÃo de situaÃÃes de proporÃÃo simples, de proporÃÃo mÃltipla, de proporÃÃo dupla, de interpretaÃÃo e construÃÃo de grÃficos lineares e compreensÃo de padrÃo de tabelas. A intervenÃÃo aconteceu apenas com o GE, no momento das aulas de MatemÃtica. Essa etapa teve duraÃÃo de 3 meses, com 18 encontros. As atividades desenvolvidas para esses encontros, utilizavam tecnologias digitais como: software Geogebra, recurso digital Equilibrando proporÃÃes, aplicativo online Cacoo, WhatsApp e blog. O GC manteve as aulas de MatemÃtica e de disciplinas eletivas, nos mesmos horÃrios do GE. Os dados foram analisados de modo a conhecer e compreender o desempenho dos alunos antes e apÃs as atividades; os teoremas-em-aÃÃo mobilizados durante a intervenÃÃo e suas evoluÃÃes; e as contribuiÃÃes das tecnologias usadas para a compreensÃo do conceito de covariaÃÃo. Os estudantes submetidos à intervenÃÃo apresentaram, estatisticamente, um desempenho superior, quando comparados aos estudantes do GC, demonstrando a eficÃcia da metodologia. Constatou-se, ainda, a modificaÃÃo de esquemas por meio de estratÃgias mais elaboradas, mesmo para situaÃÃes que jà eram conhecidas pelos estudantes do GE. As tecnologias digitais utilizadas contribuÃram para a compreensÃo da invariÃncia e da covariaÃÃo, ao relacionar mÃltiplas representaÃÃes de forma dinÃmica, possibilitar a produÃÃo de conhecimento e a significaÃÃo de contextos sociais e matemÃticos.

The Hepatitis Delta Virus (HDV) is an RNA pathogen that uses the host DNA-dependent RNA polymerase II (RNAP II) to replicate. Previous studies identified the right terminal domain of genomic polarity (R199G) of HDV RNA as an RNAP II promoter, but the features required for HDV RNA to be used as an RNA promoter were unknown. In order to identify the structural features of an HDV RNA promoter, I analyzed 473,139 sequences representing 2,351 new R199G variants generated by high-throughput sequencing of a viral population replicating in 293 cells. To complement this analysis, I also analyzed the same region from HDV sequences isolated from various hosts. Base pair covariation analysis indicates a strong selection for the rod-like conformation. Several selected RNA motifs were identified, including a GC-rich stem, a CUC/GAG motif and a uridine at the initiation site of transcription. In addition, a polarization of purine/pyrimidine content was identified, which might represent a motif favourable for the binding of the host Polypyrimidine tract-binding protein-associated-splicing-factor (PSF), p54 and Paraspeckle Protein 1 (PSP1). Previously, it was shown that R199G binds both RNAP II and PSF, that PSF increased the HDV levels during in vitro transcription and that p54 binds R199G. In the present study, I showed that PSP1 also associates with HDV RNA and I investigated whether these proteins are required for HDV replication. My results show that knockdown of PSF, p54 and PSP1 resulted in a decrease of HDV accumulation. These proteins are highly concentrated in paraspeckles, which are nuclear structures involved in storage of transcripts generated by RNAP II. I found that upon viral replication in 293 cells, PSP1 appeared as bigger foci present outside of the nucleus, while PSF and p54 foci remained in the nucleus. NEAT1 is a long non-coding RNA essential for the formation of paraspeckles. Upon HDV replication, I found an increase of the intensity and size of NEAT1 foci that correlates with an increase of NEAT1 transcripts. Altogether, these data suggest that HDV replication results in an alteration of the paraspeckles structures, providing foundation for further investigation of the paraspeckles role in HDV cycle. Overall, the present study addresses the importance of the HDV RNA structure and of the host paraspeckle proteins for HDV replication.

Motivation: Improving the prediction of structures, especially those containing pseudoknots (structures with crossing base pairs) is an ongoing challenge. Current alignment-based prediction algorithms only find the consensus structure, and their alignments can come from structure-based alignment algorithms, which is more reliable, but come with an increased cost compared to sequence-based alignment algorithms. This step can be removed; however, non-alignment based algorithms neglect structural information that can be found within similar sequences. Results: We present a new method for prediction of RNA pseudoknotted secondary structures that combines the strengths of MFE prediction and alignment-based methods. KnotAli takes an RNA sequence alignment and uses covariation and thermodynamic energy minimization to predict secondary structures for each individual sequence in the alignment. We compared KnotAli's performance to that of three other alignment-based algorithms, on a large data set of 10 families with pseudoknotted and pseudoknot-free reference structures. We produced sequence alignments for each family using two well-known sequence aligners (MUSCLE and MAFFT). We found KnotAli to be superior in 6 of the 10 families for MUSCLE and 7 of the 10 for MAFFT. We find KnotAli's predictions to be less dependent on alignment quality. In particular, KnotAli is shown to have more accurate predictions compared to other leading methods as alignment quality deteriorates. Availability: The algorithm can be found online on Github at https://github.com/mateog4712/KnotAli / Graduate / 2022-08-16

<p> A key mechanism to maintain balance during walking is the foot placement strategy,  where the person steps in the direction of an impending fall. On a clear walkway, the foot  placement strategy translates to maintaining a consistent relationship between the center of mass  state and the base of support (a body-centric constraint on foot placement), which is reflected in  a consistent step length. However, to safely navigate in the community, foot placement must  maintain certain spatial relations with environmental features as well (environmental constraints on foot placement). For stepping over obstacles, the environmental constraint takes the form of  targeting. That is, the feet must be placed at precise locations relative to the obstacle to minimize  the likelihood of tripping.  My dissertation focused on proactive adaptations to foot placements while navigating  cluttered environments. I developed the interstep covariation (ISC) index that quantifies the covariation between consecutive foot placements relative to stationary, visible environmental  features (an obstacle and a visual target). The across-step (or group) changes in this index  indicate how the two constraints (body-centric and environmental) on foot placement are  managed during adaptive gait tasks. I quantified how the ISC index changed (1) across steps  while approaching and crossing an obstacle, (2) due to healthy aging and (3) when the proximity  of two environmental features was systematically altered. Specifically, in Study 1, the ISC index  was quantified for the obstacle crossing step for healthy younger and older adults. In Study 2, proactive changes in the ISC index as healthy young adults approached and crossed an obstacle were characterized. In Study 3, the changes in the dynamics of the across-step ISC index due to  an additional visual stepping target in the approach to the obstacle were identified.  I found that there exists a covariance strategy that healthy adults use to navigate the  environment safely and successfully. First, I found that individuals prioritize the environmental  constraint at the expense of the body-centric constraint when the environment poses a larger risk  to balance (the obstacle), or to satisfy a specified constraint (stepping on a visual target). Second,  I found that the shift in prioritization is proactive, i.e., it occurs while approaching an obstacle.  The strategy to shift priorities is influenced by age (Study 1), environmental features (Study 2  and Study 3), and the proximity of two environmental features (Study 3). These studies add to  the current understanding of foot placement control by demonstrating how this well-known and 15 fundamental strategy to maintain balance while walking is systematically influenced by the  environment and task constraints. These findings can be further extended to study proactive and  reactive adaptations during walking in different populations.   </p>

There is an overemphasis on procedures and manipulation of symbols in calculus and not enough emphasis on conceptual understanding of the subject. Specifically, students struggle to understand and correctly apply concepts in calculus such as the chain rule, implicit differentiation, and related rates. Students can learn mathematics more deeply when they make connections between different mathematical ideas. I have hypothesized that students can make powerful connections between the chain rule, implicit differentiation, and related rates through the mathematical concept of nested multivariation. Based on this hypothesis, I created a hypothetical learning trajectory (HLT) rooted in nested multivariation for students to develop an understanding of these three concepts. In this study, I explore my HLT through a small-scale teaching experiment with individual first-semester calculus students using tasks based on the HLT.Based on the teaching experiment, nested multivariational reasoning proved to be critical in understanding how the variables within a function composition change together and in developing intuition and understanding for the multiplicative nature of the chain rule. Later, nested multivariational reasoning was mostly important in recognizing the existence of a nested relationship and the need to use the chain rule in differentiation. Overall, through the HLT, students gained a connected and conceptual understanding for the chain rule, implicit differentiation, and related rates. I also discuss how the HLT might be adjusted and improved for future use.

Morphological integration refers to the interdependence of two or more phenotypic structures. The morphological integration concept is based on the fact that parts of complex organisms do not vary randomly and instead display degrees of non-independence that are thought to occur from shared genetic or developmental origins, and/or functional demands. Integrated traits may develop, evolve, and be inherited together. One instance of morphological integration can be found between the vertebral column and the skull. Due to the position of the skull resting atop of the vertebral column, posture may influence skull development and overall craniofacial morphology. Morphological integration within or between structures is typically statistically assessed by exploring correlation and covariation patterns among biological structures of interest. In this study, an analysis of morphological integration was carried out by studying covariation of morphometric measures from the vertebral column and craniofacial complex. Age- and sex-matched, de-identified computed tomography images of individuals with kyphosis spinal malformation (n = 15) and controls (n = 19) were acquired from Florida Hospital. It is hypothesized that the sample of individuals with kyphosis will exhibit statistically significant covariance differences relative to the control group for T6 vertebral and midfacial linear distance measurements. Anatomical landmarks were identified on the T6 thoracic vertebrae (n = 6) and the midfacial skeleton (n = 6), and XYZ coordinates were recorded for analysis. A subset of 10 individuals (5 kyphosis, 5 controls) individuals were measured on two occasions to assess reliability and measurement error. An Euclidean Distance Matrix Analysis (EDMA) of morphological integration was carried out on the entire sample by calculating correlation values for paired linear distance measurements (one vertebral and one midfacial) separately for the kyphosis and control samples (n = 225 for each sample). Next, EDMA calculated correlation differences and statistically assessed significance using a non-parametric bootstrap (1,000 resamples) and confidence interval testing (α ≤ 0.10). Only 35 of the 225 (15.56%) correlation differences were statistically significant. Patterns of variation among these significant correlation differences were explored by examining sample directionality of differences, sign patterns, and strengths. The relevance of these results to clinical and anthropological pursuits are discussed. Several recommendations for future investigations are made.