Modeling Down Syndrome Neurodevelopment with Dosage Compensation

Due to their underlying genetic complexity, chromosomal disorders such as Down syndrome (DS), which is caused by trisomy 21, have long been understudied and continue to lack effective treatments. With over 200 genes on the extra chromosome, even the specific cell pathologies and pathways impacted in DS are not known, and it has not been considered a viable target for the burgeoning field of gene therapy. Recently, our lab demonstrated that the natural mechanism of dosage compensation can be harnessed to silence the trisomic chromosome in pluripotent cells. Using an inducible XIST transgene allows us to study the effects of trisomy in a tightly controlled system by comparing the same cells with either two or three active copies of chromosome 21. In addition, it raises the prospect that insertion of a single gene into a trisomic chromosome could potentially be developed in the future for “chromosome therapy”. This thesis aims to utilize this inducible system for dosage compensation to study the neurodevelopmental effects of trisomy 21 in vitro, and to answer basic epigenetic questions critical to the viability of chromosome silencing as a therapeutic approach. Foremost, for XIST to have any prospect as a therapeutic, and to strengthen its experimental utility, it must be able to initiate chromosome silencing beyond its natural context of pluripotency. Here I demonstrate that, contrary to the current literature, XIST is capable of initiating chromosome silencing in differentiated cells and producing fully dosage compensated DS neurons. Additionally, I show that silencing of the trisomic chromosome in neural stem cells enhances their terminal differentiation to neurons, and transcriptome analysis provides evidence of a specific pathway involved. Separate experiments utilize novel three-dimensional organoid technology and transcriptome analysis to model DS neurodevelopment in relation to isogenic euploid cells. Overall, this work demonstrates that dosage compensation provides a powerful experimental tool to examine early DS neurodevelopment, and establishes that XIST function does not require pluripotency, thereby overcoming a perceived obstacle to the potential of XIST as a therapeutic strategy for trisomy

The Construction of Double-Ended Classical Trajectories

In the present paper we describe relaxation methods for constructing double-ended classical trajectories. We illustrate our approach with an application to a model anharmonic system, the Henon-Heiles problem. Trajectories for this model exhibit a number of interesting energy-time relationships that appear to be of general use in characterizing the dynamics.Comment: (12 pages, submitted to Chemical Physics Letters. Figures are too large for convenient e-mail access. they are available via anonymous ftp on willie.chem.brown.edu and reside in the directory pub/chem-ph/9407 as the compressed tar file 9407001.tar.Z. If you have difficulty retrieving the figures, please contact J. Doll ([email protected]) for assistance

Fractal Analysis of Protein Potential Energy Landscapes

The fractal properties of the total potential energy V as a function of time t are studied for a number of systems, including realistic models of proteins (PPT, BPTI and myoglobin). The fractal dimension of V(t), characterized by the exponent \gamma, is almost independent of temperature and increases with time, more slowly the larger the protein. Perhaps the most striking observation of this study is the apparent universality of the fractal dimension, which depends only weakly on the type of molecular system. We explain this behavior by assuming that fractality is caused by a self-generated dynamical noise, a consequence of intermode coupling due to anharmonicity. Global topological features of the potential energy landscape are found to have little effect on the observed fractal behavior.Comment: 17 pages, single spaced, including 12 figure

Taming the rugged energy landscape: Techniques for the production, reordering, and stabilization of selected cluster inherent structures

We report our studies of the potential energy surface (PES) of selected binary Lennard-Jones clusters. The effect of adding selected impurity atoms to a homogeneous cluster is explored. Inherent structures and transition states are found by combination of conjugate-gradient and eigenvector-following methods while the topography of the PES is mapped with the help of a disconnectivity analysis. We show that we can controllably induce new structures as well as reorder and stabilize existing structures that are characteristic of higher-lying minima.Comment: 9 pages, 9 figures, accepted for publication in J. Chem. Phy

Associação entre os fatores sociodemográficos e bucais com o bem-estar psicológico em adolescentes escolares

Objective: To investigate the relationship between sociodemographic factors and the performance of activities related to oral function, with psychological well-being in school adolescents. Materials and Methods: School-based, cross-sectional study, conducted in 36 municipalities up to 50 thousand inhabitants from Southern Brazil. The sample was composed of 1,760 scholars, selected thorough systematic sampling. Data were collected by means of a structured questionnaire, containing information on socioeconomic status, oral impact on daily activities (OIDP) and Well-Being (Andrews Scale). Poisson Regression was used to conduct the data analyses. Results: Difficulty to smile was almost twice as high for students who did not present well-being, PR = 1.9 (95%CI = 1.30-2.80). In addition, difficulty to speak, PR = 1,57 (95%CI CI = 1,02-2,40), and disconfort to brush the teeth, PR = 1,93 (CI= 1,29-2,91), were also associated to well-being. Difficulty to eat PR = 1,1 (95% CI= 0,75-1,65), was not associated to it. The family average income was the only sociodemographic variable associated to adolescents well-being, PR = 0,65 (95% CI = 0,45-0,96). Conclusion: The results of this study showed the influence of oral health related activities, smile, speak and teeth brush on the well-being of school adolescentes in Rio Grande do Sul state. In addition, they pointed out the Family average income as a protection factor for the well-being of this population.Objetivo: Investigar a relação entre fatores sociodemográficos e o desempenho de atividades relacionadas à função oral, com o bem-estar psicológico em adolescentes escolares. Materiais e Métodos: Estudo transversal, de base escolar, realizado em 36 municípios de até 50 mil habitantes da região sul do Brasil. A amostra foi composta por 1.760 acadêmicos, selecionados por amostragem sistemática completa. Os dados foram coletados por meio de um questionário estruturado, contendo informações sobre situação socioeconômica, impacto oral nas atividades diárias (OIDP) e Bem-Estar (Escala de Andrews). Regressão de Poisson foi usada para conduzir as análises de dados. Resultados: A dificuldade para sorrir foi quase duas vezes maior para os estudantes que não apresentaram bem-estar, RP = 1,9 (IC95% = 1,30-2,80). Além disso, dificuldade para falar, RP = 1,57 (IC95% IC = 1,02-2,40) e desconforto para escovar os dentes, RP = 1,93 (IC = 1,29-2,91), também foram associados ao bem-estar. A dificuldade para comer PR = 1,1 (IC 95% = 0,75-1,65), não foi associada a ele. A renda familiar média foi a única variável sociodemográfica associada ao bem-estar dos adolescentes, RP = 0,65 (IC95% = 0,45-0,96). Conclusão: Os resultados deste estudo mostraram a influência das atividades relacionadas à saúde bucal, sorriso, fala e dentes no bem-estar de adolescentes escolares no estado do Rio Grande do Sul. Além disso, apontaram a renda média da família como fator de proteção para o bem-estar dessa população

Efficient Dynamic Importance Sampling of Rare Events in One Dimension

Exploiting stochastic path integral theory, we obtain \emph{by simulation} substantial gains in efficiency for the computation of reaction rates in one-dimensional, bistable, overdamped stochastic systems. Using a well-defined measure of efficiency, we compare implementations of ``Dynamic Importance Sampling'' (DIMS) methods to unbiased simulation. The best DIMS algorithms are shown to increase efficiency by factors of approximately 20 for a $5 k_B T$ barrier height and 300 for $9 k_B T$, compared to unbiased simulation. The gains result from close emulation of natural (unbiased), instanton-like crossing events with artificially decreased waiting times between events that are corrected for in rate calculations. The artificial crossing events are generated using the closed-form solution to the most probable crossing event described by the Onsager-Machlup action. While the best biasing methods require the second derivative of the potential (resulting from the ``Jacobian'' term in the action, which is discussed at length), algorithms employing solely the first derivative do nearly as well. We discuss the importance of one-dimensional models to larger systems, and suggest extensions to higher-dimensional systems.Comment: version to be published in Phys. Rev.

The inevitable QSAR renaissance

QSAR approaches, including recent advances in 3D-QSAR, are advantageous during the lead optimization phase of drug discovery and complementary with bioinformatics and growing data accessibility. Hints for future QSAR practitioners are also offered

A two-step target binding and selectivity support vector machines approach for virtual screening of dopamine receptor subtype-selective ligands

10.1371/journal.pone.0039076PLoS ONE76