Biology subjects

Bradly Alicea

Publications and source records attributed to Bradly Alicea.

4 recordsLinked to original sources

bioRxiv2016

Genotype-specific developmental plasticity shapes the timing and robustness of reproductive capacity in Caenorhabditis elegans

The effects of environmental stress on developmental phenotypes allows us to observe the adaptive capacity of various genotypes. In single-genotype populations, this allows for observing the effects of standing variation on the process of developmental plasticity. Typically, such efforts do not allow us to distinguish the effect of genotype from the effects of environment. In the Nematode Caenorhabditis elegans, however, the L1 stage of development allows for precise and controlled imposition of starvation on a synchronized population of individuals. This allows for systematic comparisons within and between defined genotypes.\n\nThis study provides a number of innovations in the study of Nematode developmental plasticity. The first is to demonstrate systems-level mechanisms of adaptive response for various genetic mutant phenotypes to extended L1 arrest. The effects of developmental deprivation are quantifiable by applying statistical modeling techniques to reproductive time-series. This is characterized for both a wildtype strain (N2) and a host of genetic mutant strains. A further contribution is investigating the effects of starvation at multi-generational timescales. This includes both two generations post-starvation and multiple starvation experiences with selection for fecundity over 11 generations.\n\nStatistical techniques such as Kernel Density Estimation (KDE), fold-change analysis, and Area Under the Curve (AUC) analysis reveal differences from baseline in the form of shifts in reproductive timing and kurtosis in peak reproductive capacity characterize adaptive responses that are semi-independent of environment. Extending these patterns of response to ad hoc comparisons with multi-generational contexts reveals that different genotypes characterized by mutations of specific genetic loci lead to vastly different outcomes.

Developmental Biology↗

bioRxiv2014

DevoWorm: differentiation waves and computation in C. elegans embryogenesis

Development is a complex process that, under normal circumstances, proceeds in a stable and patterned fashion. Developmental morphogenesis (called embryogenesis) can tell us a great deal about the function and structure of an adult organism. One of the most important aspects of development to understand is the progression of cell division and differentiation in what will become an adult worm. This is where the DevoWorm project can both address multiple outstanding theoretical issues and provide graphical clarity to the embryogenetic process. As a representative of mosaic development, C. elegans embryogenesis is both tractable in terms of cell number and relatively well-characterized. In this paper, we will lay out a theoretical re-interpretation of embryogenesis in addition to developing an RDF-based computational framework for visualizing the results of this theoretical effort. Our theoretical efforts will ultimately involve the construction of a differentiation tree and data analyses that support the concept of differentiation waves acting to coordinate cellular differentiation and embryonic form. The differentiation tree will also feature a means to perturb development in a manner that mimics phenotypic mutagenesis. This will allow us to understand the selective variability that is inherent in biological development, but that remains so poorly understood. In tandem, these developments will allow us to construct a conceptual and computational framework which can be applied to both mosaic and regulative development.

Developmental Biology↗

bioRxiv2014

Modeling Cellular Information Processing Using a Dynamical Approximation of Cellular mRNA

How does the regulatory machinery of an animal cell ensure its survival during large-scale biochemical and phenotypic transitions? When a cell is strongly perturbed by an environmental stimulus, it can either die or persist with compensatory changes. But what do the dynamics of individual genes look like during this process of adaptation? In a previous technical paper, two approaches (drug treatments and polysome isolation) were used in tandem to demonstrate the effects of perturbation on cellular phenotype. In this paper, we can use these data in tandem with a discrete, first-order feedback model that incorporates leaky components to better characterize adaptive responses of mRNA regulation related to information processing in the cell. By evaluating the dynamic relationship between mRNA associated with transcription (translatome) and mRNA associated with the polysome (transcriptome) at multiple timepoints, hypothetical conditions for decay and aggregation are found and discussed. Our feedback model allows for the approximation of fluctuations and other aspects of cellular information processing, in addition to the derivation of three information processing principles. These results will lead us to a better understanding of how mRNA provides variable information over time to the complex intracellular environment, particularly in the context of large-scale phenotypic change.

Systems Biology↗

bioRxiv2014

Using Polysome Isolation with Mechanism Alteration to Uncover Transcriptional and Translational Dynamics in Key Genes

What does it mean when we say a cells biochemistry is regulated during changes to the phenotype? While there are a plethora of potential mechanisms and contributions to the final outcome, a more tractable approach is to examine the dynamics of mRNA. This way, we can assess the contributions of both known and unknown decay and aggregation processes for maintaining levels of gene product on a gene-by-gene basis. In this extended protocol, drug treatments that target specific cellular functions (termed mechanism disruption) can be used in tandem with mRNA extraction from the polysome to look at the dynamics of mRNA levels associated with transcription and translation at multiple stages during a physiological perturbation. This is accomplished through validating the polysome isolation method in human cells and comparing fractions of mRNA for each experimental treatment at multiple points in time. First, three different drug treatments corresponding to the arrest of various cellular processes are administered to populations of human cells. For each treatment, the transcriptome and translatome are compared directly at different time points by assaying both cell-type specific and non-specific genes. There are two findings of note. First, extraction of mRNA from the polysome and comparison with the transcriptome can yield interesting information about the regulation of cellular mRNA during a functional challenge to the cell. In addition, the conventional application of such drugs to assess mRNA decay is an incomplete picture of how severely challenged or senescent cells regulate mRNA in response. This extended protocol demonstrates how the gene- and process-variable degradation of mRNA might ultimately require investigations into the course-grained dynamics of cellular mRNA, from transcription to ribosome.

Cell Biology↗