Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-α

Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine that can elicit distinct cellular behaviors under different molecular contexts. Mitogen activated protein kinase (MAPK) pathways, especially the extracellular signal-regulated kinase (Erk) pathway, help to integrate influences from the environmental context, and therefore modulate the phenotypic effect of TNF-α exposure. To test how variations in flux through the Erk pathway modulate TNF-α-elicited phenotypes in a complex physiological environment, we exposed mice with different Ras mutations (K-Ras activation, N-Ras activation, and N-Ras ablation) to TNF-α and observed phenotypic and signaling changes in the intestinal epithelium. Hyperactivation of Mek1, an Erk kinase, was observed in the intestine of mice with K-Ras activation and, surprisingly, in N-Ras null mice. Nevertheless, these similar Mek1 outputs did not give rise to the same phenotype, as N-Ras null intestine was hypersensitive to TNF-α-induced intestinal cell death while K-Ras mutant intestine was not. A systems biology approach applied to sample the network state revealed that the signaling contexts presented by these two Ras isoform mutations were different. Consistent with our experimental data, N-Ras ablation induced a signaling network state that was mathematically predicted to be pro-death, while K-Ras activation did not. Further modeling by constrained Fuzzy Logic (cFL) revealed that N-Ras and K-Ras activate the signaling network with different downstream distributions and dynamics, with N-Ras effects being more transient and diverted more towards PI3K-Akt signaling and K-Ras effects being more sustained and broadly activating many pathways. Our study highlights the necessity to consider both environmental and genomic contexts of signaling pathway activation in dictating phenotypic responses, and demonstrates how modeling can provide insight into complex in vivo biological mechanisms, such as the complex interplay between K-Ras and N-Ras in their downstream effects.National Institute of General Medical Sciences (U.S.) (Grant R01-GM088827)National Cancer Institute (U.S.) (U54-CA112967)United States. Army Research Office (Institute for Collaborative Biotechnologies Grant W911NF-09-D-000

Developmental Phonologies Archive

The Developmental Phonologies Archive consists of the longitudinal records from each of 280 children in production of probe words that sampled target English singletons, onset and coda clusters.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut)See Learnability Project Working Paper: Phonological Protocols in the BASICS collection of the Gierut / Learnability Project; http://dx.doi.org/10.5967/K87P8W9VZIP file approximately 158MB; CONTENTS: PhonArchive_Individual Ss (folder with individual .xlsx files); PhonArchive_Reference Files; README.pdf with instructions for use and keys to coding; SOFTWARE: Excel: Mac 2011; Adobe Acrobat XI Pro PDF/A; NOTE: It is imperative to retain Lucida Grande font to preserve the integrity of phonetic transcriptions

Demographics Archive

The Demographics Archive provides diagnostic and case information for 280 children with phonological disorders.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut)See Learnability Projects Working Paper: Participant Eligibility and Demographics in the BASICS collection of the Gierut / Learnability Project; http://dx.doi.org/10.5967/K8H41PB4ZIP file approximately 1MB; CONTENTS: DemogArchive_Across Ss.xlsx; DemogArchive_Reference File.pdf; README.pdf with instructions for use and keys to coding; SOFTWARE: Excel: Mac 2011; Adobe Acrobat XI Pro PDF/A; NOTE: It is imperative to retain Lucida Grande font to preserve the integrity of phonetic transcriptions

Learnability Project Research Team

Learnability Project Research TeamNational Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut

Learnability Project Working Paper: Participant Eligibility and Demographics

This working paper outlines, in part, the general eligibility criteria and characteristics of participants in the Learnability Project. It is the companion to the Demographic Archive of the DATA collection of the Gierut / Learnability Project.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut

Nexus to lexis: Phonological disorders in children

Research on phonological disorders in children has conventionally emphasized the speech sound in search of causes, diagnoses, treatments and prevention of the disorder. This paper aims to shift the research focus to the word instead. The motivation comes from advances in psycholinguistics that demonstrate the word is central to the perception, production and acquisition of phonological information. Three strands of potential study are outlined in evaluation of how words might initiate and boost, but perhaps also, interrupt learning for children with phonological disorders.National Institutes of Health NIDCD 00169

Experimental Archive

The Experimental Archive summarizes the conditions of clinical treatment and corresponding performance of 219 children who were enrolled in experimental training studies of production.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut)See Learnability Project Working Paper: Experimental Designs and Protocols in the BASICS collection of the Gierut / Learnability Project; http://dx.doi.org/10.5967/K8CC0XMDZIP file approximately 95MB; CONTENTS: ExpArchive_Across Ss.xlsx; ExpArchive_Individual Ss; ExpArchive_Reference Files; README.pdf with instructions and key to coding; Software: Excel: Mac 2011; Adobe Acrobat XI Pro PDF/A; NOTE: It is imperative to retain Lucida Grande font to preserve the integrity of phonetic transcriptions

Learnability Project Working Paper: Phonological Protocols

This working paper outlines, in part, the phonological protocols and stimuli that were used in descriptive and experimental research. It is the companion to the Developmental Phonologies Archive of the DATA collection of the Gierut / Learnability Project.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut

Phonological complexity and language learnability

Purpose: To extend formal models of language learnability to applications in clinical treatment of children with functional phonological delays. Method: The focus of the narrative review is on phonological complexity. This follows from learnability theory, whereby complexity in the linguistic input to children has been shown to trigger language learning. Drawing from the literature, phonological complexity is defined from epistemic, ontological, and functional perspectives, with specific emphasis on the application of language universals in the selection of target sounds for treatment. Results: The cascading effects of phonological complexity on children's generalization learning are illustrated, and frequently asked questions about complexity in treatment are addressed. Conclusion: The role of complexity in cognitive development is introduced to demonstrate the apparent robustness of effects.National Institutes of Health DC00433, RR7031K, DC00076, DC001694 (PI: Gierut

Learnability Project Working Paper: Experimental Designs and Protocols

This working paper outlines, in part, some general principles of single-subject experimental design and summarizes some core elements of the treatment and generalization protocols used in Learnability Project research. It is the companion to the Experimental Archive of the DATA collection of the Gierut / Learnability Project.National Institutes of Health DC00433, RR7031KK, DC00076, DC001694 (PI: Gierut