Biology subjects

Lin, L.

Publications and source records attributed to Lin, L..

237 records · Page 14Linked to original sources

bioRxiv2017

Loss of MECP2 leads to telomere dysfunction and neuronal stress

To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered neuronal specific gene expression changes including induction of a Senescence Associated Secretory Phenotype (SASP) program. Patient derived Neurons made without MECP2 show signs of stress, including induction of p53, and senescence. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. These disease-in-a-dish data suggest that loss of MECP2 can lead to dendritic defects due to an increase in aspects of neuronal aging.

developmental biology↗

bioRxiv2017

A model for autonomous and non-autonomous effects of the Hippo pathway in Drosophila

While significant progress has been made toward understanding morphogen-mediated patterning in development from both the experimental and the theoretical side, the control of size and shape of tissues and organs is poorly understood. Both involve adjustment of the scale of gene expression to the size of the system, but how growth and patterning are coupled to produce scale invariance and how molecular-level information is translated into organ- and organism-level functioning is one of the most difficult problems in biology. The Hippo pathway, which controls cell proliferation and apoptosis in Drosophila and mammalian cells, contains a core kinase mechanism that affects control of the cell cycle and growth. Studies involving over- and under-expression of components in the morphogen and Hippo pathways in Drosophila reveal conditions that lead to over- or undergrowth. Herein we develop a mathematical model that incorporates the current understanding of the Hippo signal transduction network and which can explain qualitatively both the observations on whole-disc manipulations and the results arising from mutant clones. We find that a number of non-intuitive experimental results can be explained by subtle changes in the balances between inputs to the Hippo pathway. Since signal transduction and growth control pathways are highly conserved across species, much of what is learned about Drosophila applies in higher organisms, and may have direct relevance to tumor dynamics in mammalian systems.

biophysics↗

bioRxiv2016

Novel computational method for predicting polytherapy switching strategies to overcome tumor heterogeneity and evolution

1The success of targeted cancer therapy is limited by drug resistance that can result from tumor genetic heterogeneity. The current approach to address resistance typically involves initiating a new treatment after clinical/radiographic disease progression, ultimately resulting in futility in most patients. Towards a potential alternative solution, we developed a novel computational framework that uses human cancer profiling data to systematically identify dynamic, pre-emptive, and sometimes non-intuitive treatment strategies that can better control tumors in real-time. By studying lung adenocarcinoma clinical specimens and preclinical models, our computational analyses revealed that the best anti-cancer strategies addressed existing resistant subpopulations as they emerged dynamically during treatment. In some cases, the best computed treatment strategy used unconventional therapy switching while the bulk tumor was responding, a prediction we confirmed in vitro. The new framework presented here could guide the principled implementation of dynamic molecular monitoring and treatment strategies to improve cancer control.

cancer biology↗