Search results for: Roderic Espin

Authors: Mitra Shokrollahi, Mia Stanic, Anisha Hundal, Janet N. Y. Chan, Defne Urman, Chris A. Jordan, Anne Hakem, Roderic Espin, Jun Hao, Rehna Krishnan, Philipp G. Maass, Brendan C. Dickson, Manoor P. Hande, Miquel A. Pujana, Razqallah Hakem, Karim Mekhail

Abstract:

Current models suggest that DNA double-strand breaks (DSBs) can move to the nuclear periphery for repair. It is unclear to what extent human DSBs display such repositioning. Here we show that the human nuclear envelope localizes to DSBs in a manner depending on DNA damage response (DDR) kinases and cytoplasmic microtubules acetylated by α-tubulin acetyltransferase-1 (ATAT1). These factors collaborate with the linker of nucleoskeleton and cytoskeleton complex (LINC), nuclear pore complex (NPC) protein NUP153, the nuclear lamina and kinesins KIF5B and KIF13B to generate DSB-capturing nuclear envelope tubules (dsbNETs). dsbNETs are partly supported by nuclear actin filaments and the circadian factor PER1 and reversed by kinesin KIFC3. Although dsbNETs promote repair and survival, they are also co-opted during poly (ADP-ribose) polymerase (PARP) inhibition to restrain BRCA1-deficient breast cancer cells and are hyper-induced in cells expressing the aging-linked lamin A mutant progerin. In summary, our results advance understanding of nuclear structure-function relationships, uncover a nuclear-cytoplasmic DDR and identify dsbNETs as critical factors in genome organization and stability.

Keywords: DNA damage response, genome stability, nuclear envelope, cancer, age-related disorders

Procedia PDF Downloads 8

Authors: Hamed Hakim, Roderic Archambault, Charles J. Kibert, Maryam Mirhadi Fard

Abstract:

Changes in the patterns of life in the late 20th and early 21st century have created new challenges for educational systems. Greening the physical environment of school buildings has emerged as a response to some of those challenges and led to the design of energy efficient K-12 school buildings. With the advancement in knowledge and technology, the successful construction of Net Zero Energy Schools, such as the Lady Bird Johnson Middle School demonstrates a cutting edge generation of sustainable schools, and solves the former challenge of attaining energy self-sufficient educational facilities. There are approximately twenty net zero energy K-12 schools in the U.S. of which about six are located in Climate Zone 5 and 6 based on ASHRAE climate zone classification. This paper aims to describe and analyze the current status of energy efficient and NZE schools in Canada. An attempt is made to study existing U.S. energy neutral strategies closest to the climate zones in Canada (zones 5 and 6) and identify the best practices for Canadian schools.

Keywords: Canada K-12 schools, green school, energy efficient, net-zero energy schools

Procedia PDF Downloads 404

Authors: Almudena Espin Perez, Tyler Risom, Carl Pelz, Isabel English, Robert M. Angelo, Rosalie Sears, Andrew J. Gentles

Abstract:

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly malignancies. The role of the tumor microenvironment (TME) is gaining significant attention in cancer research. Despite ongoing efforts, the nature of the interactions between tumors, immune cells, and stromal cells remains poorly understood. The cell-intrinsic properties that govern cell lineage plasticity in PDAC and extrinsic influences of immune populations require technically challenging approaches due to the inherently heterogeneous nature of PDAC. Understanding the cell lineage plasticity of PDAC will improve the development of novel strategies that could be translated to the clinic. Members of the team have demonstrated that the acquisition of ductal to neuroendocrine lineage plasticity in PDAC confers therapeutic resistance and is a biomarker of poor outcomes in patients. Our approach combines computational methods for deconvolving bulk transcriptomic cancer data using CIBERSORTx and high-throughput single-cell imaging using Multiplexed Ion Beam Imaging (MIBI) to study lineage plasticity in PDAC and its relationship to the infiltrating immune system. The CIBERSORTx algorithm uses signature matrices from immune cells and stroma from sorted and single-cell data in order to 1) infer the fractions of different immune cell types and stromal cells in bulked gene expression data and 2) impute a representative transcriptome profile for each cell type. We studied a unique set of 300 genomically well-characterized primary PDAC samples with rich clinical annotation. We deconvolved the PDAC transcriptome profiles using CIBERSORTx, leveraging publicly available single-cell RNA-seq data from normal pancreatic tissue and PDAC to estimate cell type proportions in PDAC, and digitally reconstruct cell-specific transcriptional profiles from our study dataset. We built signature matrices and optimized by simulations and comparison to ground truth data. We identified cell-type-specific transcriptional programs that contribute to cancer cell lineage plasticity, especially in the ductal compartment. We also studied cell differentiation hierarchies using CytoTRACE and predict cell lineage trajectories for acinar and ductal cells that we believe are pinpointing relevant information on PDAC progression. Collaborators (Angelo lab, Stanford University) has led the development of the Multiplexed Ion Beam Imaging (MIBI) platform for spatial proteomics. We will use in the very near future MIBI from tissue microarray of 40 PDAC samples to understand the spatial relationship between cancer cell lineage plasticity and stromal cells focused on infiltrating immune cells, using the relevant markers of PDAC plasticity identified from the RNA-seq analysis.

Keywords: deconvolution, imaging, microenvironment, PDAC

Procedia PDF Downloads 126