Publications

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64 Publications visible to you, out of a total of 64
Interstitial flow promotes the formation of functional microvascular networks in vitro through upregulation of matrix metalloproteinase-2.

Abstract (Expand)

Self-organized microvascular networks (MVNs) have become key to the development of many microphysiological models. However, the self-organizing nature of this process combined with variations between … types or batches of endothelial cells (ECs) often lead to inconsistency or failure to form functional MVNs. Since interstitial flow (IF) has been reported to play a beneficial role in angiogenesis, vasculogenesis, and 3D capillary morphogenesis, we systematically investigated the role IF plays during neovessel formation in a customized single channel microfluidic chip for which IF has been fully characterized. Compared to static conditions, MVNs formed under IF have higher vessel density and diameters and greater network perfusability. Through a series of inhibitory experiments, we demonstrated that IF treatment improves vasculogenesis by ECs through upregulation of matrix metalloproteinase-2 (MMP-2). We then successfully implemented a novel strategy involving the interplay between IF and MMP-2 inhibitor to regulate morphological parameters of the self-organized MVNs, with vascular permeability and perfusability well maintained. The revealed mechanism and proposed methodology were further validated with a brain MVN model. Our findings and methods have the potential to be widely utilized to boost the development of various organotypic MVNs and could be incorporated into related bioengineering applications where perfusable vasculature is desired.

Authors: S. Zhang, Z. Wan, G. Pavlou, A. X. Zhong, L. Xu, R. D. Kamm

Date Published: 21st Oct 2022

Publication Type: Journal Article

Novel In Vivo CometChip Reveals NDMA-Induced DNA Damage and Repair in Multiple Mouse Tissues.

Abstract (Expand)

The comet assay is a versatile assay for detecting DNA damage in eukaryotic cells. The assay can measure the levels of various types of damage, including DNA strand breaks, abasic sites and alkali-sensitive … sites. Furthermore, the assay can also be modified to include purified DNA glycosylases so that alkylated and oxidized bases can be detected. The CometChip is a higher throughput version of the traditional comet assay and has been used to study cultured cells. Here, we have tested its utility for studies of DNA damage present in vivo. We show that the CometChip is effective in detecting DNA damage in multiple tissues of mice exposed to the direct-acting methylating agent methylmethane sulfonate (MMS) and to the metabolically activated methylating agent N-nitrosodimethylamine (NDMA), which has been found to contaminate food, water, and drugs. Specifically, results from MMS-exposed mice demonstrate that DNA damage can be detected in cells from liver, lung, kidney, pancreas, brain and spleen. Results with NDMA show that DNA damage is detectable in metabolically competent tissues (liver, lung, and kidney), and that DNA repair in vivo can be monitored over time. Additionally, it was found that DNA damage persists for many days after exposure. Furthermore, glycosylases were successfully incorporated into the assay to reveal the presence of damaged bases. Overall, this work demonstrates the efficacy of the in vivo CometChip and reveals new insights into the formation and repair of DNA damage caused by MMS and NDMA.

Authors: N. A. Owiti, J. J. Corrigan, L. J. Pribyl, J. E. Kay, B. P. Engelward

Date Published: 4th Oct 2022

Publication Type: Journal Article

Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control

Abstract

Not specified

Authors: Hannah P. Gideon, Travis K. Hughes, Constantine N. Tzouanas, Marc H. Wadsworth, Ang Andy Tu, Todd M. Gierahn, Joshua M. Peters, Forrest F. Hopkins, Jun-Rong Wei, Conner Kummerlowe, Nicole L. Grant, Kievershen Nargan, Jia Yao Phuah, H. Jacob Borish, Pauline Maiello, Alexander G. White, Caylin G. Winchell, Sarah K. Nyquist, Sharie Keanne C. Ganchua, Amy Myers, Kush V. Patel, Cassaundra L. Ameel, Catherine T. Cochran, Samira Ibrahim, Jaime A. Tomko, Lonnie James Frye, Jacob M. Rosenberg, Angela Shih, Michael Chao, Edwin Klein, Charles A. Scanga, Jose Ordovas-Montanes, Bonnie Berger, Joshua T. Mattila, Rajhmun Madansein, J. Christopher Love, Philana Ling Lin, Alasdair Leslie, Samuel M. Behar, Bryan Bryson, JoAnne L. Flynn, Sarah M. Fortune, Alex K. Shalek

Date Published: 1st May 2022

Publication Type: Journal Article

Robust IgM responses following intravenous vaccination with Bacille Calmette–Guérin associate with prevention of Mycobacterium tuberculosis infection in macaques

Abstract

Not specified

Authors: Edward B. Irvine, Anthony O’Neil, Patricia A. Darrah, Sally Shin, Alok Choudhary, Wenjun Li, William Honnen, Smriti Mehra, Deepak Kaushal, Hannah Priyadarshini Gideon, JoAnne L. Flynn, Mario Roederer, Robert A. Seder, Abraham Pinter, Sarah Fortune, Galit Alter

Date Published: 22nd Nov 2021

Publication Type: Journal Article

CometChip enables parallel analysis of multiple DNA repair activities.

Abstract (Expand)

DNA damage can be cytotoxic and mutagenic, and it is directly linked to aging, cancer, and other diseases. To counteract the deleterious effects of DNA damage, cells have evolved highly conserved DNA … repair pathways. Many commonly used DNA repair assays are relatively low throughput and are limited to analysis of one protein or one pathway. Here, we have explored the capacity of the CometChip platform for parallel analysis of multiple DNA repair activities. Taking advantage of the versatility of the traditional comet assay and leveraging micropatterning techniques, the CometChip platform offers increased throughput and sensitivity compared to the traditional comet assay. By exposing cells to DNA damaging agents that create substrates of Base Excision Repair, Nucleotide Excision Repair, and Non-Homologous End Joining, we show that the CometChip is an effective method for assessing repair deficiencies in all three pathways. With these applications of the CometChip platform, we expand the utility of the comet assay for precise, high-throughput, parallel analysis of multiple DNA repair activities.

Authors: J. Ge, L. P. Ngo, S. Kaushal, I. J. Tay, E. Thadhani, J. E. Kay, P. Mazzucato, D. N. Chow, J. L. Fessler, D. M. Weingeist, R. W. Sobol, L. D. Samson, S. R. Floyd, B. P. Engelward

Date Published: 9th Aug 2021

Publication Type: Journal Article

Immune cells in bronchoalveolar lavage fluid of Ugandan adults who resist versus those who develop latent Mycobacterium tuberculosis infection

Abstract

Not specified

Authors: Bonnie A. Thiel, William Worodria, Sophie Nalukwago, Mary Nsereko, Ingvar Sanyu, Lalitha Rejani, Josephine Zawedde, David H. Canaday, Catherine M. Stein, Keith A. Chervenak, LaShaunda L. Malone, Ronald Kiyemba, Richard F. Silver, John L. Johnson, Harriet Mayanja-Kizza, W. Henry Boom

Date Published: 1st Apr 2021

Publication Type: Journal Article

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice.

Abstract (Expand)

N-Nitrosodimethylamine (NDMA) is a DNA-methylating agent that has been discovered to contaminate water, food, and drugs. The alkyladenine DNA glycosylase (AAG) removes methylated bases to initiate the … base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we study Aag-knockout (Aag(-/-)) and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine [3MeA]) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switches from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrate a suite of molecular, cellular, and physiological analyses. We find that unrepaired 3MeA is somewhat toxic, but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tip the balance between blocks and breaks and thus dictate the disease consequences of DNA damage.

Authors: J. E. Kay, J. J. Corrigan, A. L. Armijo, I. S. Nazari, I. N. Kohale, D. K. Torous, S. L. Avlasevich, R. G. Croy, D. N. Wadduwage, S. E. Carrasco, S. D. Dertinger, F. M. White, J. M. Essigmann, L. D. Samson, B. P. Engelward

Date Published: 16th Mar 2021

Publication Type: Journal Article

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