Christine Shamblin

Scripps Research Institute

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Amanda Walls

University of Arkansas at Fayetteville

Ishita Tandon

University of Arkansas at Fayetteville

Muralidhar Padala

Emory University

Gustavo Vaca-Diez

University of Arkansas at Fayetteville

Manuel K. Rausch

The University of Texas at Austin

Jin-Woo Kim

University of Arkansas at Fayetteville

Swastika Tandon

University of Arkansas at Fayetteville

Alan E. Woessner

University of Arkansas at Fayetteville

Kyle P. Quinn

University of Arkansas at Fayetteville

Patrick Kuczwara

University of Arkansas at Fayetteville

Cooperative Institutions

J. Craig Venter Institute

University of Maryland, Baltimore

George Washington University

University of Arkansas at Fayetteville

Johns Hopkins University

United States Army Medical Research Institute of Infectious Diseases

Biotechnology Institute

Center for Genomic Science

University of Maryland, College Park

University of the Basque Country

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Structural flexibility in the Burkholderia mallei genome

Proceedings of the National Academy of Sciences (2004)

William C. Nierman David DeShazer Sun Kim Hervé Tettelin William Nelson

The complete genome sequence of Burkholderia mallei ATCC 23344 provides insight into this highly infectious bacterium's pathogenicity and evolutionary history. B. mallei , the etiologic agent of glanders, has come under renewed scientific investigation as a result of recent concerns about its past and potential future use as a biological weapon. Genome analysis identified a number of putative virulence factors whose function was supported by comparative genome hybridization and expression profiling of the bacterium in hamster liver in vivo . The genome contains numerous insertion sequence elements that have mediated extensive deletions and rearrangements of the genome relative to Burkholderia pseudomallei . The genome also contains a vast number (>12,000) of simple sequence repeats. Variation in simple sequence repeats in key genes can provide a mechanism for generating antigenic variation that may account for the mammalian host's inability to mount a durable adaptive immune response to a B. mallei infection.

Comparative Genomics

Antigenic variation

10.1073/pnas.0403306101

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A Three-Dimensional Valve-on-Chip Microphysiological System Reveals Novel Biomarkers of Early Calcific Aortic Valve Disease Progression

Ishita Tandon Alan E. Woessner Christine Shamblin Gustavo Vaca-Diez Laís Ferreira

Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50% elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. In this study, we developed a novel, physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs was performed. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment.

10.2139/ssrn.4574962

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A Three-Dimensional Valve-on-Chip Microphysiological System Implicates Cell Cycle Progression, Cholesterol Metabolism and Protein Homeostasis in Early Calcific Aortic Valve Disease Progression

Acta Biomaterialia (2024)

Ishita Tandon Alan E. Woessner Laís Ferreira Christine Shamblin Gustavo Vaca-Diez

Homeostasis

10.1016/j.actbio.2024.07.036

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Generation of a Nonbilayer Lipid Nanoenvironment after Epitope Binding Potentiates Neutralizing HIV-1 MPER Antibody

ACS Applied Materials & Interfaces (2024)

Sara Insausti Ander Ramos-Caballero Brian Wiley Saul González-Resines Johana Torralba

Establishment of interactions with the envelope lipids is a cardinal feature of broadly neutralizing antibodies (bnAbs) that recognize the Env membrane-proximal external region (MPER) of HIV. The lipid envelope constitutes a relevant component of the full "quinary" MPER epitope, and thus antibodies may be optimized through engineering their capacity to interact with lipids. However, the role of the chemically complex lipid nanoenvironment in the mechanism of MPER molecular recognition and viral neutralization remains poorly understood. To approach this issue, we computationally and experimentally investigated lipid interactions of broadly neutralizing antibody 10E8 and optimized versions engineered to enhance their epitope and membrane affinity by grafting bulky aromatic compounds. Our data revealed a correlation between neutralization potency and the establishment of favorable interactions with small headgroup lipids cholesterol and phosphatidylethanolamine, evolving after specific engagement with MPER. Molecular dynamics simulations of chemically modified Fabs in complex with an MPER-Transmembrane Domain helix supported the generation of a nanoenvironment causing localized deformation of the thick, rigid viral membrane and identified sphingomyelin preferentially occupying a phospholipid-binding site of 10E8. Together, these interactions appear to facilitate insertion of the Fabs through their engagement with the MPER epitope. These findings implicate individual lipid molecules in the neutralization function of MPER bnAbs, validate targeted chemical modification as a method to optimize MPER antibodies, and suggest pathways for MPER peptide-liposome vaccine development.

10.1021/acsami.4c13353

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