Life Sciences Commons^™

Blood Substitution Therapy Rescues The Brain Of Mice From Ischemic Damage, Xuefang Ren, Heng Hu, Imran Farooqi, James W. Simpkins

Faculty & Staff Scholarship

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have …

Enhancement Of Immune Response Against Bordetella Spp. By Disrupting Immunomodulation, Monica C. Gestal, Laura K. Howard, Kalyan Dewan, Hannah M. Johnson, Mariette Barbier, Clare Bryant, Illiassou Hamidou Soumana, Israel Rivera, Bodo Lina, Uriel Blas-Machado, Eric T. Harvill

Faculty & Staff Scholarship

Well-adapted pathogens must evade clearance by the host immune system and the study of how they do this has revealed myriad complex strategies and mechanisms. Classical bordetellae are very closely related subspecies that are known to modulate adaptive immunity in a variety of ways, permitting them to either persist for life or repeatedly infect the same host. Exploring the hypothesis that exposure to immune cells would cause bordetellae to induce expression of important immunomodulatory mechanisms, we identified a putative regulator of an immunomodulatory pathway. The deletion of btrS in B. bronchiseptica did not affect colonization or initial growth in the …

Monocytes And Monocyte-Derived Antigen-Presenting Cells Have Distinct Gene Signatures In Experimental Model Of Multiple Sclerosis, Kelly L. Monaghan, Wen Zheng, Gangqing Hu, Edwin C. K. Wan

Faculty & Staff Scholarship

Multiple sclerosis (MS) is a chronic inflammatory disease mediated by a complex interaction between the autoreactive lymphocytes and the effector myeloid cells within the central nervous system (CNS). In a murine model of MS, experimental autoimmune encephalomyelitis (EAE), Ly6Chi monocytes migrate into the CNS and further differentiate into antigen-presenting cells (APCs) during disease progression. Currently, there is no information about gene signatures that can distinguish between monocytes and the monocyte-derived APCs. We developed a surface marker-based strategy to distinguish between these two cell types during the stage of EAE when the clinical symptoms were most severe, and performed transcriptome analysis …

Systemic Inhibition Of Tissue-Nonspecific Alkaline Phosphatase Alters The Brain-Immune Axis In Experimental Sepsis, Allison L. Brichacek, Stanely A. Benkovic, Sreeparna Chakraborty, Divine C. Nwafor, Wei Wang, Sujung Jun, Duaa Dakhlallah, Werner Geldenhuys, Anthony B. Pinkerton, José Luis Millán, Candice M. Brown

Faculty & Staff Scholarship

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, …

Bordetella Pertussis Whole Cell Immunization, Unlike Acellular Immunization, Mimics Naïve Infection By Driving Hematopoietic Stem And Progenitor Cell Expansion In Mice, Melinda E. Varney, Dylan T. Boehm, Katherine Deroos, Evan S. Nowak, Ting Y. Wong, Emel Sen-Kilic, Shebly D. Bradford, Cody Elkins, Matthew S. Epperly, William T. Witt, Mariette Barbier, F. Heath Damron

Faculty & Staff Scholarship

Hematopoietic stem and progenitor cell (HSPC) compartments are altered to direct immune responses to infection. Their roles during immunization are not well-described. To elucidate mechanisms for waning immunity following immunization with acellular vaccines (ACVs) against Bordetella pertussis (Bp), we tested the hypothesis that immunization with Bp ACVs and whole cell vaccines (WCVs) differ in directing the HSPC characteristics and immune cell development patterns that ultimately contribute to the types and quantities of cells produced to fight infection. Our data demonstrate that compared to control and ACV-immunized CD-1 mice, immunization with an efficacious WCV drives expansion of hematopoietic multipotent progenitor cells …

Approaches To Denoise The Diffuse Optical Signals For Tissue Blood Flow Measurement, Peng Zhang, Zhiguo Gui, Yu Shang

Faculty & Staff Scholarship

Various diseases are relevant to the abnormal blood flow in tissue. Diffuse correlation spectroscopy (DCS) is an emerging technology to extract the blood flow index (BFI) from light electric field temporal autocorrelation data. To account for tissue heterogeneity and irregular geometry, we developed an innovative DCS algorithm (i.e., the Nth order linear algorithm, or simply the NL algorithm) previously, in which the DCS signals are fully utilized through iterative linear regressions. Under the framework of NL algorithm, the BFI to be extracted is significantly influenced by the linear regression approach adopted. In this study, three approaches were proposed and evaluated …

Multilevel Structural Equation Modeling Of Students’ Dietary Intentions/Behaviors, Bmi, And The Healthfulness Of Convenience Stores, Tanya Horacek, Elif Dede Yildirim, Kendra Kattelmann, Carol Byrd-Bredbenner, Onikia Brown, Sarah Colby, Geoffrey Greene, Sharon Hoerr, Tandalayo Kidd, Mallory Koenings, Jesse Morrell, Melissa D. Olfert, Beatrice Phillips, Karla Shelnutt, Adrienne White

Faculty & Staff Scholarship

Background: When dietary behaviors are habitual, intentions are low, and environmental cues, such as the consumer food environment, might guide behavior. How might intentions to eat healthily and ultimately actual dietary behaviors, be influenced by the consumer food environment (including the availability and affordability of healthy foods) in convenience stores? This study will determine pathways between the healthfulness of convenience stores and college students’ dietary intentions/behaviors, and body mass index (BMI). Methods: Through multilevel structural equation modeling, a comparison was made of students’ healthful meal intentions (HMI); intake (fruits/vegetables, %kcal/fat, sugar-sweetened beverages (SSBs) and whole-grains); and measured BMI; as well …

Arabidopsis Mate45 Antagonizes Local Abscisic Acid Signaling To Mediate Development And Abiotic Stress Responses, Nikola Kovinich, Yiqun Wang, Janet Adegboye, Alexandra A. Chanoca, Marisa S. Otegui, Paige Durkin, Erich Grotewold

Faculty & Staff Scholarship

Anthocyanins provide ideal visual markers for the identification of mutations that disrupt molecular responses to abiotic stress. We screened Arabidopsis mutants of ABC (ATP‐Binding Cassette) and MATE (Multidrug And Toxic compound Extrusion) transporter genes under nutritional stress and identified four genes (ABCG25, ABCG9, ABCG5, and MATE45) required for normal anthocyanin pigmentation. ABCG25 was previously demonstrated to encode a vascular‐localized cellular expor- ter of abscisic acid (ABA). Our results show that MATE45 encodes an aerial meris- tem‐ and a vascular‐localized transporter associated with the trans‐Golgi, and that it plays an important role in controlling the levels and distribution of ABA in …

Dysregulation Of Daf-16/Foxo3a-Mediated Stress Responses Accelerates T Oxidative Dna Damage Induced Aging, Aditi U. Gurkar, Andria R. Robinson, Yuxiang Cui, Xuesen Li, Shailaja K. Allani, Amanda Webster, Mariya Muravia, Mohammad Fallahi, Herbert Weissbach, Paul D. Robbins, Yinsheng Wang, Eric E. Kelley, Claudette M. St. Croix, Laura J. Niedernhofer, Matthew S. Gill

Faculty & Staff Scholarship

DNA damage is presumed to be one type of stochastic macromolecular damage that contributes to aging, yet little is known about the precise mechanism by which DNA damage drives aging. Here, we attempt to address this gap in knowledge using DNA repair-deficient C. elegans and mice. ERCC1-XPF is a nuclear endonuclease required for genomic stability and loss of ERCC1 in humans and mice accelerates the incidence of age-related pathologies. Like mice, ercc-1 worms are UV sensitive, shorter lived, display premature functional decline and they accumulate spontaneous oxidative DNA lesions (cyclopurines) more rapidly than wild-type worms. We found that ercc-1 worms …

Spontaneous Dna Damage To The Nuclear Genome Promotes Senescence, T Redox Imbalance And Aging, Andria R. Robinson, Matthew J. Yousefzadeh, Tania A. Rozgaja, Jin Wang, Xuesen Li, Jeremy S. Tilstra, Chelsea H. Feldman, Siobhan Q. Gregg, Caroline H. Johnson, Erin M. Skoda, Marie-Celine Frantz, Harris Bell-Temin, Hannah Pope-Varsalona, Aditi U. Gurkar, Luigi A. Nasto, Rena A.S. Robinson, Heike Fuhrmann-Stroissnigg, Jolanta Czerwinska, Sara J. Mcgowan, Nadiezhda Cantu-Madellin, Jamie B. Harris, Salony Maniar, Mark A. Ross, Christy E. Trussoni, Nicholas F. Larusso, Eugenia Cifuentes-Pagano, Patrick J. Pagano, Barbara Tudek, Nam V. Vo, Lora H. Rigatti, Patricia L. Opresko, Donna B. Stolz, Simon C. Watkins, Christin E. Burd, Claudette M. St, Croix, Gary Siuzdak, Nathan A. Yates, Paul D. Robbins, Yinsheng Wang, Peter Wipf, Eric E. Kelley, Laura J. Neidernhofer

Faculty & Staff Scholarship

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that …

A Predictive 7-Gene Assay And Prognostic Protein Biomarkers For Non-Small Cell Lung Cancer, Nancy Lan Guo, Afshin Dowlati, Rebecca A. Raese, Chunlin Dong, Guoan Chen, David G. Beer, Justine Shaffer, Salvi Singh, Ujala Bokhary, Lin Liu, John Howingtown, Thomas Hensing, Yong Qian

Faculty & Staff Scholarship

This study aims to develop a multi-gene assay predictive of the clinical benefits of chemotherapy in non- small cell lung cancer (NSCLC) patients, and substantiate their protein expression as potential therapeutic tar- gets. Patients and methods: The mRNA expression of 160 genes identified from microarray was analyzed in qRT-PCR assays of independent 337 snap-frozen NSCLC tumors to develop a predictive signature. A clinical trial JBR.10 was included in the validation. Hazard ratio was used to select genes, and decision-trees were used to construct the predictive model. Protein expression was quantified with AQUA in 500 FFPE NSCLC samples.

Results: A 7-gene …