Medicine and Health Sciences Commons^™

Phase-Adjusted Estimation Of The Covid-19 Outbreak In South Korea Under Multi-Source Data And Adjustment Measures: A Modelling Study, Xiaomei Feng, Jing Chen, Kai Wang, Lei Wang, Fengqin Zhang, Zhen Jin, Lan Zou, Xia Wang

Mathematics Faculty Articles

Based on the reported data from February 16, 2020 to March 9, 2020 in South Korea including confirmed cases, death cases and recovery cases, the control reproduction number was estimated respectively at different control measure phases using Markov chain Monte Carlo method and presented using the resulting posterior mean and 95% credible interval (C_rI). At the early phase from February 16 to February 24, we estimate the basic reproduction number R₀ of COVID-19 to be 4.79(95% C_rI 4.38 - 5.2). The estimated control reproduction number dropped rapidly to R_c ≈ 0.32(95% C_rI …

Calcium Transient Assays For Compound Screening With Human Ipsc-Derived Cardiomyocytes: Evaluating New Tools, Neil J. Daily, Radleigh Santos, Joseph Vecchi, Pinar Kemanli, Tetsuro Wakatsuki

Mathematics Faculty Articles

Calcium (Ca2+) plays a central role in regulating many biological processes in the cell from muscle contraction to neurotransmitter release. The need for reliable fluorescent calcium indicator dyes is of vast importance for studying many aspects of cell biology as well as screening compounds using phenotypic high throughput assays. We have assessed two of the latest generation of calcium indicator dyes, FLIPR Calcium 6 and Cal-520 AM for studying calcium transients (CaTs) in induced pluripotent stem cell (iPSC) -derived human cardiomyocytes. FLIPR Calcium 6 and Cal-520 dyes both displayed robust CaTs with a high signal-to-noise ratio (SNR) and were non-toxic …

Discovery Of An Enzyme And Substrate Selective Inhibitor Of Adam10 Using An Exosite-Binding Glycosylated Substrate, Franck Madoux, Daniela Dreymuller, Jean-Phillipe Pettiloud, Radleigh Santos, Christoph Becker-Pauly, Andreas Ludwig, Gregg B. Fields, Thomas Bannister, Timothy P. Spicer, Mare Cudic, Louis D. Scampavia, Dmitriy Minond

Mathematics Faculty Articles

ADAM10 and ADAM17 have been shown to contribute to the acquired drug resistance of HER2-positive breast cancer in response to trastuzumab. The majority of ADAM10 and ADAM17 inhibitor development has been focused on the discovery of compounds that bind the active site zinc, however, in recent years, there has been a shift from active site to secondary substrate binding site (exosite) inhibitor discovery in order to identify non-zinc-binding molecules. In the present work a glycosylated, exosite-binding substrate of ADAM10 and ADAM17 was utilized to screen 370,276 compounds from the MLPCN collection. As a result of this uHTS effort, a selective, …

Identification Of Protein Palmitoylation Inhibitors From A Scaffold Ranking Library, Laura D. Hamel, Brian J. Lenhart, David A. Mitchell, Radleigh Santos, Marc A. Giulianotti, Robert J. Deschenes

Mathematics Faculty Articles

The addition of palmitoyl moieties to proteins regulates their membrane targeting, subcellular localization, and stability. Dysregulation of the enzymes which catalyzed the palmitoyl addition and/or the substrates of these enzymes have been linked to cancer, cardiovascular, and neurological disorders, implying these enzymes and substrates are valid targets for pharmaceutical intervention. However, current chemical modulators of zDHHC PAT enzymes lack specificity and affinity, underscoring the need for screening campaigns to identify new specific, high affinity modulators. This report describes a mixture based screening approach to identify inhibitors of Erf2 activity. Erf2 is the Saccharomyces cerevisiae PAT responsible for catalyzing the palmitoylation …

Direct Phenotypic Screening In Mice: Identification Of Individual, Novel Antinociceptive Compounds From A Library Of 734 821 Pyrrolidine Bis-Piperazines, Richard A. Houghten, Michelle L. Ganno, Jay P. Mclaughlin, Colette T. Dooley, Shainnel O. Eans Torrey Pines Institute For Molecular Studies, Radleigh Santos, Travis Lavoi, Adel Nefzi, Greg Welmaker, Marc A. Giulianotti, Lawrence Toll

Mathematics Faculty Articles

The hypothesis in the current study is that the simultaneous direct in vivo testing of thousands to millions of systematically arranged mixture-based libraries will facilitate the identification of enhanced individual compounds. Individual compounds identified from such libraries may have increased specificity and decreased side effects early in the discovery phase. Testing began by screening ten diverse scaffolds as single mixtures (ranging from 17 340 to 4 879 681 compounds) for analgesia directly in the mouse tail withdrawal model. The “all X” mixture representing the library TPI-1954 was found to produce significant antinociception and lacked respiratory depression and hyperlocomotor effects using …

Investigating The Role Of The Host Multidrug Resistance Associated Protein Transporter Family In Burkholderia Cepacia Complex Pathogenicity Using A Caenorhabditis Elegans Infection Model, Pietro Tedesco, Marco Visone, Ermenegilda Parrilli, Maria Luisa Tutino, Elena Perrin, Isabel Maida, Renato Fani, Francesco Ballestriero, Radleigh Santos, Clemencia Pinilla, Elia Di Schiavi, George Tegos, Donatella De Pascale

Mathematics Faculty Articles

This study investigated the relationship between host efflux system of the non-vertebrate nematode Caenorhabditis elegans and Burkholderia cepacia complex (Bcc) strain virulence. This is the first comprehensive effort to profile host-transporters within the context of Bcc infection. With this aim, two different toxicity tests were performed: a slow killing assay that monitors mortality of the host by intestinal colonization and a fast killing assay that assesses production of toxins. A Virulence Ranking scheme was defined, that expressed the toxicity of the Bcc panel members, based on the percentage of surviving worms. According to this ranking the 18 Bcc strains were …

Antigen Discovery For The Identification Of Vaccine Candidates And Biomarkers Using A T Cell Driven Approach In Combination With Positional Scanning Peptide Libraries, Valeria A. Judkowski, Radleigh Santos, Gonzalo R. Acevedo, Marc Giulianotti, Jon R. Appel, Silvia A. Longhi, Karina A. Gomez, Clemencia Pinilla

Mathematics Faculty Articles

The prevention and treatment of infectious diseases is highly dependent on the availability of reliable diagnostic tests and protective or therapeutic vaccines. There also exists an urgent need to develop reliable biomarkers to monitor treatment success and to predict disease progression from asymptomatic to symptomatic disease in several disease scenarios. The elucidation of the disease-relevant antigens that elicit the protective immune responses is critical and required for the development of biomarkers, diagnostics, and vaccines. However; one of the main obstacles to the study of antigen specificity in human T cells is their low frequency in PBMC samples. To overcome this …

Improvement Of Ifng Elispot Performance Following Overnight Resting Of Frozen Pbmc Samples Confirmed Through Rigorous Statistical Analysis, Radleigh Santos, Alcinette Bunying, Nazila Sabri, John Yu, Anthony Gringeri, James Bender, Sylvia Janetzki, Clemencia Pinilla, Valeria A. Judkowski

Mathematics Faculty Articles

Immune monitoring of functional responses is a fundamental parameter to establish correlates of protection in clinical trials evaluating vaccines and therapies to boost antigen-specific responses. The IFNg ELISPOT assay is a well-standardized and validated method for the determination of functional IFNg-producing T-cells in peripheral blood mononuclear cells (PBMC); however, its performance greatly depends on the quality and integrity of the cryopreserved PBMC. Here, we investigate the effect of overnight (ON) resting of the PBMC on the detection of CD8-restricted peptide-specific responses by IFNg ELISPOT. The study used PBMC from healthy donors to evaluate the CD8 T-cell response to five pooled …

Cytokine Production But Lack Of Proliferation In Peripheral Blood Mononuclear Cells From Chronic Chagas' Disease Cardiomyopathy Patients In Response To T. Cruzi Ribosomal P Proteins, Silvia A. Longhi, Augusto Atienza, Graciela Perez Prados, Alcinette Buying, Virginia Balouz, Carlos A. Buscaglia, Radleigh Santos, Laura M. Tasso, Ricardo Bonato, Pablo Chiale, Clemencia Pinilla, Valeria A. Judkowski, Karina A. Gomez

Mathematics Faculty Articles

Background

Trypanosoma cruzi ribosomal P proteins, P2β and P0, induce high levels of antibodies in patients with chronic Chagas' disease Cardiomyopathy (CCC). It is well known that these antibodies alter the beating rate of cardiomyocytes and provoke apoptosis by their interaction with β1-adrenergic and M2-muscarinic cardiac receptors. Based on these findings, we decided to study the cellular immune response to these proteins in CCC patients compared to non-infected individuals.

Methodology/Principal findings

We evaluated proliferation, presence of surface activation markers and cytokine production in peripheral blood mononuclear cells (PBMC) stimulated with P2β, the C-terminal portion of P0 (CP0) proteins and T. …

Identification Of Tetrapeptides From A Mixture Based Positional Scanning Library That Can Restore Nm Full Agonist Function Of The L106p, I69t, I102s, A219v, C271y, And C271r Human Melanocortin-4 Polymorphic Receptors (Hmc4rs), Erica M. Haslach, Huisuo Huang, Marvin Dirain, Ginamarie Debevec, Phaedra Geer, Radleigh Santos, Marc Giulianotti, Clemencia Pinilla, Jon R. Appel, Skye R. Doering, Michael A. Walters, Richard A. Houghten, Carrie Haskell-Luevano

Mathematics Faculty Articles

Human obesity has been linked to genetic factors and single nucleotide polymorphisms (SNPs). Melanocortin-4 receptor (MC4R) SNPs have been associated with up to 6% frequency in morbidly obese children and adults. A potential therapy for individuals possessing such genetic modifications is the identification of molecules that can restore proper receptor signaling and function. These compounds could serve as personalized medications improving quality of life issues as well as alleviating diseases symptoms associated with obesity including type 2 diabetes. Several hMC4 SNP receptors have been pharmacologically characterized in vitro to have a decreased, or a lack of response, to endogenous agonists …

Gm-Csf Production Allows The Identification Of Immunoprevalent Antigens Recognized By Human Cd4+ T Cells Following Smallpox Vaccination, Valeria A. Judkowski, Alcinette Bunying, Feng Ge, Jon R. Appel, Kingyee Law, Atima Sharma, Claudia Raja-Gabaglia, Patricia Norori, Radleigh Santos, Marc Giulianotti, Mark K. Slifka, Daniel C. Douek, Barney S. Graham, Clemencia Pinilla

Mathematics Faculty Articles

The threat of bioterrorism with smallpox and the broad use of vaccinia vectors for other vaccines have led to the resurgence in the study of vaccinia immunological memory. The importance of the role of CD4+ T cells in the control of vaccinia infection is well known. However, more CD8+ than CD4+ T cell epitopes recognized by human subjects immunized with vaccinia virus have been reported. This could be, in part, due to the fact that most of the studies that have identified human CD4+ specific protein-derived fragments or peptides have used IFN-γ production to evaluate vaccinia specific T cell responses. …