Irradiated Esophageal Cells are Protected from Radiation-Induced Recombination by MnSOD Gene Therapy

Radiation-induced DNA damage is a precursor to mutagenesis and cytotoxicity. During radiotherapy, exposure of healthy tissues can lead to severe side effects. We explored the potential of mitochondrial SOD (MnSOD) gene therapy to protect esophageal, pancreatic and bone marrow cells from radiation-induced genomic instability. Specifically, we measured the frequency of homologous recombination (HR) at an integrated transgene in the Fluorescent Yellow Direct Repeat (FYDR) mice, in which an HR event can give rise to a fluorescent signal. Mitochondrial SOD plasmid/liposome complex (MnSOD-PL) was administered to esophageal cells 24 h prior to 29 Gy upper-body irradiation. Single cell suspensions from FYDR, positive control FYDR-REC, and negative control C57BL/6NHsd (wild-type) mouse esophagus, pancreas and bone marrow were evaluated by flow cytometry. Radiation induced a statistically significant increase in HR 7 days after irradiation compared to unirradiated FYDR mice. MnSOD-PL significantly reduced the induction of HR by radiation at day 7 and also reduced the level of HR in the pancreas. Irradiation of the femur and tibial marrow with 8 Gy also induced a significant increase in HR at 7 days. Radioprotection by intraesophageal administration of MnSOD-PL was correlated with a reduced level of radiation-induced HR in esophageal cells. These results demonstrate the efficacy of MnSOD-PL for suppressing radiation-induced HR in vivo.National Institutes of Health (U.S.) (NIH Grant R01-CA83876-8)National Institute of Allergy and Infectious Diseases (U.S.) (NIH grant U19A1068021)National Institutes of Health (U.S.) (Grant T32-ES07020)United States. Dept. of Energy (DOE DE-FG01-04ER04)National Institutes of Health (U.S.) (NIH P01-CA26735

Pre - Service Teachers’ Perceptions of Disability as Represented in Children’s Television Programs--RESEARCH

As colleges and universities prepare pre-service teachers to teach in inclusive classrooms, it is important to understand college students’ schema of diversity. Part of creating an inclusive classroom culture is to understand how children view similarities and differences in others, and how to create a culture of acceptance. One way to create a culture of understanding is to use media representations and popular children’s television shows as a springboard for conversation and acceptance, but before pre-service teachers can use media, they have to first understand the characteristics and qualification criteria for students with disabilities, and also how the community at large perceives children with disabilities. This research investigated pre-service teachers’ understanding of proportionality and equality in children’s television programming. University undergraduate students applying to or already admitted into teacher education programs watched several hours of children’s television programs and answered questions about the number of characters they observed with disabilities, as well as the way these characters and their disabilities were presented in the show. The research showed that pre-service teachers disproportionately identified more television characters as having disabilities. Implications for practice include increasing early knowledge of IDEA categories and focusing on positive inclusive models in children’s programming and media

Babel Fortran 2003 Binding for Structured Data Types

Babel is a tool aimed at the high-performance computing community that addresses the need for mixing programming languages (Java, Python, C, C++, Fortran 90, FORTRAN 77) in order to leverage the specific benefits of those languages. Scientific codes often rely on structured data types (structs, derived data types) to encapsulate data, and Babel has been lacking in this type of support until recently. We present a new language binding that focuses on their interoperability of C/C++ with Fortran 2003. The new binding builds on the existing Fortran 90 infrastructure by using the iso-c-binding module defined in the Fortran 2003 standard as the basis for C/C++ interoperability. We present the technical approach for the new binding and discuss our initial experiences in applying the binding in FACETS (Framework Application for Core-Edge Transport Simulations) to integrate C++ with legacy Fortran codes

Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators

Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development

Bordetella pertussis Whole Cell Immunization, Unlike Acellular Immunization, Mimics Naïve Infection by Driving Hematopoietic Stem and Progenitor Cell Expansion in Mice

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 (MPPs), increases circulating white blood cells (WBCs), and alters the size and composition of lymphoid organs. In addition to MPPs, common lymphoid progenitor (CLP) proportions increase in the bone marrow of WCV-immunized mice, while B220+ cell proportions decrease. Upon subsequent infection, increases in maturing B cell populations are striking in WCV-immunized mice. RNAseq analyses of HSPCs revealed that WCV and ACV-immunized mice vastly differ in developing VDJ gene segment diversity. Moreover, gene set enrichment analyses demonstrate WCV-immunized mice exhibit unique gene signatures that suggest roles for interferon (IFN) induced gene expression. Also observed in naïve infection, these IFN stimulated gene (ISG) signatures point toward roles in cell survival, cell cycle, autophagy, and antigen processing and presentation. Taken together, these findings underscore the impact of vaccine antigen and adjuvant content on skewing and/or priming HSPC populations for immune response

How the Common Component Architecture Advances Compuational Science

Computational chemists are using Common Component Architecture (CCA) technology to increase the parallel scalability of their application ten-fold. Combustion researchers are publishing science faster because the CCA manages software complexity for them. Both the solver and meshing communities in SciDAC are converging on community interface standards as a direct response to the novel level of interoperability that CCA presents. Yet, there is much more to do before component technology becomes mainstream computational science. This paper highlights the impact that the CCA has made on scientific applications, conveys some lessons learned from five years of the SciDAC program, and previews where applications could go with the additional capabilities that the CCA has planned for SciDAC 2

COMPOSE-HPC: A Transformational Approach to Exascale

The goal of the COMPOSE-HPC project is to 'democratize' tools for automatic transformation of program source code so that it becomes tractable for the developers of scientific applications to create and use their own transformations reliably and safely. This paper describes our approach to this challenge, the creation of the KNOT tool chain, which includes tools for the creation of annotation languages to control the transformations (PAUL), to perform the transformations (ROTE), and optimization and code generation (BRAID), which can be used individually and in combination. We also provide examples of current and future uses of the KNOT tools, which include transforming code to use different programming models and environments, providing tests that can be used to detect errors in software or its execution, as well as composition of software written in different programming languages, or with different threading patterns

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer

Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development

Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed