Swords into Plowshares: Nuclear Power and the Atomic Energy Act’s Preemptive Scope in Virginia Uranium, Inc. v. Warren

This commentary highlights the considerations the Supreme Court should attend to in its decision in Virginia Uranium, Inc. v. Warren, both in construing § 2021(k) and in reviewing the Fourth Circuit’s reading of precedent from other circuits and from the Court’s prior opinions. Specifically, the Court must clarify how to interpret § 2021(k)’s activities component in concert with its “for purposes” language and determine the importance of the particular underlying activity the state seeks to regulate in a preemption analysis under the Atomic Energy Act. Clarification is necessary to ensure that courts properly effectuate Congress’s intent in regulating nuclear power, an important regulatory realm that implicates economic growth, technological development, and foreign policy

An Investigation Of Gene Regulatory Network State Space Variability

Genes are segments of DNA that provide a blueprint for cells and organisms to effectively control processes and regulations within individuals. There have been many attempts to quantify these processes, as a greater understanding of how genes operate could have large impacts on both personalized and precision medicine. Gene interactions are of particular interest, however, current biological methods can not easily reveal the details of these interactions. Therefore, we infer networks of interactions from gene expression data which we call a gene regulatory network, or GRN. Due to the robust behavior of genes and the inherent variability within interactions, models incorporating stochasticity are more realistic than those that are only deterministic. These methods are designed to bypass the need for large amounts of data and extensive knowledge about a network. In this work, we extend previous work investigating additional ways to incorporate stochasticity into gene regulatory networks. First, we use a transition function and investigate its inherent variation, then we use a statistical distribution for activating and degrading the states of genes, and finally, we use a new method incorporating spectral density to incorporate stochasticity within a GRN

Impact of the Non-structural 2 Protein on Respiratory Syncytial Virus Pathogenesis

Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in young children. The factors contributing to increased propensity of RSV-induced distal airway disease compared to other commonly encountered respiratory viruses are unknown. Using a model of the well-differentiated airway epithelium, we characterized the consequences of RSV infection of ciliated epithelial cells, the primary cellular targets of RSV infection in vivo. These studies show that RSV infection results in cell rounding and degradation of the cilia apparatus, followed by active extrusion of infected cells from the epithelium, eventually resulting in a decline in the ability of the airway epithelium to perform mucociliary transport. Using recombinant respiratory viruses, we attribute these consequences to the RSV non-structural 2 (NS2) protein. Using parainfluenza virus 3 (PIV3) to deliver and express RSV NS2 in the ciliated epithelium of hamster airways, we assessed the impact of NS2 on respiratory viral pathogenesis. These studies identified the RSV NS2 protein as a unique viral genetic determinant for RSV-induced pathogenesis, resulting in two distinct effects in vivo. First, NS2 promoted epithelial cell extrusion and accelerated clearance of whole lung virus titers, presumably by clearing virus-infected cells from the airway mucosa. Second, epithelial cell extrusion promoted by NS2 resulted in accumulation of detached, pleomorphic epithelial cells in the narrow diameter bronchiolar airway lumen, resulting in acute distal airway obstruction. Finally, we identify a role for NS2 in mediating early and robust neutrophilic influx, which may contribute to distal airway obstruction and constriction. These studies reveal a novel consequence of RSV infection of the airway epithelium, where NS2-promoted epithelial cell shedding and morphologic changes accelerate viral clearance but also cause acute distal airway obstruction. NS2-promoted epithelial cell shedding in the distal airways and the resulting obstruction of these airways represent a mechanism that may explain why RSV is the dominant virus causing bronchiolitis in young children. We identify for the first time NS2 as a pathogenesis factor for increasing the likelihood for small airway obstruction during RSV infection.Doctor of Philosoph

Rare germline mutations in African American men diagnosed with earlyâ onset prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142420/1/pros23464_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142420/2/pros23464.pd

RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction

Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in young children. The factors that contribute to the increased propensity of RSV-induced distal airway disease compared with other commonly encountered respiratory viruses remain unclear. Here, we identified the RSV-encoded nonstructural 2 (NS2) protein as a viral genetic determinant for initiating RSV-induced distal airway obstruction. Infection of human cartilaginous airway epithelium (HAE) and a hamster model of disease with recombinant respiratory viruses revealed that NS2 promotes shedding of infected epithelial cells, resulting in two consequences of virus infection. First, epithelial cell shedding accelerated the reduction of virus titers, presumably by clearing virus-infected cells from airway mucosa. Second, epithelial cells shedding into the narrow-diameter bronchiolar airway lumens resulted in rapid accumulation of detached, pleomorphic epithelial cells, leading to acute distal airway obstruction. Together, these data indicate that RSV infection of the airway epithelium, via the action of NS2, promotes epithelial cell shedding, which not only accelerates viral clearance but also contributes to acute obstruction of the distal airways. Our results identify RSV NS2 as a contributing factor for the enhanced propensity of RSV to cause severe airway disease in young children and suggest NS2 as a potential therapeutic target for reducing the severity of distal airway disease

Respiratory Syncytial Virus Grown in Vero Cells Contains a Truncated Attachment Protein That Alters Its Infectivity and Dependence on Glycosaminoglycans

Human respiratory syncytial virus (RSV) contains a heavily glycosylated 90-kDa attachment glycoprotein (G). Infection of HEp-2 and Vero cells in culture depends largely on virion G protein binding to cell surface glycosaminoglycans (GAGs). This GAG-dependent phenotype has been described for RSV grown in HEp-2 cells, but we have found that it is greatly reduced by a single passage in Vero cells. Virions produced from Vero cells primarily display a 55-kDa G glycoprotein. This smaller G protein represents a post-Golgi compartment form that is lacking its C terminus, indicating that the C terminus is required for GAG dependency. Vero cell-grown virus infected primary well-differentiated human airway epithelial (HAE) cell cultures 600-fold less efficiently than did HEp-2 cell-grown virus, indicating that the C terminus of the G protein is also required for virus attachment to this model of the in vivo target cells. This reduced infectivity for HAE cell cultures is not likely to be due to the loss of GAG attachment since heparan sulfate, the primary GAG used by RSV for attachment to HEp-2 cells, is not detectable at the apical surface of HAE cell cultures where RSV enters. Growing RSV stocks in Vero cells could dramatically reduce the initial infection of the respiratory tract in animal models or in volunteers receiving attenuated virus vaccines, thereby reducing the efficiency of infection or the efficacy of the vaccine

Human parainfluenza virus serotypes differ in their kinetics of replication and cytokine secretion in human tracheobronchial airway epithelium

Human parainfluenza viruses (PIVs) cause acute respiratory illness in children, the elderly, and immunocompromised patients. PIV3 is a common cause of bronchiolitis and pneumonia, whereas PIV1 and 2 are frequent causes of upper respiratory tract illness and croup. To assess how PIV1, 2, and 3 differ with regard to replication and induction of type I interferons, interleukin-6, and relevant chemokines, we infected primary human airway epithelium (HAE) cultures from the same tissue donors and examined replication kinetics and cytokine secretion. PIV1 replicated to high titer yet did not induce cytokine secretion until late in infection, while PIV2 replicated less efficiently but induced an early cytokine peak. PIV3 replicated to high titer but induced a slower rise in cytokine secretion. The T cell chemoattractants CXCL10 and CXCL11 were the most abundant chemokines induced. Differences in replication and cytokine secretion might explain some of the differences in PIV serotype-specific pathogenesis and epidemiology