Direct Laser Fabrication of a Gas Turbine Engine Component - Microstructure and Properties - Part I

This paper presents the development of a new technique for the production of abrasive turbine blade tips by direct laser processing. This superalloy cermet component is an integral part of the low pressure turbine sealing system in a demonstrator engine. Direct laser fabrication of this component fiom a bed a loose powder results in significant cost savings and improved performance over the currently employed production technique. The technology has been demonstrated by fabricating a prototype lot of 100 blade tips, which will be subjected to an engine test. This is the first instance of a direct fabrication method applied to the production of functional engine hardware. This research was funded by the United States Air Force contract F33615-94- C-2424 titled "Affordable Turbine Blade Tips".Mechanical Engineerin

Inhibition of LtxA Toxicity by Blocking Cholesterol Binding with Peptides

The leukotoxin (LtxA) produced by Aggregatibacter actinomycetemcomitans kills host immune cells, allowing the bacterium to establish an ecological niche in the upper aerodigestive tract of its human host. The interaction of LtxA with human immune cells is both complex and multifaceted, involving membrane lipids as well as cell-surface proteins. In the initial encounter with the host cell, LtxA associates with lymphocyte function-associated antigen-1, a cell surface adhesion glycoprotein. However, we have also demonstrated that the toxin associates strongly with the plasma membrane lipids, specifically cholesterol. This association with cholesterol is regulated by a cholesterol recognition amino acid consensus (CRAC) motif, with a sequence of 334LEEYSKR340, in the N-terminal region of the toxin. Here, we have demonstrated that removal of cholesterol from the plasma membrane or mutation of the LtxA CRAC motif inhibits the activity of the toxin in THP-1 cells. To inhibit LtxA activity, we designed a short peptide corresponding to the CRAC336 motif of LtxA (CRAC336WT). This peptide binds to cholesterol and thereby inhibits the toxicity of LtxA in THP-1 cells. Previously, we showed that this peptide inhibits LtxA toxicity against Jn.9 (Jurkat) cells, indicating that peptides derived from the cholesterol-binding site of LtxA may have a potential clinical applicability in controllinginfections of repeats-in-toxin-producing organisms. © 2016 John Wiley & Sons A/S

Lethal Mutagenesis of Picornaviruses with N-6-Modified Purine Nucleoside Analogues

RNA viruses exhibit extraordinarily high mutation rates during genome replication. Nonnatural ribonucleosides that can increase the mutation rate of RNA viruses by acting as ambiguous substrates during replication have been explored as antiviral agents acting through lethal mutagenesis. We have synthesized novel N-6-substituted purine analogues with ambiguous incorporation characteristics due to tautomerization of the nucleobase. The most potent of these analogues reduced the titer of poliovirus (PV) and coxsackievirus (CVB3) over 1,000-fold during a single passage in HeLa cell culture, with an increase in transition mutation frequency up to 65-fold. Kinetic analysis of incorporation by the PV polymerase indicated that these analogues were templated ambiguously with increased efficiency compared to the known mutagenic nucleoside ribavirin. Notably, these nucleosides were not efficient substrates for cellular ribonucleotide reductase in vitro, suggesting that conversion to the deoxyriboucleoside may be hindered, potentially limiting genetic damage to the host cell. Furthermore, a high-fidelity PV variant (G64S) displayed resistance to the antiviral effect and mutagenic potential of these analogues. These purine nucleoside analogues represent promising lead compounds in the development of clinically useful antiviral therapies based on the strategy of lethal mutagenesis

Definitions and Assessment Approaches for Emergency Medical Services for Children

Pediatric Life Support (PLS) courses and instructional programs are educational tools developed to teach resuscitation and stabilization of children who are critically ill or injured. A number of PLS courses have been developed by national professional organizations for different health care providers (eg, pediatricians, emergency physicians, other physicians, prehospital professionals, pediatric and emergency advanced practice nurses, physician assistants). PLS courses and programs have attempted to clarify and standardize assessment and treatment approaches for clinical practice in emergency, trauma, and critical care. Although the effectiveness of PLS education has not yet been scientifically validated, the courses and programs have significantly expanded pediatric resuscitation training throughout the United States and internationally. Variability in terminology and in assessment components used in education and training among PLS courses has the potential to create confusion among target groups and in how experts train educators and learners to teach and practice pediatric emergency, trauma, and critical care. It is critical that all educators use standard terminology and patient assessment to address potential or actual conflicts regarding patient evaluation and treatment. This article provides a consensus of several organizations as to the proper order and terminology for pediatric patient assessment. The Supplemental Information provides definitions for terms and nomenclature used in pediatric resuscitation and life support courses

Ethnic politics and sovereign credit risk

How does domestic politics affect sovereign credit risk? To date, scholars have largely focused on how economic interests along class-cleavages influence sovereign default risk and borrowing costs. Ethnic dynamics are another important political factor that explains governments’ creditworthiness, yet are understudied. We investigate how ethnic politics shape governments’ credit access and argue that the fiscal incentives generated by ethnic coalitions influence credit risk differently than those created by class cleavages. Because ethnic coalitions are usually smaller than class coalitions, left governments with ethnic support can commit to lower spending and receive more favorable risk assessments. Right governments that rely on ethnic support, however, will have greater spending demands because of their need to satisfy ethnic groups. We test our argument using a new indicator of government ethnic support and four indicators of sovereign credit risk. We find that, in emerging markets, the borrowing costs of right governments increase as they become more dependent on ethnic groups for political support. Our findings suggest that financial markets are attuned to multiple dimensions of domestic politics and demonstrate that ethnic divisions can have strong implications for governments’ access to credit

Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous basepairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses

Relationship of Self-Determination Theory Constructs and Physical Activity and Diet in a Mexican American Population in Nueces County, Texas

Due to disparities in stroke risk among U.S. Hispanics, the need for culturally tailored, theory based effective health behavior change interventions persists. The purpose of this study was to examine self-determination theory (SDT) constructs related to cardiovascular disease (CVD) risk factors in a predominantly Mexican American population. The Stroke Health and Risk Education (SHARE) project was a cluster-randomized, faith-based behavioral intervention trial that enrolled Mexican Americans (MAs) and non-Hispanic whites (NHWs) from Catholic Churches in Nueces County, Texas. Data regarding SDT constructs and dietary and physical activity behaviors were collected via computer-assisted interviews using standardized instruments at the baseline assessment. Of the 801 subjects who consented, 760 completed baseline interviews. After eliminating cases with missing data, 733 participants (617 MA and 116 NHW) were included in the analyses. Participants were predominantly Mexican American (84%) and female (64%), and had a median age of 53 years. There were no significant ethnic differences in any of the baseline SDT scale scores with the exception of higher autonomous motivation scores for exercise among MAs (7.00 vs. 6.67, p = 0.01). Demographic differences in mean SDT scale scores were identified for sex, age, and income. Perceived competence and autonomous motivation were both significant predictors of diet and physical activity behaviors. This study increases our understanding of SDT constructs relative to diet and physical activity in a large, predominantly Mexican American sample. The results indicate that SDT is an appropriate framework to address CVD behavioral risk factors in a predominantly Hispanic population

Proteome analysis of the HIV-1 Gag interactome

AbstractHuman immunodeficiency virus Gag drives assembly of virions in infected cells and interacts with host factors which facilitate or restrict viral replication. Although several Gag-binding proteins have been characterized, understanding of virus–host interactions remains incomplete. In a series of six affinity purification screens, we have identified protein candidates for interaction with HIV-1 Gag. Proteins previously found in virions or identified in siRNA screens for host factors influencing HIV-1 replication were recovered. Helicases, translation factors, cytoskeletal and motor proteins, factors involved in RNA degradation and RNA interference were enriched in the interaction data. Cellular networks of cytoskeleton, SR proteins and tRNA synthetases were identified. Most prominently, components of cytoplasmic RNA transport granules were co-purified with Gag. This study provides a survey of known Gag–host interactions and identifies novel Gag binding candidates. These factors are associated with distinct molecular functions and cellular pathways relevant in host–pathogen interactions