Unique Transcriptional Profile of Sustained Ligand-Activated Preconditioning in Pre- and Post-Ischemic Myocardium

BACKGROUND: Opioidergic SLP (sustained ligand-activated preconditioning) induced by 3–5 days of opioid receptor (OR) agonism induces persistent protection against ischemia-reperfusion (I-R) injury in young and aged hearts, and is mechanistically distinct from conventional preconditioning responses. We thus applied unbiased gene-array interrogation to identify molecular effects of SLP in pre- and post-ischemic myocardium. METHODOLOGY/PRINCIPAL FINDINGS: Male C57Bl/6 mice were implanted with 75 mg morphine or placebo pellets for 5 days. Resultant SLP did not modify cardiac function, and markedly reduced dysfunction and injury in perfused hearts subjected to 25 min ischemia/45 min reperfusion. Microarray analysis identified 14 up- and 86 down-regulated genes in normoxic hearts from SLP mice (≥1.3-fold change, FDR≤5%). Induced genes encoded sarcomeric/contractile proteins (Myh7, Mybpc3,Myom2,Des), natriuretic peptides (Nppa,Nppb) and stress-signaling elements (Csda,Ptgds). Highly repressed genes primarily encoded chemokines (Ccl2,Ccl4,Ccl7,Ccl9,Ccl13,Ccl3l3,Cxcl3), cytokines (Il1b,Il6,Tnf) and other proteins involved in inflammation/immunity (C3,Cd74,Cd83, Cd86,Hla-dbq1,Hla-drb1,Saa1,Selp,Serpina3), together with endoplasmic stress proteins (known: Dnajb1,Herpud1,Socs3; putative: Il6, Gadd45g,Rcan1) and transcriptional controllers (Egr2,Egr3, Fos,Hmox1,Nfkbid). Biological themes modified thus related to inflammation/immunity, together with cellular/cardiovascular movement and development. SLP also modified the transcriptional response to I-R (46 genes uniquely altered post-ischemia), which may influence later infarction/remodeling. This included up-regulated determinants of cellular resistance to oxidant (Mgst3,Gstm1,Gstm2) and other forms of stress (Xirp1,Ankrd1,Clu), and repression of stress-response genes (Hspa1a,Hspd1,Hsp90aa,Hsph1,Serpinh1) and Txnip. CONCLUSIONS: Protection via SLP is associated with transcriptional repression of inflammation/immunity, up-regulation of sarcomeric elements and natriuretic peptides, and modulation of cell stress, growth and development, while conventional protective molecules are unaltered

Design of a Resistively Heated Thermal Hydraulic Simulator for Nuclear Rocket Reactor Cores

A preliminary design study is presented for a non-nuclear test facility which uses ohmic heating to replicate the thermal hydraulic characteristics of solid core nuclear reactor fuel element passages. The basis for this testing capability is a recently commissioned nuclear thermal rocket environments simulator, which uses a high-power, multi-gas, wall-stabilized constricted arc-heater to produce high-temperature pressurized hydrogen flows representative of reactor core environments, excepting radiation effects. Initially, the baseline test fixture for this non-nuclear environments simulator was configured for long duration hot hydrogen exposure of small cylindrical material specimens as a low cost means of evaluating material compatibility. It became evident, however, that additional functionality enhancements were needed to permit a critical examination of thermal hydraulic effects in fuel element passages. Thus, a design configuration was conceived whereby a short tubular material specimen, representing a fuel element passage segment, is surrounded by a backside resistive tungsten heater element and mounted within a self-contained module that inserts directly into the baseline test fixture assembly. With this configuration, it becomes possible to create an inward directed radial thermal gradient within the tubular material specimen such that the wall-to-gas heat flux characteristics of a typical fuel element passage are effectively simulated. The results of a preliminary engineering study for this innovative concept are fully summarized, including high-fidelity multi-physics thermal hydraulic simulations and detailed design features

Language of Lullabies: The Russification and De-Russification of the Baltic States

This article argues that the laws for promotion of the national languages are a legitimate means for the Baltic states to establish their cultural independence from Russia and the former Soviet Union

Climate Change Meets the Law of the Horse

The climate change policy debate has only recently turned its full attention to adaptation - how to address the impacts of climate change we have already begun to experience and that will likely increase over time. Legal scholars have in turn begun to explore how the many different fields of law will and should respond. During this nascent period, one overarching question has gone unexamined: how will the legal system as a whole organize around climate change adaptation? Will a new distinct field of climate change adaptation law and policy emerge, or will legal institutions simply work away at the problem through unrelated, duly self-contained fields, as in the famous Law of the Horse? This Article is the first to examine that question comprehensively, to move beyond thinking about the law and climate change adaptation to consider the law of climate change adaptation. Part I of the Article lays out our methodological premises and approach. Using a model we call Stationarity Assessment, Part I explores how legal fields are structured and sustained based on assumptions about the variability of natural, social, and economic conditions, and how disruptions to that regime of variability can lead to the emergence of new fields of law and policy. Case studies of environmental law and environmental justice demonstrate the model’s predictive power for the formation of new distinct legal regimes. Part II applies the Stationarity Assessment model to the topic of climate change adaptation, using a case study of a hypothetical coastal region and the potential for climate change impacts to disrupt relevant legal doctrines and institutions. We find that most fields of law appear capable of adapting effectively to climate change. In other words, without some active intervention, we expect the law and policy of climate change adaptation to follow the path of the Law of the Horse - a collection of fields independently adapting to climate change - rather than organically coalescing into a new distinct field. Part III explores why, notwithstanding this conclusion, it may still be desirable to seek a different trajectory. Focusing on the likelihood of systemic adaptation decisions with perverse, harmful results, we identify the potential benefits offered by intervening to shape a new and distinct field of climate change adaptation law and policy. Part IV then identifies the contours of such a field, exploring the distinct purposes of reducing vulnerability, ensuring resiliency, and safeguarding equity. These features provide the normative policy components for a law of climate change adaptation that would be more than just a Law of the Horse. This new field would not replace or supplant any existing field, however, as environmental law did with regard to nuisance law, and it would not be dominated by substantive doctrine. Rather, like the field of environmental justice, this new legal regime would serve as a holistic overlay across other fields to ensure more efficient, effective, and just climate change adaptation solutions

Hyperthermal Environments Simulator for Nuclear Rocket Engine Development

An arc-heater driven hyperthermal convective environments simulator was recently developed and commissioned for long duration hot hydrogen exposure of nuclear thermal rocket materials. This newly established non-nuclear testing capability uses a high-power, multi-gas, wall-stabilized constricted arc-heater to produce hightemperature pressurized hydrogen flows representative of nuclear reactor core environments, excepting radiation effects, and is intended to serve as a low-cost facility for supporting non-nuclear developmental testing of hightemperature fissile fuels and structural materials. The resulting reactor environments simulator represents a valuable addition to the available inventory of non-nuclear test facilities and is uniquely capable of investigating and characterizing candidate fuel/structural materials, improving associated processing/fabrication techniques, and simulating reactor thermal hydraulics. This paper summarizes facility design and engineering development efforts and reports baseline operational characteristics as determined from a series of performance mapping and long duration capability demonstration tests. Potential follow-on developmental strategies are also suggested in view of the technical and policy challenges ahead. Keywords: Nuclear Rocket Engine, Reactor Environments, Non-Nuclear Testing, Fissile Fuel Development

Arc-Heater Facility for Hot Hydrogen Exposure of Nuclear Thermal Rocket Materials

A hyper-thermal environment simulator is described for hot hydrogen exposure of nuclear thermal rocket material specimens and component development. This newly established testing capability uses a high-power, multi-gas, segmented arc-heater to produce high-temperature pressurized hydrogen flows representative of practical reactor core environments and is intended to serve. as a low cost test facility for the purpose of investigating and characterizing candidate fueUstructura1 materials and improving associated processing/fabrication techniques. Design and development efforts are thoroughly summarized, including thermal hydraulics analysis and simulation results, and facility operating characteristics are reported, as determined from a series of baseline performance mapping tests

Microcraters in aluminum foils exposed by Stardust

We will present preliminary results on the nature and size frequency distribution of microcraters that formed in aluminum foils during the flyby of comet Wild 2 by the Stardust spacecraft

Anti-confocal versus confocal assessment of the middle ear simulated by Monte Carlo methods

The ability to monitor the inflammatory state of the middle ear mucosa would provide clinical utility. To enable spectral measurements on the mucosa whilst rejecting background signal from the eardrum an anti-confocal system is investigated. In contrast to the central pinhole in a confocal system the anti-confocal system uses a central stop to reject light from the in-focus plane, the eardrum, with all other light detected. Monte Carlo simulations of this system show an increase in detected signal and improved signal-to-background ratio compared to a conventional confocal set-up used to image the middle ear mucosa. System parameters are varied in the simulation and their influence on the level of background rejection are presented