1,3,4,6-Tetramethyl-1,4-dihydro-1,2,4,5-tetrazine, C_6H_(12)N_4

M_r =140∙19, monoclinic, P2_1/n, a = 10∙612(3), b=6∙820(1), c= 10∙975 (2) Å, β=95∙31(2)°, V=790.9(5) Å^3, Z=4, D_m=1.13(5) (flotation), D_x = 1∙177 g cm^(-3), Mo Kα, λ = 0.71073 Å, μ= 0.848 cm^(-1), F(000) = 304, T= 295 K, R = 0∙077 for 704 observed reflections. This potentially antiaromatic or homoaromatic ring system has a flattened boat conformation with both N-methyls in equatorial positions. Bond angles and distances (excluding H's) predicted to be symmetry equivalent exhibit variations of 0.002-0.014 Å and 0.0-2.0°. Substantial delocalization of the electron lone pairs of N(1) and N(4) is found

Noncooperatively Optimized Tolerance: Decentralized Strategic Optimization in Complex Systems

We introduce noncooperatively optimized tolerance (NOT), a generalization of highly optimized tolerance (HOT) that involves strategic (game theoretic) interactions between parties in a complex system. We illustrate our model in the forest fire (percolation) framework. As the number of players increases, our model retains features of HOT, such as robustness, high yield combined with high density, and self-dissimilar landscapes, but also develops features of self-organized criticality (SOC) when the number of players is large enough. For example, the forest landscape becomes increasingly homogeneous and protection from adverse events (lightning strikes) becomes less closely correlated with the spatial distribution of these events. While HOT is a special case of our model, the resemblance to SOC is only partial; for example, the distribution of cascades, while becoming increasingly heavy-tailed as the number of players increases, also deviates more significantly from a power law in this regime. Surprisingly, the system retains considerable robustness even as it becomes fractured, due in part to emergent cooperation between neighboring players. At the same time, increasing homogeneity promotes resilience against changes in the lightning distribution, giving rise to intermediate regimes where the system is robust to a particular distribution of adverse events, yet not very fragile to changes

Theorem-Proving Analysis of Digital Control Logic Interacting with Continuous Dynamics

AbstractThis work outlines an equation-based formulation of a digital control program and transducer interacting with a continuous physical process, and an approach using the Coq theorem prover for verifying the performance of the combined hybrid system. Considering thermal dynamics with linear dissipation for simplicity, we focus on a generalizable, physically consistent description of the interaction of the real-valued temperature and the digital program acting as a thermostat. Of interest in this work is the discovery and formal proof of bounds on the temperature, the degree of variation, and other performance characteristics. Our approach explicitly addresses the need to mathematically represent the decision problem inherent in an analog-to-digital converter, which for rare values can take an arbitrarily long time to produce a digital answer (the so-called Buridan's Principle); this constraint ineluctably manifests itself in the verification of thermostat performance. Furthermore, the temporal causality constraints in the thermal physics must be made explicit to obtain a consistent model for analysis. We discuss the significance of these findings toward the verification of digital control for more complex physical variables and fields

Approaches for scalable modeling and emulation of cyber systems : LDRD final report.

The goal of this research was to combine theoretical and computational approaches to better understand the potential emergent behaviors of large-scale cyber systems, such as networks of {approx} 10{sup 6} computers. The scale and sophistication of modern computer software, hardware, and deployed networked systems have significantly exceeded the computational research community's ability to understand, model, and predict current and future behaviors. This predictive understanding, however, is critical to the development of new approaches for proactively designing new systems or enhancing existing systems with robustness to current and future cyber threats, including distributed malware such as botnets. We have developed preliminary theoretical and modeling capabilities that can ultimately answer questions such as: How would we reboot the Internet if it were taken down? Can we change network protocols to make them more secure without disrupting existing Internet connectivity and traffic flow? We have begun to address these issues by developing new capabilities for understanding and modeling Internet systems at scale. Specifically, we have addressed the need for scalable network simulation by carrying out emulations of a network with {approx} 10{sup 6} virtualized operating system instances on a high-performance computing cluster - a 'virtual Internet'. We have also explored mappings between previously studied emergent behaviors of complex systems and their potential cyber counterparts. Our results provide foundational capabilities for further research toward understanding the effects of complexity in cyber systems, to allow anticipating and thwarting hackers

Monomerization of Far-Red Fluorescent Proteins

Anthozoa-class red fluorescent proteins (RFPs) are frequently used as biological markers, with far-red (λ_(em) ∼ 600–700 nm) emitting variants sought for whole-animal imaging because biological tissues are more permeable to light in this range. A barrier to the use of naturally occurring RFP variants as molecular markers is that all are tetrameric, which is not ideal for cell biological applications. Efforts to engineer monomeric RFPs have typically produced dimmer and blue-shifted variants because the chromophore is sensitive to small structural perturbations. In fact, despite much effort, only four native RFPs have been successfully monomerized, leaving the majority of RFP biodiversity untapped in biomarker development. Here we report the generation of monomeric variants of HcRed and mCardinal, both far-red dimers, and describe a comprehensive methodology for the monomerization of red-shifted oligomeric RFPs. Among the resultant variants is mKelly1 (emission maximum, λ_(em) = 656 nm), which, along with the recently reported mGarnet2 [Matela G, et al. (2017) Chem Commun (Camb) 53:979–982], forms a class of bright, monomeric, far-red FPs

Leveraging Formal Methods and Fuzzing to Verify Security and Reliability Properties of Large-Scale High-Consequence Systems

Formal methods describe a class of system analysis techniques that seek to prove specific propertiesabout analyzed designs, or locate flaws compromising those properties. As an analysis capability,these techniques are the subject of increased interest fromboth internal and external customersof Sandia National Laboratories. Given this lab's other areas of expertise, Sandia is uniquelypositioned to advance the state-of-the-art with respect toseveral research and application areaswithin formal methods. This research project was a one-yeareffort funded by Sandia's CyberSecurity S&T Investment Area in its Laboratory Directed Research&Development program toinvestigate the opportunities for formal methods to impactSandia's present mission areas, morefully understand the needs of the research community in the area of formal methods and whereSandia can contribute, and clarify from those potential research paths those that would best advancethe mission-area interests of Sandia. The accomplishmentsfrom this project reinforce the utilityof formal methods in Sandia, particularly in areas relevantto Cyber Security, and set the stagefor continued Sandia investments to ensure this capabilityis utilized and advanced within thislaboratory to serve the national interest.

Ferroxitosis: a cell death from modulation of oxidative phosphorylation and PKM2-dependent glycolysis in melanoma

Reliance on glycolysis is a characteristic of malignancy, yet the development of resistance to BRAF inhibitors in melanoma is associated with gain of mitochondrial function. Concurrent attenuation of oxidative phosphorylation and HIF-1α/PKM2-dependent glycolysis promotes a non-apoptotic, iron- and oxygen-dependent cell death that we term ferroxitosis. The redox cycling agent menadione causes a robust increase in oxygen consumption, accompanied by significant loss of intracellular ATP and rapid cell death. Conversely, either hypoxic adaptation or iron chelation prevents menadione-induced ferroxitosis. Ectopic expression of K213Q HIF-1α mutant blunts the effects of menadione. However, knockdown of HIF-1α or PKM2 restores menadione-induced cytotoxicity in hypoxia. Similarly, exposure of melanoma cells to shikonin, a menadione analog and a potential PKM2 inhibitor, is sufficient to induce ferroxitosis under hypoxic conditions. Collectively, our findings reveal that ferroxitosis curtails metabolic plasticity in melanoma

Peginesatide in patients with anemia undergoing hemodialysis

BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis- stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point - death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia - with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysisSupported by Affymax and Takeda Pharmaceutica

Exile Vol. XVI No. 1

DRAMA God\u27s Pocket by Robert R. Bowie, Jr. 5-12 FICTION The Wagon by John Anderson 18-19 An Infinity of Mirrors by Keith McWalter 23-25 Commitment by John Whitt 28-29 It began not long ago... by Linda Notzelman 32-33 Jaundiced Evening by John Benes 35-39 POETRY Paralysis Outline by Lauren Shakely 13 A Woman Reads Camus by Lauren Shakely 14 don\u27t sell my rings by Lauren Shakely 14 Drift by John Whitt 17 Haiku by M. S. Wallace 19 To Begin W. K. Mayo 19 Dark is Right by Louise Tate 20 I am waiting by Louise Tate 21 My mother died as I shall die by Tim Cope 20 I never blamed you by Tim Cope 26 For Miss Didawick by Tim Cope 34 Separidian by Bill Whitmore 27 He walks on into by Whitney Carman 31 As Drowned Men Rise by Paul Bennett 34 The Tolling of the Bell by Keith McWalter 39 ARTWORK by Wandi Solez 4, 13, 16, 22, 36 by W. A. Hoffman 21, 30 by Stephen Sneeringer 27 by Christine Michael 19 Cover & Title Page Design: Keith McWalter Layouts: Keith McWalter Publicity- Special thanks to Gail Moore and Karen Baker Photographs courtesy the Sierra Club- From NOT MAN APART, Copyright 196