Electron Transfer-oxy Radical Mechanism for Anti-cancer Agents: 9-anilinoacridines

A possible mode of action involving electron transfer is advanced for the 9- anilinoacridines. The mechanism entails formation of toxic oxy radicals which destroy the neoplasm. Cyclic voltammetry was performed on iminium type ions derived by protonation of the acridines. Reductions were generally reversible with potentials of about - 0.60 V. Involvement of quinoidal metabolites is also a possibility. The relationship of electrochemical behavior to structure and physiological activity is addressed

Analysis of Anion Distributions in the Developing Strata of a Constructed Wetland Used for Chlorinated Ethene Remediation

Perchloroethene (PCE), Trichloroethene (TCE) and their degradation products are among the most common organic groundwater contaminants in the United States. Constructed wetlands utilizing upward flow harbor reduction-oxidation conditions that have demonstrated the potential to promote both partial and total mineralization of PCE and TCE through the process of natural attenuation. Organic acid and inorganic anion concentrations are indicative of reduction-oxidation processes that drive chlorinated ethene degradation. These analytes were investigated to assess their development within three vertically stratified regions of a constructed wetland cell at Wright-Patterson Air Force Base fed by groundwater contaminated with PCE and TCE. Data collected during the months of January 2002, December 2002, and January 2003 revealed changes in the organic acid pool over time and in space that correlated with changes in the inorganic anion pool. Overall organic acid concentrations decreased by an average of 93% over 11 month period, indicating a substantial geochemical evolution of the organic acid pool over this time frame. Measurements dissolved oxygen and ORP supported the existence of an aerobic region at the base of the wetland, followed by an anaerobic region in the strata above. Significant nitrate and sulfate reduction in the anaerobic region occurred in unison with the emergence of higher concentrations of lactate and formate. Results indicate the reducing conditions and substrates required to support reductive dechlorination of chlorinated ethenes were present in the subsurface of the wetland

Anti-cancer Action of Metal Complexes: Electron Transfer and Oxidative Stress?

Evidence is presented in support of an electron transfer mechanism for various metal complexes possessing anti-neoplastic properties. Cyclic voltammetry was performed on several metallocenes, bis(acetato)bis(imidazole)Cu(II), and coordination compounds (Cu or Fe) of the anti-tumor agents, bipyridine, phenanthroline, hydroxyurea, diethyldithiocarbamate, and α, α1-bis(8-hydroxyquinolin-7-yl)-4-methoxytoluene. The favorable reduction potentials ranged from +0.5 to -0.5 V. Electrochemical behavior is correlated in some cases with structure and physiological activity. Relevant literature data are discussed

Charge Transfer-oxy Radical Mechanism for Anti-cancer Agents

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants

Judicial Analysis of Predation: The Emerging Trends

This Article examines the recent judicial experience in this endeavor. The purposes of the Article are twofold.The first is to describe the current state of the law regarding predation and to discern significant trends that may be developing. The second purpose is to explore the considerations that courts must weigh in evaluating the legal utility of proposed rules that may be valid as a matter of economic theory. Toward these ends,part II of the Article examines the economic and legal context in which litigants present predation claims. Specifically, this part re-views some of the academic debates that have so greatly influenced recent courtroom developments, the statutory framework within which these developments have occurred, and the legacy of Utah Pie Co. v. Continental Baking Co., which is the Supreme Court\u27s most recent predation decision. Part III then explores the standards that courts are applying in the three principal predation contexts-pricing, innovation, and promotion. Finally, part IV examines certain patterns of judicial analysis that are apparent in fifty-seven cases decided during and after 1975, the year in which Professors Areeda and Turner published their seminal article on predatory pricing. These patterns are important and predictive, for they reflect the courts\u27 views about both the frequency and competitive dangers of predation and the administrative costs of attempting to control it. This examination also includes a table summarizing the outcomes of these cases--who won, in which types of cases, at what procedural stage--and a discussion of some economic and administrative considerations underlying those outcomes.\u27 Overall, the analysis in this Article reveals both the legal trends in one specific area of antitrust law--predation-and, more broadly, the methods by which scholarly and judicial analyses can build upon one another to promote more rapid development of an evolving field of legal inquiry

Simultaneous dual-species laser cooling using an optical frequency comb

We demonstrate 1D simultaneous laser cooling of $^{87}$Rb and $^{85}$Rb atoms using an optical frequency comb. By adjusting the pulse repetition frequency and the offset frequency, the frequency comb spectrum is tuned to ensure that two distinct frequency comb modes are simultaneously red-detuned from the cooling transitions, one mode for each species. Starting from a pre-cooled cloud of $^{85,87}$Rb atoms at above-Doppler temperatures, we show simultaneous cooling of both species down to the Doppler temperature using two counter-propagating $\sigma$$^{+}$/$\sigma$$^{-}$-polarized beams from the frequency comb. The results indicate that simultaneous dual-species frequency comb cooling does not affect the cooling characteristics of individual atomic species. The results of this work imply that several atomic species could be cooled simultaneously using a single frequency comb source. This comb-based multi-channel laser cooling could bring significant advances in multi-species atom interferometers for space applications and in the study of multi-species interactions

BIM in teaching — lessons learned from exploratory study

Building Information Technology bears promise to bring integration into fragmented AEC industry, as well as large potentials for optimization and management of building performance along life cycle. However, the adoption in Central Europe is much slower than in the USA or Scandinavia; the designers and planners are sceptical about BIM benefits. In order to build up capabilities and thus support BIM adoption in the practice, BIM skills have be built up already in university teaching. This endeavour is the central aim of the BIM_sustain project accomplished at the Vienna University of Technology. In winter term 2012/13 and winter term 2013/14 we accomplished interdisciplinary BIM-supported design labs with student participants from architecture, civil engineering and building science. The teams used different modelling and simulation software constellations for building design and analysis. The software-constellations were evaluated in terms of BIMinteroperability, and the design process was documented by means of time and activity assessment, surveys on team performance, process satisfaction and technology acceptance and focus group interviews. In this paper we will present the results of the evaluation of both courses and analyse the differences resulting from the different course design in the two consequent terms. The first course was dominated by the issue of interfaces, whereas the second course, where better functioning software combinations in terms of data transfer were used, was dominated by the issues related to the collaboration and teamwork. Our results are not only informative for the configuration of interdisciplinary BIM-supported university teaching, but can be derived for the practice as well, especially in the areas of project management, software usage, modelling conventions or incentive systems

Single-strand DNA Binding by the Helix-Hairpin-Helix Domain of XPF Contributes to Substrate Specificity of ERCC1-XPF

The nucleotide excision repair protein complex ERCC1-XPF is required for incision of DNA upstream of DNA damage. Functional studies have provided insights into the binding of ERCC1-XPF to various DNA substrates. However, because no structure for the ERCC1-XPF-DNA complex has been determined, the mechanism of substrate recognition remains elusive. Here we biochemically characterize the substrate preferences of the helix-hairpin-helix (HhH) domains of XPF and ERCC-XPF and show that the binding to single-stranded DNA (ssDNA)/dsDNA junctions is dependent on joint binding to the DNA binding domain of ERCC1 and XPF. We reveal that the homodimeric XPF is able to bind various ssDNA sequences but with a clear preference for guanine-containing substrates. NMR titration experiments and in vitro DNA binding assays also show that, within the heterodimeric ERCC1-XPF complex, XPF specifically recognizes ssDNA. On the other hand, the HhH domain of ERCC1 preferentially binds dsDNA through the hairpin region. The two separate non-overlapping DNA binding domains in the ERCC1-XPF heterodimer jointly bind to an ssDNA/dsDNA substrate and, thereby, at least partially dictate the incision position during damage removal. Based on structural models, NMR titrations, DNA-binding studies, site-directed mutagenesis, charge distribution, and sequence conservation, we propose that the HhH domain of ERCC1 binds to dsDNA upstream of the damage, and XPF binds to the non-damaged strand within a repair bubble

Contemporary and Future Approaches to Precision Medicine in Inherited Cardiomyopathies: JACC Focus Seminar 3/5

Inherited cardiomyopathies are commonly occurring myocardial disorders that are associated with substantial morbidity and mortality. Clinical management strategies have focused on treatment of heart failure and arrhythmic complications in symptomatic patients according to standardized guidelines. Clinicians are now being urged to implement precision medicine, but what does this involve? Advances in understanding of the genetic underpinnings of inherited cardiomyopathies have brought new possibilities for interventions that are tailored to genes, specific variants, or downstream mechanisms. However, the phenotypic variability that can occur with any given pathogenic variant suggests that factors other than single driver gene mutations are often involved. This is propelling a new imperative to elucidate the nuanced ways in which individual combinations of genetic variation, comorbidities, and lifestyle may influence cardiomyopathy phenotypes. Here, Part 3 of a 5-part precision medicine Focus Seminar series reviews the current status and future opportunities for precision medicine in the inherited cardiomyopathies