Interval duration effects on blocking in appetitive conditioning

Three experiments examined absolute (Experiment 1) and relative (Experiments 2a and 2b) duration effects on blocking. In Experiment 1, rats were pretrained with a short or long conditioned stimulus (CS1) followed by food, after which they were given reinforced short-short or long-long CS1-CS2 simultaneous compounds. Compared to overshadowing control groups, both pretrained groups displayed blocking, and there was no clear effect of absolute stimulus duration on the magnitude of blocking. In Experiments 2a and 2b, the rats received partially overlapping short-long CS1-CS2 compounds. In both experiments, a long CS1 blocked a short CS2, but not vice versa. This was the case when the long CS1 was nine times (Experiment 2a) or only 1.5 times (Experiment 2b) the duration of the short CS2. The pattern of results is most consistent with a real-time model of conditioning, such as the Sutton and Barto [Sutton, R.S., Barto, A.G., 1990. Time derivative models of Pavlovian reinforcement. In: Gabriel, M.R., Moore, J.W. (Eds.), Learning and Computational Neuroscience: Foundations of Adaptive Networks. MIT Press, Cambridge, MA, 497-537] temporal difference model.     

Ethical issues in heart failure: overview of an emerging need

Modern therapies in cardiovascular medicine aim at preventing death and improving patients' quality of life. However, cardiologists often focus on what can be done rather than what should be done, and the latter consideration may be neglected in the midst of therapeutic optimism. The life-saving success of cardiovascular treatments, combined with an aging population, has created an epidemic of heart failure, a disease that portends considerable morbidity and mortality and raises important questions about what should be done. This and the following essays in this section address the emerging need for ethical analysis of issues raised by patients with heart failure. In this overview, we discuss end-of-life care in end-stage heart failure, new therapies for heart failure, and heart failure research.     

The effect of darbepoetin alfa on growth, oxygenation and radioresponsiveness of a breast adenocarcinoma

Tumor hypoxia is associated with poor clinical outcome in a variety of tumors, including cervical, head/neck and breast cancer. Administration of erythropoietic factors has been suggested as a means of improving tumor oxygenation (pO2). This study randomized rats to treatment with low-dose or high-dose darbepoetin alfa or a placebo to determine the effect of darbepoetin alfa on the pO2, growth and response to radiation therapy of R3230 mammary adenocarcinoma. Rats received 3 microg/kg (high dose) or 0.2 microg/kg (low dose) darbepoetin alfa or placebo for eight doses prior to either (1) pO2 measurement and pimonidazole staining or (2) irradiation or sham irradiation on post-transplant day 20. In the animals randomized to radiation treatment, placebo or darbepoetin alfa administration at a reduced dose was continued for 9 weeks or until the tumor diameter exceeded 15 mm (defined as failure for survival analysis). Treatment with high-dose and low-dose darbepoetin alfa produced hematocrits of 68 and 56% compared to 44 and 45% in their respective control groups (both P < 10(-5)). At 18 days post-transplant, tumor volume was not different for either darbepoetin alfa group compared to the placebo group. Tumor oxygenation, as measured by the fraction of pO2 measurement <10 mmHg and the intensity of pimonidazole staining, was significantly improved in the high-dose group (P = 0.046 and 0.03, respectively, compared with controls) but not in the low-dose group. Growth delay curves after irradiation did not differ significantly for high- or low-dose darbepoetin alfa compared to placebo. In this nonanemic animal model of mammary adenocarcinoma, darbepoetin alfa does not significantly alter tumor growth or radioresponsiveness, even though it improves oxygenation when administered at high doses.     

Diversity and Distribution of Planctomycetes and Related Bacteria in the Suboxic Zone of the Black Sea

Samples from six depths of the Black Sea's suboxic zone were analyzed for 16S rRNA gene sequence information. A gradient in phylotype diversity was found. The distributions of known anaerobic ammonium oxidation (anammox) bacteria, many unknown Planctomycetes, and other phylotypes were examined in relation to the local nutrient and redox conditions.     

Ethics of the heart: ethical and policy challenges in the treatment of advanced heart failure

Heart failure is a major cause of morbidity and mortality in the United States and worldwide, accounting for immense health-care costs. Advanced therapies such as transplantation, ventricular assist devices, and implantable cardioverter defibrillators have had great success in significantly improving life expectancy and morbidity, however these advances have contributed substantially to the economic burden associated with this epidemic. Concomitantly, the accessibility of these advanced therapies is limited, due to a finite number of available organs for heart transplantation and, in the future, the economic costs associated with both transplant and device therapy. This article discusses ethical and policy challenges in the treatment of advanced heart failure, including decisions regarding procurement of hearts for transplant and allocation to recipients; and the complex issues surrounding the use of implantable cardioverter defibrillators and ventricular assist devices, including quality of life, advanced directive planning in the context of these devices, and resource utilization. Based on these challenges, we recommend that a discussion of these complex matters be incorporated into cardiovascular training programs.     

Size- and coating-dependent uptake of polymer-coated gold nanoparticles in primary human dermal microvascular endothelial cells

A library-orientated approach is used to gain understanding of the interactions of well-defined nanoparticles with primary human endothelial cells, which are a key component of the vasculature. Fifteen sequentially modified gold nanoparticles (AuNPs) based on three different core sizes (18, 35, 65 nm) and five polymeric coatings were prepared. The synthetic methodology ensured homogeneity across each series of particles to allow sequential investigation of the chemical features on cellular interactions. The toxicity of these nanoparticles, their uptake behavior in primary human dermal microvascular endothelial cells (HDMECs), and quantification of uptake were all investigated. The results of our studies indicated that high concentrations of gold nanoparticles (250 μg/mL) were nontoxic and that the number of internalized nanoparticles was related to nanoparticle size and surface chemistry. In summary, the positive-charged ethanediamine-coated AuNPs were internalized to a greater extent than the negative- or neutral-charged AuNPs. Moreover, differences in the amounts of internalized AuNPs could be shown for the three neutral-charged AuNPs, whereas the uptake of hydroxypropylamine-coated particles was preferred compared with glucosamine-coated or PEGylated AuNPs. Hydroxypropylamine-coated AuNPs were found to be the most efficient neutral-charged particles in overcoming the endothelial cell barrier and entering the cell.     

Experimental and computational analyses of the energetic basis for dual recognition of immunity proteins by colicin endonucleases

Colicin endonucleases (DNases) are bound and inactivated by immunity (Im) proteins. Im proteins are broadly cross-reactive yet specific inhibitors binding cognate and non-cognate DNases with K_d values that vary between 10^− 4 and 10^− 14 M, characteristics that are explained by a ‘dual-recognition’ mechanism. In this work, we addressed for the first time the energetics of Im protein recognition by colicin DNases through a combination of E9 DNase alanine scanning and double-mutant cycles (DMCs) coupled with kinetic and calorimetric analyses of cognate Im9 and non-cognate Im2 binding, as well as computational analysis of alanine scanning and DMC data. We show that differential ΔΔGs observed for four E9 DNase residues cumulatively distinguish cognate Im9 association from non-cognate Im2 association. E9 DNase Phe86 is the primary specificity hotspot residue in the centre of the interface, which is coordinated by conserved and variable hotspot residues of the cognate Im protein. Experimental DMC analysis reveals that only modest coupling energies to Im9 residues are observed, in agreement with calculated DMCs using the program ROSETTA and consistent with the largely hydrophobic nature of E9 DNase-Im9 specificity contacts. Computed values for the 12 E9 DNase alanine mutants showed reasonable agreement with experimental ΔΔG data, particularly for interactions not mediated by interfacial water molecules. ΔΔG predictions for residues that contact buried water molecules calculated using solvated rotamer models met with mixed success; however, we were able to predict with a high degree of accuracy the location and energetic contribution of one such contact. Our study highlights how colicin DNases are able to utilise both conserved and variable amino acids to distinguish cognate from non-cognate Im proteins, with the energetic contributions of the conserved residues modulated by neighbouring specificity sites.