Molecular determinants of pH regulation in the cardiac Na+-Ca2+ exchanger.

The cardiac Na+-Ca2+ exchanger (NCX) plays a critical role in the heart by extruding Ca2+ after each contraction and thus regulates cardiac contractility. The activity of NCX is strongly inhibited by cytosolic protons, which suggests that intracellular acidification will have important effects on heart contractility. However, the mechanisms underlying this inhibition remain elusive. It has been suggested that pH regulation originates from the competitive binding of protons to two Ca2+-binding domains within the large cytoplasmic loop of NCX and requires inactivation by intracellular Na+ to fully develop. By combining mutagenesis and electrophysiology, we demonstrate that NCX pH modulation is an allosteric mechanism distinct from Na+ and Ca2+ regulation, and we show that cytoplasmic Na+ can affect the sensitivity of NCX to protons. We further identify two histidines (His 124 and His 165) that are important for NCX proton sensitivity and show that His 165 plays the dominant role. Our results reveal a complex interplay between the different allosteric mechanisms that regulate the activity of NCX. Because of the central role of NCX in cardiac function, these findings are important for our understanding of heart pathophysiology

Evaluation of Unmanned Aircraft Flying Qualities Using JSBSim

Flying qualities data can be used to predict the future performance of aircraft; however, no flying qualities requirements exist for Unmanned Aerial Vehicles (UAVs). The intent of flying qualities requirements is to guarantee the safety and operational effectiveness of the aircraft. Flying qualities requirements have been extensively researched and specified for fixed-wing and rotary-wing manned aircraft based on a substantial database of assessments. The critical issue today in flying qualities is how to extend them to pilotless aircraft. A simulation study using an open-source flight dynamics model (JSBSim) was conducted to perform various performance maneuvers and evaluate how well the aircraft followed the desired maneuver. Criteria from MIL-STD-1797 were used to evaluate the flying quality characteristics and compared to the simulation results. It was found that the application of manned criteria to autonomous UAVs did not provide an accurate depiction of its flying qualities. Instead the requirements should be focused on the closed-loop task evaluation and the limitations of the flight control system

The effect of abstract versus concrete framing on judgments of biological and psychological bases of behavior

Human behavior is frequently described both in abstract, general terms and in concrete, specific terms. We asked whether these two ways of framing equivalent behaviors shift the inferences people make about the biological and psychological bases of those behaviors. In five experiments, we manipulated whether behaviors are presented concretely (i.e. with reference to a specific person, instantiated in the particular context of that person’s life) or abstractly (i.e. with reference to a category of people or behaviors across generalized contexts). People judged concretely framed behaviors to be less biologically based and, on some dimensions, more psychologically based than the same behaviors framed in the abstract. These findings held true for both mental disorders (Experiments 1 and 2) and everyday behaviors (Experiments 4 and 5) and yielded downstream consequences for the perceived efficacy of disorder treatments (Experiment 3). Implications for science educators, students of science, and members of the lay public are discussed

Fabrication and Electric Field Dependent Transport Measurements of Mesoscopic Graphite Devices

We have developed a unique micromechanical method to extract extremely thin graphite samples. Graphite crystallites with thicknesses ranging from 10 - 100 nm and lateral size $\sim$ 2 $\mu$m are extracted from bulk. Mesoscopic graphite devices are fabricated from these samples for electric field dependent conductance measurements. Strong conductance modulation as a function of gate voltage is observed in the thinner crystallite devices. The temperature dependent resistivity measurements show more boundary scattering contribution in the thinner graphite samples.Comment: 3 pages, 3 figures included, submitted to Appl. Phys. Let

Incorporation of Thiophenes and Benzothiophenes into Novel Pi-Extended Dibenzophosphole Systems

Dibenzophospholes are molecules with extended pi conjugation. This project aims to incorporate thiophenes and benzothiophenes into dibenzophosphole systems by using 2-bromothiophene, 2-bromobenzothiophene, and 3-bromobenzothiophene as starting materials. An ethyne intermediate is created via the Sonagashira reaction, which is further reacted to form the novel dibenzophosphole system. The ultimate goal is to fuse the newly incorporated functional groups, creating an even greater degree of conjugation

Role for targeted resection in the multidisciplinary treatment of metastatic gastrointestinal stromal tumor

The management of advanced gastrointestinal stromal tumors (GISTs) has evolved in the modern era due to the discovery of c-kit mutations and the development of tyrosine kinase inhibitors (TKIs). Until the advent of TKIs such as imatinib, the median survival reported for patients with advanced GIST was 19 months. Although surgery is the treatment of choice for resectable primary GIST, its role in cases of recurrence and metastasis remains to be unclear. This review outlines the potential beneficial role of repeat surgical resection in the multidisciplinary treatment of advanced GIST in the era of TKIs

Inhibition of Lithium-Sensitive Phosphatase BPNT-1 Causes Selective Neuronal Dysfunction in C. elegans

Lithium has been a mainstay for the treatment of bipolar disorder, yet the molecular mechanisms underlying its action remain enigmatic. Bisphosphate 3′-nucleotidase (BPNT-1) is a lithium-sensitive phosphatase that catalyzes the breakdown of cytosolic 3′-phosphoadenosine 5′-phosphate (PAP), a byproduct of sulfation reactions utilizing the universal sulfate group donor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) [1–3]. Loss of BPNT-1 leads to the toxic accumulation of PAP in yeast and non-neuronal cell types in mice [4, 5]. Intriguingly, BPNT-1 is expressed throughout the mammalian brain [4], and it has been hypothesized that inhibition of BPNT-1 could contribute to the effects of lithium on behavior [5]. Here, we show that loss of BPNT-1 in Caenorhabditis elegans results in the selective dysfunction of two neurons, the bilaterally symmetric pair of ASJ chemosensory neurons. As a result, BPNT-1 mutants are defective in behaviors dependent on the ASJ neurons, such as dauer exit and pathogen avoidance. Acute treatment with lithium also causes dysfunction of the ASJ neurons, and we show that this effect is reversible and mediated specifically through inhibition of BPNT-1. Finally, we show that the selective effect of lithium on the nervous system is due in part to the limited expression of the cytosolic sulfotransferase SSU-1 in the ASJ neuron pair. Our data suggest that lithium, through inhibition of BPNT-1 in the nervous system, can cause selective toxicity to specific neurons, resulting in corresponding effects on behavior of C. elegans.National Institutes of Health (U.S.) (Grant GM084477