cssi/SciSciGPT-SciSciNet huggingface dataset:
Induction of DNA Topoisomerase II-mediated DNA Cleavage by β-Lapachone and Related Naphthoquinones

Recent studies have suggested that 3,4-dihydro-2,2-dimethyl-2H-naphtho[1,2-b]pyran-5,6-dione (beta-lapachone) inhibits DNA topoisomerase I by a mechanism distinct from that of camptothecin. To study the mechanism of action of beta-lapachone, a series of beta-lapachone and related naphthoquinones were synthesized, and their activity against drug-sensitive and -resistant cell lines and purified human DNA topoisomerases as evaluated. Consistent with the previous report, beta-lapachone does not induce topoisomerase I-mediated DNA breaks. However, beta-lapachone and related naphthoquinones, like menadione, induce protein-linked DNA breaks in the presence of purified human DNA topoisomerase IIalpha. Poisoning of topoisomerase IIalpha by beta-lapachone and related naphthoquinones is independent of ATP and involves the formation of reversible cleavable complexes. The structural similarity between menadione, a para-quinone, and beta-lapachone, an ortho-quinone, together with their similar activity in poisoning topoisomerase IIalpha, suggests a common mechanism of action involving chemical reactivity of these quinones. Indeed, both quinones form adducts with mercaptoethanol, and beta-lapachone is 10-fold more reactive. There is an apparent correlation between the rates of the adduct formation with thiols and of the topoisomerase II-poisoning activity of the aforementioned quinones. In preliminary studies, beta-lapachone and related naphthoquinones are found to be cytotoxic against a panel of drug-sensitive and drug-resistant tumor cell lines, including MDR1-overexpressing cell lines, camptothecin-resistant cell lines, and the atypical multidrug-resistant CEM/V-1 cell line.
Making Decisions About End-Stage Renal Disease Treatment: A Review of Theories and Issues

Multiple theories and models of decision-making have been reported in the popular and scientific literature. Decisions and choices about health care are some of the most dramatic and difficult that humans make. The interactive role of patient and health care professional in circumstances of urgency, stress, and possible unpredictability is complex. This article reviews some of the theories of decision-making and their implementation or usefulness in the end-stage renal disease setting. In caring for patients, health professionals need to identify their approach to the decision-making process with special concern for the patient role in this process.
Determination of penicillin G and cloxacillin residues in beef and pork tissue by high-performance liquid chromatography

Tissues were homogenized and then deproteinized with acetonitrile. The acetonitrile extract was partitioned between dichloromethane and pH 2.2 buffer and then extracted with pH 7 buffer. After addition of ammonium sulfate to the aqueous solution, it was mixed with acetonitrile. The acetonitrile extract was separated and evaporated, and the residue was taken up in water. The aqueous solution was analyzed by high-performance liquid chromatography (HPLC) on a C18, 10-microns particle size, reversed-phase column using gradient elution with 0.01 M orthophosphoric acid-acetonitrile (from 80:20 to 40:60 in 20 min) at a flow-rate of 1 ml/min and UV absorbance detection at 220 nm. Recoveries were generally greater than 90% with all tissues. Data on incurred residues from a treated cow showed recoveries of penicillin which were frequently several times higher by HPLC than by bioassay. Sensitivity limits in muscle were about 0.05 ppm for both penicillin G and cloxacillin, but higher in liver and kidney because of interferences. The method is suitable for other monobasic penicillins but not for dibasic or amphoteric penicillins.
Nonlinear gyrokinetic equations for tokamak microturbulence

A nonlinear electrostatic gyrokinetic Vlasov equation as well as a Poisson equation have been derived in a form suitable for particle simulation studies of tokamak microturbulence and associated anomalous transport. This work differs from the existing nonlinear gyrokinetic theories in toroidal geometry, since the present equations conserve energy while retaining the crucial linear and nonlinear polarization physics. In the derivation, the action‐variational Lie perturbation method is utilized in order to preserve the Hamiltonian structure of the original Vlasov–Poisson system. Emphasis is placed on the dominant physics of the collective fluctuations in toroidal geometry, rather than on details of particle orbits.
Monodisperse and Polydisperse Aerosol Deposition in a Packed Bed

Although polydisperse aerosols in ambient and occupational settings have been associated with adverse health effects, researchers have mostly used monodisperse aerosols to investigate particle deposition in the human lung. The objective of this work was to determine whether the deposition of a series of monodisperse aerosols is reasonable to simulate the deposition of a polydisperse aerosol. A packed bed was used as an approximate surrogate to the human lung. Polydisperse and monodisperse sebacate aerosols were generated by nebulizers and a Monodisperse Aerosol Generator (MAGE), respectively. A Harvard respirator pump "inhaled" and "exhaled" aerosol through the packed bed. Complete size distributions of inhaled and exhaled aerosol were measured by an Aerodynamic Particle Sizer (APS) and a Scanning Mobility Particle Sizer (SMPS). The deposition for discrete sections of polydisperse aerosols was compared with the deposition of monodisperse aerosols. Also, the total deposition of a polydisperse aerosol was c...
Fast and informative flow simulations in a building by using fast fluid dynamics model on graphics processing unit

Abstract Fast indoor airflow simulations are necessary for building emergency management, preliminary design of sustainable buildings, and real-time indoor environment control. The simulation should also be informative since the airflow motion, temperature distribution, and contaminant concentration are important. Unfortunately, none of the current indoor airflow simulation techniques can satisfy both requirements at the same time. Our previous study proposed a Fast Fluid Dynamics (FFD) model for indoor flow simulation. The FFD is an intermediate method between the Computational Fluid Dynamics (CFD) and multizone/zonal models. It can efficiently solve Navier–Stokes equations and other transportation equations for energy and species at a speed of 50 times faster than the CFD. However, this speed is still not fast enough to do real-time simulation for a whole building. This paper reports our efforts on further accelerating FFD simulation by running it in parallel on a Graphics Processing Unit (GPU). This study validated the FFD on the GPU by simulating the flow in a lid-driven cavity, channel flow, forced convective flow, and natural convective flow. The results show that the FFD on the GPU can produce reasonable results for those indoor flows. In addition, the FFD on the GPU is 10–30 times faster than that on a Central Processing Unit (CPU). As a whole, the FFD on a GPU can be 500–1500 times faster than the CFD on a CPU. By applying the FFD to the GPU, it is possible to do real-time informative airflow simulation for a small building.
Trabecular bone densitometry using interactive image analysis.

Abstract Interactive image analysis is a novel application of digital image processing to the densitometry of trabecular bone. Briefly, the exposed surfaces of bleached slices of bone are illuminated so that the trabecular tips are bright in relation to the interstices. The image is then captured by a TV camera and digitized with an interactive image analysis system. A grey scale is then chosen that differentiates the bone at the surface from the background. Finally, a computer program calculates the area fraction of bone within a user-specified box which, by Delesse's principle, is an estimate of the volume fraction of bone. The reproducibility of the technique (expressed as an average sd ) is ± 1.5 vol. % and has surface-discriminating capabilities comparable to the traditional point-counting method but is faster and more precise. Most importantly, the technique permits biomechanical testing of the sample after its density has been determined.
On control with instruments of differing frequency

Abstract When some instruments are more frequently adjustable than others — the text example is monetary and fiscal policy, but applications extend from agriculture to engineering — the control solutions must be modified to incorporate the implied restrictions. The necessary modifications are developed for two stochastic (and, implicitly, deterministic) control specifications, one a closed-loop random coefficients algorithm based on serially uncorrelated coefficient errors, and the other an open-loop solution based on (single-realization) estimated coefficients. The modifications, while essential, do not fundamentally alter the character of the solutions.
The chemical dynamics of base adducts with bis(N,N-dithiocarbamate)nickel(II)

The chemical dynamics for the adduct reactions of the nitrogen bases pyridine, 2-picoline, 3-picoline, 4-picoline and 3,5-lutidine with bis(N,N-dialkyldithiocarbamate)nickel(II) were investigated. The thermodynamic parameters for adduct formation were determined by NMR techniques. The pyridine-Ni(diR,R′dtc)2 adducts have the stability order -CH2H5 < -n-C3H7 < -n-C4H9; the order is controlled by entropy rather than by enthalpy effects contrary to previously reported results from i.r. and vis spectral studies. At low temperatures the adduct stability order of Ni-(din-butyldtc)2 with pyridine type bases is 3,5-lutidine < 3-picoline < 4-picoline < pyridine. However, at 25°C the order changes to pyridine ∼3-picoline ∼3,5-lutidine < 4-picoline, the change in stability order with temperature being attributed to the T Δ S° term. The kinetic parameters ΔH≠, and ΔS≠ for 3-picoline and 4-picoline exchange with Ni(din-butyldtc)2 were determined by NMR line broadening techniques. The rate constants, κ≠, were found to be 12·5 × 104 sec−1 for 3-picoline and 6·2 × 104 sec−1 for 4-picoline. Temperature studies of contact shifts and INDO molecular orbital calculations are used to analyze the unpaired spin density transfer between the Ni(din-butyldtc)2 and the pyridine type bases.
Mesh optimization for fluorescence molecular tomography

Fluorescence Molecular Tomography is an optical imaging technique which aims at reconstructing the 3D distribution of fluorescent markers in bio-tissues based on surface measurements of emitted photons and a model of light propagation. The gold standard of accuracy in creating this light propagation model is the Monte Carlo method (MC), which simulates the path of photon packets through a discretized model of the tissue. One drawback of MC is the computational burden associated with its stochastic nature. Mesh based MC are computational implementations of MC techniques with favorable computational costs. Herein, we investigate the effects of locally refining a mesh discretization on reconstruction accuracy in mesh based Fluorescence Molecular Tomography. Using a mouse model created from μCT data and average murine optical properties, we are investigating the performances of mesh refinement strategies in reconstructing an 48.9 mm 3 fluorescence inclusion in the center of the model. Iterative mesh optimization is applied to the inverse problem in which after each reconstruction, the mesh is refined in the area of interest. Performance of the method is evaluated in terms of in volume and center of mass position of the inclusion compared to the ground truth. Our preliminary results indicate that accuracy improves with each refinement until convergence. Moreover, a method for rescaling analytically the forward model to fit each new mesh is also proposed in order to reduce the computational expense of the procedure while maintaining the improvements in accuracy
Inhibition of Alzheimer's β-Amyloid Induced Vasoactivity and Proinflammatory Response in Microglia by a cGMP-Dependent Mechanism

beta-amyloid (Abeta) peptides are the major protein components of senile plaques in Alzheimer's disease (AD) brains. Vascular damage and reactive gliosis are found colocalized with amyloid deposits in AD brains, suggesting that the vasculature may be a clinically significant site of AD pathology. Our results show that freshly solubilized Abeta1-40 enhances the vasoconstriction induced by endothelin-1 (ET-1) and increases resistance to relaxation triggered by nitric oxide (NO), suggesting that Abeta may oppose the NO/cGMP pathway. Using specific inhibitors and activators of the NO/cGMP pathway, we show that Abeta vasoactivity is not due to a modulation of nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). However, we find that a selective cGMP phosphodiesterase (cGMP-PDE) inhibitor (dipyridamole) is able to interactively block the enhanced vasoconstriction as well as the opposition to relaxation induced by Abeta, suggesting that Abeta could effect the activity of this enzyme. Cyclic GMP levels, but not cAMP concentrations, are reduced after Abeta treatment of rat aortic rings, further substantiating this hypothesis. Moreover, in examination of this pathway in another cell type pertinent to AD, we find that Abeta induces a proinflammatory response in microglia as evidenced by increased leukotriene B4 release. We show that both dipyridamole and compounds which increase cGMP levels prevent Abeta-induced microglial inflammation. Our results suggest that therapeutic intervention aimed at reduction of microglial-mediated inflammation via inhibition of cGMP-PDE or elevation of cGMP may be beneficial in the treatment of AD.
Conducting psychosocial research with children and adolescents: A developmental perspective

Abstract In the past 10 years, childhood has become a focal point of concern. Children are viewed as symbolizing an investment in the future of societies around the world. In the past, knowledge about children's views was realized through objective measures or from representative accounts by adults (e.g., parents and teachers) who were thought to know the child best. Current research suggests that most adult representations and interpretations are only attempts to describe something that more or less represents the child's world. The literature suggests that in the past, children have been perceived mainly as objects rather than subjects of research interest. This perhaps reflects the viewpoint held by many that children are unable to comprehend and describe their world and life experiences because of developmental immaturity and/or that there are intrinsic difficulties in researching children. The purpose of this article is to describe how a child's developmental level affects the research process. Specifically discussed are developmental differences in responses to research including psychosocial research methods, assent, and consent with children. Copyright © 2000 by W.B. Saunders Company
Unimodular congruence of the Laplacian matrix of a graph

Abstract Let G be a graph with vertices 1, 2, …, n . Associated with G , there is an integral quadratic form, Q ( x ), on the n -tuple of indeterminates x = (x 1 , …, x n ) , given by Q( x ) = Σ(x i − x j ) 2 , where the sum is taken over all edges ( i , j ) of G . In this paper we prove that the quadratic forms Q 1 , Q 2 associated with graphs G 1 , G 2 are congruent by a unimodular matrix if and only if G 1 and G 2 are cycle isomorphic.
Skin dose effects of postmastectomy chest wall radiation therapy using brass mesh as an alternative to tissue equivalent bolus

Abstract Purpose The use of brass mesh as a bolus is relatively uncommon in postmastectomy chest wall radiation therapy (PMRT). This study aimed to characterize the skin dose effects of using 2-mm fine brass mesh as an alternative to the traditional tissue-equivalent bolus during chest wall PMRT. Methods and Materials Data were collected from patients who received PMRT using brass mesh at the University of California Davis Department of Radiation Oncology between January 2008 and June 2011. Several patient characteristics including age, body habitus, and ethnicity were analyzed along with several disease and treatment characteristics to determine whether or not they had an impact on the skin reaction observed during radiation treatment. Additionally, in vivo surface dose measurements were obtained for 16 of the 48 patients (33%). Results Forty-eight female patients aged 28-83 received PMRT using brass mesh. As expected, the severity of skin toxicity increased with subsequent doses of radiation with all patients beginning treatment with no skin reaction (National Cancer Institute scores [NCIS] = 0) and the majority of patients completing treatment with either faint to moderate erythema (n = 19, 40%, NCIS=1) or moderate to brisk erythema (n = 23, 48%, NCIS=2). In vivo dosimetry analysis revealed surface doses between 81% and 122% of the prescribed dose, with an average of 99% of the prescribed radiation dose and standard deviation of 10% being delivered. Conclusions For postmastectomy chest wall radiation therapy, brass mesh is an effective alternative to tissue-equivalent bolus. The brass mesh achieved moderate erythema in the majority of patients at the end of treatment and the surface dose was validated using in vivo dosimetry.
Regulation of cellular energy metabolism. The Crabtree effect

The Crabtree effect (inhibition of respiration by glycolysis) is observed in cells with approximately equal glycolytic and respiratory capacities for ATP synthesis. Addition of glucose to aerobic suspensions of glucose-starved cells (Sarcoma 180 ascites tumor cells) causes a burst of respiration and lactate production due to ATP utilization for glucose phosphorylation by hexokinase and phosphofructokinase. This burst of activity is followed by inhibition of both respiration and glycolysis, the former to below the value before glucose addition (Crabtree effect). Both the respiratory rate and the glycolytic flux appear to be regulated by the cytosolic [ATP]/[ADP][Pi] albeit by completely different mechanisms. Respiration is regulated by the free energy of hydrolysis of ATP, such that the rate increases as the [ATP]/[ADP][Pi] decreases and decreases as the [ATP]/[adp][Pi] increases. The regulatory enzymes of glycolysis are activated by ADP (AMP) and Pi and inhibited by ATP. Thus both respiration and glycolysis increase or decrease as the [ATP]/[ADP][Pi] decreases or increases. The parallel regulation of both ATP-producing pathways by this common metabolite ratio is consistent with the cytoplasmic [ATP]/[ADP][Pi] being an important determinant of homeostatic regulation of cellular energy metabolism.
Self-complementary oligoribonucleotides: Adenylic acid-uridylic acid block copolymers

Abstract A series of block oligonucleotides of adenylic and uridylic acid of the form (Ap)m(Up)n−1, where m and n vary individually from 3 to 7, have been prepared. Individual oligonucleotides were shown to form bimolecular helical complexes in solution when m ⩾ n but when m For m = n the concentration and temperature dependence of association was consistent with a dimer-monomer equilibrium. The concentration dependence of Tm yielded enthalpy changes per base pair, ΔH1, that increased from −6.4 kcal./mole for (Ap)4(Up)3U to −7.6 kcal./mole for (Ap)7(Up)6U. The slope of the thermal dissociation curve at midpoint yielded average values of only −5.5 kcal./ mole. Plots of 1 T m , versus , 1 N , where N = m + n, were linear. However, the apparent variation of ΔH1 had to be introduced in order to obtain values of β that were comparable to other estimates. The chain-length dependence of ΔH1 presumably arises from end effects and/or from variations in the stacking energy of the adenylic acid sequences at the different temperature ranges over which different chain-length dimers dissociated.
Echocardiographic demonstration of satellite lesions in aortic valvular endocarditis

Abstract Aortic valve endocarditis is associated with high morbidity and mortality rates and frequently requires surgical intervention. The role of echocardiography (echo) has been well established for the recognition of valvular vegetation, flail leaflet, acute aortic regurgitation (AR), ring abscess and subvalvular aortic root aneurysm. 1–4 This report describes the echocardiographic detection of both primary and satellite vegetations that changed morphologically during antibiotic therapy for aortic valve endocarditis.
Attention to eyes is present but in decline in 2–6-month-old infants later diagnosed with autism

Deficits in eye contact have been a hallmark of autism since the condition's initial description. They are cited widely as a diagnostic feature and figure prominently in clinical instruments; however, the early onset of these deficits has not been known. Here we show in a prospective longitudinal study that infants later diagnosed with autism spectrum disorders (ASDs) exhibit mean decline in eye fixation from 2 to 6 months of age, a pattern not observed in infants who do not develop ASD. These observations mark the earliest known indicators of social disability in infancy, but also falsify a prior hypothesis: in the first months of life, this basic mechanism of social adaptive action--eye looking--is not immediately diminished in infants later diagnosed with ASD; instead, eye looking appears to begin at normative levels prior to decline. The timing of decline highlights a narrow developmental window and reveals the early derailment of processes that would otherwise have a key role in canalizing typical social development. Finally, the observation of this decline in eye fixation--rather than outright absence--offers a promising opportunity for early intervention that could build on the apparent preservation of mechanisms subserving reflexive initial orientation towards the eyes.
Front End Readout Electronics of the MicroBooNE Experiment

Abstract MicroBooNE experiment is to build a ∼170 tons Liquid Argon (LAr) Time Projection Chamber (TPC) detector that will observe interactions of neutrinos from the on-axis Booster Neutrino Beam and off-axis NuMI Beam at Fermi National Accelerator Laboratory. The experiment will address the low energy excess observed by the MiniBooNE experiment, measure low energy neutrino cross sections, and serve as the necessary next step in a phased program towards massive Liquid Argon TPC detectors. MicroBooNE TPC will have 3 readout wire planes with 8,256 wires/signal channels. All the signals will be pre–ampliﬁed, shaped, digitized and pre-processed online before recording for offline analysis of a wide variety of physics programs. To optimize the detector performance and signal-to-noise ratio, analog front end ASIC designed in 180 nm CMOS technology will be deployed and operated in LAr. Pre-ampliﬁed and shaped detector signals will be differentially driven to ADC boards operated in detector hall where signals are digitized and prepared for online data pre-processing in FPGAs. This article is an overview of the front end readout architecture of the MicroBooNE experiment, which describes the development of the front end readout electronics and preliminary test results.
Comparison of Model and Observed Regional Temperature Changes During the Past 40 Years

Results are presented for six simulations of the Goddard Institute for Space Studies (GISS) global atmosphere-ocean model for the years 1950 to 2099. There are two control simulations with constant 1950 atmospheric composition from different initial states, two GHG experiments with observed greenhouse gases up to 1990 and compounded .5% CO2 annual increases thereafter, and two GHG+SO4 experiments with the same varying greenhouse gases plus varying tropospheric sulfate aerosols. Surface air temperature trends in the two GHG experiments are compared between themselves and with the observed temperature record from 1960 and 1998. All comparisons show high positive spatial correlation in the northern hemisphere except in summer when the greenhouse signal is weakest. The GHG+SO4 experiments show weaker correlations. In the southern hemisphere, correlations are either weak or negative which in part are due to the model's unrealistic interannual variability of southern sea ice cover. The model results imply that temperature changes due to forcing by increased greenhouse gases have risen above the level of regional interannual temperature variability in the northern hemisphere over the past 40 years. This period is thus an important test of reliability of coupled climate models.
Differential binding of the enantiomers of chloroquine and quinacrine to polynucleotides: Implications for stereoselective metabolism

Interaction of the antimalarial drugs quinacrine and chloroquine with DNA has been studied extensively in order to understand the origin of their biological activity. These studies have shown that they bind to DNA through an intercalative mode and show little sequence specificity. All previous experiments were carried out using the racemic form of these drugs. We have investigated the binding of the enantiomeric forms of quinacrine and chloroquine to synthetic polynucleotides poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly (dG-dC), and found interesting differences in their binding parameters. Quinacrine enantiomers have a much higher binding affinity for the two polynucleotides compared to those of chloroquine. The negative enantiomers were found to have higher binding affinity than the positive ones. The binding constant for the binding of quinacrine(-) to poly(dG-dC).poly(dG-dC) was found to be about 3 times that of quinacrine(+). The differences in these binding affinities were further confirmed by equilibrium dialysis of the complexes of the polynucleotides with the racemic form of the drugs, which resulted in the enrichment of the dialysate with the positive enantiomer. CD spectra of the enantiomers and their polynucleotide complexes are reported. Changes in the fluorescence properties of quinacrine in the presence of the two polynucleotides are also described. Biological implications of these findings are discussed.
The NMR spectra of lead stabilizers

High resolution proton and 13C NMR spectra of lead-based heat stabilizers and their reaction products, obtained using the magic angle spinning technique, support structural assignments inferred from IR spectra. These demonstrate that lead stabilizers are unique compounds, rather than the double salts of lead oxide found in textbooks.
Effects of typheramide and alfrutamide found in Allium species on cyclooxygenases and lipoxygenases

Abstract Typheramide (N-caffeoyltyramine) and alfrutamide (N-feruloyltyramine) are phenylpropenoic acid amides found in plants. In this article, typheramide and alfrutamide were isolated from Allium sativum (garlic) and Allium fistulosum (green onion), their chemical structures were confirmed using nuclear magnetic resonance spectroscopic methods, and the potential effects on cyclooxygenases (COXs) (COX 1 and 2) and lipoxygenases (LOXs) (5- and 15-LOX) were investigated. Typheramide and alfrutamide inhibited COX 1 by 74% (P < .01) and 60% (P < .01), respectively, at the concentration of 0.1 μM; at the same concentration, they also inhibited COX 2 by 68% (P < .02) and 54% (P < .02), respectively. Typheramide was slightly stronger than alfrutamide in inhibiting COX enzymes, and the inhibition patterns of COX 1 and 2 were uncompetitive with Ki = 0.032 and 0.047 μM, respectively. However, typheramide and alfrutamide were not able to inhibit 5-LOX, and they only moderately inhibited 15-LOX by 27% (P < .02) and...
Beliefs and expectancies in legal decision making: an introduction to the Special Issue

This introduction describes what the co-editors believe readers can expect in this Special Issue. After beliefs and expectancies are defined, examples of how these constructs influence human though...
Within- and between-individual variability in estimated energy expenditure and habitual physical activity among young adults.

Within- and between-individual variability in estimated energy expenditure and habitual physical activity among young adults
Diagnostic Value of a Pacemaker High Rate Episode Counter When Programming the Ventricular Tachycardia Zone of an ICD

A 72-year-old man with an ICD and a pacemaker was presented with an episode of sustained VT that accelerated to VF. The ICD failed to detect the event and deliver therapy, despite a VT apparently within the VT detection zone. The ICD detected the event after degeneration to VF and delivered appropriate therapy. The high rate event feature of the pacemaker was useful in determining proper function of the ICD along with optimal programming of VT detection.
Moral and professional accountability for clinical ethics consultants.

How does access to this work benefit you? Let us know! Publisher's Statement This is an Accepted Manuscript of an article published by Taylor & Francis in the American Journal of Bioethics in 2014, available online: http://wwww.tandfonline.com/10.1080/ 15265161.2014.900142. Follow this and additional works at: http://engagedscholarship.csuohio.edu/clphil_facpub Part of the Ethics and Political Philosophy Commons, and the Philosophy of Science Commons
Optical Probing of Metabotropic Glutamate Receptor Assembly and Cooperativity

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors that are found throughout the nervous system where they respond to the major excitatory neurotransmitter, glutamate, to modulate synaptic transmission and plasticity via a variety of effectors. mGluRs are class C GPCRs which are characterized by their large, bi-lobed extracellular ligand binding domains. Studies of the assembly of mGluRs have been limited to classical biochemistry and recently, bulk FRET, and have failed to fully describe how mGluRs specifically assemble as homo or heteromers and interact with G-proteins in the cellular context. We used a combination of optical techniques to examine mGluR stoichiometry and to explore how these receptors activate in response to ligand binding. Using single molecule fluorescence photobleaching in the plasma membrane of Xenopus oocytes we confirm that mGluRs form both homo- and heteromeric dimers. Furthermore, we have used truncations, mutations, and chimeras to determine the mechanism of dimerization and heterodimer specificity. Purification of full-length receptors from mammalian cells followed by immobilization on a surface and single molecule fluorescence counting have confirmed the results. In addition to studies of mGluR stoichiometry we have used light-gated mGluRs which are based on the covalent attachment of photoswitchable tethered ligands (PTLs) that work as agonists or antagonists to study receptor cooperativity. PTLs provide the ability to probe single subunit contributions to receptor activity using a ligand with an extremely high local concentration that may be isomerized in less than 1 ms. We will report on experiments that use photoswitching in one or both subunits of a dimer to determine how ligand binding couples to receptor activation. Finally, we have used the absolute subtype specifiicity afforded by PTLs to analyze the signal transduction properties and pharmacology of mGluR2/3 heterodimers.
Oscillator strength for optical absorption by silver ions in alkali halide crystals

Abstract The optical absorption oscillator strength for excitation of a silver ion dissolved in an alkali halide crystal is analyzed. The transitions involved are unallowed for the free ion; however, in a lattice the fluctuating coulomb potential due to the motion of the ions is assumed to polarize the free ion states to make such transitions possible. The zero temperature oscillator strength for Ag + ion in NaCl is calculated to be f = 0.0014. The experimental value as found by Martienssen is f = 0.0016. The temperature dependence is found to agree satisfactorily with experiment. Quadrupole transitions cannot account for this magnitude of oscillator strength.
Wie wirken Betrugskontexte in der Kartenaufgabe von Wason

Zusammenfassung. In einer Untersuchung mit 119 Zehn- und Dreizehnjahrigen und 60 Erwachsenen wurde gepruft, ob die von Gigerenzer und Hug (1992) gefundenen Effekte der Einbindung der Kartenaufgabe von Wason (1966) in so genannte Betrugskontexte auch bei Kindern nachgewiesen werden konnen. Der Untersuchung lag ein zweifaktorieller Zufallsgruppenplan mit den Faktoren Perspektive (3) und Alter (3) zu Grunde. Die Standard-Betrugsbedingung versetzte die Teilnehmer in die Perspektive einer Partei in dem Sozialvertrag, die zur Identifikation potentieller Betruger die Karten “P“ und “Nicht-Q“ prufen sollte; in der Betrugsbedingung mit vertauschter Perspektive mussten, um potentielle Betruger zu identifizieren, entgegen der logisch richtigen Losung die Karten “Nicht-P“ und “Q“ gepruft werden. Die Kontrollbedingung versetzte die Teilnehmer in eine Beobachterperspektive. Die Ergebnisse zeigen, dass etwa die Halfte der 10- und 13-Jahrigen und die Mehrheit der Erwachsenen in der Standard-Betrugsbedingung nur die Karte...
How and where the TeraGrid supercomputing infrastructure benefits science

Abstract We investigate how the benefits of the TeraGrid supercomputing infrastructure are distributed across the scientific community. Do mostly high-impact scientists benefit from the TeraGrid? Are some scientific domains more strongly represented than others in TeraGrid-supported work? To answer these questions, we examine the relation between TeraGrid usage and scientific impact for a set of scientists whose projects relied to varying degrees on the TeraGrid infrastructure. For each scientist we measure TeraGrid usage expressed in terms of allocated Service Units (SU) vs. various indicators of their scientific impact such as the h-index, total citations, and citations per article. Our results show a significant correlation between scientific impact and TeraGrid usage. We furthermore examine the distribution of TeraGrid-related publications across various scientific journals. A superposition of these journals over an existing large-scale map of science shows how TeraGrid-supported work is mostly concentrated in Physics and Chemistry, with a lesser focus on biology.
Conserved aspartate and lysine residues of RcsB are required for amylovoran biosynthesis, virulence, and DNA binding in Erwinia amylovora

In Erwinia amylovora, the Rcs phosphorelay system is essential for amylovoran production and virulence. To further understand the role of conserved aspartate residue (D56) in the phosphor receiver (PR) domain and lysine (K180) residue in the function domain of RcsB, amino acid substitutions of RcsB mutant alleles were generated by site-directed mutagenesis and complementation of various rcs mutants were performed. A D56E substitution of RcsB, which mimics the phosphorylation state of RcsB, complemented the rcsB mutant, resulting in increased amylovoran production and gene expression, reduced swarming motility, and restored pathogenicity. In contrast, D56N and K180A or K180Q substitutions of RcsB did not complement the rcsB mutant. Electrophoresis mobility shift assays showed that D56E, but not D56N, K180Q and K180A substitutions of RcsB bound to promoters of amsG and flhD, indicating that both D56 and K180 are required for DNA binding. Interestingly, the RcsBD56E allele could also complement rcsAB, rcsBC and rcsABCD mutants with restored virulence and increased amylovoran production, indicating that RcsB phosphorylation is essential for virulence of E. amylovora. In addition, mutations of T904 and A905, but not phosphorylation mimic mutation of D876 in the PR domain of RcsC, constitutively activate the Rcs system, suggesting that phosphor transfer is required for activating the Rcs system and indicating both A905 and T904 are required for the phosphatase activity of RcsC. Our results demonstrated that RcsB phosphorylation and dephosphorylation, phosphor transfer from RcsC are essential for the function of the Rcs system, and also suggested that constitutive activation of the Rcs system could reduce the fitness of E. amylovora.
Origins and future of behavioral pharmacology.

Abstract Behavioral pharmacology has started in earnest in only the last 25 years. Its development depended on the introduction of methods of continuously monitoring significant patterns of behavioral responding, objectively and quantitatively, over long periods of time. Most behavioral effects of drugs are understandable only as phenomena occurring in real time and in relation to other influences on the behavior. Findings in behavioral pharmacology have led to experiments with major implications for psychology as a whole.
The Dynamics of Morphogenesis in the Early Mouse Embryo

SUMMARYOver the past two decades, our understanding of mouse development from implantation to gastrulation has grown exponentially with an upsurge of genetic, molecular, cellular, and morphogenetic information. New discoveries have exalted the role of extraembryonic tissues in orchestrating embryonic patterning and axial specification. At the same time, the identification of unexpected morphogenetic processes occurring during mouse gastrulation has challenged established dogmas and brought new insights into the mechanisms driving germ layer formation. In this article, we summarize the key findings that have reinvigorated the contemporary view of early postimplantation mammalian development.
The Vascular Study Group of New England Cardiac Risk Index (VSG-CRI) predicts cardiac complications more accurately than the Revised Cardiac Risk Index in vascular surgery patients

Objective The Revised Cardiac Risk Index (RCRI) is a widely used model for predicting cardiac events after noncardiac surgery. We compared the accuracy of the RCRI with a new, vascular surgery-specific model developed from patients within the Vascular Study Group of New England (VSGNE). Methods We studied 10,081 patients who underwent nonemergent carotid endarterectomy (CEA; n=5293), lower extremity bypass (LEB; n=2673), endovascular abdominal aortic aneurysm repair (EVAR; n=1005), and open infrarenal abdominal aortic aneurysm repair (OAAA; n=1,110) within the VSGNE from 2003 to 2008. First, we analyzed the ability of the RCRI to predict in-hospital major adverse cardiac events, including myocardial infarction (MI), arrhythmia, or congestive heart failure (CHF) in the VSGNE cohort. Second, we used a derivation cohort of 8208 to develop a new cardiac risk prediction model specifically for vascular surgery patients. Chi-square analysis identified univariate predictors, and multivariate logistic regression was used to develop an aggregate and four procedure-specific risk prediction models for cardiac complications. Calibration and model discrimination were assessed using Pearson correlation coefficient and receiver operating characteristic (ROC) curves. The ability of the model to predict cardiac complications was assessed within a validation cohort of 1873. Significant predictors were converted to an integer score to create a practical cardiac risk prediction formula. Results The overall incidence of major cardiac events in the VSGNE cohort was 6.3% (2.5% MI, 3.9% arrhythmia, 1.8% CHF). The RCRI predicted risk after CEA reasonably well but substantially underestimated risk after LEB, EVAR, and OAAA for low- and higher-risk patients. Across all VSGNE patients, the RCRI underestimated cardiac complications by 1.7- to 7.4-fold based on actual event rates of 2.6%, 6.7%, 11.6%, and 18.4% for patients with 0, 1, 2, and ≥3 risk factors. In multivariate analysis of the VSGNE cohort, independent predictors of adverse cardiac events were (odds ratio [OR]) increasing age (1.7-2.8), smoking (1.3), insulin-dependent diabetes (1.4), coronary artery disease (1.4), CHF (1.9), abnormal cardiac stress test (1.2), long-term β-blocker therapy (1.4), chronic obstructive pulmonary disease (1.6), and creatinine ≥1.8 mg/dL (1.7). Prior cardiac revascularization was protective (OR, 0.8). Our aggregate model was well calibrated (r = 0.99, P Conclusions The RCRI substantially underestimates in-hospital cardiac events in patients undergoing elective or urgent vascular surgery, especially after LEB, EVAR, and OAAA. The VSG-CRI more accurately predicts in-hospital cardiac events after vascular surgery and represents an important tool for clinical decision making.
An approach to the optimal design of p-n heterojunction solar cells using thin film organic semiconductors

In recent work with p-n heterojunction solar cells constructed with pairs of photoconductive organic dyes, we have obtained short-circuit current yields of over 19%. The best results to date have been obtained with the pair chloroaluminum phthalocyanine (ClAlPc) and the bis-methylimide of perylenetetracarboxylic acid (DMP). The preferred configuration is SnO2/DMP/ClAlPc/Ag. This configuration has the advantage of placing the shorter wavelength absorber DMP against the transparent SnO2 input surface and facilitating Forster radiationless energy transfer from the DMP phase to the region of the active DMP/ClAlPc junction. It also makes best use of the electron-accepting and electron-donating properties of the two dyes. Through tests of single-dye Schottky cells with a variety of metal electrodes, we have learned that the Fermi levels of these two dyes lie too close together for optimum cell performance. Synthetic variants of the simple perylene dye and of ClAlPc have been prepared for stronger electron-accepting and electron-donating properties respectively.
Color myocardial perfusion images derived from ultrafast CT compared to tracer microspheres

The use of ultrafast CT (computed tomography) to measure myocardial blood flow accurately has been recently demonstrated. A significant problem was found in identifying myocardial ischemia with traditional monochrome visualization. A pseudocolor display algorithm has been developed for myocardial perfusion visualization. The authors attempt to validate the color coding algorithm by comparing the amount of ischemia as measured by ultrafast CT and radioactive tracer microspheres using flow histograms of both techniques. >
Disorders of acid-base balance

Background:Intensivists spend much of their time managing problems related to fluids, electrolytes, and blood pH. Recent advances in the understanding of acid-base physiology have resulted from the application of basic physical-chemical principles of aqueous solutions to blood plasma. All changes in
Your Journal HAND.

HAND has now been in circulation for one and a half years with six issues published. The last three have contained 80 pages of scientific content from animal research to clinical advances. The application for PubMed listing requires a minimum of four on-time publications of adequate volume. In 2007, 101 manuscripts were submitted compared to 31 in 2006. Since the 2008 annual meeting, 37 manuscripts have been submitted. The acceptance rate for 2007 was 62%. The average time for peer review was 22 days and time from submission to final decision and online publication was 58 days. Journal hits on SpringerLink were 361 (2006) and 2,136 (2007). As is the experience of new journals, advertising is slow to pick up due to the uncertainty of journal success. With the help of the AAHS Board of Directors and Review Editors at the 2008 annual meeting, the number of exhibitors who have expressed interest in advertising in our journal has expanded. I encourage AAHS members to talk in detail with persons and companies with which you interact and suggest they advertise in HAND. I noticed a quantum increase in interest in HAND at the 2008 annual meeting and many of you have volunteered to be reviewers, whereas a similar request at the 2007 meeting garnered only one. HAND will expand its international exposure by adding reviewers and Editorial Board members from other countries. I thank all who have helped HAND flourish with reviews, suggestions, ideas and political support. We are on our way, so keep up the interest, good work and keep submitting. El Zook, Editor-in-Chief
Antagonists of the Inhibitory Effect of Free Tubulin on VDAC Induce Oxidative Stress and Mitochondrial Dysfunction

Bakground: Mitochondrial membrane potential (ΔΨ) and generation of reactive oxygen species (ROS) requires a respiratory chain fueled by the flux of metabolites into mitochondria through voltage dependent anion channels (VDAC). Free tubulin induces reversible blockage of VDAC both in vitro and in cells. Erastin, a small molecule lethal to cancer cells, antagonizes the inhibitory effect of free tubulin on VDAC and upregulates mitochondrial metabolism. Here, we hypothesized that erastin and "erastin-like" compounds open VDAC, increase mitochondrial metabolism and ROS formation, and activate JNK, which in turn cause mitochondrial dysfunction. Our AIM was to evaluate the effects of erastin/erastin-like compounds on ΔΨ, NADH, ROS and JNK in intact cells. METHODS: ΔΨ was assessed by confocal microscopy of tetramethylrhodamine methylester (TMRM) fluorescence and ROS by chloromethyldichlorofluorescein (cmDCF) and MitoSOX Red fluorescence. Mitochondrial NADH autofluorescence was assessed by multiphoton microscopy. Total and phosphorylated JNK was determined by Western blotting. RESULTS: In lipid bilayers, erastin antagonized tubulin inhibition on VDAC. In HepG2 human hepatoma cells, erastin increased ΔΨ by 46% and NADH by 30%. Mitochondrial hyperpolarization plateaued after 2 h. Subsequently depolarization occurred (3-4 h), suggesting mitochondrial dysfunction. Erastin-like compounds X1 and X2, identified in a high-throughput screening, similarly caused mitochondrial hyperpolarization/depolarization. Erastin also caused increases of DCF and Mitosox Red fluorescence beginning after ∼30 min and reaching a maximum after 2 h. Additionally, erastin activated JNK (maximum pJNK at 60 min). JNK activation and ROS formation both preceded mitochondrial depolarization. Conclusion: Erastin relieves tubulin-dependent inhibition of VDAC conductance, leading to mitochondrial hyperpolarization that increases ROS production with concomitant activation of the stress kinase JNK. These events, in turn, may induce the mitochondrial permeability transition, mitochondrial dysfunction and ultimately cell death.
Transition from Curie-Weiss to enhanced Pauli paramagnetism in R NiO 3 ( R = L a , P r , … Gd )

High-oxygen-pressure annealing, cold pressing, and measurement of properties under pressure have been used to reveal and to follow in the single-valent perovskites $R{\mathrm{NiO}}_{3}$ $(R=\mathrm{lanthanide})$ a crossover from localized to itinerant electronic behavior. Cold pressing proved critical for obtaining nearly intrinsic transport properties such as electronic and thermal conductivity in polycrystalline samples not available as single crystals. Suppression of the thermal conductivity in the crossover compositions ${\mathrm{NdNiO}}_{3}$ and ${\mathrm{PrNiO}}_{3}$ suggests cooperative bond-length fluctuations in this region.
Surface reactions of monoethylgermane on Si(100)-(2×1)

Abstract The adsorption and decomposition of monoethylgermane (GeH3Et) on the Si(100)-(2×1) surface was investigated with the intent of elucidating the surface processes leading to the deposition of germanium. The low-temperature adsorption of the molecule was explored, as well as its thermal decomposition. H2 and C2H4 are observed as the desorption products in temperature-programmed desorption experiments. The ethylene is produced by a hydride elimination reaction within the adsorbed ethyl groups. The amount of Ge which can be deposited in a reaction cycle is correlated with the number of sites occupied by the ethyl groups upon the dissociation of GeH3Et.