bluuebunny/crossref_metadata_2025 huggingface dataset:
Insider Trading after Repurchase Tender Offer Announcements: Timing versus Informed Trading
Authors: Louis Henock , Sun Amy X. , White Hal
Published: March 2010

Abnormally high net insider selling is commonly observed after repurchase tender offer (RTO) announcements although, on average, firms experience positive abnormal returns in the years after the repurchases. We explore two potential explanations: liquidity trade timing and informed trading. Consistent with the notion that fixed price RTOs are more likely than Dutch‐auction RTOs to signal undervaluation, the results suggest that insider selling after fixed price RTO announcements are driven largely by insiders who time their trades with the repurchase announcements. In contrast, selling after Dutch‐auction RTOs seems to be driven primarily by informed traders who exploit mispricing associated with the repurchase announcements.
How the Legal System Affects the Equity Mix in Executive Compensation
Authors: Bryan Stephen , Nash Robert , Patel Ajay
Published: March 2010

We examine variation in relative use of equity‐based compensation (equity mix) across firms from different legal environments by studying 381 non‐US firms from 43 countries during the 1996‐2000 period. These firms are from countries that provide varying degrees of legal protection for shareholders. The data indicate association between equity mix and the degree of legal protection of shareholder rights. Specifically, firms use relatively more equity‐based compensation if in a legal environment where shareholder rights are more strongly protected and where laws are more effectively enforced. These findings add to the literature demonstrating a relationship between institutional factors and financial decisions.
Evaluation for clinical utility of GPC3, measured by a commercially available ELISA kit with Glypican‐3 (GPC3) antibody, as a serological and histological marker for hepatocellular carcinoma
Authors: Yasuda Eisuke , Kumada Takashi , Toyoda Hidenori , Kaneoka Yuji , Maeda Atsuyuki , Okuda Seiji , Yoshimi Naoki , Kozawa Osamu
Published: March 2010

Aims:  We evaluated the clinical utility of glypican‐3 (GPC3), which has been proposed as a potential novel tumor marker for hepatocellular carcinoma (HCC), as a serological and histological marker for HCC.

Methods:  The serum GPC3 level was compared between 200 patients with HCC and 200 patients with chronic liver disease (CLD). In addition, the expression of GPC3 was examined with immunohistochemistry on 38 resected specimens from patients with HCC. A commercially available GPC3 antibody was used for these analyses.

Results:  The median values of serum GPC3 in patients with HCC and with CLD were 924.8 pg/mL and 1161.6 pg/mL, respectively. We found no elevation of serum GPC3 level in patients with HCC in comparison with those with CLD; rather the level was higher in patients with CLD (P < 0.0001). In immunohistochemical analysis, 14 of 38 (36.9%) HCC tissues were positive for GPC3, whereas no corresponding non‐cancerous tissue was positive. The positivity for GPC3 tended to increase with pathologic decreased differentiation of HCC.

Conclusions:  We did not find serum GPC3 level, measured by a commercially available ELISA kit with GPC3 antibody, to be useful in the diagnosis of HCC. However, we did observe increased GPC3 staining in HCC tissue with moderate or poor differentiation, suggesting that GPC3 is produced by HCC tumors. This lack of utility could have been due to the measuring procedure used in the present study. Further evaluation of GPC3 in HCC with other measuring procedures is needed.
Chymase inhibitor prevents the nonalcoholic steatohepatitis in hamsters fed a methionine‐ and choline‐deficient diet
Authors: Tashiro Keitaro , Takai Shinji , Jin Denan , Yamamoto Hiromi , Komeda Koji , Hayashi Michihiro , Tanaka Kazuhiko , Tanigawa Nobuhiko , Miyazaki Mizuo
Published: March 2010

Aim: Mast cells may be involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). The mast cell protease chymase contributes to the formation of angiotensin II and matrix metalloproteinase (MMP)‐9, both of which are intimately involved in liver fibrosis. Therefore, we hypothesized that chymase plays an important role in the development of NASH.

Methods: Hamsters were fed a methionine‐ and choline‐deficient (MCD) diet for 8 weeks. These animals were divided into two groups and received either TY‐51469 (1 mg/kg per day) or placebo. A third group was fed a normal diet as a control.

Results: Total plasma bilirubin, triglycerides, and hyaluronic acid levels were significantly higher in the MCD diet‐fed hamsters than in the normal diet‐fed hamsters, but the levels were significantly lower in chymase inhibitor‐treated MCD diet‐fed hamsters than in placebo‐treated MCD diet‐fed hamsters. Using histological analysis, marked steatosis and fibrosis were observed in MCD diet‐fed hamsters, but these changes were significantly attenuated by treatment with the chymase inhibitor. Increases in mast cells and chymase‐positive cells were observed in the liver after the MCD diet, but the increases disappeared in the chymase inhibitor‐treated group. The significant increase observed in chymase activity in liver tissue extract from the MCD diet‐fed group was also reduced by treatment with the chymase inhibitor. Chymase inhibition significantly reduced not only angiotensin II expression but also matrix metallopeptidase 9 activity in MCD diet‐fed hamsters.

Conclusion: These findings demonstrate that the mast cell protease chymase may play a crucial role in the development of NASH in hamsters.
Analysis of HLA‐DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC): The HLA‐DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC
Authors: Nakamura Minoru , Yasunami Michio , Kondo Hisayoshi , Horie Hitomi , Aiba Yoshihiro , Komori Atsumasa , Migita Kiyoshi , Yatsuhashi Hiroshi , Ito Masahiro , Shimoda Shinji , Ishibashi Hiromi ,   PBC Study Group in NHOSLJ
Published: March 2010

Aims:  Anti‐gp210 and anti‐centromere antibodies are different risk factors for the progression of primary biliary cirrhosis (PBC). However, the association of human leukocyte antigen (HLA) polymorphisms with these risk factors is unknown.

Methods:  We determined the HLA‐DRB1 genotype in 334 Japanese PBC patients and studied their serum antibodies to gp210 and centromere during the 1–452‐month observation period.

Results:  Anti‐gp210 (odds ratio [OR] 46.56, 95% confidence interval [CI], 9.20–850.1) and anti‐centromere antibodies (OR, 2.36, 95% CI, 1.28–4.35) were significant risk factors for jaundice‐ and nonjaundice‐type progression, respectively. HLA‐DRB1*0405 and *0803 predisposed patients to anti‐gp210 (OR, 1.61, 95% CI, 1.08–2.39) and anti‐centromere (OR, 2.30, 95% CI, 1.41–3.73) antibody production, respectively. HLA‐DRB1*1502 and *0901 patients were predisposed to nonjaundice‐type progression (OR, 1.98, 95% CI, 1.13–3.40 and OR, 1.78, 95% CI, 1.02–3.03), while HLA‐DRB1*0803 and *0405 patients were predisposed to disease development (OR, 2.24, 95% CI, 1.48–3.41 and OR, 1.53, 95% CI, 1.11–2.11, respectively). Stratifying patients by HLA‐DRB1 alleles revealed that anti‐gp210 antibodies was a strong risk factor, regardless of the HLA‐DRB1 alleles for jaundice‐type progression, while anti‐centromere antibodies was a significant risk factor for nonjaundice‐type progression in patients with HLA‐DRB1*0405 (OR, 6.89, 95% CI, 2.18–26.56) and ‐DRB1*0803 (OR, 5.42, 95% CI, 1.47–24.62) but not other HLA‐DRB1 alleles.

Conclusions:  HLA‐DRB1 polymorphisms are significantly associated with not only disease development and progression but also antinuclear antibody production and the determination of the relative risk of antinuclear antibodies that contribute to PBC disease progression.
Estimates of Elastic Crack Opening Displacements of Slanted Through-Wall Cracks in Plate and Cylinder
Authors: Huh Nam-Su , Shim Do-Jun , Yoo Yeon-Sik , Choi Suhn , Park Keun-Bae
Published: March 2010

This paper provides tractable solutions for elastic crack opening displacement (COD) of slanted through-wall cracks in plates and cylinders. The solutions were developed via detailed three dimensional elastic finite element analyses. The COD values were calculated along the thickness at the center of the crack. As for the loading conditions, only remote tension was considered for the plates, whereas remote tension, global bending moment, and internal pressure were considered for the cylinders. The finite element model employed in the present analysis was verified by using existing solutions for a cylinder with an idealized circumferential through-wall crack. The present results can be used to evaluate leak rates of slanted through-wall cracks, which can be used as a part of a detailed leak-before-break analysis considering more realistic crack shape development.
Validity of Assessment Procedure in p-M Method for Multiple Volumetric Flaws
Authors: Konosu Shinji , Kano Masato , Mukaimachi Norihiko , Kanamaru Shinichiro
Published: March 2010

General components such as pressure vessels, piping, storage tanks, and so on are designed in accordance with the construction codes based on the assumption that there are no flaws in such components. There are, however, numerous instances in which in-service single or multiple volumetric flaws such as local thin areas are found in the equipment concerned. Therefore, it is necessary to establish a fitness for service rule, which is capable of evaluating these flaws. The procedure for a single flaw or multiple flaws has recently been proposed for assessing the flaws in the p-M (pressure-moment) diagram, which is an easy way to visualize the status of the component with flaws simultaneously subjected to internal pressure p and external bending moment M due to earthquake, etc. If the assessment point (Mr,pr) lies inside the p-M line, the component with flaws is judged to be safe. In this paper, numerous experiments and finite element analysis for a cylinder with external multiple volumetric flaws were conducted under (1) pure internal pressure, (2) pure external bending moment, and (3) subjected simultaneously to both internal pressure and external bending moment, in order to determine the plastic collapse load at volumetric flaws by applying the twice-elastic slope (TES) as recommended by ASME. It has been clarified that the collapse (TES) loads are much the same as those calculated under the proposed p-M line based on the measured yield stress.
Flexural Waves in Fluid-Filled Tubes Subject to Axial Impact
Authors: Inaba Kazuaki , Shepherd Joseph E.
Published: March 2010

We experimentally studied the propagation of coupled fluid stress waves and tube flexural waves generated through projectile impact along the axis of a water-filled tube. We tested mild steel tubes, 38–40 mm inner diameter and wall thicknesses of 0.8 mm, 6.4 mm, and 12.7 mm. A steel impactor was accelerated using an air cannon and struck a polycarbonate buffer placed on top of the water surface within the tube. Elastic flexural waves were observed for impact speeds of 5–10 m/s and plastic waves appeared for impact speeds approaching 20 m/s for a 0.8 mm thickness tube. We observed primary wave speeds of 1100 m/s in a 0.8 mm thickness tube, increasing to the water sound speed with 6.4 mm and 12.7 mm thickness tubes. Comparison of our measurements in the 0.8 mm thickness tube with Skalak’s water hammer theory indicates reasonable agreement between the predicted and measured peak strains as a function of the impact buffer speed (1956, “An Extension to the Theory of Water Hammer,” Trans. ASME, 78, pp. 105–116). For thick-walled tubes, the correlation between the experimentally determined peak pressures and strains reveals the importance of corrections for the through-wall stress distribution.
Relationship Between Crack-Tip Constraint and Dynamic Fracture Initiation Toughness
Authors: Chao Yuh J. , Wang Cheng , Kim Yil , Chien Chi-Hui
Published: March 2010

Two-dimensional finite element analyses are performed to study the crack-tip constraint in an elastic-plastic, three point bend specimen under dynamic load. Both strain rate-independent and strain rate-dependent materials are considered to elucidate the difference in response due to the material rate effect. It is first demonstrated that the crack-tip stress fields can be adequately characterized by the J-A2 three-term solution within the region of interest 1<r/(J/σo)<5. Consequently, A2 is used as a constraint parameter in constraint evaluations. Results show that the crack-tip constraint decreases with increasing loading rate in rate-independent material. On the other hand, in rate-dependent material, the crack-tip constraint first increases at low loading rate but later decreases at high loading rate. It appears that there is a competition between constraint loss due to dynamic load and constraint gain due to material sensitivity to strain rate. The effect of crack-tip constraint on fracture initiation toughness under dynamic load Kdyn is then studied using a critical stress failure criterion. The results are consistent with experimental data in (a) reduced dynamic fracture initiation toughness, as compared with the static fracture toughness, at low loading rate such as those obtained by ASTM E23 Charpy tests and (b) elevated fracture toughness at high loading rate as frequently reported by experimental researchers.
Theories of field and thermionic electron emissions from carbon nanotubes
Authors: Liang Shi-Dong , Chen Lu
Published: March 2010

Taking into account the effect of the low-energy band structure of carbon nanotubes (CN), we develop the theories of CN field and thermionic emissions. We give the analytic field and thermionic emission equations for both metal and semiconducting CNs. These theories modify the conventional Fowler–Nordheim (FN) and Murphy–Good (MG) theories. For large-diameter CNs and high fields, the field-emission equation reduces the FN-type field-emission equation. For small-diameter CNs and low fields, the field-emission equation goes beyond the FN-type behavior, which provides a possible way to understand the non-FN behavior observed in experimental results. Based on these theories, we give the electron-emission phase diagram on the field, thermionic, and intermediate emissions in the field-temperature space, whose boundaries have a slight shift to the corresponding boundaries of MG’s theory. These differences come from the energy-band structure difference between CN and conventional emitters. This theory provides an understanding of field and thermionic emissions for nanoscale materials.
Emission characteristics and application of graphite nanospine cathode
Authors: Jyouzuka Atsuo , Nakamura Tomonori , Onizuka Yoshihiro , Mimura Hidenori , Matsumoto Takahiro , Kume Hiroshi
Published: March 2010

The emission characteristics of graphite nanospines (GNSs) encapsulated in an x-ray tube with a system for controlling electric field crowding (SCEFC) are investigated. GNSs encapsulated in an x-ray tube can be driven at an anode current (IA) of more than 1 mA. Further, IA can be controlled using the SCEFC. During the operation of the x-ray tube with GNSs and the SCEFC at the anode voltage of 12.5 kV and IA of 640 μA for 100 h, there was no degradation in IA. The noise current superimposed on IA was observed to be ±34.5 μA. It was reduced to ±1.62 μA by using the SCEFC. The authors also demonstrated radiography and x-ray fluorescence measurement as applications of x-ray tubes with GNSs and the SCEFC.
Photo- and thermionic emission from potassium-intercalated carbon nanotube arrays
Authors: Westover Tyler L. , Franklin Aaron D. , Cola Baratunde A. , Fisher Timothy S. , Reifenberger Ronald G.
Published: March 2010

Carbon nanotubes (CNTs) are promising candidates to create new thermionic- and photoemission materials. Intercalation of CNTs with alkali metals, such as potassium, greatly reduces their work functions, and the low electron scattering rates of small-diameter CNTs offer the possibility of efficient photoemission. This work uses a Nd:YAG (YAG denotes yttrium aluminum garnet) laser to irradiate single- and multiwalled CNTs intercalated with potassium, and the resultant energy distributions of photo- and thermionic emitted electrons are measured using a hemispherical electron energy analyzer over a wide range of temperatures. For both single- and multiwalled CNTs intercalated with potassium, the authors observe a temperature dependent work function that has a minimum of approximately 2.0 eV at approximately 600 K. At temperatures above 600 K, the measured work function values increase with temperature presumably due to deintercalation of potassium atoms. Laser illumination causes the magnitudes of collected electron energy distributions to increase substantially but in many cases has little effect on their shape. Simple theoretical models are also developed that relate the photo- and thermionic emission processes and indicate that large numbers of photoexcited electrons partially thermalize (i.e., undergo one or more scattering events) before escaping from the emitter surface.
Toward an Oligonucleotide Therapy for Duchenne Muscular Dystrophy: A Complex Development Challenge
Authors: Wood Matthew J. A.
Published: March 2010

By correcting the reading frame in mutant
DMD
genes,
antisense oligonucleotides can restore the production of missing
dystrophin protein, but several difficulties must be overcome before
such drugs are broadly useful.
Complexity in Common Diseases: Big Biology for All
Authors: Lamb John R. , Gibson Neil W.
Published: March 2010

Discovery of diagnostic tools and treatments for common human diseases requires integrating research in academic and industrial institutions.
A Little Estrogen Goes a Long Way
Authors: Bentley-Lewis Rhonda
Published: March 2010

Short-term estrogen treatment in "postmenopausal" rats benefits cognition comparably to long-term estrogen therapy.
ANALOG/MIXED-SIGNAL CIRCUIT VERIFICATION USING MODELS GENERATED FROM SIMULATION TRACES
Authors: LITTLE SCOTT , WALTER DAVID , JONES KEVIN , MYERS CHRIS , SEN ALPER
Published: March 2010

Verification of analog/mixed-signal (AMS) circuits is complicated by the difficulty of obtaining circuit models at suitable levels of abstraction. We propose a method to automatically generate abstract models suitable for formal verification and system-level simulation from transistor-level simulation traces. This paper discusses the application of the proposed methodology to a switched capacitor integrator and PLL phase detector.
QUANTIFYING THE DISCORD: ORDER DISCREPANCIES IN MESSAGE SEQUENCE CHARTS
Authors: ELKIND EDITH , GENEST BLAISE , PELED DORON , SPOLETINI PAOLA
Published: March 2010

Message Sequence Charts (MSCs) and High-level Message Sequence Charts (HMSCs) are formalisms used to describe scenarios of message passing protocols. We propose using Allen's logic to represent the temporal order of the messages. We introduce the concept of discord to quantify the discrepancies between the intuition and the semantics of the ordering between messages in different nodes of an HMSC. We study the algorithmic properties of this concept: we show that while the discord of a pair of messages is hard to compute in general, the problem becomes polynomial-time computable if the number of nodes of the HMSC or the number of processes is constant. Moreover, for a given HMSC, it is always computationally easy to identify a pair of messages that exhibits the worst-case discord and compute the discord of this pair.
APPROXIMATING LÉVY PROCESSES WITH A VIEW TO OPTION PRICING
Authors: CROSBY JOHN , LE SAUX NOLWENN , MIJATOVIĆ ALEKSANDAR
Published: March 2010

We examine how to approximate a Lévy process by a hyperexponential jump-diffusion (HEJD) process, composed of Brownian motion and of an arbitrary number of sums of compound Poisson processes with double exponentially distributed jumps. This approximation will facilitate the pricing of exotic options since HEJD processes have a degree of tractability that other Lévy processes do not have. The idea behind this approximation has been applied to option pricing by Asmussen et al. (2007) and Jeannin and Pistorius (2008). In this paper we introduce a more systematic methodology for constructing this approximation which allow us to compute the intensity rates, the mean jump sizes and the volatility of the approximating HEJD process (almost) analytically. Our methodology is very easy to implement. We compute vanilla option prices and barrier option prices using the approximating HEJD process and we compare our results to those obtained from other methodologies in the literature. We demonstrate that our methodology gives very accurate option prices and that these prices are more accurate than those obtained from existing methodologies for approximating Lévy processes by HEJD processes.
MODERN LIBOR MARKET MODELS: USING DIFFERENT CURVES FOR PROJECTING RATES AND FOR DISCOUNTING
Authors: MERCURIO FABIO
Published: March 2010

We introduce an extended LIBOR market model that is compatible with the current market practice of building different yield curves for different tenors and for discounting. The new paradigm is based on modeling the joint evolution of FRA rates and forward rates belonging to the discount curve. We will start by analyzing the basic lognormal case, then we will add stochastic volatility. The dynamics of FRA rates under different measures will be obtained and closed form formulas for caplets and swaptions derived in the lognormal and Heston (1993) cases.
IT'S YOUR CHOICE: A UNIFIED APPROACH TO CHOOSER OPTIONS
Authors: SANDMANN KLAUS , WITTKE MANUEL
Published: March 2010

We propose a unified framework for the pricing and hedging of chooser options on lognormal assets. This includes e.g. exchange or inflation rates under stochastic interest rates or equities under stochastic interest rates and dividend yields. This extends and includes chooser options under deterministic interest rates by a multidimensional model of an international economy with correlated stochastic processes. In this framework we derive closed form solutions of the arbitrage price for different specifications of chooser options. Also different hedge strategies are derived and their properties compared.
IDENTIFICATION OF GRANGER CAUSALITY BETWEEN GENE SETS
Authors: FUJITA ANDRÉ , SATO JOÃO RICARDO , KOJIMA KANAME , GOMES LUCIANA RODRIGUES , NAGASAKI MASAO , SOGAYAR MARI CLEIDE , MIYANO SATORU
Published: March 2010

Wiener and Granger have introduced an intuitive concept of causality (Granger causality) between two variables which is based on the idea that an effect never occurs before its cause. Later, Geweke generalized this concept to a multivariate Granger causality, i.e. n variables Granger-cause another variable. Although Granger causality is not "effective causality" in the Aristothelic sense, this concept is useful to infer directionality and information flow in observational data. Granger causality is usually identified by using VAR (Vector Autoregressive) models due to their simplicity. In the last few years, several VAR-based models were presented in order to model gene regulatory networks. Here, we generalize the multivariate Granger causality concept in order to identify Granger causalities between sets of gene expressions, i.e. whether a set of n genes Granger-causes another set of m genes, aiming at identifying the flow of information between gene networks (or pathways). The concept of Granger causality for sets of variables is presented. Moreover, a method for its identification with a bootstrap test is proposed. This method is applied in simulated and also in actual biological gene expression data in order to model regulatory networks. This concept may be useful for the understanding of the complete information flow from one network or pathway to the other, mainly in regulatory networks. Linking this concept to graph theory, sink and source can be generalized to node sets. Moreover, hub and centrality for sets of genes can be defined based on total information flow. Another application is in annotation, when the functionality of a set of genes is unknown, but this set is Granger-caused by another set of genes which is well studied. Therefore, this information may be useful to infer or construct some hypothesis about the unknown set of genes.
Oxide Surface Science
Authors: Diebold Ulrike , Li Shao-Chun , Schmid Michael
Published: March 2010

Most metals are oxidized under ambient conditions, and metal oxides show interesting and technologically promising properties. This has motivated much recent research on oxide surfaces. The combination of scanning tunneling microscopy with first-principles density functional theory–based computational techniques provides an atomic-scale view of the properties of metal-oxide materials. Surface polarity is a key concept for predicting the stability of oxide surfaces and is discussed using ZnO as an example. This review also highlights the role of surface defects for surface reactivity, and their interplay with defects in the bulk, for the case of TiO2. Ultrathin metal-oxide films, grown either through reactive evaporation on metal single crystals or through oxidation of metal alloys (such as Al2O3/NiAl), have gained popularity as supports for planar model catalysts. The surface oxides that form upon oxidation on Pt-group metals (e.g., Ru, Rh, Pd, and Pt) are considered as model systems for CO oxidation.
Novel Computational Methods for Nanostructure Electronic Structure Calculations
Authors: Wang Lin-Wang
Published: March 2010

Experimentally relevant nanocrystals often contain a few thousands to hundreds of thousands of atoms. Yet, to understand their electronic structures, surface and impurity effects, atomic relaxations, interior electric fields, carrier dynamics, and transports, it is often necessary to carry out atomistic simulations. Owing to the advance of recent algorithm developments and improved supercomputer powers, it is now possible to calculate such nanocrystals based on ab initio methods. In this review, we discuss the numerical algorithms (the plane-wave pseudopotential method and the real-space finite-difference method) used in conventional density-functional-theory calculations, which enable the simulations of systems up to one or two thousand atoms. We also introduce methods designed specifically for nanostructure calculations. These methods [the charge-patching method (CPM) and the linear scaling three-dimensional fragment method (LS3DF)] can be used to calculate systems with hundreds of thousands of atoms. Whereas CPM is an approximation with ab initio quality, the LS3DF method is an O(N) method with essentially the same results as the direct methods. The computational aspects of the algorithms, especially for their parallelization scalability, are also emphasized in the review.
Fluctuations in Biological and Bioinspired Electron-Transfer Reactions
Authors: Skourtis Spiros S. , Waldeck David H. , Beratan David N.
Published: March 2010

Central to theories of electron transfer (ET) is the idea that nuclear motion generates a transition state that enables electron flow to proceed, but nuclear motion also induces fluctuations in the donor-acceptor (DA) electronic coupling that is the rate-limiting parameter for nonadiabatic ET. The interplay between the DA energy gap and DA coupling fluctuations is particularly noteworthy in biological ET, where flexible protein and mobile water bridges take center stage. Here, we discuss the critical timescales at play for ET reactions in fluctuating media, highlighting issues of the Condon approximation, average medium versus fluctuation-controlled electron tunneling, gated and solvent relaxation controlled electron transfer, and the influence of inelastic tunneling on electronic coupling pathway interferences. Taken together, one may use this framework to establish principles to describe how macromolecular structure and structural fluctuations influence ET reactions. This framework deepens our understanding of ET chemistry in fluctuating media. Moreover, it provides a unifying perspective for biophysical charge-transfer processes and helps to frame new questions associated with energy harvesting and transduction in fluctuating media.
Superresolution Imaging using Single-Molecule Localization
Authors: Patterson George , Davidson Michael , Manley Suliana , Lippincott-Schwartz Jennifer
Published: March 2010

Superresolution imaging is a rapidly emerging new field of microscopy that dramatically improves the spatial resolution of light microscopy by over an order of magnitude (∼10–20-nm resolution), allowing biological processes to be described at the molecular scale. Here, we discuss a form of superresolution microscopy based on the controlled activation and sampling of sparse subsets of photoconvertible fluorescent molecules. In this single-molecule-based imaging approach, a wide variety of probes have proved valuable, ranging from genetically encodable photoactivatable fluorescent proteins to photoswitchable cyanine dyes. These have been used in diverse applications of superresolution imaging: from three-dimensional, multicolor molecule localization to tracking of nanometric structures and molecules in living cells. Single-molecule-based superresolution imaging thus offers exciting possibilities for obtaining molecular-scale information on biological events occurring at variable timescales.
Functional Motifs in Biochemical Reaction Networks
Authors: Tyson John J. , Novák Béla
Published: March 2010

The signal-response characteristics of a living cell are determined by complex networks of interacting genes, proteins, and metabolites. Understanding how cells respond to specific challenges, how these responses are contravened in diseased cells, and how to intervene pharmacologically in the decision-making processes of cells requires an accurate theory of the information-processing capabilities of macromolecular regulatory networks. Adopting an engineer's approach to control systems, we ask whether realistic cellular control networks can be decomposed into simple regulatory motifs that carry out specific functions in a cell. We show that such functional motifs exist and review the experimental evidence that they control cellular responses as expected.
Electrostatics of Strongly Charged Biological Polymers: Ion-Mediated Interactions and Self-Organization in Nucleic Acids and Proteins
Authors: Wong Gerard C.L. , Pollack Lois
Published: March 2010

Charges on biological polymers in physiologically relevant solution conditions are strongly screened by water and salt solutions containing counter-ions. However, the entropy of these counterions can result in surprisingly strong interactions between charged objects in water despite short screening lengths, via coupling between osmotic and electrostatic interactions. Widespread work in theory, experiment, and computation has been carried out to gain a fundamental understanding of the rich, yet sometimes counterintuitive, behavior of these polyelectrolyte systems. Examples of polyelectrolyte association in biology include DNA packaging and RNA folding, as well as aggregation and self-organization phenomena in different disease states.
Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids
Authors: Choi Sun Ju , Kim Francis , Schwartz Michael W. , Wisse Brent E.
Published: March 2010

Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1–7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFα, as judged by induction of IκBα (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IκBα protein, and TNFα pretreatment reduced insulin-mediated p-Akt activation by 30% ( P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 μM for ≤6 h) nor palmitate exposure alone (200 μM for ≤24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.
LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo
Authors: Sun Gao , Tarasov Andrei I. , McGinty James A. , French Paul M. , McDonald Angela , Leclerc Isabelle , Rutter Guy A.
Published: March 2010

The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic β-cell and hypothalamic neurons using the rat insulin promoter (RIP2). Cre transgene (βAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the β-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the β-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to βAMPKdKO mice, βLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1- CreER mice, total β-cell mass and the size of individual islets and β-cells were increased and islet architecture was markedly altered in βLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1- CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca2+ were sharply reduced in βLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on β-cell function.
The role of amylin in the control of energy homeostasis
Authors: Lutz Thomas A.
Published: March 2010

Amylin is an important player in the control of nutrient fluxes. Amylin reduces eating via a meal size effect by promoting meal-ending satiation. This effect seems to depend on a direct action in the area postrema (AP), which is an area rich in amylin receptors. Subsequent to the activation of AP neurons, the neural signal is conveyed to the forebrain via relays involving the nucleus of the solitary tract (NTS) and the lateral parabrachial nucleus (lPBN) to the lateral hypothalamic area (LHA) and other hypothalamic nuclei. While the NTS and lPBN seem to be necessary for amylin's eating inhibitory effect, the role of the LHA has not yet been fully investigated. Amylin may also act as an adiposity signal. Plasma levels of amylin are higher in obese individuals, and chronic infusion of amylin into the brain reduces body weight gain and adiposity; chronic infusion of an amylin receptor antagonist into the brain increases body adiposity. Amylin increases energy expenditure in rats; this effect occurs under various experimental conditions after peripheral and central administration. Together, these animal data, but also clinical data in humans, indicate that amylin is a promising candidate for the treatment of obesity; effects are most pronounced when amylin is combined with leptin. Finally, recent findings indicate that amylin acts as a neurotrophic factor in specific brain stem areas. Whether this effect may be relevant under physiological conditions requires further studies.
Manipulation After Object Rotation Reveals Independent Sensorimotor Memory Representations of Digit Positions and Forces
Authors: Zhang Wei , Gordon Andrew M. , Fu Qiushi , Santello Marco
Published: March 2010

Planning of object manipulations is dependent on the ability to generate, store, and retrieve sensorimotor memories of previous actions associated with grasped objects. However, the sensorimotor memory representations linking object properties to the planning of grasp are not well understood. Here we use an object rotation task to gain insight into the mechanisms underlying the nature of these sensorimotor memories. We asked subjects to grasp a grip device with an asymmetrical center of mass (CM) anywhere on its vertical surfaces and lift it while minimizing object roll. After subjects learned to minimize object roll by generating a compensatory moment, they were asked to rotate the object 180° about a vertical axis and lift it again. The rotation resulted in changing the direction of external moment opposite to that experienced during the prerotation block. Anticipatory grasp control was quantified by measuring the compensatory moment generated at object lift onset by thumb and index finger forces through their respective application points. On the first postrotation trial, subjects failed to generate a compensatory moment to counter the external moment caused by the new CM location, thus resulting in a large object roll. Nevertheless, after several object rotations subjects reduced object roll on the initial postrotation trials by anticipating the new CM location through the modulation of digit placement but not tangential forces. The differential improvement in modulating these two variables supports the notion of independent memory representations of kinematics and kinetics and is discussed in relation to neural mechanisms underlying visuomotor transformations.
Differences in Na+Conductance Density and Na+Channel Functional Properties Between Dopamine and GABA Neurons of the Rat Substantia Nigra
Authors: Seutin Vincent , Engel Dominique
Published: March 2010

Dopamine (DA) neurons and GABA neurons of the substantia nigra (SN) promote distinct functions in the control of movement and have different firing properties and action potential (AP) waveforms. APs recorded from DA and GABA neurons differed in amplitude, maximal rate of rise, and duration. In addition, the threshold potential for APs was higher in DA neurons than in GABA neurons. The activation of voltage-gated Na+channels accounts largely for these differences as the application of a low concentration of the voltage-gated Na+channel blocker TTX had an effect on all of these parameters. We have examined functional properties of somatic Na+channels in nucleated patches isolated from DA and GABA neurons. Peak amplitudes of macroscopic Na+currents were smaller in DA neurons in comparison to those in GABA neurons. The mean peak Na+conductance density was 24.5 pS μm−2in DA neurons and almost twice as large, 41.6 pS μm−2, in GABA neurons. The voltage dependence of Na+channel activation was not different between the two types of SN neurons. Na+channels in DA and GABA neurons, however, differed in the voltage dependence of inactivation, the mean mid-point potential of steady-state inactivation curve being more positive in DA neurons than in GABA neurons. The results suggest that specific Na+channel gating properties and Na+conductance densities in the somatic membrane of SN neurons may have consequences on synaptic signal integration in the soma of both types of neurons and on somatodendritic release of dopamine by DA neurons.
Heterogeneous Response Dynamics in Retinal Ganglion Cells: The Interplay of Predictive Coding and Adaptation
Authors: Nirenberg Sheila , Bomash Illya , Pillow Jonathan W. , Victor Jonathan D.
Published: March 2010

To make efficient use of their limited signaling capacity, sensory systems often use predictive coding. Predictive coding works by exploiting the statistical regularities of the environment—specifically, by filtering the sensory input to remove its predictable elements, thus enabling the neural signal to focus on what cannot be guessed. To do this, the neural filters must remove the environmental correlations. If predictive coding is to work well in multiple environments, sensory systems must adapt their filtering properties to fit each environment's statistics. Using the visual system as a model, we determine whether this happens. We compare retinal ganglion cell dynamics in two very different environments: white noise and natural. Because natural environments have more power than that of white noise at low temporal frequencies, predictive coding is expected to produce a suppression of low frequencies and an enhancement of high frequencies, compared with the behavior in a white-noise environment. We find that this holds, but only in part. First, predictive coding behavior is not uniform: most on cells manifest it, whereas off cells, on average, do not. Overlaid on this nonuniformity between cell classes is further nonuniformity within both cell classes. These findings indicate that functional considerations beyond predictive coding play an important role in shaping the dynamics of sensory adaptation. Moreover, the differences in behavior between on and off cell classes add to the growing evidence that these classes are not merely homogeneous mirror images of each other and suggest that their roles in visual processing are more complex than expected from the classic view.
Modeling and Eigenfrequency Analysis of Sound‐Structure Interaction in a Rectangular Enclosure with Finite Element Method
Authors: Mohamady Samira , Raja Ahmad Raja Kamil , Montazeri Allahyar , Zahari Rizal , Abdul Jalil Nawal Aswan
Published: March 2010

Vibration of structures due to external sound is one of the main causes of interior noise in cavities like automobile, aircraft, and rotorcraft, which disturb the comfort of passengers. Accurate modelling of such phenomena is required in eigenfrequency analysis and in designing an active noise control system to reduce the interior noise. In this paper, the effect of periodic noise travelling into a rectangular enclosure is investigated with finite element method (FEM) using COMSOL Multiphysics software. The periodic acoustic wave is generated by a point source outside the enclosure and propagated through the enclosure wall and excites an aluminium flexible panel clamped onto the enclosure. The behaviour of the transmission of sound into the cavity is investigated by computing the modal characteristics and the natural frequencies of the cavity. The simulation results are compared with previous analytical and experimental works for validation and an acceptable match between them were obtained.
Viral Vaccines and CTL Response
Authors: Woolard Stacie N. , Kumaraguru Uday
Published: March 2010

Immune induction by successful vaccine formulations seems to involve stimulation of both humoral and cellular arms of immunity. Nevertheless, CD8+ CTLs are of critical relevance in the context of intracellular infection and tumor for many reasons. The task of exerting antipathogen activity by CD8+ T cells, which principally function to control and eradicate intracellular pathogens, is enabled by constitutive expression of MHC class-I molecules on all tissue types. CTL induction offers hope for vaccines against pathogens that are resistant to neutralizing activity. This review discusses the mechanism of immune induction by some successful vaccines and based on the accrued evidence suggests ideas for improved design of CTL-inducing vaccines.
Shaping Successful and Unsuccessful CD8 T Cell Responses Following Infection
Authors: Cox Maureen A. , Zajac Allan J.
Published: March 2010

CD8 T cells play a vital role in the immunological protection against intracellular pathogens. Ideally, robust effector responses are induced, which eradicate the pathogen, and durable memory CD8 T cells are also established, which help confer protection against subsequent reinfection. The quality and magnitude of these responses is dictated by multiple factors, including their initial interactions with professional antigen-presenting cells, as well as the cytokine milieu and availability of CD4 T cell help. These factors set the transcriptional landscape of the responding T cells, which in turn influences their phenotypic and functional attributes as well as ultimate fate. Under certain conditions, such as during chronic infections, the development of these usually successful responses becomes subverted. Here we discuss advances in our understanding of the cellular and molecular determinants of T cell quality, and the formation of effector, memory, and exhausted CD8 T cells, during acute and chronic infections.
Fertility Preservation for Cancer Patients: A Review
Authors: Ajala Tosin , Rafi Junaid , Larsen-Disney Peter , Howell Richard
Published: March 2010

Infertility can arise as a consequence of treatment of oncological conditions. The parallel and continued improvement in both the management of oncology and fertility cases in recent times has brought to the fore‐front the potential for fertility preservation in patients being treated for cancer. Oncologists must be aware of situations where their treatment will affect fertility in patients who are being treated for cancer and they must also be aware of the pathways available for procedures such as cryopreservation of gametes and/or embryos. Improved cancer care associated with increased cure rates and long term survival, coupled with advances in fertility treatment means that it is now imperative that fertility preservation is considered as part of the care offered to these patients. This can only be approached within a multidisciplinary setting. There are obvious challenges that still remain to be resolved, especially in the area of fertility preservation in prepubertal patients. These include ethical issues, such as valid consent and research in the area of tissue retrieval, cryopreservation, and transplantation.
Main Results of Phase IV BEMUSE Project: Simulation of LBLOCA in an NPP
Authors: Pérez M. , Reventós F. , Batet L. , Pericas R. , Toth I. , Bazin P. , de Crécy A. , Germain P. , Borisov S. , Glaeser H. , Skorek T. , Joucla J. , Probst P. , Ui A. , Chung B. , Oh D. Y. , Kyncl M. , Pernica R. , Manera A. , D'Auria F. , Petruzzi A. , Del Nevo A.
Published: March 2010

Phase IV of BEMUSE Program is a necessary step for a subsequent uncertainty analysis. It includes the simulation of the reference scenario and a sensitivity study. The scenario is a LBLOCA and the reference plant is Zion 1 NPP, a 4 loop PWR unit. Thirteen participants coming from ten different countries have taken part in the exercise. The BEMUSE (Best Estimate Methods plus Uncertainty and Sensitivity Evaluation) Program has been promoted by the Working Group on Accident Management and Analysis (WGAMA) and endorsed by the Committee on the Safety of Nuclear Installations (CSNI). The paper presents the results of the calculations performed by participants and emphasizes its usefulness for future uncertainty evaluation, to be performed in next phase. The objectives of the activity are basically to simulate the LBLOCA reproducing the phenomena associated to the scenario and also to build a common, well-known, basis for the future comparison of uncertainty evaluation results among different methodologies and codes. The sensitivity calculations performed by participants are also presented. They allow studying the influence of different parameters such as material properties or initial and boundary conditions, upon the behaviour of the most relevant parameters related to the scenario.