bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Wheel/Rail Loads on Concrete Tie Stresses and Rail Rollover
Authors: Marquis Brian P. , Muhlanger Michelle , Jeong David Y.
Published: March 2012

As a result of vertical and lateral wheel/rail forces, high contact stresses can develop at the interface between the rail base and tie. Under certain conditions, these stresses can exceed the strength of the concrete tie and result in deterioration of the tie and ultimately derailment due to rail rollover. This failure mode has been determined to be the probable cause of at least two derailments where the ties were found to have a triangular wear pattern. Following these derailments, a field investigation revealed this pattern of failure present in an appreciable portion of concrete ties [1]. Closed-form analyses have been conducted to examine combinations of wheel/rail loads and contact conditions that produce concrete tie rail seat deterioration or rail rollover. These results indicate that under certain circumstances truck-side L/V permitted by the Federal Railroad Administration (FRA) Safety Criterion on Wheel/Rail Loads can result in stresses above the AREMA specified minimum design compressive strength of concrete used in concrete ties. Furthermore the analysis indicated that under certain circumstances truck-side L/V permitted by the FRA Safety Criterion can result in rail rollover. The analyses show that rail rollover can be a problem for new concrete ties, but is more of a problem in the presence of rail seat deterioration described above. This work is sponsored by FRA Office of Research and Development under the track research program.
A 2D Quantum Walk Simulation of Two-Particle Dynamics
Authors: Schreiber Andreas , Gábris Aurél , Rohde Peter P. , Laiho Kaisa , Štefaňák Martin , Potoček Václav , Hamilton Craig , Jex Igor , Silberhorn Christine
Published: March 2012

Here, There, Everywhere

Random walks are a powerful mathematical method that can be used to simulate certain processes in biology, chemistry, or even the stock market. They present a statistical method for mapping the possible routes that processes can take. Quantum walks are expected to be able to probe multiple paths simultaneously. Quantum walks have been demonstrated for one-dimensional, or straight-line, walks. Now,

Schreiber
et al.

(p.
55
, published online 8 March) demonstrate an optical system that can simulate quantum walks over a two-dimensional system, thereby providing the capability of describing much more complex processes.
Genome Sequence of Mycoplasma hyorhinis Strain GDL-1
Authors: Calcutt Michael J. , Foecking Mark F. , Rosales Ruben S. , Ellis Richard J. , Nicholas Robin A. J.
Published: March 2012

Mycoplasma hyorhinis
impacts swine health and production in many countries, either as a primary pathogen or as a component of a polymicrobial infection. Isolates of this species are also common contaminants of tissue culture lines. The genome sequence of the cell culture isolate
M. hyorhinis
GDL-1 is presented herein.
Draft Genome of Halomonas Species Strain GFAJ-1 (ATCC BAA-2256)
Authors: Phung Le T. , Silver Simon , Trimble William L. , Gilbert Jack A.
Published: March 2012

Halomonasstrain GFAJ-1 was reported inSciencemagazine to be a remarkable microbe for which there was “arsenate in macromolecules that normally contain phosphate, most notably nucleic acids.” The draft genome of the bacterium was determined (NCBI accession numbersAHBC01000001throughAHBC01000103). It appears to be a typical gamma proteobacterium.
Draft Genome Sequence of Streptomyces acidiscabies 84-104, an Emergent Plant Pathogen
Authors: Huguet-Tapia José C. , Loria Rosemary
Published: March 2012

A draft genome sequence of the plant pathogen
Streptomyces acidiscabies
84-104, an emergent plant pathogen, is presented here. The genome is among the largest of streptomycetes, at more than 11 Mb, and encodes a 100-kb pathogenicity island (PAI) shared with other plant-pathogenic streptomycetes. The presence of this conserved PAI, and the remnants of a conserved integrase/recombinase at its 3′ end, supports the hypothesis that
S. acidiscabies
emerged as a plant pathogen as a result of this acquisition.
Physical exercise in southern Germany: a cross-sectional study of an urban population
Authors: Rupps Elli , Haenle Mark Martin , Steinacker Juergen , Mason Richard Andrew , Oeztuerk Suemeyra , Steiner Ronald , Kratzer Wolfgang ,   the EMIL Study group
Published: March 2012

Objectives

The aim of this study was to investigate the degree of physical exercise and self-assessment of physical fitness (PF) and their relationship to health- and behaviour-specific factors in a randomly selected sample of an urban population in southern Germany.

Design

Cross-sectional study.

Setting

In the southern German city of Leutkirch.

Participants

2187 subjects randomly selected from the registry of inhabitants. Of the selected group, aged 18–65 years, 52.1% were women and 47.9% men.

Primary and secondary outcome measures

Participants were asked how many hours per week they spent on physical exercise and sports. They were also asked to rate their own performance and/or PF.

Results

Overall, 38.9% of the participants reported no physical exercise. Men reported a higher level of physical exercise than did women. Less exercise was reported by subjects with diabetes, high body mass index and waist-to-hip ratio and by those who were underweight. Alcohol consumption, smoker status and higher educational level showed a positive association with physical exercise. A negative trend with respect to moderate physical exercise was observed for those with metabolic syndrome, diabetes, hypertension and hepatic steatosis, but this was statistically significant only for subjects with diabetes. In both men and women, there was a relationship between self-assessed ‘good’ PF and high physical exercise.

Conclusions

The data show that a large proportion of the study population is not physically active; specific risk groups (overweight subjects, older subjects, smokers or subjects with low educational level) are even less active. The data suggest that there is a great potential for measures promoting physical exercise in these groups.
Circulating miR-15b and miR-130b in serum as potential markers for detecting hepatocellular carcinoma: a retrospective cohort study
Authors: Liu Angela M , Yao Tzy-Jyun , Wang Wei , Wong Kwong-Fai , Lee Nikki P , Fan Sheung Tat , Poon Ronnie T P , Gao Chunfang , Luk John M
Published: March 2012

Objective

Serum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if circulating microRNAs (miRNAs) could outperform AFP for HCC detection.

Design

A retrospective cohort study.

Setting

Two clinical centres in China.

Participants

The exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls.

Main outcome measures

Expression of miRNAs was measured by real-time quantitative reverse transcription–PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs.

Results

In the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP.

Conclusion

The combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.
LOGARITHMIC STACKS AND MINIMALITY
Authors: GILLAM W. D.
Published: March 2012

Given a category fibered in groupoids over schemes with a log structure, one produces a category fibered in groupoids over log schemes. We classify the groupoid fibrations over log schemes that arise in this manner in terms of a categorical notion of "minimal" objects. The classification is actually a purely category-theoretic result about groupoid fibrations over fibered categories, though most of the known applications occur in the setting of log geometry, where our categorical framework encompasses many notions of "minimality" previously extant in the literature.
HIGHER RANK BRILL–NOETHER THEORY ON SECTIONS OF K3 SURFACES
Authors: FARKAS GAVRIL , ORTEGA ANGELA
Published: March 2012

We discuss the role of K3 surfaces in the context of Mercat's conjecture in higher rank Brill–Noether theory. Using liftings of Koszul classes, we show that Mercat's conjecture in rank 2 fails for any number of sections and for any gonality stratum along a Noether–Lefschetz divisor inside the locus of curves lying on K3 surfaces. Then we show that Mercat's conjecture in rank 3 fails even for curves lying on K3 surfaces with Picard number 1. Finally, we provide a detailed proof of Mercat's conjecture in rank 2 for general curves of genus 11, and describe explicitly the action of the Fourier–Mukai involution on the moduli space of curves.
POSITIVE REPRESENTATIONS OF FINITE GROUPS IN RIESZ SPACES
Authors: DE JEU MARCEL , WORTEL MARTEN
Published: March 2012

In this paper, which is part of a study of positive representations of locally compact groups in Banach lattices, we initiate the theory of positive representations of finite groups in Riesz spaces. If such a representation has only the zero subspace and possibly the space itself as invariant principal bands, then the space is Archimedean and finite-dimensional. Various notions of irreducibility of a positive representation are introduced and, for a finite group acting positively in a space with sufficiently many projections, these are shown to be equal. We describe the finite-dimensional positive Archimedean representations of a finite group and establish that, up to order equivalence, these are order direct sums, with unique multiplicities, of the order indecomposable positive representations naturally associated with transitive G-spaces. Character theory is shown to break down for positive representations. Induction and systems of imprimitivity are introduced in an ordered context, where the multiplicity formulation of Frobenius reciprocity turns out not to hold.
MODULES FOR A SHEAF OF LIE ALGEBRAS ON LOOP MANIFOLDS
Authors: BILLIG YULY
Published: March 2012

We consider a semidirect product of the sheaf of vector fields on a manifold ℂ* × X with a central extension of the sheaf of Lie algebras of maps from ℂ* × X into a finite-dimensional simple Lie algebra, viewed as sheaves on X. Using vertex algebra methods we construct sheaves of modules for this sheaf of Lie algebras. Our results extend the work of Malikov–Schechtman–Vaintrob on the chiral de Rham complex.
USE OF LIQUID–LIQUID INTERFACE FOR SYNTHESIS OF MAGHEMITE NANOCRYSTALS
Authors: BASAVARAJA S. , SAWLE BALAJI D. , BEDRE MAHESH D. , RAGUNANDAN D. , ARUNKUMAR L. , VIJAYANAND H. , VENKATARAMAN A.
Published: March 2012

Nanocrystals of maghemite (γ- Fe2O3 ) have been prepared at the interface of organic-aqueous layer by the reaction of ferric acetylacetonate in toluene with sodium hydroxide in aqueous solution. The nanocrystals of γ- Fe2O3 formed at the interface of the organic-aqueous layer have been confirmed by X-ray diffraction (XRD) pattern. The sample has been characterized morphologically by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and atomic force microscopy (AFM) techniques. Magnetic hysteresis loop and zero-field cooling measurements exhibited superparamagnetism behavior for γ- Fe2O3 nanocrystals.
THICKNESS DEPENDENCE OF BUCKLING PATTERNS OF Ta FILMS SPUTTERED ON GLASS SUBSTRATES
Authors: ZHANG YONG-JU , YU SEN-JIANG , ZHOU HONG , CHEN MIAO-GEN , JIAO ZHI-WEI
Published: March 2012

Tantalum (Ta) films deposited on glass substrates have been prepared by a direct current magnetron sputtering method, and buckling patterns induced by residual compressive stress are investigated in detail. When the film thickness increases, the buckling morphologies evolve from straight-sided buckle network to wavy or wormlike wrinkles gradually, and finally change into telephone cord buckles. The geometrical parameters of the buckling patterns are found to increase linearly with the film thickness. Based on the geometrical parameters of the buckling patterns, the mechanical properties of the Ta films are also discussed in the frame of continuum elastic theory.
BI-STABLE ANALYSES OF LAMINATED FGM SHELLS
Authors: HE X. Q. , LI L. , KITIPORNCHAI S. , WANG C. M. , ZHU H. P.
Published: March 2012

Based on an inextensional two-parameter analytical model for cylindrical shells, bi-stable analyses were carried out on laminated functionally graded material (FGM) shells with various layups of fibers. Properties of FGM shells are functionally graded in the thickness direction according to a volume fraction power law distribution. The effects of constituent volume fractions of FGM matrix are examined on the curvature and twist of laminated FGM shells. The results reveal that the optimum combination of constituents of FGM matrix can be obtained for the maximum twist of FGM shells with antisymmetric layups, which helps the design of deployable structures. The effects of Young's modulus of fibers and the symmetry of layups on bi-stable behaviors are also discussed in detail.
REMEDY FOR LOAD DISCONTINUITY IN TIME HISTORY ANALYSIS
Authors: CHANG SHUENN-YIH
Published: March 2012

Discontinuity at the end of an impulse will lead to an amplitude distortion in a time history analysis. This amplitude distortion can be effectively reduced, if a very small time step is used to perform a complete step-by-step integration procedure. As a result, a lot of computational effort is involved. In this study, it will be shown that a significant amplitude distortion may also occur for a dynamic loading, which is not classified as an impulse. Furthermore, a remedy is proposed to overcome the difficulty caused by the load discontinuity. This remedy is very simple and it involves adjusting the input load at the time instant of discontinuity. In fact, the average of the two discontinuity values at the load discontinuity is taken to be the adjusting input load for the time instant of load discontinuity. The feasibility of this remedy is analytically verified and confirmed with numerical examples not only for impulses but also for dynamic loadings. Apparently, there is no extra computational effort needed for the remedy and it will not complicate the programming of dynamic analysis codes.
ELASTIC DISTORTIONAL BUCKLING OF SINGLY SYMMETRIC I-SHAPED FLEXURAL MEMBERS WITH SLENDER WEBS
Authors: ZIRAKIAN TADEH , ZHANG JIAN
Published: March 2012

The effectiveness of the measures provided in the 2005 American Institute of Steel Construction (AISC) Specification for elastic distortional buckling of doubly symmetric I-shaped flexural members with slender webs was evaluated in a previous study. It was demonstrated that the code equations generally provide conservative strength estimates for the slender-web I-beams, and the amount of the conservatism was found to be rather dramatic for some cases. As a continuation of this effort, the effectiveness and accuracy of the 2005 AISC code provisions as well as predictions for elastic distortional buckling of slender-web singly symmetric I-shaped members is investigated in this paper. Comparisons are made with the finite strip analysis results for distortional buckling and the two design equations for elastic distortional buckling proposed by other researchers. It is demonstrated that the code predictions are by and large conservative, and even overly conservative in some cases, which does not seem to be justifiable economically.
NUMERICAL AND EXPERIMENTAL STUDY ON FREE VIBRATION OF DELAMINATED WOVEN FIBER GLASS/EPOXY COMPOSITE PLATES
Authors: MOHANTY J. , SAHU S. K. , PARHI P. K.
Published: March 2012

This paper presents a combined experimental and numerical study of free vibration of industry-driven woven fiber glass/epoxy (G/E) composite plates with delamination. Using the first-order shear deformation theory, an eight-noded two-dimensional quadratic isoparametric element was developed, which has five degrees of freedom per node. In the experimental study, the influence of various parameters such as the delamination size, boundary conditions, fiber orientations, number of layers, and aspect ratio on the natural frequencies of delaminated composite plates are investigated. Comparison of the numerical results with experimental ones shows good agreement. Fundamental natural frequencies are found to decrease with the increase in the delamination size and fiber orientation and increases with the increase in the number of layers and aspect ratio of delaminated composite plates. The natural frequency of the delaminated composite plate varies significantly for different boundary conditions.
CRYSTALLIZATION OF OXIDES AS FUNCTIONAL MATERIALS
Authors: SUN CONGTING , SONG SHUYAN , XUE DONGFENG , ZHANG HONGJIE
Published: March 2012

Crystallization is essential to the manufacture of functional materials as varies as electronic devices, energy storage and conversion devices, and highly reactive catalysts. As an important part of functional materials, metal oxides possess wide applications and the crystallization of oxide materials has thus received considerable attention from both fundamental and technological perspectives. With particular emphasis on our recent laboratory results, this feature article gives a brief review in the field of crystallization of oxides. On the basis of chemical bonding theory of single crystal growth, we have simulated thermodynamic growth behaviors of various functional oxides such as ZnO , MgO , Cu2O , Nb2O5, V2O5, MnO2, SnO2, NiO , KDP/ADP, LiNbO3, and NaNbO3. Quantitatively analyzing bonding conditions of controllable crystallographic faces enables us to design proper synthesis strategies and optimize growth parameters, consequently obtaining functional oxides with desirable crystallization behaviors.
CELLULAR UPTAKE BEHAVIOR OF FLUORESCEIN: INTERCALATED LAYERED DOUBLE HYDROXIDE
Authors: TANAKA MIYUKI , AISAWA SUMIO , HIRAHARA HIDETOSHI , NARITA EIICHI , YIN SHU , SATO TSUGIO
Published: March 2012

In order to define the ability of layered double hydroxide (LDH) as materials for drug delivery, fluorescein (Fluo) anion intercalated LDH (Fluo/LDH) was synthesized by hydrothermal treatment and observed the cellular uptake of the Fluo/LDH for mammalian cell (L929). The synthesized Fluo/LDH showed a LDH structure, high fluorescence and low cytotoxicity. According to the fluorescence, confocal and TEM images of cells, the Fluo/LDH seemed to be internalized into the L929 cell by cellular endocytosis and dissolved inside the cell to exhibit the fluorescence of cellular cytoplasm.
Hydrodynamic Cell Pairing and Cell Fusion through a Microslit on a Microfluidic Device
Authors: Sasaki Naoki , Gong Jiansheng , Sakuragi Makoto , Hosokawa Kazuo , Maeda Mizuo , Ito Yoshihiro
Published: March 2012

Positioning of two different types of cells in contact with each other is of particular importance to analyze interactions between the cells. However, previous methods require sequential injection of two different cell suspensions and flow switching during the operation. Here, we present a novel method to pair two different types of cells on microfluidic devices. Single-step pairing was achieved by introducing each cell suspension from different inlets into the microchannel which has a microslit arranged with a hydrodynamic weir. As an application of the pairing, cell fusion through the microslit was studied.
Photoluminescence Studies of Polarization Effects in InGaN/(In)GaN Multiple Quantum Well Structures
Authors: Zhang Liyang , Cheng Kai , Liang Hu , Lieten Ruben , Leys Maarten , Borghs Gustaaf
Published: March 2012

The impact of polarization fields in multiple quantum well (MQW) structures is revealed by photoluminescence measurements and band diagram calculations. We observe a blue shift of luminous energy of 33 meV and an increased light emission of 19% for In
x
Ga1-x
N/In
y
Ga1-y
N MQWs with respect to In
x
Ga1-x
N/GaN MQWs. Band diagram calculations show a lowering of the polarization fields and an increase in wave function overlap of 22% by adding indium into the barriers. We therefore attribute the observed blue shift and increased emission to an improved electron and hole wave function overlap due to lower electric fields in In
x
Ga1-x
N/In
y
Ga1-y
N structures.
Signal Enhancement at Small Gap Length in Giant Magnetoresistance Differential Response
Authors: Wang Li , Han Guchang
Published: March 2012

Micromagnetic modeling has been performed to study responses of giant magnetoresistance (GMR)-type differential readers (GDRs). Our results show that the pulse shape in GDRs is Gaussian-like, which is consistent with the counterpart in conventional heads. The key finding is that GDR signals increase with decreasing gap length. Magnetostatic interactions among the free layers, hard biases and transition bits are responsible for the signal enhancement at small gap length. Signal enhancement at small gap length is very useful in linear scaling for differential readers since media vertical fields approach zero towards a transition.
Effects of Cluster Size on Platinum–Oxygen Bonds Formation in Small Platinum Clusters
Authors: Oemry Ferensa , Padama Allan Abraham B. , Kishi Hirofumi , Kunikata Shinichi , Nakanishi Hiroshi , Kasai Hideaki , Maekawa Hiroyoshi , Osumi Kazuo , Sato Kaoru
Published: March 2012

We present the results of density functional theory calculation in oxygen dissociative adsorption process on two types of isolated platinum (Pt) clusters: Pt4 and Pt10, by taking into account the effect of cluster reconstruction. The strength of Pt–Pt bonds in the clusters is mainly defined by d–d hybridization and interstitial bonding orbitals (IBO). Oxygen that adsorbed on the clusters is weakening the IBO and thus inducing geometry reconstruction as occurred in Pt10 cluster. However, cluster that could undergo structural deformation is found to promote oxygen dissociation with no energy barrier. The details show that maintaining well-balanced of attractive and repulsive (Hellmann–Feynman) forces between atoms is considered to be the main key to avoid any considerable rise of energy barrier. Furthermore, a modest energy barrier that gained in Pt4 cluster is presumed to be originate from inequality of intramolecular forces between atoms.
Sensitivity Analysis of a Cracked Atomic Force Microscope Cantilever
Authors: Lee Haw-Long , Chang Win-Jin
Published: March 2012

The sensitivity of flexural vibration for an atomic force microscope (AFM) cantilever with a crack has been studied. An explicit expression for the sensitivity of vibration modes of the cracked cantilever has been obtained using the relationship between the resonant frequency and contact stiffness of the cantilever and sample. Results show that the sensitivities of the three modes of the cracked cantilever are higher than those of the cantilever without crack when the contact stiffness is low. When the contact stiffness is high, however, the situation is reverse. Therefore, a cracked AFM cantilever can be used for imaging soft samples such as biological molecules and polymers. In addition, the crack near the free end of cantilever that leads to a higher sensitivity. This is useful for the design of a highly sensitive cantilever.
Iterative Receiver in Time–Frequency Domain for Shallow Water Acoustic Channel
Authors: Zhao Liang , Ge Jianhua
Published: March 2012

Inter-symbol interference (ISI) caused by multi-path propagation, especially in shallow water channel, degrades the performance of underwater acoustic (UWA) communication systems. In this paper, we combine soft minimum mean squared error (MMSE) equalization and the serially concatenated trellis coded modulation (SCTCM) decoding to develop an iterative receiver in time–frequency domain (TFD) for underwater acoustic point to point communications. Based on sound speed profile (SSP) measured in the lake and finite-element ray (FER) tracing method (Bellhop), the shallow water channel is constructed to evaluate the performance of the proposed iterative receiver. The results suggest that the proposed iterative receiver can reduce the calculation complexity of the equalizer and obtain better performance using less receiving elements.
Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism
Authors: Nichols Nicole L. , Dale Erica A. , Mitchell Gordon S.
Published: March 2012

Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35–45 mmHg arterial Po2 (PaO2)] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by Gq protein-coupled metabotropic 5-HT2 receptors. An alternate pathway to pMF is induced by Gs protein-coupled metabotropic receptors, including adenosine A2A receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25–30 mmHg PaO2) and moderate (45–55 mmHg PaO2) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A2A (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P < 0.05). MSX-3 (28% ± 6%; n = 6; P < 0.05) attenuated pLTF following severe AIH, but enhanced pLTF following moderate AIH (86% ± 26%; n = 8; P < 0.05). Methysergide abolished pLTF after moderate AIH (12% ± 5%; n = 6; P = 0.035), but had no effect after severe AIH (66 ± 13%; n = 5; P > 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted.
Sex differences in hemodynamic and sympathetic neural firing patterns during orthostatic challenge in humans
Authors: Yang Huan , Cooke William H. , Reed Kristen S. , Carter Jason R.
Published: March 2012

Recent evidence suggests that young men and women may have different strategies for regulating arterial blood pressure, and the purpose of the present study was to determine if sex differences exist in diastolic arterial pressure (DAP) and muscle sympathetic nerve activity (MSNA) relations during simulated orthostatic stress. We hypothesized that young men would demonstrate stronger DAP-MSNA coherence and a greater percentage of “consecutive integrated bursts” during orthostatic stress. Fourteen men and 14 women (age 23 ± 1 yr) were examined at rest and during progressive lower body negative pressure (LBNP; −5 to −40 mmHg). Progressive LBNP did not alter mean arterial pressure (MAP) in either sex. Heart rate increased and stroke volume decreased to a greater extent during LBNP in women (interactions, P < 0.05). DAP-MSNA coherence was strong (i.e., r ≥ 0.5) at rest and increased throughout all LBNP stages in men. In contrast, DAP-MSNA coherence was lower in women, and responses to progressive LBNP were attenuated compared with men (time × sex, P = 0.029). Men demonstrated a higher percentage of consecutive bursts during all stages of LBNP (sex, P < 0.05), although the percentage of consecutive bursts increased similarly during progressive LBNP between sexes. In conclusion, men and women demonstrate different firing patterns of integrated MSNA during LBNP that appear to be related to differences in DAP oscillatory patterns. Men tend to have more consecutive bursts, which likely contribute to a stronger DAP-MSNA coherence. These findings may help explain why young women are more prone to orthostatic intolerance.
Brachial artery adaptation to lower limb exercise training: role of shear stress
Authors: Birk Gurpreet K. , Dawson Ellen A. , Atkinson Ceri , Haynes Andrew , Cable N. Timothy , Thijssen Dick H. J. , Green Daniel J.
Published: March 2012

Lower limb exercise increases upper limb conduit artery blood flow and shear stress, and leg exercise training can enhance upper limb vascular function. We therefore examined the contribution of shear stress to changes in vascular function in the nonexercising upper limbs in response to lower limb cycling exercise training. Initially, five male subjects underwent bilateral brachial artery duplex ultrasound to measure blood flow and shear responses to 30-min cycling exercise at 80% of maximal heart rate. Responses in one forearm were significantly ( P < 0.05) attenuated via cuff inflation throughout the exercise bout. An additional 11 subjects participated in an 8-wk cycle training study undertaken at a similar intensity, with unilateral cuff inflation around the forearm during each exercise bout. Bilateral brachial artery flow-mediated dilation responses to a 5-min ischemic stimulus (FMD%), an ischemic handgrip exercise stimulus (iEX), and endothelium-independent NO donor administration [glyceryl trinitrate (GTN)] were measured at 2, 4, and 8 wk. Cycle training increased FMD% in the noncuffed limb at week 2, after which time responses returned toward baseline levels (5.8 ± 4.1, 8.6 ± 3.8, 7.4 ± 3.5, 6.0 ± 2.3 at 0, 2, 4 and 8 wk, respectively; ANOVA: P = 0.04). No changes in FMD% were observed in the cuffed arm. No changes were evident in response to iEX or GTN in either the cuffed or noncuffed arms ( P > 0.05) across the 8-wk intervention period. Our data suggest that lower limb cycle training induces a transient increase in upper limb vascular function in healthy young humans, which is, at least partly, mediated via shear stress.
Metabolic and cardiac signaling effects of inhaled hydrogen sulfide and low oxygen in male rats
Authors: Stein Asaf , Mao Zhengkuan , Morrison Joanna P. , Fanucchi Michelle V. , Postlethwait Edward M. , Patel Rakesh P. , Kraus David W. , Doeller Jeannette E. , Bailey Shannon M.
Published: March 2012

Low concentrations of inhaled hydrogen sulfide (H2S) induce hypometabolism in mice. Biological effects of H2S in in vitro systems are augmented by lowering O2tension. Based on this, we hypothesized that reduced O2tension would increase H2S-mediated hypometabolism in vivo. To test this, male Sprague-Dawley rats were exposed to 80 ppm H2S at 21% O2or 10.5% O2for 6 h followed by 1 h recovery at room air. Rats exposed to H2S in 10.5% O2had significantly decreased body temperature and respiration compared with preexposure levels. Heart rate was decreased by H2S administered under both O2levels and did not return to preexposure levels after 1 h recovery. Inhaled H2S caused epithelial exfoliation in the lungs and increased plasma creatine kinase-MB activity. The effect of inhaled H2S on prosurvival signaling was also measured in heart and liver. H2S in 21% O2increased Akt-PSer473and GSK-3β-PSer9in the heart whereas phosphorylation was decreased by H2S in 10.5% O2, indicating O2dependence in regulating cardiac signaling pathways. Inhaled H2S and low O2had no effect on liver Akt. In summary, we found that lower O2was needed for H2S-dependent hypometabolism in rats compared with previous findings in mice. This highlights the possibility of species differences in physiological responses to H2S. Inhaled H2S exposure also caused tissue injury to the lung and heart, which raises concerns about the therapeutic safety of inhaled H2S. In conclusion, these findings demonstrate the importance of O2in influencing physiological and signaling effects of H2S in mammalian systems.
S-Glutathionylated Serine Proteinase Inhibitors as Plasma Biomarkers in Assessing Response to Redox-Modulating Drugs
Authors: Grek Christina L. , Townsend Danyelle M. , Uys Joachim D. , Manevich Yefim , Coker Woodrow J. , Pazoles Christopher J. , Tew Kenneth D.
Published: March 2012

Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys256 of serpin A1 and Cys263 of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways. Cancer Res; 72(9); 2383–93. ©2012 AACR.
Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities
Authors: Perez-Moreno Pablo , Brambilla Elisabeth , Thomas Roman , Soria Jean-Charles
Published: March 2012

Lung cancer is the leading cause of cancer-related deaths worldwide. Next to adenocarcinoma, squamous cell carcinoma (SCC) of the lung is the most frequent histologic subtype in non–small cell lung cancer. Encouraging new treatments (i.e., bevacizumab, EGFR tyrosine kinase inhibitors, and ALK inhibitors) have afforded benefits to patients with adenocarcinoma, but unfortunately the same is not true for SCC. However, many genomic abnormalities are present in SCC, and there is growing evidence of their biologic significance. Thus, in the short term, the molecular characterization of patients with SCC in modern profiling platforms will probably be as important as deciphering the molecular genetics of adenocarcinoma. Patients with SCC of the lung harboring specific molecular defects that are actionable (e.g., fibroblast growth factor receptor 1 amplification, discoidin domain receptor 2 mutation, and phosphoinositide 3-kinase amplification) should be enrolled in prospective clinical trials targeting such molecular defects. Clin Cancer Res; 18(9); 2443–51. ©2012 AACR.
Dual mTORC1/2 and HER2 Blockade Results in Antitumor Activity in Preclinical Models of Breast Cancer Resistant to Anti-HER2 Therapy
Authors: García-García Celina , Ibrahim Yasir H. , Serra Violeta , Calvo Maria Teresa , Guzmán Marta , Grueso Judit , Aura Claudia , Pérez José , Jessen Katti , Liu Yi , Rommel Christian , Tabernero Josep , Baselga José , Scaltriti Maurizio
Published: March 2012

Purpose: The PI3K/Akt/mTOR pathway is an attractive target in HER2-positive breast cancer that is refractory to anti-HER2 therapy. The hypothesis is that the suppression of this pathway results in sensitization to anti-HER2 agents. However, this combinatorial strategy has not been comprehensively tested in models of trastuzumab and lapatinib resistance.

Experimental Design: We analyzed in vitro cell viability and induction of apoptosis in five different cell lines resistant to trastuzumab and lapatinib. Inhibition of HER2/HER3 phosphorylation, PI3K/Akt/mTOR, and extracellular signal-regulated kinase (ERK) signaling pathways was evaluated by Western blotting. Tumor growth inhibition after treatment with lapatinib, INK-128, or the combination of both agents was evaluated in three different animal models: two cell-based xenograft models refractory to both trastuzumab and lapatinib and a xenograft derived from a patient who relapsed on trastuzumab-based therapy.

Results: The addition of lapatinib to INK-128 prevented both HER2 and HER3 phosphorylation induced by INK-128, resulting in inhibition of both PI3K/Akt/mTOR and ERK pathways. This dual blockade produced synergistic induction of cell death in five different HER2-positive cell lines resistant to trastuzumab and lapatinib. In vivo, both cell line–based and patient-derived xenografts showed exquisite sensitivity to the antitumor activity of the combination of lapatinib and INK-128, which resulted in durable tumor shrinkage and exhibited no signs of toxicity in these models.

Conclusions: The simultaneous blockade of both PI3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-HER2 therapy. Clin Cancer Res; 18(9); 2603–12. ©2012 AACR.
Choosing Phase II Endpoints and Designs: Evaluating the Possibilities
Authors: LeBlanc Michael , Tangen Catherine
Published: March 2012

Selecting the phase II design and endpoint to achieve the best possible chance of success for a confirmatory phase III study in a particular disease and treatment setting is challenging but critical. Simulating from existing clinical trial data sets and from mathematical models can be useful tools for evaluating statistical properties. Clin Cancer Res; 18(8); 2130–2. ©2012 AACR.
JAK–STAT and JAK–PI3K–mTORC1 Pathways Regulate Telomerase Transcriptionally and Posttranslationally in ATL Cells
Authors: Yamada Osamu , Ozaki Kohji , Akiyama Masaharu , Kawauchi Kiyotaka
Published: March 2012

Adult T-cell leukemia (ATL) is a heterogeneous tumor that is resistant to chemotherapy. Telomerase activity plays a critical role in tumorigenesis and is associated with the prognosis of ATL patients. Interleukin (IL)-2 commonly promotes tumor growth in chronic ATL cells. The signaling pathways involved in IL-2–regulated telomerase activation were studied in ATL cells derived from chronic ATL patients. IL-2 challenge enhanced tyrosine phosphorylation of Janus-activated kinase (JAK)1–3 and STAT5, and induced JAK1 and JAK2 to associate with STAT5 in IL-2–dependent ATL cells. Chromatin immunoprecipitation assays revealed that STAT5 directly bound to the human telomerase reverse transcriptase (hTERT) promoter. STAT5 short interfering RNA inhibited hTERT transcription in IL-2–stimulated ATL cells. Inhibitors of PI3K, HSP90, and mTOR reduced IL-2–induced hTERT mRNA, protein expression, and telomerase activity. AKT, HSP90, mTOR, S6 kinase, and hTERT immunoprecipitate from IL-2–stimulated cells contained telomerase activity, suggesting that hTERT directly interacts with, and is regulated by, these proteins. Binding of the p85 regulatory subunit of PI3K to JAK2 was enhanced in an IL-2–dependent manner, indicating that JAK2 propagates activation signals from the IL-2 receptor and links hTERT activation to both the STAT5 and PI3K pathways. Finally, IL-2–induced activation of telomerase and STAT5 was observed in primary leukemic cells. These results indicate that IL-2 stimulation induces hTERT activation through the JAK/STAT pathway and the JAK/PI3K/AKT/HSP90/mTORC1 pathway in IL-2–responsive ATL cells. These signaling proteins represent novel and promising molecular therapeutic targets for IL-2–dependent ATL. Mol Cancer Ther; 11(5); 1112–21. ©2012 AACR.
Aerosolized 3-Bromopyruvate Inhibits Lung Tumorigenesis without Causing Liver Toxicity
Authors: Zhang Qi , Pan Jing , North Paula E. , Yang Shoua , Lubet Ronald A. , Wang Yian , You Ming
Published: March 2012

3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)pyrene was used to induce lung tumors, and 3-bromopyruvate was administered by oral gavage to female A/J mice. We found that 3-bromopyruvate significantly decreased tumor multiplicity and tumor load by 58% and 83%, respectively, at a dose of 20 mg/kg body weight by gavage. Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound. Treatment with 3-bromopyruvate increased immunohistochemical staining for cleaved caspase-3, suggesting that the lung tumor inhibitory effects of 3-bromopyruvate were through induction of apoptosis. 3-Bromopyruvate also dissociated hexokinase II from mitochondria, reduced hexokinase activity, and blocked energy metabolism in cancer cells, finally triggered cancer cell death and induced apoptosis through caspase-3, and PARP in human lung cancer cell line. The ability of 3-bromopyruvate to inhibit mouse lung tumorigenesis, in part through induction of apoptosis, merits further investigation of this compound as a chemopreventive agent for human lung cancer. Cancer Prev Res; 5(5); 717–25. ©2012 AACR.
Allelic Transcripts Dosage Effect in Morphologically Normal Ovarian Cells from Heterozygous Carriers of a BRCA1/2 French Canadian Founder Mutation
Authors: Abd-Rabbo Diala , Abaji Christine , Cardin Guillaume B. , Filali-Mouhim Abdelali , Arous Caroline , Portelance Lise , Escobar Enrique , Cloutier Sophie , Tonin Patricia N. , Provencher Diane M. , Mes-Masson Anne-Marie , Maugard Christine M.
Published: March 2012

We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation. We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation. Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript. Cancer Prev Res; 5(5); 765–77. ©2012 AACR.
Association of a Genetic Polymorphism of the Alcohol-Metabolizing Enzyme ADH1C with Alcohol Dependence: Results of a Case-Control Study
Authors: Kortunay Selim , Köseler Aylin , Özdemir Fatma , Atalay Erol Ömer
Published: March 2012

Objective: Alcohol dependence causes serious problems which may be influenced by genetic factors associated with alcohol metabolism. The aim was to investigate the allelic and genotypic difference in distribution of a polymorphism in alcohol dehydrogenase 1C gene (ADH1C) between alcohol-dependent individuals and controls, and to examine if these genotypes were associated with the age at which the patient became alcohol-dependent. Methods: We conducted a case-control study including 90 alcohol-dependent cases and 100 historic controls. The genomic DNA was isolated and the alleles were analyzed with an RFLP. Results: The ADH1C*1 allele frequencies were 0.89 (95% CI 0.84–0.91) in controls and 0.68 (95% CI 0.61–0.74) in alcohol-dependent patients. The frequencies of the ADH1C*2 allele were 0.11 (95% CI 0.07–0.14) and 0.32 (95% CI 0.25–0.38) among controls and alcohol-dependent patients, respectively (p < 0.0001). The ADH1C*1/*1 genotype frequency was significantly higher in the control group (77%) compared to that of the alcohol-dependents (51%, p < 0.0001). The ADH1C*1/*2 genotype frequency was significantly lower in the control group (23%) compared to that of the alcohol-dependents (42%, p < 0.0001). We obtained no statistically significant difference among the ADH1C genotype groups regarding age. Conclusions: These findings suggest that a significantly higher presence of ADH1C*2 allele is associated with alcohol dependence in a Turkish population. Studies with other related polymorphisms are needed to more precisely estimate the association of alcohol dependence with ADH1C.
Modified Endoscopic Maxillary Medial Sinusotomy for Sinonasal Inverted Papilloma with Attachment to the Anterior Medial Wall of Maxillary Sinus
Authors: Wang Chengshuo , Han Demin , Zhang Luo
Published: March 2012

Objectives: The endoscopic management of inverted papilloma (IP) has gained in popularity over the last 15 years. However, the appropriate management of lesions involving the anterior medial wall of the maxillary sinus still has to be determined. Methods: We performed a retrospective review of the surgical results for patients with IP attached to the anterior medial wall of the maxillary sinus in the Otolaryngology, Head and Neck Surgery Department, Beijing TongRen Hospital. The tumors were removed by using our surgical technique of modified endoscopic maxillary medial sinusotomy, which was defined as an extended endoscopic medial maxillectomy with preservation of the nasolacrimal duct and inferior turbinate. Sinus endoscopy was used to screen for disease after endoscopic resection and the clinical outcomes were analyzed. Results: A total of 7 patients (4 males and 3 females) were identified. Pre- and postoperative pathological examinations revealed inverted papilloma as the diagnosis. All tumors were defined as Krouse III lesions. There were no complications recorded as a result of surgery. All patients remain disease free with a mean follow-up of 35.7 months (range 20–68 months). Conclusion: Sinonasal IP with attachment to the anterior medial portion of the maxillary sinus can be treated successfully using modified endoscopic maxillary medial sinusotomy with preservation of the nasolacrimal duct and inferior turbinate.
Alzheimer’s Disease: Genetic Polymorphisms and Rate of Decline
Authors: Schmidt Christian , Wolff Martin , von Ahsen Nicolas , Zerr Inga
Published: March 2012

Background/Aim: To investigate the influence of established genetic risk factors for Alzheimer’s disease on the speed of disease progression. Methods: Polymorphisms (in ACE, ApoE, BIN1, CLU, CR1, CST3, EXOC3L2, GWA14q32.13, IL8, LDLR, PICALM, TNK1) of 40 Alzheimer’s disease patients from a longitudinal study were analyzed. A standardized loss of Mini-Mental State Examination points was used as the progression parameter. Results: Polymorphisms in CST3 and EXOC3L2 as well as the absence of APOE4 were associated with more aggressive disease courses. A trend was observed for BIN1. Conclusion: In addition to being a risk factor for disease development, some of the polymorphisms investigated here are associated with higher rates of decline and disease progression and thus might act as prognostic disease markers. This effect needs to be considered in future treatment strategies.