bluuebunny/crossref_metadata_2025 huggingface dataset:
SKEW POLYNOMIAL RINGS WHICH ARE GENERALIZED ASANO PRIME RINGS
Authors: MARUBAYASHI H. , MUCHTADI-ALAMSYAH INTAN , UEDA A.
Published: February 2013

Let R be a prime Goldie ring with quotient ring Q and σ be an automorphism of R. We define (σ-) generalized Asano prime rings and prove that a skew polynomial ring R[x; σ] is a generalized Asano prime ring if and only if R is a σ-generalized Asano prime ring. This is done by giving explicitly the structure of all v-ideals of R[x; σ] in case R is a σ-Krull prime ring. We provide some examples of σ-generalized Asano prime rings which are not Krull prime rings.
THE FGF CONJECTURE AND THE SINGULAR IDEAL OF A RING
Authors: GÓMEZ-TORRECILLAS JOSÉ , ASENSIO PEDRO A. GUIL
Published: February 2013

We show that a left CF ring is left artinian if and only if it is von Neumann regular modulo its left singular ideal. We deduce that a left FGF is Quasi-Frobenius (QF) under this assumption. This clarifies the role played by the Jacobson radical and the singular left ideal in the FGF and CF conjectures. In Sec. 3 of the paper, we study the structure of left artinian left CF rings. We prove that they are left continuous and left CEP rings.
RELATIVE ROTA–BAXTER OPERATORS AND TRIDENDRIFORM ALGEBRAS
Authors: BAI CHENGMING , GUO LI , NI XIANG
Published: February 2013

A relative Rota–Baxter operator is a relative generalization of a Rota–Baxter operator on an associative algebra. In the Lie algebra context, it is called an [Formula: see text]-operator, originated from the operator form of the classical Yang–Baxter equation. We generalize the well-known construction of dendriform and tridendriform algebras from Rota–Baxter algebras to a construction from relative Rota–Baxter operators. In fact we give two such generalizations, on the domain and range of the operator respectively. We show that each of these generalized constructions recovers all dendriform and tridendriform algebras. Furthermore the construction on the range induces bijections between certain equivalence classes of invertible relative Rota–Baxter operators and tridendriform algebras.
QUASI ROOT SYSTEMS AND VERTEX OPERATOR REALIZATIONS OF THE VIRASORO ALGEBRA
Authors: NOYVERT BORIS
Published: February 2013

A construction of the Virasoro algebra in terms of free massless two-dimensional boson fields is studied. The ansatz for the Virasoro field contains the most general unitary scaling dimension 2 expression built from vertex operators. The ansatz leads in a natural way to a concept of a quasi root systems. This is a new notion generalizing the notion of a root system in the theory of Lie algebras. We introduce a definition of a quasi root systems and provide an extensive list of examples. Explicit solutions of the ansatz are presented for a range of quasi root systems.
DEGREE MATRICES AND ESTIMATES FOR EXPONENTIAL SUMS OF POLYNOMIALS OVER FINITE FIELDS
Authors: CAO WEI
Published: February 2013

Let f be a multivariate polynomial over a finite field and its degree matrix be composed of the degree vectors appearing in f. In this paper, we provide an elementary approach to estimating the exponential sums of the polynomials with positive square degree matrices in terms of the elementary divisors of the degree matrices.
SYMMETRIZERS AND ANTISYMMETRIZERS FOR THE BMW-ALGEBRA
Authors: DIPPER RICHARD , HU JUN , STOLL FRIEDERIKE
Published: February 2013

Let n ∈ ℕ and Bn(r, q) be the generic Birman–Murakami–Wenzl algebra with respect to indeterminants r and q. It is known that Bn(r, q) has two distinct linear representations generated by two central elements of Bn(r, q) called the symmetrizer and antisymmetrizer of Bn(r, q). These generate for n ≥ 3 the only one-dimensional two sided ideals of Bn(r, q) and generalize the corresponding notion for Hecke algebras of type A. The main result, Theorem 3.1, in this paper explicitly determines the coefficients of these elements with respect to the graphical basis of Bn(r, q).
SELF INJECTIVE AMALGAMATED DUPLICATION OF A RING ALONG AN IDEAL
Authors: CHHITI MOHAMED , MAHDOU NAJIB , TAMEKKANTE MOHAMMED
Published: February 2013

In this paper, we give a characterization for the amalgamated duplication of a ring R along an ideal I, denoted by R ⋈ I, to be self-injective.
JOINT COMPLEMENTS AND ISOMORPHISM OF MODULAR ABELIAN GROUP ALGEBRAS
Authors: MAY WARREN
Published: February 2013

For modular abelian group algebras over a perfect field of prime characteristic, a connection is given between the direct factor problem and the isomorphism problem.
FINITENESS DIMENSION AND BASS NUMBERS OF GENERALIZED LOCAL COHOMOLOGY MODULES
Authors: SAREMI HERO , MAFI AMIR
Published: February 2013

Let R be a commutative Noetherian ring, 𝔞 an ideal of R, and M, N two nonzero finitely generated R-modules. Let t be a non-negative integer. It is shown that dim Supp [Formula: see text] for all i < t if and only if there exists an ideal 𝔟 of R such that dim R/𝔟 ≤ 1 and [Formula: see text] for all i < t. As a consequence all Bass numbers and all Betti numbers of generalized local cohomology modules [Formula: see text] are finite for all i < t, provided that the projective dimension pd (M) is finite.
A NEW CHARACTERIZATION OF PGL(2, p)
Authors: ASBOEI ALIREZA KHALILI
Published: February 2013

Let G be a finite group and πe(G) be the set of element orders of G. Let k ∈ πe(G) and mk be the number of elements of order k in G. Set nse (G) ≔ {mk ∣ k ∈ πe(G)}. In this paper, it is proved if G is a group with the following properties, then G ≅ PGL (2, p).

(1) p > 3 is prime divisor of ∣G∣ but p2 does not divide ∣G∣.

(2) nse (G) = nse ( PGL (2, p)).
COOPERATIVITY BETWEEN HYDROGEN BOND AND HALOGEN BOND INHBr⋯BrX⋯HBr (X = F, Cl, Br)
Authors: LIU HEXIU , MAN RUILIN , WANG ZHAOXU , YI PINGGUI , ZENG JIANXIAN
Published: February 2013

An ab initio study has been carried out to investigate the structures, binding energies and atomic charge of the binary complexes HBr⋯BrX and ternary complexes HBr⋯BrX⋯HBr (X = F, Cl, Br) at the MP2/aug-cc-pvdz theoretical level. Four types of interactions are observed among these systems: hydrogen bond, halogen bond, unusual hydrogen bond and unusual halogen bond. Two types of stable structures existed in the trimers: acyclic and monocyclic. The stabilities of the complexes may be decided by three factors: the strength of the halogen bond, the nature of halogen or hydrogen bond of intermolecular interaction and the type of the trimer's structure. The absolute value of the cooperativity contribution in these triads is in range of 0.77 ∼ 21.59%, which shows that the cooperative energy is of importance in them. The nature of the intermolecular interactions has been also investigated through the electrostatic potential and the theory of atoms in molecules (AIM). The values of ∇2ρ at BCPs are positive in all complexes, indicating that the interactions are closed-shell. The ratio |Vc|∕Gcof all complexes ranges from 0.782 to 0.935 (satisfy the condition |Vc|∕Gc< 1) along with Hc> 0, revealing that these complexes are predominantly electrostatic in character.
THEORETICAL INVESTIGATION ON PHOTOISOMERIZATION SWITCHABLE SECOND-ORDER NONLINEAR OPTICAL PROPERTIES OF Λ-SHAPED DIARYLETHENE DERIVATIVES
Authors: DU XIAOFENG , MA NANA , SUN SHILING , XIE HAIMING , QIU YONGQING
Published: February 2013

The nonlinear optical (NLO) properties of Λ-shaped diarylethene (DAE) derivatives 1a(b)–4a(b) and their NLO switching effects were studied by using the density functional theory (DFT) methods. The results demonstrate that all of the open-ring molecules and their own closed-ring forms meet the model of NLO switching tuned by photoisomerization. The βtot values of 1b–3b are 16 times as small as that of their open-ring forms, and βtot value of 4b is 4 times as large as that of 4a. The spin interactions of open-shell closed-ring molecules are larger than that of their open-ring forms, and it could increase the NLO responses to some degree. Nature bond orbital (NBO) calculations indicate that large charge differences between electron-deficient and electron-rich centers are beneficial to charge transfer (CT), and the overlap between frontier molecular orbital (FMO) is also advantageous to the CT and NLO responses. Time-dependent density functional theory (TD-DFT) calculations show βtot values of all molecules meet the two-level model very well, and the smaller the ΔE ge , the larger the βtot value.
HOW SELF-PROLIFERATION OF CD4+T CELLS AFFECT THE HIV DYNAMICS IN AN IN-HOST TARGET-CELL LIMITED HIV MODEL WITH SATURATION INFECTION RATE: A QUASI-STEADY-STATE APPROXIMATION ANALYSIS
Authors: BAIRAGI N. , ADAK D.
Published: February 2013

In this study, we consider two target-cell limited models with saturation type infection rate and intracellular delay: one without self-proliferation and the other with self-proliferation of activated CD4+T cells. We discuss about the local and global behavior of both the systems in presence and absence of intracellular delay. It is shown that the endemic equilibrium of a target-cell limited model would be unstable in presence and absence of intracellular delay only when self-proliferation of activated CD4+T cell is considered. Otherwise, all positive solutions converge to the endemic equilibrium or disease-free equilibrium depending on whether the basic reproduction ratio is greater than or less than unity. Our study suggests that amplitude of oscillation is negatively correlated with the constant input rate of CD4+T cell when intracellular delay is absent or low. However, they are positively correlated if the delay is too high. Amplitude of oscillation, on the other hand, is always positively correlated with the proliferation rate of CD4+T cell for all delay. Our mathematical and simulation analysis also suggest that there are many potential contributors who are responsible for the variation of CD4+T cells and virus particles in the blood plasma of HIV patients.
IMAGE-BASEDIN VIVOQUANTITATIVE ASSESSMENT OF HUMAN AIRWAY OPENING AND CONTRACTILITY BY FIBER OPTICAL NASOPHARYNGOSCOPY IN HEALTHY AND ASTHMATIC SUBJECTS
Authors: DENG LINHONG
Published: February 2013

Assessment of human airway lumen opening is important in diagnosing and understanding the mechanisms of airway dysfunctions such as the excessive airway narrowing in asthma and chronic obstructive pulmonary disease (COPD). Although there are indirect methods to evaluate the airway calibre, direct in vivo measurement of the airway calibre has not been commonly available. With recent advent of the flexible fiber optical nasopharyngoscope with video recording it has become possible to directly visualize the passages of upper and lower airways. However, quantitative analysis of the recorded video images has been technically challenging. Here, we describe an automatic image processing and analysis method that allows for batch analysis of the images recorded during the endoscopic procedure, thus facilitates image-based quantification of the airway opening. Video images of the airway lumen of volunteer subject were acquired using a fiber optical nasopharyngoscope, and subsequently processed using Gaussian smoothing filter, threshold segmentation, differentiation, and Canny image edge detection, respectively. Thus the area of the open airway lumen was identified and computed using a predetermined converter of the image scale to true dimension of the imaged object. With this method we measured the opening/narrowing of the glottis during tidal breathing with or without making "Hee" sound or cough. We also used this method to measure the opening/narrowing of the primary bronchus of either healthy or asthmatic subjects in response to histamine and/or albuterol treatment, which also provided an indicator of the airway contractility. Our results demonstrate that the image-based method accurately quantified the area change waveform of either the glottis or the bronchus as observed by using the optical nasopharygoscope. Importantly, the opening/narrowing of the airway lumen generally correlated with the airflow and resistance of the airways, and could differentiate the level of airway contractility between the healthy and asthmatic subjects. Thus, this quantitative assessment of airway opening may provide a useful tool to assist clinical diagnosis of airway dysfunctions and understanding the mechanisms of associated pathophysiologies.
NUMERICAL SIMULATION AND PARAMETRIC STUDIES FOR EVALUATION OF BALANCED VENTILATION AND EARTH AIR EXCHANGERS SYSTEM COUPLED TO A DOMESTIC BUILDING
Authors: KARTACHI YOUNES , MECHAQRANE ABDELLAH
Published: February 2013

In this study, we analyze the impact of ventilation heat recovery with the heating and cooling potential of earth air heat exchanger in real climatic conditions in domestic buildings in the Middle Atlas region. In our case study, we calculate the primary energy used by a domestic building built as per the conventional house design parameters required by the Moroccan regulation. We use climate data for the city of Fes in Northern Moroccan.

Three system configurations were considered. The first was the mechanical extract ventilation system both with and without heat recovery. The second was the mechanical extract ventilation system with earth to air heat exchanger system (EAHEX), and the third system was the mechanical balanced ventilation system coupled with EAHEX system.

Primary energy use strongly influences natural resources efficiency and the environmental impacts of energy supply activities. In this study we explore the primary energy implications of the mechanical balanced ventilation system coupled with the EAHEX system in residential buildings.

The results of this study shows that the use of a balanced ventilation system, with a high efficiency instead of a mechanical extract ventilation system, decreases the final and primary energy consumption. Moreover, it decreases or increases the CO2 emission depending on the primary energy sources.
OVERALL HEAT TRANSFER COEFFICIENT OF R407C/HC290/HC600a REFRIGERANT MIXTURE FLOWING THROUGH A FIN-AND-TUBE EVAPORATOR
Authors: RAJ MARIA HERBERT , LAL DHASAN MOHAN , KUMAR SURESH PREMIL
Published: February 2013

R22 has been used as a refrigerant in residential air-conditioners and heat pumps for many decades. Even as the Montreal protocol set the phasing out of R22 due to its ODP, many alternatives to R22 are found in published literature. The M20 refrigerant mixture is one such alternative with specific advantages. This paper presents the heat transfer characteristics of the M20 refrigerant mixture, flowing through a fin-and-tube evaporator, experimentally studied in an appliance tested in a psychrometric test facility. The experimental setup consisted of a window air-conditioner fixed in a psychrometric room with instruments to measure the temperatures/pressures of the refrigerant and mass flow rate of the refrigerant as well as air. The experiment was carried out in accordance with the Bureau of Indian Standards (BIS) and American Society of Heating Refrigerating Air-Conditioning Engineers (ASHRAE) test conditions. M20 being considered as an alternative for R22, the overall heat transfer coefficient of the M20 refrigerant mixture has been evaluated, and compared with that of R22. It can be observed that the heat transfer coefficient of R22 is better than that of the M20 refrigerant mixture, for the prevailing flow conditions in the evaporator. The reduction in the overall heat transfer coefficient of the M20 refrigerant mixture as compared to R22, ranges from 7.3% to 20.7%.
Characterization of dense zones within the Danian chalks of the Ekofisk Field, Norwegian North Sea
Authors: Gennaro M. , Wonham J.P. , Sælen G. , Walgenwitz F. , Caline B. , Faÿ-Gomord O.
Published: February 2013

The Ekofisk Field is a giant field which has been producing at a high level for more than forty years and, since 1987, this production has taken place with the support of sea-water injection. The Danian-aged chalk deposits of the Ekofisk Formation and the Maastrichtian Tor Formation form the main reservoir units in the Ekofisk Field. The Ekofisk Formation principally consists of porous resedimented chalks intercalated with relatively thin and lower porosity beds, called dense zones. A multi-scale study of dense zones, from scanning electron microscopy to wells and seismic impedance data, has allowed the characterization and mapping of these deposits. Five main dense zone lithotypes have been identified: (1) argillaceous chalk; (2) chalk with abundant flint nodules; (3) chalk beds cemented with silica/nano-quartz; (4) calcite-cemented chalk; and (5) stylolitized chalk. The different types of dense zones tend to cluster in certain stratigraphic intervals, such as the EE and EM reservoir units at the base and in the middle part of the Ekofisk Formation. Dense zones have different mechanical properties compared to porous chalks and, depending on the connectivity of their fracture networks, they can act as preferential conduits or baffles for the reservoir fluids. An increased understanding of the distribution, characteristics and geological factors at the origin of the dense zones is fundamental to better define the reservoir architecture and ultimately identify unswept zones for future infill drilling targets.

Supplementary material

Descriptions of analytical procedures, composition, poro-perm and well log values of dense zone samples is available at:
www.geolsoc.org.uk/SUP18573
.
The Meaning of Stromatolites
Authors: Bosak Tanja , Knoll Andrew H. , Petroff Alexander P.
Published: February 2013

Stromatolites document microbial interactions with sediments and flowing water throughout recorded Earth history and have the potential to illuminate the long-term history of life and environments. Modern stromatolites, however, provide analogs to only a small subset of the structures preserved in Archean and Proterozoic carbonates. Thus, interpretations of secular trends in the shapes and textures of ancient columnar stromatolites require nonuniformitarian, scale-dependent models of microbial responses to nutrient availability, seawater chemistry, influx of sediment grains, shear, and burial. Models that integrate stromatolite scales, macroscopic organization, and shapes could also help test the biogenicity of the oldest stromatolites and other structures whose petrographic fabrics do not preserve direct evidence of microbial activity. An improved understanding of stromatolite morphogenesis in the presence of oxygenic and anoxygenic microbial mats may illuminate the diversity of microbial metabolisms that contributed to stromatolite growth in early oceans.
Intestinal adaptation and Reg gene expression induced by antidiabetic duodenal-jejunal bypass surgery in Zucker fatty rats
Authors: Li Bing , Lu Yarong , Srikant Coimbatore B. , Gao Zu-Hua , Liu Jun-Li
Published: February 2013

The antidiabetic mechanism of bariatric surgery includes specific changes in the secretion of incretins. To identify additional players originating from the gut, we evaluated the effects of duodenal-jejunal bypass (DJB) in morbidly obese Zucker fatty rats. A fast relief of hyperglycemia and hyperinsulinemia was achieved even before a significant weight loss occurred. Fourteen days after DJB, we characterized the changes in intestinal histochemistry in the bypassed duodenum and shortcut jejunum that was reanastomosed directly to the starting point of the duodenum and compared with the corresponding regions of sham-operated rats. The bypassed duodenum exhibited mucosal atrophy and apoptosis and decreased proliferative renewal. In shortcut jejunum, DJB resulted in 40% significantly enlarged intestinal circumference and increased epithelial proliferation, especially in putative transit-amplifying (TA) cells and the crypt. Because Reg family proteins promote cell growth and survival, we explored their expression in the intestine. With the use of immunohistochemistry, Reg1, -3α, and -3β were normally expressed in intestinal mucosa. After DJB, the level of Reg1 protein was reduced, whereas Reg3α and -3β were not changed in bypassed duodenum. Downstream in shortcut jejunum, the levels of Reg1 and -3β were greatly induced and especially concentrated in the putative TA cells. Our results revealed significant changes in the integrity and proliferation of the intestinal mucosa as a consequence of DJB, and in cell- and isoform-specific expression of Reg proteins within the replicating mucosal epithelium, and provide evidence indicating that the activation of Reg proteins may contribute to intestinal compensation against increased load and/or to improving insulin sensitivity.
Prostaglandin E2 mediates acid-induced heartburn in healthy volunteers
Authors: Kondo Takashi , Oshima Tadayuki , Tomita Toshihiko , Fukui Hirokazu , Watari Jiro , Okada Hiroki , Kikuchi Shojiro , Sasako Mitsuru , Matsumoto Takayuki , Knowles Charles H. , Miwa Hiroto
Published: February 2013

Prostaglandin E2 (PGE2) plays a major role in pain processing and hypersensitivity. This study investigated whether PGE2 levels are increased in the esophageal mucosa after acid infusion and whether increases in PGE2 are associated with heartburn. Furthermore, expression of the PGE2 receptor EP1 was investigated in human esophageal mucosa. Fourteen healthy male volunteers were randomized to 30-min lower esophageal acid (1% HCl) or saline perfusion. Before and after acid perfusion, endoscopic biopsies were taken from the distal esophagus. PGE2 concentration (pg/mg protein) and EP1 mRNA and protein in biopsy samples were measured by ELISA, RT-PCR, and Western blotting. Symptom status of heartburn was evaluated with a validated categorical rating scale with a higher values corresponding to increasing intensity. PGE2 levels in the esophageal mucosa significantly increased after acid infusion (before vs. after acid infusion: 23.2 ± 8.6 vs. 68.6 ± 18.3, P < 0.05), but not after saline infusion (before vs. after saline infusion: 9.3 ± 2.5 vs. 9.0 ± 3.2, NS). Time to first sensation (min) after acid infusion was less than after saline (saline vs. acid infusion: 22.1 ± 4.1 vs. 5.4 ± 1.5, P < 0.05). Intensity of heartburn in the acid-infusion group was also significantly greater compared with saline (saline vs. acid infusion: 54.3 ± 13.1 vs. 178.5 ± 22.8, P < 0.01). Changes in PGE2 levels in the esophagus correlated with symptom intensity score ( r = 0.80, P = 0.029). EP1 mRNA and protein expression were observed in the normal human esophageal mucosa. Esophageal PGE2 expression is associated with mucosal acid exposure and heartburn.
Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs
Authors: Xie Chaoqin , Biary Nora , Tocchetti Carlo G. , Aon Miguel A. , Paolocci Nazareno , Kauffman Justin , Akar Fadi G.
Published: February 2013

Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated ( P = 0.004) and STZ + Ins ( P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ ( P = 0.045) and STZ + Ins ( P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity ( P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.
The second member of transient receptor potential-melastatin channel family protects hearts from ischemia-reperfusion injury
Authors: Miller Barbara A. , Wang JuFang , Hirschler-Laszkiewicz Iwona , Gao Erhe , Song Jianliang , Zhang Xue-Qian , Koch Walter J. , Madesh Muniswamy , Mallilankaraman Karthik , Gu Tongda , Chen Shu-jen , Keefer Kerry , Conrad Kathleen , Feldman Arthur M. , Cheung Joseph Y.
Published: February 2013

The second member of the transient receptor potential-melastatin channel family (TRPM2) is expressed in the heart and vasculature. TRPM2 channels were expressed in the sarcolemma and transverse tubules of adult left ventricular (LV) myocytes. Cardiac TRPM2 channels were functional since activation with H2O2 resulted in Ca2+ influx that was dependent on extracellular Ca2+, was significantly higher in wild-type (WT) myocytes compared with TRPM2 knockout (KO) myocytes, and inhibited by clotrimazole in WT myocytes. At rest, there were no differences in LV mass, heart rate, fractional shortening, and +dP/d t between WT and KO hearts. At 2–3 days after ischemia-reperfusion (I/R), despite similar areas at risk and infarct sizes, KO hearts had lower fractional shortening and +dP/d t compared with WT hearts. Compared with WT I/R myocytes, expression of the Na+/Ca2+ exchanger (NCX1) and NCX1 current were increased, expression of the α1-subunit of Na+-K+-ATPase and Na+ pump current were decreased, and action potential duration was prolonged in KO I/R myocytes. Post-I/R, intracellular Ca2+ concentration transients and contraction amplitudes were equally depressed in WT and KO myocytes. After 2 h of hypoxia followed by 30 min of reoxygenation, levels of ROS were significantly higher in KO compared with WT LV myocytes. Compared with WT I/R hearts, oxygen radical scavenging enzymes (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factor) were lower, whereas NADPH oxidase was higher, in KO I/R hearts. We conclude that TRPM2 channels protected hearts from I/R injury by decreasing generation and enhancing scavenging of ROS, thereby reducing I/R-induced oxidative stress.
Distribution of venous remodeling in exercise-induced pulmonary hemorrhage of horses follows reported blood flow distribution in the equine lung
Authors: Williams Kurt J. , Robinson N. Edward , DeFeijter-Rupp Heather , Millerick-May Melissa , Stack Alice , Hauptman Joseph , Derksen Frederik J.
Published: February 2013

Exercise-induced pulmonary hemorrhage (EIPH), which has been reported in humans and a variety of domestic animals following strenuous exercise, is most often documented in racehorses. Remodeling of pulmonary veins (VR) in equine EIPH was recently described, suggesting that it contributes to the pathogenesis of the disease. The cause of VR is unknown. We tested the hypothesis that the development of VR follows pulmonary blood flow distribution, preferentially occurring in the caudodorsal lung region. Furthermore, we hypothesized that VR underpins development of the other lesions of EIPH pathology. The lungs of 10 EIPH-affected horses and 8 controls were randomly sampled for histopathology (2,520 samples) and blindly scored for presence and severity of VR, hemosiderin (H), and interstitial fibrosis (IF). Mean sample score (MSS), mean lesion score, and percent samples with lesions were determined in four dorsal and three ventral lung regions, and the frequency, spatial distribution, and severity of lesions were determined. MSS for VR and H were significantly greater dorsally than ventrally ( P < 0.001) and also decreased significantly in the caudocranial direction ( P < 0.001). IF decreased only in the caudocranial direction. The percent samples with lesions followed the same distribution as MSS. VR often was accompanied by H; IF never occurred without VR and H. Similarity of the distribution of EIPH lesions and the reported fractal distribution of pulmonary blood flow suggests that VR develops in regions of high blood flow. Further experiments are necessary to determine whether VR is central to the pathogenesis of EIPH.
Interindividual relationships between blood pressure and cerebral blood flow variability with intact and blunted cerebrovascular control
Authors: Tzeng Yu-Chieh , MacRae Braid A.
Published: February 2013

The relationships between blood pressure variability (BPV) and cerebral blood flow variability (CFV) across individuals in the presence of intact and blunted cerebrovascular control are poorly understood. This study sought to characterize the interindividual associations between spontaneous BPV and CFV under conditions of normal and blunted [calcium channel blockade (CCB)] cerebrovascular control in healthy humans. We analyzed blood pressure and flow velocity data from 12 subjects treated with CCB (60 mg oral nimodipine) and 11 subjects treated with a placebo pill. Spontaneously occurring fluctuations in mean arterial blood pressure (MAP) and middle cerebral artery flow velocity (MCAvmean; transcranial Doppler) were characterized using power spectral and transfer function analysis in the very-low- (0.02–0.07 Hz), low- (0.07–0.20 Hz), and high-frequency (0.20–0.40 Hz) ranges. Across our study sample, MAP and MCAvmeanpower were positively correlated in all three frequency ranges, both before ( R2= 0.34–0.67, all P < 0.01) and after CCB ( R2= 0.53–0.61, all P < 0.02). Compared with placebo, CCB reduced very-low-frequency MAP ( P < 0.05) and MCAvmeanpower ( P < 0.01) and the low-frequency cross-spectral phase angle ( P < 0.05). The magnitude of change in MAP and MCAvmeanpower with CCB (i.e., change scores) was positively related in the very-low-frequency range. Collectively, these findings indicate that CFV may be an explanatory factor in the association between elevated BPV and adverse cerebrovascular outcomes and support the possibility of using CCB to improve hemodynamic stability under resting conditions.
The relationship between brain cortical activity and brain oxygenation in the prefrontal cortex during hypergravity exposure
Authors: Smith Craig , Goswami Nandu , Robinson Ryan , von der Wiesche Melanie , Schneider Stefan
Published: February 2013

Artificial gravity has been proposed as a method to counteract the physiological deconditioning of long-duration spaceflight; however, the effects of hypergravity on the central nervous system has had little study. The study aims to investigate whether there is a relationship between prefrontal cortex brain activity and prefrontal cortex oxygenation during exposure to hypergravity. Twelve healthy participants were selected to undergo hypergravity exposure aboard a short-arm human centrifuge. Participants were exposed to hypergravity in the +Gz axis, starting from 0.6 +Gz for women, and 0.8 +Gz for men, and gradually increasing by 0.1 +Gz until the participant showed signs of syncope. Brain cortical activity was measured using electroencephalography (EEG) and localized to the prefrontal cortex using standard low-resolution brain electromagnetic tomography (LORETA). Prefrontal cortex oxygenation was measured using near-infrared spectroscopy (NIRS). A significant increase in prefrontal cortex activity ( P < 0.05) was observed during hypergravity exposure compared with baseline. Prefrontal cortex oxygenation was significantly decreased during hypergravity exposure, with a decrease in oxyhemoglobin levels ( P < 0.05) compared with baseline and an increase in deoxyhemoglobin levels ( P < 0.05) with increasing +Gz level. No significant correlation was found between prefrontal cortex activity and oxy-/deoxyhemoglobin. It is concluded that the increase in prefrontal cortex activity observed during hypergravity was most likely not the result of increased +Gz values resulting in a decreased oxygenation produced through hypergravity exposure. No significant relationship between prefrontal cortex activity and oxygenation measured by NIRS concludes that brain activity during exposure to hypergravity may be difficult to measure using NIRS. Instead, the increase in prefrontal cortex activity might be attributable to psychological stress, which could pose a problem for the use of a short-arm human centrifuge as a countermeasure.
Clinical Spectrum of Oral Secondary Syphilis in HIV-Infected Patients
Authors: Ramírez-Amador Velia , Anaya-Saavedra Gabriela , Crabtree-Ramírez Brenda , Esquivel-Pedraza Lilly , Saeb-Lima Marcela , Sierra-Madero Juan
Published: February 2013

Background. Oral lesions may constitute the first clinical manifestation in secondary syphilis, but detailed descriptions in HIV-infected individuals are scarce.Objective. To describe the clinical characteristics of oral secondary syphilis in HIV-infected patients and its relevance in the early diagnosis of syphilis.Methods. Twenty HIV/AIDS adult subjects with oral secondary syphilis lesions presenting at two HIV/AIDS referral centers in Mexico City (2003–2011) are described. An oral examination was performed by specialists in oral pathology and medicine; when possible, a punch biopsy was done, and Warthin-Starry stain and immunohistochemistry were completed. Intraoral herpes virus infection and erythematous candidosis were ruled out by cytological analysis. Diagnosis of oral syphilis was confirmed with positive nontreponemal test (VDRL), and, if possible, fluorescent treponemal antibody test.Results. Twenty male patients (median age 31.5, 21–59 years) with oral secondary syphilis lesions were included. Oral lesions were the first clinical sign of syphilis in 16 (80%) cases. Mucous patch was the most common oral manifestation (17, 85.5%), followed by shallow ulcers (2, 10%) and macular lesions (1, 5%).Conclusions. Due to the recent rise in HIV-syphilis coinfection, dental and medical practitioners should consider secondary syphilis in the differential diagnosis of oral lesions, particularly in HIV-infected patients.
AMPK Activation by Oncogenesis Is Required to Maintain Cancer Cell Proliferation in Astrocytic Tumors
Authors: Ríos Marcos , Foretz Marc , Viollet Benoit , Prieto Angel , Fraga Máximo , Costoya Jose A. , Señarís Rosa
Published: February 2013

5′-AMP-activated protein kinase (AMPK) is an energy sensor that controls cell metabolism, and it has been related to apoptosis and cell-cycle arrest. Although its role in metabolic homeostasis is well documented, its function in cancer is much less clear. In this study, we examined the role of AMPK in a mouse model of astrocytoma driven by oncogenic H-RasV12 and/or with PTEN deletion based on the common constitutive activation of the Raf/MEK/ERK and PI3K/AKT cascades in human astrocytomas. We also evaluated the activity and role of AMPK in human glioblastoma cells and xenografts. AMPK was constitutively activated in astrocytes expressing oncogenic H-RasV12 in parallel with high cell division rates. Genetic deletion of AMPK or attenuation of its activity in these cells was sufficient to reduce cell proliferation. The levels of pAMK were always related to the levels of phosphorylated retinoblastoma (Rb) at Ser804, which may indicate an AMPK-mediated phosphorylation of Rb. We confirmed this AMPK–Rb relationship in human glioblastoma cell lines and xenografts. In clinical specimens of human glioblastoma, elevated levels of activated AMPK appeared especially in areas of high proliferation surrounding the blood vessels. Together, our findings indicate that the initiation and progression of astrocytic tumors relies upon AMPK-dependent control of the cell cycle, thereby identifying AMPK as a candidate therapeutic target in this setting. Cancer Res; 73(8); 2628–38. ©2013 AACR.
Oncogenic Activation of Pak1-Dependent Pathway of Macropinocytosis Determines BCG Entry into Bladder Cancer Cells
Authors: Redelman-Sidi Gil , Iyer Gopa , Solit David B. , Glickman Michael S.
Published: February 2013

Bacille Calmette-Guerin (BCG) is an attenuated strain of Mycobacterium bovis that is used widely as a vaccine for tuberculosis and is used as an effective treatment for superficial bladder carcinoma. Despite being the most successful cancer biotherapy, its mechanism of action and response determinants remain obscure. Here, we establish a model system to analyze BCG interaction with bladder cancer cells, using it to show that these cells vary dramatically in their susceptibility to BCG infection. Unexpectedly, the uptake of BCG by bladder cancer cells occurs by macropinocytosis rather than phagocytosis. BCG entry into bladder cancer cells relied upon Rac1, Cdc42, and their effector kinase Pak1. The difference in susceptibility between BCG-permissive and -resistant bladder cancer cells was due to oncogenic activation of signaling pathways that activate macropinocytosis, with phosphoinositide 3-kinase inhibitor activation stimulating BCG uptake independently of Akt. Similarly, activated Ras strongly activated Pak1-dependent uptake of BCG. These results reveal that oncogenic activation of macropinocytosis determines BCG uptake by bladder cancer cells, implying that tumor responsiveness to BCG may be governed by the specific mutations present in the treated cancer cell. Cancer Res; 73(3); 1156–67. ©2013 AACR.
HDAC6 Inhibition Restores Ciliary Expression and Decreases Tumor Growth
Authors: Gradilone Sergio A. , Radtke Brynn N. , Bogert Pamela S. , Huang Bing Q. , Gajdos Gabriella B. , LaRusso Nicholas F.
Published: February 2013

Primary cilia are multisensory organelles recently found to be absent in some tumor cells, but the mechanisms of deciliation and the role of cilia in tumor biology remain unclear. Cholangiocytes, the epithelial cells lining the biliary tree, normally express primary cilia and their interaction with bile components regulates multiple processes, including proliferation and transport. Using cholangiocarcinoma as a model, we found that primary cilia are reduced in cholangiocarcinoma by a mechanism involving histone deacetylase 6 (HDAC6). The experimental deciliation of normal cholangiocyte cells increased the proliferation rate and induced anchorage-independent growth. Furthermore, deciliation induced the activation of mitogen-activated protein kinase and Hedgehog signaling, two important pathways involved in cholangiocarcinoma development. We found that HDAC6 is overexpressed in cholangiocarcinoma and overexpression of HDAC6 in normal cholangiocytes induced deciliation and increased both proliferation and anchorage-independent growth. To evaluate the effect of cilia restoration on tumor cells, we targeted HDAC6 by short hairpin RNA (shRNA) or by the pharmacologic inhibitor, tubastatin-A. Both approaches restored the expression of primary cilia in cholangiocarcinoma cell lines and decreased cell proliferation and anchorage-independent growth. The effects of tubastatin-A were abolished when cholangiocarcinoma cells were rendered unable to regenerate cilia by stable transfection of IFT88-shRNA. Finally, inhibition of HDAC6 by tubastatin-A also induced a significant decrease in tumor growth in a cholangiocarcinoma animal model. Our data support a key role for primary cilia in malignant transformation, provide a plausible mechanism for their involvement, and suggest that restoration of primary cilia in tumor cells by HDAC6 targeting may be a potential therapeutic approach for cholangiocarcinoma. Cancer Res; 73(7); 2259–70. ©2013 AACR.
Aire Deficiency Promotes TRP-1–Specific Immune Rejection of Melanoma
Authors: Zhu Meng-Lei , Nagavalli Anil , Su Maureen A.
Published: February 2013

The thymic transcription factor autoimmune regulator (Aire) prevents autoimmunity in part by promoting expression of tissue-specific self-antigens, which include many cancer antigens. For example, AIRE-deficient patients are predisposed to vitiligo, an autoimmune disease of melanocytes that is often triggered by efficacious immunotherapies against melanoma. Therefore, we hypothesized that Aire deficiency in mice may elevate immune responses to cancer and provide insights into how such responses might be triggered. In this study, we show that Aire deficiency decreases thymic expression of TRP-1 (TYRP1), which is a self-antigen in melanocytes and a cancer antigen in melanomas. Aire deficiency resulted in defective negative selection of TRP-1–specific T cells without affecting thymic numbers of regulatory T cells. Aire-deficient mice displayed elevated T-cell immune responses that were associated with suppression of melanoma outgrowth. Furthermore, transplantation of Aire-deficient thymic stroma was sufficient to confer more effective immune rejection of melanoma in an otherwise Aire wild-type host. Together, our work showed how Aire deficiency can enhance immune responses against melanoma and how manipulating TRP-1–specific T-cell negative selection may offer a logical strategy to enhance immune rejection of melanoma. Cancer Res; 73(7); 2104–16. ©2013 AACR.
The Ability of Plasma Cotinine to Predict Nicotine and Carcinogen Exposure is Altered by Differences in CYP2A6: the Influence of Genetics, Race, and Sex
Authors: Zhu Andy Z.X. , Renner Caroline C. , Hatsukami Dorothy K. , Swan Gary E. , Lerman Caryn , Benowitz Neal L. , Tyndale Rachel F.
Published: February 2013

Background: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure.

Methods: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163).

Results: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males.

Conclusions: In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure.

Impact: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes. Cancer Epidemiol Biomarkers Prev; 22(4); 708–18. ©2013 AACR.
Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts
Authors: Pratt Susan E. , Durland–Busbice Sara , Shepard Robert L. , Donoho Gregory P. , Starling James J. , Wickremsinhe Enaksha R. , Perkins Everett J. , Dantzig Anne H.
Published: February 2013

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non–small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P ≤ 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response. Mol Cancer Ther; 12(4); 481–90. ©2013 AACR.
The HSP70 and Autophagy Inhibitor Pifithrin-μ Enhances the Antitumor Effects of TRAIL on Human Pancreatic Cancer
Authors: Monma Hiroyuki , Harashima Nanae , Inao Touko , Okano Shinji , Tajima Yoshitsugu , Harada Mamoru
Published: February 2013

TRAIL and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin (PFT)-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability, and increasing apoptosis. On the basis of these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with PFT-μ. The combination of TRAIL plus PFT-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared with cells treated with either agent alone. When applied alone, PFT-μ increased Annexin V+ cells in both caspase-dependent and -independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, PFT-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared with treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that PFT-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL. Mol Cancer Ther; 12(4); 341–51. ©2013 AACR.