bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapamycin-Resistant mTORC1 Kinase Activity Is Required for Herpesvirus Replication
Authors: Moorman Nathaniel J. , Shenk Thomas
Published: February 2010

Human cytomegalovirus (HCMV) infection has been shown to activate the mTORC1 signaling pathway. However, the phosphorylation of mTORC1 targets is differentially sensitive to the mTORC1 inhibitor rapamycin, and the drug inhibits HCMV replication to a modest extent. Using Torin1, a newly developed inhibitor that targets the catalytic site of mTOR kinase, we show that HCMV replication requires both rapamycin-sensitive and rapamycin-resistant mTOR activity. The treatment of infected cells with Torin1 inhibits the phosphorylation of rapamycin-sensitive and rapamycin-resistant mTOR targets and markedly blocks the production of virus progeny. The blockade of mTOR signaling with Torin1, but not rapamycin, disrupts the assembly of the eIF4F complex and increases the association of the translational repressor 4EBP1 to the 7-methylguanosine cap-binding complex. Torin1 does not affect HCMV entry and only modestly reduces the accumulation of the immediate-early and early viral proteins that were tested despite the disruption of the eIF4F complex. In contrast, Torin1 significantly decreases the accumulation of viral DNA and the pUL99 viral late protein. Similar mTOR signaling events were observed during murine cytomegalovirus (MCMV) infection, and we utilized murine fibroblasts containing several different mutations to dissect the mechanism by which Torin1 inhibits MCMV replication. This approach demonstrated that mTORC2 and the Akt1 and Akt2 kinases are not required for the Torin1-mediated inhibition of cytomegalovirus replication. The inhibition of MCMV replication by Torin1 was rescued in cells lacking 4EBP1, demonstrating that the inactivation of 4EBP1 by mTORC1 is critical for cytomegalovirus replication. Finally, we show that Torin1 inhibits the replication of representative members of the alpha-, beta-, and gammaherpesvirus families, demonstrating the potential of mTOR kinase inhibitors as broad-spectrum antiviral agents.
Pathogenesis of Pandemic Influenza A (H1N1) and Triple-Reassortant Swine Influenza A (H1) Viruses in Mice
Authors: Belser Jessica A. , Wadford Debra A. , Pappas Claudia , Gustin Kortney M. , Maines Taronna R. , Pearce Melissa B. , Zeng Hui , Swayne David E. , Pantin-Jackwood Mary , Katz Jacqueline M. , Tumpey Terrence M.
Published: February 2010

The pandemic H1N1 virus of 2009 (2009 H1N1) continues to cause illness worldwide, primarily in younger age groups. To better understand the pathogenesis of these viruses in mammals, we used a mouse model to evaluate the relative virulence of selected 2009 H1N1 viruses and compared them to a representative human triple-reassortant swine influenza virus that has circulated in pigs in the United States for over a decade preceding the current pandemic. Additional comparisons were made with the reconstructed 1918 virus, a 1976 H1N1 swine influenza virus, and a highly pathogenic H5N1 virus. Mice were inoculated intranasally with each virus and monitored for morbidity, mortality, viral replication, hemostatic parameters, cytokine production, and lung histology. All 2009 H1N1 viruses replicated efficiently in the lungs of mice and possessed a high degree of infectivity but did not cause lethal disease or exhibit extrapulmonary virus spread. Transient weight loss, lymphopenia, and proinflammatory cytokine and chemokine production were present following 2009 H1N1 virus infection, but these levels were generally muted compared with a triple-reassortant swine virus and the 1918 virus. 2009 H1N1 viruses isolated from fatal cases did not demonstrate enhanced virulence in this model compared with isolates from mild human cases. Histologically, infection with the 2009 viruses resulted in lesions in the lung varying from mild to moderate bronchiolitis with occasional necrosis of bronchiolar epithelium and mild to moderate peribronchiolar alveolitis. Taken together, these studies demonstrate that the 2009 H1N1 viruses exhibited mild to moderate virulence in mice compared with highly pathogenic viruses.
Anti-thrombotic medications for the neurointerventionist: aspirin and clopidogrel
Authors: Fiorella David
Published: February 2010

The majority of neurological complications encountered during neuroendovascular procedures are a result of thromboembolic phenomena. This has become increasingly evident as techniques have evolved to incorporate an ever-growing volume of temporary and permanently implanted adjunctive devices. By optimizing our anti-thrombotic management strategies we can potentially improve procedural safety.

The appropriate selection of anti-thrombotic regimens for neurointerventional procedures poses a unique set of challenges when compared with endovascular interventions in other vascular territories. Neurological procedures frequently target lesions that have hemorrhaged or have a lethal hemorrhagic potential—thus requiring that the operator maintain a tenuous balance between bleeding and thrombosis. Neurological end-organs are unforgiving, even of small emboli, further magnifying the implications of inadequate therapy. The spectrum of disease processes encountered within the context of routine clinical practice is very heterogeneous and each lesion requires a specific anti-thrombotic strategy. The diseases treated (eg, aneurysms, AVM, acute ischemic stroke, chronic atherosclerotic stenosis) are relatively uncommon in comparison with coronary or peripheral atherosclerotic disease. The field of neurointervention itself is still relatively new and continues to evolve rapidly, with innovation frequently outpacing clinical evidence. Predictably, within this environment, there are no large, controlled trials to guide anti-thrombotic management in most cases. For these reasons, medical decision making is based largely upon an understanding of the pharmacology of the agents used and an extrapolation of the literature from other fields.

In this review we discuss aspirin and clopidogrel, the two anti-platelet agents commonly used in conjunction with endovascular stents and stent-like devices. We will discuss their pharmacology and applications in neuroendovascular therapeutics with a focus on practical solutions to dilemmas that are encountered during the course of daily clinical practice.
A NOTE ON THE HAWKING RADIATION CALCULATED BY THE QUASICLASSICAL TUNNELING METHOD
Authors: HU YA-PENG , ZHANG JING-YI , ZHAO ZHENG
Published: February 2010

Since Parikh and Wilczek's tunneling method was proposed, there have been many generalizations, such as its application to massive charged particles' tunneling and other spacetimes. Moreover, an invariant tunneling method was also recently proposed by Angheben et al. that it was independent of coordinates. However, there are some subtleties in the calculation of Hawking radiation, and particularly the so-called factor of 2 problem during the calculation of the Hawking temperature. The most popular opinion on this problem is that it is just a problem of the choice of coordinates. However, following other treatments we show that we can also consider this problem to be that we do not consider the contribution from P(absorption). Moreover, we also clarify some subtleties in the balance method and give some comparisons with other treatments. In addition, as Parikh and Wilczek's original works have showed that if one takes the tunneling particles' back-reaction into account, the Hawking radiation would be modified, and this modification is underlying consistent with the unitary theory, we further find that this modification is also underlying correlated with the laws of black hole thermodynamics. Furthermore, we show that this tunneling method may be valid just when the tunneling process is reversible.
QUANTUM INTERFERENCE EFFECTS IN SPACETIME OF SLOWLY ROTATING COMPACT OBJECTS IN BRANEWORLD
Authors: MAMADJANOV A. I. , HAKIMOV A. A. , TOJIEV S. R.
Published: February 2010

The relativistic quantum interference effects in the spacetime of slowly rotating object in braneworld as the Sagnac effect and phase shift effect of interfering particle in neutron interferometer are derived in unified way. It is found that in the case of the Sagnac effect, the influence of brane parameter is becoming important due to the fact that the angular velocity of the locally non-rotating observer is increased by the brane tension. In the case of neutron interferometry, it is found that an additional term in the phase shift of interfering particle emerges due to the presence of the brane parameter Q*. From the obtained expressions of phase shift in Mach–Zehnder interferometer upper limit for brane parameter has been estimated. From the results of the recent experiments we have obtained upper limit for the tidal charge as Q* ≲ 107 cm 2. Finally, as an example, we apply the obtained results to the calculation of the (ultra-cold neutrons) energy level modification in the gravitational field of slowly rotating gravitating object in the braneworld.
A KIND OF SOAP FILM PROBLEM
Authors: YANG JI-QING , ZHOU XIAO-HUA , HE LI-QING , LI XUE-QI , QU XUE-MIN , LIU JUAN
Published: February 2010

We numerically discuss a kind of minimal surface problem with fixed boundary by the software Surface Evolver. Compared with the analytic result of catenoid, it indicates that there is an obvious range for the existence of this kind of minimal surface.
SLOW ACOUSTIC WAVES WITH THE ANTI-PLANE POLARIZATION IN LAYERED SYSTEMS
Authors: ZAKHARENKO A. A.
Published: February 2010

This paper theoretically investigates the three-partial slow surface Zakharenko-type waves (SSZTW3) with the anti-plane polarization possessing single mode and propagating in layer-on-substrate systems. The dispersive SSZTW3 can exist with the conditions on both the shear elastic constants [Formula: see text] and the bulk shear wave velocities [Formula: see text], where the superscripts L and S belong to the layer and substrate, respectively. The SSZTW3 mode starts with zero-phase velocity and approaches the maximum velocity [Formula: see text] for infinite layer thicknesses. The SSZTW3 phase and group velocities were calculated for many layered structures with Vtm < 1000 m/s , for example, for Au/Paratellurite structure, where the Paratellurite is a common acousto-optic crystal. The velocities' first and higher derivatives were also obtained in order to better understand their behavior for different applications in SAW filters and sensors. The calculations of derivatives were carried out for the Au/Ftorapatite structure with the smallest value of Vtm ~ 210 m/s that is lower than any known acoustic wave velocity in tough materials. It is thought that SSZTW3 usage in MEMS-(CMUTs) technical devices can simplify technological processes. The effective masses were also calculated for different layered structures in the limit of zero-phase velocity Vph, where the dispersion relations correspond to those for free quasi-particles in a vacuum. It was found that the masses are smaller than the mass of a free electron. Hence, it is expected that the SSZTW3 appearance with Vph → 0 can be caused by electrons.
ON AMINO ACID AND CODON ASSIGNMENT IN ALGEBRAIC MODELS FOR THE GENETIC CODE
Authors: ANTONELI FERNANDO , FORGER MICHAEL , GAVIRIA PAOLA A. , HORNOS JOSÉ EDUARDO M.
Published: February 2010

We give a list of all possible schemes for performing amino acid and codon assignments in algebraic models for the genetic code, which are consistent with a few simple symmetry principles, in accordance with the spirit of the algebraic approach to the evolution of the genetic code proposed by Hornos and Hornos. Our results are complete in the sense of covering all the algebraic models that arise within this approach, whether based on Lie groups/Lie algebras, on Lie superalgebras or on finite groups.
MAGNETIC COUPLING IN PSEUDOMORPHIC 2ML OVERLAYERS AND SANDWICH SUPERLATTICE STRUCTURES OF Cr, Mn, Fe, Co AND Ni ON FCC Cu(001)
Authors: SINGH RANBER
Published: February 2010

The magnetic coupling in pseudomorphic overlayer and sandwich structures of 2ML magnetic ultrathin films on Cu (001) substrate is investigated by using spin-polarized density functional theory. The 2ML magnetic overlayers have significant magnetic moment except CrNi overlayer for which magnetic moment is very small (0.004 μB/ atom ). The overlayers having one layer of Cr turn out to be antiferromagnetically coupled except CrNi/Cu overlayer which has ferromagnetic coupling. All other overlayers have ferromagnetic coupling. In contrast to ferromagnetic MnMn/Cu overlayer, the Cu/MnMn/Cu sandwich has antiferromagnetic coupling. Similar to CrFe/Cu overlayer, the Cu/CrFe/Cu sandwich has antiferromagnetic coupling, while all other sandwiches have ferromagnetic coupling. The sandwiched structures have reduced magnetic moment as compared to their overlayer counterparts. The MnMn , MnFe , and MnCo sandwiches have highly reduced magnetic moment as compared to their overlayer counterparts.
A QUASI-VARIATIONAL INEQUALITY PROBLEM IN SUPERCONDUCTIVITY
Authors: BARRETT JOHN W. , PRIGOZHIN LEONID
Published: February 2010

We derive a class of analytical solutions and a dual formulation of a scalar two-space-dimensional quasi-variational inequality problem in applied superconductivity. We approximate this formulation by a fully practical finite element method based on the lowest order Raviart–Thomas element, which yields approximations to both the primal and dual variables (the magnetic and electric fields). We prove the subsequence convergence of this approximation, and hence prove the existence of a solution to both the dual and primal formulations, for strictly star-shaped domains. The effectiveness of the approximation is illustrated by numerical examples with and without this domain restriction.
A NUMERICAL ANALYSIS OF A REACTION–DIFFUSION SYSTEM MODELING THE DYNAMICS OF GROWTH TUMORS
Authors: ANAYA VERÓNICA , BENDAHMANE MOSTAFA , SEPÚLVEDA MAURICIO
Published: February 2010

We consider a reaction–diffusion system of 2 × 2 equations modeling the spread of early tumor cells. The existence of weak solutions is ensured by a classical argument of Faedo–Galerkin method. Then, we present a numerical scheme for this model based on a finite volume method. We establish the existence of discrete solutions to this scheme, and we show that it converges to a weak solution. Finally, some numerical simulations are reported with pattern formation examples.
WEAK SOLUTIONS TO EQUATIONS OF STEADY COMPRESSIBLE HEAT CONDUCTING FLUIDS
Authors: MUCHA PIOTR B. , POKORNÝ MILAN
Published: February 2010

We consider the steady compressible Navier–Stokes–Fourier system in a bounded three-dimensional domain. We prove the existence of a solution for arbitrarily large data under the assumption that the pressure p(ϱ, θ) ~ ϱθ + ϱγ for [Formula: see text] assuming either the slip or no-slip boundary condition for the velocity and the Newton boundary condition for the temperature. The regularity of solutions is determined by the basic energy estimates, constructed for the system.
FAULT DIAGNOSIS OF MULTIPROCESSOR SYSTEMS BASED ON GENETIC AND ESTIMATION OF DISTRIBUTION ALGORITHMS: A PERFORMANCE EVALUATION
Authors: DUARTE ELIAS P. , POZO AURORA T. R. , NASSU BOGDAN T.
Published: February 2010

As faults are unavoidable in large scale multiprocessor systems, it is important to be able to determine which units of the system are working and which are faulty. System-level diagnosis is a long-standing realistic approach to detect faults in multiprocessor systems. Diagnosis is based on the results of tests executed on the system units. In this work we evaluate the performance of evolutionary algorithms applied to the diagnosis problem. Experimental results are presented for both the traditional genetic algorithm (GA) and specialized versions of the GA. We then propose and evaluate specialized versions of Estimation of Distribution Algorithms (EDA) for system-level diagnosis: the compact GA and Population-Based Incremental Learning both with and without negative examples. The evaluation was performed using four metrics: the average number of generations needed to find the solution, the average fitness after up to 500 generations, the percentage of tests that got to the optimal solution and the average time until the solution was found. An analysis of experimental results shows that more sophisticated algorithms converge faster to the optimal solution.
LAMARCKIAN LEARNING IN CLONAL SELECTION ALGORITHM FOR NUMERICAL OPTIMIZATION
Authors: GONG MAOGUO , JIAO LICHENG , YANG JIE , LIU FANG
Published: February 2010

In this paper, we introduce Lamarckian learning theory into the Clonal Selection Algorithm and propose a sort of Lamarckian Clonal Selection Algorithm, termed as LCSA. The major aim is to utilize effectively the information of each individual to reinforce the exploitation with the help of Lamarckian local search. Recombination operator and tournament selection operator are incorporated into LCSA to further enhance the ability of global exploration. We compare LCSA with the Clonal Selection Algorithm in solving twenty benchmark problems to evaluate the performance of LCSA. The results demonstrate that the Lamarckian local search makes LCSA more effective and efficient in solving numerical optimization problems.
A TOOL FOR REMOVING UNUSED ARGUMENTS FROM LOGIC PROGRAMS AUTOMATICALLY
Authors: MARAKAKIS EMMANUIL , VASSILAKIS KOSTAS , PAPADAKIS NIKOS
Published: February 2010

This paper studies the problem of removing unused arguments from logic programs which have been constructed by a schema-based method. Our schema-based method constructs logic programs semi-automatically. These programs have clear structure which depicts the design decisions that have been taken for their construction. On the other hand, these programs have unused arguments. We propose a method that automatically removes the unused arguments from such programs. This method is based on fold-unfold transformations. We have developed a tool which implements our method and evaluates the initial and the transformed programs. This logic program transformation tool is presented as well.
NENOK — A SOFTWARE ARCHITECTURE FOR GENERIC INFERENCE
Authors: POULY MARC
Published: February 2010

Computing inference from a given knowledgebase is one of the key competences of computer science. Therefore, numerous formalisms and specialized inference routines have been introduced and implemented for this task. Typical examples are Bayesian networks, constraint systems or different kinds of logic. It is known today that these formalisms can be unified under a common algebraic roof called valuation algebra. Based on this system, generic inference algorithms for the processing of arbitrary valuation algebras can be defined. Researchers benefit from this high level of abstraction to address open problems independently of the underlying formalism. It is therefore all the more astonishing that this theory did not find its way into concrete software projects. Indeed, all modern programming languages for example provide generic sorting procedures, but generic inference algorithms are still mythical creatures. NENOK breaks a new ground and offers an extensive library of generic inference tools based on the valuation algebra framework. All methods are implemented as distributed algorithms that process local and remote knowledgebases in a transparent manner. Besides its main purpose as software library, NENOK also provides a sophisticated graphical user interface to inspect the inference process and the involved graphical structures. This can be used for educational purposes but also as a fast prototyping architecture for inference formalisms.
BASIS THEOREMS FOR NON-POTENTIALLY CLOSED SETS AND GRAPHS OF UNCOUNTABLE BOREL CHROMATIC NUMBER
Authors: LECOMTE DOMINIQUE , MILLER BENJAMIN D.
Published: February 2010

We show that there is an antichain basis for neither (1) the class of non-potentially closed Borel subsets of the plane under Borel rectangular reducibility nor (2) the class of analytic graphs of uncountable Borel chromatic number under Borel reducibility.
AN IMPROVED WAVELET DOMAIN DIGITAL WATERMARKING FOR IMAGE PROTECTION
Authors: DEJEY  , RAJESH R. S.
Published: February 2010

Watermarking is a potential method for the protection of ownership rights on digital images. A robust, invisible, non-blind watermarking scheme in the wavelet domain is proposed in this paper. The watermark is embedded in the mid frequency band after performing a single level wavelet decomposition using Discrete Wavelet Transform (DWT). The coefficients are grouped randomly prior to watermarking. The watermarked image is tested for various attacks including filtering and geometric attacks. The novelty of the proposed approach is that it provides better resistance to collusion attack also when compared with existing spatial domain approach. The appropriate mid frequency band for embedding the watermark is tested and the HL band proves to be the best.
A NEW STRUCTURE AND TRAINING PROCEDURE FOR MULTI-MOTHER WAVELET NETWORKS
Authors: OTHMANI MOHAMED , BELLIL WAJDI , BEN AMAR CHOKRI , ALIMI ADEL M.
Published: February 2010

This paper deals with the features of a new wavelet network structure founded on several mother wavelets families. This new structure is similar to the classic wavelets network but it admits some differences eventually. The wavelet network basically uses the dilations and translations versions of only one mother wavelet to construct the network, but the new one uses several mother wavelets and the objective is to maximize the probability of selection of the best wavelets. Two methods are presented to assist the training procedure of this new structure. On one hand, we have an optimal selection technique that is based on an improved version of the Orthogonal Least Squares method; on the other, the Generalized Cross-Validation method to determine the number of wavelets to be selected for every mother wavelet. Some simulation results are reported to demonstrate the performance and the effectiveness of the new structure and the training procedure for function approximation in one and two dimensions.
A RANGE FUNCTION APPROACH TO SHIFT-INVARIANT SPACES ON LOCALLY COMPACT ABELIAN GROUPS
Authors: KAMYABI GOL R. A. , RAISI TOUSI R.
Published: February 2010

This paper develops several aspects of shift-invariant spaces on locally compact abelian groups. For a second countable locally compact abelian group G we prove a useful Hilbert space isomorphism, introduce range functions and give a characterization of shift-invariant subspaces of L2(G) in terms of range functions. Utilizing these functions, we generalize characterizations of frames and Riesz bases generated by shifts of a countable set of generators from L2(ℝn) to L2(G).
SINGLE PEAKED FUZZY PREFERENCES IN ONE-DIMENSIONAL MODELS: DOES BLACK'S MEDIAN VOTER THEOREM HOLD?
Authors: MORDESON JOHN N. , NIELSEN LANCE , CLARK TERRY D.
Published: February 2010

Black's Median Voter Theorem is among the more useful mathematical tools available to political scientists for predicting choices of political actors based on their preferences over a finite set of alternatives within an institutional or constitutional setting. If the alternatives can be placed on a single-dimensional continuum such that the preferences of all players descend monotonically from their ideal point, then the outcome will be the alternative at the median position. We demonstrate that the Median Voter Theorem holds for fuzzy preferences. Our approach considers the degree to which players prefer options in binary relations.
THE CORE IN FUZZY SPATIAL MODELS
Authors: MORDESON JOHN N. , CLARK TERRY D.
Published: February 2010

Predictions concerning voting outcomes in crisp spatial models rely heavily on the existence of a core, in the absence of which political players choosing among a set of alternatives by majority rule will not be able to arrive at a stable choice. No matter which option they might initially choose, most voting rules will permit another option to defeat the previously chosen one. Such problems particularly plague majority rule spatial models at dimensionalities greater than one. In a series of recent papers, we have argued that fuzzy spatial models offer a partial solution to this problem. In this paper, we explore the existence of a fuzzy core. Our major conclusion is that a fuzzy core is more likely in two or more dimensions as the number of players increases.
CHARACTERIZATIONS OF MONOIDS BY THE PROPERTIES OF THEIR INTUITIONISTIC FUZZY SUBACTS
Authors: SHABIR MUHAMMAD , ARIF MUHAMMAD SHOAIB
Published: February 2010

In this paper, we initiate the study of intuitionistic fuzzy subacts of an S-act, where S is a monoid with zero and S-acts are representations of S. We introduce the notions of pure intuitionistic fuzzy, purely intuitionistic maximal and purely intuitionistic fuzzy prime ideals of a monoid. It is shown that the set of purely intuitionistic fuzzy prime ideals of S admits the structure of a topological space, called the pure intuitionistic fuzzy spectrum of S. We also define a pure intuitionistic fuzzy subact of an S-act and call an S-act intuitionistic fuzzy normal if each of its intuitionistic fuzzy subact is pure. Monoids, of which all S-acts are intuitionistic fuzzy normal, are characterized. It is shown among other results that such monoids are right weakly regular.
UPDATING BINDING MOAD — DATA MANAGEMENT AND INFORMATION WORKFLOW
Authors: BENSON MARK L. , SMITH RICHARD D. , KHAZANOV NICKOLAY A. , CARLSON HEATHER A. , DIMCHEFF BRANDON , DRESSLAR PETER
Published: February 2010

Binding MOAD (Mother of All Databases) is the largest collection of high-quality, protein-ligand complexes available from the Protein Data Bank. It has grown to 9837 hand-curated entries. Here, we describe our semi-annual updating procedures and BUDA (Binding Unstructured Data Analysis), a custom workflow tool that incorporates natural language processing technologies to facilitate the annotation process.
HYDROGEN STORAGE ON NANOFULLERENE CAGES
Authors: VENKATARAMANAN NATARAJAN SATHIYAMOORTHY , MIZUSEKI HIROSHI , KAWAZOE YOSHIYUKI
Published: February 2010

In this paper, we discuss and compare various nanocage materials proposed theoretically as storage medium for hydrogen. Doping of transition elements leads to clustering which reduces the gravimetric density of hydrogen, while doping of alkali and alkali-earth metals on the nanocage materials, such as carborides, boronitride, and boron cages, were stabilized by the charger transfer from the dopant to the nanocage. Further, the alkali or alkali-earth elements exist with a charge, which are found to be responsible for the higher uptake of hydrogen, through a dipole–dipole and change-induced dipole interaction. The binding energies of hydrogen on these systems were found to be in the range of 0.1 eV to 0.2 eV, which are ideal for the practical applications in a reversible system.
STM TIP-CURRENT-INDUCED POLYMERIZATION OF C60, Ce2@C80 AND Lu2@C76
Authors: OHASHI KAZUNORI , FUKUI NOBUYUKI , AKACHI MASAHIRO , AKACHI TAKAO , UMEMOTO HISASHI , ITO YASUHIRO , SUGAI TOSHIKI , KITAURA RYO , SHINOHARA HISANORI
Published: February 2010

Polymerization of C60 , Ce2@C80 , and Lu2@C76 metallofullerenes induced by electron injection from a scanning tunneling microscope (STM) tip has been studied. C60 polymerization has been observed only with C60 multilayer on Au (111) and not with C60 monolayer on Au (111). The Ce2@C80 metallofullerene on Si (111)-7 × 7 also polymerizes by electron injection but has less polymerization reactivity than C60 . Interestingly, the Lu2@C76 metallofullerene on Si (111)-7 × 7 does not show any polymerization. Based on these STM observations on the tip-induced polymerization, the direction of the bond formation and the dependence of reactivity on the kind of fullerenes are discussed.
Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion
Authors: Xiao Lan , Rao Jaladanki N. , Zou Tongtong , Liu Lan , Yu Ting-Xi , Zhu Xiao-Yu , Donahue James M. , Wang Jian-Ying
Published: February 2010

Intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis is tightly regulated by numerous factors including polyamines. Decreased levels of cellular polyamines increase activating transcription factor (ATF)-2, but the exact role and mechanism of induced ATF-2 in the regulation of intestinal epithelial cell (IEC) growth remain elusive. Cyclin-dependent kinase (CDK) 4 is necessary for the G1-to-S phase transition during the cell cycle, and its expression is predominantly controlled at the transcription level. Here, we reported that induced ATF-2 following polyamine depletion repressed CDK4 gene transcription in IECs by increasing formation of the ATF-2/JunD heterodimers. ATF-2 formed complexes with JunD as measured by immunoprecipitation using the ATF-2 and JunD antibodies and by glutathione S-transferase (GST) pull-down assays using GST-ATF-2 fusion proteins. Studies using various mutants of GST-ATF-2 revealed that formation of the ATF-2/JunD dimers depended on the COOH-terminal basic region-leucine zipper domain of ATF-2. Polyamine depletion increased ATF-2/JunD complex and inhibited CDK4 transcription as indicated by a decrease in the levels of CDK4-promoter activity and its mRNA. ATF-2 silencing not only prevented inhibition of CDK4 transcription in polyamine-deficient cells but also abolished repression of CDK4 expression induced by ectopic JunD overexpression. ATF-2 silencing also promoted IEC growth in polyamine-depleted cells. These results indicate that induced ATF-2/JunD association following polyamine depletion represses CDK4 transcription, thus contributing to the inhibition of IEC growth.
Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration
Authors: Clever Jared L. , Sakai Yuki , Wang Rong A. , Schneider Darren B.
Published: February 2010

The bone morphogenetic protein (BMP) pathway is known to be involved in limb myogenesis during development, but whether it is involved in postnatal muscle regeneration is unclear. We have found that adult inhibitor of differentiation (Id)-mutant (Id1+/−Id3−/−) mice display delayed and reduced skeletal muscle regeneration after injury compared with either wild-type littermates or Id3-null mice. Immunoblotting of wild-type muscle lysates revealed that, not only were Id1 and Id3 highly upregulated within 24 h after injury, but other upstream components of the BMP pathway were as well, including the BMP receptor type II and phosphorylated Smad1/5/8 (pSmad1/5/8). Inhibition of BMP signaling in injured skeletal muscle by Noggin injection reduced pSmad1/5/8, Id1, and Id3 protein levels. The mouse myoblast-derived cell line C2C12 also expressed Id1, Id3, BMP receptor type II, and pSmad1/5/8 during proliferation, but all were reduced upon differentiation into myotubes. In addition, these cells secreted mature BMP-4, and BMP signaling could be inhibited with exogenous Noggin, causing a reduction in pSmad1/5/8, Id1, and Id3 levels. Confocal immunofluorescence microscopy revealed that activated Pax7+ myoblasts coexpressed nuclear pSmad1/5/8, Id1, and Id3 in injured mouse skeletal muscle sections. Although we did not observe differences in the numbers of quiescent Pax7+ satellite cells in adult uninjured hindlimb muscles, we did observe a significant reduction in the number of proliferating Pax7+ cells in the Id-mutant mice after muscle injury compared with either wild-type or Id3-null mice. These data suggest a model in which BMP signaling regulates Id1 and Id3 in muscle satellite cells, which directs their proper proliferation before terminal myogenic differentiation after skeletal muscle injury in postnatal animals.
Multipotent mesenchymal progenitor cells are present in endarterectomized tissues from patients with chronic thromboembolic pulmonary hypertension
Authors: Firth Amy L. , Yao Weijuan , Ogawa Aiko , Madani Michael M. , Lin Grace Y. , Yuan Jason X-J.
Published: February 2010

Factors contributing to the development of a fibrotic vascular scar and pulmonary vascular remodeling leading to chronic thromboembolic pulmonary hypertension (CTEPH) are still unknown. This study investigates the potential contribution of multipotent progenitor cells and myofibroblasts to the development and progression of CTEPH. Histological examination of endarterectomized tissues from patients with CTEPH identified significant neointimal formation. Morphological heterogeneity was observed in cells isolated from these tissues, including a network-like growth pattern and the formation of colony-forming unit-fibroblast-like colonies (CFU-F). Cells typically coexpressed intermediate filaments vimentin and smooth muscle α-actin. Cells were characterized by immunofluorescence and quantitated by fluorescent-activated cell sorting (FACS) for the presence of cell surface markers typical of mesenchymal progenitor cells; cells were >99% CD44+ CD73+, CD90+, CD166+; >80% CD29+; 45–99% CD105+; CD34− and CD45−. Cells were capable of adipogenic and osteogenic differentiation, determined by Oil Red O and Alizarin Red staining, respectively. Additionally, a population of Stro-1+ cells, a marker of bone marrow-derived stromal cells (4.2%), was sorted by FACS and also capable of adipogenic and osteogenic differentiation. In conclusion, this study is the first to identify a myofibroblast cell phenotype to be predominant within endarterectomized tissues, contributing extensively to the vascular lesion/clot. This cell may arise from transdifferentiation of adventitial fibroblasts or differentiation of mesenchymal progenitor cells. The unique microenvironment created by the stabilized clot is likely a factor in stimulating such cellular changes. These findings will be critical in establishing future studies in the development of novel and much needed therapeutic approaches for pulmonary hypertension.
ROCK2 associates with lectin-like oxidized LDL receptor-1 and mediates oxidized LDL-induced IL-8 production
Authors: Mattaliano Mark D. , Wooters Joe , Shih Heather H. , Paulsen Janet E.
Published: February 2010

Oxidatively modified low-density lipoprotein (OxLDL) is a contributing factor of endothelial dysfunction, an early cellular event during atherogenesis. In endothelial cells, OxLDL has been shown to stimulate proinflammatory responses, increase lipid accumulation, and induce the expression of adhesion and extracellular matrix degrading molecules. The primary receptor for OxLDL on endothelial cells has been identified as a member of the scavenger receptor family called lectin-like OxLDL receptor-1 (LOX-1). A number of studies on LOX-1 have implicated its role in multiple cardiovascular diseases including atherosclerosis. To better understand the molecular mechanisms underlying the role of LOX-1 in endothelial cells, we identified interacting proteins in an affinity-purified LOX-1 receptor complex from human aortic endothelial HAECT cells by mass spectrometry. Two molecules involved in Rho signaling pathway, ARHGEF1 and ROCK2, were identified, and their associations with LOX-1 were confirmed in reciprocal immunoprecipitation studies. Particularly, ROCK2 was found to dynamically associate with LOX-1 in the presence of OxLDL. In addition, OxLDL treatment stimulated ROCK2 catalytic activity, and ROCK2 inhibition attenuated NF-κB activation and IL-8 production resulting from OxLDL activation of LOX-1. In summary, a functional proteomics approach has enabled us to identify novel LOX-1 interactors that potentially contribute to the cellular and signaling functions of LOX-1.
Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells
Authors: Abaci Hasan Erbil , Truitt Rachel , Luong Eli , Drazer German , Gerecht Sharon
Published: February 2010

Hypoxia plays an important role in vascular development through hypoxia-inducible factor-1α (HIF-1α) accumulation and downstream pathway activation. We sought to explore the in vitro response of cultures of human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human endothelial progenitor cells (hEPCs), and human umbilical cord vein endothelial cells (HUVECs) to normoxic and hypoxic oxygen tensions. We first measured dissolved oxygen (DO) in the media of adherent cultures in atmospheric (21% O2), physiological (5% O2), and hypoxic oxygen conditions (1% O2). In cultures of both hEPCs and HUVECs, lower oxygen consumption was observed when cultured in 1% O2. At each oxygen tension, feeder-free cultured hESCs and iPSCs were found to consume comparable amounts of oxygen. Transport analysis revealed that the oxygen uptake rate (OUR) of hESCs and iPSCs decreased distinctly as DO availability decreased, whereas the OUR of all cell types was found to be low when cultured in 1% O2, demonstrating cell adaptation to lower oxygen tensions by limiting oxygen consumption. Next, we examined HIF-1α accumulation and the expression of target genes, including VEGF and angiopoietins ( ANGPT; angiogenic response), GLUT-1 (glucose transport), BNIP3, and BNIP3L (autophagy and apoptosis). Accumulations of HIF-1α were detected in all four cell lines cultured in 1% O2. Corresponding upregulation of VEGF, ANGPT2, and GLUT-1 was observed in response to HIF-1α accumulation, whereas upregulation of ANGPT1 was detected only in hESCs and iPSCs. Upregulation of BNIP3 and BNIP3L was detected in all cells after 24-h culture in hypoxic conditions, whereas apoptosis was not detectable using flow cytometry analysis, suggesting that BNIP3 and BNIP3L can lead to cell autophagy rather than apoptosis. These results demonstrate adaptation of all cell types to hypoxia but different cellular responses, suggesting that continuous measurements and control over oxygen environments will enable us to guide cellular responses.
Role of urotensin II in health and disease
Authors: Ross Bryan , McKendy Katherine , Giaid Adel
Published: February 2010

Urotensin II (UII) is an 11 amino acid cyclic peptide originally isolated from the goby fish. The amino acid sequence of UII is exceptionally conserved across most vertebrate taxa, sharing structural similarity to somatostatin. UII binds to a class of G protein-coupled receptor known as GPR14 or the urotensin receptor (UT). UII and its receptor, UT, are widely expressed throughout the cardiovascular, pulmonary, central nervous, renal, and metabolic systems. UII is generally agreed to be the most potent endogenous vasoconstrictor discovered to date. Its physiological mechanisms are similar in some ways to other potent mediators, such as endothelin-1. For example, both compounds elicit a strong vascular smooth muscle-dependent vasoconstriction via Ca2+release. UII also exerts a wide range of actions in other systems, such as proliferation of vascular smooth muscle cells, fibroblasts, and cancer cells. It also 1) enhances foam cell formation, chemotaxis of inflammatory cells, and inotropic and hypertrophic effects on heart muscle; 2) inhibits insulin release, modulates glomerular filtration, and release of catecholamines; and 3) may help regulate food intake and the sleep cycle. Elevated plasma levels of UII and increased levels of UII and UT expression have been demonstrated in numerous diseased conditions, including hypertension, atherosclerosis, heart failure, pulmonary hypertension, diabetes, renal failure, and the metabolic syndrome. Indeed, some of these reports suggest that UII is a marker of disease activity. As such, the UT receptor is emerging as a promising target for therapeutic intervention. Here, a concise review is given on the vast physiologic and pathologic roles of UII.
Role of the energy sensor AMP-activated protein kinase in renal physiology and disease
Authors: Hallows Kenneth R. , Mount Peter F. , Pastor-Soler Núria M. , Power David A.
Published: February 2010

The ultrasensitive energy sensor AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and energy-consuming pathways. AMPK is highly expressed in the kidney where it is reported to be involved in a variety of physiological and pathological processes including ion transport, podocyte function, and diabetic renal hypertrophy. Sodium transport is the major energy-consuming process in the kidney, and AMPK has been proposed to contribute to the coupling of ion transport with cellular energy metabolism. Specifically, AMPK has been identified as a regulator of several ion transporters of significance in renal physiology, including the cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial sodium channel (ENaC), the Na+-K+-2Cl−cotransporter (NKCC), and the vacuolar H+-ATPase (V-ATPase). Identified regulators of AMPK in the kidney include dietary salt, diabetes, adiponectin, and ischemia. Activation of AMPK in response to adiponectin is described in podocytes, where it reduces albuminuria, and in tubular cells, where it reduces glycogen accumulation. Reduced AMPK activity in the diabetic kidney is associated with renal accumulation of triglyceride and glycogen and the pathogenesis of diabetic renal hypertrophy. Acute renal ischemia causes a rapid and powerful activation of AMPK, but the functional significance of this observation remains unclear. Despite the recent advances, there remain significant gaps in the present understanding of both the upstream regulating pathways and the downstream substrates for AMPK in the kidney. A more complete understanding of the AMPK pathway in the kidney offers potential for improved therapies for several renal diseases including diabetic nephropathy, polycystic kidney disease, and ischemia-reperfusion injury.
Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition
Authors: Ko Gang Jee , Grigoryev Dmitry N. , Linfert Douglas , Jang Hye Ryoun , Watkins Tonya , Cheadle Chris , Racusen Lorraine , Rabb Hamid
Published: February 2010

Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 ( Havcr1) and lipocalin 2 ( Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.
Modulation of chronic hypoxia-induced chemoreceptor hypersensitivity by NADPH oxidase subunits in rat carotid body
Authors: He L. , Liu X. , Chen J. , Dinger B. , Stensaas L. , Fidone S.
Published: February 2010

Previous studies in our laboratory established that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) facilitate the open state of a subset of K+ channels in oxygen-sensitive type I cells of the carotid body. Thus pharmacological inhibition of NOX or deletion of a NOX gene resulted in enhanced chemoreceptor sensitivity to hypoxia. The present study tests the hypothesis that chronic hypoxia (CH)-induced hypersensitivity of chemoreceptors is modulated by increased NOX activity and elevated levels of ROS. Measurements of dihydroethidium fluorescence in carotid body tissue slices showed that increased ROS production following CH (14 days, 380 Torr) was blocked by the specific NOX inhibitor 4-(2-amino-ethyl)benzenesulfonyl fluoride (AEBSF, 3 μM). Consistent with these findings, in normal carotid body AEBSF elicited a small increase in the chemoreceptor nerve discharge evoked by an acute hypoxic challenge, whereas after 9 days of CH the effect of the NOX inhibitor was some threefold larger ( P < 0.001). Evaluation of gene expression after 7 days of CH showed increases in the isoforms NOX2 (∼1.5-fold) and NOX4 (∼3.8-fold) and also increased presence of the regulatory subunit p47phox (∼4.2-fold). Involvement of p47phox was further implicated in studies of isolated type I cells that demonstrated an ∼8-fold and an ∼11-fold increase in mRNA after 1 and 3 days, respectively, of hypoxia in vivo. These findings were confirmed in immunocytochemical studies of carotid body tissue that showed a robust increase of p47phox in type I cells after 14 days of CH. Our findings suggest that increased ROS production by NOX enzymes in type I cells dampens CH-induced hypersensitivity in carotid body chemoreceptors.
Fine Temporal Structure of Beta Oscillations Synchronization in Subthalamic Nucleus in Parkinson's Disease
Authors: Park Choongseok , Worth Robert M. , Rubchinsky Leonid L.
Published: February 2010

Synchronous oscillatory dynamics in the beta frequency band is a characteristic feature of neuronal activity of basal ganglia in Parkinson's disease and is hypothesized to be related to the disease's hypokinetic symptoms. This study explores the temporal structure of this synchronization during episodes of oscillatory beta-band activity. Phase synchronization (phase locking) between extracellular units and local field potentials (LFPs) from the subthalamic nucleus (STN) of parkinsonian patients is analyzed here at a high temporal resolution. We use methods of nonlinear dynamics theory to construct first-return maps for the phases of oscillations and quantify their dynamics. Synchronous episodes are interrupted by less synchronous episodes in an irregular yet structured manner. We estimate probabilities for different kinds of these “desynchronization events.” There is a dominance of relatively frequent yet very brief desynchronization events with the most likely desynchronization lasting for about one cycle of oscillations. The chances of longer desynchronization events decrease with their duration. The observed synchronization may primarily reflect the relationship between synaptic input to STN and somatic/axonal output from STN at rest. The intermittent, transient character of synchrony even on very short time scales may reflect the possibility for the basal ganglia to carry out some informational function even in the parkinsonian state. The dominance of short desynchronization events suggests that even though the synchronization in parkinsonian basal ganglia is fragile enough to be frequently destabilized, it has the ability to reestablish itself very quickly.