bluuebunny/crossref_metadata_2025 huggingface dataset:
RESONANT FLAVOR CONVERSION OF SUPERNOVA NEUTRINOS AND NEUTRINO PARAMETERS
Authors: CHIU S. H.
Published: December 2009

The unknown neutrino parameters may leave detectable signatures in the supernova (SN) neutrino flux. However, even the contribution from the MSW flavor transition alone could cause ambiguity in the interpretation to the neutrino signals because of the uncertain local density profile of the SN matter and the model-dependent SN neutrino spectral parameters. A specific parametrization to the unknown local density profile is proposed in this work, and the contribution from the standard MSW effect is investigated through a multi-detector analysis of the SN neutrinos. In establishing the model-independent scheme, results based on the existing spectral models are included. The limitation of the analysis is also discussed.
PHASE INTERVAL VALUE ANALYSIS FOR THE MOTOR IMAGERY TASK IN BCI
Authors: LI JIE , ZHANG LIQING
Published: November 2009

In neuroscience, phase is assumed to contain more important information about the neural activity than amplitude. However, the most exploited feature in electroencephalogram (EEG) based brain computer interface (BCI) is the amplitude change, phase has been largely ignored, and only phase locking values (PLV) has been introduced in EEG classification recently. In this paper, we define phase interval value (PIV) to explore the phase information of EEG from a new perspective and propose a computational model based on the ordered Parallel Factors (PARAFAC) algorithm to extract feature from multi-way PIV data for single trial EEG classification. Application to the motor imagery task demonstrates that PIV is quite effective for EEG classification, providing significant and discriminative features in spatial and spectral dimension. PIV might become an important new tool in the analysis of EEG phase characteristic, and has the great potential use in BCI.
A NEW METHOD FOR MEASURING THE UNCERTAINTY IN INCOMPLETE INFORMATION SYSTEMS
Authors: QIAN YUHUA , LIANG JIYE , WANG FENG
Published: November 2009

Based on an intuitionistic knowledge content nature of information gain, the concept of combination entropy CE(A) in incomplete information systems is first introduced, and some of its important properties are given. Then, the conditional combination entropy CE(Q | P) and the mutual information CE(P;Q) are defined. Unlike all existing measures for the uncertainty in incomplete information systems, the relationships among these three concepts can be established, which are formally expressed as CE(Q | P) = CE(P ⋃ Q)-CE(P) and CE(P;Q) = CE(P)-CE(P | Q). Furthermore, a variant CE(CA) of the combination entropy with maximal consistent block nature is introduced to measure the uncertainty of an incomplete information system in the view of maximal consistent block technique. Its monotonicity is the same as that of the combination entropy. Finally, the combination granulation CG(A) and its variant CG(CA) with maximal consistent block nature are defined to measure discernibility ability of an incomplete information system, and the relationship between the combination entropy and the combination granulation is established as well. These results will be very helpful for understanding the essence of knowledge content and uncertainty measurement in incomplete information systems. Note that the combination entropy also can be further extended to measure the uncertainty in non-equivalence-based information systems.
The Cyclicity of a Cubic System
Authors: Levandovskyy Viktor , Logar Alessandro , Romanovski Valery G.
Published: November 2009

Using algorithms of computational algebra we prove that at most eight limit cycles can bifurcate from any center or focus at the origin of the cubic system [Formula: see text]. That is, an upper bound for cyclicity of the origin of the system is eight.
Beam Delivery Systems for Particle Radiation Therapy: Current Status and Recent Developments
Authors: Schippers J. M.
Published: November 2009

An overview is given of different techniques of dose delivery applied in currently operating and planned particle therapy systems. Their advantages and disadvantages will be compared and consequences of the methods for the rest of the instrumentation will be discussed. The interrelationship between beam delivery at the patient and the accelerator system is shown by means of several concrete examples. Apart from a description of several subsystems in a particle therapy facility, design rules for optimizing the reliability of an accelerator and beam delivery system will be discussed, as well as some remarks concerning how to deal with future developments.
Microwave Electron Linacs for Oncology
Authors: Whittum David H.
Published: November 2009

The history and technology of medical linacs are reviewed, focusing on machine requirements for radiotherapy. Configurations used in modern machines are described and operational aspects of a gantry-style linac system are illustrated with reference to the state of the art. Aspects of structure design, modeling and testing are discussed.
Change analysis in spatial datasets by interestingness comparison
Authors: Rinsurongkawong Vadeerat , Eick Christoph F.
Published: November 2009

Detecting changes in spatial datasets is important for many fields such as early warning systems that monitor environmental conditions, epidemiology, crime monitoring, and automatic surveillance. The goal of the presented research is the development of methodologies for change analysis in spatial datasets. An approach to change analysis is presented that analyses how the interesting regions in one time frame differ from the interesting regions in the next time frame with respect to a given interestingness perspective. Users are allowed to define their own interestingness perspectives that are captured in form of a reward-based fitness function. A change analysis framework is proposed in which reward-based fitness functions are maximized by clustering algorithms to find interesting regions for each dataset. Next, the relationships between interesting regions are analyzed. Two approaches to analyze correspondence between interesting regions are proposed. The first approach directly compares cluster models and strongly relies on analyzing relationships between polygons that capture the scope of an interesting region. The second approach compares cluster extensions that are computed by re-clustering. Finally, a knowledge base of change predicates is provided that allows analyzing various aspects of change, and report generators that are associated with particular predicates are proposed to generate summaries of change. Moreover, in contrast to most existing research, the framework does not assume that the identity of objects in the analyzed environment is known. The proposed framework is demonstrated in a case study that analyzes changes in earthquake patterns.
Evaluating hydrology preservation of simplified terrain representations
Authors: Stuetzle Christopher , Franklin W. Randolph , Cutler Barbara
Published: November 2009

We present an error metric based on the potential energy of water flow to evaluate the quality of lossy terrain simplification algorithms. Typically, terrain compression algorithms seek to minimize RMS (root mean square) and maximum error. These metrics fail to capture whether a reconstructed terrain preserves the drainage network. A quantitative measurement of how accurately a drainage network captures the hydrology is important for determining the effectiveness of a terrain simplification technique. Having a measurement for testing and comparing different models has the potential to be widely used in numerous applications (flood prevention, erosion measurement, pollutant propagation, etc). In this paper, we transfer the drainage network computed on reconstructed geometry onto the original uncompressed terrain and use our error metric to measure the level of error created by the simplification. We also present a novel terrain simplification algorithm based on the compression of hydrology features. This method and other terrain compression schemes are then compared using our new metric.
Mining in Large Noisy Domains
Authors: Dash Manoranjan , Singhania Ayush
Published: November 2009

In this article we address the issue of how to mine efficiently in large and noisy data. We propose an efficient sampling algorithm (
Concise
) as a solution for large and noisy data. Concise is far more superior than the Simple Random Sampling (
SRS
) in selecting a representative sample. Particularly when the data is very large and noisy, Concise achieves the maximum gain over SRS. The comparison is in terms of their impact on subsequent data mining tasks, specifically, classification, clustering, and association rule mining. We compared Concise with a few existing noise removal algorithms followed by SRS. Although the accuracy of mining results are similar, Concise spends very little time compared to the existing algorithms because Concise has linear time complexity.
Representing Data Quality in Sensor Data Streaming Environments
Authors: Klein A. , Lehner W.
Published: November 2009

Sensors in smart-item environments capture data about product conditions and usage to support business decisions as well as production automation processes. A challenging issue in this application area is the restricted quality of sensor data due to limited sensor precision and sensor failures. Moreover, data stream processing to meet resource constraints in streaming environments introduces additional noise and decreases the data quality. In order to avoid wrong business decisions due to dirty data, quality characteristics have to be captured, processed, and provided to the respective business task. However, the issue of how to efficiently provide applications with information about data quality is still an open research problem.

In this article, we address this problem by presenting a flexible model for the propagation and processing of data quality. The comprehensive analysis of common data stream processing operators and their impact on data quality allows a fruitful data evaluation and diminishes incorrect business decisions. Further, we propose the data quality model control to adapt the data quality granularity to the data stream interestingness.
The musical heritage of futurism
Authors: Götzen Amalia De , Serafin Stefania
Published: November 2009

This article presents a digital simulation of the
intonarumori
, musical instruments invented by the Italian Futurist composer and painter Luigi Russolo. By building the physical models of different members of the intonarumori family and a physical interface, a preservation of an important contribution to the musical heritage of the beginning of the 20th century is achieved.
Divide-and-conquer scheme for strictly optimal retrieval of range queries
Authors: Tosun Ali Şaman
Published: November 2009

Declustering distributes data among parallel disks to reduce retrieval cost using I/O parallelism. Many schemes were proposed for single copy declustering of spatial data. Recently, declustering using replication gained a lot of interest and several schemes with different properties were proposed. It is computationally expensive to verify optimality of replication schemes designed for range queries and existing schemes verify optimality for up to 50 disks. In this article, we propose a novel method to find replicated declustering schemes that render all spatial range queries optimal. The proposed scheme uses threshold based declustering, divisibility of large queries for optimization and optimistic approach to compute maximum flow. The proposed scheme is generic and works for any number of dimensions. Experimental results show that using 3 copies there exist allocations that render all spatial range queries optimal for up to 750 disks in 2 dimensions and with the exception of several values for up to 100 disks in 3 dimensions. The proposed scheme improves search for strictly optimal replicated declustering schemes significantly and will be a valuable tool to answer open problems on replicated declustering.
A hybrid nano/CMOS dynamically reconfigurable system—Part I
Authors: Zhang Wei , Jha Niraj K. , Shang Li
Published: November 2009

Rapid progress on nanodevices points to a promising direction for future circuit design. However, since nanofabrication techniques are not yet mature, implementation of nanocircuits, at least on a large scale, in the near future is infeasible. To ease fabrication and overcome the problem of high defect levels in nanotechnology, hybrid nano/CMOS reconfigurable architectures are attractive choices. Moreover, if the current photolithography fabrication process can be used to manufacture the hybrid chips, the benefits of nanotechnologies can be realized today.

Traditional reconfigurable architectures can only support partial or coarse-grain runtime reconfiguration due to their limited on-chip storage and long off-chip reconfiguration latency. Recent progress on nano Random Access Memories (RAMs), such as carbon nanotube-based RAM (NRAM), Phase-Change Memory (PCM), magnetoresistive RAM (MRAM), etc., provides us with a chance to realize on-chip fine-grain runtime reconfiguration. These nano RAMs have good compatibility with the current fabrication process. By utilizing them in the hybrid design, we can take advantage of both CMOS and nanotechnology, and greatly improve the logic density, resource utilization, and performance of our design.

In this article, we propose a high-performance reconfigurable architecture, called NATURE, that utilizes CMOS logic and nano RAMs. An automatic design flow for NATURE is presented in Part II of the article. In NATURE, the highly dense nonvolatile nano RAMs are distributed throughout the chip to allow large embedded on-chip configuration storage, which enables fast reading and hence supports fine-grain runtime reconfiguration and temporal logic folding of a circuit before being mapped to the architecture. Temporal logic folding can significantly increase the logic density of NATURE (by over an order of magnitude for large circuits) while remaining competitive in performance and power consumption. For ease of exposition, we use NRAMs to illustrate various concepts in this article due to the excellent properties of NRAMs. However, other nano RAMs can also be used instead. Experimental results based on NRAMs establish the efficacy of NATURE.
A defect/error-tolerant nanosystem architecture for DSP
Authors: Tang Weiguo , Wang Lei , Lombardi Fabrizio
Published: November 2009

Emerging technologies such as silicon NanoWires (NW) and Carbon NanoTubes (CNT) have shown great potential for building the next generation of computing systems in the nano ranges. However, the excessive number of defects originating from bottom-up fabrication (such as a self-assembly process) poses a pressing challenge for achieving scalable system integration. This article proposes a new nanosystem architecture that employs nanowire crossbars for Digital Signal Processing (DSP) applications. Distributed arithmetic is utilized such that complex signal processing computation can be mapped into regular memory operations, thus making this architecture well suited for implementation by nanowire crossbars. Furthermore, the inherent features of DSP-type computation provide new insights to remedy errors (as logic/computational manifestation of defects). A new defect/error-tolerant technique that exploits algorithmic error compensation is proposed; at system level different trade-offs between correctness in output and performance are established while retaining low overhead in its implementation. As an instance of its application, the proposed approach has been utilized to a generic DSP nanosystem performing frequency-selective filtering. Simulation results show that the proposed nanoDSP introduces only a minor performance degradation under high defect rates and at a range of operational conditions. The proposed technique also features good scalability and viability for various DSP applications.
Organizing wires for reliability in magnetic QCA
Authors: Dysart Timothy J. , Kogge Peter M.
Published: November 2009

This article investigates, via analytic modeling, how a magnetic QCA wire should be organized to provide the highest reliability. We compare a nonredundant wire and two redundant wire organizations. For all three organizations, a fault rate per unit length is used for comparison; additionally, since extra components are necessary to implement the redundant organizations, these components are faulty as well. We show that the difference between these two fault rates is the main driver for selecting a wire organization. Lastly, we develop a guideline for selecting the most reliable wire organization during the circuit design process.
Molecular identification of ancient and modern mammalian magnesium transporters
Authors: Quamme Gary A.
Published: November 2009

A large number of mammalian Mg2+ transporters have been hypothesized on the basis of physiological data, but few have been investigated at the molecular level. The recent identification of a number of novel proteins that mediate Mg2+ transport has enhanced our understanding of how Mg2+ is translocated across mammalian membranes. Some of these transporters have some similarity to those found in prokaryocytes and yeast cells. Human Mrs2, a mitochondrial Mg2+ channel, shares many of the properties of the bacterial CorA and yeast Alr1 proteins. The SLC41 family of mammalian Mg2+ transporters has a similarity with some regions of the bacterial MgtE transporters. The mammalian ancient conserved domain protein (ACDP) Mg2+ transporters are found in prokaryotes, suggesting an ancient origin. However, other newly identified mammalian transporters, including TRPM6/7, MagT, NIPA, MMgT, and HIP14 families, are not represented in prokaryotic genomes, suggesting more recent development. MagT, NIPA, MMgT, and HIP14 transporters were identified by differential gene expression using microarray analysis. These proteins, which are found in many different tissues and subcellular organelles, demonstrate a diversity of structural properties and biophysical functions. The mammalian Mg2+ transporters have no obvious amino acid similarities, indicating that there are many ways to transport Mg2+ across membranes. Most of these proteins transport a number of divalent cations across membranes. Only MagT1 and NIPA2 are selective for Mg2+. Many of the identified mammalian Mg2+ transporters are associated with a number of congenital disorders encompassing a wide range of tissues, including intestine, kidney, brain, nervous system, and skin. It is anticipated that future research will identify other novel Mg2+ transporters and reveal other diseases.
Coordinated control of volume regulatory Na+/H+ and K+/H+ exchange pathways in Amphiuma red blood cells
Authors: Ortiz-Acevedo Alejandro , Rigor Robert R. , Maldonado Hector M. , Cala Peter M.
Published: November 2009

The Na+/H+ and K+/H+ exchange pathways of Amphiuma tridactylum red blood cells (RBCs) are quiescent at normal resting cell volume yet are selectively activated in response to cell shrinkage and swelling, respectively. These alkali metal/H+ exchangers are activated by net kinase activity and deactivated by net phosphatase activity. We employed relaxation kinetic analyses to gain insight into the basis for coordinated control of these volume regulatory ion flux pathways. This approach enabled us to develop a model explaining how phosphorylation/dephosphorylation-dependent events control and coordinate the activity of the Na+/H+ and K+/H+ exchangers around the cell volume set point. We found that the transition between initial and final steady state for both activation and deactivation of the volume-induced Na+/H+ and K+/H+ exchange pathways in Amphiuma RBCs proceed as a single exponential function of time. The rate of Na+/H+ exchange activation increases with cell shrinkage, whereas the rate of Na+/H+ exchange deactivation increases as preshrunken cells are progressively swollen. Similarly, the rate of K+/H+ exchange activation increases with cell swelling, whereas the rate of K+/H+ exchange deactivation increases as preswollen cells are progressively shrunken. We propose a model in which the activities of the controlling kinases and phosphatases are volume sensitive and reciprocally regulated. Briefly, the activity of each kinase-phosphatase pair is reciprocally related, as a function of volume, and the volume sensitivities of kinases and phosphatases controlling K+/H+ exchange are reciprocally related to those controlling Na+/H+ exchange.
Protein-protein interaction between cPLA2 and splice variants of α-subunit of BK channels
Authors: Li Juan , Al-Khalili Otor , Ramosevac Semra , Eaton Douglas C. , Denson Donald D.
Published: November 2009

Altering the splice variant composition of large-conductance Ca2+-activated potassium (BK) channels can alter their activity and apparent sensitivity to Ca2+ and other regulators of activity. We hypothesized that differences in the responsiveness to arachidonic acid of GH3 and GH4 cells was due to a difference in two splice variants, one present in GH3 cells and the other in GH4 cells. The sequences of the two splice variants differ from one another in several ways, but the largest difference is the presence or absence of 27 amino acids in the COOH terminus of the BK α-subunit. Open probability of the variant containing the 27 amino acids is significantly increased by arachidonic acid, while the variant lacking the 27 amino acids is insensitive to arachidonic acid. In addition, sensitivity of BK channels to arachidonic acid depends on cytosolic phospholipase A2 (cPLA2). Here we used the Mammalian Matchmaker two-hybrid assay and two BK α-subunit constructs with [rSlo(27)] and without [rSlo(0)] the 27-amino acid motif to determine whether cPLA2 associates with one construct [rSlo(27)] and not the other. We hypothesized that differential association of cPLA2 might explain the differing responsiveness of the two constructs and GH3 and GH4 cells to arachidonic acid. We found that cPLA2 is strongly associated with the COOH terminus of rSlo(27) and only very weakly associated with rSlo(0). We also found that arachidonic acid has a lower affinity for rSlo(0) than for rSlo(27). We conclude that the lack of response of BK channels in GH4 cells to arachidonic acid can be explained, in part, by the poor binding of cPLA2 to the COOH terminus of the rSlo(0) α-subunit, which is very similar to the splice variant found in the arachidonic acid-insensitive GH4 cells.
Mechanistic basis of Rho GTPase-induced extracellular matrix synthesis in trabecular meshwork cells
Authors: Pattabiraman Padmanabhan P. , Rao Ponugoti Vasantha
Published: November 2009

Elevated intraocular pressure arising from impaired aqueous humor drainage through the trabecular pathway is a major risk factor for glaucoma. To understand the molecular basis for Rho GTPase-mediated resistance to aqueous humor drainage, we investigated the possible interrelationship between actomyosin contractile properties and extracellular matrix (ECM) synthesis in human trabecular meshwork (TM) cells expressing a constitutively active form of RhoA (RhoAV14). TM cells expressing RhoAV14 exhibited significant increases in fibronectin, tenascin C, laminin, α-smooth muscle actin (α-SMA) levels, and matrix assembly in association with increased actin stress fibers and myosin light-chain phosphorylation. RhoAV14-induced changes in ECM synthesis and actin cytoskeletal reorganization were mimicked by lysophosphatidic acid and TGF-β2, known to increase resistance to aqueous humor outflow and activate Rho/Rho kinase signaling. RhoAV14, lysophosphatidic acid, and TGF-β2 stimulated significant increases in Erk1/2 phosphorylation, paralleled by profound increases in fibronectin, serum response factor (SRF), and α-SMA expression. Treatment of RhoA-activated TM cells with inhibitors of Rho kinase or Erk, on the other hand, decreased fibronectin and α-SMA levels. Although suppression of SRF expression (both endogenous and RhoA, TGF-β2-stimulated) via the use of short hairpin RNA decreased α-SMA levels, fibronectin was unaffected. Conversely, fibronectin induced α-SMA expression in an SRF-dependent manner. Collectively, data on RhoA-induced changes in actomyosin contractile activity, ECM synthesis/assembly, and Erk activation, along with fibronectin-induced α-SMA expression in TM cells, reveal a potential molecular interplay between actomyosin cytoskeletal tension and ECM synthesis/assembly. This interaction could be significant for the homeostasis of aqueous humor drainage through the pressure-sensitive trabecular pathway.
Junctophilin damage contributes to early strength deficits and EC coupling failure after eccentric contractions
Authors: Corona B. T. , Balog E. M. , Doyle J. A. , Rupp J. C. , Luke R. C. , Ingalls C. P.
Published: November 2009

Junctophilins (JP1 and JP2) are expressed in skeletal muscle and are the primary proteins involved in transverse (T)-tubule and sarcoplasmic reticulum (SR) membrane apposition. During the performance of eccentric contractions, the apposition of T-tubule and SR membranes may be disrupted, resulting in excitation-contraction (EC) coupling failure and thus reduced force-producing capacity. In this study, we made three primary observations: 1) through the first 3 days after the performance of 50 eccentric contractions in vivo by the left hindlimb anterior crural muscles of female mice, both JP1 and JP2 were significantly reduced by ∼50% and 35%, respectively, while no reductions were observed after the performance of nonfatiguing concentric contractions; 2) following the performance of a repeated bout of 50 eccentric contractions in vivo, only JP1 was immediately reduced (∼30%) but recovered by 3-day postinjury in tandem with the recovery of strength and EC coupling; and 3) following the performance of 10 eccentric contractions at either 15° or 35°C by isolated mouse extensor digitorum longus (EDL) muscle, isometric force, EC coupling, and JP1 and JP2 were only reduced after the eccentric contractions performed at 35°C. Regression analysis of JP1 and JP2 content in tibialis anterior and EDL muscles from each set of experiments indicated that JP damage is significantly associated with early (0–3 days) strength deficits after performance of eccentric contractions ( R = 0.49; P < 0.001). As a whole, the results of this study indicate that JP damage plays a role in early force deficits due to EC coupling failure following the performance of eccentric contractions.
Ammonium-dependent sodium uptake in mitochondrion-rich cells of medaka (Oryzias latipes) larvae
Authors: Wu Shu-Chen , Horng Jiun-Lin , Liu Sian-Tai , Hwang Pung-Pung , Wen Zhi-Hong , Lin Chan-Shing , Lin Li-Yih
Published: November 2009

In this study, a scanning ion-selective electrode technique (SIET) was applied to measure H+, Na+, and NH4+ gradients and apparent fluxes at specific cells on the skin of medaka larvae. Na+ uptake and NH3/NH4+ excretion were detected at most mitochondrion-rich cells (MRCs). H+ probing at MRCs revealed two group of MRCs, i.e., acid-secreting and base-secreting MRCs. Treatment with EIPA (100 μM) blocked 35% of the NH3/NH4+ secretion and 54% of the Na+ uptake, suggesting that the Na+/H+ exchanger (NHE) is involved in Na+ and NH3/NH4+ transport. Low-Na+ water (<0.001 mM) or high-NH4+ (5 mM) acclimation simultaneously increased Na+ uptake and NH3/NH4+ excretion but decreased or even reversed the H+ gradient at the skin and MRCs. The correlation between NH4+ production and H+ consumption at the skin surface suggests that MRCs excrete nonionic NH3 (base) by an acid-trapping mechanism. Raising the external NH4+ significantly blocked NH3/NH4+ excretion and Na+ uptake. In contrast, raising the acidity of the water (pH 7 to pH 6) enhanced NH3/NH4+ excretion and Na+ uptake by MRCs. In situ hybridization and real-time PCR showed that the mRNAs of the Na+/H+ exchanger ( slc9a3) and Rhesus glycoproteins ( Rhcg1 and Rhbg) were colocalized in MRCs of medaka, and their expressions were induced by low-Na+ acclimation. This study suggests a novel Na+/NH4+ exchange pathway in apical membranes of MRCs, in which a coupled NHE and Rh glycoprotein is involved and the Rh glycoprotein may drive the NHE by generating H+ gradients across apical membranes of MRCs.
Differential effects of hypoxia on osteochondrogenic potential of human adipose-derived stem cells
Authors: Merceron Christophe , Vinatier Claire , Portron Sophie , Masson Martial , Amiaud Jérôme , Guigand Lydie , Chérel Yan , Weiss Pierre , Guicheux Jérôme
Published: November 2009

Human adipose tissue-derived stem cells (hATSC) have been contemplated as reparative cells for cartilage engineering. Chondrogenic differentiation of hATSC can be induced by an enriched culture medium and a three-dimensional environment. Given that bone is vascularized and cartilage is not, oxygen tension has been suggested as a regulatory factor for osteochondrogenic differentiation. Our work aimed at determining whether hypoxia affects the osteochondrogenic potential of hATSC. hATSC were cultured in chondrogenic or osteogenic medium for 28 days, in pellets or monolayers, and under 5% or 20% oxygen tension. Cell differentiation was monitored by real-time PCR (COL2A1, aggrecan, Runx2, and osteocalcin). The chondrogenic differentiation was further evaluated by Alcian blue and immunohistological staining for glycosaminoglycans (GAGs) and type II collagen, respectively. Osteogenic differentiation was also assessed by the staining of mineralized matrix (Alizarin Red) and measurement of alkaline phosphatase (ALP) activity. The expression of chondrogenic markers was upregulated when hATSC were exposed to hypoxia in chondrogenic medium. Conversely, osteocalcin expression, mineralization, and ALP activity were severely reduced under hypoxic conditions even in the presence of osteogenic medium. Our data strongly suggest that hypoxia favors the chondrogenic differentiation of hATSC as evidenced by the expression of the chondrogenic markers, whereas it could alter their osteogenic potential. Our results highlight the differential regulatory role of hypoxia on the chondrogenic and osteogenic differentiation processes of hATSC. These data could help us exploit the potential of tissue engineering and stem cells to replace or restore the function of osteoarticular tissues.
Electrophysiological and morphological features underlying neurotransmission efficacy at the splanchnic nerve-chromaffin cell synapse of bovine adrenal medulla
Authors: de Diego Antonio M. G.
Published: November 2009

The ability of adrenal chromaffin cells to fast-release catecholamines relies on their capacity to fire action potentials (APs). However, little attention has been paid to the requirements needed to evoke the controlled firing of APs. Few data are available in rodents and none on the bovine chromaffin cell, a model extensively used by researchers. The aim of this work was to clarify this issue. Short puffs of acetylcholine (ACh) were fast perifused to current-clamped chromaffin cells and produced the firing of single APs. Based on the currents generated by such ACh applications and previous literature, current waveforms that efficiently elicited APs at frequencies up to 20 Hz were generated. Complex waveforms were also generated by adding simple waveforms with different delays; these waveforms aimed at modeling the stimulation patterns that a chromaffin cell would conceivably undergo upon strong synaptic stimulation. Cholinergic innervation was assessed using the acetylcholinesterase staining technique on the supposition that the innervation pattern is a determinant of the kind of stimuli chromaffin cells can receive. It is concluded that 1) a reliable method to produce frequency-controlled APs by applying defined current injection waveforms is achieved; 2) the APs thus generated have essentially the same features as those spontaneously emitted by the cell and those elicited by fast-ACh perifusion; 3) the higher frequencies attainable peak at around 30 Hz; and 4) the bovine adrenal medulla shows abundant cholinergic innervation, and chromaffin cells show strong acetylcholinesterase staining, consistent with a tight cholinergic presynaptic control of firing frequency.
CCK activates RhoA and Rac1 differentially through Gα13 and Gαq in mouse pancreatic acini
Authors: Sabbatini Maria E. , Bi Yan , Ji Baoan , Ernst Stephen A. , Williams John A.
Published: November 2009

Cholecystokinin (CCK) has been shown to activate RhoA and Rac1, as well as reorganize the actin cytoskeleton and, thereby, modify acinar morphology and amylase secretion in mouse pancreatic acini. The aim of the present study was to determine which heterotrimeric G proteins activate RhoA and Rac1 upon CCK stimulation. Gα13, but not Gα12, was identified in mouse pancreatic acini by RT-PCR and Western blotting. Using specific assays for RhoA and Rac1 activation, we showed that only active Gα13 activated RhoA. By contrast, active Gα13 and Gαq, but not Gαs, slightly increased GTP-bound Rac1 levels. A greater increase in Rac1 activation was observed when active Gα13 and active Gαq were coexpressed. Gαi was not required for CCK-induced RhoA or Rac1 activation. The regulator of G protein signaling (RGS) domain of p115-Rho guanine nucleotide exchange factor (p115-RGS), a specific inhibitor of Gα12/13-mediated signaling, abolished CCK-stimulated RhoA activation. By contrast, both RGS-2, an inhibitor of Gαq, and p115-RGS abolished CCK-induced Rac1 activation, which was PLC pathway-independent. Active Gαq and Gα13, but not Gαs, induced morphological changes and actin redistribution similar to 1 nM CCK. CCK-induced actin cytoskeletal reorganization was inhibited by RGS-2, but not by p115-RGS, whereas CCK-induced amylase secretion was blocked by both inhibitors. Together, these findings indicate that, in mouse pancreatic acini, Gα13 links CCK stimulation to the activation of RhoA, whereas both Gα13 and Gαq link CCK stimulation to the activation of Rac1. CCK-induced actin cytoskeletal reorganization is mainly mediated by Gαq. By contrast, Gα13 and Gαq signaling are required for CCK-induced amylase secretion.
Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis
Authors: Mizushima Takashi , Sasaki Makoto , Ando Tomoaki , Wada Tsuneya , Tanaka Mamoru , Okamoto Yasuyuki , Ebi Masahide , Hirata Yosikazu , Murakami Kenji , Mizoshita Tsutomu , Shimura Takaya , Kubota Eiji , Ogasawara Naotaka , Tanida Satoshi , Kataoka Hiromi , Kamiya Takeshi , Alexander J. S. , Joh Takashi
Published: November 2009

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is an important target in the treatment of inflammatory bowel disease (IBD). Recently, treatment of IBD with an antibody to α4β7-integrin, a ligand for MAdCAM-1, has been an intense focus of research. Our aim was to clarify the mechanism by which MAdCAM-1 is regulated via angiotensin II type 1 receptor (AT1R), and to verify if AT1R might be a novel target for IBD treatment. The role of AT1R in the expression of MAdCAM-1 in SVEC (a murine high endothelial venule cell) and MJC-1 (a mouse colonic endothelial cell) was examined following cytokine stimulation. We further evaluated the effect of AT1R on the pathogenesis of immune-mediated colitis using AT1R-deficient (AT1R−/−) mice and a selective AT1R blocker. AT1R blocker significantly suppressed MAdCAM-1 expression induced by TNF-α, but did not inhibit phosphorylation of p38 MAPK or of IκB that modulate MAdCAM-1 expression. However, NF-κB translocation into the nucleus was inhibited by these treatments. In a murine colitis model induced by dextran sulfate sodium, the degree of colitis, judged by body weight loss, histological damage, and the disease activity index, was much milder in AT1R−/− than in wild-type mice. The expression of MAdCAM-1 was also significantly lower in AT1R−/− than in wild-type mice. These results suggest that AT1R regulates the expression of MAdCAM-1 under colonic inflammatory conditions through regulation of the translocation of NF-κB into the nucleus. Furthermore, inhibition of AT1R ameliorates colitis in a mouse colitis model. Therefore, AT1R might be one of new therapeutic target of IBD via regulation of MAdCAM-1.
TGF-β downregulates PTEN via activation of NF-κB in pancreatic cancer cells
Authors: Chow Jimmy Y. C. , Ban Makiko , Wu Helen L. , Nguyen Flang , Huang Mei , Chung Heekyung , Dong Hui , Carethers John M.
Published: November 2009

TGF-β utilizes receptor-activated SMAD signaling to mediate growth suppression; however, non-SMAD signaling that modulates the TGF-β response in epithelial cells become apparent when the SMAD signaling is abrogated, a common occurrence in pancreatic cancers. Here, we examined whether TGF-β utilized NF-κB to downregulate PTEN, a gene that is rarely mutated in pancreatic cancers. SMAD4-null BxPc3 and CAPAN-1 pancreatic cancer cells were treated with TGF-β (10 ng/ml) and lysed, and cellular proteins were analyzed by Western blots using p-IκB, p65, and PTEN antibodies. PTEN promoter and NF-κB activities were assessed by PTEN-luc and p-NF-luc constructs, respectively. Dominant negative p-IκB-α-M (NF-κB superrepressor) was used to block activation of NF-κB. Cell motility was assessed by Boyden chamber migration assay. TGF-β induced IκB-α phosphorylation followed by NF-κB p65 subunit nuclear translocation and increased NF-κB activity. IκB-α-M blocked TGF-β-induced NF-κB activity, reversed downregulated PTEN promoter activity and PTEN expression, and prevented augmentation of cell motility induced by TGF-β. SMAD4 restoration, but not knockdown of SMAD2 and/or 3, reversed TGF-β-induced NF-κB activity. Thus TGF-β suppresses PTEN in pancreatic cancer cells through NF-κB activation and enhances cell motility and invasiveness in a SMAD4-independent manner that can be counteracted when TGF-β-SMAD signaling is restored. The TGF-β/NF-κB/PTEN cascade may be a critical pathway for pancreatic cancer cells to proliferate and metastasize.
Mechanisms of transcriptional modulation of the human anion exchanger SLC26A3 gene expression by IFN-γ
Authors: Saksena Seema , Singla Amika , Goyal Sonia , Katyal Shivani , Bansal Nikhil , Gill Ravinder K. , Alrefai Waddah A. , Ramaswamy Krishnamurthy , Dudeja Pradeep K.
Published: November 2009

Two members of the SLC26 gene family, SLC26A3 or DRA (downregulated in adenoma) and SLC26A6 (putative anion transporter 1, PAT1), are known to play a major role in apical Cl−/OH−(HCO3−) exchange process in the human intestine. We have previously shown the inhibitory effects of IFN-γ (30 ng/ml, 24 h) on both SLC26A3 and A6 expression and promoter activity. We also demonstrated that the effects of IFN-γ on SLC26A6 gene expression were mediated via IRF-1 transcription factor. However, the molecular mechanisms underlying the transcriptional modulation of SLC26A3 gene expression by IFN-γ in the intestine are not known. The present studies were, therefore, designed to elucidate the signaling mechanisms and transcription factor(s) involved in mediating the inhibitory effects of IFN-γ on DRA promoter (p-−1183/+114) activity. Deletion analysis indicated that the IFN-γ response element is located within the −1183 to −790 region, and sequence analysis of this region revealed the presence of potential γ-activated site (GAS), a binding site (−933/−925 bp) for signal transducer and activator of transcription factor 1 (STAT1). Mutations in the potential GAS element abrogated the inhibitory effects of IFN-γ. These studies provide evidence for the involvement of STAT1 in the inhibition of SLC26A3 gene expression by IFN-γ in the human intestine.
Noninvasive functional liver blood flow measurement: comparison between bolus dose and steady-state clearance of sorbitol in a small-rodent model
Authors: van der Hoven Ben , van Pelt Hans , Swart Eleonore L. , Bonthuis Fred , Tilanus Huug W. , Bakker Jan , Gommers Diederik
Published: November 2009

Plasma clearance of d-sorbitol, a nontoxic polyol, occurs predominantly in the liver and has been used to measure functional liver blood flow after bolus and steady- state intravenous administration. However, it is not known which of these two administration methods is superior. Therefore, plasma d-sorbitol clearance was studied in an animal model both after a bolus dose and under steady-state (SS) conditions and compared directly with liver blood flow, under normal conditions, and after the induction of endotoxin (LPS) sepsis. Adult male Wistar rats (526 ± 38 g body wt; n = 27) were anesthetized and mechanically ventilated. Hemodynamics, hepatic arterial flow, and portal venous flow were measured. Two groups were studied, namely healthy animals that served as controls and a sepsis group that received 5 mg/kg LPS intravenously ( Escherichia coli O127:B8). Each animal received either a SS infusion (0.1 mg/100 g body wt per min) or a bolus (3 mg/100 g body wt) of a 5% d-sorbitol solution intravenously in a randomized order. After the initial measurements and a 60-min pause time in between ( T1/2,sorbitol= 9 min), a crossover was done. The hepatic clearance of d-sorbitol in the control group showed a good correlation between bolus and SS (Spearman's r = 0.7681, P = 0.0004), and both techniques correlated well with total liver blood flow (TLBF) ( r = 0.7239, P = 0.0023 and r = 0.7226, P = 0.0023, respectively). Also in the sepsis group there was a good correlation between bolus and SS sorbitol clearance ( r = 0.6655, P = 0.0182). In the sepsis group, only the SS clearance correlated with TLBF ( r = 0.6434, P = 0.024). In conclusion, in normal and under septic conditions, hepatic clearance of d-sorbitol either by bolus or a SS infusion is comparable. In healthy animals, this also correlated well with TLBF but not in septic conditions. However, this is expected because of the changes in the liver microcirculation, shunting, and decreased hepatocyte function in sepsis.
Adipose tissue-derived stem cells inhibit neointimal formation in a paracrine fashion in rat femoral artery
Authors: Takahashi Masao , Suzuki Etsu , Oba Shigeyoshi , Nishimatsu Hiroaki , Kimura Kenjiro , Nagano Tetsuo , Nagai Ryozo , Hirata Yasunobu
Published: November 2009

Subcutaneous adipose tissue contains a lot of stem cells [adipose-derived stem cells (ASCs)] that can differentiate into a variety of cell lineages. In this study, we isolated ASCs from Wistar rats and examined whether ASCs would efficiently differentiate into vascular endothelial cells (ECs) in vitro. We also administered ASCs in a wire injury model of rat femoral artery and examined their effects. ASCs expressed CD29 and CD90, but not CD34, suggesting that ASCs resemble bone marrow-derived mesenchymal stem cells. When induced to differentiate into ECs with endothelial growth medium (EGM), ASCs expressed Flt-1, but not Flk-1 or mature EC markers such as CD31 and vascular endothelial cadherin. ASCs produced angiopoietin-1 when they were cultured in EGM. ASCs stimulated the migration of EC, as assessed by chemotaxis assay. When ASCs that were cultured in EGM were injected in the femoral artery, the ASCs potently and significantly inhibited neointimal formation without being integrated in the endothelial layer. EGM-treated ASCs significantly suppressed neointimal formation even when they were administered from the adventitial side. ASC administration significantly promoted endothelial repair. These results suggested that although ASCs appear to have little capacity to differentiate into mature ECs, ASCs have the potential to secrete paracrine factors that stimulate endothelial repair. Our results also suggested that ASCs inhibited neointimal formation via their paracrine effect of stimulation of EC migration in situ rather than the direct integration into the endothelial layer.
Transthoracic Doppler echocardiography to noninvasively assess coronary vasoconstrictor and dilator responses in humans
Authors: Momen Afsana , Kozak Mark , Leuenberger Urs A. , Ettinger Steven , Blaha Cheryl , Mascarenhas Vernon , Lendel Vasili , Herr Michael D. , Sinoway Lawrence I.
Published: November 2009

Human studies of coronary circulation are limited because of methodological issues. Recently, a noninvasive transthoracic duplex ultrasound (TTD) technique has emerged as an important tool to measure coronary blood flow velocity (CBV) in conscious humans. We employed two protocols to determine whether noninvasive “native” coronary artery velocity responses to constrictor or dilator stimuli assessed by TTD provide reliable data. In the first protocol, coronary vascular resistance (CVR = diastolic blood pressure/CBV) responses to static handgrip were examined in the left internal mammary artery (LIMA) and native left anterior descending artery (LAD) into which the graft was inserted (patient age 63 ± 3 years). Our prior report documented increased CVR in the LIMA graft during static handgrip (Momen et al., J Appl Physiol 102: 735–739, 2007). We hypothesized that the magnitude of increases in CVR during handgrip would be similar in the LIMA graft and LAD in the same individual. Percent increases in CVR were similar in the LIMA and distal native LAD (27 ± 4% vs. 28 ± 6%). In the second protocol, we studied six patients (age 61 ± 3 years) who underwent cardiac catheterization of the LAD. We compared coronary vasodilator responses to intravenous adenosine infusion (0.14 mg·kg−1·min−1) obtained by intracoronary Doppler guidewire technique and TTD on separate studies. The relative increases in CBV with adenosine obtained by intracoronary Doppler guidewire and TTD were similar (62 ± 10% vs. 65 ± 12%). Noninvasive TTD provides reliable human coronary circulatory constrictor and dilator data.
Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite
Authors: Ingram Thomas E. , Pinder Andrew G. , Bailey Damian M. , Fraser Alan G. , James Philip E.
Published: November 2009

Inorganic nitrite has recently been recognized to possess vascular activity that is enhanced in hypoxia. This has been demonstrated in humans in the forearm vascular bed. In animal models nitrite reduces pulmonary vascular resistance, but its effects upon the pulmonary circulation of humans have not yet been demonstrated. This paradigm is of particular interest mechanistically since the pulmonary vasculature is known to behave differently to the systemic. To investigate, 18 healthy volunteers were studied in a hypoxic chamber (inspired oxygen, 12%) or while breathing room air. Each received an infusion of sodium nitrite (1 μmol/min) or 0.9% saline. Three protocols were performed: nitrite/hypoxia ( n = 12), saline/hypoxia ( n = 6), and nitrite/normoxia ( n = 6). Venous blood was sampled for plasma nitrite, forearm blood flow was measured by strain-gauge plethysmography, and pulmonary arterial pressure was measured by transthoracic echocardiography. Plasma nitrite doubled and clearance kinetics were similar whether nitrite was infused in hypoxia or normoxia. During hypoxia, nitrite increased forearm blood flow (+36%, P < 0.001) and reduced three separate indirect indexes of pulmonary arterial pressure by 16%, 12%, and 17% ( P < 0.01). Pulmonary, but not systemic, arterial effects persisted 1 h after stopping the infusion, at a time when plasma nitrite had returned to baseline. No effects were observed during normoxia. Therefore, in hypoxic but not normoxic subjects, sodium nitrite causes arterial and pulmonary vasodilatation. In addition, hypoxia-induced pulmonary vasoconstriction was attenuated for a prolonged period and not dependent on a simultaneous elevation of plasma nitrite. This finding is consistent with the direct extravascular metabolism of nitrite to nitric oxide to effect hypoxia-associated bioactivity.