bluuebunny/crossref_metadata_2025 huggingface dataset:
Origine et formation de différents types de vacuoles induites par la multiplication d'Alphavirus Sindbis dans divers systemes cellulaires
Authors: Lombard Yves , Poindron Philippe , Porte Aimé
Published: April 2010

Spherule-containing vacuoles and nucleocapsid-bearing vacuoles (cytopathic vacuoles types 1 and 2 respectively of Grimley et al. 1968) induced by Alphavirus Sindbis were studied in brains from newborn mice, chicken embryo fibroblasts, and two lines of tumoral glial cells from muridae. Endoplasmic reticulum (ER) elements and finely granular electron-dense material also seen in contact with nucleocapsids seemed to be involved in the formation of the classical single-membrane spherule-containing vacuoles. A second type of spherule-containing vacuoles were characterized by their double membrane and an amorphous electron-dense content and were probably derived from mitochondria. Nucleocapsid-bearing vacuoles were formed from modified ER elements and seemed to be linked to excessive synthesis of viral material. Such ER alterations were not observed in RG6 cells. In these cells, there were only spherule-containing vacuoles, while nucleocapsids were seen associated with the cytoplasmic membrane only.
A method for establishing stable concentration gradients in agar suitable for studying chemotaxis on a solid surface
Authors: Shimkets Lawrence J. , Dworkin Martin , Keller Kenneth H.
Published: April 2010

A simple technique has been developed for establishing stable gradients of a substance in agar. The technique involves the creation of a spherically symmetric concentration profile in which concentration varies inversely with the distance from the source and is independent of the diffusion coefficient of the substance. It has been shown that the gradients established with this technique are stable forat least 190 h, and, on a theoretical basis, they can be kept stable for more than 1000 h. Time-variant gradients can also be established, if desired, using the same system and limiting either the source or the agar sink. It must be emphasized that a stable gradient cannot be obtained by using a shallow agar layer as a sink. The use of such conditions (e.g. the agar in a standard petri dish) can result only in time-variant gradients. The solution to the diffusion equation in a spherically symmetric system establishes the expected concentration profile, the basis for adjusting it, and the parameters that control the behavior of the system. Some useful applications for examining chemotaxis on a solid surface as well as possible further developments are discussed.
Interspecific relationships of antibiotic resistance in Staphylococcus sp.: isolation and comparison of plasmids determining tetracycline resistance in S. aureus and S. epidermidis
Authors: Groves David J.
Published: April 2010

Tetracycline resistance in Staphylococcus aureus and S. epidermidis was confirmed to be determined by plasmids of the same size. Digestion of plasmids from each strain with restriction endonucleases EcoRl, HindIII, and AluI showed a high degree of similarity in their DNA sequences. At least 10 cleavage sites which appear to be common to both plasmids were detected. An additional three cleavage sites appear to be unique to the S. epidermidis plasmid. Further, a survey of recent clinical isolates of tetracycline-resistant staphylococci detected 7 of 10 S. aureus strains and 8 of 9 S. epidermidis strains with plasmids which were of similar size to the purified reference plasmids and which, by hybridization, showed extensive DNA homology to the S. aureus reference plasmid DNA.
AN ADAPTIVE LAYER-BASED LOCAL BINARIZATION TECHNIQUE FOR DEGRADED DOCUMENTS
Authors: MAKRIDIS MICHAEL , PAPAMARKOS N.
Published: April 2010

This paper presents a new technique for adaptive binarization of degraded document images. The proposed technique focuses on degraded documents with various background patterns and noise. It involves a preprocessing local background estimation stage, which detects for each pixel that is considered as background one, a proper grayscale value. Then, the estimated background is used to produce a new enhanced image having uniform background layers and increased local contrast. That is, the new image is a combination of background and foreground layers. Foreground and background layers are then separated by using a new transformation which exploits efficiently, both grayscale and spatial information. The final binary document is obtained by combining all foreground layers. The proposed binarization technique has been extensively tested on numerous documents and successfully compared with other well-known binarization techniques. Experimental results, which are based on statistical, visual and OCR criteria, verify the effectiveness of the technique.
ACCURATE IMAGE RETRIEVAL BASED ON COMPACT COMPOSITE DESCRIPTORS AND RELEVANCE FEEDBACK INFORMATION
Authors: CHATZICHRISTOFIS SAVVAS A. , ZAGORIS KONSTANTINOS , BOUTALIS YIANNIS S. , PAPAMARKOS NIKOS
Published: April 2010

In this paper a new set of descriptors appropriate for image indexing and retrieval is proposed. The proposed descriptors address the tremendously increased need for efficient content-based image retrieval (CBIR) in many application areas such as the Internet, biomedicine, commerce and education. These applications commonly store image information in large image databases where the image information cannot be accessed or used unless the database is organized to allow efficient storage, browsing and retrieval. To be applicable in the design of large image databases, the proposed descriptors are compact, with the smallest requiring only 23 bytes per image. The proposed descriptors' structure combines color and texture information which are extracted using fuzzy approaches. To evaluate the performance of the proposed descriptors, the objective Average Normalized Modified Retrieval Rank (ANMRR) is used. Experiments conducted on five benchmarking image databases demonstrate the effectiveness of the proposed descriptors in outperforming other state-of-the-art descriptors. Also, a Auto Relevance Feedback (ARF) technique is introduced which is based on the proposed descriptors. This technique readjusts the initial retrieval results based on user preferences improving the retrieval score significantly. An online demo of the image retrieval system img(Anaktisi) that implements the proposed descriptors can be found at .
LINEAR MOTION BLUR IDENTIFICATION IN NOISY IMAGES USING BISPECTRUM AND FEED-FORWARD BACK PROPAGATION NEURAL NETWORKS
Authors: MOGHADDAM MOHSEN EBRAHIMI
Published: April 2010

Motion blur is one of the most common causes of image corruptions caused by blurring. Several methods have been presented up to now, which precisely identify linear motion blur parameters, but most of them possessed low precision in the presence of the noise. The present paper is aimed to introduce an algorithm for estimating linear motion blur parameters in noisy images. This study presents a method to estimate motion direction by using Radon transform, which is followed by the application of two other different methods to estimate motion length; the first of which is based on one-dimensional power spectrum to estimate parameters of noise free images and the second uses bispectrum modeling in noisy images. A Feed-Forward Back Propagation neural network has been designed on the basis of Weierstrass approximation theorem to model bispectrum and the Delta rule as the network learning rule. The methods were tested on several standard images like Camera man, Lena, Lake, etc. that were degraded by linear motion blur and additive noise. The experimental results have been satisfactory. The proposed method, compared to other related methods, suggests an improvement in the supported lowest SNR and precision of estimation.
A BOOSTED MANIFOLD LEARNING FOR AUTOMATIC FACE RECOGNITION
Authors: LU CHUNYUAN , JIANG JIANMIN , FENG GUOCAN
Published: April 2010

Manifold learning is an effective dimension reduction method to extract nonlinear structures from high dimensional data. Recently, manifold learning has received much attention within the research communities of image analysis, computer vision and document data analysis. In this paper, we propose a boosted manifold learning algorithm towards automatic 2D face recognition by using AdaBoost to select the best possible discriminating projection for manifold learning to exploit the strength of both techniques. Experimental results support that the proposed algorithm improves over existing benchmarks in terms of stability and recognition precision rates.
INTERPRETATION OF AMBIGUOUS ZONE TO IMPROVE THINNING RESULTS OF HANDWRITTEN CHINESE CHARACTERS
Authors: SU ZHE-WEN , CAO ZHONG-SHENG , WANG YUAN-ZHEN
Published: April 2010

The skeleton representation of characters is a fundamental step to handwriting recognition, but traditional skeletonization algorithms always produce unwanted artifacts or pattern distortions at regions with intersections or junctions of strokes. In this paper, we propose a novel method to eliminate these unreliable skeleton segments and improve the skeletonization of handwritten Chinese characters on the basis of ambiguous zone interpretation. This method consists of two main phases. In the first phase, the parts of characters which contain the distortions of skeleton, called ambiguous zones, are detected. Instead of exploiting any corner or dominant point detection, a set of feature points from the original skeleton and the contour information around them are manipulated in our approach. In the phase of interpretation, the continuity of skeleton segments of substrokes is estimated based on the minimum curvature variation criterion, and compensations are made to fix interstices of terminated skeleton segments. Finally, the distorted parts of characters are reconstructed by applying a cubic B-spline interpolation. Experimental results show that the proposed method can detect ambiguous zones with arbitrary shapes accurately, and produce skeletons that are close to human perceptions.
ANALYSIS OF A PHASE-FIELD MODEL FOR TWO-PHASE COMPRESSIBLE FLUIDS
Authors: FEIREISL EDUARD , PETZELTOVÁ HANA , ROCCA ELISABETTA , SCHIMPERNA GIULIO
Published: April 2010

A model describing the evolution of a binary mixture of compressible, viscous, and macroscopically immiscible fluids is investigated. The existence of global-in-time weak solutions for the resulting system coupling the compressible Navier–Stokes equations governing the motion of the mixture with the Allen–Cahn equation for the order parameter is proved without any restriction on the size of initial data.
A METHOD TO FIND IDEAL POINTS FROM IDEAL TRIANGULATIONS
Authors: KABAYA YUICHI
Published: April 2010

We give a method to find ideal points of the character variety of a 3-manifold with toral boundary. This can be easily carried out by using linear algebra.
ALMOST ALTERNATING KNOTS PRODUCING AN ALTERNATING KNOT
Authors: HORIUCHI SUMIKO , OHYAMA YOSHIYUKI
Published: April 2010

Adams et al. introduce the notion of almost alternating links; non-alternating links which have a projection whose one crossing change yields an alternating projection. For an alternating knot K, we consider the number Alm (K) of almost alternating knots which have a projection whose one crossing change yields K. We show that for any given natural number n, there is an alternating knot K with Alm (K) ≥ n.
A BRACKET POLYNOMIAL FOR GRAPHS, II: LINKS, EULER CIRCUITS AND MARKED GRAPHS
Authors: TRALDI LORENZO
Published: April 2010

Let D be an oriented classical or virtual link diagram with directed universe [Formula: see text]. Let C denote a set of directed Euler circuits, one in each connected component of U. There is then an associated looped interlacement graph [Formula: see text] whose construction involves very little geometric information about the way D is drawn in the plane; consequently [Formula: see text] is different from other combinatorial structures associated with classical link diagrams, like the checkerboard graph, which can be difficult to extend to arbitrary virtual links. [Formula: see text] is determined by three things: the structure of [Formula: see text] as a 2-in, 2-out digraph, the distinction between crossings that make a positive contribution to the writhe and those that make a negative contribution, and the relationship between C and the directed circuits in [Formula: see text] arising from the link components; this relationship is indicated by marking the vertices where C does not follow the incident link component(s). We introduce a bracket polynomial for arbitrary marked graphs, defined using either a formula involving matrix nullities or a recursion involving the local complement and pivot operations; the marked-graph bracket of [Formula: see text] is the same as the Kauffman bracket of D. This provides a unified combinatorial description of the Jones polynomial that applies seamlessly to both classical and non-classical virtual links.
NON-GAUSSIAN NOISE-INDUCED FIRING TRANSITIONS AND ORDERED BURSTING IN A THERMO-SENSITIVE NEURON
Authors: GONG YUBING , LIN XIU , HAO YINGHANG , XIE YANHANG , MA XIAOGUANG
Published: April 2010

In this letter, we investigate how a particular kind of non-Gaussian colored noise (NGN), especially the correlation time τ and the departure q from Gaussian noise, affects the chaotic firing behavior in a thermo-sensitive neuron. It is found that transitions between spiking and bursting occur with changing τ or q, and ordered bursting appears when τ is optimal. As τ is increased, the neuron alternately exhibits spiking and bursting when q < 1, but always bursts when q > 1, and chaotic bursts may become ordered at an optimal τ. As q is increased, the neuron also exhibits transitions between spiking and bursting.

These findings provide a new mechanism for the firing transitions in the neuron and present the constructive role of the NGN in the firing activity in the neuron. This reveals that the NGN would play subtle roles in the communication and information processing in the neurons.
INCREASING CHEMICAL SELECTIVITY OF CARBON NANOTUBE-BASED SENSORS BY FLUCTUATION-ENHANCED SENSING
Authors: MOLNÁR DÁNIEL , HESZLER PÉTER , MINGESZ RÓBERT , GINGL ZOLTÁN , KUKOVECZ ÁKOS , KÓNYA ZOLTÁN , HASPEL HENRIK , MOHL MELINDA , SÁPI ANDRÁS , KIRICSI IMRE , KORDÁS KRISZTIÁN , MÄKLIN JANI , HALONEN NIINA , TÓTH GÉZA , MOILANEN HANNU , ROTH SIEGMAR , VAJTAI RÓBERT , AJAYAN PULICKEL M. , POUILLON YANN , RUBIO ANGEL
Published: April 2010

Nowadays gas detection in the ppm and sub-ppm domain is essential in terms of environmental protection as well as reducing sanitary risks. However, detecting systems to perform these measurements (e.g., gas chromatographs) are expensive and take up too much space, thus their use is not likely to become wide-spread. Small, cheap and easily mountable sensors, such as resistive sensors are more applicable for this purpose. But the main disadvantage of these sensors is the lack of chemical selectivity. Yet, a novel method called fluctuation-enhanced sensing (FES), which considers the sensor noise as the source of chemical information, can be used to improve selectivity. Since carbon nanotube (CNT)-based sensors are regarded as promising devices for FES measurements, we investigated whether stationary fluctuations in output signal (dc-resistance) of a CNT sensor could be used to increase chemical selectivity. In this work we prove that FES is applicable to increase selectivity of CNT sensors: air polluting gases ( N2O , NH 3 and H2S ) and their mixtures can be distinguished. Furthermore, we also show that different concentrations of the same analyte can be differentiated and chemical selectivity can be extended into the sub-ppm region.
Glacial Earthquakes in Greenland and Antarctica
Authors: Nettles Meredith , Ekström Göran
Published: April 2010

Glacial earthquakes are a new class of seismic events, first discovered as signals in long-period seismograms recorded on the Global Seismographic Network. Most of these events occur along the coasts of Greenland, where they are spatially related to large outlet glaciers. Glacial earthquakes show a strong seasonality, with most events occurring during the late summer. The rate of glacial-earthquake occurrence increased between 2000 and 2005, with a stabilization of earthquake frequency at 2003–2004 levels in 2006–2008. Recent observations establish a strong temporal correlation between the distinct seismic signals of glacial earthquakes and large ice-loss events in which icebergs of cubic-kilometer scale collapse against the calving face, linking the seismogenic process to the force exerted by these icebergs on the glacier and the underlying solid earth. A sudden change in glacier speed results from these glacial-earthquake calving events. Seasonal and interannual variations in glacier-terminus position account for general characteristics of the temporal variation in earthquake occurrence. Glacial earthquakes in Antarctica are less well studied, but they exhibit several characteristics similar to glacial earthquakes in Greenland.
The Miocene-to-Present Kinematic Evolution of the Eastern Mediterranean and Middle East and Its Implications for Dynamics
Authors: Le Pichon Xavier , Kreemer Corné
Published: April 2010

The present kinematics in the eastern Mediterranean and Middle East is now well constrained by GPS measurements and dominated by a circular counterclockwise motion. While Arabia rotates rigidly, the rotational velocities increase from the Levant to Aegea, causing extension in western Anatolia. We place the present pattern in light of the post–Middle Miocene geological history and propose that in addition to the effects of the Hellenic subduction and Zagros collision-subduction zones on driving the surface motion, an underlying asthenospheric flow is also required. This counterclockwise toroidal flow is expected to exist around the eastern edge of the African slab owing to subduction rollback, and it helps explain the initiation of the North Anatolia Fault, the extrusion and uplift of Anatolia, and the Mid-Miocene to Recent volcanism in eastern Anatolia. The Afar plume had a similar effect on the acceleration of Arabia at 40 Mya.
Isoscapes: Spatial Pattern in Isotopic Biogeochemistry
Authors: Bowen Gabriel J.
Published: April 2010

Isotope ratios of actively cycled elements vary as a function of the biogeochemical processes in which they participate and the conditions under which those processes occur. The resultant spatiotemporal distribution of isotopes in environmental materials can be predicted using models of isotope-fractionating processes and data describing environmental conditions across space and time, and it has been termed an isoscape, or isotopic landscape. Analysis of isoscapes and comparison of isoscape predictions with observational data have been used to test biogeochemical models, calculate aerially integrated biogeochemical fluxes based on isotope mass balance, and determine spatial connectivity in biogeochemical, ecological, and anthropological systems. Isoscape models of varying quality are available for stable H, C, N, and O isotopes in a range of Earth surface systems, but significant opportunities exist to refine our understanding of biogeochemical cycles and our ability to predict isoscapes through the development of more mechanistic and more comprehensive isoscape models.
Orographic Controls on Climate and Paleoclimate of Asia: Thermal and Mechanical Roles for the Tibetan Plateau
Authors: Molnar Peter , Boos William R. , Battisti David S.
Published: April 2010

Prevailing opinion assigns the Tibetan Plateau a crucial role in shaping Asian climate, primarily by heating of the atmosphere over Tibet during spring and summer. Accordingly, the growth of the plateau in geologic time should have written a signature on Asian paleoclimate. Recent work on Asian climate, however, challenges some of these views. The high Tibetan Plateau may affect the South Asian monsoon less by heating the overlying atmosphere than by simply acting as an obstacle to southward flow of cool, dry air. The East Asian “monsoon” seems to share little in common with most monsoons, and its dynamics may be affected most by Tibet's lying in the path of the subtropical jet stream. Although the growing plateau surely altered Asian climate during Cenozoic time, the emerging view of its role in present-day climate opens new challenges for interpreting observations of both paleoclimate and modern climate.
Forming Planetesimals in Solar and Extrasolar Nebulae
Authors: Chiang E. , Youdin A.N.
Published: April 2010

Planets are built from planetesimals: solids larger than a kilometer that grow by colliding in pairs. Planetesimals themselves are unlikely to form by two-body collisions alone; subkilometer objects have gravitational fields individually too weak, and electrostatic attraction is too feeble for growth beyond a few centimeters. We review the possibility that planetesimals form when self-gravity brings together vast ensembles of small particles. Even when self-gravity is weak, aerodynamic processes can accumulate solids relative to gas, paving the way for gravitational collapse. Particles pile up as they drift radially inward. Gas turbulence stirs particles but can also seed collapse by clumping them. Whereas the feedback of solids on gas triggers vertical-shear instabilities that obstruct self-gravity, this same feedback triggers streaming instabilities that strongly concentrate particles. Numerical simulations find that solids ∼10–100 cm in size gravitationally collapse in turbulent disks. We outline areas for progress, including the possibility that still smaller objects self-gravitate.
Lessons Learned from the 2004 Sumatra-Andaman Megathrust Rupture
Authors: Shearer Peter , Bürgmann Roland
Published: April 2010

The 2004 Sumatra-Andaman earthquake has been extensively studied because of its great size and devastating consequences. Large amounts of high-quality seismic, geodetic, and geologic data have led to a number of proposed models for its length, duration, fault geometry, rupture velocity, and slip history. The latest of these models vary in their details but now largely agree in their large-scale features, which include significant coseismic slip along the entire 1300- to 1500-km rupture, the bulk of which occurred fast enough to radiate seismic waves. The earthquake's enormous size has challenged conventional processing approaches and stimulated the development of new analysis and inversion methods, including multiple-source inversions, high-frequency body-wave imaging, and satellite observations of tsunami heights and gravity changes. The Sumatra megathrust earthquake was the largest in 40 years and is by far the best documented, but it does not seem fundamentally different in its properties from other large subduction-zone earthquakes.
The Hellenic Subduction System: High-Pressure Metamorphism, Exhumation, Normal Faulting, and Large-Scale Extension
Authors: Ring Uwe , Glodny Johannes , Will Thomas , Thomson Stuart
Published: April 2010

The Cenozoic history of the retreating Hellenic subduction system in the eastern Mediterranean involves subduction, accretion, arc magmatism, exhumation, normal faulting, and large-scale continental extension from ∼60 Mya until the Recent. Ages for high-pressure metamorphism in the central Aegean Sea region range from ∼53 Ma in the north (the Cyclades islands) to ∼25−20 Ma in the south (Crete). Younging of high-pressure metamorphism reflects the southward retreat of the Hellenic subduction zone. The shape of pressure-temperature-time paths of high-pressure rocks is remarkably similar across all tectonic units, suggesting a steady-state thermal profile of the subduction system and persistence of deformation and exhumation styles. The high-pressure metamorphic events were caused by the underthrusting of fragments of continental crust that were superimposed on slab retreat. Most of the exhumation of high-pressure units occurred in extrusion wedges during ongoing lithospheric convergence. At 23–19 Mya large-scale lithospheric extension commenced, causing metamorphic core complexes and the opening of the Aegean Sea basin. This extensional stage caused limited exhumation at the margins of the Aegean Sea but accomplished the major part of the exhumation of high-grade rocks that formed between 21 and 16 Mya in the central Aegean. The age pattern of extensional faults and contoured maps of fission-track cooling ages do not show a simple southward progression. Our review of lithologic, structural, metamorphic, and geochronologic data is consistent with a temporal link between the draping of the subducted slab over the 660-km discontinuity and the large-scale extension causing the opening of the Aegean Sea basin.
The apical (hPepT1) and basolateral peptide transport systems of Caco-2 cells are regulated by AMP-activated protein kinase
Authors: Pieri Myrtani , Christian Helen C. , Wilkins Robert J. , Boyd C. A. R. , Meredith David
Published: April 2010

The effect of 5-aminoimidazole-4-carboxamide-ribonucleoside (AICAR) activation of the AMP-activated protein kinase (AMPK) on the transport of the model radiolabeled dipeptide [3H]-D-Phe-L-Gln was investigated in the human epithelial colon cancer cell line Caco-2. Uptake and transepithelial fluxes of [3H]-D-Phe-L-Gln were carried out in differentiated Caco-2 cell monolayers, and hPepT1 and glucose transporter 2 (GLUT2) protein levels were quantified by immunogold electron microscopy. AICAR treatment of Caco-2 cells significantly inhibited apical [3H]-D-Phe-L-Gln uptake, matched by a decrease in brush-border membrane hPepT1 protein but with a concomitant increase in the facilitated glucose transporter GLUT2. A restructuring of the apical brush-border membrane was seen by electron microscopy. The hPepT1-mediated transepithelial (A-to-B) peptide flux across the Caco-2 monolayers showed no significant alteration in AICAR-treated cells. The electrical resistance in the AICAR-treated monolayers was significantly higher compared with control cells. Inhibition of the sodium/hydrogen exchanger 3 (NHE3) had an additive effect to AICAR, suggesting that the AMPK effect is not via NHE3. Fluorescence measurement of intracellular pH showed no reduction in the proton gradient driving PepT1-mediated apical uptake. The reduction in apical hPepT1 protein and dipeptide uptake after AICAR treatment in Caco-2 cells demonstrates a regulatory effect of AMPK on hPepT1, along with an influence on both the microvilli and tight junction structures. The absence of an associated reduction in transepithelial peptide movement implies an additional stimulatory effect of AICAR on the basolateral peptide transport system in these cells. These results provide a link between the hPepT1 transporter and the metabolic state of this model enterocyte.
CHOP and AP-1 cooperatively mediate PUMA expression during lipoapoptosis
Authors: Cazanave Sophie C. , Elmi Nafisa A. , Akazawa Yuko , Bronk Steven F. , Mott Justin L. , Gores Gregory J.
Published: April 2010

Endoplasmic reticulum (ER) stress-mediated apoptosis is a key feature of hepatocyte cytotoxicity by saturated free fatty acids (FFA). This lipoapoptosis is dependent, in part, on the transcriptional upregulation of the BH3-only protein PUMA (p53 upregulated modulator of apoptosis). Although the activator protein (AP)-1 complex facilitates PUMA expression by saturated FFA, the transcription factor CAAT/enhancer binding homologous protein (CHOP) is also induced by ER stress and promotes apoptosis. To integrate the role of these two transcription factors in ER stress-induced apoptosis, we examined the relative contribution of CHOP and AP-1 in mediating PUMA induction by saturated FFA. Our results demonstrate that short-hairpin RNA-targeted knockdown of CHOP attenuates palmitate-induced apoptosis in Huh-7 cells. Loss of CHOP induction also reduced the increase in PUMA mRNA and protein levels as well as Bax activation by palmitate. No functional CHOP binding sites were identified in the PUMA promoter sequence. Rather, we observed that CHOP physically interacts with the AP-1 complex protein c-Jun upon palmitate treatment, and a CHOP:phosphorylated c-Jun heteromeric complex binds to the AP-1 consensus binding sequence within the PUMA promoter region. Finally, loss of function studies suggest that both transcription factors are necessary for maximal PUMA induction. Collectively, these data suggest that CHOP and AP-1 cooperatively mediate PUMA induction during hepatocyte lipoapoptosis.
Recent advances in the regulation of cholangiocarcinoma growth
Authors: Francis Heather , Alpini Gianfranco , DeMorrow Sharon
Published: April 2010

Cholangiocarcinomas arise after the neoplastic transformation of the cholangiocytes that line the intra- and extrahepatic biliary epithelium. Symptoms usually do not present until late in the course of the disease, at which time they are relatively resistant to chemotherapeutic agents and as such are difficult to treat and display a poor prognosis. Because of the relative rarity of this disease, the overall volume of research into the molecular pathophysiology associated with this disease is small compared with other more prevalent tumors. However, the incidence of this devastating cancer is on the rise and renewed efforts to understand the pathogenesis of cholangiocarcinoma is needed to design novel therapeutic strategies to combat this disease. This review summarizes the recent advances into our knowledge and understanding of cholangiocarcinoma and highlights potential novel therapeutic strategies that may prove useful to treat this deadly disease.
Pathophysiological preconditions promoting mixed “black” pigment plus cholesterol gallstones in a ΔF508 mouse model of cystic fibrosis
Authors: Freudenberg Folke , Leonard Monika R. , Liu Shou-An , Glickman Jonathan N. , Carey Martin C.
Published: April 2010

Gallstones are frequent in patients with cystic fibrosis (CF). These stones are generally “black” pigment (i.e., Ca bilirubinate) with an appreciable cholesterol admixture. The pathophysiology and molecular mechanisms for this “mixed” gallstone in CF are unknown. Here we investigate in a CF mouse model with no overt liver or gallbladder disease whether pathophysiological changes in the physical chemistry of gallbladder bile might predict the occurrence of “mixed” cholelithiasis. Employing a ΔF508 mouse model with documented increased fecal bile acid loss and induced enterohepatic cycling of bilirubin ( Am J Physiol Gastrointest Liver Physiol 294: G1411–G1420, 2008), we assessed gallbladder bile chemistry, morphology, and microscopy in CF and wild-type mice, with focus on the concentrations and compositions of the common biliary lipids, bilirubins, Ca2+, and pH. Our results demonstrate that gallbladder bile of CF mice contains significantly higher levels of all bilirubin conjugates and unconjugated bilirubin with lower gallbladder bile pH values. Significant elevations in Ca bilirubinate ion products in bile of CF mice increase the likelihood of supersaturating bile and forming black pigment gallstones. The risk of potential pigment cholelithogenesis is coupled with higher cholesterol saturations and bile salt hydrophobicity indexes, consistent with a proclivity to cholesterol phase separation during pigment gallstone formation. This is an initial step toward unraveling the molecular basis of CF gallstone disease and constitutes a framework for investigating animal models of CF with more severe biliary disease, as well as the human disease.
Influence of prenatal nicotine exposure on development of the ventilatory response to hypoxia and hypercapnia in neonatal rats
Authors: Huang Yu-Hsien , Brown Amanda Rose , Cross Seres J. B. , Cruz Jesus , Rice Amber , Jaiswal Stuti , Fregosi Ralph F.
Published: April 2010

In a recent study (Huang YH et al. Respir Physiol Neurobiol 143: 1–8, 2004), we showed that prenatal nicotine exposure (PNE) increased the frequency of spontaneous apneic events on the first 2 days of life in unanesthetized neonatal rats. Here we test the hypothesis that PNE blunts chemoreceptor reflexes. Ventilatory responses to three levels each of hypoxia (inspired O2fraction: 16, 12, and 10%) and hypercapnia (3, 6, and 9% inspired CO2fraction, all in 50% O2, balance N2), and one level each of combined hypoxia-hypercapnia (H/H; 12% inspired O2fraction/5% inspired CO2fraction) and hyperoxia (50% O2, 50% N2) were recorded with head-out plethysmography in neonatal rats exposed to either nicotine ( N = 12) or physiological saline ( N = 12) in the prenatal period. Recordings were made on postnatal day 1 (P1), P3, P6, P9, P12, and P18, in each animal. The change in ventilation in response to hypoxia was blunted in PNE animals on P1 and P3, but there were no other treatment effects. Hyperoxia significantly depressed ventilation in both groups from P3–P18, but there were no significant treatment effects. The ventilatory response to 3, 6, and 9% inspired CO2was significantly blunted in PNE animals at all ages studied, due exclusively to a blunted tidal volume response. PNE also blunted the ventilatory response to H/H at all ages, due primarily to blunting of the tidal volume response. PNE had no significant effect on body mass or metabolic rate, except that PNE animals had a slightly higher mass on P18 and a lower metabolic rate on P1. As shown by others, PNE has small and inconsistent effects on hypoxic ventilatory responses, but here we show that responses to hypercapnia and H/H are consistently blunted by PNE due to a diminished tidal volume response. The combination of reduced hypoxic and hypercapnic sensitivity over the first 3 days of life may define an especially vulnerable developmental period.
Effects of hyperoxia on ventilation and pulmonary hemodynamics during immersed prone exercise at 4.7 ATA: possible implications for immersion pulmonary edema
Authors: Peacher Dionne F. , Pecorella Shelly R. H. , Freiberger John J. , Natoli Michael J. , Schinazi Eric A. , Doar P. Owen , Boso Albert E. , Walker Aaron J. , Gill Matthew , Kernagis Dawn , Uguccioni Donna , Moon Richard E.
Published: April 2010

Immersion pulmonary edema (IPE) can occur in otherwise healthy swimmers and divers, likely because of stress failure of pulmonary capillaries secondary to increased pulmonary vascular pressures. Prior studies have revealed progressive increase in ventilation [minute ventilation (V̇e)] during prolonged immersed exercise. We hypothesized that this increase occurs because of development of metabolic acidosis with concomitant rise in mean pulmonary artery pressure (MPAP) and that hyperoxia attenuates this increase. Ten subjects were studied at rest and during 16 min of exercise submersed at 1 atm absolute (ATA) breathing air and at 4.7 ATA in normoxia and hyperoxia [inspired PO2(PiO2) 1.75 ATA]. V̇e increased from early (E, 6th minute) to late (L, 16th minute) exercise at 1 ATA (64.1 ± 8.6 to 71.7 ± 10.9 l/min BTPS; P < 0.001), with no change in arterial pH or Pco2. MPAP decreased from E to L at 1 ATA (26.7 ± 5.8 to 22.7 ± 5.2 mmHg; P = 0.003). V̇e and MPAP did not change from E to L at 4.7 ATA. Hyperoxia reduced V̇e (62.6 ± 10.5 to 53.1 ± 6.1 l/min BTPS; P < 0.0001) and MPAP (29.7 ± 7.4 to 25.1 ± 5.7 mmHg, P = 0.002). Variability in MPAP among subjects was wide (range 14.1–42.1 mmHg during surface and depth exercise). Alveolar-arterial Po2difference increased from E to L in normoxia, consistent with increased lung water. We conclude that increased V̇e at 1 ATA is not due to acidosis and is more consistent with respiratory muscle fatigue and that progressive pulmonary vascular hypertension does not occur during prolonged immersed exercise. Wide variation in MPAP among healthy subjects is consistent with variable individual susceptibility to IPE.
Platelet Serotonin Content and Transpulmonary Platelet Serotonin Gradient in Patients with Pulmonary Hypertension
Authors: Ulrich Silvia , Huber Lars C. , Fischler Manuel , Treder Ursula , Maggiorini Marco , Eberli Franz Robert , Speich Rudolf
Published: April 2010

Background: The serotonin system has repeatedly been associated with the pathogenesis of pulmonary hypertension (PH). Objective: To comparatively analyze plasmatic and intrathrombocytic serotonin levels in arterial and mixed venous blood of patients with PH and unaffected controls to elucidate pulmonary serotonin metabolisms. Patients and Methods: Catheters were placed in the radial and pulmonary artery in patients with PH (n = 13) for diagnosis and in age-matched controls (n = 6) undergoing percutaneous closure of the patent foramen ovale. Arterial and mixed venous blood samples were immediately centrifuged to obtain plasma and platelets and thereafter frozen at –20°C. After careful thawing, plasmatic and platelet serotonin levels were determined by ELISA. Results: PH was classified as arterial in 4 and chronic thromboembolic in 9 patients with a mean pulmonary artery pressure of 37 (interquartile range: 32–43) mm Hg. Platelet serotonin content was significantly lower in the PH patients than in the controls. The mean transpulmonary gradient (arterial-mixed venous) was negative in the PH group and positive in the controls. An inverse correlation was found between the arterial blood platelet serotonin content and pulmonary hemodynamics. Plasmatic serotonin levels did not differ between the PH and control groups. Conclusion: The lower platelet serotonin concentration in PH patients compared with unaffected controls is an unprecedented finding. The negative transpulmonary platelet serotonin gradient and the strong negative correlation of arterial blood platelet serotonin with pulmonary hemodynamics might indicate increased serotonin uptake in the lungs of PH patients.
Therapeutic Angiogenesis by Implantation of a Capillary Structure Constituted of Human Adipose Tissue Microvascular Endothelial Cells
Authors: Yoshida Tomoko , Komaki Motohiro , Hattori Hideshi , Negishi Jun , Kishida Akio , Morita Ikuo , Abe Mayumi
Published: April 2010

Objective—

We previously reported a novel technology for the engineering of a capillary network using an optical lithographic technique. To apply this technology to the therapy of ischemic diseases, we tested human omental microvascular endothelial cells (HOMECs) as an autologous cell source and decellularized human amniotic membranes (DC-AMs) as a pathogen-free and low immunogenic transplantation scaffold.

Methods and Results—

Human umbilical vein endothelial cells were aligned on a patterned glass substrate and formed a capillary structure when transferred onto an amniotic membrane (AM). In contrast, HOMECs were scattered and did not form a capillary structure on AMs. Treatment of HOMECs with sphingosine 1-phosphate (S1P) inhibited HOMEC migration and enabled HOMEC formation of a capillary structure on AMs. Using quantitative RT-PCR and Western blot analyses, we demonstrated that the main S1P receptor in HOMECs is S1P
2
, which is lacking in human umbilical vein endothelial cells, and that inhibition of cell migration by S1P is mediated through an S1P
2
–Rho–Rho-associated kinase signaling pathway. Implantation of capillaries engineered on DC-AMs into a hindlimb ischemic nude mouse model significantly increased blood perfusion compared with controls.

Conclusion—

A capillary network consisting of HOMECs on DC-AMs can be engineered ex vivo using printing technology and S1P treatment. This method for regeneration of a capillary network may have therapeutic potential for ischemic diseases.
Targeted
Vezf1
-Null Mutation Impairs Vascular Structure Formation During Embryonic Stem Cell Differentiation
Authors: Zou Zhongmin , Ocaya Pauline A. , Sun Huiqin , Kuhnert Frank , Stuhlmann Heidi
Published: April 2010

Objective—

Vezf1
encodes an early zinc finger transcription factor that is essential for normal vascular development and functions in a dose-dependent manner. Here, we investigated the role of
Vezf1
during processes of endothelial cell differentiation and maturation by studying mutant
Vezf1
embryonic stem (ES) cells using the in vitro embryoid body differentiation model and the in vivo teratocarcinoma model.

Methods and Results—

Vezf1
−/− ES cell–derived embryoid bodies failed to form a well-organized vascular network and showed dramatic vascular sprouting defects. Our results indicate that the retinol pathway is an important mediator of
Vezf1
function and that loss of
Vezf1
results in reduced retinol/vitamin A signaling and aberrant extracellular matrix (ECM) formation. Unexpectedly, we also uncovered defects during in vitro differentiation of
Vezf1
−/− ES cells along hematopoietic cell lineages.
Vezf1
−/− ES cell–derived teratocarcinomas were able to spontaneously differentiate into cell types of all 3 germ layers. However, histological and immunohistochemical examination of these tumors showed decreased cell proliferation, delayed differentiation, and large foci of cells with extensive deposition of ECM. Embryoid bodies and teratocarcinomas derived from heterozygous ES cells displayed an intermediate phenotype.

Conclusion—

Together, these results suggest that
Vezf1
is involved in early differentiation processes of the vasculature by regulating cell differentiation, proliferation, and ECM distribution and deposition.
Comparative Proteomics Profiling Reveals Role of Smooth Muscle Progenitors in Extracellular Matrix Production
Authors: Simper David , Mayr Ursula , Urbich Carmen , Zampetaki Anna , Prokopi Marianna , Didangelos Athanasios , Saje Angelika , Mueller Michael , Benbow Ulrike , Newby Andrew C. , Apweiler Rolf , Rahman Salman , Dimmeler Stefanie , Xu Qingbo , Mayr Manuel
Published: April 2010

Objective—

Recent studies on cardiovascular progenitors have led to a new appreciation that paracrine factors may support the regeneration of damaged tissues.

Methods and Results—

We used a shotgun proteomics strategy to compare the secretome of peripheral blood–derived smooth muscle progenitors (SPCs) with human aortic smooth muscle cells. The late-outgrowth SPCs produced fewer proteolytic enzymes and inflammatory cytokines and showed reduced invasive capacity. Similar to smooth muscle cells, SPCs secreted extracellular matrix. However, SPCs produced different matrix proteins, as evidenced by the truncation of proangiogenic domains in collagen α-1 (I) and increased production of periostin. Moreover, SPCs retained serum proteins, including proteoglycans, regulating collagen assembly; and pigment epithelium–derived factor, a potent inhibitor of angiogenesis. As a functional consequence, their conditioned medium was less angiogenic, as demonstrated by endothelial tube formation assays in vitro and implantation of Matrigel plugs into nude, severe combined immunodeficient mice (NOD/SCID).

Conclusion—

The present study represents an important conceptual development, suggesting that SPCs may contribute to extracellular matrix production.
Restoration of High-Density Lipoprotein Levels by Cholesteryl Ester Transfer Protein Expression in Scavenger Receptor Class B Type I (SR-BI) Knockout Mice Does Not Normalize Pathologies Associated With SR-BI Deficiency
Authors: Hildebrand Reeni B. , Lammers Bart , Meurs Illiana , Korporaal Suzanne J.A. , De Haan Willeke , Zhao Ying , Kruijt J. Kar , Praticò Domenico , Schimmel Alinda W.M. , Holleboom Adriaan G. , Hoekstra Menno , Kuivenhoven Jan Albert , Van Berkel Theo J.C. , Rensen Patrick C.N. , Van Eck Miranda
Published: April 2010

Objective—

Disruption of scavenger receptor class B type I (SR-BI) in mice impairs high-density lipoprotein (HDL)–cholesterol (HDL-C) delivery to the liver and induces susceptibility to atherosclerosis. In this study, it was investigated whether introduction of cholesteryl ester transfer protein (CETP) can normalize HDL-C transport to the liver and reduce atherosclerosis in SR-BI knockout (KO) mice.

Methods and Results—

Expression of human CETP in SR-BI
KO
mice resulted in decreased plasma HDL-C levels, both on chow diet (1.8-fold,
P
<0.001) and on challenge with Western-type diet (1.6-fold,
P
<0.01). Furthermore, the presence of CETP partially normalized the abnormally large HDL particles observed in SR-BI
KO
mice. Unexpectedly, expression of CETP in SR-BI
KO
mice did not reduce atherosclerotic lesion development, probably because of consequences of SR-BI deficiency, including the persistence of higher VLDL-cholesterol (VLDL-C) levels, unchanged elevated free cholesterol/total cholesterol ratio, and the increased oxidative status of the animals. In addition, CETP expression did not normalize other characteristics of SR-BI deficiency, including female infertility, reticulocytosis, thrombocytopenia, and impaired platelet aggregation.

Conclusion—

CETP restores HDL-C levels in SR-BI
KO
mice, but it does not change the susceptibility to atherosclerosis and other typical characteristics that are associated with SR-BI disruption. This may indicate that the pathophysiology of SR-BI deficiency is not a direct consequence of changes in the HDL pool.
Overexpression of Integrin β5 Enhances the Paracrine Properties of Circulating Angiogenic Cells via Src Kinase–Mediated Activation of STAT3
Authors: Leifheit-Nestler Maren , Conrad Gaby , Heida Nana-Maria , Limbourg Anne , Limbourg Florian P. , Seidler Tim , Schroeter Marco R. , Hasenfuss Gerd , Konstantinides Stavros , Schäfer Katrin
Published: April 2010

Objective—

To determine the intracellular mechanisms mediating the angiogenic effects of integrin αvβ5 overexpression in circulating angiogenic cells (CACs).

Methods and Results—

Integrin αvβ5 is expressed on angiogenic endothelial cells, and integrin αvβ5 activation was shown to improve the reparative functions of endothelial progenitors within the cardiovascular system. CACs were transiently transfected with the full-length cDNA of human integrin β5 (CAC-ITGB5) or control-vector (CAC-vector). Integrin β5 overexpression was confirmed using flow cytometry, Western blot, and PCR analysis; it enhanced the angiogenic capacities of CACs in vitro (spheroid and Matrigel angiogenesis assay) and stimulated new vessel formation in vivo (murine hind limb ischemia model). Overexpression of ITGB5 resulted in integrin αvβ5 phosphorylation and activation of Src kinase and signal transducer and activator of transcription (STAT) 3. Furthermore, elevated mRNA and protein expression of the CXC chemokine CXCL8 and the CC chemokine CCL2 was detected in CAC-ITGB5, and conditioned medium from CAC-ITGB5 enhanced the sprouting of coincubated human endothelial cells in a STAT3-, CXCL8-, and CCL2-dependent manner.

Conclusion—

Src kinase–mediated activation of STAT3 and subsequent angiogenic gene expression mediate the effects of integrin αvβ5 and may be exploited to enhance the paracrine activities of CACs.