bluuebunny/crossref_metadata_2025 huggingface dataset:
A composite mud volcano system in the Chalk Group of the North Sea Central Graben
Authors: Andresen Katrine J. , Clausen Ole R. , Jørgensen Rune B.
Published: October 2010

The study describes a large (kilometre-scale) composite mud volcano system within the North Sea Chalk Group, containing both intrusion and extrusion features. The upper part of the system consists of three stacked constructive components. At the top, a Late Palaeocene mound-shaped extrusion with subtle onlaps is observed. Below, a Danian near-surface intrusion caused forced-folding of the
c
. 100 m thick overburden. This is underlain by a shallow intrusion. The lower part of the mud volcano system is defined by a depletion-related depression and the fluid conduit. Seismic data suggest that the source unit for the linked intrusion–extrusion is to be found either within a Lower Cretaceous diapiric siliciclastic structure or within the fine-grained carbonates of the Chalk Group. The latter is more probable, implying that chalk may generate hitherto undocumented intrusions and extrusions comparable with siliciclastic mud volcano systems. Remobilization is inferred to have been driven by fluidization caused by the influx of mainly pore water expelled from the Lower Cretaceous succession. A distinct depositional variation within the Chalk Group caused early diagenetic differences in porosity preservation and mechanical properties of the chalk units, allowing the remobilization of certain chalk units even at burial depths as great as 200 m.
3D seismic imaging of lower delta-plain beach ridges: lower Brent Group, northern North Sea
Authors: Jackson Christopher A.-L. , Grunhagen Henrike , Howell John A. , Larsen Ane L. , Andersson Annika , Boen Frede , Groth Audun
Published: October 2010

Three-dimensional seismic reflection data are used to image littoral deposits within the lower Brent Group, northern North Sea. Seismic attribute maps within the unit indicate the development of parallel, high-amplitude stripes up to 15 km in length, 50–100 m wide and spaced 150–200 m apart. In map view these features trend NE–SW to ENE–WSW and are arranged into ‘sets' that display subtly different orientations. Well data in regions where these anomalies are well developed indicate pronounced anomaly-perpendicular thickness variations in sand-rich beach-ridge facies within the Etive Formation and coals and mudstones within the overlying Ness Formation. Based on these observations, the high-amplitude anomalies are interpreted as the seismic expression of coal-filled swales, whereas the adjacent zones of low amplitude are interpreted to represent the cores of sand-rich beach ridges. The geometry of beach ridges identified in the Etive Formation compares favourably with sedimentological and geometric data from modern beach ridges. The results of this study have implications for (1) the stratigraphic context and preservation of beach ridges, (2) datum selection when attempting stratigraphic correlations within the Brent Group, and (3) the exploration and production of hydrocarbons from beach ridge-type reservoirs.
High-Mg andesite genesis by upper crustal differentiation
Authors: Shellnutt J.Gregory , Zellmer Georg F.
Published: October 2010

Whereas arc magmas typically undergo early degassing-induced crystallization and viscous stagnation at mid-crustal levels, hotter and less hydrous melts that are associated with elevated surface heat flux may experience delayed crystallization at shallower levels. Using MELTS modelling, we demonstrate here that high-Mg andesites, which have been regarded as particularly hydrous primary melts generated in equilibrium with mantle peridotite, can form by crystal fractionation from low-H
2
O primitive arc basalts in the upper crust. This is consistent with many characteristics previously attributed to their primary origin, including forsteritic olivines that contain chromite inclusions and lack significant reaction rims, and Cr-rich pyroxenes.

Supplementary material:

Mineral compositional variations and partition coefficients are available at
http://www.geolsoc.org.uk/SUP18428
.
Efficient algorithms for large-scale local triangle counting
Authors: Becchetti Luca , Boldi Paolo , Castillo Carlos , Gionis Aristides
Published: October 2010

In this article, we study the problem of approximate local triangle counting in large graphs. Namely, given a large graph
G
=(
V,E
) we want to estimate as accurately as possible the number of triangles incident to every node
v
∈
V
in the graph. We consider the question both for undirected and directed graphs. The problem of computing the
global
number of triangles in a graph has been considered before, but to our knowledge this is the first contribution that addresses the problem of approximate
local
triangle counting with a focus on the efficiency issues arising in massive graphs and that also considers the directed case. The distribution of the local number of triangles and the related local clustering coefficient can be used in many interesting applications. For example, we show that the measures we compute can help detect the presence of spamming activity in large-scale Web graphs, as well as to provide useful features for content quality assessment in social networks.

For computing the local number of triangles (undirected and directed), we propose two approximation algorithms, which are based on the idea of min-wise independent permutations [Broder et al. 1998]. Our algorithms operate in a semi-streaming fashion, using
O
(|
V
|) space in main memory and performing
O
(log |
V
|) sequential scans over the edges of the graph. The first algorithm we describe in this article also uses
O
(|
E
|) space of external memory during computation, while the second algorithm uses only main memory. We present the theoretical analysis as well as experimental results on large graphs, demonstrating the practical efficiency of our approach.
Using learning objects to enhance the systems administration lab
Authors: Stockman Mark , Wulf Tom
Published: October 2010

The traditional model for students' performing labs in a systems administration course is to follow precise step-by-step instructions to complete the tasks at hand. The authors have run into multiple problems using this method including students' rushing through labs with little comprehension, errors in the lab steps, and keeping the labs sufficiently up-to-date. To address these problems the authors have changed the delivery of labs such that students are now given a goal-focused task list to perform for each lab. It is hoped that this approach to the lab will increase the students' problem solving ability and comprehension of the material. To assist with the implementation of this solution, the authors have created multimedia learning objects for students to view if they cannot remember how to perform the tasks or if the instructions from the book are not understandable. Initial observations of this implementation have been quite positive in both student satisfaction and comprehension of the material.
Teaching IT hardware concepts using computer forensics as a motivator
Authors: Conklin Megan S.
Published: October 2010

This paper details experiences using computer forensics as a teaching tool to improve student performance and engagement in the "Introductory Hardware and Systems Software" course at a small, liberal arts institution. Students majoring in information systems often approach the hardware course expecting the standard lecture and textbook readings supplemented by an occasional hardware lab. Computer forensics, on the other hand, captures the interest of most students immediately. How to use hardware, software, and networking tools to help solve computer crimes is a problem most students can be easily motivated to investigate. This paper addresses whether the same hardware concepts can be taught using computer forensics as a motivator as would be taught in a "traditional" information technology (IT) hardware class, and whether there are any additional benefits to doing so. Metrics will include: student performance on examinations and an analysis of the breadth of subjects covered and the associated depth of the covered subjects in both scenarios. The discussion includes strategies for matching traditional IT hardware course content to related computer forensics techniques. Additionally, ideas for forensic lab activities in each subject area are outlined.
Utilizing authentic, real-world projects in information technology education
Authors: Preston Jon A.
Published: October 2010

Computer science courses have utilized real-world, customer-driven projects with mixed success for years. There is a large body of anecdotal and empirical evidence to support the idea that students learn via authentic customer interactions in database, software engineering, and other computer science courses. This paper demonstrates that such real-world projects are also applicable to Information Technology classes. By allowing students to apply the theoretical principles learned in prerequisite courses, they are able to solidify and deepen their knowledge of project management, customer relations management, requirements elicitation and management, software development, human-computer interaction (specifically interface design), database technology, communication skills, testing, debugging, and system design. Results from over 50 projects involving over 300 students and spanning seven years of courses are presented and analyzed; these projects range from traditional Windows projects to dynamic, data-driven Webs and cutting-edge projects involving PDA and TabletPC applications. The author was involved in Computer Science Software Engineering and programming courses and then transitioned into the field of Information Technology Education; consequently, the results span the domains of CS and IT education and present a convincing argument that group-based, authentic projects that involve developing solutions for real-world customers benefit Information Technology courses and students. Issues such as appropriate project scope, suggested milestones, reasonable project structure, and how to assign students to teams are discussed. A lightweight process is also provided to assist the reader in applying the recommendations with minimal effort.
Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats
Authors: Hsiao Gene , Chapman Justin , Ofrecio Jachelle M. , Wilkes Jason , Resnik Jamie L. , Thapar Divya , Subramaniam Shankar , Sears Dorothy D.
Published: October 2010

Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.
Assessment of collateral artery function and growth in a pig model of stepwise coronary occlusion
Authors: de Groot Daphne , Grundmann Sebastian , Timmers Leo , Pasterkamp Gerard , Hoefer Imo E.
Published: October 2010

Therapeutic stimulation of collateral artery growth is a promising approach for treatment of cardiovascular diseases. Unfortunately, translation into clinical practice yet remains cumbersome. Cardiovascular physiology and anatomy are major determinants of vascular growth processes. Hence, large-animal models are needed to improve clinical translatability of preclinical research. Furthermore, acute complete occlusions are mostly applied in experimental research, whereas stepwise occlusions are more often observed in human disease. We developed a model of coronary collateral artery growth in which 1) the artery is occluded in a step wise approach, and 2) effects of local treatment can be measured individually for each supplying coronary vessel. A hemodynamically relevant stenosis was created by implantation of a tapered stent at day 0 (d0) in the left circumflex artery (LCX), followed by complete arterial occlusion at day 14 (d14). Fluorescent microspheres were injected for demarcation of perfusion territories at each time point. Three and four weeks after induction of stenosis, collateral conductance measurements were performed for each coronary artery separately using differently labeled fluorescent microspheres. Postmortem angiography after acute LCX occlusion confirmed the presence of preexistent coronary anastomoses in the pig. The tapered stent created a hemodynamically significant stenosis immediately postplacement (fractional flow reserve, 0.70 ± 0.03). Between day 21 and 28, collateral conductance significantly increased in both the left anterior descending (LAD) and the right coronary artery (RCA)-supplied, collateral-dependent territories (LAD d21, 0.77 ± 0.14; LAD d28, 1.35 ± 0.12; RCA d21, 0.88 ± 0.29; RCA d28, 1.70 ± 0.16 ml·min−1·g−1·100 mmHg−1), indicating collateral artery growth. We here describe a new translational minimally invasive model of coronary collateral artery growth in pigs, according to a defined protocol of LCX-stenosis and subsequent occlusion, allowing preclinical evaluation of arteriogenic therapies.
Endothelial FGF receptor signaling accelerates atherosclerosis
Authors: Che Jishan , Okigaki Mitsuhiko , Takahashi Tomosaburo , Katsume Asako , Adachi Yasushi , Yamaguchi Shinichiro , Matsunaga Shinsaku , Takeda Mitsuo , Matsui Akihiro , Kishita Eigo , Ikeda Koji , Yamada Hiroyuki , Matsubara Hiroaki
Published: October 2010

Members of the fibroblast growth factor (FGF) family have been clinically applied to the treatment of ischemic diseases because of their strong angiogenic actions. Although tissue ischemia is predominantly caused by atherosclerosis, the roles of endothelial FGF receptors (FGF-Rs) in atherosclerosis remain obscure. We generated endothelial cell (EC)-targeted constitutively active FGF-R2-overexpressing mice, using the Tie2 promoter (Tie2-FGF-R2-Tg), and crossed them with apolipoprotein E (ApoE)-deficient mice (ApoE-KO) to generate Tie2-FGF-R2-Tg/ApoE-deficient mice (Tie2-FGF-R2-Tg/ApoE-KO). After being fed a Western diet for 8 wk, the Tie2-FGF-R2-Tg/ApoE-KO demonstrated 2.0-fold greater atherosclerotic lesion area on the luminal surfaces of the aortas than the ApoE-KO ( P < 0.01). The level of p21Cip1protein, a cell cycle inhibitor, in the FGF-R2-overexpressing EC was 2.5-fold greater than that in the wild-type (WT) EC at the baseline ( P < 0.01). FGF-R2 overexpression in the EC resulted in increased expression of VCAM-1 and ICAM-1, acceleration of apoptosis, and decreased proliferative activity, all of which were normalized by small interfering RNA (siRNA)-mediated knockdown of p21Cip1(75% reduction in protein level, P < 0.01). Furthermore, the expression of PDGF-B and Egr-1, a PDGF/p21Cip1-inducible transcription factor, in the aortic endothelium of Tie2-FGF-R2-Tg/ApoE-KO was significantly greater than that in ApoE-KO. The proliferation of vascular smooth muscle cells in the aortic media of Tie2-FGF-R2-Tg/ApoE-KO was 2.0-fold higher than that in ApoE-KO ( P < 0.01). Thus our study reveals that endothelial FGF-R2 signaling aggravates atherosclerosis by promoting p21Cip1-mediated EC dysfunction and cautions against the use of FGF for therapeutic angiogenesis in the setting of atherosclerosis.
Altered hemodynamic regulation and reflex control during exercise and recovery in obese boys
Authors: Dipla K. , Zafeiridis A. , Koidou I. , Geladas N. , Vrabas I. S.
Published: October 2010

The aims of the present study were to assess in obese and lean boys 1) the hemodynamic responses and baroreflex sensitivity (BRS) to isometric handgrip exercise (HG) and recovery and 2) the muscle metaboreflex-induced blood pressure response and the variables that determine this response. Twenty-seven boys (14 obese and 13 lean boys, body mass index: 29.2 ± 0.9 vs. 18.9 ± 0.3kg/m2, respectively) participated. The testing protocol involved 3 min of baseline, 3 min of HG (30% maximum voluntary contraction), 3 min of circulatory occlusion, and 3 min of recovery. The same protocol was repeated without occlusion. At baseline, no differences were detected between groups in beat-to-beat arterial pressure (AP), heart rate (HR), and BRS; however, obese boys had higher stroke volume and lower total peripheral resistance than lean boys ( P < 0.05). During HG, lean boys exhibited higher HR and lower BRS compared with their obese counterparts. In lean boys, BRS decreased during HG compared with baseline, whereas in obese boys, it was not significantly modified. In lean boys, TPR was elevated during HG and declined after exercise, whereas in obese boys, TPR did not significantly decrease after exercise cessation. In the postexercise period, BRS in lean boys returned to baseline, whereas an overshoot was observed in obese boys. Postexercise BRS was correlated with body mass index ( R = 0.56, P < 0.05). Although the metaboreflex-induced increase in AP was similar between obese and lean children, it was achieved via different mechanisms: in lean children, total peripheral resistance was the main contributor to AP maintenance during the metaboreflex, whereas in obese children, stroke volume significantly contributed to AP maintenance during the metaboreflex. In conclusion, obese normotensive children demonstrated altered cardiovascular hemodynamics and reflex control during exercise and recovery.
Mice expressing ouabain-sensitive α1-Na,K-ATPase have increased susceptibility to pressure overload-induced cardiac hypertrophy
Authors: Wansapura Arshani N. , Lasko Valerie M. , Lingrel Jerry B , Lorenz John N.
Published: October 2010

The Na,K-ATPase is a ubiquitous transmembrane pump and a specific receptor for cardiac glycosides such as ouabain and digoxin, which are used in the management of congestive heart failure (CHF). A potential role for these so-called endogenous cardiotonic steroids (CS) has been explored, and it has become apparent that such compounds are elevated and may play an important role in a variety of physiological and pathophysiological conditions such as hypertension and CHF. Recent evidence suggests that the Na,K-ATPase may act as a signal transducer upon CS binding and induce nonproliferative cardiac growth, implicating a role for endogenous CS in the development of cardiac hypertrophy and progressive failure of the heart. In the present study, we tested whether hypertrophic responses to pressure overload would be altered in mutant mice that specifically express ouabain-sensitive or ouabain-resistant α1- and α2-Na,K-ATPase subunits, as follows: α1-resistant, α2-resistant (α1R/Rα2R/R); α1-sensitive, α2-resistant (α1S/Sα2R/R); and α1-resistant, α2-sensitive (α1R/Rα2S/S, wild-type). In α1S/Sα2R/Rmice, pressure overload by transverse aortic coarctation induced severe left ventricular (LV) hypertrophy with extensive perivascular and replacement fibrosis at only 4 wk. Responses in α1R/Rα2S/Sand α1R/Rα2R/Rmice were comparatively mild. Mutant α1S/Sα2R/Rmice also had LV dilatation and depressed LV systolic contractile function by 4 wk of pressure overload. In separate experiments, chronic Digibind treatment prevented the rapid progression of cardiac hypertrophy and fibrosis in α1S/Sα2R/Rmice. These data demonstrate that mice with a ouabain-sensitive α1-Na,K-ATPase subunit have a dramatic susceptibility to the development of cardiac hypertrophy, and failure from LV pressure overload and provide evidence for the involvement of endogenous CS in this process.
Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat
Authors: Farnham Melissa M. J. , Inglott Melissa A. , Pilowsky Paul M.
Published: October 2010

The rostral ventrolateral medulla contains presympathetic neurons that project monosynaptically to sympathetic preganglionic neurons (SPN) in the spinal cord and are essential for the tonic and reflex control of the cardiovascular system. SPN directly innervate the adrenal medulla and, via postganglionic axons, affect the heart, kidneys, and blood vessels to alter sympathetic outflow and hence blood pressure. Over 80% of bulbospinal, catecholaminergic (C1) neurons contain pituitary adenylate cyclase-activating polypeptide (PACAP) mRNA. Activation of PACAP receptors with intrathecal infusion of PACAP-38 causes a robust, prolonged elevation in sympathetic tone. Given that a common feature of most forms of hypertension is elevated sympathetic tone, this study aimed to determine in the spontaneously hypertensive rat (SHR) and the Wistar Kyoto rat (normotensive control) 1) the proportion of C1 neurons containing PACAP mRNA and 2) responsiveness to intrathecal PACAP-38. We further investigated whether intrathecal infusion of the PACAP antagonist, PACAP(6–38), reduces the hypertension in the SHR. The principal findings are that 1) the proportion of PACAP mRNA-containing C1 neurons is not different between normotensive and hypertensive rats, 2) intrathecal PACAP-38 causes a strain-dependent, sustained sympathoexcitation and tachycardia with variable effects on mean arterial pressure in normotensive and hypertensive rats, and 3) PACAP(6–38) effectively attenuated the effects of intrathecal PACAP-38, but had no effect alone, on any baseline variables. This finding indicates that PACAP-38 is not tonically released in the spinal cord of rats. A role for PACAP in hypertension in conscious rats remains to be determined.
Minor contribution of cytosolic Ca2+transients to the pacemaker rhythm in guinea pig sinoatrial node cells
Authors: Himeno Yukiko , Toyoda Futoshi , Satoh Hiroyasu , Amano Akira , Cha Chae Young , Matsuura Hiroshi , Noma Akinori
Published: October 2010

The question of the extent to which cytosolic Ca2+affects sinoatrial node pacemaker activity has been discussed for decades. We examined this issue by analyzing two mathematical pacemaker models, based on the “Ca2+clock” (C) and “membrane clock” (M) hypotheses, together with patch-clamp experiments in isolated guinea pig sinoatrial node cells. By applying lead potential analysis to the models, the C mechanism, which is dependent on potentiation of Na+/Ca2+exchange current via spontaneous Ca2+release from the sarcoplasmic reticulum (SR) during diastole, was found to overlap M mechanisms in the C model. Rapid suppression of pacemaker rhythm was observed in the C model by chelating intracellular Ca2+, whereas the M model was unaffected. Experimental rupturing of the perforated-patch membrane to allow rapid equilibration of the cytosol with 10 mM BAPTA pipette solution, however, failed to decrease the rate of spontaneous action potential within ∼30 s, whereas contraction ceased within ∼3 s. The spontaneous rhythm also remained intact within a few minutes when SR Ca2+dynamics were acutely disrupted using high doses of SR blockers. These experimental results suggested that rapid disruption of normal Ca2+dynamics would not markedly affect spontaneous activity. Experimental prolongation of the action potentials, as well as slowing of the Ca2+-mediated inactivation of the L-type Ca2+currents induced by BAPTA, were well explained by assuming Ca2+chelation, even in the proximity of the channel pore in addition to the bulk cytosol in the M model. Taken together, the experimental and model findings strongly suggest that the C mechanism explicitly described by the C model can hardly be applied to guinea pig sinoatrial node cells. The possible involvement of L-type Ca2+current rundown induced secondarily through inhibition of Ca2+/calmodulin kinase II and/or Ca2+-stimulated adenylyl cyclase was discussed as underlying the disruption of spontaneous activity after prolonged intracellular Ca2+concentration reduction for >5 min.
Heart rate reduction with ivabradine prevents the global phenotype of left ventricular remodeling
Authors: Ceconi Claudio , Comini Laura , Suffredini Silvia , Stillitano Francesca , Bouly Muriel , Cerbai Elisabetta , Mugelli Alessandro , Ferrari Roberto
Published: October 2010

The aim of this study was to investigate the effect of chronic heart rate (HR) reduction with the hyperpolarization-activated current inhibitor ivabradine on the global phenotype of left ventricular (LV) remodeling in a ligated rat model. Seven days after coronary artery ligation, Wistar rats received ivabradine (10 mg·kg−1·day−1administered in drinking water) [myocardial infarction + ivabradine (MI+IVA), n = 22] or vehicle only (drinking water) (MI, n = 20) for 90 days. A sham group ( n = 20) was included for model validation. MI+IVA rats had 12% lower HR ( P < 0.01), improved LV volumes, 15% higher LV ejection fraction (LVEF, P < 0.01) than MI rats, and 33% reductions in both plasma atrial natriuretic peptide (ANP, P = 0.052) and cardiac hydroxyproline. Using patch-clamp, action potential duration was reduced and transient outward current density increased ( P < 0.05). Cardiac energy metabolism was also improved (+33% creatine phosphate, P < 0.001; +15% ATP; and +9% energy charge, P < 0.05). Significant correlations were found between HR and parameters of cardiac metabolism, ANP, and LVEF (all P < 0.05). The HR-reducing properties of ivabradine prevent changes in the global phenotype of LV remodeling in the rat, optimize energy consumption, and avoid electrophysiological and structural remodeling.
MAPK signaling pathways regulate IL-8 mRNA stability and IL-8 protein expression in cystic fibrosis lung epithelial cell lines
Authors: Bhattacharyya Sharmistha , Gutti Usha , Mercado Jose , Moore Chad , Pollard Harvey B. , Biswas Roopa
Published: October 2010

Cystic fibrosis (CF) is characterized by a massive proinflammatory phenotype in the lung, caused by mutations in the CFTR gene. IL-8 and other proinflammatory mediators are elevated in the CF airway, and the immediate mechanism may depend on disease-specific stabilization of IL-8 mRNA in CF lung epithelial cells. MAPK signaling pathways impact directly on IL-8 protein expression in CF cells, and we have hypothesized that the mechanism may also involve stabilization of the IL-8 mRNA. To test this hypothesis, we have examined the effects of pharmacological and molecular inhibitors of p38, and downstream MK2, ERK1/2, and JNK, on stability of IL-8 mRNA in CF lung epithelial cells. We previously showed that tristetraprolin (TTP) was constitutively low in CF and that raising TTP destabilized the IL-8 mRNA. We therefore also tested these effects on CF lung epithelial cells stably expressing TTP. TTP binds to AU-rich elements in the 3′-UTR of the IL-8 mRNA. We find that inhibition of p38 and ERK1/2 reduces the stability of IL-8 mRNA in parental CF cells. However, neither intervention further lowers TTP-dependent destabilization of IL-8 mRNA. By contrast, inhibition of the JNK-2 pathway has no effect on IL-8 mRNA stability in parental CF cell, but rather increases the stability of the message in cells expressing high levels of TTP. However, we find that inhibition of ERK1/2 or p38 leads to suppression of the effect of JNK-2 inhibition on IL-8 mRNA stability. These data thus lend support to our hypothesis that constitutive MAPK signaling and proteasomal activity might also contribute, along with aberrantly lower TTP, to the proinflammatory phenotype in CF lung epithelial cells by increasing IL-8 mRNA stability and IL-8 protein expression.
Intrinsically Photosensitive Retinal Ganglion Cells
Authors: Do Michael Tri Hoang , Yau King-Wai
Published: October 2010

Life on earth is subject to alternating cycles of day and night imposed by the rotation of the earth. Consequently, living things have evolved photodetective systems to synchronize their physiology and behavior with the external light-dark cycle. This form of photodetection is unlike the familiar “image vision,” in that the basic information is light or darkness over time, independent of spatial patterns. “Nonimage” vision is probably far more ancient than image vision and is widespread in living species. For mammals, it has long been assumed that the photoreceptors for nonimage vision are also the textbook rods and cones. However, recent years have witnessed the discovery of a small population of retinal ganglion cells in the mammalian eye that express a unique visual pigment called melanopsin. These ganglion cells are intrinsically photosensitive and drive a variety of nonimage visual functions. In addition to being photoreceptors themselves, they also constitute the major conduit for rod and cone signals to the brain for nonimage visual functions such as circadian photoentrainment and the pupillary light reflex. Here we review what is known about these novel mammalian photoreceptors.
Ca2+-Activated K+Channels: From Protein Complexes to Function
Authors: Berkefeld Henrike , Fakler Bernd , Schulte Uwe
Published: October 2010

Molecular research on ion channels has demonstrated that many of these integral membrane proteins associate with partner proteins, often versatile in their function, or even assemble into stable macromolecular complexes that ensure specificity and proper rate of the channel-mediated signal transduction. Calcium-activated potassium (KCa) channels that link excitability and intracellular calcium concentration are responsible for a wide variety of cellular processes ranging from regulation of smooth muscle tone to modulation of neurotransmission and control of neuronal firing pattern. Most of these functions are brought about by interaction of the channels' pore-forming subunits with distinct partner proteins. In this review we summarize recent insights into protein complexes associated with KCachannels as revealed by proteomic research and discuss the results available on structure and function of these complexes and on the underlying protein-protein interactions. Finally, the results are related to their significance for the function of KCachannels under cellular conditions.
Cellular Energy Absorbing TRIP-Steel/Mg-PSZ Composite: Honeycomb Structures Fabricated by a New Extrusion Powder Technology
Authors: Martin Ulrich , Ehinger David , Krüger Lutz , Martin Stefan , Mottitschka Thomas , Weigelt Christian , Aneziris Christos G. , Herrmann Mathias
Published: October 2010

Lightweight linear cellular composite materials on basis of austenite stainless TRIP- (TRansformation Induced Plasticity-) steel as matrix with reinforcements of MgO partially stabilized zirconia (Mg-PSZ) are described. Two-dimensional cellular materials for structural applications are conventionally produced by sheet expansion or corrugation processes. The presented composites are fabricated by a modified ceramic extrusion powder technology. Characterization of the microstructure in as-received and deformed conditions was carried out by optical and scanning electron microscopy. Magnetic balance measurements and electron backscatter diffraction (EBSD) were used to identify the deformation-induced martensite evolution in the cell wall material. The honeycomb composite samples exhibit an increased strain hardening up to a certain engineering compressive strain and an extraordinary high specific energy absorption per unit mass and unit volume, respectively. Based on improved property-to-weight ratio such linear cellular structures will be of interest as crash absorbers or stiffened core materials for aerospace, railway, or automotive applications.
Animal Models of Typical Heterotopic Ossification
Authors: Kan Lixin , Kessler John A.
Published: October 2010

Heterotopic ossification (HO) is the formation of
marrow‐containing bone outside of the normal skeleton. Acquired HO
following traumatic events is a common and costly clinical
complication. In contrast, hereditary HO is rarer, progressive,
and life‐threatening. Substantial effort has been directed towards
understanding the mechanisms underlying HO and finding efficient
treatments. However, one crucial limiting factor has been the lack
of relevant animal models. This article reviews the major
currently available animal models, summarizes some of the insights
gained from these studies, and discusses the potential future
challenges and directions in HO research.
Suppression of Ongoing Experimental Arthritis by a Chinese Herbal Formula (Huo‐Luo‐Xiao‐Ling Dan) Involves Changes in Antigen‐Induced Immunological and Biochemical Mediators of Inflammation
Authors: Yang Ying-Hua , Rajaiah Rajesh , Lee David Y.-W , Ma Zhongze , Yu Hua , Fong Harry H. S. , Lao Lixing , Berman Brian M. , Moudgil Kamal D.
Published: October 2010

Rheumatoid arthritis (RA) is one of the major autoimmune diseases of global prevalence. The use of the anti‐inflammatory drugs for the treatment of RA is associated with severe adverse reactions and toxicity. This limitation has necessitated the search for novel therapeutic products. We report here a traditional Chinese medicine‐based herbal formula, Huo luo xiao ling dan (HLXL), which has potent antiarthritic activity as validated in the rat adjuvant‐induced arthritis (AA) model. HLXL (2.3 g/Kg) was fed to Lewis (RT.11) rats daily by gavage beginning at the onset of arthritis and then continued through the observation period. HLXL inhibited the severity of ongoing AA. This suppression of arthritis was associated with significant alterations in the T cell proliferative and cytokine responses as well as the antibody response against the disease‐related antigen, mycobacterial heat‐shock protein 65 (Bhsp65). There was a reduction in the level of the proinflammatory cytokines IL‐17 and IL‐1β but enhancement of the anti‐inflammatory cytokine IL‐10 level. In addition, there was inhibition of both the anti‐Bhsp65 antibody response and the serum level of nitric oxide. Thus, HLXL is a promising CAM modality for further testing in RA patients.
HGF/c-Met Acts as an Alternative Angiogenic Pathway in Sunitinib-Resistant Tumors
Authors: Shojaei Farbod , Lee Joseph H. , Simmons Brett H. , Wong Anthony , Esparza Carlos O. , Plumlee Pamela A. , Feng Junli , Stewart Albert E. , Hu-Lowe Dana D. , Christensen James G.
Published: October 2010

Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic. Cancer Res; 70(24); 10090–100. ©2010 AACR.
Transcription Factor NF-Y Induces Apoptosis in Cells Expressing Wild-Type p53 through E2F1 Upregulation and p53 Activation
Authors: Gurtner Aymone , Fuschi Paola , Martelli Fabio , Manni Isabella , Artuso Simona , Simonte Giacoma , Ambrosino Valeria , Antonini Annalisa , Folgiero Valentina , Falcioni Rita , Sacchi Ada , Piaggio Giulia
Published: October 2010

The CCAAT-binding transcription factor NF-Y plays a central role in regulating cellular proliferation by controlling the expression of genes required for cell-cycle progression such as cyclin A, cyclin B1, cyclin B2, cdc25A, cdc25C, and cdk1. Here we show that unrestricted NF-Y activity leads to apoptosis in an E2F1- and wild-type p53 (wtp53)-dependent manner. Unrestricted NF-Y activity induced an increase in E2F1 mRNA and protein levels. Furthermore, NF-Y directly bound the E2F1 promoter and this correlated with the appearance of open chromatin marks. The ability of NF-Y to induce apoptosis was impaired in cells lacking E2F1 and wtp53. Moreover, NF-Y overexpression elicited phosphorylation of wt p53Ser18 in an E2F1-dependent manner. Our findings establish that NF-Y acts upstream of E2F1 in p53-mediated apoptosis. Cancer Res; 70(23); 9711–20. ©2010 AACR.
p53 Status in Stromal Fibroblasts Modulates Tumor Growth in an SDF1-Dependent Manner
Authors: Addadi Yoseph , Moskovits Neta , Granot Dorit , Lozano Guillermina , Carmi Yaron , Apte Ron N. , Neeman Michal , Oren Moshe
Published: October 2010

The p53 tumor suppressor exerts a variety of cell-autonomous effects that are aimed to thwart tumor development. In addition, however, there is growing evidence for cell nonautonomous tumor suppressor effects of p53. In the present study, we investigated the impact of stromal p53 on tumor growth. Specifically, we found that ablation of p53 in fibroblasts enabled them to promote more efficiently the growth of tumors initiated by PC3 prostate cancer-derived cells. This stimulatory effect was dependent on the increased expression of the chemokine SDF-1 in the p53-deficient fibroblasts. Notably, fibroblasts harboring mutant p53 protein were more effective than p53-null fibroblasts in promoting tumor growth. The presence of either p53-null or p53-mutant fibroblasts led also to a markedly elevated rate of metastatic spread of the PC3 tumors. These findings implicate p53 in a cell nonautonomous tumor suppressor role within stromal fibroblasts, through suppressing the production of tumor stimulatory factors by these cells. Moreover, expression of mutant p53 by tumor stroma fibroblasts might exert a gain of function effect, further accelerating tumor development. Cancer Res; 70(23); 9650–8. ©2010 AACR.
Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene
Authors: Chen Zhao , Sasaki Takaaki , Tan Xiaohong , Carretero Julian , Shimamura Takeshi , Li Danan , Xu Chunxiao , Wang Yuchuan , Adelmant Guillaume O. , Capelletti Marzia , Lee Hyun Joo , Rodig Scott J. , Borgman Christa , Park Seung-il , Kim Hyeong Ryul , Padera Robert , Marto Jarrod A. , Gray Nathanael S. , Kung Andrew L. , Shapiro Geoffrey I. , Jänne Pasi A. , Wong Kwok-Kin
Published: October 2010

Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non–small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.Cancer Res; 70(23); 9827–36. ©2010 AACR.
Genomic Deregulation during Metastasis of Renal Cell Carcinoma Implements a Myofibroblast-Like Program of Gene Expression
Authors: López-Lago Miguel A. , Thodima Venkata J. , Guttapalli Asha , Chan Timothy , Heguy Adriana , Molina Ana M. , Reuter Victor E. , Motzer Robert J. , Chaganti Raju S. K.
Published: October 2010

Clear cell renal cell carcinoma (RCC) is the most common and invasive adult kidney cancer. The genetic and biological mechanisms that drive metastatic spread of RCC remain largely unknown. We have investigated the molecular signatures and underlying genomic aberrations associated with RCC metastasis, using an approach that combines a human xenograft model; expression profiling of RNA, DNA, and microRNA (miRNA); functional verification; and clinical validation. We show that increased metastatic activity is associated with acquisition of a myofibroblast-like signature in both tumor cell lines and in metastatic tumor biopsies. Our results also show that the mesenchymal trait did not provide an invasive advantage to the metastatic tumor cells. We further show that some of the constituents of the mesenchymal signature, including the expression of the well-characterized myofibroblastic marker S100A4, are functionally relevant. Epigenetic silencing and miRNA-induced expression changes accounted for the change in expression of a significant number of genes, including S100A4, in the myofibroblastic signature; however, DNA copy number variation did not affect the same set of genes. These findings provide evidence that widespread genetic and epigenetic alterations can lead directly to global deregulation of gene expression and contribute to the development or progression of RCC metastasis culminating in a highly malignant myofibroblast-like cell. Cancer Res; 70(23); 9682–92. ©2010 AACR.
Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase
Authors: Oi Naomi , Jeong Chul-Ho , Nadas Janos , Cho Yong-Yeon , Pugliese Angelo , Bode Ann M. , Dong Zigang
Published: October 2010

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A4 hydrolase (LTA4H) as a relevant target in pancreatic cancer. LTA4H knockdown limited the formation of leukotriene B4 (LTB4), the enzymatic product of LTA4H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA4H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA4H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB4 production and expression of the LTB4 receptor 1 (BLT1). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA4H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA4H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA4H activity. Our findings identify LTA4H as a functionally important target for mediating the anticancer properties of resveratrol. Cancer Res; 70(23); 9755–64. ©2010 AACR.
Rapid Progression of Diabetic Nephropathy Is Linked to Inflammation and Episodes of Acute Renal Failure
Authors: Kelly K.J. , Dominguez Jesus H.
Published: October 2010

Background/Aims: Chronic kidney disease (CKD) from diabetic nephropathy is characterized by progressive loss of renal function. The renal decline has been viewed as a linear fall, presumably dependent on metabolic, hemodynamic and dietary stresses. However, renal injury in diabetic nephropathy can be rapidly aggravated by unpredictable external and internal factors, a state of affairs inconsistent with a linear loss of function. Acute renal injury and subsequent inflammation are potential factors, and we investigated their presence in renal biopsies from patients with nephropathy. Methods: In a protocol approved by the Indiana University School of Medicine Institutional Review Board, renal biopsy specimens, estimated GFR, proteinuria and renal survival were examined in patients with diabetic nephropathy. Results: Prominent clusters of inflammatory cells, particularly macrophages, were detected in the renal biopsy specimens. CKD progressed rapidly but not linearly, in that CKD was characterized by a succession of seemingly random episodes of self-limited acute renal failure. Episodes of acute kidney injury were associated with progression to end-stage renal disease. Conclusions: We propose that diabetic nephropathy is complicated by unpredictable and possibly random episodes of usually self-limited acute renal failure, and by subsequent renal inflammation, which appear to accelerate progression and eventual kidney loss.
Antibody Screening by the Solid-Phase Assay Capture R Compared to Tube Test and Gel Centrifugation
Authors: König A.L. , Luz B. , Schabel A. , Sugg U.
Published: October 2010

An 5780 unausgewählten Patientenseren wurde der Antikörpersuchtest durchgeführt: (l)im Röhrchen(3-Stufen)-Test, mikroskopische Ablesung, (2)im Gelzentrifugationstest (DiaMed) mit einem modifizierten Ansatz Antiglobulin bei Raum-temperatur und (3)im Festphasentest Capture R (Immucor) mit photometrischer Ablesung. Transfusionsrelevante IgG-Antikörper waren nachweisbar: im Röhrchen 45, im Geltest 72 und im Capture R 85. Bedingt transfusionsrelevante IgM-Antikörper fanden sich: im Röhrchen 48, im Geltest 23 und im Capture R 6. Irrelevante Befunde traten auf: im Röhrchen 29, im Geltest 10 und im Capture R 42. Drei Patienten zeigten Anzeichen einer verzögerten hämolytischen Transfusionsreaktion durch Antikörper [2Anti-E und 1 Anti-Fy(a)], die im Geltest und im Capture R, nicht jedoch im Röhrchentest nachweisbar waren; eine fragliche Reaktion wurde beobachtet durch ein Anti-s, das ausschließlich im Capture R erfaßt wurde.