bluuebunny/crossref_metadata_2025 huggingface dataset:
LAYOUT OF AN ARBITRARY PERMUTATION IN A MINIMAL RIGHT TRIANGLE AREA
Authors: ARTISHCHEV-ZAPOLOTSKY MARIA , DINITZ YEFIM , EVEN SHIMON , YANOVSKY VLADIMIR
Published: August 2007

In VLSI layout of interconnection networks, routing two-point nets in some restricted area is one of the central operations. The main aim is usually minimization of the layout area, while reducing the number of wire bends is also very useful. In this paper, we consider connecting a set of N inputs on a line to a set of N outputs on a perpendicular line inside a right triangle shaped area, where the order of the outputs is a given permutation of the order of the corresponding inputs. Such triangles were used, for example, by Dinitz, Even, and Artishchev-Zapolotsky for an optimal layout of the Butterfly network. That layout was of a particular permutation, while here we solve the problem for an arbitrary permutation case. We show two layouts in an optimal area of ½ N2 + o(N2), with O (N) bends each. We prove that the first layout requires the absolutely minimum area and yields the irreducible number of bends, while containing knock-knees. The second one eliminates knock-knees, still keeping a constant number, 7, of bends per connection. As well, we prove a lower bound of 3N - o(N) for the number of bends in the worst case layout in an optimal area of ½ N2 + o(N2).
EXTENDED SKIP GRAPHS FOR EFFICIENT KEY SEARCH IN PEER-TO-PEER ENVIRONMENT
Authors: FUJITA SATOSHI , OHTSUBO AKIRA , MITO MASAYA
Published: August 2007

In this paper, we propose three techniques to improve the cost/performance of the skip graph that was recently proposed by Aspnes and Shah. The skip graph, which is a distributed data structure that could efficiently support find, insert, and delete operations of a key drawn from a totally ordered set, consists of N nodes each of which is connected with exactly log 2 N nodes determined by a set of random binary vectors called membership vectors. In the following, we will extend the construction of the skip graph in the following two directions: 1) proposal of a subgraph of the skip graph which realizes a graceful degradation of the routing performance when the number of neighbors reduces from log 2 N, and 2) proposal of a supergraph of the skip graph which realizes a significant performance improvement when the number of neighbors increases from log 2 N. The performance of those extended graphs will be evaluated analytically.
HAMILTONIAN LACEABILITY OF FAULTY HYPERCUBES
Authors: SUN CHAO-MING , HUNG CHUN-NAN , HUANG HUA-MIN , HSU LIH-HSING , JOU YUE-DAR
Published: August 2007

We consider the occurrence of the combination of edge faults and vertex faults in hypercubes. To preserve the equitability of Qn, we restrict the faults on vertex occurring only on disjoint adjacent pairs. Let F be a subset of V(Qn) ∪ E(Qn) such that F can be decomposed into two parts Fav and Fe where Fav is a union of fav disjoint adjacent pairs of Qn and Fe consists of fe edges of Qn. We show that the Qn - F is still hamiltonian if fav + fe ≤ n - 2. In addition, we prove that there exists a hamiltonian path in Qn - {v} - F between any two vertices in the partite set not containing v if fav + fe ≤ n - 3. Furthermore, all bounds are tight. This generalizes a recent result of Fu (2006).
The estimation of ‘natural’ summer outflows from the Permo-Triassic Sandstone aquifer, UK
Authors: Shepley M.G. , Streetly M.
Published: July 2007

This paper examines some techniques that have been applied to estimate the ‘natural’ summer outflow for the Permo-Triassic aquifer of England, the second most important aquifer in the UK for public water supply. A method for naturalizing groundwater models is discussed and the naturalized flows predicted by the groundwater models of three Permo-Triassic Sandstone aquifers are compared against results of an analytical method to determine natural summer outflows for the equivalent aquifer properties. The results from the naturalization of the three groundwater models are broadly comparable and indicate that the simulated naturalized Q85 (i.e. the flow exceeded for 85% of the time) lies in the range of 70–90% of the naturalized long-term average recharge with a mean of 80% long-term average recharge. This provides the basis for a reasonably robust ‘first pass’ method to determine the natural summer outflows of an unconfined Permo-Triassic Sandstone aquifer unit. Some of this variability in the estimated natural summer outflows can be accounted for by the average distance from the ‘upstream’ edge of the aquifer unit to the discharge boundary (i.e. the perpendicular length). Comparison of the results of the naturalized simulations with the predictions of an analytical solution shows that the typical minimum summer baseflow of the analytical solution appears to be most consistent with the Q85 flow condition simulated by the groundwater models. However, it is clear that, at shorter perpendicular lengths (<1.5 km), the simple idealization of the aquifer implicit in the analytical solution is unable to predict natural summer outflows for the Permo-Triassic Sandstone aquifer system. This is likely to be a result of the increased significance of vertical components of flow in smaller aquifer units.
Transcurrent fault activity on the Dead Sea Transform in Lebanon and its implications for plate tectonics and seismic hazard
Authors: BUTLER R. W. H. , SPENCER S. , GRIFFITHS H. M.
Published: July 2007

Fault activity within the Lebanese transpression zone, one of the classic examples of restraining bend development on a continental transform, is here investigated using dated geomorphological features. The northern part of the Yammouneh Fault, commonly considered to be the principal active strand on this part of the Dead Sea Transform, has been inactive for the past 5 Ma. Field observations show that basalts, dated as late Pliocene hi age, apparently offset by the Yammouneh fault, unconformably overlie it. The active transcurrent structure is principally, perhaps exclusively, the Roum Fault. The Lebanese transpressive zone has evolved through tune, with migration of fault activity. These results confirm the overlapping transform hypothesis for the Dead Sea system, require the active triple junction between the transform and the Tethyan collision belt to lie offshore SE Cyprus, and have profound implications for assessing seismic hazard hi the Levant.
Tectonic influences in piecemeal caldera collapse at Glencoe Volcano, Scotland
Authors: MOORE I.A.N. , KOKELAAR PETER
Published: July 2007

Glencoe Volcano is renowned as the archetype for caldera collapse that results from piston-like subsidence of a coherent crustal block on a ring fault. However, the caldera-floor rocks, and the geometry of seven intracaldera units that record large volume explosive eruptions, show that the collapse involved incremental and haphazard subsidence of numerous crustal blocks
before
development of the ring fault. Some subsidence involved flexure (downsag) with associated development of extensional crevasses hundreds of metres deep. A system of orthogonal faults and related grabens records the influence of two intersecting basement discontinuities, one of which is inferred to have linked with the active Great Glen fault. Substantial extensional and/or transtensional faulting, with distinct related sedimentary responses, occurred without eruptions. The tectonic framework substantially controlled the magmatic plumbing and the locations of vents, caldera depocentres, and through-going rivers. The related sediments influenced contrasting eruption styles (e.g. transitions between phreatomagmatic and magmatic) and the shallow-level emplacement of sills.
Deformation and emplacement of the Lizard Ophiolite Complex, SW England, based on evidence from the Basal Unit
Authors: JONES K. A.
Published: July 2007

The Basal Unit of the Lizard Ophiolite Complex preserves evidence of a protracted deformation and accretion history. The earliest recognizable events record the construction of ocean crust and the generation of the Lizard Ophiolite Complex in a slow-spreading ridge-axis environment. The initial stages of deformation involved the development of a sub-horizontal crustal-scale shear zone and its progressive deformation by ductile thrusting and folding. Subsequent deformation progressed with the out-of-sequence stacking of ocean lithosphere in which detachment, initiated at mid-crustal levels, culminated in mantle decoupling as thrust slices were derived from progressively deeper crustal levels. The progressive emplacement of a coherent slice of ocean lithosphere over previously accreted units and the generation of a dynamothermal aureole are consistent with models suggesting rapid overthrusting of young ocean lithosphere. Evidence from the dynamothermal aureole indicates that syn-emplacement extensional collapse of the complex occurred in response to thrust loading. Foreland-directed offsliding and lateral thrusting mark the final stages in the collapse of the complex.
Glaucony from the Eocene of the Isle of Wight (southern UK): implications for basin analysis and sequence-stratigraphic interpretation
Authors: AMOROSI ALESSANDRO , CENTINEO MARIA CARLA
Published: July 2007

The Lower-Middle Eocene sequence of the Hampshire Basin, which includes an alternation of sands, silts and clays, interpreted as fluvial to open-marine deposits, is exposed at two locations on the western (Alum Bay) and eastern (Whitecliff Bay) margin of the Isle of Wight. Glaucony is encountered throughout the study units: sand-clay alternations of lagoonal origin and estuarine channel-fill sands include less than 10% of predominantly poorly evolved, allochthonous glaucony; shelf silts and sands generally comprise more than 20% of evolved, mostly autochthonous glaucony.

Vertical changes in maturity of glaucony confirm the trend predicted by recent models, indicating an overall upward increase in the transgressive systems tracts and decrease in the highstand systems tracts, with maximum values in coincidence with the condensed sections, where a remarkable peak in glaucony concentration is invariably recorded.

Comparison of glaucony characteristics at different sites of depositional sequences shows a slight increase in maturity and abundance from the proximal to the distal areas. This lateral tendency is interpreted to reflect more suitable conditions for glauconitization in open-marine environments than in shallow waters.

Despite documented intrasequential variability of glaucony characteristics, glaucony assemblages from distinct depositional sequences may be generally identified on the basis of more pronounced differences in maturity. Consequently, glaucony attributes can be used as an index for characterization of third-order sedimentary cycles.
Allochthonous metamorphic blocks on the Hebridean passive margin, Scotland
Authors: BLUCK B. J. , DEMPSTER T. J. , ROGERS G.
Published: July 2007

Radiometric age determinations on syn-orogenic intrusive rocks coupled with evidence from field relationships, indicate that metamorphism and ductile deformation was taking place hi the Scottish metamorphic blocks coeval with extension on the Hebridean foreland. Consequently metamorphic rocks now found east and south of the Moine Thrust are regarded as substantially allochthonous, being located within the region where there was formerly a Cambrian-Early Ordovician passive margin sequence and its attendant oceanic crust. We regard these blocks as displaced terranes which acquired their metamorphic and structural signatures outside of the present Hebridean foreland regime. This may have occurred initially at the tune of megacontinent splitting and later on the destructive margin which was initiated hi Laurentia.
Neotectonic fault activity in Hong Kong: evidence from seismic events and thermoluminescence dating of fault gouge
Authors: DING Y. Z. , LAI K. W.
Published: July 2007

Hong Kong lies within a major NE-trending fault zone that has been reactivated during several tectonic episodes since the Palaeozoic. Three main faults sets are recognized in Hong Kong: a dominant NE-trending set, an ENE- varying to E-trending set and a subordinate NW-trending set. Over the last 1000 years, within a distance of 350 km of Hong Kong, there have been about 40 earthquakes with magnitudes of over 4.75, and of these 11 had magnitudes of over 6.0. Microseismic events in the last ten years are diffuse but may be associated with a major NE-trending fault and a fault intersection. Thermoluminescence (TL) dates of fault gouge suggest that there have been three episodes of recent fault activity in Hong Kong; these occurred at approximately at 100 000, 190 000 and 270 000 years BP. TL dating of alluvial sediments also indicates fault activity in the Late Pleistocene.
Syntectonic magnetization of the mid-Palaeozoic Sierra Grande Formation: further constraints on the tectonic evolution of Patagonia
Authors: RAPALINI A. E.
Published: July 2007

A palaeomagnetic study was carried out in the Silurian-Devonian clastic sedimentary rocks of the Sierra Grande Formation, exposed in northeastern Patagonia (41.6°S, 65.3°W). Thirteen sites (
n
=88) were located on opposite limbs of a syncline-anticline structure. Stepwise thermal demagnetization permitted the identification of a very stable magnetic component of reversed polarity carried by hematite. Stepwise performance of the fold test yielded negative results both
in situ
and after 100% bedding correction, but positive after partial unfolding (19%). This indicates a syntectonic origin for the isolated magnetization. A pole position was computed for the partially (19%) corrected remanence: SG3: 77.3°S, 310.7°E, δ
p
=7.7°, δ
m
=6.6°,
N=13.
Its position is coincident with late Early to Late Permian palaeomagnetic poles from South America, suggesting that age for the previously undated folding of the Sierra Grande sequence and therefore for the main tectonic event that affected the northern boundary of Patagonia. Palaeozoic palaeomagnetic poles from Patagonia obtained to date agree with those from Gondwana of Devonian or younger age, suggesting that Patagonia did not undergo important displacements relative to South America since those times. This and the Permian age of deformation determined in this study invalidates tectonic models involving collision of a far-travelled Patagonia with Gondwana in the mid- or Late Palaeozoic.
The Hølonda Porphyrites, Norwegian Caledonides: geochemistry and tectonic setting of Early–Mid-Ordovician shoshonitic volcanism
Authors: GRENNE T.O.R. , ROBERTS DAVID
Published: July 2007

Petrological and geochemical data denote that the Late Arenig–Early Llanvirn Hølonda Porphyrites belong to the subduction-related shoshonite association. Original compositions ranged from absarokite through shoshonite to latite, and their very evolved nature signifies a mature arc aYnity in an active continental margin setting. Much of the geochemical variation can be interpreted in terms of fractional crystallization followed by a varying admixture of cumulus phases to the ascending melt and accumulation of phenocrysts within the magmatic feeder system. Their eruptive products covered an area which was at least 20–25 km across, forming local islands with carbonate-rich shelves in a shallow to deeper marine environment.

The immediate substrate to the volcanosedimentary ‘Hølonda basin’ is the Løkken Ophiolite, which formed in a primitive oceanic arc/marginal basin setting some 10–20 Ma prior to the shoshonitic magmatic event. Arc–continent collision led to emplacement of the oceanic, arc and marginal basin crust onto the continental margin in pre-Late Arenig times. Strong uplift of the obducted oceanic plate occurred in response to the buoyancy effect of the underthrusting, less dense, continental margin. This is interpreted to have been followed by a reversal of subduction polarity and formation of a steeply dipping subduction zone against the continental margin lithosphere, and was succeeded by the very evolved Hølonda Porphyrite shoshonitic magmatism in volcanic islands along this submerged continental margin.
Metamorphism and
40
Ar/
39
Ar dating of the Halaban Ophiolite and associated units: evidence for two-stage orogenesis in the eastern Arabian Shield
Authors: AL-SALEH AHMAD M. , BOYLE ALAN P. , MUSSETT ALAN E.
Published: July 2007

The Arabian Shield has long been recognized as a region where plate-tectonic processes have been in action during most of the Late Proterozoic resulting in the amalgamation of the shield’s five constituent terranes along four major suture zones. Studies thus far carried out on these collisional belts have concentrated on the origin and dating of intermediate to acidic igneous rocks, and very little emphasis has been placed on the understanding of metamorphic processes operative during plate convergence. The Al-Amar Suture separates the Afif microplate from the Ar Rayn Block in the easternmost section of the Shield. Among several ophiolite occurrences in this suture, the Halaban Belt is by far the largest and preserves within and around it a record of a number of thermal/structural events related to the opening and eventual closure of a supra-subduction zone back-arc basin that existed in the period 695–680 Ma. The bimodal nature of
40
Ar/
39
Ar dates from the Halaban Ophiolite and associated units is indicative of a two-stage orogenesis climaxing at 680 and 600 Ma, instead of the previously proposed model of a single orogenic episode between 670 and 630 Ma. The first stage (680 Ma) is believed to be related to basin closure and ophiolite emplacement as the Ar Rayn island arc collided with the Afif microcontinent. The second episode (600 Ma) was the outcome of a major collisional event between the Arabian craton and a large continental mass east of the Ar Rayn Block.
Unidirectional slip vectors in the western Betic Cordillera: implications for the formation of the Gibraltar arc
Authors: KIRKER ANDREW I. , PLATT JOHN P.
Published: July 2007

We have investigated the kinematics of deformation in a sector of the Gibraltar arc in SW Spain, by synthesizing lineation data from major faults, the variation in structural trends, and palaeomagnetically determined vertical-axis rotations. The kinematic data show that transport directions throughout formation of the arc were consistently WNW, regardless of structural trend, which varies between 050 and 350 in the study area. The data suggest that this part of the Gibraltar arc can be explained simply by oblique convergence with a curved indenter. Taken together with other published data it appears likely that the variation in thrust transport direction within the Betic Cordillera as a whole may be considerably less than that in the Moroccan part of the arc. Unidirectional convergence, combined with the presence of palaeomagnetic rotations, implies either eYcient overprinting of old, rotated lineations, and/or a convergence rate that is much greater than the rotation rate. Also required is a low degree of partitioning in the thrust wedge. The latter probably increases east of the study area, where the structural trend becomes more oblique to the transport direction, and major strike-slip faults occur.
Syntectonic emplacement of the Maladeta granite (Pyrenees) deduced from relationships between Hercynian deformation and contact metamorphism
Authors: EVANS N. G. , GLEIZES G. , LEBLANC D. , BOUCHEZ J. L.
Published: July 2007

The relationships between Hercynian deformation and contact metamorphism in the aureole of the Aneto unit, a constituent pluton of the Maladeta granite complex (Spanish Pyrenees), provide new data relevant to the controversy between the syn- and post-tectonic models of emplacement for the Pyrenean granites. The deformation in the Aneto aureole is related to two superimposed Hercynian episodes. The first was a ‘top to the SW’ thrusting which induced SW-verging recumbent folds. The second, which was essentially compressive in the Aneto area, is represented by E–W-trending subvertical cleavage and folds with subhorizontal axes. This second episode can be assigned to the D2 main Hercynian tectonic event of the Pyrenees. The contact metamorphic assemblages grew during the D2 event and were deformed by it close to the contact. The conclusion that the pluton was emplaced during D2 is strengthened by the structural and kinematic similarities between the magmatic deformation in the southern rim of the pluton and the D2 deformation in the country rocks. This syntectonic timing is supported by new geochronological data that conflict with an existing Rb–Sr post-tectonic Permian whole-rock age for the Maladeta granite. More generally, in accordance with some very recent structural and U–Pb zircon studies, our results contradict the geodynamical models of the Pyrenees which relate the granite intrusions to a late extensional event.
Biotin Sensing: Universal Influence of Biotin Status on Transcription
Authors: Beckett Dorothy
Published: August 2007

Although the role of biotin in metabolic reactions has long been recognized, its influence on transcription has only recently been discovered. A key protein in biotin-mediated transcription regulation is the biotin protein ligase, the enzyme responsible for catalyzing covalent linkage of the vitamin to biotin-dependent carboxylases. In the biotin regulatory system of Escherichia coli, the best characterized of the biotin-sensing systems, the biotin protein ligase functions both as the biotinylating enzyme and as a transcription repressor. Detailed mechanistic studies of this system are reviewed. In addition, recent studies have revealed other biotin-sensing systems in organisms ranging from bacteria to humans. These systems and the central role of the biotin protein ligase in each are also reviewed.
Trace Element Transport in the Mammary Gland
Authors: Lönnerdal Bo
Published: August 2007

The mammary gland has a remarkable capacity to adapt to maternal deficiency or excess of iron, copper, and zinc and to homeostatically control milk concentrations of these essential nutrients. Similarly, it can regulate changes in concentrations of iron, copper, and zinc change during lactation. For iron, this regulation is achieved by transferrin receptor, DMT1, and ferroportin, whereas mammary gland copper metabolism is regulated by Ctr1, ATP7A, and ATP7B. Zinc homeostasis is complex, involving both zinc importers (Zip3) and zinc exporters (ZnT-1, ZnT-2, and ZnT-4). Both transcriptional and post-translational regulation can affect protein abundance and cellular localization of these transporters, finely orchestrating uptake, intracellular trafficking, and secretion of iron, copper, and zinc. The control of mammary gland uptake and milk secretion of iron, copper, and zinc protects both the mammary gland and the breast-fed infant against deficiency and excess of these nutrients.
11β-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues
Authors: Berthiaume Magalie , Laplante Mathieu , Festuccia William T. , Cianflone Katherine , Turcotte Lorraine P. , Joanisse Denis R. , Olivecrona Gunilla , Thieringer Rolf , Deshaies Yves
Published: August 2007

Tissue-specific alterations in 11β-hydroxysteroid dehydrogenase (HSD) type 1 activity, which amplifies glucocorticoid action, are thought to contribute to some of the metabolic complications of obesity. The present study tested whether hypertriglyceridemia is one such complication by investigating the effects of an 11β-HSD1 inhibitor (compound A, 3 mg·kg−1·day−1, 21 days) on triglyceride (TG) metabolism in a rat model of diet-induced obesity. The dose of compound A used did not affect food intake or final body weight. Compound A improved fasting triglyceridemia (−42%) through a robust reduction (−41%) in hepatic TG secretion rate, without change in plasma TG clearance rate. Uptake of TG-derived fatty acids was, however, increased in oxidative tissues, including red gastrocnemius (+47%), heart (+39%), and brown adipose tissue (BAT, +46%) at the expense of the liver, with a concomitant increase in plasma membrane fatty acid-binding protein. Lipid oxidation products were increased in red gastrocnemius (+35%) and heart (+33%), as were levels of uncoupling protein 1 mRNA in BAT (+48%), and carnitine palmitoyltransferase 1 activity tended to be increased in some oxidative tissues. These findings demonstrate that pharmacological inhibition of 11β-HSD1 at a dose that does not affect food intake improves triglyceridemia by reducing hepatic very low density lipoprotein-TG secretion, with a shift in the pattern of TG-derived fatty acid uptake toward oxidative tissues, in which lipid accumulation is prevented by increased lipid oxidation.
Reactive oxygen species and the regulation of renal Na+-K+-ATPase in opossum kidney cells
Authors: Silva Elisabete , Soares-da-Silva Patrício
Published: August 2007

Culture of opossum kidney (OK) cells over 40 passages resulted in marked overexpression of α1-subunit and β1-subunit Na+-K+-ATPase, which paralleled with increases in Na+-K+-ATPase activity, and enhanced availability in hydrogen peroxide (H2O2) ( J Membr Biol 212: 163–175, 2006). The present study evaluated the mechanisms involved in increased H2O2 production in OK cells cultured over 40 passages (up to passage 80) and whether H2O2 plays a role in the regulation of Na+-K+-ATPase expression and activity. The accumulation of H2O2 in the extracellular medium over 24 h (236.5 ± 2.7 vs. 319.3 ± 2.9 nM) and the rate of H2O2 production (5.21 ± 0.02 vs. 7.37 ± 0.02 nM/min) in cells with 40 passages was lower ( P < 0.05) than in cells with 80 passages. The increase in H2O2 production in cells with 80 passages was accompanied by overexpression of NOX1, but not of NOX2, and overexpression of SOD1, SOD2, and SOD3. Apocynin, a NADPH inhibitor, markedly attenuated the increase in H2O2 production in cells with 80 passages and significantly decreased Na+-K+-ATPase activity (26% reduction) and α1-subunit Na+-K+-ATPase overexpression. Increases in Na+-K+-ATPase α1-subunit mRNA abundance were also observed in OK cells with increased number of cell passages, but apocynin did not affect transcript abundance. In conclusion, the increased availability of H2O2 in the intracellular milieu plays an important role in the long-term regulation of Na+-K+-ATPase expression and activity. These cells may constitute an interesting model to study events related to oxidative stress, in which adaptation to increases in H2O2 had progressively adapted in a more natural manner.
Fructose, but not dextrose, accelerates the progression of chronic kidney disease
Authors: Gersch Michael S. , Mu Wei , Cirillo Pietro , Reungjui Sirirat , Zhang Li , Roncal Carlos , Sautin Yuri Y. , Johnson Richard J. , Nakagawa Takahiko
Published: August 2007

The metabolic syndrome has recently been recognized as a risk factor for kidney disease, but the mechanisms mediating this risk remain unclear. High fructose consumption by animals produces a model of the metabolic syndrome with hypertension, hyperlipidemia, and insulin resistance. The present study was conducted to test the hypothesis that consumption of a high-fructose diet could accelerate the progression of chronic kidney disease. Three groups of 14 male Sprague-Dawley rats were pair fed a specialized diet containing 60% fructose (FRU) or 60% dextrose (DEX) or standard rat chow (CON). After the animals were fed their assigned diet for 6 wk, five-sixths nephrectomy was performed, and the assigned diet was continued for 11 wk. Proteinuria was significantly increased and creatinine clearance was decreased in the FRU group compared with the CON and DEX groups, and blood urea nitrogen was higher in the FRU group than in the CON and DEX groups. Kidneys from the FRU group were markedly larger than kidneys from the CON and DEX groups. Glomerular sclerosis, tubular atrophy, tubular dilatation, and cellular infiltration appeared markedly worse in kidneys from the FRU group than in kidneys from the DEX and CON groups. Monocyte chemoattractant protein-1 (MCP-1) was measured in renal tissue homogenate and found to be increased in the FRU group. In vitro studies were conducted to determine the mechanism for increased renal MCP-1, and fructose stimulation of proximal tubular cells resulted in production of MCP-1. In conclusion, consumption of a high-fructose diet greatly accelerates progression of chronic kidney disease in the rat remnant kidney model.
Effects of pioglitazone and candesartan on renal fibrosis and the intrarenal plasmin cascade in spontaneously hypercholesterolemic rats
Authors: Omasu Fumihiro , Oda Takashi , Yamada Muneharu , Yoshizawa Nobuyuki , Yamakami Kazuo , Sakurai Yutaka , Miura Soichiro
Published: August 2007

The profibrotic effect of plasminogen activator inhibitor-1 (PAI-1) in renal fibrosis is widely recognized, but its mechanism remains controversial especially in chronic progressive kidney disease. In the present study, pioglitazone (Pio) and candesartan (CD), which are reported to inhibit PAI-1, were administered to spontaneously hypercholesterolemic (SHC) rats, a model of chronic progressive kidney disease. Therapeutic effects and effects on the intrarenal plasmin cascade were examined. Eight-wk-old SHC rats were used as controls. Oral administration of vehicle alone, Pio, or CD was performed starting at 8 wk of age and was continued for 24 wk. The degree of renal fibrosis was evaluated by sirius red staining of kidney sections and by total collagen assay of renal homogenates. The renal PAI-1 protein level was assessed by Western blotting, and plasmin activity was analyzed by chromogenic assay and casein gel zymography. Urinary protein and blood urea nitrogen were significantly increased in the vehicle-treated group, but the increase was attenuated in the Pio- and CD-treated groups. This correlated well with the degree of fibrosis as assessed by sirius red staining and total collagen assay. The PAI-1 protein level was also increased significantly in the vehicle-treated group, and the increase was attenuated in the Pio- and CD-treated groups. Despite the presumed plasmin-inhibitory function of PAI-1, plasmin activity changed in parallel with PAI-1. These results suggest that Pio and CD inhibit PAI-1 and exert renoprotective effects against chronic progressive renal disease, but its action is independent of the regulatory function on plasmin activity.
Transcriptomic approach to the study of osmoregulation in the European eelAnguilla anguilla
Authors: Kalujnaia Svetlana , McWilliam Iain S. , Zaguinaiko Vitalii A. , Feilen Anja L. , Nicholson John , Hazon Neil , Cutler Christopher P. , Cramb Gordon
Published: August 2007

In euryhaline teleosts, osmoregulation is a fundamental and dynamic process that is essential for the maintenance of ion and water balance, especially when fish migrate between fresh water (FW) and sea water (SW) environments. The European eel has proved to be an excellent model species to study the molecular and physiological adaptations associated with this osmoregulatory plasticity. The life cycle of the European eel includes two migratory periods, the second being the migration of FW eels back to the Sargasso Sea for reproduction. Various anatomical and physiological changes allow the successful transition to SW. The aim of this study was to use a microarray approach to screen the osmoregulatory tissues of the eel for changes in gene expression following acclimation to SW. Tissues were sampled from fish at selected intervals over a 5-mo period following FW/SW transfer, and RNA was isolated. Suppressive subtractive hybridization was used for enrichment of differentially expressed genes. Microarrays comprising 6,144 cDNAs from brain, gill, intestine, and kidney libraries were hybridized with appropriate targets and analyzed; 229 differentially expressed clones with unique sequences were identified. These clones represented the sequences for 95 known genes, with the remaining sequences (59%) being unknown. The results of the microarray analysis were validated by quantification of 28 differentially expressed genes by Northern blotting. A number of the differentially expressed genes were already known to be involved in osmoregulation, but the functional roles of many others, not normally associated with ion or water transport, remain to be characterized.
Human Tumor-Derived Exosomes Selectively Impair Lymphocyte Responses to Interleukin-2
Authors: Clayton Aled , Mitchell J. Paul , Court Jacquelyn , Mason Malcolm D. , Tabi Zsuzsanna
Published: August 2007

Exosomes are nanometer-sized vesicles, secreted by normal and neoplastic cells. The outcome following interaction between the cellular immune system and cancer-derived exosomes is not well understood. Interleukin-2 (IL-2) is a key factor supporting expansion and differentiation of CTL and natural killer (NK) cells but can also support regulatory T cells and their suppressive functions. Our study examined whether tumor-derived exosomes could modify lymphocyte IL-2 responses. Proliferation of healthy donor peripheral blood lymphocytes in response to IL-2 was inhibited by tumor exosomes. In unfractionated lymphocytes, this effect was seen in all cell subsets. Separating CD4+ T cells, CD8+ T cells, and NK cells revealed that CD8+ T-cell proliferation was not inhibited in the absence of CD4+ T cells and that NK cell proliferation was only slightly impaired. Other exosome effects included selective impairment of IL-2–mediated CD25 up-regulation, affecting all but the CD3+CD8− T-cell subset. IL-2–induced Foxp3 expression by CD4+CD25+ cells was not inhibited by tumor exosomes, and the suppressive function of CD4+CD25+ T cells was enhanced by exosomes. In contrast, exosomes directly inhibited NK cell killing function in a T-cell–independent manner. Analysis of tumor exosomes revealed membrane-associated transforming growth factor β1 (TGFβ1), which contributed to the antiproliferative effects, shown by using neutralizing TGFβ1-specific antibody. The data show an exosome-mediated mechanism of skewing IL-2 responsiveness in favor of regulatory T cells and away from cytotoxic cells. This coordinated “double hit” to cellular immunity strongly implicates the role of exosomes in tumor immune evasion. [Cancer Res 2007;67(15):7458–66]
Lysis of Dysplastic but not Normal Oral Keratinocytes and Tissue-Engineered Epithelia with Conditionally Replicating Adenoviruses
Authors: Gaballah Kamis , Hills Allison , Curiel David , Hallden Gunnel , Harrison Paul , Partridge Max
Published: August 2007

There is no effective medical treatment for oral precancer, and surgery to remove these lesions is imprecise because abnormal mucosa extends beyond the visible lesion. Development of vectors for tumor-selective viral replication has been a significant advance, and viral lysis is well suited to destruction of oral precancerous mucosa. To facilitate evaluation of new treatments, we engineered dysplastic oral epithelium using keratinocytes isolated from dysplastic lesions. We show that these model systems recapitulate the key characteristics of the clinical lesions closely, and that topical delivery of the conditionally replicating adenovirus (CRAd) dl922-947 can lyse tissue-engineered epithelia that show mild, moderate, or severe dysplasia, but normal oral epithelia are very resistant to this treatment. The lytic effect is determined by various factors, including the grade and proliferation index of the dysplastic epithelia. The presence of suprabasal cycling cells, expression of the coxsackie adenovirus receptor (CAR), the transcription cofactor p300, and other aberrations that affect the regulation of the cell cycle or apoptosis and promote viral replication may also be important. The ability of dl922-947 to destroy engineered oral dysplasia was significantly greater than that observed using wild-type adenovirus, d/1520, or viruses modified to bypass cell entry dependent on the presence of CAR. Evidence of infection in clinical dysplastic lesions was also shown ex vivo using tissue explants. We conclude that dl922-947 may provide an efficient molecular cytotoxic to dissolve oral dysplastic lesions. [Cancer Res 2007;67(15):7284–94]
The Survival Kinase Mirk/Dyrk1B Is a Downstream Effector of Oncogenic K-ras in Pancreatic Cancer
Authors: Jin Kideok , Park Sunju , Ewton Daina Z. , Friedman Eileen
Published: August 2007

The kinase Mirk is overexpressed in many resected pancreatic adenocarcinomas and is amplified in a subset of pancreatic cancer cell lines. Depletion of Mirk has been shown to lead to apoptosis in pancreatic cancer cell lines, and thus to inhibit their clonogenic growth. Mirk is activated by signaling from activated Rac1 to MKK3 in MDCK cells, but the mechanism of activation of Mirk in pancreatic cancers is unknown. In this report, Mirk is shown to be a novel effector of K-ras, a gene mutated in ∼90% of pancreatic cancers. Activation of Mirk signaling from oncogenic K-ras through Rac1 was shown in transient expression systems and reporter assays. Mirk activation in pancreatic cancer cells was blocked by RNA interference using three different synthetic duplex RNAis to K-ras, or two RNAis to Rac1, by pharmacologic inhibition of Rac1, or by expression of dominant negative K-rasS17N. Rac1 was activated in four out of five pancreatic cancer cell lines, and was activated by signaling from oncogenic K-ras. Mirk knockout does not induce embryonic lethality, and depletion of Mirk had no effect on the survival of normal diploid fibroblasts. In contrast, the clonogenic ability of Panc1 and AsPc1 pancreatic cancer cell lines was reduced 8- to 12-fold by the depletion of Mirk, with a greater reduction seen following the depletion of K-ras or both genes. Mirk is a novel downstream effector of oncogenic K-ras and mediates some of the survival signals activated by ras signaling. [Cancer Res 2007;67(15):7247–55]
Therapeutic Relevance of Osteoprotegerin Gene Therapy in Osteosarcoma: Blockade of the Vicious Cycle between Tumor Cell Proliferation and Bone Resorption
Authors: Lamoureux François , Richard Peggy , Wittrant Yohann , Battaglia Séverine , Pilet Paul , Trichet Valérie , Blanchard Frédéric , Gouin François , Pitard Bruno , Heymann Dominique , Redini Françoise
Published: August 2007

Osteosarcoma is the most frequent primary bone tumor that develops mainly in the young, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% at 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options, and among them, osteoprotegerin (OPG), a naturally occurring protein that inhibits bone resorption, is very promising in blocking the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. As OPG binds and inhibits the activity of tumor necrosis factor–related apoptosis-inducing ligand, the truncated form of murine OPG 1-194 was used. The cDNA encoding OPG was administered by gene transfer using replication-defective adenoviral vector or was associated with an amphiphilic polymer in two models of rodent osteosarcoma. In both models, OPG gene transfer was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development, in reducing the tumor incidence and the local tumor growth, leading to a 4-fold augmentation of mice survival 28 days postimplantation. On the contrary, OPG did not prevent the development of pulmonary metastasis alone, suggesting that bone environment is necessary for OPG therapeutic efficacy. Because OPG has no direct activity on osteosarcoma cells in vitro (cell binding, cell proliferation, apoptosis, or cell cycle distribution), we show that OPG exerts indirect inhibitory effect on tumor progression through the inhibition of RANKL whose production is enhanced in bone tumor environment, leading to osteolysis inhibition as reflected by osteoclast number decrease. [Cancer Res 2007;67(15):7308–18]
Estrogen Plus Progestin Use, Microsatellite Instability, and the Risk of Colorectal Cancer in Women
Authors: Newcomb Polly A. , Zheng Yingye , Chia Victoria M. , Morimoto Libby M. , Doria-Rose V. Paul , Templeton Allyson , Thibodeau Stephen N. , Potter John D.
Published: August 2007

Current users of postmenopausal hormones (PMH) have ∼30% to 40% lower risk of colorectal cancer (CRC), although associations with specific types of hormones have been inconsistent. Further, it is not clear whether some tumor types have a different risk. We conducted a case-control study to examine the relationship between PMH and CRC. Cases (n = 1,004), ages 50 to 74 years, were identified from the Surveillance Epidemiology and End Results registry in Washington from 1998 to 2002; controls (n = 1,062) were randomly selected from population lists. Case tissue samples were obtained for microsatellite instability (MSI) analyses. Interviews collected risk-factor data for CRC, including detailed information on PMH. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Current use of any PMH was associated with a 20% reduction in CRC risk (95% CI 0.6–0.9). This reduction in risk was limited to women who had taken estrogen plus progestin (EP) preparations only (OR = 0.6, 95% CI 0.5–0.9); there was no association with estrogen-only (E alone) use (OR = 0.9, 95% CI 0.7–1.1). For women with MSI-low or MSI-stable tumors, there was a statistically significant 40% reduction in CRC risk associated with EP use (95% CI 0.4–0.9); there was no clear association with MSI-high tumors. EP use was associated with a decreased risk of CRC; however, there seemed to be no association with E alone data that are consistent with the recent Women's Health Initiative findings. Progestin may enhance the estrogenic effect of conjugated estrogen so the combination may be more biologically active in the colon than E alone. [Cancer Res 2007;67(15):7534–9]
Identification of S664 TSC2 Phosphorylation as a Marker for Extracellular Signal-Regulated Kinase–Mediated mTOR Activation in Tuberous Sclerosis and Human Cancer
Authors: Ma Li , Teruya-Feldstein Julie , Bonner Pauline , Bernardi Rosa , Franz David Neal , Witte David , Cordon-Cardo Carlos , Pandolfi Pier Paolo
Published: August 2007

Constitutive activation of extracellular signal-regulated kinases (Erk1/2) is frequently implicated in human cancers. Recently, aberrantly activated Erk was also found in brain lesions associated with tuberous sclerosis (TSC). We reported previously that Erk might contribute to tumorigenesis by phosphorylating TSC2 at specific residues, particularly S664. In our present study, 25 TSC-related cortical tubers or subependymal giant cell astrocytomas, as well as tissue microarrays of six types of human cancers, were analyzed for the expression of phospho-Erk (pErk) 1/2, S664-phospho-TSC2 (pTSC2), and phospho-S6 (pS6) by immunohistochemistry. We found that Erk-mediated TSC2 phosphorylation occurred at a high incidence and positively correlated with mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) activation in TSC-associated brain lesions as well as in various cancers. Interestingly, in certain types of cancers (e.g., breast carcinoma and colon carcinoma), S664-pTSC2 seemed to be a more sensitive marker than pErk. Furthermore, most of the pTSC2-positive samples (∼75%) were positive for pS6, but only 40% to 55% of the pS6-positive tumors exhibited TSC2 phosphorylation. Our results show that S664 TSC2 phosphorylation is a marker for Erk-mediated (as opposed to Akt-mediated) mTOR activation in TSC and human cancer. On the basis of these findings, TSC2 phosphorylation at S664 can be used to identify patients that may benefit from antitumor therapy with MAPK and mTOR inhibitors. Importantly, our results indicate that Erk-mediated phosphorylation and inactivation of TSC2 can be critical in development of hamartomatous lesions in TSC and cancer pathogenesis. [Cancer Res 2007;67(15):7106–12]
Clinical Validity of the Lung Cancer Biomarkers Identified by Bioinformatics Analysis of Public Expression Data
Authors: Kim Bumjin , Lee Hyun Joo , Choi Hye Young , Shin Youngah , Nam Seungyoon , Seo Gilju , Son Dae-Soon , Jo Jisuk , Kim Jaesang , Lee Jinseon , Kim Jhingook , Kim Kwhanmien , Lee Sanghyuk
Published: August 2007

Identification of molecular markers often leads to important clinical applications such as early diagnosis, prognosis, and drug targeting. Lung cancer, the leading cause of cancer-related deaths, still lacks reliable molecular markers. We have combined the bioinformatics analysis of the public gene expression data and clinical validation to identify biomarker genes for non–small-cell lung cancer. The serial analysis of gene expression and the expressed sequence tag data were meta-analyzed to produce a list of the differentially expressed genes in lung cancer. Through careful inspection of the predicted genes, we selected 20 genes for experimental validation using semiquantitative reverse transcriptase-PCR. The microdissected clinical specimens used in the study consisted of three groups: lung tissues from benign diseases and the paired (cancer and pathologic normal) tissues from non–small-cell lung cancer patients. After extensive statistical analyses, seven genes (CBLC, CYP24A1, ALDH3A1, AKR1B10, S100P, PLUNC, and LOC147166) were identified as potential diagnostic markers. Quantitative real-time PCR was carried out to additionally assess the value of the seven identified genes leading to the confirmation of at least two genes (CBLC and CYP24A1) as highly probable novel biomarkers. The gene properties of the identified markers, especially their relationship to lung cancer and cell signaling pathway regulation, further suggest their potential value as drug targets as well. [Cancer Res 2007;67(15):7431–8]
Environmental Tobacco Smoke and Bladder Cancer Risk in Never Smokers of Los Angeles County
Authors: Jiang Xuejuan , Yuan Jian-Min , Skipper Paul L. , Tannenbaum Steven R. , Yu Mimi C.
Published: August 2007

Cigarette smoking is a major risk factor for bladder cancer and a prominent point source of 4-aminobiphenyl (4-ABP), a recognized human bladder carcinogen. 4-ABP-hemoglobin (Hb) adducts are established biomarkers of 4-ABP exposure in humans. The role of environmental tobacco smoke (ETS) in the etiology of bladder cancer is largely unknown. As part of a large population-based bladder cancer study in Los Angeles County, California, lifetime exposure to ETS was ascertained for 148 cases and 292 control subjects who had never used any tobacco products over their lifetime. 4-ABP-Hb adducts were quantitatively measured on 230 control subjects. Female lifelong nonsmokers living with two or more smokers during childhood were significantly related to risk of bladder cancer [odds ratio (OR), 3.08; 95% confidence interval (95% CI), 1.16–8.22]. During adulthood, ∼2-fold risks were seen among women living with a spouse/domestic partner who smoked for ≥10 years or having a coworker who smoked in an indoor environment for ≥10 years. When all sources of ETS exposure were combined, a statistically significant, dose-dependent association (P for trend = 0.03) was noted in women, with the OR for the highest category of ETS exposure being 5.48 (95% CI, 1.06–28.36). Levels of 4-ABP-Hb adducts varied by ETS exposure status among female control subjects. Mean level was lowest in women never exposed to ETS (16.4 pg/g Hb) and highest in those with current ETS exposure (23.6 pg/g Hb). ETS exposure was associated with neither bladder cancer risk nor 4-ABP-Hb adduct levels in male lifelong nonsmokers. In conclusion, ETS is a risk factor for bladder cancer in women who were lifelong nonusers of any tobacco products. [Cancer Res 2007;67(15):7540–5]