bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Genome Sequence and Lytic Phase Transcription Profile of a
Coccolithovirus
Authors: Wilson William H. , Schroeder Declan C. , Allen Michael J. , Holden Matthew T. G. , Parkhill Julian , Barrell Bart G. , Churcher Carol , Hamlin Nancy , Mungall Karen , Norbertczak Halina , Quail Michael A. , Price Claire , Rabbinowitsch Ester , Walker Danielle , Craigon Marie , Roy Douglas , Ghazal Peter
Published: August 2005

The genus
Coccolithovirus
is a recently discovered group of viruses that infect the globally important marine calcifying microalga
Emiliania huxleyi
. Among the 472 predicted genes of the 407,339–base pair genome are a variety of unexpected genes, most notably those involved in biosynthesis of ceramide, a sphingolipid known to induce apoptosis. Uniquely for algal viruses, it also contains six RNA polymerase subunits and a novel promoter, suggesting this virus encodes its own transcription machinery. Microarray transcriptomic analysis reveals that 65% of the predicted virus-encoded genes are expressed during lytic infection of
E. huxleyi
.
Integration of Spatial and Temporal Information During Floral Induction in
Arabidopsis
Authors: Wigge Philip A. , Kim Min Chul , Jaeger Katja E. , Busch Wolfgang , Schmid Markus , Lohmann Jan U. , Weigel Detlef
Published: August 2005

Flowering of
Arabidopsis
is regulated by several environmental and endogenous signals. An important integrator of these inputs is the
FLOWERING LOCUS T
(
FT
) gene, which encodes a small, possibly mobile protein. A primary response to floral induction is the activation of
FT
RNA expression in leaves. Because flowers form at a distant site, the shoot apex, these data suggest that
FT
primarily controls the timing of flowering. Integration of temporal and spatial information is mediated in part by the bZIP transcription factor FD, which is already expressed at the shoot apex before floral induction. A complex of FT and FD proteins in turn can activate floral identity genes such as
APETALA1
(
AP1
).
Origin of Brittle Cleavage in Iridium
Authors: Cawkwell Marc J. , Nguyen-Manh Duc , Woodward Christopher , Pettifor David G. , Vitek Vaclav
Published: August 2005

Iridium is unique among the face-centered cubic metals in that it undergoes brittle cleavage after a period of plastic deformation under tensile stress. Atomistic simulation using a quantum-mechanically derived bond-order potential shows that in iridium, two core structures for the screw dislocation are possible: a glissile planar core and a metastable nonplanar core. Transformation between the two core structures is athermal and leads to exceptionally high rates of cross slip during plastic deformation. Associated with this athermal cross slip is an exponential increase in the dislocation density and strong work hardening from which brittle cleavage is a natural consequence.
Amplification of Surface Temperature Trends and Variability in the Tropical Atmosphere
Authors: Santer B. D. , Wigley T. M. L. , Mears C. , Wentz F. J. , Klein S. A. , Seidel D. J. , Taylor K. E. , Thorne P. W. , Wehner M. F. , Gleckler P. J. , Boyle J. S. , Collins W. D. , Dixon K. W. , Doutriaux C. , Free M. , Fu Q. , Hansen J. E. , Jones G. S. , Ruedy R. , Karl T. R. , Lanzante J. R. , Meehl G. A. , Ramaswamy V. , Russell G. , Schmidt G. A.
Published: August 2005

The month-to-month variability of tropical temperatures is larger in the troposphere than at Earth's surface. This amplification behavior is similar in a range of observations and climate model simulations and is consistent with basic theory. On multidecadal time scales, tropospheric amplification of surface warming is a robust feature of model simulations, but it occurs in only one observational data set. Other observations show weak, or even negative, amplification. These results suggest either that different physical mechanisms control amplification processes on monthly and decadal time scales, and models fail to capture such behavior; or (more plausibly) that residual errors in several observational data sets used here affect their representation of long-term trends.
Refocusing Disaster Aid
Authors: Linnerooth-Bayer Joanne , Mechler Reinhard , Pflug Georg
Published: August 2005

With new modeling techniques for estimating and pricing the risks of natural disasters, the donor community is now in a position to help the poor cope with the economic repercussions of disasters by assisting before they happen. Such assistance is possible with the advent of novel insurance instruments for transferring catastrophe risks to the global financial markets. Donor-supported risk-transfer programs not only would leverage limited disaster-aid budgets but also would free recipient countries from depending on the vagaries of postdisaster assistance. Both donors and recipients stand to gain, especially because the instruments can be closely coupled with preventive measures.
NEUTRINO PHYSICS – THEORY
Authors: DE GOUVÊA ANDRÉ
Published: August 2005

I discuss the new physics unveiled by neutrino oscillation experiments. It is fair to say that, while significant theoretical progress has been made, we are yet to construct a unique coherent picture that naturally explains non-zero, yet tiny, neutrino masses and the newly revealed pattern of lepton mixing. I discuss what the challenges are, and point to the fact that more experimental input is required. Finally, I draw attention to the fact that neutrinos may have only just begun to reshape fundamental physics, given the fact that we are still to explain the LSND anomaly and because the neutrino oscillation phenomenon is ultimately sensitive to very small new-physics effects.
SCALE OF MASS GENERATION FOR MAJORANA NEUTRINOS
Authors: HE HONG-JIAN , DICUS DUANE A.
Published: August 2005

Scales of mass generation for Majorana neutrinos (as well as quarks and leptons) can be probed from high energy 2 → n inelastic scattering involving a multiple longitudinal gauge boson final state. We demonstrate that the unitarity of 2 → n scattering puts the strongest new upper limit on the scale of fermion mass generation, independent of the electroweak symmetry breaking scale [Formula: see text]. Strikingly, for Majorana neutrinos (quarks and leptons), we find that the strongest 2 → n limits fall in a narrow range, 136 - 170 TeV (3 - 107 TeV ) with n = 20 - 24 (n = 2 - 12), depending on the observed fermion masses. Physical implications are discussed.
THE JUPITER ELECTRON SCATTERING PROGRAM AT JEFFERSON LAB
Authors: Bodek Arie
Published: August 2005

JUPITER (Jlab Unified Program to Investigate nuclear Targets and Electroproduction of Resonances) is a new collaboration between the Nuclear Physics electron scattering and High Energy Physics neutrino scattering communities to investigate the structure of nucleons and nuclei with electron and neutrino Beams. The first phase of JUPITER is Hall C experiment E04-001 on Inclusive Electron Scattering from Nuclear Targets. First data run of E04-001 is currently scheduled for January of 2005.
The Dark Energy Survey
Authors:   for the Dark Energy Survey Collaboration: Fermilab, University of Illinois at Urbana-Champaign, University of Chicago, Lawrence Berkeley National Laboratory, Cerro-Tololo Inter-American Observatory, Flaugher Brenna
Published: August 2005

Dark Energy is the dominant constituent of the universe and we have little understanding of it. We describe a new project aimed at measuring the dark energy equation of state parameter, w, to a statistical precision of ~5% with four separate techniques. The survey will image 5000 deg2 in the southern sky and collect 300 million galaxies, 30,000 galaxy clusters, and 2000 Type Ia supernovae. The survey will be carried out using a new 3 deg2 mosaic camera mounted at the prime focus of the 4m Blanco telescope at CTIO.
Exploring Properties of Dark and Visible Mass Distribution on Different Scales in the Universe
Authors: Mishchenko Yuriy , Ji Chueng-Ryong
Published: August 2005

In this short note we discuss recent observation of linear correlation on log-log scale between distribution of dark and visible mass in gravitationally bound systems. The coefficient of such correlation appears to be essentially the same for various systems of dramatically different scales such as spiral galaxies of different luminosities and galaxy clusters. We briefly touch possible interpretations of this observation and implications for the mass of dark matter particle.
GEV TO PEV ENERGY PHOTON INTERACTIONS IN GAMMA-RAY BURST FIREBALLS AND SURROUNDINGS
Authors: RAZZAQUE SOEBUR , MÉSZÁROS PETER , ZHANG BING
Published: August 2005

Shock acceleration mechanism in gamma-ray bursts may produce photons up to a few PeV energy. Photons above 10-100 GeV and below a PeV energy are trapped inside the fireball due to a high opacity of electron-positron pair production with other photons. High energy photons escaping the fireball may interact with cosmic background radiation and provide delayed gamma-ray emission detectable by GLAST. Detection of the prompt and delayed emission may provide useful constraints on the gamma-ray burst model and also on the inter-galactic magnetic field.
THEORETICAL STATUS OF THE TOP QUARK CROSS SECTION
Authors: KIDONAKIS NIKOLAOS , VOGT RAMONA
Published: August 2005

We discuss the most recent calculations of the top quark total cross section and transverse momentum distributions at the Tevatron and the LHC. These calculations include the soft-gluon corrections at next-to-next-to-leading order (NNLO). The soft NNLO corrections stabilize the scale dependence of the cross section.
Age and origin of granitic rocks of the eastern Vardar Zone, Greece: new constraints on the evolution of the Internal Hellenides
Authors: Anders B. , Reischmann T. , Poller U. , Kostopoulos D.
Published: August 2005

The Vardar Zone is an integral part of the Internal Hellenides and has long been regarded as an ophiolite-decorated suture zone separating two distinct continental blocks, namely the Pelagonian Zone to the west and the Serbo-Macedonian Massif to the east. Several bodies of granites, gneisses and volcanic rocks are associated with the ophiolitic rocks and can provide additional constraints on the evolution of the suture. Single-zircon and monazite dating of felsic rocks yields accurate ages for the processes of accretion of the suture. The igneous formation ages obtained range from 155 to 164 Ma, suggesting an important magmatic phase in the Late Jurassic. The chemical and isotopic composition of these rocks is in accord with their formation in a volcanic-arc setting at an active continental margin. Older continental material incorporated in the Vardar Zone is documented by 319 Ma gneisses and by inherited zircons of mainly Mid-Palaeozoic ages. The Late Jurassic magmatic event overprinted such gneisses, as is evident in monazite ages of 158 Ma. The prevalence of Late Jurassic subduction-related igneous rocks indicates that arc formation and accretion orogeny were the most important processes during the evolution of this part of the Internal Hellenides.
Cambrian reworking of the southern Australian Proterozoic Curnamona Province: constraints from regional shear-zone systems
Authors: Dutch Rian A. , Hand Martin , Clark Chris
Published: August 2005

Palaeoproterozoic to early Mesoproterozoic metamorphic rocks of the Curnamona Province, southern Australia, are crosscut by a system of regional-scale shear zones that locally dominate the terrain. Combined metamorphic and geochronological data from localities across the southern Curnamona Province indicate that the peak metamorphic shear-zone assemblages formed during the Cambrian (
c
. 500 Ma) Delamerian Orogeny, and not during the waning stages of the
c
. 1600 Ma Olarian Orogeny as has been previously asserted. A combination of monazite chemical U–Th–Pb and garnet Sm–Nd geochronology indicates that shear-zone fabrics formed between 497 and 517 Ma. Peak metamorphic conditions obtained from prograde garnet–staurolite–biotite–muscovite–chlorite–quartz assemblages are between 530 and 600 °C at pressures of around 5 kbar. The apparent absence of significant up-pressure prograde paths recorded by the mineral assemblages, together with modest (10–20%) Delamerian shortening, suggests that attainment of burial to depths of around 18 km was largely a function of pre-Delamerian sedimentation over the interval from
c
. 700 to 530 Ma. The spatial association between the pattern of basement metamorphism and reactivation during the Delamerian Orogeny is interpreted to reflect in part the distribution of pre-Delamerian sedimentation, and highlights the potential importance of pre-orogenic processes such as basin development in controlling the style and pattern of later terrain reactivation and reworking.
Palaeothermal and compaction studies in the Mochras borehole (NW Wales) reveal early Cretaceous and Neogene exhumation and argue against regional Palaeogene uplift in the southern Irish Sea
Authors: Holford Simon P. , Green Paul F. , Turner Jonathan P.
Published: August 2005

The North Atlantic continental margins have been subject to widespread exhumation, although the timing, magnitude and causes of this uplift and erosion are debated. Exhumation is thought to be most severe across the Irish Sea basin system (Western UK), and recent years have seen an increasing emphasis on the role of Palaeogene underplating as the primary mechanism of uplift. We present a study of palaeothermal and compaction data from the Mochras borehole (NW Wales). Located near the presumed locus of exhumation, Mochras penetrated thick successions of Lower Jurassic and Oligo-Miocene sediments. Our results indicate that both these successions experienced considerably deeper burial prior to early Cretaceous and Neogene exhumation, respectively. Apatite fission-track analysis (AFTA) and vitrinite reflectance data from the borehole reveal evidence for exhumation-related cooling episodes beginning during the Cretaceous (150–80 Ma) and Cenozoic (50–0 Ma). Regional AFTA results and stratigraphic constraints refine the timing estimates to the early Cretaceous (120–115 Ma) and Neogene (20–0 Ma). Estimates of exhumation magnitudes during these episodes based on palaeothermal and compaction data are
c
. 2.5 km and
c
. 1.5 km, respectively. Palaeothermal data provide no evidence for elevated Palaeogene palaeotemperatures indicative of deeper burial, and thus question the basis of Palaeogene exhumation.
Tertiary–Quaternary faulting and uplift in the northern Oman Hajar Mountains
Authors: Kusky Timothy , Robinson Cordula , El-Baz Farouk
Published: August 2005

Field mapping and remote sensing investigations reveal two new major fault sets cutting through Tertiary rocks, Quaternary terraces and a several-hundred-year-old irrigation canal system in the Hajar Mountains of northern Oman. They extend for tens of kilometres, forming fracture intensification zones several hundred metres wide. WNW- to NW-oriented faults run parallel to the mountain fronts in the plains adjoining the central Hajar range then obliquely crosscut the mountains in the north. Motion along these faults explains how Quaternary marine terraces became elevated 190 m above sea level. A second fault set strikes north to NNE. The associated juvenile topography suggests that they also accommodate recent uplift, subsidiary to the WNW-striking faults, with minor strike-slip and differential movement between various segments of the Hajar Mountains. Both fault systems, and the amount of Quaternary uplift (between 100 and 500 m), are similar to those in other active and ancient forebulge environments. Using the fracture patterns observed, it is proposed here that the Hajar range lies on the active forebulge of a collision zone between the NE margins of the Arabian plate, the Zagros fold belt and the Makran accretionary prism, which resulted in the recent uplift.
Biodiversity and Litter Decomposition in Terrestrial Ecosystems
Authors: Hättenschwiler Stephan , Tiunov Alexei V. , Scheu Stefan
Published: August 2005

▪ Abstract  We explore empirical and theoretical evidence for the functional significance of plant-litter diversity and the extraordinary high diversity of decomposer organisms in the process of litter decomposition and the consequences for biogeochemical cycles. Potential mechanisms for the frequently observed litter-diversity effects on mass loss and nitrogen dynamics include fungi-driven nutrient transfer among litter species, inhibition or stimulation of microorganisms by specific litter compounds, and positive feedback of soil fauna due to greater habitat and food diversity. Theory predicts positive effects of microbial diversity that result from functional niche complementarity, but the few existing experiments provide conflicting results. Microbial succession with shifting enzymatic capabilities enhances decomposition, whereas antagonistic interactions among fungi that compete for similar resources slow litter decay. Soil-fauna diversity manipulations indicate that the number of trophic levels, species identity, and the presence of keystone species have a strong impact on decomposition, whereas the importance of diversity within functional groups is not clear at present. In conclusion, litter species and decomposer diversity can significantly influence carbon and nutrient turnover rates; however, no general or predictable pattern has emerged. Proposed mechanisms for diversity effects need confirmation and a link to functional traits for a comprehensive understanding of how biodiversity interacts with decomposition processes and the consequences of ongoing biodiversity loss for ecosystem functioning.
The Evolutionary Psychology of Facial Beauty
Authors: Rhodes Gillian
Published: August 2005

What makes a face attractive and why do we have the preferences we do? Emergence of preferences early in development and cross-cultural agreement on attractiveness challenge a long-held view that our preferences reflect arbitrary standards of beauty set by cultures. Averageness, symmetry, and sexual dimorphism are good candidates for biologically based standards of beauty. A critical review and meta-analyses indicate that all three are attractive in both male and female faces and across cultures. Theorists have proposed that face preferences may be adaptations for mate choice because attractive traits signal important aspects of mate quality, such as health. Others have argued that they may simply be by-products of the way brains process information. Although often presented as alternatives, I argue that both kinds of selection pressures may have shaped our perceptions of facial beauty.
Pacemaker activity in urethral interstitial cells is not dependent on capacitative calcium entry
Authors: Bradley Eamonn , Hollywood Mark A. , McHale Noel G. , Thornbury Keith D. , Sergeant Gerard P.
Published: August 2005

The aim of the present study was to investigate the properties and role of capacitative Ca2+ entry (CCE) in interstitial cells (IC) isolated from the rabbit urethra. Ca2+ entry in IC was larger in cells with depleted intracellular Ca2+ stores compared with controls, consistent with influx via a CCE pathway. The nonselective Ca2+ entry blockers Gd3+ (10 μM), La3+ (10 μM), and Ni2+ (100 μM) reduced CCE by 67% ( n = 14), 65% ( n = 11), and 55% ( n = 9), respectively. These agents did not inhibit Ca2+ entry when stores were not depleted. Conversely, CCE in IC was resistant to SKF-96365 (10 μM), wortmannin (10 μM), and nifedipine (1 μM). Spontaneous transient inward currents were recorded from IC voltage-clamped at −60 mV. These events were not significantly affected by Gd3+ (10 μM) or La3+ (10 μM) and were only slightly decreased in amplitude by 100 μM Ni2+. The results from this study demonstrate that freshly dispersed IC from the rabbit urethra possess a CCE pathway. However, influx via this pathway does not appear to contribute to spontaneous activity in these cells.
Spatiotemporal electrical and motility mapping of distension-induced propagating oscillations in the murine small intestine
Authors: Seerden T. C. , Lammers W. J. E. P. , De Winter B. Y. , De Man J. G. , Pelckmans P. A.
Published: August 2005

Since the development of knockout animals, the mouse has become an important model to study gastrointestinal motility. However, little information is available on the electrical and contractile activities induced by distension in the murine small intestine. Spatiotemporal electrical mapping and mechanical recordings were made from isolated intestinal segments from different regions of the murine small intestine during distension. The electrical activity was recorded with 16 extracellular electrodes while motility was assessed simultaneously by tracking the border movements with a digital camera. Distension induced propagating oscillatory contractions in isolated intestinal segments. These propagating contractions were dictated by the underlying propagating slow wave with superimposed spikes. The frequencies, velocities, and direction of the propagating oscillations strongly correlated with the frequencies ( r = 0.86), velocities ( r = 0.84), and direction ( r = 1) of the electrical slow waves. Nω-nitro-l-arginine methyl ester decreased the maximal diameter of the segment and reduced the peak contraction amplitude of the propagating oscillatory contractions, whereas atropine and verapamil blocked the propagating oscillations. Tetrodotoxin had little effect on the maximal diameter and peak contraction amplitude. In conclusion, distension in the murine small intestine does not initiate peristaltic reflexes but induces a propagating oscillatory motor pattern that is determined by propagating slow waves with superimposed spikes. These spikes are cholinergic and calcium dependent.
Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-α
Authors: Martinsen Tom C. , Bakke Ingunn , Chen Duan , Sandvik Arne K. , Zahlsen Kolbjørn , Aamo Trond , Waldum Helge L.
Published: August 2005

The lipid-lowering drug ciprofibrate stimulates gastrin-producing cells in the rat stomach without lowering gastric acidity. Although suggested to be a luminal action on antral peroxisome proliferator-activated receptor-α (PPAR-α), the mechanism is still not fully elucidated. Gastric bypass was surgically prepared in male Sprague-Dawley rats. Gastric-bypassed and sham-operated rats were either given ciprofibrate (50 mg·kg−1·day−1 in methocel) or vehicle alone for 7 wk. PPAR-α knockout (KO) and wild-type (WT) mice were either given ciprofibrate (500 mg·kg−1·day−1 in methocel) or vehicle alone for 2 wk. The concentration of gastrin in blood was analyzed. Antral G cell density and gastrin mRNA abundance were determined by using immunostaining and Northern blot analysis. Ciprofibrate did not raise plasma gastrin or G cell density in gastric-bypassed rats, although the gastrin mRNA level was slightly increased. In contrast, ciprofibrate induced hypergastrinemia, a 50% increase in G cell density, and a threefold increase in gastrin mRNA in sham-operated rats. In PPAR-α KO mice, ciprofibrate did not raise G cell density or the gastrin mRNA level. The serum gastrin level was reduced by ciprofibrate. In WT mice, ciprofibrate induced hypergastrinemia, a doubling of G cell density, and a threefold increase in gastrin mRNA. Comparing animals dosed with vehicle only, PPAR-α KO mice had higher serum gastrin concentration than WT mice. We conclude that the main effects of ciprofibrate on G cells are mediated from the antrum lumen, and the mechanism is dependent on PPAR-α. The results indicate that PPAR-α may have a role in the physiological regulation of gastrin release.
Mechanical properties of the interaction between fibronectin and α5β1-integrin on vascular smooth muscle cells studied using atomic force microscopy
Authors: Sun Zhe , Martinez-Lemus Luis A. , Trache Andreea , Trzeciakowski Jerome P. , Davis George E. , Pohl Ulrich , Meininger Gerald A.
Published: August 2005

The mechanical properties of integrin-extracellular matrix (ECM) interactions are important for the mechanotransduction of vascular smooth muscle cells (VSMC), a process that is associated with focal adhesions, and can be of particular significance in cardiovascular disease. In this study, we characterized the unbinding force and binding activity of the initial fibronectin (FN)-α5β1 interaction on the surface of VSMC using atomic force microscopy (AFM). It is postulated that these initial binding events are important to the subsequent focal adhesion assembly. FN-VSMC adhesions were selectively blocked by antibodies against α5- and β1-integrins as well as RGD-containing peptides but not by antibodies against α4- and β3-integrins, indicating that FN primarily bound to α5β1. A characteristic unbinding force of 39 ± 8 pN was observed and interpreted to represent the FN-α5β1 single-bond strength. The ability of FN to adhere to VSMC (binding probability) was significantly reduced by integrin antagonists, serum starvation, and platelet-derived growth factor (PDGF)-BB, whereas lysophosphatidic acid (LPA) increased FN binding. However, no significant change in the resolved unbinding force was observed. After engagement, the force required to dislodge the FN-coated bead from VSMC increased with increasing of contact time, suggesting a time-dependent increase in number of adhesions and/or altered binding affinity. LPA enhanced this process, whereas PDGF reduced it, suggesting that these factors also affect the multimolecular process of focal contact assembly. Thus AFM is a powerful tool for the characterization of the mechanical properties of integrin-ECM interactions and their regulation. Our results indicate that the functional activity of α5β1 and focal contact assembly can be rapidly regulated.
Medullary lateral tegmental field mediates the cardiovascular but not respiratory component of the Bezold-Jarisch reflex in the cat
Authors: Barman Susan M. , Phillips Shaun W. , Gebber Gerard L.
Published: August 2005

We determined the effects of bilateral microinjection of muscimol and excitatory amino acid receptor antagonists into the medullary lateral tegmental field (LTF) on changes in sympathetic nerve discharge (SND), mean arterial pressure (MAP), and phrenic nerve activity (PNA; artificially ventilated cats) or intratracheal pressure (spontaneously breathing cats) elicited by right atrial administration of phenylbiguanide (PBG; i.e., the Bezold-Jarisch reflex) in dial-urethane anesthetized cats. The PBG-induced depressor response (−66 ± 8 mmHg; mean ± SE) was converted to a pressor response after muscimol microinjection in two of three spontaneously breathing cats and was markedly reduced in the other cat; however, the duration of apnea (20 ± 3 vs. 17 ± 7 s) was essentially unchanged. In seven paralyzed, artificially ventilated cats, muscimol microinjection significantly ( P < 0.05) attenuated the PBG-induced fall in MAP (−39 ± 7 vs. −4 ± 4 mmHg) and the magnitude (−98 ± 1 vs. −35 ± 13%) and duration (15 ± 2 vs. 3 ± 2 s) of the sympathoinhibitory response. In contrast, the PBG-induced inhibition of PNA was unaffected (3 cats). Similar results were obtained by microinjection of an N-methyl-d-aspartate (NMDA) receptor antagonist, d(-)-2-amino-5-phosphonopentanoic acid, into the LTF. In contrast, neither the cardiovascular nor respiratory responses to PBG were altered by blockade of non-NMDA receptors with 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[ f]quinoxaline-7-sulfonamide. We conclude that the LTF subserves a critical role in mediating the sympathetic and cardiovascular components of the Bezold-Jarisch reflex. Moreover, these data show separation of the pathways mediating the respiratory and cardiovascular responses of this reflex at a level central to bulbospinal outflows to phrenic motoneurons and preganglionic sympathetic neurons.
Posttranscriptional mechanisms contribute to osmotic regulation of ANG type 1 receptors in cultured rat renomedullary interstitial cells
Authors: Lee Sunghou , Wu Zheng , Sandberg Kathryn , Yoo S-E. , Maric Christine
Published: August 2005

Previously, we showed that ANG II receptors in cultured rat renomedullary interstitial cells (RMICs) are osmotically regulated ( 19 ). The current study examined the mechanisms underlying this osmotic regulation in RMICs cultured in isoosmotic (300 mosmol/kgH2O) and hyperosmotic (600 mosmol/kgH2O) conditions. Radioligand competition analysis coupled with RNase protection assays (RPA) and ligand-mediated receptor internalization studies revealed that RMICs primarily express the type 1a angiotensin receptor (AT1aR). When cultured under hyperosmotic conditions, the density (Bmax) of AT1R in RMIC membranes decreased by 31% [Bmax(pmol/mg protein): 300 mosmol/kgH2O, 6.44 ± 0.46 vs. 600 mosmol/kgH2O, 4.42 ± 0.37, n = 8, P < 0.01], under conditions in which no detectable changes in AT1aR mRNA expression or in the kinetics of ligand-mediated AT1R internalization were observed. RNA electromobility shift assays showed that RNA protein complex (RPC) formation between RMIC cytosolic RNA binding proteins and the 5′ leader sequence (5′LS) of the AT1aR was increased 1.5-fold under hyperosmotic conditions [5′LS RPC (arbitrary units): 300 mosmol/kgH2O, 0.79 ± 0.08 vs. 600 mosmol/kgH2O, 1.17 ± 0.07, n = 4, P < 0.01]. These results suggest that the downregulation of AT1aR expression in RMICs cultured under hyperosmotic conditions is regulated at the posttranscriptional level by RNA binding proteins that interact within the 5′LS of the AT1aR mRNA. The downregulation of AT1aR expression under hyperosmotic conditions may be an important mechanism by which the activity of ANG II is regulated in the hyperosmotic renal medulla.
Reduced Vascular Remodeling, Endothelial Dysfunction, and Oxidative Stress in Resistance Arteries of Angiotensin II–Infused Macrophage Colony-Stimulating Factor–Deficient Mice
Authors: De Ciuceis Carolina , Amiri Farhad , Brassard Pascal , Endemann Dierk H. , Touyz Rhian M. , Schiffrin Ernesto L.
Published: August 2005

Objective—Angiotensin (Ang) II-induced vascular damage may be partially mediated by reactive oxygen species generation and inflammation. Homozygous osteopetrotic mice (Op/Op), deficient in macrophage colony-stimulating factor (m-CSF), exhibit reduced inflammation. We therefore investigated Ang II effects on vascular structure, function, and oxidant stress generation in this model.

Methods and Results—Adult Op/Op, heterozygous (Op/+), and wild type (+/+) mice underwent 14-day Ang II (1000 ng/kg per minute) or saline infusion. Blood pressure (BP) was assessed by radiotelemetry, mesenteric resistance artery vascular reactivity was studied on a pressurized myograph, and vascular superoxide and NAD(P)H oxidase activity by lucigenin chemiluminescence. Ang II increased BP in Op/+ and +/+ mice but not in Op/Op. Ang II-treated Op/+ and +/+ mice showed reduced acetylcholine-mediated relaxation (maximal relaxation, respectively, 64% and 67% versus 84% and 93% in respective controls;P<0.05), which was unaffected byl-NAME. Ang II-infused Op/Op mice arteries showed significantly less endothelial dysfunction than vehicle-infused counterparts (maximal relaxation 87% versus 96% in shams). Resistance arteries from Ang II-infused +/+ and Op/+ mice had significantly increased media-to-lumen ratio and media thickness, neither of which was altered in Op/Op mice compared with untreated littermates. Vascular media cross-sectional area, NAD(P)H oxidase activity and expression, and vascular cell adhesion molecule (VCAM)-1 expression were significantly increased by Ang II only in +/+ mice (P<0.05).

Conclusions—m-CSF–deficient mice (Op/Op) developed less endothelial dysfunction, vascular remodeling, and oxidative stress induced by Ang II than +/+ littermates, suggesting a critical role of m-CSF and proinflammatory mediators in Ang II-induced vascular injury.
Extracellular Signal-Regulated Kinase–Dependent Stabilization of Hepatic Low-Density Lipoprotein Receptor mRNA by Herbal Medicine Berberine
Authors: Abidi Parveen , Zhou Yue , Jiang Jian-Dong , Liu Jingwen
Published: August 2005

Objective—

Our recent studies identified berberine (BBR) as a novel cholesterol-lowering drug that upregulates low-density lipoprotein (LDL) receptor expression through mRNA stabilization. Here, we investigated mechanisms underlying regulatory effects of BBR on LDL receptor (LDLR) messenger.

Methods and Results—

We show that the extracellular signal-regulated kinase (ERK) signaling pathway is used primarily by BBR to attenuate the decay of LDLR mRNA in HepG2 cells. Using different reporter constructs, we demonstrate that BBR affects LDLR mRNA stability entirely through 3′ untranslated region (UTR) in an ERK-dependent manner, and this stabilizing effect is more prominent in liver-derived cells than nonhepatic cell lines. In contrast to BBR, the mRNA stabilizing effect of bile acid chenodeoxycholic acid is mediated through the LDLR coding sequence, whereas the 5′UTR, 3′UTR, and the coding sequence of LDLR mRNA are all implicated in the action of phorbol 12-myristate 13-acetate. By performing UV cross-linking and SDS-PAGE, we identify 2 cytoplasmic proteins of 52 and 42 kDa that specifically bind to the LDLR 3′UTR in BBR-inducible and ERK-dependent manners.

Conclusions—

These new findings demonstrate that the BBR-induced stabilization of LDLR mRNA is mediated by the ERK signaling pathway through interactions of
cis
-regulatory sequences of 3′UTR and mRNA binding proteins that are downstream effectors of this signaling cascade.
Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats
Authors: Ishizaka Nobukazu , Saito Kan , Mori Ichiro , Matsuzaki Gen , Ohno Minoru , Nagai Ryozo
Published: August 2005

Objective—

We have investigated whether long-term administration of angiotensin (Ang) II causes ferritin induction and iron accumulation in the rat aorta, and their possible relation to regulatory effects on gene expression and vascular function in Ang II-infused animals.

Methods and Results—

Sprague-Dawley rats were given Ang II for 7 days via subcutaneously implanted osmotic minipumps. Ang II infusion caused a >20-fold increase in ferritin protein expression over control values. Immunohistochemistry showed that Ang II infusion markedly increased the ferritin expression in the aortic endothelial and adventitial cells, with some of the latter being identified as monocytes/macrophages. Prussian blue staining showed that stainable iron was observed in the adventitial layer of aorta from Ang II-infused animals, but not in the endothelial layer. Chelation of iron suppressed aortic induction of ferritin and also the oxidative stress markers, heme oxygenase-1 and 4-hydroxynonenal-modified protein adducts. In addition, iron chelation attenuated Ang II-induced impairment of aortic relaxations in response to acetylcholine and sodium nitroprusside and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1. Iron chelation also partially attenuated the medial thickening and perivascular fibrosis induced by Ang II infusion for 4 weeks.

Conclusion—

Ang II infusion caused ferritin induction and iron deposition in the aortas. These phenomena might have a role in the regulation of gene expression, impairment of vascular function, and arterial remodeling induced by Ang II, which are presumably mediated in part by enhancement of oxidative stress.
Effects of Estrogen Replacement Therapies on Mouse Platelet Function and Glycoprotein VI Levels
Authors: Leng Xing-Hong , Zhang Wei , Nieswandt Bernhard , Bray Paul F.
Published: August 2005

Clinical trials have shown estrogen replacement therapy (ERT) is associated with adverse arterial vascular events. Arterial thrombosis is initiated by platelet activation, but the in vivo effects of estrogens on platelet function are not well understood. We used a murine model of menopause to examine 3 major ERT regimes and test the hypothesis that ERT affects the intrinsic platelet response to agonists. The 3 ERT regimes studied were: (1) oral conjugated equine estrogen (CEE), (2) oral 17-β estradiol (E2), and (3) subcutaneously implanted E2 (SQ E2). Paired ovariectomized littermates were treated with these regimes or placebo for 21 days. Two platelet agonists, thrombin and the GPVI-specific agonist collagen-related peptide (COL-RP), were used to evaluate platelet reactivity. Among the 3 regimens, (1) oral CEE enhanced platelet reactivity to COL-RP, (2) oral E2 had no effect on platelet reactivity to COL-RP and (3) SQ E2 increased platelet sensitivity to thrombin but lowered reactivity to COL-RP. Thus, the in vivo effects of estrogen on platelet function are agonist specific and dependent on hormone formulation and mode of delivery. The GPVI collagen receptor likely mediated some of these effects, because the ERT regimens induced changes in platelet surface GPVI expression corresponding to the observed platelet activation.
Bone Morphogenetic Protein 4 Promotes Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension
Authors: Frank David B. , Abtahi Amir , Yamaguchi D.J. , Manning Suzanne , Shyr Yu , Pozzi Ambra , Baldwin H. Scott , Johnson Joyce E. , de Caestecker Mark P.
Published: August 2005

We show that 1 of the type II bone morphogenetic protein (BMP) receptor ligands, BMP4, is widely expressed in the adult mouse lung and is upregulated in hypoxia-induced pulmonary hypertension (PH). Furthermore, heterozygous null
Bmp4

lacZ/+

mice are protected from the development of hypoxia-induced PH, vascular smooth muscle cell proliferation, and vascular remodeling. This is associated with a reduction in hypoxia-induced Smad1/5/8 phosphorylation and Id1 expression in the pulmonary vasculature. In addition, pulmonary microvascular endothelial cells secrete BMP4 in response to hypoxia and promote proliferation and migration of vascular smooth muscle cells in a BMP4-dependent fashion. These findings indicate that BMP4 plays a dominant role in regulating BMP signaling in the hypoxic pulmonary vasculature and suggest that endothelium-derived BMP4 plays a direct, paracrine role in promoting smooth muscle proliferation and remodeling in hypoxic PH.
Asymmetric Dimethylarginine and the Risk of Cardiovascular Events and Death in Patients With Coronary Artery Disease
Authors: Schnabel Renate , Blankenberg Stefan , Lubos Edith , Lackner Karl J. , Rupprecht Hans J. , Espinola-Klein Christine , Jachmann Nicole , Post Felix , Peetz Dirk , Bickel Christoph , Cambien François , Tiret Laurence , Münzel Thomas
Published: August 2005

As a competitive inhibitor of endothelial nitric oxide synthase, asymmetric dimethylarginine (ADMA) has been related to atherosclerotic disease. Little is known about the prognostic impact of baseline ADMA determination. In a prospective cohort of 1908 patients with coronary artery disease, we assessed baseline serum concentration of ADMA in 1874 consecutive patients with coronary artery disease. One hundred fourteen individuals developed the primary end point of death from cardiovascular causes or nonfatal myocardial infarction during a mean follow-up of 2.6±1.2 years. Median concentrations of ADMA levels were higher among individuals who subsequently developed the primary end point than among those who did not (0.70 versus 0.63 μmol/L;
P
<0.001). The risk of future cardiovascular event was associated with increasing thirds of baseline ADMA (
P
for trend, <0.001) such that individuals in the highest third at entry had a hazard ratio 2.48 times higher than those in the lowest third (95% confidence interval, 1.52 to 4.06;
P
<0.001). This relationship remained nearly unchanged after adjustment for most potential confounders. Prediction models that simultaneously incorporated ADMA, B-type natriuretic peptide, C-reactive protein, and creatinine in addition to traditional risk factors revealed B-type natriuretic peptide (hazard ratio, 1.96; 95% confidence interval, 1.3 to 3.0;
P
=0.002) and ADMA (hazard ratio, 1.90; 95% confidence interval, 1.3 to 2.8;
P
=0.001) as the strongest risk predictors. High levels of baseline ADMA independently predict future cardiovascular risk. ADMA has prognostic value beyond traditional risk factors and novel biomarkers and might guide therapeutic strategies.
Thyroid Hormone Targets Matrix Gla Protein Gene Associated With Vascular Smooth Muscle Calcification
Authors: Sato Yoji , Nakamura Ryo , Satoh Mitsutoshi , Fujishita Kayoko , Mori Satoko , Ishida Seiichi , Yamaguchi Teruhide , Inoue Kazuhide , Nagao Taku , Ohno Yasuo
Published: August 2005

Thyroid hormones have marked cardiovascular effects in vivo. However, their direct effects on vascular smooth muscle cells have been unclear. Because thyroid hormones play critical roles in bone remodeling, we hypothesized that they are also associated with vascular smooth muscle calcification, one of the pathological features of vascular sclerosis. To test this hypothesis, we examined the effects of 3′,3,5-triiodo-
l
-thyronine (T
3
) on the expression of calcification-associated genes in rat aortic smooth muscle cells (RAOSMCs). Quantitative RT-PCRs revealed that a physiological concentration of T
3
(15 pmol/L free T
3
) increased mRNA level of matrix Gla protein (MGP), which acts as a potent inhibitor of vascular calcification in vivo, by 3-fold in RAOSMCs, as well as in cultured human coronary artery smooth muscle cells. In RAOSMCs transiently transfected with a luciferase reporter gene driven by the MGP promoter, T
3
significantly stimulated luciferase activity. In addition, RNA interference against thyroid hormone receptor-α gene diminished the effect of T
3
on MGP expression. Aortic smooth muscle tissues from methimazole-induced hypothyroid rats (400 mg/L drinking water; 4 weeks) also showed a 68% decrease in the MGP mRNA level, as well as a 33% increase in calcium content compared with that from the control euthyroid animals, whereas hyperthyroidism (0.2 mg T
3
/kg IP; 10 days) upregulated MGP mRNA by 4.5-fold and reduced calcium content by 11%. Our findings suggest that a physiological concentration of thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to prevention of vascular calcification in vivo.
Progressive Symptomatic Carotid Dissection Treated With Multiple Stents
Authors: Biondi Alessandra , Katz Jeffrey M. , Vallabh Janardhan , Segal Alan Z. , Gobin Y. Pierre
Published: August 2005

Background and Purpose—

Internal carotid artery (ICA) dissection remains a major cause of stroke in the young. Although systemic anticoagulation and antiplatelet therapy allow healing of the dissection in most patients, medical treatment can fail or be contraindicated. In selected cases of carotid dissections, the use of endovascular stent-assisted angioplasty has been reported to permit reconstruction of the extracranial ICA.

Methods—

We report a case of symptomatic spontaneous carotid dissection which progressively extended from the cervical to the supraclinoid segments of the ICA in a 48-year-old patient under anticoagulant therapy. Because of failed medical therapy and further transient ischemic attacks (TIAs), the patient was treated by 5 tandem stents deployed in an overlapping fashion from the terminal ICA to the cervical segment.

Results—

Postprocedure angiography demonstrated reconstitution of the luminal diameter of the ICA. The patient progressively improved and no further TIAs were observed. At 8-month follow-up, the vessel remained patent with a slight intra-extracranial reduction in size suggesting myointimal hyperplasia. Neurological exam was normal.

Conclusions—

The successful angiographic and clinical results observed in our case of intra-extracranial stenting of a long dissection contributes to the literature of carotid dissection treated with multiple stents. The excellent mid-term follow-up in our patient confirms the efficacy of this treatment and good tolerance to multiple stents. To our knowledge this is the first case of spontaneous dissection treated with stenting including the distal supraclinoid segment, through an extensive proximally dissected artery.
The Clinical Pharmacokinetics of Phosphodiesterase‐5 Inhibitors for Erectile Dysfunction
Authors: Gupta Manish , Kovar Andreas , Meibohm Bernd
Published: August 2005

Differences in the clinical pharmacology of the 3 currently available oral phosphodiesterase‐5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, are largely determined by their clinical pharmacokinetics as well as their PDE inhibitory activity profile. This review comparatively discusses the major characteristics of the pharmacokinetic profile of all 3 PDE5 inhibitors, including bioavailability and rate of absorption, Biopharmaceutical Classification System categorization, elimination mechanisms, and metabolic profile including active metabolites, as well as the drug‐drug interaction potential and modification of pharmacokinetic properties under selected physiologic and pathophysiologic conditions. The review is aimed at providing comparative clinical pharmacology data to allow for scientifically rational, evidence‐based prescribing and dosing decisions regarding the clinical use of these medications for the treatment of erectile dysfunction.
A Preliminary Assessment of the Critical Differences Between Novel Oral Anticoagulants Currently in Development
Authors: McBride Brian F.
Published: August 2005

Chronic anticoagulation represents a clinical conundrum for the health care community that balances unquestionable morbidity and mortality benefits against interindividual variability, leading to drug interactions, adverse events, and thromoembolic events related to underdosing. Despite the growing data regarding the appropriate use and dosing of agents used for chronic anticoagulation, use in clinical practice remains low, thus leading to a theoretical reduction in the risk‐to‐benefit ratio in the clinical setting relative to that reported in the literature. Oral anticoagulants currently in development represent a heterogeneous group of compounds that are specific for the final common pathway in the coagulation cascade and show indications toward a reduced drug interaction profile, reduced interpatient variation in pharmacokinetic parameters, and morbidity and mortality benefits that might be similar to currently available treatment modalities. This review highlights the critical differences among oral anticoagulants in development and places their role in the context of the benefits and limitations of currently available anticoagulants.
Effect of Exenatide on the Steady‐State Pharmacokinetics of Digoxin
Authors: Kothare Prajakti A. , Soon Danny K. W. , Linnebjerg Helle , Park Soomin , Chan Clark , Yeo Adeline , Lim Maggie , Mace Kenneth F. , Wise Stephen D.
Published: August 2005

This open‐label study investigated the effect of exenatide coadministration on the steady‐state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2–12, 0.25 mg once daily) and exenatide (days 8–12, 10 μg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24‐hour steady‐state digoxin exposure (AUCτ,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady‐state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.