bluuebunny/crossref_metadata_2025 huggingface dataset:
Prey consumption by the burbot (Lota lota) population in Green Bay, Lake Michigan, based on a bioenergetics model
Authors: Rudstam Lars G. , Peppard Paul E. , Fratt Thomas W. , Bruesewitz Richard E. , Coble Daniel W. , Copes Fred A. , Kitchell James F.
Published: August 2008

We estimated prey consumption by burbot (Lota lota) based on diet, mortality, growth, maturity, thermal history, population density and a bioenergetics model derived for a similar, cold-water gadoid, the Atlantic cod (Gadus morhua). In Green Bay, Lake Michigan, burbot >400 mm fed primarily on fish; smaller burbot probably fed mostly on invertebrates and sculpins (Cottus sp.). Our calculations indicate that burbot of age ≥1 consumed 16 kg/ha of prey (12.2 kg/ha of fish) in 1988 in the Wisconsin waters of Green Bay including 3.3, 2.1, 1.9, 1.2, and 0.8 kg/ha of rainbow smelt (Osmerus mordax), sculpins, alewife (Alosa pseudoharengus), yellow perch (Perca flavescens), and bloater (Coregnus hoyi), respectively. On an areal basis, piscivory by burbot in Green Bay was higher than the reported lake-wide average for consumption by all salmonids in Lake Michigan. Burbot consumed about 25% of the lake-wide salmonid consumption of alewife per unit area and close to the estimated combined commercial and sport harvest of yellow perch in the Bay the same year (271 vs. 325 tons). Thus, burbot should be included when considering the balance between predatory demand and forage fish production in Green Bay and probably also in other areas of Lake Michigan.
An individual-based analysis of the variability of eggs and their newly hatched larvae of Atlantic cod (Gadus morhua) on the Scotian Shelf
Authors: Miller Thomas J. , Herra Tomasz , Leggett William C.
Published: August 2008

We assessed the seasonal pattern of size variation in cod eggs on the Scotian Shelf region of the Northwest Atlantic during the period March 1991–May 1993. Cod eggs were present from October to May during the surveys. Spawning was not strongly bimodal. There was a dominant autumn peak, in contrast to the historically dominant spring spawning. Egg diameter varied seasonally. Seasonal temperature patterns explained 52% of the variation in egg diameter. By incubating the eggs on-board ship, we also assessed the seasonality of the standard length (SL) of larvae that hatched from these eggs. Larval SL also varied seasonally. Egg diameter and SL were significantly correlated, but the correlation was weak (r2 = 0.3). However, the strength of correlation was consistent with laboratory estimates based on individual data. The results suggest that previous estimates of the egg size – larval size correlations are inflated. Temperature exerted a significant effect on both egg diameter and larval size, and is hypothesized to be the agent responsible for the observed seasonal variation.
Endothelin receptor B-mediated induction of c-jun and AP-1 in response to shear stress in human endothelial cellsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Morawietz H. , Wagner A.H. , Hecker M. , Goettsch W.
Published: August 2008

In vivo, endothelial cells are constantly exposed to shear stress by flowing blood. Short-term exposure of endothelial cells to shear stress has been shown to induce endothelin-1 release. It is currently unknown, however, whether this shear stress-dependent endothelin-1 release affects the expression and activity of transcription factors. In this study, primary cultures of human endothelial cells from the umbilical vein were exposed to laminar shear stress in a cone-and-plate viscometer. Laminar shear stress for 30 min induced a 2-fold increase in mRNA expression of c-jun , but not c-fos, in human endothelial cells. Blockade of endothelin receptor subtype B (ETB) with BQ788 prevented this shear stress-dependent induction of c-jun expression. The induction of c-jun by shear stress involved protein kinase C and endothelial NO synthase. In addition, exposure of endothelial cells to arterial laminar shear stress for 1 h increased the binding of transcription factor AP-1 to its consensus sequence by 1.7-fold in electrophoretic mobility shift assays. This induction was also mediated by an ETB-dependent pathway. Supershift analysis supports an AP-1 complex containing c-jun, but not c-fos, in human endothelial cells. In conclusion, our data suggest endothelin-1-mediated induction of c-jun expression and activation of AP-1 (possibly as a c-jun homodimer) by laminar shear stress in human endothelial cells.
Polymorphisms ofEDNRB,ATG, andACEgenes in salt-sensitive hypertensionThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Caprioli Jessica , Mele Caterina , Mossali Chiara , Gallizioli Laura , Giacchetti Gilberta , Noris Marina , Remuzzi Giuseppe , Benigni Ariela
Published: August 2008

Almost 50% of hypertensive individuals manifest blood pressure changes in response to salt depletion or repletion and are termed “salt sensitive” (SS). Blunted activity of the endothelin (ET) system and the renin–angiotensin–aldosterone system (RAAS) have been reported as possible mechanisms contributing to salt sensitivity. Data are available that endothelin receptor subtype B (ETBR)-deficient rats develop salt-sensitive hypertension when fed a high-salt diet. Whether the ETBR gene (EDNRB) is involved in genetic predisposition to human salt-sensitive hypertension has not been studied so far. We screened EDNRB in 104 hypertensive patients (49 salt sensitive and 55 salt resistant) and 110 normotensive controls. No new sequence variation was found, but genotype distribution of the common polymorphism G1065A revealed that the AA + GA genotypes were significantly more frequent in salt-resistant than in salt-sensitive individuals (p = 0.007), suggesting a protective role for the A allele. We also screened angiotensinogen gene AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism ACE I/D and found an association between TT genotype and hypertension. A possible synergistic effect to salt-sensitive hypertension was found by combining EDNRB GG with ACE DD/ID genotypes. In conclusion, our data confirm the role of ET system and RAAS in salt-sensitive hypertension.
Inhalation of an endothelin receptor A antagonist attenuates pulmonary inflammation in experimental acute lung injuryThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Kalk Philipp , Senf Philine , Deja Maria , Petersen Bodil , Busch Thilo , Bauer Christian , Boemke Willehad , Kaisers Udo , Hocher Berthold
Published: August 2008

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg·kg–1, ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in Pao2 (316 ± 47 mm Hg vs. control 53 ± 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% ± 1% positive cells vs. control 12% ± 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 ± 1 pg·100 mg–1 wet weight vs. control 7 ± 1 pg·100 mg–1 wet weight, p < 0.05). Concentrations of TNF-α, IL-1β, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.
Nonpeptidic antagonists of ETAand ETBreceptors reverse the ET-1-induced sustained increase of cytosolic and nuclear calcium in human aortic vascular smooth muscle cellsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Bkaily Ghassan , Choufani Sanaa , Avedanian Levon , Ahmarani Lena , Nader Moni , Jacques Danielle , D’Orléans-Juste Pedro , Al Khoury Johny
Published: August 2008

Our previous work showed that ET-1 induced a concentration-dependent increase of cytosolic Ca2+([Ca]c) and nuclear Ca2+([Ca]n) in human aortic vascular smooth muscle cells (hVSMCs). In the present study, using hVSMCs and 3-dimensional confocal microscopy coupled to the Ca2+fluorescent probe Fluo-3, we showed that peptidic antagonists of ETAand ETBreceptors (BQ-123 (10−6mol/L) and BQ-788 (10−7mol/L), respectively) prevented, but did not reverse, ET-1-induced sustained increase of [Ca]cand [Ca]n. In contrast, nonpeptidic antagonists of ETAand ETB(respectively, BMS-182874 (10−8–10−6mol/L) and A-192621 (10−7mol/L)) both prevented and reversed ET-1-induced sustained increase of [Ca]cand [Ca]n. Furthermore, activation of the ETBreceptor alone using the specific agonist IRL-1620 (10−9mol/L) induced sustained increases of [Ca]cand [Ca]n, and subsequent administration of ET-1 (10−7mol/L) further increased nuclear Ca2+. ET-1-induced increase of [Ca]cand [Ca]nwas completely blocked by extracellular application of the Ca2+chelator EGTA. Pretreatment with the G protein inhibitors pertussis toxin (PTX) and cholera toxin (CTX) also prevented the ET-1 response; however, strong membrane depolarization with KCl (30 mmol/L) subsequently induced sustained increase of [Ca]cand [Ca]n. Pretreatment of hVSMCs with either the PKC activator phorbol-12,13-dibutyrate or the PKC inhibitor bisindolylmaleimide did not affect ET-1-induced sustained increase of intracellular Ca2+. These results suggest that both ETA- and ETB-receptor activation contribute to ET-1-induced sustained increase of [Ca]cand [Ca]nin hVSMCs. Moreover, in contrast to the peptidic antagonists of ET-1 receptors, the nonpeptidic ETA-receptor antagonist BMS-182874 and the nonpeptidic ETB-receptor antagonist A-192621 were able to reverse the effect of ET-1. Nonpeptidic ETA- and ETB-receptor antagonists may therefore be better pharmacological tools for blocking ET-1-induced sustained increase of intracellular Ca2+in hVSMCs. Our results also suggest that the ET-1-induced sustained increase of [Ca]cand [Ca]nis not mediated via activation of PKC, but via a PTX- and CTX-sensitive G protein calcium influx through the R-type Ca2+channel.
Urinary protein profiling with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry in ETBreceptor-deficient ratsThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Raila Jens , Kalk Philipp , Pfab Thiemo , Thöne-Reineke Christa , Godes Michael , Yanagisawa Masashi , Schweigert Florian J. , Hocher Berthold
Published: August 2008

The pathways leading to salt-sensitive hypertension and renal damage in rescued ETBreceptor-deficient (ETBRd) rats are still unknown. The objective of the study was therefore to identify modifications of urinary peptide and protein expression in ETBRd rats (n = 9) and wild-type controls (n = 6) using SDS – polyacrylamide gel electrophoresis (SDS-PAGE) and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology. Glomerular filtration rate, glomerulosclerosis, and tubulointerstitial fibrosis did not differ between the groups. ETBRd rats showed slightly higher blood pressure (p < 0.001), media/lumen ratio of intrarenal arteries (p < 0.01), and albuminuria (p < 0.01). SDS-PAGE confirmed albuminuria, but showed no differences in the urinary excretion of low molecular weight proteins (<60 kDa). SELDI-TOF-MS profiling revealed 9 proteomic features at molecular masses (Da) of 2720, 2980, 3130, 3345, 6466, 6682, 8550, 18 729, and 37 492, which were significantly elevated (p < 0.02) in urine of ETBRd rats. The results demonstrate that, independent of structural changes in the kidneys, ETB-receptor deficiency causes specific differences in urinary peptide and protein excretion. SELDI-TOF-MS may be a valuable tool for the characterization of urinary biomarkers helping to uncover the mechanism of ETBR action in the kidney.
Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature deliveryThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.
Authors: Olgun Nicole , Patel Hardik J. , Stephani Ralph , Wang Wei , Yen Haoting , Reznik Sandra E.
Published: August 2008

Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%–80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated PTB. In our previous work, we have shown that blockade of ET-1 synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-1 action with 5–50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50, 70 nmol/L), prevents PTB induced with up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.
Refractoriness of sural nerve in humans
Authors: Stevens Paige , Bawa Parveen
Published: August 2008

High-frequency stimulation of peripheral nerve bundles is frequently used in clinical tests and physiologic experiments to study presynaptic and postsynaptic effects. To understand the postsynaptic effects, it is important to ensure that each pulse in the train is equally effective in stimulating the presynaptic nerve bundle; however, the optimal interpulse interval (IPI) and the stimulus intensity at which each pulse is equally effective in stimulating the same number of axons are not known. The magnitude of the compound action potential produced by each pulse in a train was tested on the sural nerve of 4 healthy human subjects. The stimulus train (2–4 pulses) was applied to the sural nerve at the lateral malleolus, and neural responses were recorded from just below the knee. With 2-pulse trains, families of curves between IPIs (1–6 ms) and normalized amplitudes of the second response were plotted for different stimulus intensities. Visual inspection of the data showed that the curves fell into 2 groups: with stimulus intensities <2.5× perception threshold (Th), the test response appeared partially at longer IPIs, whereas with stimulus intensities ≥3× Th, partial recovery of the test response was earlier. The interval for complete recovery was statistically the same for low- and high-intensity stimulation. With more than 2 pulses in a stimulus train (IPI = 5 ms), the amplitude of the compound action potential (CAP) was not affected significantly. These results are important in understanding both the presynaptic and postsynaptic responses when presynaptic axon bundles are stimulated at high frequencies.
Acute depletion of heme by succinylacetone alters vascular responses but does not induce hypertension
Authors: Soong Jonathan , Adams Michael A. , Nakatsu Kanji
Published: August 2008

Heme plays a critical role in blood pressure regulation because it is required by a number of enzymes that synthesize vascular modulators, including nitric oxide (NO), carbon monoxide (CO), guanosine 3′,5′-cyclic monophosphate (cGMP), endothelium-derived hyperpolarizing factor (EDHF), and prostacyclin. The goal of this study was to examine the vascular effects of a short-term depletion of heme achieved through administration of the heme-synthesis inhibitor succinylacetone (SA), an irreversible inhibitor of aminolevulinic acid dehydratase (ALAD). Rats were depleted of heme by using a 4-day treatment with SA. This treatment impacted hemoenzyme function, decreasing renal nitric oxide synthase (NOS) activity (as indicated by decreased in vitro NOS activity), and increasing kidney microsomal heme oxygenase (HO) activity by 27%. SA treatment also resulted in enhanced reduction in blood pressure after infusions of exogenous NO donor MAHMA NONOate (at high dose) and acetylcholine (at low doses). Nevertheless, this SA treatment was insufficient to produce an overt elevation of basal arterial pressure. This latter lack of effect may be the result of multiple compensatory mechanisms for the regulation of blood pressure.
Changes of action potential and L-type calcium channel current of Sprague–Dawley rat ventricular myocytes by different amlodipine isomers
Authors: Wang Ru-xing , Jiang Wen-ping
Published: August 2008

To investigate the effects of S- and R-amlodipine (Aml) on action potential (AP) and L-type calcium channel current (ICa-L), the whole-cell patch-clamp technique was used on rat ventricular myocytes to record AP, ICa-L, peak currents, steady-state activation currents, steady-state inactivation currents, and recovery currents from inactivation with S-Aml and R-Aml at various concentrations. Increasing concentrations of S-Aml gradually shortened AP durations (APDs). At concentrations of 0.1, 0.5, 1, 5, and 10 μmol/L, S-Aml blocked 1.5% ± 0.2%, 25.4% ± 5.3%, 65.2% ± 7.3%, 78.4% ± 8.1%, and 94.2% ± 5.0% of ICa-L, respectively (p < 0.05), and the half-inhibited concentration was 0.62 ± 0.12 µmol/L. Current–voltage curves were shifted upward; steady-state activation and inactivation curves were shifted to the left. At these concentrations of S-Aml, the half-activation voltages were –16.01 ± 1.65, –17.61 ± 1.60, –20.17 ± 1.46, –21.87 ± 1.69, and –24.09 ± 1.87 mV, respectively, and the slope factors were increased (p < 0.05). The half-inactivation voltages were –27.16 ± 4.48, –28.69 ± 4.52, –31.19 ± 4.17, –32.63 ± 4.34, and –35.16 ± 4.46 mV, respectively, and the slope factors were increased (p < 0.05). The recovery times from inactivation of S-Aml were prolonged (p < 0.05). In contrast, R-Aml had no effect on AP and ICa-L (p > 0.05) at the concentrations tested. Thus, only S-Aml has calcium channel blockade activity, whereas R-Aml has none of the pharmacologic actions associated with calcium channel blockers.
Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?
Authors: Kinobe Robert T. , Dercho Ryan A. , Nakatsu Kanji
Published: August 2008

The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This ‘next generation’ of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.
Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptorPresented in part at the American College of Cardiology meeting March 2003 in Orlando, USA, and the Society for Pediatric Research meeting May 2007 in Toronto, Canada.
Authors: Osorio Juan C. , Cheema Faisal H. , Martens Timothy P. , Mahmut Naila , Kinnear Caroline , Gonzalez Ana M.D. , Bonney William , Homma Shunichi , Liao James K. , Mital Seema
Published: August 2008

Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12–14/group): control (vehicle); nitro-l-arginine methyl ester (l-NAME) an NO synthase inhibitor; simvastatin (SIM), an NO synthase activator; and SIM+l-NAME. Serial echocardiography was performed and blood pressure (BP) at 6 weeks was recorded using a micromanometer. Myocardial eNOS and mitogen-activated protein kinase (MAPK, including ERK, p38, and JNK) protein expression were measured. Results showed that (i) B2RKO mice had significantly lower ejection fraction than did WT mice (61% ± 1% vs. 73% ± 1%), lower myocardial eNOS and phospho-eNOS, normal systolic BP, and higher LV mass, phospho-p38, and JNK; (ii) l-NAME increased systolic BP in KO mice (117 ± 19 mm Hg) but not in WT mice and exacerbated LV hypertrophy and dysfunction; and (iii) in KO mice, SIM decreased hypertrophy, p38, and JNK, improved function, increased capillary eNOS and phospho-eNOS, and prevented l-NAME-induced LV hypertrophy without lowering BP. We conclude that disruption of the B2R causes maladaptive cardiac hypertrophy with myocardial eNOS downregulation and MAPK upregulation. SIM reverses these abnormalities and prevents the development of primary cardiac hypertrophy as well as hypertrophy secondary to l-NAME-induced hypertension.
Circulating free fatty acids are increased independently of PPARγ activity after administration of poloxamer 407 to mice
Authors: Johnston Thomas P. , Waxman David J.
Published: August 2008

Poloxamer 407 (P-407) is a copolymer surfactant that induces a dose-controlled dyslipidemia in both mice and rats. Human macrophages cultured with P-407 exhibit a concentration-dependent reduction in cholesterol efflux to apolipoprotein A1 (apoA1) linked to downregulation of the ATP-binding cassette transporter A1 (ABCA1). Activators of peroxisome proliferator-activated receptor gamma (PPARγ), as well as PPARα, increase expression of liver X receptor alpha (LXRα) in macrophages and promote the expression of ABCA1, which, in turn, mediates cholesterol efflux to apoA1. The present study investigated whether P-407 interferes with this signaling pathway. A transactivation assay was used to evaluate whether P-407 can either activate or inhibit the transcriptional activity of PPARγ. Because thiazolidinedione drugs (PPARγ agonists) improve glycemic control in type 2 diabetes by reducing blood glucose concentrations, P-407 was also evaluated for its potential to alter plasma insulin and blood glucose concentrations in wild-type (C57BL/6) and PPARγ-deficient mice. Additionally, because thiazolidinediones attenuate release of free fatty acids (FFAs) from adipocytes and, consequently, decrease circulating plasma levels of FFAs, plasma concentrations of circulating FFAs were also determined in P-407-treated mice. P-407 was unable to modulate PPARγ activity in cell-based transactivation assays. Furthermore, P-407 did not perturb plasma insulin and blood glucose concentrations after administration to mice. However, by an as yet unidentified mechanism, P-407 caused a significant increase in the serum concentration of FFAs in mice beginning 3 h after administration and lasting more than 24 h postdosing. It is concluded that P-407 does not interfere with the functional activity of PPARγ after administration to mice.
The Future of Mouse QTL Mapping to Diagnose Disease in Mice in the Age of Whole-Genome Association Studies
Authors: Hunter Kent W. , Crawford Nigel P.S.
Published: August 2008

Genome-wide association analysis is emerging as a powerful tool to define novel genes and molecular pathways involved in susceptibility to human complex disorders. However, in spite of recent successes, this approach is not without its limitations, the most notable of which is inconsistent phenotype penetrance due to varied environmental exposures. Mouse models do, however, circumvent some of these drawbacks by allowing for a much higher degree of control over genetic variation and environmental exposure, and although their application to human complex genetics is not always straightforward, they do serve as a powerful means of complementing observations in human populations. Mouse quantitative trait locus mapping has proven a successful, yet technically demanding method for defining trait susceptibility. In this review, we focus upon recent advances that are both reducing the technical burden traditionally associated with quantitative trait locus mapping, and enhancing the applicability of these approaches to human disease.
Ocean Acidification: The Other CO2Problem
Authors: Doney Scott C. , Fabry Victoria J. , Feely Richard A. , Kleypas Joan A.
Published: August 2008

Rising atmospheric carbon dioxide (CO2), primarily from human fossil fuel combustion, reduces ocean pH and causes wholesale shifts in seawater carbonate chemistry. The process of ocean acidification is well documented in field data, and the rate will accelerate over this century unless future CO2emissions are curbed dramatically. Acidification alters seawater chemical speciation and biogeochemical cycles of many elements and compounds. One well-known effect is the lowering of calcium carbonate saturation states, which impacts shell-forming marine organisms from plankton to benthic molluscs, echinoderms, and corals. Many calcifying species exhibit reduced calcification and growth rates in laboratory experiments under high-CO2conditions. Ocean acidification also causes an increase in carbon fixation rates in some photosynthetic organisms (both calcifying and noncalcifying). The potential for marine organisms to adapt to increasing CO2and broader implications for ocean ecosystems are not well known; both are high priorities for future research. Although ocean pH has varied in the geological past, paleo-events may be only imperfect analogs to current conditions.
Understanding and Reducing Variation in Surgical Mortality
Authors: Birkmeyer John D. , Dimick Justin B.
Published: August 2008

Surgical mortality varies widely across hospitals and surgeons, more so than would be predicted by chance alone or differences in case mix. Although a large body of research has suggested the importance of procedure volume, clinical mechanisms underlying variation in surgical mortality remain largely unknown. Payers, policy makers, and professional organizations have implemented a variety of large-scale strategies aimed at improving outcomes. Selective referral, process compliance, and outcomes measurement reflect different philosophies on how best to improve surgical quality and have distinct advantages and disadvantages. The optimal strategy may depend on both the clinical context (e.g., which procedure) and political realities.
Additive effect of red blood cell rigidity and adherence to endothelial cells in inducing vascular resistance
Authors: Kaul D. K. , Koshkaryev A. , Artmann G. , Barshtein G. , Yedgar S.
Published: August 2008

To explore the contribution of red blood cell (RBC) deformability and interaction with endothelial cells (ECs) to circulatory disorders, these RBC properties were modified by treatment with hydrogen peroxide (H2O2), and their effects on vascular resistance were monitored following their infusion into rat mesocecum vasculature. Treatment with 0.5 mM H2O2 increased RBC/EC adherence without significant alteration of RBC deformability. At 5.0 mM H2O2, RBC deformability was considerably reduced, inducing a threefold increase in the number of undeformable cells, whereas RBC/EC adherence was not further affected by the increased H2O2 concentration. This enabled the selective manipulation of RBC adherence and deformability and the testing of their differential effect on vascular resistance. Perfusion of RBCs with enhanced adherence and unchanged deformability (treatment with 0.5 mM H2O2) increased vascular resistance by about 35% compared with untreated control RBCs. Perfusion of 5.0 mM H2O2-treated RBCs, with reduced deformability (without additional increase of adherence), further increased vascular resistance by about 60% compared with untreated control RBCs. These results demonstrate the specific effects of elevated adherence and reduced deformability of oxidized RBCs on vascular resistance. These effects can be additive, depending on the oxidation conditions. The oxidation-induced changes applied in this study are moderate compared with those observed in RBCs in pathological states. Yet, they caused a considerable increase in vascular resistance, thus demonstrating the potency of RBC/EC adherence and RBC deformability in determining resistance to blood flow in vivo.
Pulmonary gas exchange response to exercise- and mannitol-induced bronchoconstriction in mild asthma
Authors: Muñoz Phillip A. , Gómez Federico P. , Manrique Hernán A. , Roca Josep , Barberà Joan A. , Young Iven H. , Anderson Sandra D. , Rodríguez-Roisin Roberto
Published: August 2008

Both exercise (EIB) and mannitol challenges were performed in asthmatic patients to assess and compare their pulmonary gas exchange responses for an equivalent degree of bronchoconstriction. In 11 subjects with EIB [27 ± 4 (SD) yr; forced expiratory volume in 1 s (FEV1), 86 ± 8% predicted], ventilation-perfusion (V̇a/Q̇) distributions (using multiple inert gas elimination technique) were measured 5, 15, and 45 min after cycling exercise (FEV1fall, 35 ± 12%) and after mannitol (33 ± 10%), 1 wk apart. Five minutes after EIB, minute ventilation (V̇e; by 123 ± 60%), cardiac output (Q̇t, by 48 ± 29%), and oxygen uptake (V̇o2; by 54 ± 25%) increased, whereas arterial Po2(PaO2; by 14 ± 11 Torr) decreased due to moderate V̇a/Q̇ imbalance, assessed by increases in dispersions of pulmonary blood flow (log SDQ̇; by 0.53 ± 0.16) and alveolar ventilation (log SDV̇; by 0.28 ± 0.15) (dimensionless) ( P < 0.01 each). In contrast, for an equivalent degree of bronchoconstriction and minor increases in V̇e, Q̇t, and V̇o2, mannitol decreased PaO2more intensely (by 24 ± 9 Torr) despite fewer disturbances in log SDQ̇ (by 0.27 ± 0.12). Notwithstanding, mannitol-induced increase in log SDV̇ at 5 min (by 0.35 ± 0.15) was similar to that observed during EIB, as was the slow recovery in log SDV̇and high V̇a/Q̇ ratio areas, at variance with the faster recovery of log SDQ̇and low V̇a/Q̇ ratio areas. In asthmatic individuals, EIB provokes more V̇a/Q̇ imbalance but less hypoxemia than mannitol, primarily due to postexercise increases in V̇e and Q̇t benefiting PaO2. V̇a/Q̇ inequalities during both challenges most likely reflect uneven airway narrowing and blood flow redistribution generating distinctive V̇a/Q̇ patterns, including the development of areas with low and high V̇a/Q̇ ratios.
Dynamic adaptation of cardiac baroreflex sensitivity to prolonged exposure to microgravity: data from a 16-day spaceflight
Authors: Di Rienzo M. , Castiglioni P. , Iellamo F. , Volterrani M. , Pagani M. , Mancia G. , Karemaker J. M. , Parati G.
Published: August 2008

This study explored the process of arterial baroreflex adaptation to microgravity, starting from the first day of flight, during the 16-day STS-107 Columbia Space Shuttle mission. Continuous blood pressure (BP), ECG, and respiratory frequency were collected in four astronauts on ground (baseline) and during flight at days 0–1, 6–7, and 12–13, both at rest and during moderate exercise (75 W) on a cycle ergometer. Sensitivity of the baroreflex heart rate control (BRS) was assessed by sequence and spectral alpha methods. Baroreflex effectiveness index (BEI); low-frequency (LF) power and high-frequency (HF) power of systolic BP (SBP), diastolic BP (DBP), and R-R interval (RRI); the RRI LF/HF ratio; and the RRI root mean square of successive differences (RMSSD) index were also estimated. We found that, at rest, BRS increased in early flight phase, compared with baseline (means ± SE: 18.3 ± 3.4 vs. 10.4 ± 1.2 ms/mmHg; P < 0.05), and it tended to return to baseline in subsequent days. During exercise, BRS was lower than at rest, without differences between preflight and in-flight values. At rest, in the early flight phase, RMSSD and RRI HF power increased ( P < 0.05) compared with baseline, whereas LF powers of SBP and DBP decreased. No statistical difference was found in these parameters during exercise before vs. during flight. These findings demonstrate that heart rate baroreflex sensitivity and markers of cardiac vagal modulation are enhanced during early exposure to microgravity, likely because of the blood centralization, and return to baseline values in subsequent flight phases, possibly because of the fluid loss. No deconditioning seems to occur in the baroreflex control of the heart.
Effect of oxygen and heliox breathing on air bubbles in adipose tissue during 25-kPa altitude exposures
Authors: Randsøe T. , Kvist T. M. , Hyldegaard O.
Published: August 2008

At altitude, bubbles are known to form and grow in blood and tissues causing altitude decompression sickness. Previous reports indicate that treatment of decompression sickness by means of oxygen breathing at altitude may cause unwanted bubble growth. In this report we visually followed the in vivo changes of micro air bubbles injected into adipose tissue of anesthetized rats at 101.3 kPa (sea level) after which they were decompressed from 101.3 kPa to and held at 25 kPa (10,350 m), during breathing of oxygen or a heliox(34:66) mixture (34% helium and 66% oxygen). Furthermore, bubbles were studied during oxygen breathing preceded by a 3-h period of preoxygenation to eliminate tissue nitrogen before decompression. During oxygen breathing, bubbles grew from 11 to 198 min (mean: 121 min, ±SD 53.4) after which they remained stable or began to shrink slowly. During heliox breathing bubbles grew from 30 to 130 min (mean: 67 min, ±SD 31.0) from which point they stabilized or shrank slowly. No bubbles disappeared during either oxygen or heliox breathing. Preoxygenation followed by continuous oxygen breathing at altitude caused most bubbles to grow from 19 to 179 min (mean: 51 min, ±SD 47.7) after which they started shrinking or remained stable throughout the observation period. Bubble growth time was significantly longer during oxygen breathing compared with heliox breathing and preoxygenated animals. Significantly more bubbles disappeared in preoxygenated animals compared with oxygen and heliox breathing. Preoxygenation enhanced bubble disappearance compared with oxygen and heliox breathing but did not prevent bubble growth. The results indicate that oxygen breathing at 25 kPa promotes air bubble growth in adipose tissue regardless of the tissue nitrogen pressure.
Preparation and crystal structure of SbV1.50InIII0.50(PO4)3 and (SbV0.50InIII0.50)P2O7
Authors: Aatiq Abderrahim , Bakri Rachid , Sakulich Aaron Richard
Published: August 2008

Synthesis and structure of two phosphates belonging to the ternary Sb2O5–In2O3–P2O5 system are realized. Structures of SbV1.50InIII0.50(PO4)3 and (SbV0.50InIII0.50)P2O7 phases, obtained by solid state reaction in air at 950 °C, were determined at room temperature from X-ray powder diffraction using the Rietveld method. SbV1.50InIII0.50(PO4)3 have a monoclinic (space group P21/n) distortion of the Sc2(W
O4)3-type framework. Its structure is constituted by corner-shared SbO6 or InO6 octahedra and PO4 tetrahedra. Monoclinic unit cell parameters are a=11.801(2) Å, b=8.623(1) Å, c=8.372(1) Å, and β=90.93(1)°. (Sb0.50In0.50)P2O7 is isotypic with (Sb0.50Fe0.50)P2O7 and crystallizes in orthorhombic system (space group Pna21) with a=7.9389(1) Å, b=16.0664(2) Å, and c=7.9777(1) Å. Its structure is built up from corner-shared SbO6 or InO6 octahedra and P2O7 groups (two group-types). Each P2O7 group shares its six vertices with three SbO6 and three InO6 octahedra, and each octahedron is connected to six P2O7 groups.
Structural elucidation of synthetic calcium silicates
Authors: Borrmann Thomas , Johnston James H. , McFarlane Andrew J. , MacKenzie Kenneth J. D. , Nukui Akihiko
Published: August 2008

A series of synthetic calcium silicates has been produced comprising nano-sized plates. The starting calcium silicate referred to as nano-structured calcium silicate, NCS, appears itself X-ray amorphous but contains impurities of calcite. These impurities decompose during the dry thermal conversion of the material into wollastonite. NCS can be enriched with calcium or silicon, respectively. The silicon enriched NCS can be hydrothermally transformed into a sheet material related to Ca7Si16O38(OH)2. The X-ray pattern of this material was sufficient to allow the calculation of its unit cell with a comparatively high figure of merit. The calcium enriched NCS can form two very distinctly different ceramic materials upon hydrothermal treatment, one a band material (formed below 200 °C) and the other a rose petal shaped material (formed above 210 °C). The X-ray diffraction patterns could not be resolved. The fit between the observed and calculated patterns was less than 50% as expressed in comparatively low figures of merit (unusually <20), which is attributed to calcium carbonate impurities in the samples disrupting the long range order. The patterns of these calcium enriched samples could be best compared to those of tobermorite or truscotite.
X-ray powder diffraction study of Sn0.59Ti0.41Te3O8
Authors: Aribia W. Ben , Loukil M. , Kabadou A. , Salah A. Ben
Published: August 2008

The crystal structure of titanium-tin tellurium oxide Sn0.59Ti0.41Te3O8 has been determined using X-ray powder diffraction techniques. At room temperature, the title compound crystallizes in cubic space group Ia-3, with lattice parameter a=11.05515(6) Å. Rietveld refinement of the structure led to final confidence factors Rp=0.0395 and Rwp=0.0577. The structure of Sn0.59Ti0.41Te3O8 consists of isolated Ti/SnO6-octahedra slightly deformed in the a direction. The TeO4E [E=lone pair of Te(IV) atoms] groups are located between the octahedra ensuring the stability of the structure by Ti/Sn-O-Te bonding contacts. Only one peak in thermal behavior was detected for this compound at 488 K by differential scanning calorimetry experiment. An IR spectroscopic study is employed as a means to obtain preliminary structural information and shows the presence of the Ti/SnO6 and TeO4E groups. This result is later confirmed by X-ray diffraction studies.
Semaphorin-3B Is an Angiogenesis Inhibitor That Is Inactivated by Furin-Like Pro-Protein Convertases
Authors: Varshavsky Asya , Kessler Ofra , Abramovitch Sivan , Kigel Boaz , Zaffryar Shelly , Akiri Gal , Neufeld Gera
Published: August 2008

Semaphorin-3B (sema3B) and semaphorin-3F (sema3F) are secreted tumor suppressors of lung cancer. Sema3F functions as an antiangiogenic factor that repels endothelial cells and compromises their proliferation/survival. However, tumor cells expressing either endogenous or recombinant sema3B fail to repel endothelial cells efficiently. Sema3B found in the conditioned medium of such cells is almost completely cleaved by furin-like pro-protein convertases, generating inactive 61- and 22-kDa fragments. We have generated a sema3B variant that was point mutated at the cleavage site (sema3B-m), thereby conferring partial resistance to cleavage. Conditioned medium from HEK293 cells expressing sema3b-m and conditioned medium of HEK293 cells expressing sema3B contained similar concentrations of semaphorin but sema3B-m was cleaved much less than sema3B. In contrast to HEK293 cells expressing native sema3B, cells expressing sema3b-m strongly repel endothelial cells. Conditioned medium from sema3B-m–expressing cells rapidly caused disassembly of focal adhesions and a collapse of the actin cytoskeleton of endothelial cells, inhibited vascular endothelial growth factor–induced phosphorylation of extracellular signal-regulated kinase 1/2, induced apoptosis of endothelial cells, and inhibited the formation of tubes from endothelial cells in an in vitro angiogenesis assay more potently than conditioned medium from cells expressing sema3B. Furthermore, HEK293 cells expressing sema3B-m inhibited basic fibroblast growth factor–induced angiogenesis in vivo much more potently than cells expressing sema3B. Repulsion of human umbilical vascular endothelial cells by sema3B-m was mediated primarily by the neuropilin-1 (np1) receptor but sema3B-m was also able to transduce signals via neuropilin-2 (np2). These results suggest that up-regulation of furin-like pro-protein convertases in malignant cells may enable tumors to evade the antiangiogenic effects of sema3B. [Cancer Res 2008;68(17):6922–31]
A Stochastic Model for Cancer Stem Cell Origin in Metastatic Colon Cancer
Authors: Odoux Christine , Fohrer Helene , Hoppo Toshitaka , Guzik Lynda , Stolz Donna Beer , Lewis Dale W. , Gollin Susanne M. , Gamblin T. Clark , Geller David A. , Lagasse Eric
Published: August 2008

Human cancers have been found to include transformed stem cells that may drive cancer progression to metastasis. Here, we report that metastatic colon cancer contains clonally derived tumor cells with all of the critical properties expected of stem cells, including self-renewal and the ability to differentiate into mature colon cells. Additionally, when injected into mice, these cells initiated tumors that closely resemble human cancer. Karyotype analyses of parental and clonally derived tumor cells expressed many consistent (clonal) along with unique chromosomal aberrations, suggesting the presence of chromosomal instability in the cancer stem cells. Thus, this new model for cancer origin and metastatic progression includes features of both the hierarchical model for cancerous stem cells and the stochastic model, driven by the observation of chromosomal instability. [Cancer Res 2008;68(17):6932–41]
Glycogen Synthase Kinase 3β Regulates Cell Death Induced by Synthetic Triterpenoids
Authors: Venè Roberta , Larghero Patrizia , Arena Giuseppe , Sporn Michael B. , Albini Adriana , Tosetti Francesca
Published: August 2008

The induction of programmed cell death in premalignant or malignant cancer cells by chemopreventive agents could be a valuable tool to control prostate cancer initiation and progression. In this work, we present evidence that the C-28 methyl ester of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-Me) induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at nanomolar and low micromolar concentrations. CDDO-Me induced caspase-3, caspase-8, and caspase-9 activation; poly(ADP-ribose) polymerase cleavage; internucleosomal DNA fragmentation; and loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction in PC3 and DU145 cells. However, caspase-3 and caspase-8 inhibition by Z-DEVD-fmk and Z-IETD-fmk, respectively, or general caspase inhibition by BOC-D-fmk or Z-VAD-fmk did not rescue loss of cell viability induced by CDDO-Me, suggesting the activation of additional caspase-independent mechanisms. Interestingly, CDDO-Me induced inactivating phosphorylation at Ser9 of glycogen synthase kinase 3β (GSK3β), a multifunctional kinase that mediates essential events promoting prostate cancer development and acquisition of androgen independence. The GSK3 inhibitor lithium chloride and, more effectively, GSK3 gene silencing sensitized PC3 and DU145 prostate cancer cells to CDDO-Me cytotoxicity. These data suggest that modulation of GSK3β activation is involved in the cell death pathway engaged by CDDO-Me in prostate cancer cells. [Cancer Res 2008;68(17):6987–96]
Mitochondrial/Cell-Surface Protein p32/gC1qR as a Molecular Target in Tumor Cells and Tumor Stroma
Authors: Fogal Valentina , Zhang Lianglin , Krajewski Stan , Ruoslahti Erkki
Published: August 2008

A tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as p32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for p32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-p32 antibodies showed that p32-positive cell lines expressed p32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total p32 expression in the cells. Like the LyP-1 peptide, p32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant p32 expression was common in human cancers and the p32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish p32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make p32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]
Efficient Cross-presentation Depends on Autophagy in Tumor Cells
Authors: Li Yuhuan , Wang Li-Xin , Yang Guojun , Hao Fang , Urba Walter J. , Hu Hong-Ming
Published: August 2008

Cross-presentation of antigens is critical for the induction of adaptive immunity against tumor cells and infectious pathogens. Currently, it is not known how cross-presentation of tumor antigens is regulated by autophagy. Using both HEK 293T cells that expressed the model antigen OVA and melanoma cells as antigen donors, we show that macroautophagy in tumor cells is essential for cross-presentation by dendritic cells both in vitro and in vivo. Inhibition of autophagy abolished cross-presentation almost completely, whereas induction of autophagy dramatically enhanced the cross-presentation of tumor antigens. Moreover, purified autophagosomes were found to be efficient antigen carriers for cross-presentation. Our findings not only identified a novel role for autophagy as an active process in antigen sequestration and delivery to dendritic cells for cross-presentation, but also suggested, for the first time, that isolated autophagosomes may have potential as potent vaccines for immunotherapy against cancer and infectious diseases. [Cancer Res 2008;68(17):6889–95]