bluuebunny/crossref_metadata_2025 huggingface dataset:
STARCH DEGRADATION
Authors: Smith Alison M. , Zeeman Samuel C. , Smith Steven M.
Published: January 2005

Recent research reveals that starch degradation in Arabidopsis leaves at night is significantly different from the “textbook” version of this process. Although parts of the pathway are now understood, other parts remain to be discovered. Glucans derived from starch granules are hydrolyzed via β-amylase to maltose, which is exported from the chloroplast. In the cytosol maltose is the substrate for a transglucosylation reaction, producing glucose and a glucosylated acceptor molecule. The enzyme that attacks the starch granule to release glucans is not known, nor is the nature of the cytosolic acceptor molecule. An Arabidopsis-type pathway may operate in leaves of other species, and in nonphotosynthetic organs that accumulate starch transiently. However, in starch-storing organs such as cereal endosperms and legume seeds, the process differs from that in Arabidopsis and may more closely resemble the textbook pathway. We discuss the differences in relation to the biology of each system.
VOLCANIC SEISMOLOGY
Authors: McNutt Stephen R.
Published: January 2005

▪ Abstract  Recent developments in volcanic seismology include new techniques to improve earthquake locations that have changed clouds of earthquakes to lines (faults) for high-frequency events and small volumes for low-frequency (LF) events. Spatial mapping of the b-value shows regions of normal b and high b anomalies at depths of 3–4 and 7–10 km. Increases in b precede some eruptions. LF events and very-long-period (VLP) events have been recorded at many volcanoes, and models are becoming increasingly sophisticated. Deep long-period (LP) events are fairly common, but may represent several processes. Acoustic sensors have greatly improved the study of volcanic explosions. Volcanic tremor is stronger for fissure eruptions, phreatic eruptions, and higher gas contents. Path and site effects can be extreme at volcanoes. Seismicity at volcanoes is triggered by large earthquakes, although mechanisms are still uncertain. A number of volcanoes have significant deformation with very little seismicity. Tomography has benefited from improved techniques and better instrumental arrays.
Mathematical Modeling of Whole Landscape Evolution
Authors: Willgoose Garry
Published: January 2005

▪ Abstract   The mathematical modeling of landform evolution consists of two components: the processes represented (i.e., considered dominant) in the model and the (typically computer) model representation of these processes. This review discusses the current debates surrounding processes represented in landform evolution. The potential impact on both evolving landforms and computer model structure is discussed. Issues specifically discussed include (a) the fundamental nature of mass conservation and the role of detachment- and transport-limited processes in mass conservation equations, (b) the interaction between detachment- and transport-limitation in channels, (c) the role of hillslope erosion and soil properties and their interaction with channel processes, (d) the interactions with tectonics when applying these models at large scale, (e) depositional structures and implications for paleo-climatic interpretation, (f) engineering applications of these models, and (g) numerical issues in the computer implementations. This review is not a model comparison. However, many applications are at the boundaries of computer capabilities so a comparison of existing models is provided.
Personality Development: Stability and Change
Authors: Caspi Avshalom , Roberts Brent W. , Shiner Rebecca L.
Published: January 2005

In this review, we evaluate four topics in the study of personality development where discernible progress has been made since 1995 (the last time the area of personality development was reviewed in this series). We (a) evaluate research about the structure of personality in childhood and in adulthood, with special attention to possible developmental changes in the lower-order components of broad traits; (b) summarize new directions in behavioral genetic studies of personality; (c) synthesize evidence from longitudinal studies to pinpoint where and when in the life course personality change is most likely to occur; and (d) document which personality traits influence social relationships, status attainment, and health, and the mechanisms by which these personality effects come about. In each of these four areas, we note gaps and identify priorities for further research.
Presidential Leadership
Authors: Goethals George R.
Published: January 2005

This chapter reviews psychological theories of leadership and selected literature on the American presidency to highlight key psychological principles of presidential leadership. Psychological theories, framed by the principles of leadership outlined by Freud (1921), include those of Burns (1978, 2003) on transformational leadership, Bass (1997) and House & Shamir (1993) on charismatic and transformational leadership, Gardner (1995) on stories of identity, Hogg (2001, 2003) on social identity, and Tyler & Lind (1992) on procedural justice. The discussion of presidential scholarship considers work by Barber (1992) on presidential character, Simonton (1986, 1987) on presidential personality and success, Skowronek (1997) on reconstructive politics, and Winter (1987) on presidential motive profiles. These studies suggest that followers have high expectations for presidents and that successful presidential leadership depends on opportunity, high levels of activity, intelligence, optimistic resilience, and flexibility.
Thromboxane A2from Kupffer cells contributes to the hyperresponsiveness of hepatic portal circulation to endothelin-1 in endotoxemic rats
Authors: Xu Hongzhi , Korneszczuk Katarzyna , Karaa Amel , Lin Tian , Clemens Mark G. , Zhang Jian X.
Published: January 2005

We examined the role of thromboxane A2(TXA2) in LPS-induced hyperresponsiveness of hepatic portal circulation to endothelins (ETs) and whether Kupffer cells are the primary source of TXA2release in response to ET-1 in endotoxemia. After 6 h of LPS (1 mg/kg body wt ip) or saline (control), liver was isolated and perfused with recirculating Krebs-Henseleit bicarbonate buffer at a constant flow rate (100 ml·min−1·kg body wt−1). ET-1 (10 pmol/min) was infused for 10 min. Portal pressure (PP) was continuously monitored during perfusion. Perfusate was sampled for enzyme immunoassay of thromboxane B2(TXB2; the stable metabolite of TXA2) and lactate dehydrogenase (LDH) assay. ET-1 infusion resulted in a significantly greater increase of PP in the LPS group than in controls. Both TXA2synthase inhibitor furegrelate (Fureg) and TXA2receptor antagonist SQ-29548 (SQ) substantially blocked enhanced increase of PP in the LPS group (4.9 ± 0.4 vs. 3.6 ± 0.5 vs. 2.6 ± 0.6 mmHg for LPS alone, LPS + Fureg, and LPS + SQ, respectively; P < 0.05) while having no significant effect on controls. GdCl3for inhibition of Kupffer cells had similar effects (4.9 ± 0.4 mmHg vs. 2.9 ± 0.4 mmHg for LPS alone and GdCl3+ LPS, respectively; P < 0.05). In addition, the attenuated PP after ET-1 was found concomitantly with significantly decreased releases of TXB2and LDH in LPS rats treated with Fureg, SQ, and GdCl3(886.6 ± 73.4 vs. 110.8 ± 0.8 vs. 114.8 ± 54.7 vs. 135.2 ± 45.2 pg/ml, respectively; P < 0.05). After 6 h of LPS, Kupffer cells in isolated cell preparations released a significant amount of TXA2in response to ET-1. These results clearly indicate that hyperresponsiveness of hepatic portal circulation to ET-1 in endotoxemia is mediated at least in part by TXA2-induced receptor activation, and Kupffer cells are likely the primary source of increased TXA2release.
Hypercholesterolemia abolishes voltage-dependent K+ channel contribution to adenosine-mediated relaxation in porcine coronary arterioles
Authors: Heaps C. L. , Tharp D. L. , Bowles D. K.
Published: January 2005

Hypercholesterolemic patients display reduced coronary flow reserve in response to adenosine infusion. We previously reported that voltage-dependent K+ (Kv) channels contribute to adenosine-mediated relaxation of coronary arterioles isolated from male miniature swine. For this study, we hypothesized that hypercholesterolemia attenuates Kv channel contribution to adenosine-induced vasodilatation. Pigs were randomly assigned to a control or high fat/high cholesterol diet for 20–24 wk, and then killed. After completion of the experimental treatment, arterioles (∼150 μm luminal diameter) were isolated from the left-ventricular free wall near the apical region of the heart, cannulated, and pressurized at 40 mmHg. Adenosine-mediated relaxation was significantly attenuated in both endothelium-intact and -denuded arterioles from hypercholesterolemic compared with control animals. The classic Kv channel blocker, 4-aminopyridine (1 mM), significantly attenuated adenosine-mediated relaxation in arterioles isolated from control but not hypercholesterolemic animals. Furthermore, the nonselective K+ channel blocker, tetraethylammonium (TEA; 1 mM) significantly attenuated adenosine-mediated relaxation in arterioles from control but not hypercholesterolemic animals. In additional experiments, coronary arteriolar smooth muscle cells were isolated, and whole cell K v currents were measured. Kv currents were significantly reduced (∼15%) in smooth muscle cells from hypercholesterolemic compared with control animals. Furthermore, Kv current sensitive to low concentrations of TEA was reduced (∼45%) in smooth muscle cells from hypercholesterolemic compared with control animals. Our data indicate that hypercholesterolemia abolishes Kv channel contribution to adenosine-mediated relaxation in coronary arterioles, which may be attributable to a reduced contribution of TEA-sensitive K v channels in smooth muscle of hypercholesterolemic animals.
Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction
Authors: Merkus Daphne , Houweling Birgit , van den Meiracker Anton H. , Boomsma Frans , Duncker Dirk J.
Published: January 2005

Left ventricular dysfunction in swine with a recent myocardial infarction (MI) is associated with neurohumoral activation, including increased catecholamines and endothelin (ET). Although the increase in ET may serve to maintain blood pressure and, hence, perfusion of essential organs such as the heart and brain, it could also compromise myocardial perfusion by evoking coronary vasoconstriction. In the present study, we tested the hypothesis that endogenous ET contributes to perturbations in myocardial O2 balance during exercise in remodeled myocardium of swine with a recent MI. For this purpose, 26 chronically instrumented swine (10 with and 16 without MI) were studied at rest and while running on a treadmill at 1–4 km/h. After MI, plasma ET increased from 3.2 ± 0.4 to 4.9 ± 0.3 pM ( P < 0.05). In normal swine, blockade of ETA (by EMD-122946) or ETA-ETB (by tezosentan) receptors resulted in an increase in coronary venous Po2, i.e., coronary vasodilation at rest, which decreased during exercise. In contrast, neither ETA nor ETA-ETB receptor blockade resulted in coronary vasodilation in swine with MI. Coronary vasoconstriction to intravenous ET-1 infusion in awake resting swine was blunted after MI. To investigate whether factors released by cardiac myocytes contributed to decreased vascular responsiveness to ET, we performed ET-1 dose-response curves in isolated coronary arterioles (70–200 μm). Vasoconstriction to ET-1 in isolated arterioles from MI swine was enhanced. In conclusion, the vasoconstrictor influence of endogenous as well as exogenous ET on coronary circulation in vivo is reduced. Because the response of isolated coronary arterioles to ET is increased after MI, the reduced vasoconstrictor influence in vivo suggests modulation of ET receptor sensitivity by cardiac myocytes, which may serve to maintain adequate myocardial perfusion.
Transmural strain distribution in the blood vessel wall
Authors: Guo Xiaomei , Lu Xiao , Kassab Ghassan S.
Published: January 2005

The transmural distributions of stress and strain at the in vivo state have important implications for the physiology and pathology of the vessel wall. The uniform transmural strain hypothesis was proposed by Takamyzawa and Hayashi (Takamizawa K and Hayashi K. J Biomech 20: 7–17, 1987; Biorheology 25: 555–565, 1988) as describing the state of arteries in vivo. From this hypothesis, they derived the residual stress and strain at the no-load condition and the opening angle at the zero-stress state. However, the experimental evidence cited by Takamyzawa and Hayashi ( J Biomech 20: 7–17, 1987; and Biorheology 25: 555–565, 1988) to support this hypothesis was limited to arteries whose opening angles (θ) are <180°. It is well known, however, that θ > 180° do exist in the cardiovascular system. Our hypothesis is that the transmural strain distribution cannot be uniform when θ is >180°. We present both theoretical and experimental evidence for this hypothesis. Theoretically, we show that the circumferential stretch ratio cannot physically be uniform across the vessel wall when θ exceeds 180° and the deviation from uniformity will increase with an increase in θ beyond 180°. Experimentally, we present data on the transmural strain distribution in segments of the porcine aorta and coronary arterial tree. Our data validate the theoretical prediction that the outer strain will exceed the inner strain when θ > 180°. This is the converse of the gradient observed when the residual strain is not taken into account. Although the strain distribution may not be uniform when θ exceeds 180°, the uniformity of stress distribution is still possible because of the composite nature of the blood vessel wall, i.e., the intima-medial layer is stiffer than the adventitial layer. Hence, the larger strain at the adventitia can result in a smaller stress because the adventitia is softer at physiological loading.
Control of oxidative stress in microcirculation of spontaneously hypertensive rats
Authors: DeLano F. A. , Balete R. , Schmid-Schönbein G. W.
Published: January 2005

One mechanism for organ damage in individuals with arterial hypertension may be due to oxygen free radical production. This study was designed to localize free radicals in a microvascular network of mature spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Because glucocorticoids play a role in pressure elevation of SHRs, we investigated their role in microvascular free radical formation. Oxygen radical production in mesentery was detected by tetranitroblue tetrazolium reduction to formazan aided by digital light-absorption measurements. Formazan deposits were observed in the endothelial cells and lumens of all microvessels and in lymphatic endothelia but were fewer in tissue parenchyma. The formazan distribution in younger (14–16 wk old) WKY rats and SHRs was heterogeneous with low values in capillaries and small arterioles/venules (<30 μm) but enhanced deposits in larger venules. Adrenalectomy served to reduce the formazan density in SHRs to the level of WKY rats, whereas dexamethasone supplementation of the adrenalectomized rats caused elevation in the larger venules of SHRs. In older (40 wk old) SHRs, formazan levels were elevated in all hierarchies of microvessels. After pressure reduction was employed with chronic hydralazine treatment, the formazan deposits were reduced in all locations of the microcirculation in both WKY rats and SHRs. Elevated formazan deposits were also found in lymphatic endothelium. These results suggest that oxygen free radical production is elevated in both high- and low-pressure regions of SHR microcirculation via a process that is controlled by glucocorticoids. Older SHRs have higher formazan levels than younger SHRs in all microvessels. Chronic hydralazine treatment, which serves to reduce arterial blood pressure, attenuates tetranitroblue tetrazolium reduction in WKY rats and SHRs even in venules of the microcirculation, which has no micropressure elevation. Free radical production may be a more global condition in SHRs and may not be limited to arteries and arterioles.
Altered expression of COX-1, COX-2, and mPGES in rats with nephrogenic and central diabetes insipidus
Authors: Kotnik Primož , Nielsen Jakob , Kwon Tae-Hwan , Kržišnik Ciril , Frøkiær Jørgen , Nielsen Søren
Published: January 2005

Prostaglandins have an important role in renal salt and water reabsorption. PGE2is the main kidney prostaglandin and is thought to be mainly produced in the kidney inner medulla (IM). There are indications that PGE2synthesis in nephrogenic (NDI) and central (CDI) diabetes insipidus is altered. We hypothesize that the expression of the major PGE2synthesis enzymes cyclooxygenases 1 and 2 (COX-1, COX-2) and membrane-associated PGE2synthase (mPGES) is altered in the kidneys of rats with NDI and CDI. Wistar rats treated with lithium for 4 wk were used as the NDI model. One-half of the NDI model rats were additionally dehydrated for 48 h. Brattleboro (BB) rats that lack endogenous antidiuretic hormone were used as the CDI model. Expression and localization of COX-1, COX-2, and mPGES in IM, inner stripe of outer medulla (ISOM), and cortex were determined by immunoblotting and immunohistochemistry. In lithium-induced NDI, expression of COX-1, COX-2, and mPGES was markedly decreased in IM. In ISOM and cortex, COX-1 expression was marginally reduced and mPGES expression was unaltered. COX-2 expression was undetected in ISOM and marginally increased in cortex. Consistent with this, the density of COX-2-expressing cells in macula densa was significantly increased, indicating differential regulation of COX-2 in IM and cortex. Dehydration of NDI rats resulted in a marked increase in COX-2 immunolabeling in IM interstitial cells, and there was no significant change in COX-1 and mPGES expression in any kidney zone. Treatment of DDAVP in BB rats for 6 days resulted in a markedly increased expression of COX-1, COX-2, and mPGES in IM. In the cortex, there were no changes in the expression of COX-1 and mPGES, whereas COX-2 expression was decreased. These results identify markedly reduced expression of COX-1, COX-2, and mPGES in IM in lithium-induced NDI. Furthermore, there were major changes in the expression of COX-1, COX-2, and mPGES in rats with CDI.
The involvement of hydroxyl radical and cyclooxygenase metabolites in the activation of lung vagal sensory receptors by circulatory endotoxin in rats
Authors: Lai Ching Jung , Ruan Ting , Kou Yu Ru
Published: January 2005

Circulatory endotoxin can stimulate vagal pulmonary C fibers and rapidly adapting receptors (RARs) in rats, but the underlying mechanisms are not clear. We investigated the involvement of hydroxyl radicals and cyclooxygenase metabolites in the stimulation of C fibers and RARs by circulatory endotoxin (50 mg/kg) in 112 anesthetized, paralyzed, and artificially ventilated rats. In rats pretreated with the vehicle, endotoxin stimulated C fibers and RARs and caused a slight increase in total lung resistance (Rl) and a decrease in dynamic lung compliance. In rats pretreated with dimethylthiourea (a hydroxyl radical scavenger) alone, indomethacin (a cyclooxygenase inhibitor) alone, or a combination of the two, C-fiber and RAR responses [C fiber: change (Δ) = −62, −79, and −85%; RAR: Δ = −80, −84, and −84%, respectively] were reduced, and the Rl response was prevented. The suppressive effects of a combination of dimethylthiourea and indomethacin on the C-fiber and RAR responses were not superior to indomethacin alone. In rats pretreated with isoproterenol (a bronchodilator), the C-fiber response was not significantly affected (Δ = −26%), the RAR response was reduced (Δ = −88%), and the Rl response was prevented. None of these pretreatments affected the dynamic lung compliance response. These results suggest that 1) both hydroxyl radicals and cyclooxygenase metabolites are involved in the endotoxin-induced stimulation of C fibers and RARs, and 2) the involvement of these two metabolites in the C-fiber stimulation may be due to their chemical effects, whereas that in the RAR stimulation may be due to their bronchoconstrictive effects.
Effects of disrupted β1-integrin function on the skeletal response to short-term hindlimb unloading in mice
Authors: Iwaniec U. T. , Wronski T. J. , Amblard D. , Nishimura Y. , van der Meulen M. C. H. , Wade C. E. , Bourgeois M. A. , Damsky C. D. , Globus R. K.
Published: January 2005

The study was designed to determine whether β1-integrin plays a role in mediating the acute skeletal response to mechanical unloading. Transgenic (TG) mice were generated to express a dominant negative form of β1-integrin under the control of the osteocalcin promoter, which targets expression of the transgene to mature osteoblasts. At 63 days of age, wild-type (WT) and TG mice were subjected to hindlimb unloading by tail suspension for 1 wk. Pair-fed, normally loaded WT and TG mice served as age-matched controls. Bone samples from each mouse were processed for quantitative bone histomorphometry and biomechanical testing. The skeletal phenotype of TG mice was characterized by lower cancellous bone mass in the distal femoral metaphysis (−52%) and lumbar vertebral body (−20%), reduced curvature of the proximal tibia (−20%), and decreased bone strength (−20%) and stiffness (−23%) of the femoral diaphysis with relatively normal indexes of cancellous bone turnover. Hindlimb unloading for only 1 wk induced a 10% decline in tibial curvature and a 30% loss of cancellous bone in the distal femur due to a combination of increased bone resorption and decreased bone formation in both WT and TG mice. However, the strength and stiffness of the femoral diaphysis were unaffected by short-term hindlimb unloading in both genotypes. The observed increase in osteoclast surface was greater in unloaded TG mice (92%) than in unloaded WT mice (52%). Cancellous bone formation rate was decreased in unloaded WT (−29%) and TG (−15%) mice, but, in contrast to osteoclast surface, the genotype by loading interaction was not statistically significant. The results indicate that altered integrin function in mature osteoblasts may enhance the osteoclastic response to mechanical unloading but that it does not have a major effect on the development of cancellous osteopenia in mice during the early stages of hindlimb unloading.
Activation of the vasoactive intestinal peptide 2 receptor modulates normal and atrophying skeletal muscle mass and force
Authors: Hinkle Richard T. , Donnelly Elizabeth , Cody David B. , Sheldon Russell J. , Isfort Robert J.
Published: January 2005

Of the two known vasoactive intestinal peptide receptors (VPAC1R and VPAC2R), the VPAC2R is expressed in skeletal muscle. To evaluate the function of the VPAC2R in the physiological control of skeletal muscle mass, we utilized the VPAC1R selective agonist [K15,R16,L27]VIP(1-7) GRF(8-27)-NH2 and the VPAC2R selective agonist Ro-25-1553 to treat mice and rats undergoing either nerve damage-, corticosteroid-, or disuse-induced skeletal muscle atrophy. These analyses demonstrated that activation of VPAC2R, but not VPAC1R, reduced the loss of skeletal muscle mass and force during conditions of skeletal muscle atrophy resulting from corticosteroid administration, denervation, casting-induced disuse, increased skeletal muscle mass, and force of nonatrophying muscles. These studies indicate that VPAC2R agonists may have utility for the treatment of skeletal muscle-wasting diseases.
Hypoxia, leukocytes, and the pulmonary circulation
Authors: Stenmark Kurt R. , Davie Neil J. , Reeves John T. , Frid Maria G.
Published: January 2005

Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-β1in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.
Latrunculin B increases force fluctuation-induced relengthening of ACh-contracted, isotonically shortened canine tracheal smooth muscle
Authors: Dowell M. L. , Lakser O. J. , Gerthoffer W. T. , Fredberg J. J. , Stelmack G. L. , Halayko A. J. , Solway J. , Mitchell R. W.
Published: January 2005

We hypothesized that differences in actin filament length could influence force fluctuation-induced relengthening (FFIR) of contracted airway smooth muscle and tested this hypothesis as follows. One-hundred micromolar ACh-stimulated canine tracheal smooth muscle (TSM) strips set at optimal reference length ( Lref) were allowed to shorten against 32% maximal isometric force (Fmax) steady preload, after which force oscillations of ±16% Fmax were superimposed. Strips relengthened during force oscillations. We measured hysteresivity and calculated FFIR as the difference between muscle length before and after 20-min imposed force oscillations. Strips were relaxed by ACh removal and treated for 1 h with 30 nM latrunculin B (sequesters G-actin and promotes depolymerization) or 500 nM jasplakinolide (stabilizes actin filaments and opposes depolymerization). A second isotonic contraction protocol was then performed; FFIR and hysteresivity were again measured. Latrunculin B increased FFIR by 92.2 ± 27.6% Lref and hysteresivity by 31.8 ± 13.5% vs. pretreatment values. In contrast, jasplakinolide had little influence on relengthening by itself; neither FFIR nor hysteresivity was significantly affected. However, when jasplakinolide-treated tissues were then incubated with latrunculin B in the continued presence of jasplakinolide for 1 more h and a third contraction protocol performed, latrunculin B no longer substantially enhanced TSM relengthening. In TSM treated with latrunculin B + jasplakinolide, FFIR increased by only 3.03 ± 5.2% Lref and hysteresivity by 4.14 ± 4.9% compared with its first (pre-jasplakinolide or latrunculin B) value. These results suggest that actin filament length, in part, determines the relengthening of contracted airway smooth muscle.
Activation of BK Channels in GH3 Cells by ac-PLA2-Dependent G-Protein Signaling Pathway
Authors: Denson D. D. , Li J. , Wang X. , Eaton D. C.
Published: January 2005

BK-channels in GH3 cells are activated by arachidonic acid produced by c-PLA2. β-adrenergic agonists also activate BK channels and were presumed to do so via production of cAMP. We, however, show for the first time in GH3 cells that a β-adrenergic agonist activates a pertussis-toxin-sensitive G protein that activates c-PLA2. The arachidonic acid produced by c-PLA2then activates BK channels. We examined BK channels in cell-attached patches and in excised patches from untreated GH3 cells and from GH3 cells exposed to c-PLA2antisense oligonucleotides. For the cell-attached patch experiments, physiologic pipette and bath solutions were used. For the excised patches, 150 mM KCl was used in both the pipette and bath solutions, and the cytosolic surface contained 1 μM free Ca2+(buffered with 5 mM K2EGTA). Treatment of GH3 cells with the G protein activator, fluoroaluminate, (AlF4−) produced an increase in the Poof BK channels of 177 ± 41% (mean ± SD) in cell-attached patches. Because G proteins are membrane associated, we also added an activator of G proteins, 100 μM GTP-γ-S, to the cytosolic surface of excised patches. This treatment leads to an increase in Poof 50 ± 9%. Similar treatment of excised patches with GDP-β-S had no effect on Po. Isoproterenol (1 μM), an activator of β-adrenergic receptors and, consequently, some G proteins, increased BK channel activity 229 ± 37% in cell-attached patches from cultured GH3 cells. Western blot analysis showed that GH3 cells have β-adrenergic receptor protein and that isoproterenol acts through these receptors because the β-adrenergic receptor antagonist, propanolol, blocks the action of isoproterenol. To test whether G protein activation of BK channels involves c-PLA2, we studied the effects of GTP-γ-S on excised patches and isoproterenol on cell attached patches from GH3 cells previously treated with c-PLA2antisense oligonucleotides or pharmacological inhibitors of c-PLA2. Neither isoproterenol nor GTP-γ-S had any effect on Poin these patches. Similarly, neither isoproterenol nor GTP-γ-S had any effect on Poin cultured GH3 cells pretreated with pertussis toxin. Isoproterenol also significantly increased the rate of arachidonic production in GH3 cells. These results show that some receptor-linked, pertussis-toxin-sensitive G protein in GH3 cells can activate c-PLA2to increase the amount of arachidonic acid present and ultimately increase BK-channel activity.
Role of GABAergic Inhibition in the Coding of Interaural Time Differences of Low-Frequency Sounds in the Inferior Colliculus
Authors: D’Angelo W. R. , Sterbing S. J. , Ostapoff E.-M. , Kuwada S.
Published: January 2005

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting γ-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.
Thermal Effects of Urban Canyon Structure on the Nocturnal Heat Island: Numerical Experiment Using a Mesoscale Model Coupled with an Urban Canopy Model
Authors: Kusaka Hiroyuki , Kimura Fujio
Published: January 2005

A single-layer urban canopy model is incorporated into a simple two-dimensional atmospheric model in order to examine the individual impacts of anthropogenic heating, a large heat capacity, and a small sky-view factor on mesoscale heat island formation. It is confirmed that a nocturnal heat island on a clear, calm summer day results from the difference in atmospheric stability between a city and its surroundings. The difference is caused by anthropogenic heating and the following two effects of urban canyon structure: (i) a larger heat capacity due to the walls and (ii) a smaller sky-view factor. Sensitivity experiments show that the anthropogenic heating increases the surface air temperature though the day. (This factor strongly affects the nocturnal temperature, and the maximum increase of 0.67°C occurs at 0500 LST.) The larger heat capacity due to the walls decreases the daytime temperature and increases the nocturnal temperature. (The maximum increase of 0.39°C occurs at 0600 LST.) The smaller sky-view factor increases the temperature though the day, particularly during the first several hours after sunset. (The maximum increase of 0.52°C occurs at midnight.) In urban areas, this factor results in uniform cooling that occurs at a constant rate. The impact of the canyon structure is shown to be as significant as anthropogenic heating.
An Organizing Center for Thermohaline Excitability
Authors: Abshagen Jan , Timmermann Axel
Published: January 2005

The bifurcation behavior of a conceptual heat–salt oscillator model is analyzed by means of numerical continuation methods. A global (homoclinic) bifurcation acts as an organizing center for the dynamics of the simplified convective model. It originates from a codimension-2 bifurcation in an extended parameter space. Comparison with earlier work by Cessi shows that the intriguing stochastic thermohaline excitability can be understood from the bifurcation structure of the model. It is argued that global bifurcations may play a crucial role in determining long-term variability of the thermohaline circulation.
Dynamic Potential Vorticity Initialization and the Diagnosis of Mesoscale Motion
Authors: Viúdez Álvaro , Dritschel David G.
Published: January 2005

A new method for diagnosing the balanced three-dimensional velocity from a given density field in mesoscale oceanic flows is described. The method is referred to as dynamic potential vorticity initialization (PVI) and is based on the idea of letting the inertia–gravity waves produced by the initially imbalanced mass density and velocity fields develop and evolve in time while the balanced components of these fields adjust during the diagnostic period to a prescribed initial potential vorticity (PV) field. Technically this is achieved first by calculating the prescribed PV field from given density and geostrophic velocity fields; then the PV anomaly is multiplied by a simple time-dependent ramp function, initially zero but tending to unity over the diagnostic period. In this way, the PV anomaly builds up to the prescribed anomaly. During this time, the full three-dimensional primitive equations—except for the PV equation—are integrated for several inertial periods. At the end of the diagnostic period the density and velocity fields are found to adjust to the prescribed PV field and the approximate balanced vortical motion is obtained. This adjustment involves the generation and propagation of fast, small-amplitude inertia–gravity waves, which appear to have negligible impact on the final near-balanced motion. Several practical applications of this method are illustrated. The highly nonlinear, complex breakup of baroclinically unstable currents into eddies, fronts, and filamentary structures is examined. The capability of the method to generate the balanced three-dimensional motion is measured by analyzing the ageostrophic horizontal and vertical velocity—the latter is the velocity component most sensitive to initialization, and one for which a quasigeostrophic diagnostic solution is available for comparison purposes. The authors find that the diagnosed fields are closer to the actual fields than are either the geostrophic or the quasigeostrophic approximations. Dynamic PV initialization thus appears to be a promising way of improving the diagnosis of balanced mesoscale motions.
Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine
Authors: Dowell James A. , Stogniew Martin , Krause David , Henkel Timothy , Weston Irving E.
Published: January 2005

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H‐cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple‐dose, open‐label clinical study of 12 healthy volunteers. Subjects received a 200‐mg intravenous loading dose of anidulafungin, followed by a daily 100‐mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose‐limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.
Pharmacokinetic Interaction Study of Indinavir/Ritonavir and the Enteric‐Coated Capsule Formulation of Didanosine in Healthy Volunteers
Authors: la Porte C. , Verweij‐van Wissen C. , van Ewijk N. , Aarnoutse R. , Koopmans P. , Reiss P. , Stek M. , Hekster Y. , Burger D.
Published: January 2005

Didanosine enteric‐coated should be taken on an empty stomach, but the once‐daily combination of indinavir/ritonavir can be taken with food. Because these drugs are frequently included in 1 regimen, the food effects on the pharmacokinetics were evaluated. This was a randomized, 4‐way crossover study of single doses of didanosine enteric‐coated 400 mg and indinavir/ritonavir 1200/400 mg in 8 healthy subjects. The following regimens were given: didanosine enteric‐coated 2 hours after breakfast (reference regimen A), indinavir/ritonavir with breakfast (reference regimen B), didanosine enteric‐coated + indinavir/ritonavir 2 hours after breakfast (test regimen C), and didanosine enteric‐coated + indinavir/ritonavir with breakfast (test regimen D). Breakfast was 550 kcal, 28% fat. Blood samples were drawn before and up to 24 hours after ingestion. Statistical comparisons of test regimens C and D with reference regimens A and B were made using the equivalence approach for indinavir and didanosine area under the curve and Cmax (0.80–1.25). Eight subjects (5 men, 3 women) were enrolled and completed the study. Indinavir area under the curves were bioequivalent in test regimens C and D compared to reference regimen B. A 14% increased Cmax was observed in test regimen C. Didanosine area under the curve in test regimen D was 4% lower and suggestive of bioequivalence compared to reference regimen A. However, test regimen C didanosine area under the curve was 23% lower and bioinequivalent compared to reference regimen A. Didanosine Cmax decreased 42% and 46% in test regimens C and D, respectively, in comparison to reference regimen A. In this study, dosing didanosine enteric‐coated 400 mg once daily + indinavir/ritonavir 1200/400 mg once daily with breakfast indicated no decrease in the amount of absorption for either didanosine and indinavir and that this regimen could be administered with food.
Paradoxical Cyclosporine A Requirements in Pediatric Renal Transplants Receiving High‐Dose Steroids
Authors: Hardy Karolyn W. , Crocker John F. S. , McLellan Heather , Goralski Kerry B. , Renton Ken W. , Acott Philip D.
Published: January 2005

The potent immunosuppressant cyclosporine A (CyA) is a mainstay of treatment in the renal transplant population. During episodes of acute allograft rejection, therapy also includes the pulse administration of high‐dose steroids such as prednisone or methylprednisolone. Both steroids and CyA are metabolized by the CYP3A4 isoenzyme of the cytochrome P450 catalytic system. On a theoretical basis, high steroid concentrations during a rejection episode could competitively inhibit CyA metabolism, increasing its systemic concentration and decreasing its dose requirements. A database was compiled consisting of pediatric patients who had undergone an acute renal rejection event during the years 1993 to 2003. The severity of rejection events, as well as the CyA and prednisone dosing regimens used during rejection, were assessed using a comprehensive chart analysis. The presence or absence of additional medications that could potentially interact with CyA was also examined. Although some patients responded in the predicted manner, the authors also found that a subgroup of pediatric patients placed on high‐dose pulse steroid therapy for acute graft rejection required increased amounts of CyA to maintain therapeutic concentrations. The authors recommend monitoring of patients on high‐dose steroids for paradoxical CyA requirements intermittently during high‐dose steroid treatment to individualize CyA therapy appropriately during renal allograft rejection and thereby maximize efficacy while minimizing potential toxic side effects of CyA such as under‐immunosuppression and organ rejection.
Internet Abuse
Authors: Morahan-Martin Janet
Published: January 2005

As Internet use has proliferated worldwide, there has been debate whether some users develop disturbed patterns of Internet use (i.e., Internet abuse). This article highlights relevant literature on Internet abuse and computer-mediated communication effects that supports and disputes major questions about Internet abuse. Is the addiction paradigm appropriate for Internet use? Is behavior that has been labeled Internet abuse symptomatic of other problems such as depression, sexual disorders, or loneliness? What are alternative explanations for this phenomenon? Is there adequate research to support Internet abuse as a distinct disorder?
Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin
Authors: Hopkins Philip A. , Fraser John D. , Pridmore Alison C. , Russell Hugh H. , Read Robert C. , Sriskandan Shiranee
Published: January 2005

The devastating systemic effects of bacterial superantigens may be explained by powerful proinflammatory synergy with lipopolysaccharide (LPS). However, the mechanism underlying this phenomenon remains unclear and has never been investigated in humans. Specifically, there is no known link between superantigen-induced immune effects and the pattern recognition of LPS at toll-like receptor 4 (TLR4). Here we show that bacterial superantigens induce rapid transcription and increased membrane expression of TLR4 in primary human monocytes by ligation of major histocompatibility complex (MHC) class II. We also demonstrate that superantigens are solely responsible for monocyte TLR4 up-regulation induced by products from Gram-positive bacteria. In parallel with enhanced TLR4 expression, priming of purified monocytes or mixed peripheral blood mononuclear cells with superantigens significantly enhanced the induction of proinflammatory cytokines by known TLR4 ligands. Staphylococcal enterotoxin A constructs containing targeted mutations were used to demonstrate a requirement for MHC class II ligation in both TLR4 up-regulation and enhanced responses to endotoxin. In contrast to results from animal models, superantigen-endotoxin interaction was not dependent on T-cell receptor ligation by superantigen or interferon gamma production. Pattern recognition of bacterial superantigens by MHC class II receptors may exacerbate the proinflammatory response of monocytes to Gram-negative infection or endotoxin by up-regulation of TLR4.
A systematic scan of interactions with tyrosine motifs in the erythropoietin receptor using a mammalian 2-hybrid approach
Authors: Montoye Tony , Lemmens Irma , Catteeuw Dominiek , Eyckerman Sven , Tavernier Jan
Published: January 2005

Signaling via the erythropoietin receptor (EpoR) depends on the interaction of several proteins with phosphorylated tyrosine-containing motifs in its cytosolic domain. Detailed mapping of these interactions is required for an accurate insight into Epo signaling. We recently developed a mammalian protein-protein interaction trap (MAPPIT), a cytokine receptor-based 2-hybrid method that operates in intact Hek293-T mammalian cells. As baits, we used intracellular segments of the EpoR containing 1 or 2 tyrosines. Several known signaling molecules, including cytokine-inducible SH2-containing protein (CIS), suppressor of cytokine signaling-2 (SOCS2), phosphatidylinositol 3′-kinase (PI3-K), phospholipase C-γ (PLC-γ), and signal transducer and activator of transcription 5 (STAT5) were used as prey. We also extended the MAPPIT method to enable interaction analysis with wild-type EpoR. In this relay MAPPIT approach, instead of using isolated EpoR fragments as bait, we used the full-length EpoR itself as a “receptor bait.” Finally, we introduced MAPPIT in the erythroleukemic TF-1 cell line, which is a more natural setting of the EpoR. With these strategies several known interactions with the EpoR were analyzed and evidence for new interactions was obtained.