bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal variations of the gravity wave momentum flux in the Antarctic mesosphere and lower thermosphere
Authors: Espy P. J. , Jones G. O. L. , Swenson G. R. , Tang J. , Taylor M. J.
Published: December 2004

Airglow imager and dynasonde/imaging Doppler interferometer (IDI) radar wind measurements at Halley Station, Antarctica (75.6°S, 26.6°W) have been used to estimate the seasonal variation of the vertical fluxes of horizontal momentum carried by high‐frequency atmospheric gravity waves. The cross‐correlation coefficients between the vertical and horizontal wind perturbations were calculated from sodium (Na) airglow imager data collected during the austral winter seasons of 2000 and 2001. These were combined with wind velocity variances from coincident radar measurements to estimate the daily averaged upper limit of the vertical flux of horizontal momentum due to gravity waves. The resulting momentum flux at the Na airglow altitudes, while displaying a large day‐to‐day variability, showed a marked rotation from the northwest to the southeast throughout the winter season. Calculations show that this rotation is consistent with seasonal changes in the wind field filtering of gravity waves below the Na airglow region. The calculations also indicate that while the magnitude of the meridional wind is small, this filtering leads to the observed seasonal changes in the meridional momentum flux.
The 2002–2003 eruption of Stromboli (Italy): Evaluation of the volcanic activity by means of continuous monitoring of soil temperature, CO2 flux, and meteorological parameters
Authors: Brusca Lorenzo , Inguaggiato Salvatore , Longo Manfredi , Madonia Paolo , Maugeri Roberto
Published: December 2004

From December 2002 to July 2003, Stromboli volcano was characterized by a new effusive stage of eruption after a period of extraordinary strombolian activity. Signals recorded in two continuous monitoring stations during the eruption, which have already been presented in very recent papers, evidenced anomalies in the CO2 flux just before the onset of the eruption. A more detailed analysis carried out on the data subset acquired during the eruption, integrated by daily field observations of the scientific personnel working at the volcanological observatory in Stromboli, showed that CO2 flux and soil temperature are strictly related to volcanic events. Furthermore, the relative minima and maxima of the two parameters showed a strong correlation with wind speed and direction. This fact was especially true at the summit station, whereas at the coastal sites seasonal and meteorological effects masked the volcanic signal. The analysis of the wind data, particularly the relationships between wind speed and direction, air and soil temperature, and local circulation of atmospheric air masses revealed that during the eruption, in the summit area of Stromboli air movements were not only related to atmospheric circulation but were also significantly affected, and in certain cases caused, by volcanic activity. This conclusion was reached by observing several anomalies, such as the discrepancies in the wind direction between the two stations, higher air temperatures at the summit site, and inversion of direction for wind before and after the reopening of the conduit in a major explosion on 5 April 2003. The relationships found between volcanic activity, soil temperatures, CO2 fluxes, and wind speed and direction indicate that soil temperature measurements, in an open conduit volcano such as in this case, could be used to monitor the level of volcanic activity, along with CO2 flux. Furthermore, the possible volcanic origin of a peculiar type of air circulation identified in the summit area of Stromboli suggests that the separation between volcanic and atmospheric signals might not be obvious, requiring monitoring over a wide area, rather than a single location.
Short‐term variations in the distribution of hydrothermal plumes along a superfast spreading center, East Pacific Rise, 27°30′–32°20′S
Authors: Walker Sharon L. , Baker Edward T. , Massoth Gary J. , Hey Richard N.
Published: December 2004

A multidisciplinary expedition to the southern East Pacific Rise (27°30′–32°20′S) provided an opportunity to compare the efficiency and effectiveness of two methods for mapping hydrothermal plumes: the standard conductivity‐temperature‐depth‐optical (CTDO) tow‐yo method and a towed fixed array of hydrographic and optical sensors (Miniature Autonomous Plume Recorders (MAPRs)). Six second‐order segments were mapped twice: once with CTDO tow‐yos, and then again with a fixed array of MAPRs attached to the cable of a deep‐towed side‐scan sonar. We found a high degree of overall agreement between the two methods in both the distribution and optical intensity of hydrothermal plumes. Between‐survey differences increased as time between surveys increased from <0.5 to >6 days, presumably because of advection of the plumes by local currents. Plume locations changed by as much as ∼10 km, implying a confidence limit in predicting vent site location using segment‐scale hydrothermal plume surveys. Towed MAPR arrays proved an efficient and effective method for acquiring coregistered geological and hydrothermal plume data.
The influence of the transition zone water filter on convective circulation in the mantle
Authors: Leahy Garrett M. , Bercovici David
Published: December 2004

The “transition zone water filter” model of mantle convection attempts to reconcile geochemical evidence for isolated mantle reservoirs with geophysical evidence for whole mantle circulation by decoupling incompatible elements from bulk mantle circulation via a melt layer above the 410 km discontinuity. This would result in a stratified heating distribution similar to layered convection models, but would permit bulk mass and heat transfer across mantle interfaces. Here we test the basic effect of the water filter mechanism on mantle flow, in particular to see whether it induces layered convection and/or strong upwelling plumes above strongly heated layers. We investigate the influence of ten likely heating distributions on the planform of convection. Excepting an extreme case where all heating occurs in the transition zone, convection is not significantly influenced by the heating distribution. For Earth‐like internal heating, the flow is dominated by downwellings which extend across the entire model mantle, as in uniformly internally heated layers.
Impact of electron thermal effects on Farley‐Buneman waves at arbitrary aspect angles
Authors: Kagan L. M. , St.‐Maurice J.‐P.
Published: December 2004

Using a standard 8‐moment expansion of the fluid equations, we have extended fluid calculations of the effect of electron temperature feedback on the linear Farley‐Buneman instability theory to include the contribution of field‐aligned heat flow and field‐aligned wave electric fields through nonzero‐aspect angles. Our treatment includes arbitrary ion magnetization and neutral winds but is limited, for simplicity, to zero flow angles. Our results indicate that, for 3‐m waves, electron thermal corrections are significant (threshold phase velocities greater than predicted by isothermal theory by 20% or more) at aspect angles less than 0.35° for altitudes less than 103 km. Similar but smaller numbers are obtained for 10‐m waves. The impact of the thermal corrections normally also decreases rapidly with increasing altitude. These results provide a straightforward explanation for equatorial observations of 3‐m phase velocities that are at least 30% greater than the isothermal ion‐acoustic speed below 105 km in the equatorial regions. The altitude dependence of the observed phase speeds also mimics very well the behavior seen in our calculations. The implication is that the aspect angles of the structures must be smaller than 0.3°. This is consistent with recent findings from radar interferometry.
Changes in the photochemical environment of the temperate North Pacific troposphere in response to increased Asian emissions
Authors: Parrish D. D. , Dunlea E. J. , Atlas E. L. , Schauffler S. , Donnelly S. , Stroud V. , Goldstein A. H. , Millet D. B. , McKay M. , Jaffe D. A. , Price H. U. , Hess P. G. , Flocke F. , Roberts J. M.
Published: December 2004

Measurements during the Intercontinental Transport and Chemical Transformation 2002 (ITCT 2K2) field study characterized the springtime, eastern Pacific ozone distribution at two ground sites, from the National Oceanic and Atmospheric Administration WP‐3D aircraft, and from a light aircraft operated by the University of Washington. D. Jaffe and colleagues compared the 2002 ozone distribution with measurements made in the region over the two previous decades and show that average ozone levels over the eastern midlatitude Pacific have systematically increased by ∼10 ppbv in the last two decades. Here we provide substantial evidence that a marked change in the photochemical environment in the springtime troposphere of the North Pacific is responsible for this increased O3. This change is evidenced in the eastern North Pacific ITCT 2K2 study region by (1) larger increases in the minimum observed ozone levels compared to more modest increases in the maximum levels, (2) increased peroxyacetyl nitrate (PAN) levels that parallel trends in NOx emissions, and (3) decreased efficiency of photochemical O3 destruction, i.e., less negative O3 photochemical tendency (or net rate of O3 photochemical production; P(O3)). This changed photochemical environment is hypothesized to be due to anthropogenic emissions from Asia, which are believed to have substantially increased over the two decades preceding the study. We propose that their influence has changed the springtime Pacific tropospheric photochemistry from predominately ozone destroying to more nearly ozone producing. However, chemical transport model calculations indicate the possible influence of a confounding factor; unusual transport of tropical air to the western North Pacific during one early field study may have played a role in this apparent change in the photochemistry.
Oligocene climate dynamics
Authors: Wade Bridget S. , Pälike Heiko
Published: December 2004

A planktonic and benthic foraminiferal stable isotope stratigraphy of the Oligocene equatorial Pacific (Ocean Drilling Program, Site 1218) was generated at 6 kyr resolution between magnetochrons C9n and C11n.2n (∼26.4–30 Ma on a newly developed astronomically calibrated timescale). Our data allow a detailed examination of Oligocene paleoceanography, the evolution of the early cryosphere, and the influence of orbital forcing on glacioeustatic sea level variations. Spectral analysis reveals power and coherency for obliquity (40 kyr period) and eccentricity (∼110, 405 kyr) orbital bands, with an additional strong imprint of the eccentricity and 1.2 Myr obliquity amplitude cycle, driving ice sheet oscillations in the Southern Hemisphere. Planktonic and benthic foraminifera δ18O are used to constrain the magnitude and timing of major fluctuations in ice volume and global sea level change. Glacial episodes, related to obliquity and eccentricity variations, occurred at 29.16, 27.91, and 26.76 Ma, corresponding to glacioeustatic sea level fluctuations of 50–65 m. Alteration of high‐latitude temperatures and Antarctic ice volume had a significant impact on the global carbon burial and equatorial productivity, as cyclic variations are also recorded in the carbon isotope signal of planktonic and benthic foraminifera, the water column carbon isotope gradient, and estimated percent carbonate of bulk sediment. We also investigate the implications of a close correspondence between oxygen and carbon isotope events and long‐term amplitude envelope extrema in astronomical calculations during the Oligocene, and develop a new naming scheme for stable isotope events, on the basis of the 405 kyr eccentricity cycle count.
Pharmacodynamics and pharmacokinetics of SQ109, a new diamine‐based antitubercular drug
Authors: Jia Lee , Tomaszewski Joseph E , Hanrahan Colleen , Coward Lori , Noker Patricia , Gorman Gregory , Nikonenko Boris , Protopopova Marina
Published: December 2004

SQ109 is a novel [1,2]‐diamine‐based ethambutol (EMB) analog developed from high‐throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics.

The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis‐infected murine macrophages) and in vivo (M. tuberculosis‐infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1–25 mg kg−1 day−1) to the mice for 28 days resulted in dose‐dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg−1 day−1, but was less potent than INH at 25 mg kg−1 day−1. Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28‐day oral administration (10 mg kg−1 day−1) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC.

Pharmacokinetic profiles of SQ109 in mice following a single administration showed its Cmax as 1038 (intravenous (i.v.)) and 135 ng ml−1 (p.o.), with an oral Tmax of 0.31 h. The elimination t1/2 of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120‐fold (p.o.) and 180‐fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h).

This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

British Journal of Pharmacology (2005) 144, 80–87. doi:10.1038/sj.bjp.0705984
Antimony‐induced cardiomyopathy in guinea‐pig and protection by L‐carnitine
Authors: Alvarez Marco , Malécot Claire O , Gannier François , Lignon Jacques M
Published: December 2004

Antimony (Sb) is the mainstay for the treatment of Leishmaniasis. It has serious, often lethal, cardiovascular side effects. The objective of this study was to examine the effects of Sb treatment upon the electrocardiogram (ECG), myocyte contractility (assessed by monitoring sarcomere length during field stimulation), whole‐cell action potential (AP) and calcium current (ICa) of the guinea‐pig and to evaluate L‐carnitine as a cardioprotective agent.

Guinea‐pigs received daily injections of either saline, Sb(V), Sb(III), L‐carnitine or L‐carnitine with Sb(III). Eight lead ECGs were recorded under halothane anaesthesia every 4 days. At the end of each treatment regime, animals were killed and ventricular myocytes were enzymatically isolated.

Treatment with Sb(V) for 26 days prolonged the QT interval of the ECG. Treatment with Sb(III) was lethal within 2 days for ∼50% of the animals. The survivors showed ECG alterations similar to those described in man: T wave flattening and/or inversion, depression of the ST segment, and elongation of RR and QT intervals. Their ventricular myocytes showed impaired contraction responses to changes in stimulus frequency, elongated AP and reduced ICa.

Combined treatment with L‐carnitine and Sb(III) delayed mortality. Prior treatment with L‐carnitine followed by combined treatment with L‐carnitine and Sb(III) reduced mortality to <10% over 12 days and these animals showed normal ECG. Their myocytes showed normal contractility and AP.

It is concluded that L‐carnitine has a preventive cardioprotective role against antimony‐induced cardiomyopathy. The mechanism of action of L‐carnitine may be to counter oxidative stress caused by Sb(III).

British Journal of Pharmacology (2005) 144, 17–27. doi:10.1038/sj.bjp.0706030
Two for the price of one?
Authors: Wyllie Mike
Published: December 2004

British Journal of Pharmacology (2005) 144, 1–2. doi:10.1038/sj.bjp.0706038
Prevention of progressive joint destruction in collagen‐induced arthritis in rats by a novel matrix metalloproteinase inhibitor, FR255031
Authors: Ishikawa Takeshi , Nishigaki Fusako , Miyata Susumu , Hirayama Yoshitaka , Minoura Kyoko , Imanishi Junko , Neya Masahiro , Mizutani Tsuyoshi , Imamura Yoshimasa , Naritomi Yoichi , Murai Hidetsugu , Ohkubo Yoshitaka , Kagayama Akira , Mutoh Seitaro
Published: December 2004

FR255031 (2‐[(7S)‐7‐[5‐(4‐ethylphenyl)‐2‐thienyl]‐1,1‐dioxido‐4‐(2‐pyridinylcarbonyl)hexahydro‐1,4‐thiazepin‐7‐yl]‐N‐hydroxyacetamide) is a novel synthetic matrix metalloproteinase (MMP) inhibitor that inhibits human collagenases (MMP‐1, MMP‐8 and MMP‐13), gelatinases (MMP‐2 and MMP‐9) and membrane type 1 MMP (MT1‐MMP/MMP‐14). FR255031 also inhibits rat collagenase and gelatinase. We studied the effect of FR255031 and Trocade, an inhibitor of collagenase and MMP‐14, on a rat collagen‐induced arthritis (CIA) model.

Rat CIA was induced by intradermal injection of type II collagen (IIC) and oral administration of FR255031 or Trocade was performed for 28 days. Body weight loss, hind paw swelling, elevation of serum anti‐IIC antibody, and histological and radiographic scores were evaluated.

FR255031 markedly inhibited cartilage degradation in a dose‐dependent manner in the CIA model, but Trocade failed to prevent the degradation.

FR255031 at a dose of 100 mg kg−1also had statistically significant effects on bone destruction and pannus formation and on the recovery of body weight loss on day 28.

These results indicate that FR255031 is effective for rat CIA, especially on joint cartilage destruction. These data suggest that as well as collagenases or MT‐MMP, gelatinases are also involved in joint destruction in arthritis.

British Journal of Pharmacology(2005)144, 133–143. doi:10.1038/sj.bjp.0706054
Positron emission tomography using 18F‐labelled endothelin‐1 reveals prevention of binding to cardiac receptors owing to tissue‐specific clearance by ETB receptors in vivo
Authors: Johnström Peter , Fryer Tim D , Richards Hugh K , Harris Neil G , Barret Olivier , Clark John C , Pickard John D , Davenport Anthony P
Published: December 2004

Our aim was to synthesise an 18F analogue of endothelin‐1 (ET‐1), to dynamically image ET receptors in vivo by positron emission tomography (PET) and to elucidate the function of the ETB subtype as a clearing receptor in organs expressing high densities including kidney and lung.

[18F]‐ET‐1 was characterised in vitro and bound with a single subnanomolar affinity (KD=0.43±0.05 nM, Bmax=27.8±2.1 fmol mg−1 protein) to human left ventricle (n=4).

The in vivo distribution of [18F]‐ET‐1 in anaesthetised rats was measured using a dedicated small animal PET scanner (microPET) and ex vivo analysis.

Dynamic PET data demonstrated that high levels of radioligand accumulated rapidly in the lung, kidney and liver, consistent with receptor binding. The in vivo distribution correlated with the anatomical localisation of receptors detected in vitro using [125I]‐ET‐1. However, the receptor density visualised in the heart was unexpectedly low compared with that predicted from the in vitro measurements.

[18F]‐ET‐1 binding in lungs could not be displaced by the ETB selective antagonist BQ788, in agreement with the proposed internalisation of ET‐1 by ETB receptors. In contrast, infusion of BQ788 prior to injecting [18F]‐ET‐1 significantly reduce the amount of radioligand visualised in the ETB rich lung and kidney by 85% (P<0.05, n=3) and 55% (P<0.05, n=3), respectively.

Under conditions of ETB receptor blockade, the heart could be visualised by microPET imaging.

These results suggest that clearance by ETB receptors in the lung and kidney prevents binding of ET‐1 to receptors in the heart.

British Journal of Pharmacology (2005) 144, 115–122. doi:10.1038/sj.bjp.0706064
Molecular cloning and characterization of ZFF29: a protein containing a unique Cys2His2 zinc-finger motif
Authors: ASANO Haruhiko , MURATE Takashi , NAOE Tomoki , SAITO Hidehiko , STAMATOYANNOPOULOS George
Published: December 2004

We have cloned a gene, ZFF29 (zinc-finger protein of human fetal liver erythroid cells 29), from human fetal liver erythroid cells. Two types of mature mRNA were identified and designated ZFF29a and ZFF29b. In human genome the ZFF29 gene is on chromosome 9q, and the two forms are splice variants. There is a unique transcription start site, which predicts major mRNAs composed of 2485 bases for ZFF29a and 1801 bases for ZFF29b. The anticipated mRNAs were demonstrated in K562 cells, but not in any adult human tissues examined by Northern blotting. In the mouse, reverse transcription–PCR revealed that the ZFF29 mRNA is present in adult bone marrow and ovary at a higher level than in any other tissues examined. These findings suggest that ZFF29 proteins are expressed in embryonic/fetal erythroid tissues. The deduced polypeptide chains of ZFF29a and ZFF29b are composed of 306 and 350 amino acids respectively. A unique zinc-finger motif composed of two contiguous Cys2His2-type fingers is common to both forms of ZFF29. They are nuclear proteins and ZFF29b, but not ZFF29a, is an activator of erythroid gene promoters.
IκBα (inhibitory κBα) identified as labile repressor of MnSOD (manganese superoxide dismutase) expression
Authors: KININGHAM Kelley K. , DAOSUKHO Chotiros , ST. CLAIR Daret K.
Published: December 2004

Cytokines, phorbol esters, radiation and chemotherapeutic drugs up-regulate the expression of MnSOD (manganese superoxide dismutase). Using the VA-13 cell line, we studied the regulation of SOD2 upon treatment with PMA. Pre-treatment with CHX (cycloheximide) followed by PMA led to significantly higher levels of MnSOD mRNA compared with those with either agent alone, suggesting de novo synthesis of an inhibitory protein. PMA treatment modulates redox-sensitive transcription factors, therefore we evaluated the effects of this combination treatment upon AP-1 (activator protein 1) and NF-κB (nuclear factor κB), two trans-acting factors suggested to play a role in SOD2 regulation. Co-administration of CHX and PMA led to a time-dependent increase in the binding activity of NF-κB. Therefore we evaluated IκBα (inhibitory κBα) and found that co-administration decreased its steady-state level compared with either agent alone, suggesting that enhanced NF-κB activation is due to inhibition of IκBα synthesis. PMA activates PKC (protein kinase C) enzymes which phosphorylate IκBα, leading to its degradation, therefore we used GF109203X to inhibit PKC activity. Stable transfection utilizing a PMA-responsive element in the human SOD2 gene, showed a concentration-dependent decrease in luciferase and NF-κB-binding activity with GF109203X. Western blot analysis indicated the presence of several PKC isoforms in the VA-13 cell line; however, PMA pre-treatment specifically down-regulated α and βI, suggesting a role for one or more of these proteins in SOD2 induction. Taken together, these results indicate that the PKC pathway leading to SOD2 induction proceeds at least in part through NF-κB and that inhibition of IκBα synthesis might serve as a potential pharmacological approach to up-regulate MnSOD.
Domain-specific characteristics of the bifunctional key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase
Authors: BLUME Astrid , WEIDEMANN Wenke , STELZL Ulrich , WANKER Erich E. , LUCKA Lothar , DONNER Peter , REUTTER Werner , HORSTKORTE Rüdiger , HINDERLICH Stephan
Published: December 2004

UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase is a bifunctional enzyme, which initiates and regulates sialic acid biosynthesis. Sialic acids are important compounds of mammalian glycoconjugates, mediating several biological processes, such as cell–cell or cell–matrix interactions. In order to characterize the function of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a number of deletion mutants were generated, lacking either parts of the N-terminal epimerase or the C-terminal kinase domain. N-terminal deletion of only 39 amino acids results in a complete loss of epimerase activity. Deletions in the C-terminal part result in a reduction or complete loss of kinase activity, depending on the size of the deletion. Deletions at either the N- or the C-terminus also result in a reduction of the other enzyme activity. These results indicate that a separate expression of both domains is possible, but that a strong intramolecular dependency of the two domains has arisen during evolution of the enzyme. N-terminal, as well as C-terminal, mutants tend to form trimers, in addition to the hexameric structure of the native enzyme. These results and yeast two-hybrid experiments show that structures required for dimerization are localized within the kinase domain, and a potential trimerization site is possibly located in a region between the two domains. In conclusion, our results reveal that the activities, as well as the oligomeric structure, of this bifunctional enzyme seem to be organized and regulated in a complex manner.
Farnesol is glucuronidated in human liver, kidney and intestine in vitro, and is a novel substrate for UGT2B7 and UGT1A1
Authors: STAINES Adam G. , SINDELAR Pavel , COUGHTRIE Michael W. H. , BURCHELL Brian
Published: December 2004

Farnesol is an isoprenoid found in many aromatic plants and is also produced in humans, where it acts on numerous nuclear receptors and has received considerable attention due to its apparent anticancer properties. Although farnesol has been studied for over 30 years, its metabolism has not been well characterized. Recently, farnesol was shown to be metabolized by cytochromes P450 in rabbit; however, neither farnesol hydroxylation nor glucuronidation in humans have been reported to date. In the present paper, we show for the first time that farnesol is metabolized to farnesyl glucuronide, hydroxyfarnesol and hydroxyfarnesyl glucuronide by human tissue microsomes, and we identify the specific human UGTs (uridine diphosphoglucuronosyltransferases) involved. Farnesol metabolism was examined by a sensitive LC (liquid chromatography)–MS/MS method. Results indicate that farnesol is a good substrate for glucuronidation in human liver, kidney and intestine microsomes (values in nmol/min per mg). Initial analysis using expressed human UGTs indicated that UGTs 1A1 and 2B7 were primarily responsible for glucuronidation in vitro, with significantly lower activity for all the other UGTs tested (UGTs 1A3, 1A4, 1A6, 1A9 and 2B4). Kinetic analysis and inhibition experiments indicate that, in liver microsomes, UGT1A1 is primarily responsible for farnesol glucuronidation; however, in intestine microsomes, UGT2B7 is probably the major isoform involved, with a very-low-micromolar Km. We also show the first direct evidence that farnesol can be metabolized to hydroxyfarnesol by human liver microsomes and that hydroxyfarnesol is metabolized further to hydroxyfarnesyl glucuronide. Thus glucuronidation may modulate the physiological and/or pharmacological properties of this potent signalling molecule.
Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3
Authors: MURRAY James T. , CAMPBELL David G. , MORRICE Nicholas , AULD Gillian C. , SHPIRO Natalia , MARQUEZ Rodolpho , PEGGIE Mark , BAIN Jenny , BLOOMBERG Graham B. , GRAHAMMER Florian , LANG Florian , WULFF Peer , KUHL Dietmar , COHEN Philip
Published: December 2004

We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by SGK1 (serum- and glucocorticoid-induced kinase 1), but not by protein kinase Bα, and identified it as NDRG2 (N-myc downstream-regulated gene 2). SGK1 phosphorylated NDRG2 at Thr330, Ser332 and Thr348in vitro. All three residues were phosphorylated in skeletal muscle from wild-type mice, but not from mice that do not express SGK1. SGK1 also phosphorylated the related NDRG1 isoform at Thr328, Ser330 and Thr346 (equivalent to Thr330, Ser332 and Thr348 of NDRG2), as well as Thr356 and Thr366. Residues Thr346, Thr356 and Thr366 are located within identical decapeptide sequences GTRSRSHTSE, repeated three times in NDRG1. These threonines were phosphorylated in NDRG1 in the liver, lung, spleen and skeletal muscle of wild-type mice, but not in SGK1−/− mice. Knock-down of SGK1 in HeLa cells using small interfering RNA also suppressed phosphorylation of the threonine residues in the repeat region of NDRG1. The phosphorylation of NDRG1 by SGK1 transformed it into an excellent substrate for GSK3 (glycogen synthase kinase 3), which could then phosphorylate Ser342, Ser352 and Ser362 in the repeat region. Incubation of HeLa cells with the specific GSK3 inhibitor CT 99021 increased the electrophoretic mobility of NDRG1 in HeLa cells, demonstrating that this protein is phosphorylated by GSK3 in cells. Our results identify NDRG1 and NDRG2 as physiological substrates for SGK1, and demonstrate that phosphorylation of NDRG1 by SGK1 primes it for phosphorylation by GSK3.
Identification of filamin C as a new physiological substrate of PKBα using KESTREL
Authors: MURRAY James T. , CAMPBELL David G. , PEGGIE Mark , ALFONSO Mora , COHEN Philip
Published: December 2004

We detected a protein in rabbit skeletal muscle extracts that was phosphorylated rapidly by PKBα (protein kinase Bα), but not by SGK1 (serum- and glucocorticoid-induced kinase 1), and identified it as the cytoskeletal protein FLNc (filamin C). PKBα phosphorylated FLNc at Ser2213in vitro, which lies in an insert not present in the FLNa and FLNb isoforms. Ser2213 became phosphorylated when C2C12 myoblasts were stimulated with insulin or epidermal growth factor, and phosphorylation was prevented by low concentrations of wortmannin, at which it is a relatively specific inhibitor of phosphoinositide 3-kinase. PD 184352 [an inhibitor of the classical MAPK (mitogen-activated protein kinase) cascade] and/or rapamycin [an inhibitor of mTOR (mammalian target of rapamycin)] had no effect. Insulin also induced the phosphorylation of FLNc at Ser2213 in cardiac muscle in vivo, but not in cardiac muscle that does not express PDK1 (3-phosphoinositide-dependent kinase 1), the upstream activator of PKB. These results identify the muscle-specific isoform FLNc as a new physiological substrate for PKB.
Expression and refolding of Omp38 from Burkholderia pseudomallei and Burkholderia thailandensis, and its function as a diffusion porin
Authors: SIRITAPETAWEE Jaruwan , PRINZ Heino , KRITTANAI Chartchai , SUGINTA Wipa
Published: December 2004

In the present paper, we describe cloning and expression of two outer membrane proteins, BpsOmp38 (from Burkholderia pseudomallei) and BthOmp38 (from Burkholderia thailandensis) lacking signal peptide sequences, using the pET23d(+) expression vector and Escherichia coli host strain Origami(DE3). The 38 kDa proteins, expressed as insoluble inclusion bodies, were purified, solubilized in 8 M urea, and then subjected to refolding experiments. As seen on SDS/PAGE, the 38 kDa band completely migrated to ∼110 kDa when the purified monomeric proteins were refolded in a buffer system containing 10% (w/v) Zwittergent® 3-14, together with a subsequent heating to 95 °C for 5 min. CD spectroscopy revealed that the 110 kDa proteins contained a predominant β-sheet structure, which corresponded completely to the structure of the Omp38 proteins isolated from B. pseudomallei and B. thailandensis. Immunoblot analysis using anti-BpsOmp38 polyclonal antibodies and peptide mass analysis by MALDI–TOF (matrix-assisted laser-desorption ionization–time-of-flight) MS confirmed that the expressed proteins were BpsOmp38 and BthOmp38. The anti-BpsOmp38 antibodies considerably exhibited the inhibitory effects on the permeation of small sugars through the Omp38-reconstituted liposomes. A linear relation between relative permeability rates and Mr of neutral sugars and charged antibiotics suggested strongly that the in vitro re-assembled Omp38 functioned fully as a diffusion porin.
From Arab Land to ‘Israel Lands’: The Legal Dispossession of the Palestinians Displaced by Israel in the Wake of 1948
Authors: Forman Geremy , Kedar Alexandre (Sandy)
Published: December 2004

In this paper we examine the Israeli government's use of law to institutionalize the dispossession of Palestinian Arabs displaced by the 1948 war and trace the legal transformation of their land during the formative years of Israel's land regime (1948–60). This legal transformation facilitated the expropriation and reallocation of formerly Arab land to primarily Jewish hands and was therefore a central component of the legal reordering of space within Israel after 1948. Based on close examination of Israeli legislation, archival documents, Knesset proceedings, and other sources we delineate a 12-year legislative process consisting of four phases, each concluding with the enactment of major legislation. The process was led by senior and second-tier Israeli officials, and the result was the construction of a new Israeli legal geography. The culmination of the process was the integration of appropriated Arab land into the country's new system of Jewish-Israeli ‘national land’ known as ‘Israel Lands’.
Tracing Displacements: Or Evictions in the Nomosphere
Authors: Delaney David
Published: December 2004

In this paper I sketch some of the practical connections between two kinds of displacement: experiential–material displacement and discursive or metaphorical displacement. I examine these connections in the context of legal struggles over the eviction of families from public housing. The evictions were authorized on the basis of interpretations of the Anti-Drug Abuse Act of 1988 (the “One Strike and You're Out” law) which allows public-housing authorities to evict blameless tenants if anyone in their family had been convicted of drug possession. The paper introduces a neologism, “the nomosphere”, and offers suggestions as to its utility for advancing the project of critical legal geography.
Anxious Reconciliation(s): Unsettling Foundations and Spatializing History
Authors: Bhandar Brenna
Published: December 2004

In this paper I explore the relationship between law, history, and reconciliation in the Canadian context. I argue that linear, teleological forms of history are employed by courts to continually reiterate the myth of a legitimate assertion of colonial sovereignty. By doing so, any potential for political transformation that lies in the objective of reconciliation is stunted; political challenges brought in the form of aboriginal rights claims are folded back into the existing political, economic, and juridical structures of the nation-state. I conclude with an examination of how spatializing history in a nonlinear, nonteleological way could open up possibilities for political change and transformation.
The Global E-rotic Subject, the Ban, and the Prostitute-Free Zone: Sex Work and the Theory of Differential Exclusion
Authors: Sanchez Lisa E
Published: December 2004

In this paper I analyze questions of displacement and exclusion through the lens of sexual commerce and its regulation. Using three frames of analysis, including a historical reading of the figure of the prostitute in Western law and culture, an analysis of a model exclusionary zoning law, the ‘Prostitution-free Zone Ordinance’, and a reflection upon the changing position of sex workers within heavily mediated contemporary networks of global e-rotic commerce, I argue that the prostitute is an originary figure of exclusion relative to homo sacer, the masculine sacred outlaw, who is an originary figure of displacement. I bracket popular themes of agency, resistance, and performance to interrogate a disturbing reactionary trend: just as important strides have been made in constituting sex workers and performers as rights-bearing legal subjects and workers, we see a reconfiguration of sexual labor through globalization and technology that renders incomprehensible any traditional subject of labor and rights, and a resurgence of legal and regulatory strategies of total exclusion or banishment. I conclude by positing a theory of ‘differential exclusion’ to describe the positioning of similarly situated sex workers relative to constructions of legality. In contrast to the theory of differential inclusion, which argues that groups are organized differentially and hierarchically through the notion of biopower, according to the relative value of their labor at any given historical moment, the theory of differential exclusion focuses on those groups whose labor is disacknowledged entirely, and who are consequently organized relative to categories of criminality and to their exclusion as subjects of labor and biopower. The work emphasizes both the critical importance and the difficulty of conceiving novel discourses and strategies for achieving worker status and human rights for women and men working in all segments of the sex industry.
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features
Authors: Proks Peter , Antcliff Jennifer F. , Lippiat Jon , Gloyn Anna L. , Hattersley Andrew T. , Ashcroft Frances M.
Published: December 2004

Inwardly rectifying potassium channels (Kir channels) control cell membrane K
+
fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (
KCNJ11
), the pore-forming subunit of the ATP-sensitive (K
ATP
) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in
Xenopus
oocytes. All mutations increased resting whole-cell K
ATP
currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K
ATP
currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased K
ATP
currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K
ATP
currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.
Molecular and genetic analysis of disseminated neoplastic cells in lymphangioleiomyomatosis
Authors: Crooks Denise M. , Pacheco-Rodriguez Gustavo , DeCastro Rosamma M. , McCoy J. Philip , Wang Ji-an , Kumaki Fumiyuki , Darling Thomas , Moss Joel
Published: December 2004

Lymphangioleiomyomatosis (LAM) is a multisystem disorder of women, characterized by cystic degeneration of the lungs, renal angiomyolipomas (AML), and lymphatic abnormalities. LAM lesions result from the proliferation of benign-appearing, smooth muscle-like LAM cells, which are characterized by loss of heterozygosity (LOH) of one of the tuberous sclerosis complex (TSC) genes. LAM cells are believed to migrate among the involved organs. Because of the apparently metastatic behavior of LAM, we tried to isolate LAM cells from body fluids. A cell fraction separated by density gradient centrifugation from blood had
TSC2
LOH in 33 of 60 (55%) LAM patients. Cells with
TSC2
LOH were also found in urine from 11 of 14 (79%) patients with AML and in chylous fluid from 1 of 3 (33%) patients. Identification of LAM cells with
TSC2
LOH in body fluids was not correlated with severity of lung disease or extrapulmonary involvement and was found in one patient after double lung transplantation. These studies are compatible with a multisite origin for LAM cells. They establish the existence of disseminated, potentially metastatic LAM cells through a relatively simple, noninvasive procedure that should be valuable for molecular and genetic studies of somatic mutations in LAM and perhaps other metastatic diseases.
Catalysis of protein folding by chaperones in pathogenic bacteria
Authors: Bann James G. , Pinkner Jerome S. , Frieden Carl , Hultgren Scott J.
Published: December 2004

Molecular chaperones are thought to inhibit off-pathway interactions such as aggregation from occurring without influencing the on-pathway formation of native structure. Here, we present a mechanism whereby the family of PapD-like chaperones, which are involved in the formation of adhesive pili in pathogenic bacteria, function by suppressing aggregation while simultaneously catalyzing the folding of subunits that make up the pilus. We also show that the Arg-8 residue, invariant in the cleft of all known PapD-like chaperones, makes up part of the active site of the chaperone. The data argue for a temporal mechanism of catalyzed folding. The terminal carboxylate group of a pilus subunit anchors to the active site of the chaperone by hydrogen bonding. This bonding spatially fixes the COOH terminus of the subunit in the correct context for β-sheet formation, using the edge of the NH
2
-terminal domain of the chaperone as a nucleation site.
The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na
+
transport
Authors: Náray-Fejes-Tóth Anikó , Snyder Peter M. , Fejes-Tóth Géza
Published: December 2004

WNK1 belongs to a unique family of Ser/Thr kinases that have been implicated in the control of blood pressure. Intronic deletions in the
WNK1
gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. How overexpression of WNK1 leads to Na
+
retention and hypertension is not entirely clear. Similarly, there is no information on the hormonal regulation of expression of WNK kinases. There are two main WNK1 transcripts expressed in the kidney: the originally described “long” WNK1 and a shorter transcript that is specifically expressed in the kidney (KS-WNK1). The goal of this study was to determine the effect of aldosterone, the main hormonal regulator of Na
+
homeostasis, on the transcription of WNK1 isoforms in renal target cells, by using an unique mouse cortical collecting duct cell line that stably expresses functional mineralocorticoid receptors. Our results demonstrate that aldosterone, at physiological concentrations, rapidly induces the expression of the KS-WNK1 but not that of the long-WNK1 in these cells. Importantly, stable overexpression of KS-WNK1 significantly increases transepithelial Na
+
transport in cortical collecting duct cells. Similarly, coexpression of KS-WNK1 and the epithelial Na
+
channel in Fischer rat thyroid epithelial cells also stimulates Na
+
current, suggesting that KS-WNK1 affects the subcellular location or activity but not the expression of epithelial Na
+
channel. These observations suggest that stimulation of KS-WNK1 expression might be an important element of aldosterone-induced Na
+
retention and hypertension.
Inhaling to mitigate exhaled bioaerosols
Authors: Edwards David A. , Man Jonathan C. , Brand Peter , Katstra Jeffrey P. , Sommerer K. , Stone Howard A. , Nardell Edward , Scheuch Gerhard
Published: December 2004

Humans commonly exhale aerosols comprised of small droplets of airway-lining fluid during normal breathing. These “exhaled bioaerosols” may carry airborne pathogens and thereby magnify the spread of certain infectious diseases, such as influenza, tuberculosis, and severe acute respiratory syndrome. We hypothesize that, by altering lung airway surface properties through an inhaled nontoxic aerosol, we might substantially diminish the number of exhaled bioaerosol droplets and thereby provide a simple means to potentially mitigate the spread of airborne infectious disease independently of the identity of the airborne pathogen or the nature of any specific therapy. We find that some normal human subjects expire many more bioaerosol particles than other individuals during quiet breathing and therefore bear the burden of production of exhaled bioaerosols. Administering nebulized isotonic saline to these “high-producer” individuals diminishes the number of exhaled bioaerosol particles expired by 72.10 ± 8.19% for up to 6 h.
In vitro
and
in vivo
experiments with saline and surfactants suggest that the mechanism of action of the nebulized saline relates to modification of the physical properties of the airway-lining fluid, notably surface tension.
Consideration of the bioavailability of iron in the North American Great Lakes: Development of novel approaches toward understanding iron biogeochemistry
Authors: McKay R. Michael L. , Bullerjahn George S. , Porta David , Brown Erik T. , Sherrell Robert M. , Smutka Tanya M. , Sterner Robert W. , Twiss Michael R. , Wilhelm Steven W.
Published: December 2004

There is increasing recognition that iron distribution and availability is significant in terms of global oceanic production. Low availability of iron and other nutritive trace metals may also constrain productivity in the North American Great Lakes. Despite its importance, the biogeochemistry of iron in the water column of lacustrine systems remains poorly characterized. In addressing the current state of iron biogeochemistry, a workshop organized a decade ago at the Bermuda Biological Station for Research brought together a cross-disciplinary team of chemists and biologists who sought to synthesize current knowledge and identify research priorities in this field. Key among goals identified during the workshop, and one that remains today for the most part unfulfilled, was to ‘develop techniques to quantify those fractions of Fe that are accessible to phytoplankton.’ Here we review recent progress toward meeting this objective, drawing on specific examples from Lake Superior where these approaches have been applied.
Escaping from the straitjacket: UK MPs and their e‐newsletters
Authors: Jackson Nigel
Published: December 2004

Members of Parliament (MPs) want to communicate their ideas, messages and activities to their constituents. Within the modern political campaigning era the central party organisation has dominated most political communication through its control of national media management. As a result many MPs have sought to reach constituents via their local media. The rise of the post‐modern era has encouraged many MPs to consider unmediated communication via the internet. E‐newsletters represent a mechanism by which MPs can reduce their reliance on party hierarchies and journalists to communicate with constituents. This article will look at the growth of e‐newsletters, and whether certain factors make some MPs more likely than others to provide an e‐newsletter. The findings suggest that e‐newsletters are a slow‐moving bandwagon, with MPs in marginal seats and certain parties more likely to hop on, but that MPs have not yet escaped from the straitjacket of the centrally controlled campaign.