bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiscale simulations of tropospheric chemistry in the eastern Pacific and on the U.S. West Coast during spring 2002
Authors: Tang Youhua , Carmichael Gregory R. , Horowitz Larry W. , Uno Itsushi , Woo Jung‐Hun , Streets David G. , Dabdub Donald , Kurata Gakuji , Sandu Adrian , Allan James , Atlas Elliot , Flocke Franck , Huey Lewis Gregory , Jakoubek Roger O. , Millet Dylan B. , Quinn Patricia K. , Roberts James M. , Worsnop Douglas R. , Goldstein Allen , Donnelly Stephen , Schauffler Sue , Stroud Verity , Johnson Kristen , Avery Melody A. , Singh Hanwant B. , Apel Eric C.
Published: July 2004

Regional modeling analysis for the Intercontinental Transport and Chemical Transformation 2002 (ITCT 2K2) experiment over the eastern Pacific and U.S. West Coast is performed using a multiscale modeling system, including the regional tracer model Chemical Weather Forecasting System (CFORS), the Sulfur Transport and Emissions Model 2003 (STEM‐2K3) regional chemical transport model, and an off‐line coupling with the Model of Ozone and Related Chemical Tracers (MOZART) global chemical transport model. CO regional tracers calculated online in the CFORS model are used to identify aircraft measurement periods with Asian influences. Asian‐influenced air masses measured by the National Oceanic and Atmospheric Administration (NOAA) WP‐3 aircraft in this experiment are found to have lower ΔAcetone/ΔCO, ΔMethanol/ΔCO, and ΔPropane/ΔEthyne ratios than air masses influenced by U.S. emissions, reflecting differences in regional emission signals. The Asian air masses in the eastern Pacific are found to usually be well aged (>5 days), to be highly diffused, and to have low NOy levels. Chemical budget analysis is performed for two flights, and the O3 net chemical budgets are found to be negative (net destructive) in the places dominated by Asian influences or clear sites and positive in polluted American air masses. During the trans‐Pacific transport, part of gaseous HNO3 was converted to nitrate particle, and this conversion was attributed to NOy decline. Without the aerosol consideration, the model tends to overestimate HNO3 background concentration along the coast region. At the measurement site of Trinidad Head, northern California, high‐concentration pollutants are usually associated with calm wind scenarios, implying that the accumulation of local pollutants leads to the high concentration. Seasonal variations are also discussed from April to May for this site. A high‐resolution nesting simulation with 12‐km horizontal resolution is used to study the WP‐3 flight over Los Angeles and surrounding areas. This nested simulation significantly improved the predictions for emitted and secondary generated species. The difference of photochemical behavior between the coarse (60‐km) and nesting simulations is discussed and compared with the observation.
Tropical tropopause parameters derived from GPS radio occultation measurements with CHAMP
Authors: Schmidt T. , Wickert J. , Beyerle G. , Reigber C.
Published: July 2004

The temperature structure in the tropical upper troposphere and lower stratosphere (UTLS) region is discussed based on Global Positioning System (GPS) radio occultation (RO) data from the German CHAMP (CHAllenging Minisatellite Payload) satellite mission. Several climatologies for tropopause parameters based on radiosonde data and model analyses have been published in recent years. Both data sources suffer either from low global coverage or poor vertical resolution. The GPS RO technique, on the other hand, is characterized by global coverage, high vertical resolution, all‐weather viewing, and long‐term stability. CHAMP RO data are available since February 2001. Since May 2001, up to 200 high‐ resolution temperature profiles per day are available. The temperature bias between CHAMP temperature profiles and radiosonde data as well as ECMWF analyses is less than 0.5 K between 300–30 hPa. On the basis of the May 2001 to November 2003 data set of CHAMP RO data the structure and temporal and spatial variability of the tropical tropopause based on several tropopause definitions (thermal and cold‐point tropopause) are discussed. This includes an overview of the global tropopause characteristics, the discussion of the annual cycle and the latitudinal‐longitudinal structure of the tropical tropopause. In the CHAMP RO temperature data, clear evidence of the stratospheric quasi‐biennial oscillation (QBO) was found. The goal of this study is to show the potential of GPS RO for global monitoring of the temperature demonstrated exemplarily for the tropical UTLS region and based on the first 31 months (as of November 2003) of CHAMP RO data.
Propagating behavior of rectangular waveguide loaded with dissipative magnetic slab by using new algorithm
Authors: Tian Yu‐Bo , Qian Jian , Guo Wen‐Feng
Published: July 2004

Propagating constants of rectangular waveguide loaded with dissipative slab obey complex transcendental equation, of which the property of multiroot and the dependence of modes on those roots often make people puzzled, especially for dissipative magnetic materials in an asymmetrically filling situation. An effective new algorithm combining Genetic Algorithm (GA) with Parameter Tracking Scheme (PTS) and Dynamic Searching Area (DSA) technique is developed. By using the algorithm, the propagating constants of waveguide symmetrically or asymmetrically loaded with dissipative magnetic slab are solved successfully and tightly linked to certain designated modes. The results also reveal some interesting phenomena, such as for some high‐order modes and certain thickness of loaded slab, the negative phase velocity may occur.
A Sun‐to‐Mud Education in Two Weeks
Authors: Simpson Sarah
Published: July 2004

Hands‐on computer simulations and interactive teaching give students at the CISM summer school an intensive tour of the entire space weather system.
Long-chain saturated fatty acids induce annexin II translocation to detergent-resistant membranes
Authors: ZHAO Hong , HARDY Robert W.
Published: July 2004

DRM (detergent-resistant membranes), which are resistant to solublization by non-ionic detergents, have been demonstrated to be involved in many key cell functions such as signal transduction, endocytosis and cholesterol trafficking. Covalent modification of proteins by fatty acylation has been proposed to be an important protein-targeting mechanism for DRM association. However, little is known concerning the effects of LCSFA (long-chain saturated fatty acids) on protein composition of DRM in human cancer cells. In the present study, we found that, in Hs578T human breast cancer cells, the major protein increased in DRM in response to the LCSFA stearate (C18:0) was annexin II. Our results demonstrated that annexin II accumulated in DRM specifically in response to physiological concentrations of stearate and palmitate (C16:0), but not long-chain unsaturated fatty acids, in a time- and concentration-dependent manner. This process was reversible and dependent on cholesterol and intracellular calcium. Although calcium was necessary for this translocation, it was not sufficient to induce the annexin II translocation to DRM. We also demonstrate that stearate induced the acylation of caveolin but not that of annexin II. Association of annexin II with caveolin, although not necessarily direct, specifically occurs in DRM in response to stearate. Finally, bromostearate, a stearate analogue that effectively blocks protein acylation, does not induce annexin II translocation to DRM. We conclude that exogenously added LCSFA strongly induces the translocation of annexin II to DRM in Hs578T human breast cancer cells at least partially by association with acylated caveolin.
The vaccinia virus-stimulated mitogen-activated protein kinase (MAPK) pathway is required for virus multiplication
Authors: ANDRADE Anderson A. , SILVA Patrícia N. G. , PEREIRA Anna C. T. C. , de SOUSA Lirlândia P. , FERREIRA Paulo C. P. , GAZZINELLI Ricardo T. , KROON Erna G. , ROPERT Catherine , BONJARDIM Cláudio A.
Published: July 2004

Early events play a decisive role in virus multiplication. We have shown previously that activation of MAPK/ERK1/2 (mitogen-activated protein kinase/extracellular-signal-regulated kinase 1/2) and protein kinase A are pivotal for vaccinia virus (VV) multiplication [de Magalhães, Andrade, Silva, Sousa, Ropert, Ferreira, Kroon, Gazzinelli and Bonjardim (2001) J. Biol. Chem. 276, 38353–38360]. In the present study, we show that VV infection provoked a sustained activation of both ERK1/2 and RSK2 (ribosomal S6 kinase 2). Our results also provide evidence that this pattern of kinase activation depends on virus multiplication and ongoing protein synthesis and is maintained independently of virus DNA synthesis. It is noteworthy that the VGF (VV growth factor), although involved, is not essential for prolonged ERK1/2 activation. Furthermore, our findings suggest that the VV-stimulated ERK1/2 activation also seems to require actin dynamics, microtubule polymerization and tyrosine kinase phosphorylation. The VV-stimulated pathway MEK/ERK1/2/RSK2 (where MEK stands for MAPK/ERK kinase) leads to phosphorylation of the ternary complex factor Elk-1 and expression of the early growth response (egr-1) gene, which kinetically paralleled the kinase activation. The recruitment of this pathway is biologically relevant, since its disruption caused a profound effect on viral thymidine kinase gene expression, viral DNA replication and VV multiplication. This pattern of sustained kinase activation after VV infection is unique. In addition, by connecting upstream signals generated at the cytoskeleton and by tyrosine kinase, the MEK/ERK1/2/RSK2 cascade seems to play a decisive role not only at early stages of the infection, i.e. post-penetration, but is also crucial to define the fate of virus progeny.
Intracellular transport of human lysosomal α-mannosidase and α-mannosidosis-related mutants
Authors: HANSEN Gaute , BERG Thomas , RIISE STENSLAND Hilde M. F. , HEIKINHEIMO Pirkko , KLENOW Helle , EVJEN Gry , NILSSEN Øivind , TOLLERSRUD Ole K.
Published: July 2004

Human LAMAN (lysosomal α-mannosidase) was synthesized as a 120 kDa precursor in transfected COS cells [African-green-monkey kidney cells], which was partly secreted as a single-chain form and partly sorted to the lysosomes being subsequently cleaved into three peptides of 70, 40 and 15 kDa respectively. Both the secreted and the lysosomal forms contained endo H (endoglucosidase H)-resistant glycans, suggesting a common pathway through the trans-Golgi network. A fraction of LAMAN was retained intracellularly as a single-chain endo H-sensitive form, probably in the ER (endoplasmic reticulum). The inherited lack of LAMAN causes the autosomal recessive storage disease α-mannosidosis. To understand the biochemical consequences of the disease-causing mutations, 11 missense mutations and two in-frame deletions were introduced into human LAMAN cDNA by in vitro mutagenesis and the resulting proteins were expressed in COS cells. Some selected mutants were also expressed in Chinese-hamster ovary cells. T355P (Thr355→Pro), P356R, W714R, R750W and L809P LAMANs as well as both deletion mutants were misfolded and arrested in the ER as inactive single-chain forms. Six of the mutants were transported to the lysosomes, either with less than 5% of normal specific activity (H72L, D196E/N and R220H LAMANs) or with more than 30% of normal specific activity (E402K LAMAN). F320L LAMAN resulted in much lower activity in Chinese-hamster ovary cells when compared with COS cells. Modelling into the three-dimensional structure revealed that the mutants with highly reduced specific activities contained substitutions of amino acids involved in the catalysis, either co-ordinating Zn2+ (His72 and Asp196), stabilizing the active-site nucleophile (Arg220) or positioning the active-site residue Asp319 (Phe320).
Differential signalling for enhanced hexose uptake by interleukin (IL)-3 and IL-5 in male germ cells
Authors: RAUCH M. Cecilia , BRITO Mónica , ZAMBRANO Angara , ESPINOZA Mónica , PÉREZ Marisol , YAÑEZ Alejandro , RIVAS Coralia I. , SLEBE Juan Carlos , VERA Juan Carlos , CONCHA Ilona I.
Published: July 2004

We studied the expression and function of the IL (interleukin)-3 and IL-5 family of receptors in male germ cells. RT (reverse transcription)-PCR showed expression of mRNAs encoding the α and β subunits of the IL-3 and IL-5 receptors in human testis, and the presence of IL-3 and IL-5 receptors α and β proteins was confirmed by immunoblotting with anti-α and anti-β antibodies. The immunolocalization studies showed expression of these receptors in the germ line in the human testis and in human and bovine ejaculated spermatozoa. Functional studies with bull spermatozoa indicated that IL-3 signalled for increased uptake of hexoses in these cells at picomolar concentrations compatible with expression of functional high-affinity IL-3 receptors in these cells. In contrast, IL-5 failed to induce increased hexose uptake in bull spermatozoa. Experiments using HL-60 eosinophils that express functional IL-3 and IL-5 receptors confirmed that IL-3, but not IL-5, signalled for increased hexose uptake. Our findings suggest that differential signalling for increased hexose uptake by heteromeric high-affinity IL-3 and IL-5 receptors in mammalian spermatozoa is a property that depends on the identity of the α-subunit forming part of the αβ-complex and is not a property specific to the germ cells.
Control of expression of the lectin-like protein Reg-1 by gastrin: role of the Rho family GTPase RhoA and a C-rich promoter element
Authors: ASHCROFT Felicity J. , VARRO Andrea , DIMALINE Rod , DOCKRAY Graham J.
Published: July 2004

The expression of members of the Reg family of secreted lectin-like proteins is increased in response to stress, inflammation and damage in many tissues. In the stomach, Reg is located in enterochromaffin-like cells, where its expression is stimulated by the gastric hormone gastrin. We have examined the mechanisms by which gastrin stimulates expression of Reg-1. Deletional mutations of 2.1 to 0.1 kb of the rat Reg-1 promoter in a luciferase reporter vector were transiently transfected into gastric cancer AGS-GR cells. All promoter fragments tested showed similar relative increases in luciferase expression in response to gastrin (1 nM). The response to gastrin of the smallest (104 bp) construct was 4.2±0.4-fold over basal. These responses were reduced by Ro-32-0432, a protein kinase C inhibitor, by C3-transferase, a Clostridium botulinum toxin and a selective inhibitor of the Rho family GTPase RhoA, and by co-transfection with a dominant negative form of RhoA. Co-transfection with a constitutively active form of RhoA stimulated expression 11.6±1.7-fold over basal. Mutations through the 104 bp construct identified a C-rich element (C−79CCCTCCC−72) required for responses to gastrin, PKC (protein kinase C) and L63RhoA (the constitutively active form of human RhoA protein containing a glutamine-to-leucine substitution at position 63). EMSAs (electrophoretic-mobility-shift assays) using nuclear extracts of control and gastrin-stimulated AGS-GR cells and a probe spanning −86 to −64 bp revealed multiple binding proteins. There was no effect of gastrin on the pattern of binding. Supershift assays indicated that transcription factors Sp1 and Sp3 bound the C-rich sequence. We conclude that gastrin stimulates Reg expression via activation of PKC and RhoA, that a C-rich region (−79 to −72) is critical for the response and that Sp-family transcription factors bind to this region of the promoter.
The water- and salt-stress-regulated Asr1 (abscisic acid stress ripening) gene encodes a zinc-dependent DNA-binding protein
Authors: KALIFA Yossi , GILAD Ayelet , KONRAD Zvia , ZACCAI Michele , SCOLNIK Pablo A. , BAR-ZVI Dudy
Published: July 2004

Tomato (Lycopersicon esculantum) ASR1 (abscisic acid stress ripening protein), a small plant-specific protein whose cellular mode of action defies deduction based on its sequence or homology analyses, is one of numerous plant gene products with unknown biological roles that become over-expressed under water- and salt-stress conditions. Steady-state cellular levels of tomato ASR1 mRNA and protein are transiently increased following exposure of plants to poly(ethylene glycol), NaCl or abscisic acid. Western blot and indirect immunofluorescence analysis with anti-ASR1 antibodies demonstrated that ASR1 is present both in the cytoplasmic and nuclear subcellular compartments; approx. one-third of the total ASR1 protein could be detected in the nucleus. Nuclear ASR1 is a chromatin-bound protein, and can be extracted with 1 M NaCl, but not with 0.5% Triton X-100. ASR1, overexpressed in Escherichia coli and purified to homogeneity, possesses zinc-dependent DNA-binding activity. Competitive-binding experiments and SELEX (systematic evolution of ligands by exponential enrichment) analysis suggest that ASR1 binds at a preferred DNA sequence.
Regio- and stereo-chemical oxidation of linoleic acid by human myoglobin and hydrogen peroxide: Tyr103 affects rate and product distribution
Authors: RAYNER Benjamin S. , STOCKER Roland , LAY Peter A. , WITTING Paul K.
Published: July 2004

Mb (myoglobin) plus H2O2 catalyses the oxidation of various substrates via a peroxidase-like activity. A Y103F (Tyr103→Phe) variant of human Mb has been constructed to assess the effect of exchanging an electron-rich oxidizable amino acid on the peroxidase activity of human Mb. Steady-state analyses of reaction mixtures containing Y103F Mb, purified linoleic acid and H2O2 revealed a lower total yield of lipid oxidation products than mixtures containing the wild-type protein, consistent with the reported decrease in the rate constant for reaction of Y103F Mb with H2O2 [Witting, Mauk and Lay (2002) Biochemistry 41, 11495–11503]. Irrespective of the Mb employed, lipid oxidation yielded 9(R/S)-HODE [9(R,S)-hydroxy-10E,12Z-octadecadienoic acid] in preference to 13(R/S)-HODE [13(R,S)-hydroxy-9Z,11E-octadecadienoic acid], while 9- and 13-keto-octadecadienoic acid were formed in trace amounts. However, lipid oxidation by the Y103F variant of Mb proceeded with a lower Vmax value and an increased Km value relative to the wild-type control. Consistent with the increased Km, the product distribution from reactions with Y103F Mb showed decreased selectivity compared with the wild-type protein, as judged by the decreased yield of 9(S)-relative to 9(R)-HODE. Together, these data verify that Tyr103 plays a significant role in substrate binding and orientation in the haem pocket of human Mb. Also, the midpoint potential for the Fe(III)/(II) one-electron reduction was shifted slightly, but significantly, to a higher potential, confirming the importance of Tyr103 to the hydrogen-bonding network involving residues that line the haem crevice of human Mb.
Selective binding to transthyretin and tetramer stabilization in serum from patients with familial amyloidotic polyneuropathy by an iodinated diflunisal derivative
Authors: ALMEIDA Maria Rosário , MACEDO Bárbara , CARDOSO Isabel , ALVES Isabel , VALENCIA Gregorio , ARSEQUELL Gemma , PLANAS Antoni , SARAIVA Maria João
Published: July 2004

In familial amyloidotic polyneuropathy, TTR (transthyretin) variants are deposited as amyloid fibrils. It is thought that this process involves TTR tetramer dissociation, which leads to partially unfolded monomers that aggregate and polymerize into amyloid fibrils. This process can be counteracted by stabilization of the tetramer. Several small compounds, such as diclofenac, diflunisal and flufenamic acid, have been reported to bind to TTR in vitro, in the T4 (thyroxine) binding channel that runs through the TTR tetramer, and consequently are considered to stabilize TTR. However, if these agents bind plasma proteins other than TTR, decreased drug availability will occur, compromising their use as therapeutic agents for TTR amyloidosis. In the present work, we compared the action of these compounds and of new derivatives designed to increase both selectivity of binding to TTR and inhibitory potency in relation to TTR amyloid fibril formation. We found two diflunisal derivatives that, in contrast with diclofenac, flufenamic acid and diflunisal, displaced T4 from TTR in plasma preferentially over binding to albumin and thyroxine binding globulin. The same diflunisal derivatives also had a stabilizing effect on TTR tetramers in plasma, as studied by isoelectric focusing of whole plasma under semi-denaturing conditions. In addition, by transmission electron microscopy, we demonstrated that, in contrast with other proposed TTR stabilizers (namely diclofenac, flufenamic acid and diflunisal), one of the diflunisal derivatives tested efficiently inhibited TTR aggregation. Taken together, our ex vivo and in vitro studies present evidence for the selectivity and efficiency of novel diflunisal derivates as TTR stabilizers and as inhibitors of fibril formation.
Suppression of matrix metalloproteinase-9 transcription by transforming growth factor-β is mediated by a nuclear factor-κB site
Authors: OGAWA Kenji , CHEN Feifei , KUANG Chenzhong , CHEN Yan
Published: July 2004

TGF-β (transforming growth factor-β) plays a critical role in modulating the inflammatory response and other biological processes through its regulation of the production of MMPs (matrix metalloproteinases). In both Mono-Mac-6 and RAW264.7 monocyte/macrophage cells, TGF-β abrogated lipopolysaccharide-induced increases in the enzymic activity and mRNA level of MMP-9. A fragment of the human MMP-9 promoter was used to characterize its regulation by TGF-β signalling. In RAW264.7 cells, TGF-β or its downstream signalling protein, Smad3 (Sma- and Mad-related protein 3), inhibited lipopolysaccharide-stimulated promoter activity. The suppressive activity of TGF-β on the MMP-9 promoter was abrogated by an inhibitory Smad, Smad7. The MMP-9 promoter contains a putative TIE (TGF-β inhibitory element). However, neither mutation nor deletion of the TIE had any effect on the inhibitory activity of TGF-β on MMP-9 transcription, indicating that the consensus TIE is not required for this effect of TGF-β. Analysis using a series of deletion mutants of the MMP-9 promoter revealed that a region containing a consensus NF-κB (nuclear factor-κB) site is required for the basal activity and TGF-β-mediated suppression of the promoter. Mutation of the putative NF-κB site not only markedly reduced the basal transcriptional activity of the promoter, but also abrogated the responsiveness of the promoter to TGF-β. In addition, a minimal promoter containing one copy of the NF-κB sequence was responsive to TGF-β treatment. Furthermore, an electrophoretic mobility shift assay was performed with the nuclear extracts from RAW264.7 cells, and it was found that TGF-β treatment did not disrupt the binding of NF-κB p50 and p65 proteins to the NF-κB sequence. Taken together, these studies indicate that the NF-κB site is indispensable for the suppressive activity of TGF-β in the regulation of MMP-9 transcription.
Human hereditary glutathione synthetase deficiency: kinetic properties of mutant enzymes
Authors: NJÅLSSON Runa , CARLSSON Katarina , BHANSALI Vikas , LUO Jia-Li , NILSSON Lennart , LADENSTEIN Rudolf , ANDERSON Mary , LARSSON Agne , NORGREN Svante
Published: July 2004

Patients with hereditary glutathione synthetase deficiency suffer from haemolytic anaemia, 5-oxoprolinuria, metabolic acidosis, recurrent bacterial infections and various degrees of central nervous system dysfunction. To investigate the molecular basis of the mutations associated with this disease, seven naturally occurring missense mutations [L188P (Leu188→Pro), D219A, D219G, Y270C, Y270H, R283C and P314L] were expressed using a His-tagged, Escherichia coli-based expression system. Effects of the mutations on kinetic properties, including negative co-operative binding of γ-glutamyl substrate, were evaluated. The mutation P314L did not have any major effect on these parameters and was classified as a neutral mutation. The remaining mutations decreased Vmax to 2–27% of wild-type activity. Negative co-operativity for γ-gluABA (L-γ-glutamyl-L-α-aminobutyric acid) was abolished in five mutant recombinant enzymes, whereas for one mutant enzyme, this co-operativity changed from negative to positive. The structural consequences of the mutations were interpreted on the basis of the known structure of the wild-type enzyme.
Restoration of sterol-regulatory-element-binding protein-1c gene expression in HepG2 cells by peroxisome-proliferator-activated receptor-γ co-activator-1α
Authors: OBERKOFLER Hannes , SCHRAML Elisabeth , KREMPLER Franz , PATSCH Wolfgang
Published: July 2004

The expression of SREBP-1 (sterol-regulatory-element-binding protein-1) isoforms differs between tissues and cultured cell lines in that SREBP-1a is the major isoform in established cell lines, whereas SREBP-1c predominates in liver and most other human tissues. SREBP-1c is transcriptionally less active than SREBP-1a, but is a main mediator of hepatic insulin action and is selectively up-regulated by LXR (liver X receptor) agonists. LXR-mediated transactivation is co-activated by PGC-1α (peroxisome-proliferator-activated receptor-γ co-activator-1α), which displays deficient expression in skeletal-muscle-derived cell lines. In the present paper, we show that PGC-1α expression is also deficient in HepG2 cells and in a human brown adipocyte cell line (PAZ6). In transient transfection studies, PGC-1α selectively amplified the LXR-mediated transcription from the human SREBP-1c promoter in HepG2 and PAZ6 cells via two LXR-response elements with extensive similarity to the respective murine sequence. Mutational analysis showed that the human LXR-response element-1 (hLXRE-1) was essential for co-activation of LXR-mediated SREBP-1c gene transcription by PGC-1α. Ectopic overexpression of PGC-1α in HepG2 cells enhanced basal SREBP-1c and, to a lesser extent, -1a mRNA expression, but only SREBP-1c expression was augmented further in an LXR/RXR (retinoic X receptor)-dependent fashion, thereby inducing mRNA abundance levels of SREBP-1c target genes, fatty acid synthase and acetyl-CoA carboxylase. These results indicate that PGC-1α contributes to the regulation of SREBP-1 gene expression, and can restore the SREBP-1 isoform expression pattern of HepG2 cells to that of human liver.
Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide
Authors: BUFLER Philip , GAMBONI-ROBERTSON Fabia , AZAM Tania , KIM Soo-Hyun , DINARELLO Charles A.
Published: July 2004

IL-1F7b, a novel homologue of the IL-1 (interleukin 1) family, was discovered by computational cloning. We demonstrated that IL-1F7b shares critical amino acid residues with IL-18 and binds to the IL-18-binding protein enhancing its ability to inhibit IL-18-induced interferon-γ. We also showed that low levels of IL-1F7b are constitutively present intracellularly in human blood monocytes. In this study, we demonstrate that similar to IL-18, both mRNA and intracellular protein expression of IL-1F7b are up-regulated by LPS (lipopolysaccharide) in human monocytes. In stable transfectants of murine RAW264.7 macrophage cells, there was no IL-1F7b protein expression despite a highly active CMV promoter. We found that IL-1F7b-specific mRNA was rapidly degraded in transfected cells, via a 3′-UTR (untranslated region)-independent control of IL-1F7b transcript stability. After LPS stimulation, there was a rapid transient increase in IL-1F7b-specific mRNA and concomitant protein levels. Using sequence alignment, we found a conserved ten-nucleotide homology box within the open reading frame of IL-F7b, which is flanking the coding region instability elements of some selective genes. In-frame deletion of downstream exon 5 from the full-length IL-1F7b cDNA markedly increased the levels of IL-1F7b mRNA. A similar coding region element is located in IL-18. When transfected into RAW264.7 macrophages, IL-18 mRNA was also unstable unless treated with LPS. These results indicate that both IL-1F7b and IL-18 mRNA contain functional instability determinants within their coding region, which influence mRNA decay as a novel mechanism to regulate the expression of IL-1 family members.
Crystal structure of NS-134 in complex with bovine cathepsin B: a two-headed epoxysuccinyl inhibitor extends along the entire active-site cleft
Authors: ŠTERN Igor , SCHASCHKE Norbert , MORODER Luis , TURK Dušan
Published: July 2004

The crystal structure of the inhibitor NS-134 in complex with bovine cathepsin B reveals that functional groups attached to both sides of the epoxysuccinyl reactive group bind to the part of active-site cleft as predicted. The -Leu-Pro-OH side binds to the primed binding sites interacting with the His110 and His111 residues with its C-terminal carboxy group, whereas the -Leu-Gly-Meu (-Leu-Gly-Gly-OMe) part (Meu, methoxycarbonylmethyl) binds along the non-primed binding sites. Comparison with the propeptide structures of cathepsins revealed that the binding of the latter part is least similar to the procathepsin B structure; this result, together with the two-residue shift in positioning of the Leu-Gly-Gly part, suggests that the propeptide structures of the cognate enzymes may not be the best starting point for the design of reverse binding inhibitors.
The second RNA-binding domain of the human splicing factor ASF/SF2 is the critical domain controlling adenovirus E1A alternative 5′-splice site selection
Authors: DAUKSAITE Vita , AKUSJÄRVI Göran
Published: July 2004

The human splicing factor ASF/SF2 (alternative splicing factor/splicing factor 2) is modular in structure with two RNA-binding domains (RBD1 and RBD2) and a C-terminal domain rich in arginine–serine dipeptide repeats. ASF/SF2 is an essential splicing factor that also functions as an important regulator of alternative splicing. In adenovirus E1A (early region 1A) alternative pre-mRNA splicing, ASF/SF2 functions as a strong inducer of proximal 5′-splice-site selection, both in vitro and in vivo. In the present study, we tested the functional role of individual domains of ASF/SF2 in alternative splicing in vitro. We show that ASF/SF2-RBD2 is the critical domain controlling E1A alternative splicing. In fact, RBD2 alone is sufficient to mimic the activity of the full-length ASF/SF2 protein as an inducer of proximal 5′-splice-site selection in vitro. The RBD2 domain induces a switch to E1A-proximal 5′-splice-site usage by repressing distal 12 S splicing and simultaneously stimulates proximal 13 S splicing. In contrast, the ASF/SF2-RBD1 domain has a more general splicing enhancer phenotype and appears to stimulate preferentially cap-proximal 5′-splice-site selection. Furthermore, the SWQDLKD motif, which is conserved in all SR proteins (serine/arginine-rich proteins) containing two RBDs, and the ribonucleoprotein-1-type RNA recognition motif were both found to be necessary for the alternative splice-site-switching activity of ASF/SF2. The RNP-1 motif was necessary for efficient RNA binding, whereas the SWQDLKD motif most probably contributes by functioning as a surface-mediating critical protein–protein contact during spliceosome assembly.
Bounds on the dragging rate of slowly and differentially rotating relativistic stars
Authors: Pareja M. J.
Published: July 2004

For relativistic stars rotating slowly and differentially with a positive angular velocity, some properties in relation to the positiveness of the rate of rotational dragging and of the angular momentum density are derived. Moreover, the proof for the bounds on the rotational mass-energy, which we have generalized (outside the slow rotation limit) in a previous paper, is briefly exposed.
Laser-guided focusing of intense relativistic electron beams for fast ignition
Authors: Winterberg F.
Published: July 2004

As an alternative to the fast ignition by petawatt lasers of small spherical deuterium–tritium (DT) targets compressed to thousand times solid density, the fast ignition by terawatt relativistic electron beams of thin cylindrical (or conical) DT targets, compressed to several ten times solid density and magnetized to 108 G through a high current discharge along the cylindrical axis of the targets, has been proposed. One problem of this approach is the guiding and focusing of the relativistic electron beam onto the target. It is proposed to transport the beam through a laser-triggered ionized channel in a low density background gas, or by letting it propagate along the surface of a thin wire crossing the diode gap, with the final focusing done by repulsive image currents in a conducting convergent cone. A second problem is the stopping of the electron beam in the target. This can hopefully be done by a combination of classical electron stopping power, the electrostatic two-stream instability and collisionless shocks in the presence of a strong perpendicular magnetic field.
Balian–Low phenomenon for subspace Gabor frames
Authors: Gabardo Jean-Pierre , Han Deguang
Published: July 2004

In this work, the Balian–Low theorem is extended to Gabor (also called Weyl–Heisenberg) frames for subspaces and, more particularly, its relationship with the unique Gabor dual property for subspace Gabor frames is pointed out. To achieve this goal, the subspace Gabor frames which have a unique Gabor dual of type I (resp. type II) are defined and characterized in terms of the Zak transform for the rational parameter case. This characterization is then used to prove the Balian–Low theorem for subspace Gabor frames. Along the same line, the same characterization is used to prove a duality theorem for the unique Gabor dual property which is an analogue of the Ron and Shen duality theorem.
Scaling of forced magnetic reconnection in the Hall-magnetohydrodynamical Taylor problem with arbitrary guide field
Authors: Fitzpatrick Richard
Published: July 2004

Two-dimensional, nonlinear, Hall-magnetohydrodynamical (MHD) numerical simulations are used to investigate the scaling of the rate of forced magnetic reconnection in the so-called Taylor problem. In this problem, a small amplitude boundary perturbation is suddenly applied to a tearing stable, slab plasma equilibrium. The perturbation is such as to drive magnetic reconnection within the plasma. This type of reconnection, which is not due to an intrinsic plasma instability, is generally termed “forced reconnection.” Hall effects are found to greatly accelerate the rate of magnetic reconnection, relative to the well-known Sweet–Parker rate. In the nonlinear Hall-MHD regime with arbitrary guide field, the peak reconnection rate is found to be independent of the resistivity, and to scale like dψ/dt∼[β/(1+β)]3/4di3/2Ⅺ02, where β is the plasma beta calculated using the guide field, di the collisionless ion skin depth, and Ⅺ0 the amplitude of the boundary perturbation.
Dirac theory within the Standard-Model Extension
Authors: Lehnert Ralf
Published: July 2004

The modified Dirac equation in the Lorentz-violating Standard-Model Extension (SME) is considered. Within this framework, the construction of a Hermitian Hamiltonian to all orders in the Lorentz-breaking parameters is investigated, discrete symmetries and the first-order roots of the dispersion relation are determined, and various properties of the eigenspinors are discussed.
Nonlinear canonical transformations in classical and quantum mechanics
Authors: Brodlie Alastair
Published: July 2004

p-mechanics is a consistent physical theory which describes both classical and quantum mechanics simultaneously through the representation theory of the Heisenberg group. In this paper we describe how nonlinear canonical transformations affect p-mechanical observables and states. Using this we show how canonical transformations change a quantum mechanical system. We seek an operator on the set of p-mechanical observables which corresponds to the classical canonical transformation. In order to do this we derive a set of integral equations which when solved will give us the coherent state expansion of this operator. The motivation for these integral equations comes from the work of Moshinsky and a variety of collaborators. We consider a number of examples and discuss the use of these equations for non-bijective transformations.
Linear and nonlinear investigation of a coaxial-waveguide cyclotron autoresonance maser amplifier
Authors: Zhang Shi-Chang
Published: July 2004

A different concept of gyrodevices in the form of a coaxial-waveguide cyclotron autoresonance maser (CARM) is proposed. Embodying the salient features of large cross-sectional area, low guiding magnetic field, and good mode selectivity as compared to the gyrotron and to the conventional CARM, the proposed device is well suited for operation at both high power and ultrahigh gain in the millimeter wave and far infrared regions. Gyrokinetic analysis and nonlinear simulation are given in detail for a coaxial configuration—with outer and inner radii of 1.83 and 0.50 cm—designed to operate in the TE28,16 mode at 335 GHz, yielding a gain of 64 dB on using a 90 keV and 50 A electron beam confined by a 9.35 T magnetic field. Nonlinear simulation demonstrates the possibility of power enhancement via a tapered magnetic field. The competition of the degenerate mode and the excitation of the absolute instability are discussed.
Magnetically insulated electron flow with ions with application to the rod-pinch diode
Authors: Oliver B. V. , Ottinger P. F. , Genoni T. C. , Schumer J. W. , Strasburg S. , Swanekamp S. B. , Cooperstein G.
Published: July 2004

A one-dimensional, steady-state, relativistic electron-flow model is developed that describes magnetically insulated electron flow in the presence of ions produced by space-charge-limited emission from the anode. The model is applied to the rod-pinch diode which is a cylindrical pinched-beam diode consisting of a small radius anode rod extending through the hole of an annular cathode. The diode is designed to run at critical current so that electrons emitted from the cathode are magnetically insulated and flow axially along the anode rod until they pinch radially onto the rod tip. Ions are emitted along the length of rod and flow radially outward. Without these ions, magnetically insulated electron flow cannot be established and electrons cannot propagate to the rod tip. Both fluid and Vlasov treatments of the electrons are considered. An analytic expression for the critical current is derived and is compared with the critical current determined from experimental data and particle-in-cell simulations. Reasonable agreement is obtained when the electron flow is nonlaminar, suggesting that a significant radial electron pressure is required to correctly describe the flow.
Loss of locus coeruleus neurons and reduced startle in parkin null mice
Authors: von Coelln Rainer , Thomas Bobby , Savitt Joseph M. , Lim Kah Leong , Sasaki Masayuki , Hess Ellen J. , Dawson Valina L. , Dawson Ted M.
Published: July 2004

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized pathologically by degeneration of catecholaminergic neurons of the substantia nigra pars compacta and locus coeruleus, among other regions. Autosomal-recessive juvenile Parkinsonism (ARJP) is caused by mutations in the PARK2 gene coding for parkin and constitutes the most common familial form of PD. The majority of ARJP-associated parkin mutations are thought to be loss of function-mutations; however, the pathogenesis of ARJP remains poorly understood. Here, we report the generation of parkin null mice by targeted deletion of parkin exon 7. These mice show a loss of catecholaminergic neurons in the locus coeruleus and an accompanying loss of norepinephrine in discrete regions of the central nervous system. Moreover, there is a dramatic reduction of the norepinephrine-dependent startle response. The nigrostriatal dopaminergic system does not show any impairment. This mouse model will help gain a better understanding of parkin function and the mechanisms underlying parkin-associated PD.
Wild chimpanzee dentition and its implications for assessing life history in immature hominin fossils
Authors: Zihlman Adrienne , Bolter Debra , Boesch Christophe
Published: July 2004

Data from three African field sites onPan troglodytesdemonstrate an unambiguous pattern of a slower growth rate in wild vs. captive chimpanzee populations. A revised dental growth chronology for chimpanzees is similar to estimated timing ofHomo erectusand therefore has implications for interpreting life history in hominins.
The voltage-gated Na
+
channel Na
V
BP has a role in motility, chemotaxis, and pH homeostasis of an alkaliphilic
Bacillus
Authors: Ito Masahiro , Xu Haoxing , Guffanti Arthur A. , Wei Yi , Zvi Lior , Clapham David E. , Krulwich Terry A.
Published: July 2004

The prokaryotic voltage-gated Na
+
channel, NaChBac, is one of a growing channel superfamily of unknown function. Here we show that Na
V
BP, the NaChBac homologue encoded by
ncbA
in alkaliphilic
Bacillus pseudofirmus
OF4, is a voltage-gated Na
+
channel potentiated by alkaline pH. Na
V
BP has roles in motility, chemotaxis, and pH homeostasis at high pH. Reduced motility of bacteria lacking functional Na
V
BP was reversed by restoration of the native channel but not by a mutant Na
V
BP engineered to be Ca
2+
-selective. Motile
ncbA
mutant cells and wild-type cells treated with a channel inhibitor exhibited behavior opposite to the wild type in response to chemoeffectors. Mutants lacking functional Na
V
BP were also defective in pH homeostasis in response to a sudden alkaline shift in external pH under conditions in which cytoplasmic [Na
+
] is limiting for this crucial process. The defect was exacerbated by mutation of
motPS
, the motility channel genes. We hypothesize that activation of Na
V
BP at high pH supports diverse physiological processes by a combination of direct and indirect effects on the Na
+
cycle and the chemotaxis system.
Niche tradeoffs, neutrality, and community structure: A stochastic theory of resource competition, invasion, and community assembly
Authors: Tilman David
Published: July 2004

Stochastic niche theory resolves many of the differences between neutral theory and classical tradeoff-based niche theories of resource competition and community structure. In stochastic niche theory, invading species become established only if propagules can survive stochastic mortality while growing to maturity on the resources left unconsumed by established species. The theory makes three predictions about community structure. First, stochastic niche assembly creates communities in which species dominate approximately equally wide “slices” of the habitat's spatial heterogeneity. These niche widths generate realistic distributions of species relative abundances for which, contrary to neutral theory but consistent with numerous observations, there are strong correlations among species traits, species abundances, and environmental conditions. Second, slight decreases in resource levels are predicted to cause large decreases in the probability that a propagule would survive to be an adult. These decreases cause local diversity to be limited by the inhibitory effects of resource use by established species on the establishment (recruitment) of potential invaders. If resource pulses or disturbance allowed invaders to overcome this recruitment limitation, many more species could indefinitely coexist. Third, the low invasibility of high diversity communities is predicted to result not from diversity
per se
, but from the uniformly low levels of resources that occur in high-diversity communities created by stochastic competitive assembly. This prediction provides a potential solution to the invasion paradox, which is the tendency for highly diverse regions to be more heavily invaded.
Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD1d-restricted T cells
Authors: Fischer Karsten , Scotet Emmanuel , Niemeyer Marcus , Koebernick Heidrun , Zerrahn Jens , Maillet Sophie , Hurwitz Robert , Kursar Mischo , Bonneville Marc , Kaufmann Stefan H. E. , Schaible Ulrich E.
Published: July 2004

A group of T cells recognizes glycolipids presented by molecules of the CD1 family. The CD1d-restricted natural killer T cells (NKT cells) are primarily considered to be self-reactive. By employing CD1d-binding and T cell assays, the following structural parameters for presentation by CD1d were defined for a number of mycobacterial and mammalian lipids: two acyl chains facilitated binding, and a polar head group was essential for T cell recognition. Of the mycobacterial lipids tested, only a phosphatidylinositol mannoside (PIM) fulfilled the requirements for CD1d binding and NKT cell stimulation. This PIM activated human and murine NKT cells via CD1d, thereby triggering antigen-specific IFN-γ production and cell-mediated cytotoxicity, and PIM-loaded CD1d tetramers identified a subpopulation of murine and human NKT cells. This phospholipid, therefore, represents a mycobacterial antigen recognized by T cells in the context of CD1d.
Enhanced TCR-induced Apoptosis in Interferon Regulatory Factor 4–deficient CD4+ Th Cells
Authors: Lohoff Michael , Mittrücker Hans-Willi , Brüstle Anne , Sommer Frank , Casper Bärbel , Huber Magda , Ferrick David A. , Duncan Gordon S. , Mak Tak W.
Published: July 2004

Transcription factors of the interferon regulatory factor (IRF) family contribute to the regulation of cell proliferation and apoptosis. Here, we show that CD4+ T helper (Th) cells lacking IRF4 (IRF4−/−) are highly sensitive to apoptosis. After infection of IRF4−/− mice with the protozoan parasite Leishmania major, the lesion-draining lymph nodes developed the prototypic lymphadenopathy of wild-type mice after 4 wk, but demonstrated almost total loss of cellularity and enhanced apoptosis after 7 wk. In vitro, activation of IRF4−/− CD4+ Th cells led to greatly increased apoptosis compared with wild-type cells. Coculture of IRF4−/− and IRF4+/+ CD4+ cells did not increase survival of IRF4−/− CD4+ cells, indicating that the enhanced rate of IRF4−/− Th cell apoptosis was neither transferable nor due to lack of a cytokine. Enhanced CD4+ cell apoptosis was also observed after anti-CD95 mAb treatment, despite normal CD95 expression. Removal of endogenous cytokines, notably interleukin (IL)-4, led to increased and equally high levels of IRF4−/− and IRF4+/+ cell apoptosis, whereas the protective activity of exogenous IL-4 was reduced in IRF4−/− CD4+ cells despite normal expression of the IL-4 receptor. Therefore, IRF4 is central in protecting CD4+ cells against proapoptotic stimuli.
Global Survey of Chromatin Accessibility Using DNA Microarrays
Authors: Weil M. Ryan , Widlak Piotr , Minna John D. , Garner Harold R.
Published: July 2004

An increasing number of studies indicate a central role for chromatin remodeling in the regulation of gene expression. Current methods for high-resolution studies of the relationship between chromatin accessibility and transcription are low throughput, making a genome-wide study impractical. To enable the simultaneous measurement of the global chromatin accessibility state at the resolution of single genes, we developed the Chromatin Array technique, in which chromatin is separated by its condensation state using either the solubility differences of mono- and oligonucleosomes in specific buffers or controlled DNase I digestion and selection of the large refractory (condensed) DNA fragments. By probing with a comparative genomic hybridization style microarray, we can determine the condensation state of thousands of individual loci and correlate this with transcriptional activity. Applying this technique to the breast tumor model cell line, MCF7, we found that when the condensation is homogeneous in the population of cells, expression is inversely proportional to the level of accessibility and the two methods of accessibility-based target selection correlate well. Using functional annotation and comparative genomic hybridization data, we have begun to decipher the possible biological implications of the relationship between chromatin accessibility and expression.