bluuebunny/crossref_metadata_2025 huggingface dataset:
Receptor-binding residues lie in central regions of Duffy-binding–like domains involved in red cell invasion and cytoadherence by malaria parasites
Authors: Mayor Alfredo , Bir Nivedita , Sawhney Ritica , Singh Shailja , Pattnaik Priyabrata , Singh Saurabh Kumar , Sharma Amit , Chitnis Chetan E.
Published: September 2004

Erythrocyte invasion by malaria parasites and cytoadherence of Plasmodium falciparum-infected erythrocytes to host capillaries are 2 key pathogenic mechanisms in malaria. The receptor-binding domains of erythrocyte-binding proteins (EBPs) such as Plasmodium falciparum EBA-175, which mediate invasion, and P falciparum erythrocyte membrane protein 1 (PfEMP-1) family members, which are encoded by var genes and mediate cytoadherence, have been mapped to conserved cysteine-rich domains referred to as Duffy-binding–like (DBL) domains. Here, we have mapped regions within DBL domains from EBPs and PfEMP-1 that contain receptor-binding residues. Using biochemical and molecular methods we demonstrate that the receptor-binding residues of parasite ligands that bind sialic acid on glycophorin A for invasion as well as complement receptor-1 and chondroitin sulfate A for cytoadherence map to central regions of DBL domains. In contrast, binding to intercellular adhesion molecule 1 (ICAM-1) requires both the central and terminal regions of DBLβC2 domains. Determination of functional regions within DBL domains is the first step toward understanding the structure-function bases for their interaction with diverse host receptors.
Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections
Authors: Paul REL , Lafond T , Müller-Graf CDM , Nithiuthai S , Brey PT , Koella JC
Published: September 2004

Background

Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia) and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections.

Results

Whereas there was a trade-off between transmission success and virulence as defined by host mortality, contradictory clone-specific patterns occurred when defining virulence by anaemia. A negative relationship between anaemia and transmission success was found for one of the parasite clones, whereas there was no relationship for the other. Notably the two parasite clones also differed in a transmission phenotype (gametocyte sex ratio) that has previously been shown to respond adaptively to a changing blood environment. In addition, as predicted by evolutionary theory, mixed infections resulted in increased anaemia. The increased anaemia was, however, not correlated with any discernable parasite trait (e.g. parasite density) or with increased transmission.

Conclusions

We found some evidence supporting the hypothesis that there is an adaptive basis correlating virulence (as defined by host mortality) and transmission success in malaria parasites. This confirms the validity of applying evolutionary virulence theory to biomedical research and adds support to the prediction that partially effective vaccines may select for increasingly virulent malaria parasite strains. By contrast, there was no consistent correlation between transmission and sub-lethal anaemia, a more common outcome of malaria infection. However, overall, the data are not inconsistent with the recent proposal that sub-lethal effects may impose an upper limit on virulence. Moreover, clone specific differences in transmission phenotypes linked to anaemia do suggest that there is considerable adaptive potential relating anaemia and transmission that may lead to uncertain consequences following intervention strategies.
A method for detecting and correcting feature misidentification on expression microarrays
Authors: Tu I-Ping , Schaner Marci , Diehn Maximilian , Sikic Branimir I , Brown Patrick O , Botstein David , Fero Michael J
Published: September 2004

Background

Much of the microarray data published at Stanford is based on mouse and human arrays produced under controlled and monitored conditions at the Brown and Botstein laboratories and at the Stanford Functional Genomics Facility (SFGF). Nevertheless, as large datasets based on the Stanford Human array began to accumulate, a small but significant number of discrepancies were detected that required a serious attempt to track down the original source of error. Due to a controlled process environment, sufficient data was available to accurately track the entire process leading to up to the final expression data. In this paper, we describe our statistical methods to detect the inconsistencies in microarray data that arise from process errors, and discuss our technique to locate and fix these errors.

Results

To date, the Brown and Botstein laboratories and the Stanford Functional Genomics Facility have together produced 40,000 large-scale (10–50,000 feature) cDNA microarrays. By applying the heuristic described here, we have been able to check most of these arrays for misidentified features, and have been able to confidently apply fixes to the data where needed. Out of the 265 million features checked in our database, problems were detected and corrected on 1.3 million of them.

Conclusion

Process errors in any genome scale high throughput production regime can lead to subsequent errors in data analysis. We show the value of tracking multi-step high throughput operations by using this knowledge to detect and correct misidentified data on gene expression microarrays.
Dam inactivation in Neisseria meningitidis: prevalence among diverse hyperinvasive lineages
Authors: Jolley Keith A , Sun Li , Moxon E Richard , Maiden Martin CJ
Published: September 2004

Background

DNA adenine methyltransferase (Dam) activity is absent in many, but not all, disease isolates of Neisseria meningitidis, as a consequence of the insertion of a restriction endonuclease-encoding gene, the 'dam replacing gene' (drg) at the dam locus. Here, we report the results of a survey to assess the prevalence of drg in a globally representative panel of disease-associated meningococci.

Results

Of the known meningococcal hyper-invasive lineages investigated, drg was absent in all representatives of the ST-8 and ST-11 clonal complexes tested, but uniformly present in the representatives of the other hyper-invasive lineages present in the isolate collection (the ST-1, ST-4, ST-5, ST-32 and ST-41/44 clonal complexes). The patterns of sequence diversity observed in drg were consistent with acquisition of this gene from a source organism with a different G+C content, at some time prior to the emergence of present-day meningococcal clonal complexes, followed by spread through the meningococcal population by horizontal genetic exchange. During this spread a number of alleles have arisen by mutation and intragenic recombination.

Conclusion

These findings are consistent with the idea that possession of the drg gene may contribute to the divergence observed among meningococcal clonal complexes, but does not have a direct mechanistic involvement in virulence.
Plasticity of histamine H3receptor expression and binding in the vestibular nuclei after labyrinthectomy in rat
Authors: Lozada Adrian F , Aarnisalo Antti A , Karlstedt Kaj , Stark Holger , Panula Pertti
Published: September 2004

Background

In rat, deafferentation of one labyrinth (unilateral labyrinthectomy) results in a characteristic syndrome of ocular and motor postural disorders (e.g., barrel rotation, circling behavior, and spontaneous nystagmus). Behavioral recovery (e.g., diminished symptoms), encompassing 1 week after unilateral labyrinthectomy, has been termed vestibular compensation. Evidence suggesting that the histamine H3 receptor plays a key role in vestibular compensation comes from studies indicating that betahistine, a histamine-like drug that acts as both a partial histamine H1 receptor agonist and an H3 receptor antagonist, can accelerate the process of vestibular compensation.

Results

Expression levels for histamine H3 receptor (total) as well as three isoforms which display variable lengths of the third intracellular loop of the receptor were analyzed using in situ hybridization on brain sections containing the rat medial vestibular nucleus after unilateral labyrinthectomy. We compared these expression levels to H3 receptor binding densities.

Total H3 receptor mRNA levels (detected by oligo probe H3X) as well as mRNA levels of the three receptor isoforms studied (detected by oligo probes H3A, H3B, and H3C) showed a pattern of increase, which was bilaterally significant at 24 h post-lesion for both H3X and H3C, followed by significant bilateral decreases in medial vestibular nuclei occurring 48 h (H3X and H3B) and 1 week post-lesion (H3A, H3B, and H3C). Expression levels of H3B was an exception to the forementioned pattern with significant decreases already detected at 24 h post-lesion. Coinciding with the decreasing trends in H3 receptor mRNA levels was an observed increase in H3 receptor binding densities occurring in the ipsilateral medial vestibular nuclei 48 h post-lesion.

Conclusion

Progressive recovery of the resting discharge of the deafferentated medial vestibular nuclei neurons results in functional restoration of the static postural and occulomotor deficits, usually occurring within a time frame of 48 hours in rats. Our data suggests that the H3 receptor may be an essential part of pre-synaptic mechanisms required for reestablishing resting activities 48 h after unilateral labyrinthectomy.
The FK506 binding protein 13 kDa (FKBP13) interacts with the C-chain of complement C1q
Authors: Neye Holger , Verspohl Eugen J
Published: September 2004

Background

The pharmacological action of specific immunosuppressants is mediated by immunophilins. While cyclosporin A binds to cyclophilins, FK506/tacrolimus, rapamycin, and others bind to FK506 binding proteins (FKBPs). Different physiological actions of immunophilins were described but their genuine function, however, remains elusive and is still under investigation. A yeast two-hybrid screen was performed using the FK506 binding protein 13 kDa (FKBP13) as a bait and a fetal liver expression library as a prey.

Results

The C-chain of complement C1q (C1q-C) was detected to interact with FKBP13 in the yeast two-hybrid system and in a protein complementation assay. Neither FKBP12, FKBP25, FKBP52 nor the unrelated immunophilin CypA did react with C1q-C in the yeast system stressing the specificity of the interaction. Binding of C1q-C to FKBP13 could not be prevented in the presence of FK506, demonstrating that possibly other regions than the binding pocket of the drug are responsible for the interaction of the two proteins.

Conclusion

It is concluded that exclusively FKBP13 but no other FKBPs tested so far interact with the C-chain of complement C1q in the two different assays and further work will be initiated to investigate the physiological relevance of the interaction.
ISSR and AFLP analysis of the temporal and spatial population structure of the post-fire annual, Nicotiana attenuata, in SW Utah
Authors: Bahulikar Rahul A , Stanculescu Dominic , Preston Catherine A , Baldwin Ian T
Published: September 2004

Background

The native annual tobacco, Nicotiana attenuata, is found primarily in large ephemeral populations (typically for less than 3 growing seasons) after fires in sagebrush and pinyon-juniper ecosystems and in small persistent populations (for many growing seasons) in isolated washes typically along roadsides throughout the Great Basin Desert of the SW USA. This distribution pattern is due to its unusual germination behavior. Ephemeral populations are produced by the germination of dormant seeds from long-lived seed banks which are stimulated to germinate by a combination of unidentified positive cues found in wood smoke and the removal of inhibitors leached from the unburned litter of the dominant vegetation. Persistent populations may result where these inhibitors do not exist, as in washes or along disturbed roadsides. To determine if this germination behavior has influenced population structure, we conducted an AFLP (244 individuals), ISSR (175 individuals) and ISSR+ AFLP (175 individuals) analysis on plants originating from seed collected from populations growing in 11 wash and burns over 11 years from the SW USA.

Results

Genetic variance as measured by both ISSR and AFLP markers was low among sites and comparatively higher within populations. Cluster analysis of the Utah samples with samples collected from Arizona, California, and Oregon as out-groups also did not reveal patterns. AMOVA analysis of the combined AFLP and ISSR data sets yielded significantly low genetic differentiation among sites (Φct), moderate among populations within sites (Φsc) and higher genetic differentiation within populations (Φst).

Conclusions

We conclude that the seed dormancy of this post-fire annual and its resulting age structure in conjunction with natural selection processes are responsible for significantly low among sites and comparatively high within-population genetic variation observed in this species.
Immunological evaluation of the new stable ultrasound contrast agent LK565: a phase one clinical trial
Authors: Funke B , Maerz HK , Okorokow S , Polata S , Lehmann I , Sack U , Wild P , Geisler T , Zotz RJ
Published: September 2004

Background

Ultrasound contrast agents (UCAs) allow the enhancement of vascular definition, thereby providing more diagnostic information. LK565 is a new second-generation UCA based on synthetic polymers of aspartic acid which is eliminated from the blood stream via phagocytosis. LK565 forms very stable air-filled microspheres and is capable of repeated passage through the pulmonary capillary bed after peripheral intravenous injection. This characteristic allows examination of the cardiac function or extracardiac vessel abnormalities up to 15 minutes.

Methods

A phase one clinical study was conducted on 15 healthy volunteers to identify the development of an undesirable immune response. Phagocytosis capacity, TNF-α secretion, and MHC class II upregulation of monocytes was monitored, as well as microsphere specific antibody development (IgM, IgG). Furthermore, the kinetics of the activation surface markers CD69, CD25, CD71, and CD11b on leukocytes were analyzed.

Results

Due to LK565-metabolism the administration of the UCA led to saturation of phagocytes which was reversible after 24 hrs. Compared to positive controls neither significant TNF-α elevation, neither MHC class II and activation surface markers upregulation, nor specific antibody development was detectable.

Conclusion

The administration of LK565 provides a comfortable duration of signal enhancement, esp. in echocardiography, without causing a major activation cascade or triggering an adaptive immune response. To minimize the risk of undesirable adverse events such as anaphylactoid reactions, immunological studies should be included in clinical trials for new UCAs. The use of LK565 as another new ultrasound contrast agent should be encouraged as a safe means to provide additional diagnostic information.
Protein-polymer nano-machines. Towards synthetic control of biological processes
Authors: Pennadam Sivanand S , Firman Keith , Alexander Cameron , Górecki Dariusz C
Published: September 2004

The exploitation of nature's machinery at length scales below the dimensions of a cell is an exciting challenge for biologists, chemists and physicists, while advances in our understanding of these biological motifs are now providing an opportunity to develop real single molecule devices for technological applications. Single molecule studies are already well advanced and biological molecular motors are being used to guide the design of nano-scale machines. However, controlling the specific functions of these devices in biological systems under changing conditions is difficult. In this review we describe the principles underlying the development of a molecular motor with numerous potential applications in nanotechnology and the use of specific synthetic polymers as prototypic molecular switches for control of the motor function. The molecular motor is a derivative of a TypeI Restriction-Modification (R-M) enzyme and the synthetic polymer is drawn from the class of materials that exhibit a temperature-dependent phase transition.

The potential exploitation of single molecules as functional devices has been heralded as the dawn of new era in biotechnology and medicine. It is not surprising, therefore, that the efforts of numerous multidisciplinary teams [1, 2]. have been focused in attempts to develop these systems. as machines capable of functioning at the low sub-micron and nanometre length-scales [3]. However, one of the obstacles for the practical application of single molecule devices is the lack of functional control methods in biological media, under changing conditions. In this review we describe the conceptual basis for a molecular motor (a derivative of a TypeI Restriction-Modification enzyme) with numerous potential applications in nanotechnology and the use of specific synthetic polymers as prototypic molecular switches for controlling the motor function [4].
Fusion of green fluorescent protein to the C-terminus of granulysin alters its intracellular localization in comparison to the native molecule
Authors: Hanson Dennis A , Ziegler Steven F
Published: September 2004

The engineering of green fluorescent protein (GFP) fusion constructs in order to visibly tag a protein of interest has become a commonly used cell biology technique. Although caveats to this approach are obvious, literature reports in which the chimeric molecule behaves differently than the native molecule are scant. This brief report describes one such case. Granulysin, a small lytic and antimicrobial protein produced by cytotoxic lymphocytes, traffics to the regulated secretory system and is subsequently released from cells upon proper stimulus. In an attempt to elucidate mechanisms by which it accumulates in and is released from cytolytic granules, GFP was fused to the C-terminus of granulysin and expressed in an NK cell line. A control construct expressing the native protein was similarly expressed. The data demonstrate that, while the fusion protein is expressed and secreted, its subcellular localization is altered in comparison to native granulysin. Thus, the addition of GFP to the C-terminus of granulysin obscures the signal(s) that cytotoxic lymphocytes use to sort it to the regulated secretory pathway despite its normal biosynthesis and secretion. This example is offered as a cautionary account for other researchers who contemplate using this technology.
Stabilin-1 localizes to endosomes and the trans-Golgi network in human macrophages and interacts with GGA adaptors
Authors: Kzhyshkowska Julia , Gratchev Alexei , Martens Jan-Henning , Pervushina Olga , Mamidi Srinivas , Johansson Sophie , Schledzewski Kai , Hansen Berit , He Xiangyuan , Tang Jordan , Nakayama Kazuhisa , Goerdt Sergij
Published: September 2004

Stabilin-1 and stabilin-2 constitute a novel family of fasciclin domain-containing hyaluronan receptor homologues recently described by us. Whereas stabilin-1 is expressed in sinusoidal endothelial cells and in macrophages in vivo, stabilin-2 is absent from the latter. In the present study, we analyzed the subcellular distribution of stabilin-1 in primary human macrophages. Using flow cytometry, expression of stabilin-1 was demonstrated on the surface of interleukin-4/dexamethasone-stimulated macrophages (MΦ2). By immunofluorescense and confocal microscopy, we established that stabilin-1 is preferentially localized in early endosome antigen-1-positive early/sorting endosomes and in recycling endosomes identified by transferrin endocytosis. Association of stabilin-1 was infrequently seen with p62 lck ligand-positive late endosomes and with CD63-positive lysosomes but not in lysosome-associated membrane protein-1-positive lysosomes. Stabilin-1 was also found in the trans-Golgi network (TGN) but not in Golgi stack structures. Glutathione S-transferase pull-down assay revealed that the cytoplasmic tail of stabilin-1 but not stabilin-2 binds to recently discovered Golgi-localized, γ-ear-containing, adenosine 5′-diphosphate-ribosylation factor-binding (GGA) adaptors GGA1, GGA2, and GGA3 long, mediating traffic between Golgi and endosomal/lysosomal compartments. Stabilin-1 did not bind to GGA3 short, which lacks a part of the Vps27p/Hrs/STAM domain. Deletion of DDSLL and LL amino acid motifs resulted in decreased binding of stabilin-1 with GGAs. A small portion of stabilin-1 colocalized with GGA2 and GGA3 in the TGN in MΦ2. Treatment with brefeldin A resulted in accumulation of stabilin-1 in the TGN. Our results suggest that stabilin-1 is involved in the GGA-mediated sorting processes at the interface of the biosynthetic and endosomal pathways; similarly to other GGA-interacting proteins, stabilin-1 may thus function in endocytic and secretory processes of human macrophages.
Population pharmacokinetics of 5-fluorouracil in colorectal cancer patients
Authors: Porta-Oltra B , Pérez-Ruixo JJ , Climente-Martí M , Merino-Sanjuán M , Almenar-Cubells D , Jiménez-Torres NV
Published: September 2004

Aims. The pharmacokinetics of 5-fluorouracil (5-FU) after intravenous administration in color- ectal cancer patients were examined using population analysis. The relevant covariates and the extent of inter- and intraindividual variability were evaluated.

Methods. Data from 27 patients with diagnosis of nonmetastatic colorectal adenocarcinoma receiving weekly 5-FU (450 mg/m2), plus levamisol 50 mg/8 hours by oral route for 3 days every 15 days, were pooled with data from 17 patients with diagnosis of metastatic colorectal adenocarcinoma, receiving daily 5-FU (425 mg/m2) and intravenous folinic acid (20 mg/m2) over five consecutive days (daily times five), every four weeks. In both groups 5-FU was administered as a 60-minute infusion and blood samples were collected at 10, 30 and 60 minutes from the end of the infusion, and analysed using a validated high-performance liquid chromatography assay. An open two-compartmental pharmacokinetic model with first-order elimination from central compartment was fitted to the plasma concentration data using nonlinear mixed effect modelling (NONMEM). The potential effect of patient covariates was evaluated using a stepwise method. Model evaluation was performed using bootstrap method.

Results. The pharmacokinetic model was successfully fitted to the data. None of the covariates tested were significantly correlated to the pharmacokinetic parameters. The mean parameters’ estimates (%CV) and the percent coefficient of variation of the central tendency parameters, interindividual (IIV), interoccasion (IOV) and residual variability (s) for the final model were: CL (L/h), 65.3 (13.2); Vc (L), 14.7 (11.8); Vp (L), 334.0 (31.4); Q (L/h), 19.6 (25.5); IIVCL (%), 76.5 (34.6); IIVVc (%), 82.3 (31.0); IIVVp (%), 137.5 (35.1); IIVQ (%), 117.5 (38.5); IOVCL (%), 66.1 (45.3); IOVVc (%), 70.8 (39.5); IOVQ (%), 81.1 (27.8) and s (%), 3.0 (25.4). The bootstrap resampling method confirmed the stability of the final model. The estimates of the central tendency parameters, IIV, IOV and residual variability were essentially equal to those generated with the original dataset (0% to 18% deviation) and the 95% confidence intervals included the mean parameters’ estimates obtained from the former set.

Conclusions. The two-compartmental model accurately described the pharmacokinetics of 5-FU administered by short-term infusion. A population pharmacokinetic approach is a useful tool to integrate the knowledge gathered in the clinical setting. The model developed may help in dose adaptation and will further be used in PK/PD modelling of therapeutic outcomes and adverse events.
Should CA-125 Response Criteria Be Preferred to Response Evaluation Criteria in Solid Tumors (RECIST) for Prognostication During Second-Line Chemotherapy of Ovarian Carcinoma?
Authors: Gronlund Bo , Høgdall Claus , Hilden Jørgen , Engelholm Svend A. , Høgdall Estrid V.S. , Hansen Heine H.
Published: September 2004

Purpose

The aim of the study was to compare the prognostic value of a response by the Gynecologic Cancer Intergroup (GCIG) Cancer Antigen (CA) -125 response criteria and the Response Evaluation Criteria in Solid Tumors (RECIST) on survival in patients with ovarian carcinoma receiving second-line chemotherapy.

Patients and Methods

From a single-institution registry of 527 consecutive patients with primary ovarian carcinoma, 131 records satisfied the inclusion criteria: ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IC to IV, first-line chemotherapy with paclitaxel and a platinum compound, refractory or recurrent disease, and second-line chemotherapy consisting of topotecan or paclitaxel plus carboplatin. Univariate and multivariate analyses of survival were performed using the landmark method.

Results

In patients with measurable disease by RECIST and with assessable disease by the CA-125 criteria (n = 68), the CA-125 criteria were 2.6 times better than the RECIST at disclosing survival. In a multivariate Cox analysis with inclusion of nine potential prognostic parameters, CA-125 response (responders v nonresponders; hazard ratio, 0.21; P < .001) and number of relapse sites (solitary v multiple; hazard ratio, 0.47; P = .020) were identified as contributory prognostic factors for survival, whereas the parameters of RECIST (responders v nonresponders), as well as the remaining variables, had nonsignificant prognostic impact.

Conclusion

The GCIG CA-125 response criteria are a better prognostic tool than RECIST in second-line treatment with topotecan or paclitaxel plus carboplatin in patients with ovarian carcinoma.
Histologic Grade, But Not SYT-SSX Fusion Type, Is an Important Prognostic Factor in Patients With Synovial Sarcoma: A Multicenter, Retrospective Analysis
Authors: Guillou Louis , Benhattar Jean , Bonichon Françoise , Gallagher Gabrielle , Terrier Philippe , Stauffer Edouard , de Saint Aubain Somerhausen Nicolas , Michels Jean-Jacques , Jundt Gernot , Vince Dominique Ranchère , Taylor Sophia , Genevay Muriel , Collin Françoise , Trassard Martine , Coindre Jean-Michel
Published: September 2004

Purpose

To assess the prognostic value of SYT-SSX fusion type, in comparison with other factors, in a population of 165 patients with synovial sarcoma (SS).

Patients and Methods

Data on 165 patients with SS (141 with localized disease at diagnosis) were studied retrospectively. The following parameters were examined for their potential prognostic value: age at diagnosis, sex, tumor site (extremities v proximal/truncal), size, histology, mitotic count, necrosis, histologic grade (Fédération Nationale des Centres de Lutte Contre le Cancer system), stage (1997 tumor-node-metastasis system classification), surgical margin status (assessed histologically), and fusion type (SYT-SSX1 v SYT-SSX2). Median follow-up time was 37 months (range, 2 to 302 months).

Results

Among those patients with localized disease at diagnosis, median and 5-year disease-specific survivals (DSS) for the SYT-SSX1 and SYT-SSX2 subgroups were 126 months and 67.4% versus 82 months and 63.2%, respectively (P = .12). Median and 5-year metastasis-free survivals (MFS) were 84 months and 54.2% for SYT-SSX1 versus 50 months and 47.6% for SYT-SSX2 (P = .76). Univariate analyses showed that high histologic grade (grade 3), high mitotic count (≥ 10 mitoses/10 high-power fields), stage III disease, size greater than 7 cm, tumor necrosis, and presence of areas of poorly differentiated morphology were significant adverse prognostic factors for DSS and MFS, whereas SYT-SSX fusion type, tumor histology (biphasic v monophasic), and patient sex were not. Age greater than 35 years adversely affected DSS but not MFS. In multivariate analyses, histologic grade was the most significant prognostic factor for both DSS and MFS.

Conclusion

For patients with localized SS, histologic grade but not SYT-SSX fusion type is a strong predictor of survival.
Thyrotropin-Releasing Hormone-Stimulated Thyrotropin Expression Involves Islet-Brain-1/c-Jun N-Terminal Kinase Interacting Protein-1
Authors: Abe Hiroshi , Murao Koji , Imachi Hitomi , Cao Wen M. , Yu Xiao , Yoshida Kazuya , Wong Norman C. W. , Shupnik Margaret A. , Haefliger Jacques-Antoine , Waeber Gérard , Ishida Toshihiko
Published: September 2004

Islet-brain-1 (IB1)/c-Jun N-terminal kinase interacting protein 1 (JIP-1) is a scaffold protein that is expressed at high levels in neurons and the endocrine pancreas. IB1/JIP-1 interacts with the c-Jun N-terminal kinase and mediates the specific physiological stimuli (such as cytokines). However, the potential role of the protein in the pituitary has not been evaluated. Herein, we examined expression of the gene encoding IB1/JIP-1 and its translated product in the anterior pituitary gland and a pituitary cell line, GH3. We then examined the potential role of IB1/JIP-1 in controlling TSH-β gene expression. Exposure of GH3 cells to TRH stimulated the expression of IB1/JIP-1 protein levels, mRNA, and transcription of the promoter. The increase of IB1/JIP-1 content by transient transfection study of a vector encoding IB1/JIP-1 or by the stimulation of TRH stimulates TSH-β promoter activity. This effect is not found in the presence of a mutated nonfunctional (IB1S59N) IB1/JIP-1 protein. Together, these facts point to a central role of the IB1/JIP-1 protein in the control of TRH-mediated TSH-β stimulation.
Rapid Nongenomic Effects of 3,5,3′-Triiodo-l-Thyronine on the Intracellular pH of L-6 Myoblasts Are Mediated by Intracellular Calcium Mobilization and Kinase Pathways
Authors: D’Arezzo Silvia , Incerpi Sandra , Davis Faith B. , Acconcia Filippo , Marino Maria , Farias Ricardo N. , Davis Paul J.
Published: September 2004

l-T3 and l-T4 activated the Na+/H+ exchanger of L-6 myoblasts, with a fast nongenomic mechanism, both in the steady state and when cells undergo acid loading with ammonium chloride. Monitored with the intracellular pH-sensitive fluorescent probe 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein, activation of the exchanger appeared to be initiated at the plasma membrane, because T3-agarose reproduced the effect of l-T3, and triiodothyroacetic acid, a hormone analog previously shown to inhibit membrane actions of thyroid hormone, blocked the action of l-T3 on the exchanger. We show here for the first time that transduction of the hormone signal in this nongenomic response requires tyrosine kinase-dependent phospholipase C activation and two different signaling pathways: 1) mobilization of intracellular calcium, assessed by the fluorescent probe fura-2, through activation of inositol trisphosphate receptors and without contributions from extracellular calcium or ryanodine receptors; and 2) protein phosphorylation involving protein kinase C and MAPK (ERK1/2), as shown by the use of kinase inhibitors and by immunoblotting for activated kinases.
Autumnal precipitation distribution on the southern flank of the Alps: A numerical‐model study of the mechanisms
Authors: Gheusi François , Davies Huw C.
Published: September 2004

During the autumn there are frequent events of heavy precipitation on the southern slopes of the meso‐α‐scale Alpine chain. Moreover, the accompanying climatology exhibits a distinctive spatial distribution with some meso‐β‐scale regions of enhanced precipitation such as the ‘wet spot’ in the vicinity of Lago Maggiore.

Possible mechanisms to account for the observed spatial distribution are established using a heuristic model‐based approach. It is shown using a mesoscale model that the response to a steady, horizontally uniform, and moisture‐laden flow impinging upon a comparatively realistic representation of the Alpine chain can reproduce both the overall meso‐α‐scale precipitation distribution and its meso‐β‐scale sub‐structure. The nature of the simulated flow regime (over, around or intermediate) is sensitive to the strength of the ambient geostrophic flow and its modification in the planetary boundary layer. Contrariwise, the simulated precipitation distribution in the Lago Maggiore ‘wet spot’ is comparatively insensitive to the changes in direction of the incident geostrophic flow from south to south‐west, and in strength in the range 10–30 m s−1, although there is a marked change in the structure of the near‐Alpine flow. This systematic precipitation enhancement appears to be related to the relative strength and compensating effects of an easterly barrier jet tracking along the zonally elongated part of the Alps and an air stream channelled between the Maritime Alps and the Apennines.

Further evidence to the above interpretation of the meso‐β‐scale precipitation distribution is given with simulations conducted using a smoothed and schematic representation of the Alpine chain. Likewise, the sensitivity to the presence of a Lago Maggiore‐like indentation of the topography is tested, and evidence is provided of a further ‘indentation‐induced’ precipitation enhancement at the local scale. Copyright © 2004 Royal Meteorological Society
Flux–gradient relationship, self‐correlation and intermittency in the stable boundary layer
Authors: Klipp Cheryl L. , Mahrt Larry
Published: September 2004

The correlation between dimensionless shear ϕm and dimensionless height z/L, where L is the Obukhov length, for stable conditions is strongly influenced by self‐correlation for the present datasets. This effect is quite large for stronger stability but still significant for near‐neutral conditions. A conditional analysis of nocturnal stable boundary‐layer data, where ‘non‐turbulent’ parts of the record are removed, reduces the impact of nonstationarity and therefore reduces the scatter. The conditional analysis also reduces the relative importance of self‐correlation. Difficulties with estimating self‐correlation are also discussed. Copyright © 2004 Royal Meteorological Society
Sensitivity of dynamics and ozone to different representations of SSTs in the Unified Model
Authors: Braesicke P. , Pyle J. A.
Published: September 2004

We use a version of the Met Office Unified Model with a simple stratospheric chemistry to perform a set of multi‐annual integrations of 20 years each. The runs have different representations of ozone in the radiation and use prescribed sea surface temperatures (SSTs). In one experiment the same long‐term mean monthly mean SSTs are used each model year, whereas all other experiments use annual varying AMIP II monthly mean SSTs instead. All runs have the same simplified ozone chemistry included (regardless of which ozone is used in the radiation), so we can estimate the impact of dynamical changes on ozone. We contrast the sensitivity of the model system towards the representation of ozone with the changes associated with the removal of the interannual variability in SSTs. We show that the appearance of extreme events in the northern hemisphere winter stratosphere as modelled with the Unified Model is linked more to the representation of SSTs than it is to ozone. Copyright © 2004 Royal Meteorological Society
Agradient velocity, vortical motion and gravity waves in a rotating shallow‐water model
Authors: Sutyrin Georgi G.
Published: September 2004

A new approach to modelling slow vortical motion and fast inertia‐gravity waves is suggested within the rotating shallow‐water primitive equations with arbitrary topography. The velocity is exactly expressed as a sum of the gradient wind, described by the Bernoulli function, B, and the remaining agradient part, proportional to the velocity tendency. Then the equation for inverse potential vorticity, Q, as well as momentum equations for agradient velocity include the same source of intrinsic flow evolution expressed as a single term J(B, Q), where J is the Jacobian operator (for any steady state J(B,Q)=0). Two components of agradient velocity are responsible for the fast inertia‐gravity wave propagation similar to the traditionally used divergence and ageostrophic vorticity.

This approach allows for the construction of balance relations for vortical dynamics and potential vorticity inversion schemes even for moderate Rossby and Froude numbers assuming the characteristic value of |J(B,Q)|=ε to be small. The components of agradient velocity are used as the fast variables slaved to potential vorticity that allows for diagnostic estimates of the velocity tendency, the direct potential vorticity inversion with the accuracy of ε2 and the corresponding potential vorticity‐conserving agradient velocity balance model (AVBM). The ultimate limitations of constructing the balance are revealed in the form of the ellipticity condition for balanced tendency of the Bernoulli function which incorporates both known criteria of the formal stability: the gradient wind modified by the characteristic vortical Rossby wave phase speed should be subcritical. The accuracy of the AVBM is illustrated by considering the linear normal modes and coastal Kelvin waves in the f‐plane channel with topography. Copyright © 2004 Royal Meteorological Society
Investigating Impropriety in Jury Deliberations: A Recipe for Disaster?
Authors: Haralambous Nicola
Published: September 2004

In light of recent case law, this article explores the principles underlying the common law prohibition against investigating into jury deliberations. It considers the effect of judicial refusal to inquire into genuine and serious allegations of impropriety in the jury room and examines the effect of the Contempt of Court Act 1981, s. 8. It proposes that the restrictive secrecy laws be qualified in order to safeguard against miscarriages of justice and to preserve the moral integrity of the criminal justice process.
Platelet-Activating Factor Acetylhydrolase Is Not Associated with Carotid Intima-Media Thickness in Hypercholesterolemic Sicilian Individuals
Authors: Campo Salvatore , Sardo Maria A , Bitto Alessandra , Bonaiuto Antonio , Trimarchi Giuseppe , Bonaiuto Michele , Castaldo Maria , Saitta Carlo , Cristadoro Simona , Saitta Antonino
Published: September 2004

Background: Atherosclerosis is a complex, chronic disease that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlipidemia, obesity, and the accumulation of oxidized LDL. Platelet-activating factor acetylhydrolase (PAF-AH) is a LDL- and HDL-bound enzyme that hydrolyzes and inactivates PAF and prevents LDL-cholesterol oxidation, thus delaying the onset of atherosclerotic disease.

Methods: We evaluated the relationship between variants of the PAF-AH gene polymorphisms Arg92His, Ile198Thr, and Ala379Val and the presence of carotid atherosclerosis in 190 hypercholesterolemic Sicilian individuals. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of early atherosclerotic disease. The participants were classified according to having normal (≤1 mm) or abnormal (≥1 mm) IMT and were also investigated for physical characteristics and biochemical indices, including PAF-AH activity.

Results: PAF-AH activity and LDL concentrations were significantly correlated in hypercholesterolemic patients, but plasma PAF-AH activity and HDL were not significantly correlated in either IMT group. No significant differences were detected among the PAF-AH gene polymorphisms in both groups after correction for age, sex, body mass index, plasma glucose and lipid concentrations, PAF-AH activity, blood pressure, and smoking habits. The analysis of PAF-AH genotype distribution showed no significant differences in percentage of 92, 198, and 379 genotypes in both IMT groups.

Conclusion: Our data provided no evidence that PAF-AH polymorphisms influence PAF-AH activity and atherosclerosis in hypercholesterolemic Sicilian patients.
The dying dreamer: architecture of parallel realities
Authors: Zimm Malin
Published: September 2004

Architectural experience and creation is studied through a selection of projects, each driven by an obsessive creator towards particular levels of architectural experience, both physical and virtual. The article investigates the processes of turning dreams into physical space, exemplified
by four extraordinary creators and collectors of space, each one a pursuer of obsessive architectural activities, all haunted by transitive dreams: Baron Des Esseintes, Joris-Karl Huysmans’ fictional character in the novel À Rebours (Against Nature) from 1884; Kurt Schwitters,
the dadaist painter and constructor of the Merzbau created in Hannover between 1919 and 1937; Sir John Soane, the architect and collector, who arranged his home as a museum from 1790 until 1837; and the German artist Gregor Schneider, whose home in Rheydt since 1985 is slowly folding in on
itself under the name Haus Ur. Whereas Des Esseintes is a fictional builder of dreams in physical form; Schwitters, Soane and Schneider are real builders of dreams in physical form - the author Huysmans is a real builder of dreams in fictional form. Three of the four selected projects introduce
layers of hybrid existence into ordinary building shells, and one represents the virtual architecture of narrative space. Their creators are driving architectural space into different ontological states, providing a field of perceptional and representational problems. The architects of parallel
realities are subsequently challenging our basic understanding of architectural organization, aesthetics and methods. This erratic field of subjective and obsessive architecture serves my purposes of investigating architectural imagination as the main asset of virtual space.
Use of Animal Proteins to Limit Leaching of Active Copper Ions Preservatives from Treated Wood
Authors: Mazela B. , Polus-Ratajczak I.
Published: September 2004

The concept of animal protein utilization aiming to reduce leaching of treatment salts from wood
was tested and verified. Animal proteins in the form of spray-dried animal blood plasma were used
as an addition to the water solution of fungicidal salt or included in the solution for soaking pre-treated
wood. The wood was subjected to thermal treatment which caused protein denaturation, a
process which changes the proteins' spatial conformation and reduces their solubility in water.
Scots pine wood (Pinus sylvestris L.) was treated with a water solution of copper sulfate using vacuum,
vacuum-soaking and vacuum-pressure methods. The animal proteins were added to the
treatment solutions or applied by soaking to samples pre-treated with the salt. After treatment, the
samples were heated to 100°C. After suitable conditioning, the wood was subjected to leaching.
The content of Cu2+ in the water extracts was determined by Atomic Absorption Spectrophotometry
(AAS).
Mode I Fracture Behaviour on the Growth Ring Scale and Cellular Level of Spruce (Picea abies [L.] Karst.) and Beech (Fagus sylvatica L.) Loaded in the TR Crack Propagation System
Authors: Frühmann K. , Burgert I. , Stanzl-Tschegg S. E. , Tschegg E. K.
Published: September 2004

Crack propagation in wood is strongly influenced by the microscopic structure of the material. The
relationship between structure and function with regard to damage and fracture behaviour can
only be understood with a sufficiently fine level of examination. An experimental approach to perform
micro-wedge splitting tests on spruce and beech inside the chamber of an Environmental
Scanning Electron Microscope and under atmospheric conditions is presented. The specimens are
loaded in mode I in the TR crack propagation system. Based on the load-displacement diagram,
the characteristic parameters of fracture energy, critical load and initial elasticity are determined.
The load and displacement data for the in situ experiments are related to the obtained ESEM images
and allow a discussion of the fracture process on the cellular level. Density was found to be an
important factor for fracture mode and several crack arresting phenomena depending on the variation
of elasticity could be identified.
Mapping Radial,Tangential and Longitudinal Shrinkages and Relation to Tension Wood in Discs of the Tropical Tree Symphonia globulifera
Authors: Clair B. , Jaouen G. , Beauchêne J. , Fournier M.
Published: September 2004

A method for measuring shrinkage resulting from drying in the three anisotropic directions is developed
and tested. Measurements are performed on sawn discs, a technique which simplifies
preparation and enables large numbers of measurements. Shrinkage values can be represented as
a map of the disc surface. The results indicate that comparisons between shrinkage distribution
and tension wood distribution on the discs show a clear relationship and can be measured with relatively
high accuracy in reference to the “shrinkage map”. In the long term, this method could be
useful in the timber industry as a means for choosing the direction in which logs are cut depending
on their type of wood composition.
Identification of volatile organic compounds (VOCs) from bacteria and yeast causing growth inhibition of sapstain fungi
Authors: Bruce A. , Verrall S. , Hackett C. A. , Wheatley R. E.
Published: September 2004

This paper describes an experiment to identify volatile
organic compounds (VOCs) from a range of three bacteria
and one yeast strain that had previously been
shown to be inhibitory to selected sapstain fungi. The
bacteria and yeast were cultured on two media, malt
extract (ME) and tryptone soya (TS) and the VOCs
trapped on chromatographic adsorbant before being
analysed by Integrated Thermal Desorption—GC-MS.
Since sapstain fungi were only inhibited by VOCs produced
on the TS media, it was possible to use Principle
Component Analysis to highlight the individual VOCs that
are most likely to be responsible for the inhibition. A number
of ketones together with dimethyl disulphide and
dimethyl trisulphide were highlighted. The importance of
VOC production by organisms during the biological control
of sapstain is discussed.