bluuebunny/crossref_metadata_2025 huggingface dataset:
Artificial Neural Network-embedded Expert System for the Design of Canopy Fabrics
Authors: Behera B. K. , Karthikeyan B.
Published: September 2006

Engineered fabric manufacturing needs a thorough understanding of the functional properties and their key control construction parameters. When the relationship between a set of interrelated properties goes beyond the complete comprehension of the human brain, neural networks (NNs) could be used to find the unknown function. This study describes the method of applying artificial NNs for the prediction of both construction and performance parameters of canopy fabrics. Based on the influence on the performance of the canopy fabric, constructional parameters are chosen. Accordingly, constructional parameters are used as input for predicting the performance parameter in forward engineering, and the parameters are reversed for the reverse engineering prediction. Comparison between actual results and predicted results is made. An expert system with an embedded artificial neural network (ANN) is also discussed, with its functionality toward engineered fabric manufacturing.
A Modified Micromechanical Model for the Prediction of Tensile Behavior of Nonwoven Structures
Authors: Rawal Amit
Published: September 2006

Nonwoven structures have a range of applications which include geotextiles, interlinings, carpet backing and as reinforcements in composites. In this study, the tensile behavior of nonwoven structures including needlepunched and thermal bonded has been predicted by modifying the micromechanical model based upon the geometrical and mechanical properties of the constituent fibers (Adanur, S. and Liao, T. (1999). Fiber Arrangements Characteristics and Their Effects on Nonwoven Tensile Behavior, Textile Research Journal, 69(11): 816-824). In the modified model, the effects of fiber orientation in addition to the fiber curl factor are incorporated. The theoretical models have been validated with experimental results. The effects of lapping angle and curl factor have also been investigated on the thermal bonded nonwoven structures. Furthermore, the distribution of fiber orientation within a nonwoven structure is related to the lapping and fiber orientation angles using Fourier series.
Impact of Stitching Processes on the Compaction Behavior of Glass Fiber Reinforcements
Authors: Floeck Martin , Stadtfeld Hubert C. , Mitschang Peter , Bickerton Simon
Published: September 2006

The objective of this project is to investigate the application influences of stitching techniques on the compaction and relaxation behavior of preforms made of three different semi-finished glass fabric types. Particular attention is directed to the impact of stitching parameters (i.e., thread tension and seam spacing) and the compaction procedure (single-stage vs multi-stage) on the experimental results. The experiments prove that there is no difference between single-stage and multi-stage compaction. Furthermore, it is shown that the stitching of the preforms leads to an increase in compaction force due to the additional volume of thread to be compacted. Comparing high and low thread tension reveals that an increasing thread tension causes pre-compaction of the preform, thus reducing the required compaction force, though the degree of pre-compaction seems to be confined to a limit above which no reduction in compaction force can be observed any more. Regarding the spacing of the seams, it turns out that only the narrow spacing (5 mm) has a significant influence on compaction, whereas the wide spacing (20 mm) does not lead to a notable change in compaction behavior compared to the unstitched preforms. Finally, visual inspection of the preforms during compaction and relaxation shows that the morphologic change of the preform surfaces is a very complex phenomenon which cannot easily be modeled. No visual change of the preform surfaces are observed during relaxation. Therefore, it is assumed that relaxation is caused by invisible microstructural reorientation of glass filaments within single rovings.
Active MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation
Authors: Varga Georg , Balkow Sandra , Wild Martin K. , Stadtbaeumer Andrea , Krummen Mathias , Rothoeft Tobias , Higuchi Tetsuya , Beissert Stefan , Wethmar Klaus , Scharffetter-Kochanek Karin , Vestweber Dietmar , Grabbe Stephan
Published: September 2006

The β2 integrins are important for transendothelial migration of leukocytes as well as for T-cell activation during antigen presentation. Despite abundant expression of β2 integrins on antigen-presenting cells (APCs), their functional relevance for antigen presentation is completely unclear. We show here that dendritic cells (DCs) from CD18-deficient mice, which lack all functional β2 integrins, have no defect in antigen presentation. Moreover, DCs from normal mice express inactive β2 integrins that do not become activated on contact with T cells, at least in vitro. Pharmacologic activation of β2 integrins on DCs results in a significant reduction of their T cell–activating capacity. This effect is mediated by Mac-1 (CD11b/CD18) on DCs because it could be reversed via blocking antibodies against CD18 and CD11b. Furthermore, the antigen-presenting capacity of macrophages, which express constitutively active β2 integrins, is significantly enhanced on Mac-1 blockade. We therefore conclude that active CD11b/CD18 (Mac-1) on APCs directly inhibits T-cell activation.
Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG)
Authors: Schultz Kirk R. , Pullen D. Jeanette , Sather Harland N. , Shuster Jonathan J. , Devidas Meenakshi , Borowitz Michael J. , Carroll Andrew J. , Heerema Nyla A. , Rubnitz Jeffrey E. , Loh Mignon L. , Raetz Elizabeth A. , Winick Naomi J. , Hunger Stephen P. , Carroll William L. , Gaynon Paul S. , Camitta Bruce M.
Published: September 2006

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n = 4986) and POG (January 1986 to November 1999, n = 6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.
Eosinophils are a major intravascular location for tissue factor storage and exposure
Authors: Moosbauer Christine , Morgenstern Eberhard , Cuvelier Susan L. , Manukyan Davit , Bidzhekov Kiril , Albrecht Sybille , Lohse Peter , Patel Kamala D. , Engelmann Bernd
Published: September 2006

Blood cell progenitors were scanned for the presence of the coagulation starter protein tissue factor (TF) by immunoelectron microscopy. Thereby, substantial TF expression was observed in the precursor cells of eosinophils. TF levels were lower in basophil precursors and barely detectable in neutrophil progenitors. In peripheral blood immediately processed to avoid activation of the TF gene, mature eosinophils were found to considerably express TF, unique among the granulocyte and monocyte fractions. TF was preferentially located in the specific granules in resting eosinophils. Platelet-activating factor (PAF), and more pronounced, granulocyte-macrophage colony-stimulating factor (GM-CSF) plus PAF, caused translocation of preformed TF to the eosinophil cell membrane. GM-CSF/PAF also increased the TF transcript levels. The activated eosinophils exhibited procoagulant activity that was abrogated by TF inhibition. Targeting the extracellular domain of TF with specific antibodies markedly suppressed the initial phase of the eosinophil passage across the IL-4–activated endothelium. Eosinophil rolling and firm adhesion remained unaffected. This suggests that TF specifically facilitates the early transendothelial migration of the eosinophils. In summary, eosinophils maintain a high TF expression during maturation, providing a main source of preformed TF in blood, which might be relevant for the thrombogenesis promoted by hypereosinophilic conditions.
B-cell receptor signaling in chronic lymphocytic leukemia cells is regulated by overexpressed active protein kinase CβII
Authors: Abrams Simon T. , Lakum Tasneem , Lin Ke , Jones Gemma M. , Treweeke Andrew T. , Farahani Mosavar , Hughes Mair , Zuzel Mirko , Slupsky Joseph R.
Published: September 2006

Signals through the B-cell antigen receptor (BCR) are important for the survival of chronic lymphocytic leukemia (CLL) cells. Therefore, factors that influence these signals have important pathophysiological roles in this disease. One key mediator of BCR signaling is protein kinase C β (PKCβ), which regulates the activation of I-κB kinases and the deactivation of Bruton tyrosine kinase within the signaling pathways initiated by BCR engagement. The present study demonstrates that overexpression of the PKCβII isoform is a feature of CLL cells and that activity of this enzyme strongly correlates with CLL cell response to BCR engagement. Thus, intracellular Ca2+ release and increases in cell survival after BCR cross-linking were significantly greater in CLL patients with low levels than in CLL patients with high levels of active PKCβII. Furthermore, BCR-induced Ca2+ fluxes could be restored in CLL patients with high levels of active PKCβII by pretreating the cells with the PKCβ-specific inhibitor LY379196. Conversely, BCR-mediated intracellular Ca2+ release could be inhibited in CLL cells with low levels of active PKCβII by pretreatment with the PKC agonist bryostatin. Taken together, these results demonstrate that overexpressed active PKCβII plays a role in the regulation and outcome of BCR signals that can be important for the progression of CLL.
Increased plasma transferrin, altered body iron distribution, and microcytic hypochromic anemia in ferrochelatase-deficient mice
Authors: Lyoumi Saïd , Abitbol Marie , Andrieu Valérie , Henin Dominique , Robert Elodie , Schmitt Caroline , Gouya Laurent , de Verneuil Hubert , Deybach Jean-Charles , Montagutelli Xavier , Beaumont Carole , Puy Hervé
Published: September 2006

Patients with deficiency in ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, experience a painful type of skin photosensitivity called erythropoietic protoporphyria (EPP), which is caused by the excessive production of protoporphyrin IX (PPIX) by erythrocytes. Controversial results have been reported regarding hematologic status and iron status of patients with EPP. We thoroughly explored these parameters in Fechm1Pas mutant mice of 3 different genetic backgrounds. FECH deficiency induced microcytic hypochromic anemia without ringed sideroblasts, little or no hemolysis, and no erythroid hyperplasia. Serum iron, ferritin, hepcidin mRNA, and Dcytb levels were normal. The homozygous Fechm1Pas mutant involved no tissue iron deficiency but showed a clear-cut redistribution of iron stores from peripheral tissues to the spleen, with a concomitant 2- to 3-fold increase in transferrin expression at the mRNA and the protein levels. Erythrocyte PPIX levels strongly correlated with serum transferrin levels. At all stages of differentiation in our study, transferrin receptor expression in bone marrow erythroid cells in Fechm1Pas was normal in mutant mice but not in patients with iron-deficiency anemia. Based on these observations, we suggest that oral iron therapy is not the therapy of choice for patients with EPP and that the PPIX–liver transferrin pathway plays a role in the orchestration of iron distribution between peripheral iron stores, the spleen, and the bone marrow.
Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts
Authors: Gajate Consuelo , Mollinedo Faustino
Published: September 2006

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain–containing protein, and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid, were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-XL overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation, and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L) independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft–mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.
ADAP is required for normal αIIbβ3 activation by VWF/GP Ib-IX-V and other agonists
Authors: Kasirer-Friede Ana , Moran Barry , Nagrampa-Orje Jennifer , Swanson Ken , Ruggeri Zaverio M. , Schraven Burkhart , Neel Benjamin G. , Koretzky Gary , Shattil Sanford J.
Published: September 2006

Interaction between von Willebrand factor (VWF) and platelet GP Ib-IX-V is required for hemostasis, in part because intracellular signals from VWF/GP Ib-IX-V activate the ligand-binding function of integrin αIIbβ3. Because they also induce tyrosine phosphorylation of the ADAP adapter, we investigated ADAP's role in GP Ib-IX-V signal transduction. Fibrinogen or ligand-mimetic POW-2 Fab binding to αIIbβ3 was stimulated by adhesion of ADAP+/+ murine platelets to dimeric VWF A1A2 but was significantly reduced in ADAP−/− platelets (P < .01). αIIbβ3 activation by ADP or a Par4 thrombin receptor agonist was also decreased in ADAP−/− platelets. ADAP stabilized the expression of another adapter, SKAP-HOM, via interaction with the latter's SH3 domain. However, no abnormalities in αIIbβ3 activation were observed in SKAP-HOM−/− platelets, which express normal ADAP levels, further implicating ADAP as a modulator of αIIbβ3 function. Under shear flow conditions over a combined surface of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and αIIbβ3, respectively, ADAP−/− platelets displayed reduced αIIbβ3-dependent stable adhesion. Furthermore, ADAP−/− mice demonstrated increased rebleeding from tail wounds. These studies establish ADAP as a component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to αIIbβ3 activation.
STAT3 and MAPK signaling maintain overexpression of heat shock proteins 90α and β in multiple myeloma cells, which critically contribute to tumor-cell survival
Authors: Chatterjee Manik , Jain Sarika , Stühmer Thorsten , Andrulis Mindaugas , Ungethüm Ute , Kuban Ralf-Jürgen , Lorentz Heike , Bommert Kurt , Topp Max , Krämer Doris , Müller-Hermelink Hans Konrad , Einsele Hermann , Greiner Axel , Bargou Ralf C.
Published: September 2006

The combined blockade of the IL-6R/STAT3 and the MAPK signaling pathways has been shown to inhibit bone marrow microenvironment (BMM)–mediated survival of multiple myeloma (MM) cells. Here, we identify the molecular chaperones heat shock proteins (Hsp) 90α and β as target genes of both pathways. The siRNA-mediated knockdown of Hsp90 or treatment with the novel Hsp90 inhibitor 17-DMAG attenuated the levels of STAT3 and phospho-ERK and decreased the viability of MM cells. Although knockdown of Hsp90β—unlike knockdown of Hsp90α—was sufficient to induce apoptosis, this effect was strongly increased when both Hsp90s were targeted, indicating a cooperation of both. Given the importance of the BMM for drug resistance and MM-cell survival, apoptosis induced by Hsp90 inhibition was not mitigated in the presence of bone marrow stromal cells, osteoclasts, or endothelial cells. These observations suggest that a positive feedback loop consisting of Hsp90α/β and major signaling pathways supports the survival of MM cells. Finally, in situ overexpression of both Hsp90 proteins was observed in most MMs but not in monoclonal gammopathy of undetermined significance (MGUS) or in normal plasma cells. Our results underpin a role for Hsp90α and β in MM pathogenesis.
When is a mouse basophil not a basophil?
Authors: Lee James J. , McGarry Michael P.
Published: September 2006

The identification and characterization of mouse basophils have historically been hampered by the extreme rarity of this cell type. Virtually no photomicrographs of hematologically stained (eg, Wright-Giemsa) examples of mouse basophils exist in the literature. However, 4 recent studies in the past 2 years have used flow cytometry and a defined set of cell-surface markers to identify and subsequently isolate mouse “basophils,” including the publication of stained cytospin preparations of these cells. Surprisingly, a reevaluation of the data from all 4 of the studies revealed several issues of concern that suggest that the cells under study are not necessarily basophils. Nonetheless, we propose that these studies do provide the foundation for a reevaluation of the defining characteristics of a basophil and/or provide support for the provocative conclusion that a new previously overlooked leukocyte subtype has been identified. The purpose of this commentary is to revisit these previously published studies, highlight the relevant issues, and provide a different perspective in the hope of developing a consensus within the research community as to the true identity of the “basophils” described in these studies.
Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment
Authors: Anjos-Afonso Fernando , Bonnet Dominique
Published: September 2006

It is believed that a primitive cell type that maintains the mesenchymal compartment exists in the bone marrow. However, this putative mesenchymal stem/progenitor cell is yet to be identified and isolated. We are reporting the identification, isolation, and detailed characterization of the most primitive mesenchymal progenitor cells in the adult murine bone marrow, based on the expression of stage-specific embryonic antigen–1 (SSEA-1). This primitive subset can be identified in mesenchymal cell cultures and also directly in the bone marrow, thus ascertaining for the first time their existence in an adult organism. Characterization of SSEA-1+ mesenchymal cells revealed that upon purification these cells gave rise to SSEA-1− mesenchymal cells, whereas the reverse could not be observed. Also, these SSEA-1+ cells have a much higher capacity to differentiate than their negative counterparts, not only to several mesenchymal cell types but also to unconventional cell types such as astrocyte-, endothelial-, and hepatocyte-like cells in vitro. Most importantly, a single-cell–derived population was capable of differentiating abundantly into different mesenchymal cell types in vivo. Altogether we are proposing a hierarchical organization of the mesenchymal compartment, placing SSEA-1+ cells at the apex of this hierarchy.
Altered intercellular communication in lung fibroblast cultures from patients with idiopathic pulmonary fibrosis
Authors: Trovato-Salinaro Angela , Trovato-Salinaro Elisa , Failla Marco , Mastruzzo Claudio , Tomaselli Valerio , Gili Elisa , Crimi Nunzio , Condorelli Filippo Daniele , Vancheri Carlo
Published: September 2006

Rationale

Gap junctions are membrane channels formed by an array of connexins which links adjacent cells realizing an electro- metabolic synapse. Connexin-mediated communication is crucial in the regulation of cell growth, differentiation, and development. The activation and proliferation of phenotypically altered fibroblasts are central events in the pathogenesis of idiopathic pulmonary fibrosis. We sought to evaluate the role of connexin-43, the most abundant gap-junction subunit in the human lung, in the pathogenesis of this condition.

Methods

We investigated the transcription and protein expression of connexin-43 and the gap-junctional intercellular communication (GJIC) in 5 primary lung fibroblast lines derived from normal subjects (NF) and from 3 histologically proven IPF patients (FF).

Results

Here we show that connexin-43 mRNA was significantly reduced in FF as demonstrated by standard and quantitative RT-PCR. GJIC was functionally evaluated by means of flow-cytometry. In order to demonstrate that dye spreading was taking place through gap junctions, we used carbenoxolone as a pharmacological gap-junction blocker. Carbenoxolone specifically blocked GJIC in our system in a concentration dependent manner. FF showed a significantly reduced homologous GJIC compared to NF. Similarly, GJIC was significantly impaired in FF when a heterologous NF line was used as dye donor, suggesting a complete defect in GJIC of FF.

Conclusion

These results suggest a novel alteration in primary lung fibroblasts from IPF patients. The reduced Cx43 expression and the associated alteration in cell-to-cell communication may justify some of the known pathological characteristic of this devastating disease that still represents a challenge to the medical practice.
Comparative assessment of performance and genome dependence among phylogenetic profiling methods
Authors: Snitkin Evan S , Gustafson Adam M , Mellor Joseph , Wu Jie , DeLisi Charles
Published: September 2006

Background

The rapidly increasing speed with which genome sequence data can be generated will be accompanied by an exponential increase in the number of sequenced eukaryotes. With the increasing number of sequenced eukaryotic genomes comes a need for bioinformatic techniques to aid in functional annotation. Ideally, genome context based techniques such as proximity, fusion, and phylogenetic profiling, which have been so successful in prokaryotes, could be utilized in eukaryotes. Here we explore the application of phylogenetic profiling, a method that exploits the evolutionary co-occurrence of genes in the assignment of functional linkages, to eukaryotic genomes.

Results

In order to evaluate the performance of phylogenetic profiling in eukaryotes, we assessed the relative performance of commonly used profile construction techniques and genome compositions in predicting functional linkages in both prokaryotic and eukaryotic organisms. When predicting linkages inE. coliwith a prokaryotic profile, the use of continuous values constructed from transformed BLAST bit-scores performed better than profiles composed of discretized E-values; the use of discretized E-values resulted in more accurate linkages when usingS. cerevisiaeas the query organism. Extending this analysis by incorporating several eukaryotic genomes in profiles containing a majority of prokaryotes resulted in similar overall accuracy, but with a surprising reduction in pathway diversity among the most significant linkages. Furthermore, the application of phylogenetic profiling using profiles composed of only eukaryotes resulted in the loss of the strong correlation between common KEGG pathway membership and profile similarity score. Profile construction methods, orthology definitions, ontology and domain complexity were explored as possible sources of the poor performance of eukaryotic profiles, but with no improvement in results.

Conclusion

Given the current set of completely sequenced eukaryotic organisms, phylogenetic profiling using profiles generated from any of the commonly used techniques was found to yield extremely poor results. These findings imply genome-specific requirements for constructing functionally relevant phylogenetic profiles, and suggest that differences in the evolutionary history between different kingdoms might generally limit the usefulness of phylogenetic profiling in eukaryotes.
How a well-grounded minimal important difference can enhance transparency of labelling claims and improve interpretation of a patient reported outcome measure
Authors: Brożek Jan L , Guyatt Gordon H , Schünemann Holger J
Published: September 2006

The evaluation and use of patient reported outcome (PRO) measures requires detailed understanding of the meaning of the outcome of interest. The Food and Drug Administration (FDA) recently presented its draft guidance and view on the use of PRO measures as endpoints in clinical trials. One section of the guidance document specifically deals with advice about the use of the minimal important difference (MID) that we redefined as the smallest difference in score in the outcome of interest that informed patients or informed proxies perceive as important. The advice, however, is short, indeed much too short. We believe that expanding the section and making it more specific will benefit all stakeholders: patients, clinicians, other clinical decision makers, those designing trials and making claims, payers and the FDA.

There is no "gold standard" methodology of estimating the MID or achieving the meaningfulness of clinical trial results based on patient reported outcomes. There are many methods of estimating the MID usually grouped into two distinct categories: anchor-based methods, that examine the relationship between scores on the target instrument and some independent measure, and distribution-based methods resorting to the statistical characteristics of the obtained scores.

Estimation of an MID and interpretation of clinical trial results that present patient important outcomes is demanding but vital for informing the decision to recommend approve a given intervention. Investigators are encouraged to use reliable and valid methods to achieve meaningfulness of their results, preferably those that rely on patients to estimate what constitutes a minimal important, small, moderate, or large difference. However, acquiring the meaningfulness of PRO measures transcends beyond a concept of the MID and we advocate that dichotomizing the scores of patient-reported outcome measures facilitate interpretability of clinical trial results for those who need to understand trial results after a labelling claim has been granted. Irrespective of the strategy investigators use to estimate these values, from the individual patient perspective it is much more relevant if investigators report both the estimated thresholds and the proportion of patients achieving that benefit.
Individual freedoms versus collective responsibility: immunization decision-making in the face of occasionally competing values
Authors: Salmon Daniel A , Omer Saad B
Published: September 2006

Modern public health strives for maximizing benefits for the highest number of people while protecting individual rights. Restrictions on individual rights are justified for two reasons-for the benefit of the individual or the benefit of the community.

In extreme situations there may be a need to protect the health of an individual and particularly a child; even by overriding individual/parental autonomy. However, The American Academy of Pediatrics recently concluded that "Continued (vaccine) refusal after adequate discussion should be respected unless the child is put at significant risk of serious harm (as, for example, might be the case during an epidemic). Only then should state agencies be involved to override parental discretion on the basis of medical neglect".

Many countries have compulsory immunization requirements. These laws curtail individual autonomy in order to protect the community from infectious diseases because unvaccinated individuals pose risk to the community – including vaccinated individuals (since vaccines are not 100% efficacious), children too young to be vaccinated, and persons who have medical vaccine contraindications. There are situations where there can be a real or perceived divergence between individual and community benefits of vaccination. This divergence may occasionally be based upon current scientific evidence and may exemplify the need for overriding individual autonomy. A divergence between individual and community benefits may also exist when there are ideological beliefs incongruent with vaccination or individuals are unaware of or do not accept available scientific evidence.

When the state curtails individual freedoms for the collective good, it should address several issues including the magnitude of the individual and community risk, the strength of the individual's conviction, wider and long-term consequences of restricting individual autonomy, effective risk communication, best available scientific evidence, and transparency of the decision making process.
Multiple effects govern endogenous retrovirus survival patterns in human gene introns
Authors: van de Lagemaat Louie N , Medstrand Patrik , Mager Dixie L
Published: September 2006

Background

Endogenous retroviruses (ERVs) and solitary long terminal repeats (LTRs) have a significant antisense bias when located in gene introns, suggesting strong negative selective pressure on such elements oriented in the same transcriptional direction as the enclosing gene. It has been assumed that this bias reflects the presence of strong transcriptional regulatory signals within LTRs but little work has been done to investigate this phenomenon further.

Results

In the analysis reported here, we found significant differences between individual human ERV families in their prevalence within genes and degree of antisense bias and show that, regardless of orientation, ERVs of most families are less likely to be found in introns than in intergenic regions. Examination of density profiles of ERVs across transcriptional units and the transcription signals present in the consensus ERVs suggests the importance of splice acceptor sites, in conjunction with splice donor and polyadenylation signals, as the major targets for selection against most families of ERVs/LTRs. Furthermore, analysis of annotated human mRNA splicing events involving ERV sequence revealed that the relatively young human ERVs (HERVs), HERV9 and HERV-K (HML-2), are involved in no human mRNA splicing events at all when oriented antisense to gene transcription, while elements in the sense direction in transcribed regions show considerable bias for use of strong splice sites.

Conclusion

Our observations suggest suppression of splicing among young intronic ERVs oriented antisense to gene transcription, which may account for their reduced mutagenicity and higher fixation rate in gene introns.
Increased Visfatin Messenger Ribonucleic Acid and Protein Levels in Adipose Tissue and Adipocytes in Women with Polycystic Ovary Syndrome: Parallel Increase in Plasma Visfatin
Authors: Tan Bee K. , Chen Jing , Digby Janet E. , Keay Stephen D. , Kennedy C. Richard , Randeva Harpal S.
Published: September 2006

Context: Polycystic ovary syndrome (PCOS) is a multifaceted metabolic disease linked with insulin resistance (IR) and obesity. Recent studies have shown that plasma levels of the insulin-mimetic adipokine visfatin increase with obesity. Currently, no data exist on the relative expression of visfatin in either plasma or adipose tissue of PCOS women.

Objectives: We investigated the mRNA expression of visfatin from sc and omental (om) adipose tissue and sc adipocytes in women with PCOS compared with matched normal women, as well as visfatin protein in adipose tissue; plasma visfatin was also assessed.

Design: Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of visfatin. Biochemical measurements were performed.

Results: There was significant up-regulation of visfatin mRNA in both sc (P < 0.05) and om (P < 0.05) adipose tissue of PCOS women, when compared with normal controls; these findings were also reflected in isolated sc adipocytes (PCOS > controls; P < 0.05). In addition to elevated plasma visfatin levels in women with PCOS (mean ± sd, 30.2 ± 10.4 vs. 11.2 ± 6.2 ng/ml; P < 0.01) when compared with normal controls, visfatin protein levels were significantly greater in both sc and om adipose tissue of PCOS women (P < 0.05 and P < 0.01, respectively).

Conclusions: The precise reason for the up-regulation of visfatin seen in women with PCOS, a proinflammatory state, is unknown. Additional studies are needed to clarify the potential role of visfatin in the pathophysiology of PCOS.
Mutational Analysis of the Vitamin D Receptor Does Not Support Its Candidacy as a Tumor Suppressor Gene in Parathyroid Adenomas
Authors: Samander Elizabeth Hanna , Arnold Andrew
Published: September 2006

Context: The vitamin D receptor gene (VDR) is a compelling candidate tumor suppressor gene for parathyroid adenomas based on existing evidence of the vitamin D system’s antiproliferative actions in parathyroid and other tissues, its reported inhibition of PTH gene transcription, and the decreased expression of VDR mRNA and VDR protein observed in parathyroid adenomas.

Objective: Because demonstration of intragenic mutations is required to establish the authenticity and primary role in pathogenesis for any candidate tumor suppressor gene, we examined the VDR gene in parathyroid adenomas for the presence of such mutations and other loss-of-function abnormalities.

Methods and Results: Genomic DNA samples from 37 sporadic parathyroid adenomas and matched normal control DNA from the same individuals were subjected to direct sequencing of the entire VDR coding region and all intron-exon boundaries. No VDR coding region or junctional mutations were identified. The tumors were also analyzed for loss of heterozygosity, a frequent mechanism of tumor suppressor gene inactivation, by molecular allelotyping at three microsatellite markers located near the VDR gene, D12S85, D12S96, and D12S368, and a polymorphism within VDR itself. In all 37 cases, at least one marker was informative and no tumor-specific loss of heterozygosity was observed.

Conclusion: We found no evidence of allelic loss within or near the VDR locus and no mutations within the splice junctions and coding regions of the VDR gene in 37 typical sporadic parathyroid adenomas. Thus, VDR is most unlikely to commonly serve as a classical tumor suppressor gene in sporadic parathyroid adenomas.
Changes in lamina structure are followed by spatial reorganization of heterochromatic regions in caspase-8-activated human mesenchymal stem cells
Authors: Raz Vered , Carlotti Françoise , Vermolen Bart J. , van der Poel Egge , Sloos Willem C. R. , Knaän-Shanzer Shoshan , de Vries Antoine A. F. , Hoeben Rob C. , Young Ian T. , Tanke Hans J. , Garini Yuval , Dirks Roeland W.
Published: September 2006

Apoptosis is fundamental to the regulation of homeostasis of stem cells in vivo. Whereas the pathways underlying the molecular and biochemical details of nuclear breakdown that accompanies apoptosis have been elucidated, the precise nature of nuclear reorganization that precedes the demolition phase is not fully understood. Here, we expressed an inducible caspase-8 in human mesenchymal stem cells, and quantitatively followed the early changes in nuclear organization during apoptosis. We found that caspase-8 induces alteration of the nuclear lamina and a subsequent spatial reorganization of both centromeres, which are shifted towards a peripheral localization, and telomeres, which form aggregates. This nuclear reorganization correlates with caspase-3 sensitivity of lamina proteins, because the expression of lamin mutant constructs with caspase-3 hypersensitivity resulted in a caspase-8-independent appearance of lamina intranuclear structures and telomere aggregates, whereas application of a caspase inhibitor restrains these changes in nuclear reorganization. Notably, upon activation of apoptosis, we observed no initial changes in the spatial organization of the promyelocytic leukemia nuclear bodies (PML-NBs). We suggest that during activation of the caspase-8 pathway changes in the lamina structure precede changes in heterochromatin spatial organization, and the subsequent breakdown of lamina and PML-NB.
Fab1p and AP-1 are required for trafficking of endogenously ubiquitylated cargoes to the vacuole lumen in S. cerevisiae
Authors: Phelan John P. , Millson Stefan H. , Parker Peter J. , Piper Peter W. , Cooke Frank T.
Published: September 2006

In S. cerevisiae synthesis of phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] by Fab1p is required for several cellular events, including an as yet undefined step in the ubiquitin-dependent trafficking of some integral membrane proteins from the trans-Golgi network to the vacuole lumen. AP-1 is a heterotetrameric clathrin adaptor protein complex that binds cargo proteins and clathrin coats, and regulates bi-directional protein trafficking between the trans-Golgi network and the endocytic/secretory pathway. Like fab1Δ cells, AP-1 complex component mutants have lost the ability to traffic ubiquitylated cargoes to the vacuole lumen – the first demonstration that AP-1 is required for this process. Deletion mutants of AP-1 complex components are compromised in their ability to synthesize PtdIns(3,5)P2, indicating that AP-1 is required for correct in vivo activation of Fab1p. Furthermore, wild-type protein sorting can be restored in AP-1 mutants by overexpression of Fab1p, implying that the protein-sorting defect in these cells is as a result of disruption of PtdIns(3,5)P2 synthesis. Finally, we show that Fab1p and Vac14p, an activator of Fab1p, are also required for another AP-1-dependent process: chitin-ring deposition in chs6Δ cells. Our data imply that AP-1 is required for some Fab1p and PtdIns(3,5)P2-dependent processes.
Role of the C-terminal di-leucine motif of 5-HT1A and 5-HT1B serotonin receptors in plasma membrane targeting
Authors: Carrel Damien , Hamon Michel , Darmon Michèle
Published: September 2006

The 5-HT1A and 5-HT1B serotonin receptors exhibit different subcellular localizations in neurons. Evidence has been reported that the C-terminal domain is involved in the somato-dendritic and axonal targeting of 5-HT1AR and 5-HT1BR, respectively. Here we analyzed the consequences of the mutation of a di-leucine motif and palmitoylated cysteines within this domain. Replacement of I414-I415 by a di-alanine in 5-HT1AR led to endoplasmic reticulum (ER) sequestration of the corresponding mutant expressed in cell lines as well as in hippocampal neurons in culture. Furthermore, di-leucine-mutated receptors were unable to bind 5-HT1A agonists and presented a major deficit in their glycosylation state, suggesting that they are misfolded. By contrast, mutation of the di-leucine motif in the C-terminal domain of 5-HT1BR had no major consequence on its subcellular targeting. However, in the case of the 1ActB chimera (substitution of the C-terminal domain of the 5-HT1BR into 5-HT1AR), this mutation was also found to cause sequestration within the ER. Replacement of palmitoylated cysteines by serines had no consequence on either receptor type. These data indicate that the di-leucine motif of the 5-HT1AR and 5-HT1BR tails is implicated in proper folding of these receptors, which is necessary for their ER export.
Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor C-terminal tail
Authors: Sørensen Vigdis , Wiedlocha Antoni , Haugsten Ellen Margrethe , Khnykin Denis , Wesche Jørgen , Olsnes Sjur
Published: September 2006

Members of the fibroblast growth factor family bind to one or more of the four closely related membrane-spanning FGF receptors. In addition to signaling through the receptors, exogenous FGF-1 and FGF-2 are endocytosed and translocated to the cytosol and nucleus where they stimulate RNA and DNA synthesis. Here we have studied the ability of the four FGF receptors to facilitate translocation of exogenous FGF-1 to the cytosol and nucleus. FGFR1 and FGFR4 were able to mediate translocation, whereas FGFR2 and FGFR3 completely lacked this ability. By analyzing mutant FGFRs we found that the tyrosine kinase domain could be deleted from FGFR1 without abolishing translocation, whereas the C-terminal tail of the FGFRs, constituted by approximately 50 amino acids downstream of the kinase domain, plays a crucial role in FGF-1 translocation. Three amino acids residues within the C-terminal tail were found to be of particular importance for translocation. For FGFR2, the two amino acid substitutions Q774M and P800H were sufficient to enable the receptor to support FGF-1 translocation. The results demonstrate a striking diversity in function of the four FGFRs determined by their C-terminal domain.
Electroplating of CoNiMnP-based permanent magnet and its application in bidirectionally actuated micro-electro-mechanical systems
Authors: Su Y , Wang H , Ding G , Cui F , Zhang W , Chen W
Published: September 2006

This article reports the preparation and characterization of CoNiMnP-based permanent magnetic material using various sulphate and chloride solutions under different conditions. Five samples are under study, and all the five samples show vertical magnetic anisotropy, among which sample 5 electroplated from the low concentration chloride solution under external magnetic field demonstrates the best magnetic properties with coercivity of 2632 Oe, remanence of 0.2 T, and maximum magnetic energy density of 10.185 kJ/m3. Experiments indicate that an array structure rather than a monolithic plate can suppress the stress and enhance the adhesion between the electroplated layer and the seed layer. Furthermore, the resistivity of the electroplated CoNiMnP is measured as 160–200 μω cm. The low-stress electroplated CoNiMnP-based permanent magnetic material has potential for bidirectional actuators in micro-electro-mechanical system applications such as micropump, microswitch, and microgripper.
Finite-element-based methodology for predicting the thermo-mechanical behaviour of superplastic forming tools
Authors: Shang J , Leen S B , Hyde T H
Published: September 2006

The time-dependent, thermo-mechanical behaviour of superplastic forming (SPF) dies is studied using finite-element (FE) analysis and experimental testing. The objective of the work is to predict the cyclic, non-linear stress-strain response of the dies under the severe cyclic thermal conditions that lead to short lives in service. Experiments are carried out on a simple rectangular-shaped die within a laboratory SPF press for a 20%Ni-24%Cr high-temperature tool steel to validate the FE modelling methodology. Tensile tests at four different temperatures up to 900 °C and short-term tensile creep tests at 900 °C are carried out to measure the high-temperature mechanical behaviour of the 40%Ni-20%Cr die material XN40F. Finally, time-dependent, non-linear, sequentially coupled, FE analyses are employed to study the behaviour of a representative XN40F SPF die. Attention is focused on the practical combined thermal cycles consisting of (a) major cycles, which correspond to controlled heat-up and free cool-down, and (b) minor cycles, which correspond to smaller temperature changes associated with the opening and closing of the press and die for part removal and blank insertion. It is shown that significant cyclic inelastic strains develop at die locations that correspond to locations at which major cracking has been observed during service. Elastic-plastic-creep, stress-strain loops are presented corresponding to these locations as a basis for die life prediction.
Effect of chlorine on polyethylene pipes in water distribution networks
Authors: Dear J P , Mason N S
Published: September 2006

With the increasing worry over water supplies, there is much interest worldwide in measures to be taken to retain the integrity of water distribution networks. This paper reports on a study of the integrity of polyethylene water distribution pipes related to the effect of chlorine in the water. Pipes used in water distribution networks are subject to demanding environmental, functional, and other stresses. Their working lifespan depends much on retention by the material of its antioxidant. In dry air, polyethylene can retain its properties for many decades. However, when polyethylene pipes are used in water distribution networks, the diffusion and loss of antioxidant from the material is increased from the inner pipe surface. When chlorine is present in the water, it can enter and spread through the material to increase the depletion rate of the antioxidant population. In this research, samples of pipe materials and sections of manufactured pipes have been subjected to accelerated life assessments. Also, modelling techniques have been devised to simulate the depletion of antioxidants in the pipe materials and used to research different possibilities including varying the concentrations of aggressive agents.
Effects of material morphology and processing conditions on the characteristics of hydroxyapatite and high-density polyethylene biocomposites by selective laser sintering
Authors: Hao L , Savalani M M , Zhang Y , Tanner K E , Harris R A
Published: September 2006

Hydroxyapatite (HA), a ceramic to which bone inherently bonds, incorporated into a polymer matrix enhances the bioactivity of implants. In order to rapid-manufacture bioactive implants, selective laser sintering (SLS) has been used to fabricate HA and high-density polyethylene (HDPE) composite (HA-HDPE). The properties of SLS-fabricated specimens have been investigated. The main aspects to be considered in the SLS technology are the properties of the materials used in the process and processing parameters (PPs). HA-HDPE composite specimens have been fabricated using five different powders with variations in particle size (PS), PS distribution, and five different laser PPs. The sintering height, the width, and the shrinkage of the specimens were determined and the effects of the particles and PPs on the physical properties were investigated. The HA-HDPE specimens were found to be highly porous and the sintered density and porosity of the specimens were influenced by the PS and PPs. The interparticle connectivity and the pore size range of the specimens were found to be predominantly determined by the PS and to a lesser extent also influenced by the PPs. The strength of these specimens and the relationship with porosity are discussed.