bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of apoptosis in IL-3–dependent hematopoietic cell lines by guanine nucleotide depletion
Authors: Gu Jing Jin , Gathy Karen , Santiago Lalaine , Chen Eric , Huang Min , Graves Lee M. , Mitchell Beverly S.
Published: March 2003

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch point of purine nucleotide biosynthesis, leading to the generation of guanine nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, prevents cell growth by G1 arrest, and induces cell differentiation in a cell-type–specific manner. The molecular and sensing mechanisms underlying these effects are not clear. We have examined the induction of apoptosis by mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 (IL-3)–dependent murine hematopoietic cell lines. MPA treatment, at clinically relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented by the addition of guanosine at time points up to 12 hours, after which caspase 3 activity increased and apoptosis was not reversible. MPA treatment caused marked down-regulation of the MAP kinase kinase/extracellular regulatory kinase (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not induce apoptosis in IL-3–dependent cells, whereas inhibition of both pathways simulated the effects of MPA treatment. These results indicate that IMPDH inhibitors may be effective in modulating signal transduction pathways in hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for hematologic malignancies.
Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis
Authors: Nutku Esra , Aizawa Hideyuki , Hudson Sherry A. , Bochner Bruce S.
Published: March 2003

Sialic acid binding immunoglobulin-like lectin 8 (Siglec-8), which exists in 2 isoforms including one possessing cytoplasmic tyrosine motifs, is expressed only on human eosinophils, basophils, and mast cells. Until now, its function was unknown. Here we define a novel function of Siglec-8 on eosinophils. Siglec-8 cross-linking with antibodies rapidly generated caspase-3–like activity and reduced eosinophil viability through induction of apoptosis. The pancaspase inhibitor benzyloxycarbonyl (Cbz)–Val-Ala-Asp-(Ome)-fluoromethyl ketone (zVAD-FMK) completely blocked this response, implicating caspases in Siglec-8 cross-linking–induced apoptosis. Eosinophil survival-promoting cytokines such as interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) failed to block apoptosis and instead enhanced the sensitivity of eosinophils to undergo apoptosis in response to Siglec-8 antibody. Siglec-8 activation may provide a useful therapeutic approach to reduce numbers of eosinophils (and perhaps basophils and mast cells) in disease states where these cells are important.
Generation of low-toxicity interleukin-2 fusion proteins devoid of vasopermeability activity
Authors: Hu Peisheng , Mizokami Myra , Ruoff Gina , Khawli Leslie A. , Epstein Alan L.
Published: March 2003

Because of its key role in immunity, interleukin-2 (IL-2) has been studied extensively for the adoptive immunotherapy of cancer. Although systemic administration of IL-2 has been shown to stimulate antitumor responses in vivo, its efficacy in the clinic has been limited by the development of serious side effects, including the induction of vascular leak syndrome. Previously, we have identified a small peptide fragment of IL-2 that was found to contain the entire vasopermeability activity of the cytokine. The identification of the location of this potentially undesirable property of IL-2 enabled us to focus on the generation of mutant derivatives that might be lacking vasopermeability activity but that retain cytokine functionality. In addition to this discovery, our laboratory has constructed monoclonal antibody/IL-2 fusion proteins that can target this potent cytokine directly to tumor for the immunotherapy of both solid and lymphoid malignancies. Using this fusion protein technology, we have constructed a series of point mutations in the newly identified vasopermeability region of IL-2 for the purpose of deleting this activity. Fusion proteins showing reduced or deleted vasopermeability activity were then tested for their cytokine potency by several methods, including their binding to IL-2 receptors, T-cell proliferation assays, the induction of secondary cytokines, dose-escalating toxicity, and finally their ability to treat established solid tumors in syngeneic immunocompetent mice. The results of these studies clearly show that the vasopermeability activity of IL-2 can be substantially deleted by single point mutations such as Arg38Trp without grossly affecting the immune function of the cytokine.
CCR7 ligands induce rapid endocytosis in mature dendritic cells with concomitant up-regulation of Cdc42 and Rac activities
Authors: Yanagawa Yoshiki , Onoé Kazunori
Published: March 2003

Although chemokines are well known to function in chemotaxis, additional roles for these molecules in the immune system are not well understood. Dendritic cells (DCs) developmentally regulate the expression of chemokine receptors to facilitate their migration from the peripheral tissues to regional lymph nodes. Expressions of CCR1 and CCR5 on immature DCs are down-regulated on maturation, whereas CCR7 is selectively expressed on mature DCs. In the present study, we examined the effects of CCL19 and CCL21, 2 CCR7 ligands, on endocytosis of fluorescein isothiocyanate (FITC)–dextran by murine DCs. Both CCL19 and CCL21 markedly induced rapid uptake of FITC-dextran by mature DCs but not immature DCs. In contrast, CCL3, a ligand of CCR1 and CCR5, induced rapid uptake of FITC-dextran by immature DCs but not mature DCs. CCL19-induced endocytosis could be completely blocked by Clostridium difficile toxin B, which inhibits the Rho guanosine triphosphatase proteins, Rho, Rac, and Cdc42. This process was not abrogated by Y-27632, a specific inhibitor of Rho-associated kinase. In addition, CCL19 rapidly enhanced Cdc42 and Rac activity in mature DCs. These findings demonstrate that certain chemokines induce rapid endocytosis in each relevant DC population. It is suggested that CCR7 ligands activate Cdc42 and Rac, thereby inducing the endocytosis in mature DCs.
Platelet factor 4 enhances generation of activated protein C in vitro and in vivo
Authors: Slungaard Arne , Fernandez Jose A. , Griffin John H. , Key Nigel S. , Long Janel R. , Piegors Donald J. , Lentz Steven R.
Published: March 2003

Platelet factor 4 (PF4), an abundant platelet α-granule protein, accelerates in vitro generation of activated protein C (APC) by soluble thrombin/thrombomodulin (TM) complexes up to 25-fold. To test the hypothesis that PF4 similarly stimulates endothelium-associated TM, we assessed the influence of human PF4 on thrombin-dependent APC generation by cultured endothelial monolayers. APC generated in the presence of 1 to 100 μg PF4 was up to 5-fold higher than baseline for human umbilical vein endothelial cells, 10-fold higher for microvascular endothelial cells, and unaltered for blood outgrowth endothelial cells. In an in vivo model, cynomolgus monkeys (n = 6, each serving as its own control) were infused with either PF4 (7.5 mg/kg) or vehicle buffer, then with human thrombin (1.0 μg/kg/min) for 10 minutes. Circulating APC levels (baseline 3 ng/mL) peaked at 10 minutes, when PF4-treated and vehicle-treated animals had APC levels of 67 ± 5 ng/mL and 39 ± 2 ng/mL, respectively (P < .001). The activated partial thromboplastin time (APTT; baseline, 28 seconds) increased maximally by 27 ± 6 seconds in PF4-treated animals and by 9 ± 1 seconds in control animals at 30 minutes (P < .001). PF4-dependent increases in circulating APC and APTT persisted more than 2-fold greater than that of control's from 10 through 120 minutes (P ≤ .04). All APTT prolongations were essentially reversed by monoclonal antibody C3, which blocks APC activity. Thus, physiologically relevant concentrations of PF4 stimulate thrombin-dependent APC generation both in vitro by cultured endothelial cells and in vivo in a primate thrombin infusion model. These findings suggest that PF4 may play a previously unsuspected physiologic role in enhancing APC generation. (Blood. 2003;102:146-151)
Highly effective treatment of acquired immunodeficiency syndrome–related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology
Authors: Little Richard F. , Pittaluga Stefania , Grant Nicole , Steinberg Seth M. , Kavlick Mark F. , Mitsuya Hiroaki , Franchini Genoveffa , Gutierrez Martin , Raffeld Mark , Jaffe Elaine S. , Shearer Gene , Yarchoan Robert , Wilson Wyndham H.
Published: March 2003

The outcome of acquired immunodeficiency syndrome–related lymphomas (ARLs) has improved since the era of highly active antiretroviral therapy, but median survival remains low. We studied dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with suspension of antiretroviral therapy in 39 newly diagnosed ARLs and examined protein expression profiles associated with drug resistance and histogenesis, patient immunity, and HIV dynamics and mutations. The expression profiles from a subset of ARL cases were also compared with a matched group of similarly treated HIV-negative cases. Complete remission was achieved in 74% of patients, and at 53 months median follow-up, disease-free and overall survival are 92% and 60%, respectively. Following reinstitution of antiretroviral therapy after chemotherapy, the CD4+ cells recovered by 12 months and the viral loads decreased below baseline by 3 months. Compared with HIV-negative cases, the ARL cases had lower bcl-2 and higher CD10 expression, consistent with a germinal center origin and good prognosis, but were more likely to be highly proliferative and to express p53, adverse features with standard chemotherapy. Unlike HIV-negative cases, p53 overexpression was not associated with a poor outcome, suggesting different pathogenesis. High tumor proliferation did not correlate with poor outcome and may partially explain the high activity of dose-adjusted EPOCH. The results suggest that the improved immune function associated with highly active antiretroviral therapy (HAART) may have led to a shift in pathogenesis away from lymphomas of post–germinal center origin, which have a poor prognosis. These results suggest that tumor pathogenesis is responsible for the improved outcome of ARLs in the era of HAART.
Severe thrombocytopenic purpura due to rubella infection in a patient with systemic lupus erythematosus
Authors: Boehlen F , Balavoine J-F , de Moerloose P
Published: March 2003

We report the case of a woman suffering from systemic lupus erythematosus who developed a severe thrombocytopenic purpura (platelet count< 1 ×10 9=1) secondary to rubella infection. The search for antiplatelet antibodies revealed transient circulating anti-GPIIb-IIIa and anti-GPIb-IX platelet antibodies. After a few weeks, bound anti-GPIIb-IIIa antiplatelet antibodies were still detectable and they persisted several months after recovery, probably in relation to a mild autoimmune thrombocytopenia related to systemic lupus erythematosus. To our knowledge, this is the first case report of severe thrombocytopenic purpura due to rubella in an adult with systemic lupus erythematosus.
Profound difference in pharmacokinetics between morin and its isomer quercetin in rats
Authors: Hou Y C , Chao P D L , Ho H J , Wen C C , Hsiu S L
Published: March 2003

Morin and quercetin are isomeric antioxidant flavonols widely distributed in plant foods and herbs. The pharmacokinetics of both flavonols at two doses were investigated and compared in rats. Parent forms and their glucuronides and sulfates in serum were determined by HPLC before and after enzymatic hydrolysis, respectively. After oral dosing of morin, both the parent form, morin, and its glucuronides and sulfates were present in the bloodstream. The conjugated metabolites predominated at the dose of 25 mg kg−1, whereas the parent form was predominant at the dose of 50 mg kg−1. Moreover, the AUC of morin parent form increased by a factor of 37 when the dose doubled, indicating that morin showed nonlinear pharmacokinetics. On the other hand, quercetin presented only as glucuronides and sulfates in the blood, indicating negligible bioavailability of quercetin, and the metabolites showed linear pharmacokinetics at the two doses studied. When considering the total AUC of parent form with conjugated metabolites, the extent of absorption of morin was 3 fold that of quercetin at the dose of 50 mg kg−1. The results indicated that the difference in hydroxylation pattern on B-ring of flavonol markedly affected their fates in rats.
Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu-To, a traditional Chinese medicine, to rats
Authors: Yasuda Takaaki , Takasawa Akie , Nakazawa Takahiro , Ueda Joji , Ohsawa Keisuke
Published: March 2003

Shimotsu-To, which consists of four herbal extracts, has been used clinically for improving abnormal blood coagulation, fibrinolysis, atherosclerosis and chronic inflammation in Japan and China. We have investigated the pharmacological relationship between the effects and chemical components of Shimotsu-To after oral administration to rats. The urinary constituents were separated and identified by three dimensional (3D-) HPLC equipped with a photodiode array detector as a new tool and the chemical structures were determined by spectroscopic methods to be trans-ferulic acid-3-O-sulfate (1), vanillic acid (2), m-hydroxyphenylpropionic acid (3), trans-ferulic acid (4) and cis-ferulic acid (5). Of these compounds, 2–5 strongly inhibited platelet aggregation induced by ADP and arachidonic acid. Compound 1, the sulfate conjugate of 4, did not show any inhibitory effect, which suggested that the inhibitory effect on platelet aggregation was inactivated by sulfate conjugation. These results indicated that compounds 2–5 partly contributed to the anti-Oketsu effect of Shimotsu-To through the inhibition of platelet aggregation.
Targeted immunotherapy of cancer: development of antibody-induced cellular immunity
Authors: Lu Yingjuan , Low Philip S
Published: March 2003

Although immunotherapy of cancer encompasses a large variety of distinct protocols, virtually all therapeutic strategies require the enabling/training of the immune system to distinguish tumour tissue from healthy tissue. In the case of antibody-based therapies, specificity obviously arises from the selectivity of the antibodies for tumour antigens, and tumour cell death derives from either direct cytotoxicity of the antibody or antibody-dependent cellular cytotoxicity. However, even when both of the above killing mechanisms are simultaneously active, we suggest that antibody-based immunotherapies may fall far short of their full potential. In this editorial, we first summarize the mechanisms by which current antibody-based therapies mediate cancer cell removal, and then propose two strategies by which this class of immunotherapies might be further improved. These suggested improvements involve the decoration of tumour cell surfaces with foreign haptens against which an endogenous humoral immune response can be mounted and the recruitment of the cellular arm of the immune system in an antibody-dependent process.
Regulation of membrane expansion at the nerve growth cone
Authors: Pfenninger Karl H. , Laurino Lisandro , Peretti Diego , Wang Xiaoxin , Rosso Silvana , Morfini Gerardo , Cáceres Alfredo , Quiroga Santiago
Published: March 2003

Exocytotic incorporation of plasmalemmal precursor vesicles (PPVs) into the cell surface is necessary for neurite extension and is known to occur mainly at the growth cone. This report examines whether this is a regulated event controlled by growth factors. The Golgi complex and nascent PPVs of hippocampal neurons in culture were pulse-labeled with fluorescent ceramide. We studied the dynamics of labeled PPVs upon arrival at the axonal growth cone. In controls and cultures stimulated with brain-derived neurotrophic factor (BDNF), PPV clusters persisted in growth cones with a half-life(t1/2) of >14 minutes. Upon challenge with IGF-1,however, fluorescent elements cleared from the growth cones with a t1/2 of only 6 minutes. Plasmalemmal expansion was measured directly as externalization of membrane glycoconjugates in resealed growth cone particles (GCPs) isolated from fetal forebrain. These assays demonstrated that membrane expansion could be stimulated by IGF-1 in a dose-dependent manner but not by BDNF, even though intact, functional BDNF receptor was present on GCPs. Because both BDNF and IGF-1 are known to enhance neurite growth, but BDNF did not stimulate membrane expansion at the growth cone, we studied the effect of BDNF on the IGF-1 receptor. BDNF was found to cause the translocation of the growth-cone-specific IGF-1 receptor subunitβ gc to the distal axon, in a KIF2-dependent manner. We conclude that IGF-1 stimulates axonal assembly at the growth cone, and that this occurs via regulated exocytosis of PPVs. This mechanism is affected by BDNF only indirectly, by regulation of the βgc level at the growth cone.
Internalization signals in synaptotagmin VII utilizing two independent pathways are masked by intramolecular inhibitions
Authors: Dasgupta Shoumita , Kelly Regis B.
Published: March 2003

The synaptotagmin family of membrane proteins has been implicated in both exocytosis and endocytosis. Synaptotagmin I, a protein containing two tandem C2 domains (the C2A and the C2B) in its cytoplasmic tail, is involved in regulated exocytosis of synaptic vesicles as well as compensatory endocytosis. A related family member, synaptotagmin VII, is involved in multiple forms of regulated exocytosis of lysosomes and secretory granules. In this study we show that the cytoplasmic C2 domains in synaptotagmin VII contain unique internalization signals and regulators of these signals. The C-terminal portion of the C2B is internalized in much the same way as the corresponding region of synaptotagmin I. This signal is tryptophan-based and dynamin and eps15 dependent. In contrast, the C2A contains an unusual internalization signal that is not seen in the C2A of synaptotagmin I. This signal is not based on the homologous tryptophan in its C-terminus. Moreover,internalization of the C2A domain is both dynamin and eps15 independent. Finally, the C2B domain of synaptotagmin VII contains an inhibitory motif that prevents internalization. Endocytic trafficking of synaptotagmin VII is thus governed by these two latent internalization signals, which are concealed by intramolecular inhibition. We propose that endocytosis of synaptotagmin VII is regulated in this way to allow it to couple the processes of regulated exocytosis and compensatory endocytosis.
Drosophila miniatureandduskyencode ZP proteins required for cytoskeletal reorganisation during wing morphogenesis
Authors: Roch Fernando , Alonso Claudio R. , Akam Michael
Published: March 2003

We have characterised the function of two Drosophila genes, miniature and dusky, that are required for the morphological reorganisation of the apical membrane during wing epidermis differentiation. These genes encode transmembrane proteins containing a ZP (zona pellucida)domain and are homologous to several vertebrate and invertebrate apical matrix components. miniature and dusky are only expressed in tissues secreting a cuticle, and the Min protein localises to the apical membrane during the early stages of cuticle formation. We propose that Min and Dusky form a novel subfamily within the ZP domain proteins and are specifically involved in the interactions between the apical membrane, the cytoskeleton and the forming cuticle.
The lipoma preferred partner LPP interacts with α-actinin
Authors: Li Bo , Zhuang Lei , Reinhard Matthias , Trueb Beat
Published: March 2003

The lipoma preferred partner LPP is a member of the zyxin family of proteins. In this paper, we demonstrate that the structural similarities observed between zyxin and LPP also extend to their interaction capabilities. Similar to zyxin, LPP was found to bind to α-actinin in vitro. This interaction was confirmed in yeast and mammalian cells. Studies utilizing the three-hybrid system further indicated that zyxin and LPP compete for the same binding site in α-actinin. This site was mapped to the central rod ofα-actinin, which contains spectrin-like repeats 2 and 3. In the case of LPP, a conserved motif present at the N-terminus was shown to be responsible for the interaction. Constructs lacking this motif did not bind toα-actinin in the yeast two-hybrid system and were not able to recruitα-actinin to an ectopic site in mammalian cells. Quantitative data obtained with the two-hybrid and the three-hybrid system suggest that LPP has a lower affinity for α-actinin than zyxin. It is likely that this difference leads to slightly different roles played by LPP and zyxin during the assembly and disassembly of focal adhesions.
The cancer antigen CA125 represents a novel counter receptor for galectin-1
Authors: Seelenmeyer Claudia , Wegehingel Sabine , Lechner Johannes , Nickel Walter
Published: March 2003

CA125 is an ovarian cancer antigen whose recently elucidated primary structure suggests that CA125 is a giant mucin-like glycoprotein present on the cell surface of tumor cells. Here, we establish a functional link between CA125 and β-galactoside-binding, cell-surface lectins, which are components of the extracellular matrix implicated in the regulation of cell adhesion, apoptosis, cell proliferation and tumor progression. On the basis of mass spectrometry and immunological analyses, we find that CA125 is a counter receptor for galectin-1, as both soluble and membrane-associated fragments of CA125 derived from HeLa cell lysates are shown to bind specifically to human galectin-1 with high efficiency. This interaction is demonstrated (1) to depend on β-galactose-terminated, O-linked oligosaccharide chains of CA125, (2) to be preferential for galectin-1 versus galectin-3 and (3) to be regulated by the cellular background in which CA125 is expressed. Despite lacking a conventional signal peptide, a CA125 C-terminal fragment of 1148 amino acids, representing less than 10% of the full-length protein, retains the ability to integrate into secretory membranes such as the endoplasmic reticulum (ER) and the Golgi, and is targeted to the plasma membrane by conventional secretory transport. As demonstrated by a novel assay that reconstitutes non-conventional secretion of galectin-1 based on fluorescence-activated cell sorting (FACS), we find that tumor-derived HeLa cells expressing endogenous CA125 present more than ten times as much galectin-1 on their surface compared with non-tumor-derived, CA125-deficient CHO cells. Intriguingly, both the galectin-1 expression level and the cell-surface binding capacity for galectin-1 are shown to be similar in CHO and HeLa cells, suggesting that CA125 might be a factor involved in the regulation of galectin-1 export to the cell surface.
Myosin Va facilitates the distribution of secretory granules in the F-actin rich cortex of PC12 cells
Authors: Rudolf Rüdiger , Kögel Tanja , Kuznetsov Sergei A. , Salm Thorsten , Schlicker Oliver , Hellwig Andrea , Hammer John A. , Gerdes Hans-Hermann
Published: March 2003

Neuroendocrine secretory granules, the storage organelles for neuropeptides and hormones, are formed at the trans-Golgi network, stored inside the cell and exocytosed upon stimulation. Previously, we have reported that newly formed secretory granules of PC12 cells are transported in a microtubule-dependent manner from the trans-Golgi network to the F-actin-rich cell cortex, where they undergo short directed movements and exhibit a homogeneous distribution. Here we provide morphological and biochemical evidence that myosin Va is associated with secretory granules. Expression of a dominant-negative tail domain of myosin Va in PC12 cells led to an extensive clustering of secretory granules close to the cell periphery, a loss of their cortical restriction and a strong reduction in their motility in the actin cortex. Based on this data we propose a model that implies a dual transport system for secretory granules: after microtubule-dependent delivery to the cell periphery, secretory granules exhibit a myosin Va-dependent transport leading to their restriction and even dispersal in the F-actin-rich cortex of PC12 cells.
Intracellular localisation of human HIF-1α hydroxylases:implications for oxygen sensing
Authors: Metzen Eric , Berchner-Pfannschmidt Utta , Stengel Petra , Marxsen Jan H. , Stolze Ineke , Klinger Matthias , Huang Wei Qi , Wotzlaw Christoph , Hellwig-Bürgel Thomas , Jelkmann Wolfgang , Acker Helmut , Fandrey Joachim
Published: March 2003

Hypoxia-inducible factor1 (HIF-1) is an essential transcription factor for cellular adaptation to decreased oxygen availability. In normoxia the oxygen-sensitive α-subunit of HIF-1 is hydroxylated on Pro564 and Pro402 and thus targeted for proteasomal degradation. Three human oxygen-dependent HIF-1α prolyl hydroxylases (PHD1, PHD2, and PHD3) function as oxygen sensors in vivo. Furthermore, the asparagine hydroxylase FIH-1 (factor inhibiting HIF) has been found to hydroxylate Asp803 of the HIF-1 C-terminal transactivation domain, which results in the decreased ability of HIF-1 to bind to the transcriptional coactivator p300/CBP. We have fused these enzymes to the N-terminus of fluorescent proteins and transiently transfected the fusion proteins into human osteosarcoma cells (U2OS). Three-dimensional 2-photon confocal fluorescence microscopy showed that PHD1 was exclusively present in the nucleus, PHD2 and FIH-1 were mainly located in the cytoplasm and PHD3 was homogeneously distributed in cytoplasm and nucleus. Hypoxia did not influence the localisation of any enzyme under investigation. In contrast to FIH-1, each PHD inhibited nuclear HIF-1α accumulation in hypoxia. All hydroxylases suppressed activation of a cotransfected hypoxia-responsive luciferase reporter gene. Endogenous PHD2mRNA and PHD3mRNA were hypoxia-inducible, whereas expression of PHD1mRNA and FIH-1mRNA was oxygen independent. We propose that PHDs and FIH-1 form an oxygen sensor cascade of distinct subcellular localisation.
Adherens junctions and tight junctions are regulated via different pathways by progastrin in epithelial cells
Authors: Hollande Frédéric , Lee Debra J. , Choquet Armelle , Roche Serge , Baldwin Graham S.
Published: March 2003

Adhesion between neighbouring epithelial cells is a crucial and tightly controlled process. In the gastrointestinal tract, the integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumour metastasis. We recently showed that migration of the gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone gastrin17. Here, we examine the effect on cell-cell adhesion of the prohormone progastrin, the concentration of which is increased in the plasma of patients with colorectal carcinoma.

Progastrin induced the dissociation of both tight junction (TJ) and adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin construct restored membrane localisation of zonula occludens-1 (ZO-1),occludin, β-catenin and E-cadherin. This restoration was reversed by treatment with exogenous progastrin. Endogenous or exogenous progastrin also increased the paracellular flux of mannitol, and induced cell migration of several gastrointestinal cell lines. In addition, progastrin enhanced Src tyrosine kinase activity and induced a spatial delocalisation of protein kinase Cα. Using dominant-negative mutants and pharmacological inhibitors, we showed that the stimulation of Src kinase activity was essential for the regulation of TJs. By contrast, the dissociation of AJs involved phosphatidylinositol 3-kinase, partly through the formation of a complex with protein kinase Cα. We conclude that separate pathways mediate the disruption of AJs and TJs by progastrin. Either pathway may contribute to the co-carcinogenic role of this prohormone in colorectal carcinoma.
Tensegrity I. Cell structure and hierarchical systems biology
Authors: Ingber Donald E.
Published: March 2003

In 1993, a Commentary in this journal described how a simple mechanical model of cell structure based on tensegrity architecture can help to explain how cell shape, movement and cytoskeletal mechanics are controlled, as well as how cells sense and respond to mechanical forces (J. Cell Sci.104, 613-627). The cellular tensegrity model can now be revisited and placed in context of new advances in our understanding of cell structure,biological networks and mechanoregulation that have been made over the past decade. Recent work provides strong evidence to support the use of tensegrity by cells, and mathematical formulations of the model predict many aspects of cell behavior. In addition, development of the tensegrity theory and its translation into mathematical terms are beginning to allow us to define the relationship between mechanics and biochemistry at the molecular level and to attack the larger problem of biological complexity. Part I of this two-part article covers the evidence for cellular tensegrity at the molecular level and describes how this building system may provide a structural basis for the hierarchical organization of living systems — from molecule to organism. Part II, which focuses on how these structural networks influence information processing networks, appears in the next issue.
GSK-3: tricks of the trade for a multi-tasking kinase
Authors: Doble Bradley W. , Woodgett James R.
Published: March 2003

Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes. The enzyme is a key regulator of numerous signalling pathways, including cellular responses to Wnt, receptor tyrosine kinases and G-protein-coupled receptors and is involved in a wide range of cellular processes, ranging from glycogen metabolism to cell cycle regulation and proliferation. GSK-3 is unusual in that it is normally active in cells and is primarily regulated through inhibition of its activity. Another peculiarity compared with other protein kinases is its preference for primed substrates,that is, substrates previously phosphorylated by another kinase. Several recent advances have improved our understanding of GSK-3 regulation in multiple pathways. These include the solution of the crystal structure of GSK-3, which has provided insight into GSK-3's penchant for primed substrates and the regulation of GSK-3 by serine phosphorylation, and findings related to the involvement of GSK-3 in the Wnt/β-catenin and Hedgehog pathways. Finally, since increased GSK-3 activity may be linked to pathology in diseases such as Alzheimer's disease and non-insulin-dependent diabetes mellitus,several new GSK-3 inhibitors, such as the aloisines, the paullones and the maleimides, have been developed. Although they are just starting to be characterized in cell culture experiments, these new inhibitors hold promise as therapeutic agents.
Adsorption of Copper, Zinc and Nickel Ions from Single and Binary Metal Ion Mixtures on to Chicken Feathers
Authors: Al-Asheh Sameer , Banat Fawzi , Al-Rousan Dheaya‘
Published: March 2003

Certain industries often produce mixtures of heavy metal ions in their waste products. Because of the nature of heavy metal ions and the adsorption process, such metal ions can compete with each other for the sorption sites on an adsorbent during adsorption processes. In the present work, binary systems composed of copper, zinc and nickel ions were selected as examples of heavy metal ion mixtures and tested via batch adsorption processes using chicken feathers as an adsorbent. The uptake of individual metal ions was depressed by the presence of another. Thus, the uptake of copper ions from an initial copper ion solution of 20 ppm concentration was reduced from 0.042 mmol/g to ca. 0.019 mmol/g by the presence of a similar concentration of nickel ions. The Freundlich, Langmuir and Sips multi-component adsorption models were employed to predict the uptake of metal ions from binary metal ion solutions using constants obtained from adsorption isotherm models applied to single-solute systems.
Relationship between the Catalytic and Detection Properties of SnO2 and Pt/SnO2 Systems
Authors: Kocemba Ireneusz , Szafran Sławomir , Rynkowski Jacek , Paryjczak Tadeusz
Published: March 2003

Semiconductor gas sensors based on metal oxides have been widely accepted as an important tool for the detection of different gases in air. An understanding of all the mechanisms related to such detection is essential in order to improve the sensitivity and selectivity of these gas detectors. This paper considers the mechanism of detection by semiconductor oxide gas sensors in terms of catalytic reactions described by Rideal–Eley and Langmuir–Hinshelwood mechanisms. Some relationships were discussed between the catalytic and detection properties of SnO2 and Pt/SnO2 systems used on the one hand as catalysts of low-temperature CO oxidation and on the other hand as sensors of CO in air.
Effect of Treatment on the Adsorption Capacity of Activated Carbon
Authors: Nouri Sirous
Published: March 2003

The adsorption of p-cresol by three activated carbons, one untreated S.E.I. and the other two treated S.E.I., was carried out under controlled conditions. Such treatment led to a change in the point of zero charge (PZC) and the adsorption capacity (Qmax) of the carbon concerned. The adsorption capacity and affinity (K1) of each carbon was determined using the Langmuir homogeneous and binary models to compare the effects of different treatments on these and relative parameters. The variation of the model parameters with the solution pH was also studied.

The fitted parameters obtained from both models showed the pH value had the most significant effect on the adsorption capacity (Qmax) and the adsorption affinity (K1) of a given carbon, with both quantities showing a decrease with increasing pH. It was found that the uptake of the molecular forms of the aromatic solute was dependent on the PZC of the carbons. Treatment with H2 increased the PZC whilst treatment with H2SO4 led to a decrease in this factor. At higher pH (when the solute was in an ionic form), it was found that electrostatic forces played a significant role on the extent of adsorption. Under these conditions, the adsorption of the solute depended on the concentration of its anionic form. It was shown that the effect of pH must be considered from the viewpoint of its combined effect on the carbon surface and on the solute molecules.
Hydrophilicity–Hydrophobicity Characteristics of Solid Surfaces and the State of Water near Surfaces of a Various Nature
Authors: Tarasevich Yu.I. , Polyakova I.G. , Polyakov V.E.
Published: March 2003

Values for the surface tension, π, of 85 mJ/m2 and for the contact angle of wetting by water as its saturated vapour, θV, of 75° are proposed as criteria for distinguishing between hydrophilic and hydrophobic solid surfaces. It is shown that the water boundary layers at hydrophilic surfaces are more ordered while those at hydrophobic surfaces are less ordered relative to the situation in the bulk water structure. The localised model can be used to describe the state of motion of water molecules at a hydrophilic surface, while the motion of water molecules near a hydrophobic surface conforms to the non-localised model.
Dividend behavior surrounding LIFO adoption
Authors: Ettredge Michael , Youn Kim Jeong
Published: March 2003

This study investigates the influence of LIFO adoption on changes in cash dividends. Descriptive studies of dividend policy have found that changes in cash dividends are positively associated with both operating cash flows and accounting earnings. LIFO adoption is interesting because it typically decreases earnings while increasing cash flows through deferral of U.S. taxes. We regress changes in annual cash dividends against a proxy for the earnings effect and the cash flow effect of LIFO usage, as well as additional control variables. The model is estimated for each of five years, centered on the adoption year, using a sample of 361 LIFO adopters. The results suggest that adoption year changes in cash dividends are associated with the negative earnings effect rather than the positive cash flow effect of LIFO adoption.
Professional portfolio managers and the January effect: theory and evidence
Authors: Athanassakos George , Schnabel Jacques A.
Published: March 2003

While many researchers have documented a pronounced seasonality of stock returns in the month of January, a universally accepted theory of why this so‐called “January effect” occurs has yet to be put forward. This paper develops a theory of portfolio rebalancing which is based on the effects induced by the calendar year planning horizon of professional portfolio managers. A simple model of portfolio choice and leisure consumption is developed via which it is shown that portfolio allocations early in the calendar year should be more heavily weighted towards the stock market and less heavily weighted towards cash and cash equivalents than later in the calendar year. The paper provides evidence on the impact systematic shifts in the portfolio holdings of institutional investors have had on the aggregate stock market in Canada over the period 1973:Q1 to 1992:Q4. It is shown that institutional trading actively influences stock price changes and that portfolio rebalancing on the part of professional fund managers, prompted by conflict‐of‐interest considerations, causes the bidding up of stock prices in January.
Rational price limits in futures markets: tests of a simple optimizing model
Authors: Ackert Lucy F. , Hunter William C.
Published: March 2003

This paper tests a simple descriptive model of optimal futures price limits under the assumption that futures exchanges operate under the criterion of minimizing the long‐run average cost associated with market making. This cost is composed of a “running cost,” reflecting the expenses associated with providing for the continuous operation of the market, and a cost associated with trading interruptions resulting from limit moves. The model implies that the optimal daily limit increases with the cost of trading interruptions and decreases with running costs and that at the margin, the limit should be set so as to just balance these costs. The model is tested using price limits in place on ten contracts traded on the Chicago Board of Trade between 1977 and 1979. The econometric results indicate that for seven of the ten contracts examined, the actual level of the daily price limit is, on average, equal to that implied by the optimizing model.
A millennial-scale record of Holocene tsunamis on the Kronotskiy Bay coast, Kamchatka, Russia
Authors: Pinegina Tatiana K. , Bourgeois Joanne , Bazanova Lilia I. , Melekestsev Ivan V. , Braitseva Olga A.
Published: March 2003

Deposits from as many as 50 large tsunamis during the last 7000 years are preserved on the Pacific coast of the Kamchatka Peninsula near the mouth of the Zhupanova River, southern Kronotskiy Bay. These deposits are dated and correlated using Holocene marker tephra layers. The combined, preserved record of tsunami deposits and of numerous marker tephras on Kamchatka offers an unprecedented opportunity to study tsunami frequency. For example, from the stratigraphy along southern Kronotskiy Bay, we estimate frequency of large tsunamis (>5 m runup). In the last 3000 years, the minimum frequency is about one large tsunami per 100 years, and the maximum about one large tsunami per 30 years; the latter frequency occurred from about 0 to 1000 A.D. This time interval corresponds to a period of increased seismicity and volcanic activity that appears to be recorded in many places on the Kamchatka Peninsula.
Tree-ring dated landslide movements and their relationship to seismic events in southwestern Montana, USA
Authors: Carrara Paul E. , O’Neill J. Micheal
Published: March 2003

To determine periods of incremental landslide movement and their possible relationship to regional seismic events, the tree-ring records of 32 tilted and damaged conifers at three sites on landslides in the Gravelly Range of southwestern Montana were examined. Several signs of disturbance in the tree-ring record indicating landslide movement were observed. Commonly, the tree-ring record displayed a marked reduction in annual ring width and/or the reaction wood formation. The tree-ring records from the three landslide sites indicate multiple periods of movement during the 20th century. Many of the periods of movement indicated by the strongest signals (most trees) at the sites occurred the year following significant earthquakes in the region. Those seismic events for which evidence in the tree-ring record was found at one or more of the three sites are the 1983 Borah Peak, 1959 Hebgen Lake, 1935 Helena, 1925 Clarkson, and 1908 Virginia City earthquakes. This study suggests that many of the landslide movements were triggered by, or are coincident with, earthquakes as much as 200 km from the study area.
Phytolith assemblages as a promising tool for reconstructing Mediterranean Holocene vegetation
Authors: Delhon Claire , Alexandre Anne , Berger Jean-François , Thiébault Stéphanie , Brochier Jacques-Léopold , Meunier Jean-Dominique
Published: March 2003

The reliability of phytolith assemblage analysis for characterizing Mediterranean vegetation is investigated in this study. Phytolith assemblages are extracted from modern and buried Holocene soils from the middle Rhône valley (France). The relation between modern phytolith assemblages and the surrounding vegetation, as well as between fossil assemblages and contemporaneous vegetation, already reconstructed through other proxies, is discussed. We demonstrate that the main northwestern Mediterranean biomes are well distinguished by soil phytolith assemblage analysis. In particular, the density of pine and nonconiferous trees (densities expressed relatively to the grass cover) and the overall degree of opening of the vegetation appear well recorded by three phytolith indexes. North Mediterranean vegetation changes during the Holocene period, mainly tree line shifts, pine wood development and deforestation are poorly documented, due to the scarcity of proxy-preserving sites. Phytolith assemblage analysis of soils, buried soils, and sediments appears to be a promising technique to fill this gap.
Precise radiocarbon dating of Late-Glacial cooling in mid-latitude South America
Authors: Hajdas Irka , Bonani Georges , Moreno Patricio I. , Ariztegui Daniel
Published: March 2003

Variability of atmospheric 14C content often complicates radiocarbon-based chronologies; however, specific features such as periods of constant 14C age or steep changes in radiocarbon ages can be useful stratigraphic markers. The Younger Dryas event in the Northern Hemisphere is one of those periods, showing conspicuous 14C wiggles. Although the origin of those variations is not fully understood, we can make practical use of them and determine: (i) whether the Younger Dryas was global in extent; if so, (ii) were the initial cooling and the final warming synchronous worldwide; and (iii) what are the implications of these similarities/differences? Here we report high-resolution AMS 14C chronologies from the mid-latitudes of South America that pinpoint a cool episode between 11,400 and 10,20014C yr B.P. The onset of the final cool episode of the Late Glacial in the southern mid-latitudes, i.e., the Huelmo/Mascardi Cold Reversal, preceded the onset of the Younger Dryas cold event by ∼550 calendar years. Both events ended during a radiocarbon-age plateau at ∼10,20014C yr B.P. Thus, the Huelmo/Mascardi Cold Reversal encompasses the Younger Dryas, as well as a couple of short-term cool/warm oscillations that immediately preceded its onset in the North Atlantic region.
Land–sea correlations for the last glaciation inferred from a pollen and dinocyst record from the Portuguese margin
Authors: Turon Jean-Louis , Lézine Anne-Marie , Denèfle Michelle
Published: March 2003

Pollen and dinoflagellate cyst assemblages from Core SU 81-18 recovered off Portugal (37°46′N, 10°11′W; 3135-m water depth) have been used to document the short-term environmental changes that occurred in southwest Europe since 25,000 yr B.P. The relationship between the oceanic and continental environments has been further examined by the use of other marine proxies (coarse sedimentary fraction, foraminifera) and by comparison with proximal land pollen records. Heinrich 2 (H2) and Heinrich 1 (H1) events were the most extreme parts of the highly variable last glacial period, with the maximum extension of dry steppe on land and the occurrence of cool and dilute waters at the core site. Our study shows that H1 and H2 are divided in two distinct phases: one with Neogloboquadrina pachyderma left coiling associated with the maximum input of ice rafted debris, reflecting the in situ release of icebergs and the occurrence of cool and dilute seawater at the core site; the other with dinoflagellate cysts of subpolar affinity, Bitectatodinium tepikiense, reflecting a seasonal control marked by warm summer SST and cold winter SST.
Regular self-similar solutions of the nonlinear heat equation with initial data above the singular steady state
Authors: Souplet Philippe , Weissler Fred B
Published: March 2003

We prove the existence of positive regular solutions of the Cauchy problem for the nonlinear heat equation

u_t=Δu+|u|^αu

, with initial value

μV

, for all

μ>1

close enough to

1

, where

V

is the singular stationary solution in

\mathbb{R}^{N}

. This result is obtained when

N>2

and

\frac{2}{N - 2} < \alpha < \alpha^*

, where

α^∗

is the critical power for the intersection properties of

V

with regular stationary solutions. Moreover, for

μ

as above, there exist at least two positive regular solutions with initial value

μV

. These results are optimal since it is known that no such solution exists if

α≥α^∗

.

Nous montrons l’existence de solutions positives régulières du problème de Cauchy pour l’équation de la chaleur non linéaire

u_t=Δu+|u|^αu

, avec donnée initiale

μV

, pour tout

μ>1

assez proche de

1

, où

V

est la solution stationnaire singulière dans

\mathbb{R}^{N}

. Ce résultat est obtenu pour

N>2

et

\frac{2}{N - 2} < \alpha < \alpha^*

, où

α^∗

est la puissance critique pour les propriétés d’intersection de

V

avec les solutions stationnaires régulières. De plus, pour

μ

comme ci-dessus, il existe au moins deux solutions positives régulières avec donnée initiale

μV

. Ces résultats sont optimaux, car on savait déjà que de telles solutions ne peuvent exister si

α≥α^∗

.