bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions between the PAS and HAMP Domains of theEscherichia coliAerotaxis Receptor Aer
Authors: Watts Kylie J. , Ma Qinhong , Johnson Mark S. , Taylor Barry L. 
Published: October 2004

ABSTRACTTheEscherichia colienergy-sensing Aer protein initiates aerotaxis towards environments supporting optimal cellular energy. The Aer sensor is an N-terminal, FAD-binding, PAS domain. The PAS domain is linked by an F1 region to a membrane anchor, and in the C-terminal half of Aer, a HAMP domain links the membrane anchor to the signaling domain. The F1 region, membrane anchor, and HAMP domain are required for FAD binding. Presumably, alterations in the redox potential of FAD induce conformational changes in the PAS domain that are transmitted to the HAMP and C-terminal signaling domains. In this study we used random mutagenesis and intragenic pseudoreversion analysis to examine functional interactions between the HAMP domain and the N-terminal half of Aer. Missense mutations in the HAMP domain clustered in the AS-2 α-helix and abolished FAD binding to Aer, as previously reported. Three amino acid replacements in the Aer-PAS domain, S28G, A65V, and A99V, restored FAD binding and aerotaxis to the HAMP mutants. These suppressors are predicted to surround a cleft in the PAS domain that may bind FAD. On the other hand, suppression of an Aer-C253R HAMP mutant was specific to an N34D substitution with a predicted location on the PAS surface, suggesting that residues C253 and N34 interact or are in close proximity. No suppressor mutations were identified in the F1 region or membrane anchor. We propose that functional interactions between the PAS domain and the HAMP AS-2 helix are required for FAD binding and aerotactic signaling by Aer.
THE SMALLEST ENCLOSING BALL OF BALLS: COMBINATORIAL STRUCTURE AND ALGORITHMS
Authors: FISCHER KASPAR , GÄRTNER BERND 
Published: October 2004

We develop algorithms for computing the exact smallest enclosing ball of a set of n balls in d-dimensional space. Unlike previous methods, we explicitly address small cases (n≤d+2), derive the necessary primitive operations and show that they can efficiently be realized with rational arithmetic. An implementation (along with a fast and robust floating-point version) is available as part of the CGAL library. We show that Welzl's randomized linear-time algorithm for computing the ball spanned by a set of points fails to work for balls. Consequently, the existing adaptations of the method to the ball case are incorrect. In solving the small cases we may assume that the ball centers are affinely independent. Via a geometric transformation and suitable generalization, it fits into the combinatorial model of unique sink orientations whose rich structure has recently received considerable attention. One consequence is that Welzl's algorithm does work for small instances; moreover, there is a variety of pivoting methods for unique sink orientations which have the potential of being fast in practice even for high dimensions. As a by-product, we show that the problem of finding the smallest enclosing ball of balls with a fixed point on the boundary is equivalent to the problem of finding the minimum-norm point in the convex hull of a union of balls.
Intracellular Labile Iron Modulates Adhesion of Human Monocytes to Human Endothelial Cells
Authors: Kartikasari Apriliana E.R. , Georgiou Niki A. , Visseren Frank L.J. , van Kats-Renaud Henny , van Asbeck B. Sweder , Marx Joannes J.M. 
Published: October 2004

Objective—Elevated iron stores and high plasma iron concentration have been linked to an increased risk of atherosclerosis. Iron may thereby affect the interaction of monocytes to endothelium, an initial event in the formation of atherosclerotic plaques.Methods and Results—Addition of 10 μmol/L non–transferrin-bound iron to the incubation medium caused a 2-fold increase in monocyte adhesion to human umbilical vein endothelial cells (HUVECs). A concordant increase in the expression of the following adhesion molecules was observed: vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial selectin on HUVECs as well as very late antigen-4, and lymphocyte function–associated antigen-1 on monocytes. The inclusion of either deferiprone or salicylaldehyde isonicotinoylhydrazone counteracted these effects. Intracellular iron chelation by deferoxamine was completed only after 10 hours of incubation, shown by reversal of iron-quenched intracellular calcein signal, and concurrently the effects of iron were blunted. The membrane-impermeable chelator, diethylenetriamine pentaaceticacid, failed to negate iron effects, even after 48 hours of treatment. Furthermore, only membrane-permeable superoxide or hydroxyl radical scavengers were capable of preventing HUVEC activation by iron.Conclusions—Non–transferrin-bound iron increases the level of intracellular labile iron, which promotes monocyte recruitment to endothelium and may thereby contribute to the pathogenesis of atherosclerosis. Iron-induced adhesion molecule expression was observed, and this event may involve the production of oxygen radicals.
Ultrasensitive Confocal Fluorescence Microscopy of C-Reactive Protein Interacting With FcγRIIa
Authors: Manolov Dimitar E. , Röcker Carlheinz , Hombach Vinzenz , Nienhaus G. Ulrich , Torzewski Jan 
Published: October 2004

Background—C-Reactive protein (CRP) is an acute phase protein with a suggested pathogenic role in cardiovascular disease. Previous reports proposed that the low-affinity IgG receptor FcγRIIa is the major receptor for CRP. However, these reports were met with criticism because the use of anti-CRP antibodies in the detection of CRP binding to FcγRIIa may have caused false-positive results.Methods and Results—To resolve this controversy, we used ultrasensitive fluorescence microscopy to study the association, dissociation, and equilibrium of CRP binding to FcγRIIa. CRP indeed binds to FcγRIIa, with low association rates and dissociation rates. Anti-CRP antibodies markedly enhance binding, as is evident from the decrease of the equilibrium dissociation coefficient by 2 orders of magnitude.Conclusions—Our study demonstrates the virtues of single fluorophore labeling and highlights the pitfalls of immunolabeling in investigating CRP/Fc receptor interactions. Importantly, this article provides the first quantitative characterization of CRP binding to FcγRIIa and explains and reconciles the diverse and conflicting data presented in the literature.
Transcription Factor Sterol Regulatory Element Binding Protein 2 Regulates Scavenger Receptor Cla-1 Gene Expression
Authors: Tréguier Morgan , Doucet Chantal , Moreau Martine , Dachet Christiane , Thillet Joëlle , Chapman M. John , Huby Thierry 
Published: October 2004

Objective—The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested thatCla-1gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whetherCla-1is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family.Methods and Results—Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform. The 5′-deletion analysis of 3 kb of the 5′-flanking sequence of theCla-1gene, combined with site-directed mutagenesis and electrophoretic mobility shift assay, allowed identification of a unique sterol responsive element. SREBP-mediated Cla-1 regulation was confirmed in stably transfected human embryonic kidney 293 cells expressing the active form of SREBP-2 at incremental levels. In these cell lines, Cla-1 mRNA and protein levels were increased in direct proportion to the level of SREBP-2 expression.Conclusions—These findings provide evidence that SREBP-2, a key regulator of cellular cholesterol uptake through modulation of the expression of the low-density lipoprotein receptor gene, may influence cellular cholesterol homeostasis via regulation ofCla-1gene expression.
Die Symbolik chthonischer Götter in Sophokles' Ödipus auf Kolonos
Authors: Tilg Stefan 
Published: October 2004

AbstractThe significant import of chthonic elements, especially chthonic deities, in Sophocles' Oedipus Coloneus has been widely noticed and variously discussed. The focus of this discussion traced, however, historical cult and religion without regard to a possible literary aspect. This paper tries to show how Sophocles throughout the play intentionally associates his protagonist with the sphere of the chthonic and dark as a means of creating a symbolic language and as a device of personal characterization.
Hera in Sappho, fr. 17 L-P, V—and Aeneid I?
Authors: Lidov Joel 
Published: October 2004

AbstractIn current commentaries and translations, the first stanza of Sappho fr. 17 is read as a prayer for Hera's presence. This understanding was created by modifying Wilamowitz's interpretation of the fragment as a dream narrative, but it depends on an improbable use of the opening word πλασιον involves an awkward third-person periphrasis for the second-person appeal, and creates insoluble difficulties of supplementation and usage in the third line. It is more fruitful to read the stanza as a deprecation of the god's anger, as in fr. 1.1-4; a suggested reading of χαλεπην ϑυελλαν (cf.Il. 21.335) gives αραταν a meaning within its normal, somewhat pejorative connotation, and allows a more plausible reconstruction of the end of line 3; attributing the source of the Atridae's distress to Hera is consistent with a number of indications of a narrative pattern in which Hera sends disruptive storms.
Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species
Authors: Kim Jeong H. , Chu Stephanie C. , Gramlich Jessica L. , Pride Yuri B. , Babendreier Emily , Chauhan Dharminder , Salgia Ravi , Podar Klaus , Griffin James D. , Sattler Martin 
Published: October 2004

AbstractBCR-ABL oncoprotein-expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3′-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an overactive mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy. (Blood. 2005; 105:1717-1723)
Activated protein C induces the release of microparticle-associated endothelial protein C receptor
Authors: Pérez-Casal Margarita , Downey Colin , Fukudome Kenji , Marx Gernot , Toh Cheng Hock 
Published: October 2004

AbstractActivated protein C (APC) treatment is now used for patients with severe sepsis. We investigated its effect in vitro on primary, physiologically relevant cells and demonstrate a novel mechanism of endothelial protein C receptor (EPCR) release that is not inhibited by metalloproteinase inhibitors. Exposure of human umbilical vein endothelial cells or monocytes to APC (6.25-100 nM) results in the release of EPCR-containing microparticles, as demonstrated by confocal microscopy and characterized through flow cytometry, enzyme-linked immunosorbent assay quantitation of isolated microparticles, and Western blotting. The phenomenon is time- and concentration-dependent and requires the APC active site, EPCR, and protease activated receptor 1 (PAR1) on endothelial cells. Neither protein C nor boiled or d-Phe-Pro-Arg-chloromethylketone–blocked APC can induce microparticle formation and antibody blockade of EPCR or PAR1 cleavage and activation abrogates this APC action. Coincubation with hirudin does not alter the APC effect. The released microparticle bound is full-length EPCR (49 kDa) and APC retains factor V–inactivating activity. Although tumor necrosis factor-α (10 ng/mL) can also induce microparticle-associated EPCR release to a similar extent as APC (100 nM), it is only APC-induced microparticles that contain bound APC. This novel observation could provide new insights into the consequences of APC therapy in the septic patient.
Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias
Authors: Faderl Stefan , Gandhi Varsha , O'Brien Susan , Bonate Peter , Cortes Jorge , Estey Elihu , Beran Miloslav , Wierda William , Garcia-Manero Guillermo , Ferrajoli Alessandra , Estrov Zeev , Giles Francis J. , Du Min , Kwari Monica , Keating Michael , Plunkett William , Kantarjian Hagop 
Published: October 2004

AbstractClofarabine (2-chloro-2′-fluoro-deoxy-9-β-D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).1 Clofarabine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m2 per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy.
Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies
Authors: May Kenneth F. , Roychowdhury Sameek , Bhatt Darshna , Kocak Ergun , Bai Xue-Feng , Liu Jin-Qing , Ferketich Amy K. , Martin Edward W. , Caligiuri Michael A. , Zheng Pan , Liu Yang 
Published: October 2004

AbstractWhen adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a “translation” fails because of an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is, therefore, desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti–mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T-cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of Epstein-Barr virus (EBV)–associated lymphoma development to screen a panel of anti–human CTLA-4 monoclonal antibodies (mAbs) for their effect on human lymphocytes in an in vivo “humanized” environment. We report significant heterogeneity of anti–human CTLA-4 mAbs in enhancing the expansion of human T cells in mice, and this heterogeneity cannot be attributed to immunoglobulin isotypes or affinity for CTLA-4. These data validate the development of additional screening tools, such as the one described, to further characterize functional activity of antihuman antibodies before proceeding with clinical translation to human studies.
Phytosphingosine in combination with ionizing radiation enhances apoptotic cell death in radiation-resistant cancer cells through ROS-dependent and -independent AIF release
Authors: Park Moon-Taek , Kim Min-Jung , Kang Young-Hee , Choi Soon-Young , Lee Jae-Hoon , Choi Jung-A , Kang Chang-Mo , Cho Chul-Koo , Kang Seongman , Bae Sangwoo , Lee Yun-Sil , Chung Hee Yong , Lee Su-Jae 
Published: October 2004

AbstractThe use of chemical modifiers as radiosensitizers in combination with low-dose irradiation may increase the therapeutic effect on cancer by overcoming a high apoptotic threshold. Here, we showed that phytosphingosine treatment in combination with γ-radiation enhanced apoptotic cell death of radiation-resistant human T-cell lymphoma in a caspase-independent manner. Combination treatment induced an increase in intracellular reactive oxygen species (ROS) level, mitochondrial relocalization of B-cell lymphoma-2(Bcl-2)-associated X protein (Bax), poly-adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) activation, and nuclear translocation of apoptosis-inducing factor (AIF). siRNA targeting of AIF effectively protected cells from the combination treatment-induced cell death. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited Bax relocalization and AIF translocation but not PARP-1 activation. Moreover, transfection of Bax-siRNA significantly inhibited AIF translocation. Pretreatment of PARP-1 inhibitor, DPQ (3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]-1(2H)-isoquinolinone), or PARP-1-siRNA also partially attenuated AIF translocation, whereas the same treatment did not affect intracellular ROS level and Bax redistribution. Taken together, these results demonstrate that enhancement of cell death of radiation-resistant cancer cells by phytosphingosine treatment in combination with γ-radiation is mediated by nuclear translocation of AIF, which is in turn mediated both by ROS-dependent Bax relocalization and ROS-independent PARP-1 activation. The molecular signaling pathways that we elucidated in this study may provide potential drug targets for radiation sensitization of cancers refractive to radiation therapy. (Blood. 2005;105:1724-1733)
Hepcidin is decreased in TFR2 hemochromatosis
Authors: Nemeth Elizabeta , Roetto Antonella , Garozzo Giovanni , Ganz Tomas , Camaschella Clara 
Published: October 2004

Abstract
The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. Urinary hepcidin was low or undetectable in 8 of 10 cases irrespective of the previous phlebotomy treatments. The only 2 cases with normal hepcidin values had concomitant inflammatory conditions. Our data indicate that TFR2 is a modulator of hepcidin production in response to iron. (Blood. 2005;105:1803-1806)
Binding of β2–glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells
Authors: Kuwana Masataka , Matsuura Eiji , Kobayashi Kazuko , Okazaki Yuka , Kaburaki Junichi , Ikeda Yasuo , Kawakami Yutaka 
Published: October 2004

AbstractAntiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)–binding plasma proteins, such as β2-glycoprotein I (β2GPI). We have recently found that CD4+ T cells autoreactive to β2GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to β2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β2GPI is induced as a direct consequence of antigen processing from β2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β2GPI induced a response of p276-290–specific CD4+ T-cell lines generated from the patients in an HLA-DR–restricted and antigen-processing–dependent manner but those with β2GPI or PL alone did not. In addition, the p276-290–reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound β2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β2GPI and should be useful in clarifying the pathogenesis of APS.
Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors
Authors: Lehar Sophie M. , Dooley James , Farr Andrew G. , Bevan Michael J. 
Published: October 2004

AbstractSignaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow–derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages.
Marburg I polymorphism of factor VII–activating protease is associated with idiopathic venous thromboembolism
Authors: Hoppe Berthold , Tolou Farzaneh , Radtke Hartmut , Kiesewetter Holger , Dörner Thomas , Salama Abdulgabar 
Published: October 2004

AbstractThe factor VII–activating protease (FSAP) variant Marburg I is known to attenuate the profibrinolytic system in vitro and was recently shown to be a significant predictor for the evolution and progression of carotid stenosis. The objective of this case-control study was to assess FSAP Marburg I's role in the occurrence of venous thromboembolism (VTE). The frequency of FSAP Marburg I was significantly increased in patients with a history of VTE (17 of 213 patients, 8.0%, P = .014) or idiopathic VTE (12 of 103 patients, 11.7%, P = .002) compared to healthy controls (5 of 213 controls, 2.3%). Logistic regression analysis confirmed FSAP Marburg I to be an independent risk factor for VTE (odds ratio, 3.5; 95% confidence interval [CI], 1.2-10.0) and idiopathic VTE (odds ratio, 6.2; 95% CI, 2.0-18.9).