bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Impairment of Lytic and Cytokine Functions in Senescent Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes
Authors: Dagarag Mirabelle , Ng Hwee , Lubong Rachel , Effros Rita B. , Yang Otto O.
Published: February 2003

Telomere length is abnormally short in the CD8+T-cell compartment of human immunodeficiency virus type 1 (HIV-1)-infected persons, likely because of chronic cell turnover. Although clonal exhaustion of CD8+cytotoxic T lymphocytes (CTL) has been proposed as a mechanism for loss of antigen-specific responses, the functional consequences of exhaustion are poorly understood. Here we used telomerase transduction to evaluate the impact of senescence on CTL effector functions. Constitutive expression of telomerase in an HIV-1-specific CTL clone results in enhanced proliferative capacity, in agreement with prior studies of other human cell types. Whereas the CTL remain phenotypically normal in terms of antigenic specificity and requirements for proliferation, their cytolytic and antiviral capabilities are superior to those of control CTL. In contrast, their ability to produce gamma interferon and RANTES is essentially unchanged. The selective enhancement of cytolytic function in memory CTL by ectopic telomerase expression implies that loss of this function (but not cytokine production) is a specific consequence of replicative senescence. These data suggest a unifying mechanism for the in vivo observations that telomere lengths are shortened in the CD8+cells of HIV-1-infected persons and that HIV-1-specific CTL are deficient in perforin. Telomerase transduction could therefore be a tool with which to explore a potential therapeutic approach to an important pathophysiologic process of immune dysfunction in chronic viral infection.
Effects of Point Mutations in the Major Capsid Protein of Beet Western Yellows Virus on Capsid Formation, Virus Accumulation, and Aphid Transmission
Authors: Brault V. , Bergdoll M. , Mutterer J. , Prasad V. , Pfeffer S. , Erdinger M. , Richards K. E. , Ziegler-Graff V.
Published: February 2003

Point mutations were introduced into the major capsid protein (P3) of cloned infectious cDNA of the polerovirus beet western yellows virus (BWYV) by manipulation of cloned infectious cDNA. Seven mutations targeted sites on the S domain predicted to lie on the capsid surface. An eighth mutation eliminated two arginine residues in the R domain, which is thought to extend into the capsid interior. The effects of the mutations on virus capsid formation, virus accumulation in protoplasts and plants, and aphid transmission were tested. All of the mutants replicated in protoplasts. The S-domain mutant W166R failed to protect viral RNA from RNase attack, suggesting that this particular mutation interfered with stable capsid formation. The R-domain mutant R7A/R8A protected ∼90% of the viral RNA strand from RNase, suggesting that lower positive-charge density in the mutant capsid interior interfered with stable packaging of the complete strand into virions. Neither of these mutants systemically infected plants. The six remaining mutants properly packaged viral RNA and could invade
Nicotiana clevelandii
systemically following agroinfection. Mutant Q121E/N122D was poorly transmitted by aphids, implicating one or both targeted residues in virus-vector interactions. Successful transmission of mutant D172N was accompanied either by reversion to the wild type or by appearance of a second-site mutation, N137D. This finding indicates that D172 is also important for transmission but that the D172N transmission defect can be compensated for by a “reverse” substitution at another site. The results have been used to evaluate possible structural models for the BWYV capsid.
Reversible Oxidative Modification as a Mechanism for Regulating Retroviral Protease Dimerization and Activation
Authors: Davis David A. , Brown Cara A. , Newcomb Fonda M. , Boja Emily S. , Fales Henry M. , Kaufman Joshua , Stahl Stephen J. , Wingfield Paul , Yarchoan Robert
Published: February 2003

Human immunodeficiency virus protease activity can be regulated by reversible oxidation of a sulfur-containing amino acid at the dimer interface. We show here that oxidation of this amino acid in human immunodeficiency virus type 1 protease prevents dimer formation. Moreover, we show that human T-cell leukemia virus type 1 protease can be similarly regulated through reversible glutathionylation of its two conserved cysteine residues. Based on the known three-dimensional structures and multiple sequence alignments of retroviral proteases, it is predicted that the majority of retroviral proteases have sulfur-containing amino acids at the dimer interface. The regulation of protease activity by the modification of a sulfur-containing amino acid at the dimer interface may be a conserved mechanism among the majority of retroviruses.
Defects in Virion Production Caused by Mutations Affecting the C-Terminal Portion of the Moloney Murine Leukemia Virus Capsid Protein
Authors: Wang Margaret Q. , Goff Stephen P.
Published: February 2003

The capsid (CA) domain of the Moloney murine leukemia virus (Mo-MuLV) Gag protein has a unique carboxy terminus with a highly charged arginine-rich sequence. Mutant viruses harboring arginine-to-alanine mutations affecting this region of CA displayed significant defects in virion release, and the few viral particles produced were noninfectious. The interaction between the mutant Gag precursors was affected, as judged by the yeast two-hybrid assay. The results suggest that the unique carboxy terminus of CA in the Mo-MuLV plays an important role in Gag-Gag association during virion production.
ELECTORALFRAUD: Causes, Types, and Consequences
Authors: Lehoucq Fabrice
Published: February 2003

▪ Abstract  This article reviews research on electoral fraud—clandestine and illegal efforts to shape election results. Only a handful of works classify reports on electoral fraud to identify its nature, magnitude, and causes. This review therefore looks at the larger number of historical works (as well as some ethnographies and surveys) that discuss ballot rigging. Its conclusions are threefold. First, fraud takes on a panoply of forms; it ranges from procedural violations of electoral law (that may or may not intend to distort results) to the outright use of violence against voters. Second, even when ballot rigging is an integral part of electoral competition, it is infrequently decisive. Fraud, nevertheless, undermines political stability because, in close races, it can be crucial. Third, political competition shapes the rhythm and nature of electoral fraud. Efforts to steal elections increase with inequality, but competitiveness—which institutions help to shape—determines the ballot-rigging strategies parties adopt.
Endothelium-Derived Hyperpolarizing Factor in Human Internal Mammary Artery Is 11,12-Epoxyeicosatrienoic Acid and Causes Relaxation by Activating Smooth Muscle BK
Ca
Channels
Authors: Archer Stephen L. , Gragasin Ferrante S. , Wu Xichen , Wang Shaohua , McMurtry Sean , Kim Daniel H. , Platonov Michael , Koshal Arvind , Hashimoto Kyoko , Campbell William B. , Falck J.R. , Michelakis Evangelos D.
Published: February 2003

Background—

Left internal mammary arteries (LIMAs) synthesize endothelium-derived hyperpolarizing factor (EDHF), a short-lived K
+
channel activator that persists after inhibition of nitric oxide (NO) and prostaglandin synthesis. EDHF hyperpolarizes and relaxes smooth muscle cells (SMCs). The identity of EDHF in humans is unknown. We hypothesized that EDHF (1) is 11,12-epoxyeicosatrienoic acid (11,12-EET); (2) is generated by cytochrome P450-2C, CYP450-2C; and (3) causes relaxation by opening SMC large-conductance Ca
2+
-activated K
+
channels (BK
Ca
).

Methods and Results—

The identity of EDHF and its mechanism of action were assessed in 120 distal human LIMAs and 20 saphenous veins (SVs) obtained during CABG. The predominant EET synthesized by LIMAs is 11,12-EET. Relaxations to exogenous 11,12-EET and endogenous EDHF are of similar magnitudes. Inhibition of EET synthesis by chemically distinct CYP450 inhibitors (17-octadecynoic acid,
N
-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide), or a selective EET antagonist (4,15-epoxyeicosa-5(
Z
)-enoic acid) impairs EDHF relaxation. 11,12-EET activates a BK
Ca
current and hyperpolarizes LIMA SMCs. Inhibitors of BK
Ca
but not inward-rectifier or small-conductance K
Ca
channels abolish relaxation to endogenous EDHF and exogenous 11,12-EET. BK
Ca
and CYP450-2C mRNA and proteins are more abundant in LIMAs than in SVs, perhaps explaining the lack of EDHF activity of the SV. Laser capture microdissection and quantitative RT-PCR demonstrate that BK
Ca
channels are primarily in vascular SMCs, whereas the CYP450-2C enzyme is present in both the endothelium and SMCs.

Conclusions—

In human LIMAs, EDHF is 11,12-EET produced by an EDHF synthase CYP450-2C and accounting for ≈40% of net endothelial relaxation. 11,12-EET causes relaxation by activating SMC BK
Ca
channels.
Characterization of Left Atrial Activation in the Intact Human Heart
Authors: Markides Vias , Schilling Richard J. , Yen Ho Siew , Chow Anthony W.C. , Davies D. Wyn , Peters Nicholas S.
Published: February 2003

Background—

The patterns of activation of the human left atrium (LA), how they relate to atrial myocardial architecture, and their role in arrhythmogenesis remain largely unknown.

Methods and Results—

Left atrial endocardial activation was mapped in 19 patients with a percutaneous noncontact mapping system. Earliest endocardial breakthrough during sinus rhythm (SR) occurred more frequently in the septal (63%, principally posteroseptal) than anterosuperior (37%) LA and varied little with isoproterenol or high right atrial pacing rate. Regardless of site of breakthrough, LA activation was characterized in all patients by propagation around a variably complete line of functional conduction block, descending on the posterior wall from the roof, passing between the ostia of the superior and then inferior pulmonary veins (PVs) before turning septally, passing below the oval fossa, and merging further anteriorly with the septal mitral annulus. Examination of the myocardial architecture in 10 normal adult postmortem hearts revealed an abrupt change in subendocardial fiber orientation along a line following the same course. During episodes of focal initiation of atrial fibrillation (AF), interaction was observed between wavefronts entering the LA from PVs and this functional line of conduction block that resulted in LA macroreentry or formation of daughter wavefronts.

Conclusions—

The LA endocardium has complex but characteristic patterns of activation during sinus rhythm, pacing, and AF initiation by PV ectopy that are determined largely by the functional properties of atrial musculature. These findings have important implications for both pacing and ablative strategies for the prevention of initiation of AF.
Intensive Blood Pressure Control Reduces the Risk of Cardiovascular Events in Patients With Peripheral Arterial Disease and Type 2 Diabetes
Authors: Mehler Philip S. , Coll Joseph R. , Estacio Raymond , Esler Anne , Schrier Robert W. , Hiatt William R.
Published: February 2003

Background—

Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established.

Methods and Results—

The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137±0.7/81±0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128±0.8/75±0.3 mm Hg (
P
<0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (
P
=0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (
P
=0.009), but not with intensive treatment (
P
=0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD.

Conclusions—

In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.
Reciprocal Association of C-Reactive Protein With Adiponectin in Blood Stream and Adipose Tissue
Authors: Ouchi Noriyuki , Kihara Shinji , Funahashi Tohru , Nakamura Tadashi , Nishida Makoto , Kumada Masahiro , Okamoto Yoshihisa , Ohashi Koji , Nagaretani Hiroyuki , Kishida Ken , Nishizawa Hitoshi , Maeda Norikazu , Kobayashi Hideki , Hiraoka Hisatoyo , Matsuzawa Yuji
Published: February 2003

Background—

High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue.

Methods and Results—

We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (
r
=−0.29,
P
<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipose tissue. A significant inverse correlation was observed between the CRP and adiponectin mRNA levels in human adipose tissue (
r
=−0.89,
P
<0.01). In addition, the CRP mRNA level of white adipose tissue in adiponectin deficient mice was higher than that of wild-type mice.

Conclusions—

The reciprocal association of adiponectin and CRP levels in both human plasma and adipose tissue might participate in the development of atherosclerosis.
Cardiorenal and Humoral Properties of a Novel Direct Soluble Guanylate Cyclase Stimulator BAY 41-2272 in Experimental Congestive Heart Failure
Authors: Boerrigter Guido , Costello-Boerrigter Lisa C. , Cataliotti Alessandro , Tsuruda Toshihiro , Harty Gail J. , Lapp Harald , Stasch Johannes-Peter , Burnett John C.
Published: February 2003

Background—

BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG).

Methods and Results—

CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 μg · kg
−1
· min
−1
; n=8) or NTG (1 and 5 μg · kg
−1
· min
−1
; n=6). Administration of 10 μg · kg
−1
· min
−1
BAY 41-2272 reduced mean arterial pressure (113±8 to 94±6 mm Hg;
P
<0.05), pulmonary artery pressure (29±2 to 25±2 mm Hg;
P
<0.05), and pulmonary capillary wedge pressure (25±2 to 20±2 mm Hg;
P
<0.05). Cardiac output (2.1±0.2 to 2.3±0.2 L/min;
P
<0.05) and renal blood flow (131±17 to 162±18 mL/min;
P
<0.05) increased. Glomerular filtration rate was maintained. There were no changes in plasma renin activity, angiotensin II, or aldosterone. NTG mediated similar hemodynamic changes and additionally decreased right atrial pressure and pulmonary vascular resistance.

Conclusion—

The new sGC stimulator BAY 41-2272 potently unloaded the heart, increased cardiac output, and preserved glomerular filtration rate without activation of the renin-angiotensin-aldosterone system in experimental CHF. These beneficial properties make direct sGC stimulation with BAY 41-2272 a promising new strategy for the treatment of cardiovascular diseases such as CHF.
Osteopontin Transgenic Mice Fed a High-Cholesterol Diet Develop Early Fatty-Streak Lesions
Authors: Isoda Kikuo , Kamezawa Yashuhiro , Ayaori Makoto , Kusuhara Masatoshi , Tada Norihiro , Ohsuzu Fumitaka
Published: February 2003

Background—

Osteopontin (OPN) is a noncollagenous adhesion protein found at the site of atherosclerotic lesions. However, it has not yet been clarified whether or not OPN can promote atherosclerotic lesions.

Methods and Results—

We investigated the contribution of OPN to atherosclerosis by evaluating aortic sinus lesions of both OPN transgenic (Tg) and non-Tg mice fed an atherogenic diet (1.25% cholesterol) for 16 weeks. The atherosclerotic lesions were found to be significantly larger in OPN-Tg compared with those in non-Tg (17 859±2010 versus 6469±485 μm
2
,
P
<0.01). The lesions in both mice were fatty-streak lesions with an accumulation of mononuclear cells and lipids. We next investigated the production of interleukin (IL)-10 by macrophages from both mice. Compared with the non-Tg mice, a 42% (
P
<0.01) and 73% (
P
<0.001) decrease in the IL-10 production was identified in the OPN-Tg mice either without or with lipopolysaccharide.

Conclusions—

The expression of OPN induces fatty-streak lesion formation in mice fed an atherogenic diet and inhibits IL-10 production by macrophages, thus suggesting that OPN plays an important role in the development of fatty-streak lesions in vivo.
Stromal inhibition of megakaryocytic differentiation is associated with blockade of sustained Rap1 activation
Authors: Delehanty Lorrie L. , Mogass Michael , Gonias Sara L. , Racke Frederick K. , Johnstone Brian , Goldfarb Adam N.
Published: February 2003

Coculture with stromal cells tends to maintain normal hematopoietic progenitors and their leukemic counterparts in an undifferentiated, proliferative state. An example of this effect is seen with megakaryocytic differentiation, wherein stromal contact renders many cell types refractory to potent induction stimuli. This inhibitory effect of stroma on megakaryocytic differentiation correlates with a blockade within hematopoietic cells of protein kinase C-ε (PKC-ε) up-regulation and of extracellular signal-regulated kinase/mitogen-activated protein (ERK/MAP) kinase activation, both of which have been implicated in promoting megakaryocytic differentiation. In this study K562ΔRafER.5 cells, expressing an estradiol-responsive mutant of the protein kinase Raf-1, were used to determine the relevance and stage of ERK/MAPK pathway blockade by stromal contact. Activation of ΔRafER by estradiol overrode stromal blockade of megakaryocytic differentiation, implicating the proximal stage of the ERK/MAPK pathway as a relevant control point. Because stromal contact blocked delayed but not early ERK activation, the small guanosine triphosphatase (GTPase) Rap1 was considered as a candidate inhibitory target. Activation assays confirmed that Rap1 underwent sustained activation as a result of megakaryocytic induction, as previously described. As with ERK activation, stromal contact selectively blocked delayed but not early Rap1 activation, having no effect on Ras activation. Enforced expression of either wild-type Rap1 or the GTPase (GAP) resistant mutant Rap1 V12 failed to override stromal inhibition, suggesting that the inhibitory mechanism does not involve GAP up-regulation but rather may target upstream guanine nucleotide exchange factor (GEF) complexes. Accordingly, coimmunoprecipitation demonstrated stromally induced alterations in a protein complex associated with c-Cbl, a scaffolding factor for Rap1-GEF complexes.
The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis
Authors: Bhagwat Shripad V. , Petrovic Nenad , Okamoto Yasuhiro , Shapiro Linda H.
Published: February 2003

Angiogenesis, the formation of new blood vessels, is a critical step for tumor growth and metastasis and an integral component of the pathologic inflammatory response in arthritis and the proliferative retinopathies. The CD13/aminopeptidase N (CD13/APN) metalloprotease is an important regulator of angiogenesis where its expression on activated blood vessels is induced by angiogenic signals. Here, we show that cytokine induction of CD13/APN in endothelial cells is regulated by distinct Ras effector pathways involving Ras/mitogen-activated protein kinase (MAPK) or PI-3K. Signals transduced by activated Ras, Raf, and mitogen-induced extracellular kinase (MEK) stimulate transcription from theCD13/APN proximal promoter. Inhibition of these pathways and extracellular signal–regulated serine/threonine kinase (ERK-2) and PI-3K by expression of dominant-negative proteins or chemical inhibitors prevented induction of CD13/APNtranscription in response to basic fibroblast growth factor (bFGF). We show that Ras-induced signal transduction is required for growth factor–induced angiogenesis, because inhibition of downstream mediators of Ras signaling (MEK or PI-3K) abrogated endothelial cell migration, invasion, and morphogenesis in vitro. Reintroduction of CD13/APN, a shared downstream target of these pathways, overrode the suppressive effect of these inhibitors and restored the function of endothelial cells in migration/invasion and capillary morphogenesis assays. Similarly, inhibition of MEK abrogated cell invasion and the formation of endothelial-lined capillaries in vivo, which was effectively rescued by addition of exogenous CD13/APN protein. These studies provide strong evidence that CD13/APN is an important target of Ras signaling in angiogenesis and is a limiting factor in angiogenic progression.
Neutrophil elastase enzymatically antagonizes the in vitro action of G-CSF: implications for the regulation of granulopoiesis
Authors: El Ouriaghli Frank , Fujiwara Hiroshi , Melenhorst J. Joseph , Sconocchia Giuseppe , Hensel Nancy , Barrett A. John
Published: February 2003

There is evidence that neutrophil production is a balance between the proliferative action of granulocyte–colony-stimulating factor (G-CSF) and a negative feedback from mature neutrophils (the chalone). Two neutrophil serine proteases have been implicated in granulopoietic regulation: pro–proteinase 3 inhibits granulocyte macrophage–colony-forming unit (CFU-GM) growth, and elastase mutations cause cyclic and congenital neutropenia. We further studied the action of the neutrophil serine proteases (proteinase 3, elastase, azurocidin, and cathepsin G) on granulopoiesis in vitro. Elastase inhibited CFU-GM in methylcellulose culture. In serum-free suspension cultures of CD34+ cells, elastase completely abrogated the proliferation induced by G-CSF but not that of GM-CSF or stem cell factor (SCF). The blocking effect of elastase was prevented by inhibition of its enzymatic activity with phenylmethylsulfonyl fluoride (PMSF) or heat treatment. When exposed to enzymatically active elastase, G-CSF, but not GM-CSF or SCF, was rapidly cleaved and rendered inactive. These results support a role for neutrophil elastase in providing negative feedback to granulopoiesis by direct antagonism of G-CSF.
Induction of fetal hemoglobin expression by the histone deacetylase inhibitor apicidin
Authors: Witt Olaf , Mönkemeyer Sven , Rönndahl Gabi , Erdlenbruch Bernhard , Reinhardt Dirk , Kanbach Katrin , Pekrun Arnulf
Published: February 2003

Pharmacologic stimulation of fetal hemoglobin (HbF) expression may be a promising approach for the treatment of β-thalassemia. In this study, we have investigated the HbF-inducing activity and molecular mechanisms of specific histone deacetylase (HDAC) inhibitors in human K562 erythroleukemia cells. Apicidin was the most potent agent compared with other HDAC inhibitors (trichostatin A, MS-275, HC-toxin, suberoylanilide hydroxamic acid [SAHA]) and previously tested compounds (butyrate, phenylbutyrate, isobutyramide, hydroxyurea, 5-aza-cytidine), leading to a 10-fold stimulation of HbF expression at nanomolar to micromolar concentrations. Hyperacetylation of histones correlated with the ability of HDAC inhibitors to stimulate HbF synthesis. Furthermore, analysis of different mitogen-activated protein (MAP) kinase signaling pathways revealed that p38 signaling was activated following apicidin treatment of cells and that inhibition of this pathway abolished the HbF-inducing effect of apicidin. Additionally, activation of the Aγ-globin promoter by apicidin could be inhibited by p38 inhibitor SB203580. In summary, the novel HDAC inhibitor apicidin was found to be a potent inducer of HbF synthesis in K562 cells. The present data outline the role of histone hyperacetylation and p38 MAP kinase signaling as molecular targets for pharmacologic stimulation of HbF production in erythroid cells.
The HTLV receptor is an early T-cell activation marker whose expression requires de novo protein synthesis
Authors: Manel Nicolas , Kinet Sandrina , Battini Jean-Luc , Kim Felix J. , Taylor Naomi , Sitbon Marc
Published: February 2003

The human T-cell leukemia virus type 1 (HTLV) is the first isolated human retrovirus, but its receptor has yet to be identified, in part due to its ubiquitous expression. Here we report that quiescent CD4 and CD8 T lymphocytes do not express this receptor, as monitored with a soluble receptor-binding domain derived from the HTLV envelope. However, HTLV receptor is an early activation marker in neonatal and adult T lymphocytes, detected as early as 4 hours following T-cell–receptor (TCR) stimulation. This induced surface expression of the HTLV receptor requires de novo protein synthesis and results in a wide distribution on the surface of activated lymphocytes. Moreover, the distribution of the HTLV receptor is independent of TCR/CD3-capped membrane structures, as observed by confocal immunofluorescence microscopy. To determine whether HTLV receptor up-regulation specifically requires TCR-mediated signals or, alternatively, is dependent on more generalized cell cycle entry/proliferation signals, its expression was monitored in interleukin 7 (IL-7)–stimulated neonatal and adult T cells. Neonatal, but not adult, lymphocytes proliferate in response to IL-7 and HTLV receptor expression is restricted to the former population. Thus, HTLV receptor expression appears to be an early marker of cell cycle entry. Up-regulation of the HTLV receptor, via signals transmitted through the IL-7 cytokine receptor as well as the TCR, is likely to contribute to the mother-to-infant transmission and spreading of HTLV-1.
Heterotypic interactions between transferrin receptor and transferrin receptor 2
Authors: Vogt Todd M. , Blackwell Aaron D. , Giannetti Anthony M. , Bjorkman Pamela J. , Enns Caroline A.
Published: February 2003

Cellular iron uptake in most tissues occurs via endocytosis of diferric transferrin (Tf) bound to the transferrin receptor (TfR). Recently, a second transferrin receptor, transferrin receptor 2 (TfR2), has been identified and shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated iron uptake and mutations in this gene result in a rare form of hereditary hemochromatosis unrelated to the hereditary hemochromatosis protein, HFE. Unlike TfR, TfR2 expression is not controlled by cellular iron concentrations and little information is currently available regarding the role of TfR2 in cellular iron homeostasis. To investigate the relationship between TfR and TfR2, we performed a series of in vivo and in vitro experiments using antibodies generated to each receptor. Western blots demonstrate that TfR2 protein is expressed strongest in erythroid/myeloid cell lines. Metabolic labeling studies indicate that TfR2 protein levels are approximately 20-fold lower than TfR in these cells. TfR and TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to only a very limited extent. Western analysis of the receptors under nonreducing conditions reveals that they can form heterodimers.
Platelet-endothelial interaction in tumor angiogenesis and microcirculation
Authors: Manegold Philipp C. , Hutter Joerg , Pahernik Sascha A. , Messmer Konrad , Dellian Marc
Published: February 2003

Activated platelets release angiogenic growth factors and have therefore been proposed to contribute to tumor angiogenesis within a potentially prothrombotic tumor microcirculation. The aim of the study was to investigate interactions of platelets with the angiogenic microvascular endothelium of highly vascularized solid tumors during growth and in response to endothelial stimulation in comparison with normal subcutaneous tissue. Experiments were performed in the dorsal skinfold chamber preparation of C57BL/6J mice bearing the Lewis lung carcinoma (LLC-1) or methylcholanthrene-induced fibrosarcoma (BFS-1). Fluorescently labeled rolling and adherent platelets, red blood cell velocity, and vessel diameters were assessed by intravital fluorescence microscopy on days 1, 3, 8, and 14 after tumor cell implantation. Slightly elevated numbers of rolling platelets were observed in the early stages of tumor angiogenesis at day 1 (control, 1.7 ± 0.6; LLC-1, 3.4 ± 1.8; BFS-1, 3.0 ± 0.7 [1/mm/s],P < .05) and day 3 (control, 1.6 ± 0.6; LLC-1, 4.1 ± 1.7, P < .05; BFS-1, 2.3 ± 0.5 [1/mm/s]) after tumor cell implantation. Endothelial stimulation with calcium ionophore A23187 at day 14 after tumor cell implantation resulted in a minor increase to 2.1 ± 0.4 (LLC-1) and 1.8 ± 0.8 (BFS-1) rolling platelets (1/mm/s) in tumor microvessels compared with 4.9 ± 0.9 in controls (P < .05). Platelet adherence was not observed. We therefore conclude that in the 2 experimental tumors under study, (1) slightly increased platelet rolling is a transient phenomenon after tumor cell implantation, and (2) platelet-endothelial interaction in response to endothelial stimulation is reduced in tumor microvessels.
Comparison of maintenance policies with monotone failure rate distributions
Authors: Frostig Esther
Published: February 2003

We compare different maintenance policies assuming that the system lifetime has either increasing failure rate (IFR), or decreasing failure rate (DFR) distribution. We show that these assumptions yield strongly stochastic comparisons between the process' intensities. This yields weaker stochastic comparison between the processes than the stochastic comparison that hold when the system lifetime is new better than used (NBU) or new worse than used (NWU). Copyright © 2002 John Wiley & Sons, Ltd.
Latent variable modelling of price‐change in 295 manufacturing industries
Authors: Georganta Zoe
Published: February 2003

In contrast to traditional regression analysis, latent variable modelling (LVM) can explicitly differentiate between measurement errors and other random disturbances in the specification and estimation of econometric models. This paper argues that LVM could be a promising approach to test economic theories because applied research in business and economics is based on statistical information, which is frequently inaccurately measured. Considering the theory of industry‐price determination, where the price variables involved are known to include a large measurement error, a latent variable, structural‐equations model is constructed and applied to data on 7381 product categories classified into 295 manufacturing industries of the USA economy. The obtained estimates, compared and evaluated against a traditional regression model fitted to the same data, show the advantages of the LVM analytical framework, which could lead a long drawn‐out conflict between empirical results and theory to a satisfactory reconciliation. Copyright © 2003 John Wiley & Sons, Ltd.
Altered expression of insulins I and II and their mRNAs in the islets of Langerhans in dexamethasone‐induced diabetic rats
Authors: Toriumi Chifuyu , Imai Kazuhiro
Published: February 2003

Rats have two isomeric insulins (insulins I and II). There have been no reports on the expression of the isomeric insulins in glucocorticoid‐induced diabetic rats. To clarify the relation of the expression of each insulin and its mRNAs in dexamethasone‐induced diabetic rats, the amounts of the isomeric insulins and mRNAs in the islets of Langerhans were determined in vivo and in vitro. A sensitive and selective HPLC‐fluorescence determination method for the isomeric insulins and a newly developed real‐time quantitative RT–PCR method for their mRNAs were used. There was a greater reduction of insulin II than insulin I in the islets of Langerhans in dexamethasone‐induced diabetic rats. This alteration may be caused by a disproportionate expression of the respective mRNA for the isomeric insulins that resulted from the direct effect of dexamethasone. In addition, continuous hyperglycemia may also suppress the expression of the insulin II mRNA. The overall effects of dexamethasone and hyperglycemia may cause a greater reduction of insulin II than insulin I in the dexamethasone‐induced diabetic rat. Conversely, an elevated ratio of insulin I to II in the islets could suggest a diabetic condition. Copyright © 2003 John Wiley & Sons, Ltd.
Evidence for the Intermediacy of Arylbenzylnitrenium Ions in the Thermal Rearrangement of Isoxazolidines Derived from C,N‐Diarylnitrones and 2‐Morpholin‐4‐yl‐acrylonitrile
Authors: Liard Annie , Nguyen Thi‐Huu , Djelloul Smir Abdel Illah , Vaultier Michel , Derdour Aïcha , Mortier Jacques
Published: February 2003

In contrast to the diaryl, dialkyl, alkylaryl, and parent series, nothing is known about the generation and chemical behavior of arylbenzylnitrenium ions. Herein, we report that these species can be generated by a process involving an unprecedented thermal rearrangement of isoxazolidines derived from C,N‐diarylnitrones and 2‐morpholin‐4‐yl‐acrylonitrile. The products from these reactions are dramatically dependent upon the nature of the nitrone. Most of the observed chemistry originates from the singlet state.
Towards a Universal Polymer Backbone: Design and Synthesis of Polymeric Scaffolds Containing Terminal Hydrogen‐Bonding Recognition Motifs at Each Repeating Unit
Authors: Stubbs Ludger P. , Weck Marcus
Published: February 2003

Polymers containing terminal hydrogen‐bonding recognition motifs based on diaminotriazine and diaminopyridine groups in their side chains for the self‐assembly of appropriate receptors have been prepared by ring‐opening metathesis polymerization (ROMP) of norbornenes. A new synthetic method for the preparation of norbornene monomers based on pure alkyl spacers is introduced. These monomers show unprecedented high reactivity using ROMP. To suppress self‐association of diaminotriazine‐based polymers, polymerizations were run in presence of N‐butylthymine. The butylthymine acts as a protecting group via self‐assembly onto the hydrogen‐bonding sites of the polymeric scaffold, thereby solubilizing the polymer. Diaminopyridine monomers do not require the presence of a protecting group due to their low propensity to dimerize. In addition, they exhibit a high affinity for hydrogen‐bonded receptors on both monomeric and polymeric level. These polymers present our first building blocks towards the design and synthesis of a “universal polymer scaffold”.
Synthetic Scheme for the Preparation of 13C‐Labeled 3,4‐Didehydro‐Retinal, 3‐Hydroxyretinal, and 4‐Hydroxyretinal up to Uniform 13C‐Enrichment
Authors: van Wijk Arjan A. C. , van de Weerd Michiel B. , Lugtenburg Johan
Published: February 2003

A modular synthetic scheme has been developed for the synthesis of 13C‐labeled naturally occurring visual pigment chromophores; 3,4‐didehydroretinal, 3‐hydroxyretinal, and 4‐hydroxyretinal. These compounds can now be made with > 99% 13C enrichment at any position or combination of positions. We used the common C10+C5+C5 scheme for the synthesis of retinals, and by making variations in the C10 part we can now prepare the desired retinal derivatives with selective or uniform 13C enrichment. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Experimental Assessment of the Effect of a Bicyclo[1.1.0]butane System in Strain‐Induced Localisation of Aromatic π‐Bonds
Authors: Cohrs Carsten , Reuchlein Horst , Musch Patrick W. , Selinka Carola , Walfort Bernhard , Stalke Dietmar , Christl Manfred
Published: February 2003

The geometrical parameters of the dimethyl pyridazine‐1,4‐dicarboxylates 13−16, in which a σ‐bond system is annulated at the C5−C6 bond, have been determined by X‐ray diffraction. As compared to the cyclopentene subunit in 16, which is believed to exert no significant influence on the bond lengths of the aromatic moiety, the norbornene, benzvalene, and bicyclo[2.1.1]hexene subunits of 13−15, respectively, cause alternating bond elongations and shortenings in the pyridazine moiety, with increasing magnitudes, in that order. These effects are in line with the heats of the isodesmic reactions that convert norbornene (8), benzvalene (6), and bicyclo[2.1.1]hex‐2‐ene (4) with buta‐1,3‐diene into ethene as well as 2,3‐bis(methylene)norbornane (9), 3,4‐bis(methylene)tricyclo[3.1.0.02,6]hexane (7), and 2,3‐bis(methylene)bicyclo[2.1.1]hexane (5), respectively. Calculated originally by W. L. Jorgensen and W. T. Borden in the 1970s, the reactions have now been reexamined by employing much higher levels of theory. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
Spectroelectrochemical and Voltammetric Studies of L‐DOPA
Authors: Liu Xiaoqiang , Zhang Zheling , Cheng Guangjin , Dong Shaojun
Published: February 2003

The electrooxidation of L‐dopa at GC electrode was studied by in situ UV‐vis spectroelectrochemistry (SEC) and cyclic voltammetry. The mechanism of electrooxidation and some reaction parameters were obtained. The results showed that the whole electrooxidation reaction of L‐dopa at glassy carbon (GC) electrode was an irreversible electrochemical process followed by a chemical reaction in neutral solution (EC mechanism). The spectroelectrochemical data were treated by the double logarithm method together with nonlinear regression, from which the formal potential E0=228 mV, the apparent electron‐transfer number of the electrooxidation reaction αn=0.376 (R=0.99, SD=0.26), the standard electrochemical rate constant k0=(3.93±0.12)×10−4 cm s−1 (SD=1.02×10−2), and the formation equilibrium constant of the following chemical reaction kc=(5.38±0.34)×10−1 s−1 (SD=1.02×10−2) were also obtained.
Novel Liquid Membrane Electrode for Selective Determination of Monohydrogenphosphate
Authors: Ganjali Mohammad Reza , Mizani Farhang , Emami Mehdi , Niasari Masoud Salavati , Shamsipur Mojtaba , Yousefi Mohammad , Javanbakht Mehran
Published: February 2003

A highly selective and sensitive membrane electrode based on vanadyl salen complex (VS), which responds to monohydrogenphosphate (MHP) ions is described. The response of the sensor is Nernstian over the wide concentration range (1.0×10−1 − 5.0×10−6 M) of MHP. The sensitivity of the electrode is high enough to permit the detection of as little as 0.6 μg/mL of MHP without any significant interference from high levels of other anions. The potentiometric selectivity coefficient data revealed negligible interference from 11 common anions. The electrode has a fast response time (<25 s), good slope stability at pH 8.2 for a period of at least eight weeks. It was successfully applied for the direct determination of monohydrogenphosphate in fertilizer and, as indicator electrode, in potentiometric titration of HPO42− ion with barium chloride.
Isoperimetric problems and roses of neighborhood for stationary flat processes
Authors: Spodarev Eugene
Published: February 2003

The paper yields necessary conditions for the directional distributions of stationary k–flat processes in ℝd that maximize their intersection density of order 2, that is, the mean (2k – d)–volume of their self–intersections in an observation window of unit d–volume. The conditions are given in terms of the rose of intersections (i.e., the intensity of intersections of the flat process with test flats). The notion of the rose of neighborhood is introduced which is an analogue of the rose of intersections for lower dimensional flat processes. Some properties of the rose of neighborhood are studied and an asymptotically unbiased estimator is given.
Cooperative R&D and the Canadian forest products industry
Authors: Nakamura Masao , Nelson Harry , Vertinsky Ilan
Published: February 2003

In the past decade the share of cooperative R&D has increased. In this paper, using a case study of the forest industry in Canada, the antecedents of cooperative R&D and the forms it take are investigated. We show how market failures are corrected in the industry largely through industry wide R&D consortia. The share of government funding to maintain the cooperation reflects the degree to which the consortia can appropriate the full value of their knowledge products (i.e. prevent spillover of innovations to non‐members in Canada and elsewhere). The case study indicates that the prime role of these nationwide consortia is the provision of potential access to R&D expertise, technological intelligence, and technology transfer services. The success and stability of these consortia depend on the degree to which their governance systems allow for better alignment of the costs and benefits that accrue to members from the consortia. Copyright © 2003 John Wiley & Sons, Ltd.
Interaction between public research organizations and industry in biotechnology
Authors: Dalpé Robert
Published: February 2003

This paper summarizes the most important findings of the literature on the close interaction between public research organizations and industry in biotechnology. The first question deals with why researchers in academic organizations were and are still important players in the biotechnology industry. Three arguments explain why biotechnology emerged as an organization network: its origins in academic research, the impact of participation in networks on competitiveness and the weight of these networks on R&D intensity and innovation. The second focuses on the factors that explain the regional concentration of such interactions and of biotechnology firms. The paper concludes with a discussion of policy implications. The dynamic of biotechnology is rather unique and can be attributed to the specific institutional arrangements characterizing the American scientific system. Its replication to other sectors or countries seems rather difficult. Copyright © 2003 John Wiley & Sons, Ltd.
Intergenerational value discrepancies in immigrant and host‐national families and their impact on psychological adaptation
Authors: Sam David Lackland , Virta Erkki
Published: February 2003

This study investigated the relationship between intergenerational value discrepancies and psychological adaptation among adolescents with immigrant background (mean age=15.5 years) in Norway and Sweden. Results from two cohorts (parents and their children) of immigrant and host‐national families in the two countries (n=574) indicated that immigrant adolescents on the whole neither differed from their host peers with respect to psychological adaptation nor on value discrepancies. Value discrepancies were weakly related to psychological adaptation. Results are discussed as to whether the findings may reflect a general phenomenon for all adolescents or specific to those with immigrant background.
Competition between autoionization and radiative emission in the decay of excited states of the oxygen atom
Authors: Dehmer P. M. , Luken W. L. , Chupka W. A.
Published: February 2003

High resolution relative photoionization cross sections are reported for a number of autoionizing states of atomic oxygen, including the metastable 3s″ 3P0, and 2s2p5 3P0 states. The wavelength resolution of the present data (0.04 Å, FWHM) is a factor of 4 better than that of the previously reported data, and is sufficient to allow observation of lifetime broadening for rapidly (LS-allowed) autoionizing states. In addition, the present resolution separates nearly all of the fine structure components of the above-mentioned 3P0 states. Autoionization, which is forbidden in an LS coupling scheme for these two 3P0 states, proceeds at a substantially reduced rate, and, consequently, radiative emission is a significantly competitive decay process. Since the autoionization rates of these states depend on the total angular momentum J of the decaying level, the lifetimes of the states and the branching ratios for autoionization versus radiative emission are different for each 3PJ0 fine structure level. The present high resolution autoionization data, which represent a significant improvement over the previous data, were combined with previously reported relative emission intensity data for these states to determine accurate branching ratios for autoionization versus emission. The lifetimes of these states were determined using the experimental branching ratios and the theoretical radiative emission rates calculated using the non-closed-shell many electron theory (NCMET) of Sinanoglu. The present work also reports lifetimes of ∼1×10−12 sec for the (LS-allowed) autoionizing 3d′, 3S0, 3D0 and 4s′ 3D0 states, determined from observations of lifetime broadening of these spectral lines.
General isotopic rules involving the vibrational frequencies and the anharmonicity constants for heavy atom substitution
Authors: Mohan N. , Müller A.
Published: February 2003

A simple isotopic rule based on first order perturbation theory is proposed to study the shift in each vibrational fundamental due to the substitution of heavy atoms. In analogy with the isotopic rule for frequencies, a similar one pertaining to the anharmonicity constants Xab is also derived. The numerical data obtained give excellent support to the validity of the isotopic rules.
Effects of exchange energy and orbital orthogonality on barriers to internal rotation
Authors: Christiansen Phillip A. , Palke William E.
Published: February 2003

In order to determine the effect of the Pauli principle on internal rotation barriers, we have calculated exchange and orbital orthogonality contributions to barriers for a small group of molecules: ethane, methanol, acetaldehyde, and hydrogen peroxide. To evaluate exchange contributions it was necessary to formulate variation equations and to energy-optimize simple product wavefunctions of orthogonal orbitals (Hartree-product wavefunctions). The resulting orbitals resemble very closely the Edmiston–Ruedenberg localized Hartree–Fock orbitals. Our results indicate that exchange contributions to the barriers in ethane and acetaldehyde are quite small. For methanol and hydrogen peroxide, our calculated contributions are considerably larger and suggest that, at least in some molecules, exchange contributions cannot be ignored. For all of the molecules, however, the exchange contribution is greatly overshadowed by that of end-to-end orbital orthogonality.
Oxygen isotope fractionation in H2O and the structure of liquid water
Authors: King W. T. , Barletta R. E.
Published: February 2003

The difference between the atomic force constant for oxygen in ice I and liquid water, and that in the vapor phase is determined from an analysis of H2 16O/H2 18O isotope fractionation factors. It is shown that the force constants in liquid water depend explicitly upon the hydrogen-bond distribution in the liquid phase, and upon fusion the average number of hydrogen bonds per H2O decreases from 4 to 3. This result and the number of hydrogen bonds in water above the ice point are compared with the numbers obtained from molecular dynamics calculations and the cluster and lattice–gas theories of liquid water.