bluuebunny/crossref_metadata_2025 huggingface dataset:
Close identity of a pressure-stabilized intermediate with a kinetic intermediate in protein folding
Authors: Kitahara Ryo , Akasaka Kazuyuki
Published: March 2003

Atomic detailed structural study of a transiently existing folding intermediate is severely limited because of its short life. In ubiquitin, we found that a pressure-stabilized equilibrium conformer shares a common structural feature with the proline-trapped kinetic intermediate found in a pulse-labeling
1
H/
2
H exchange NMR study [Briggs, M. S. & Roder, H. (1992)
Proc. Natl. Acad. Sci. USA
89, 2017–2021]. The conformer is locally unfolded in the entire segment from residues 33 to 42 and in C-terminal residues 70–76. The close structural identity of an equilibrium intermediate stabilized under pressure with a transiently observed folding intermediate is likely to be general in terms of a folding funnel common to both experiments.
Sequences in the
A
γ–δ intergenic region are not required for stage-specific regulation of the human β-globin gene locus
Authors: Gaensler Karin M. L. , Zhang Zemin , Lin Chin , Yang Suya , Hardt Karin , Flebbe-Rehwaldt Linda
Published: March 2003

The human β-globin locus has been extensively studied as a model of tissue and developmental stage-specific gene expression. Structural mapping of naturally occurring mutations, including transfection and transgenic studies, and the recent finding of intergenic transcripts have suggested that there are cis-acting sequence elements in the
A
γ–δ intergenic region involved in regulating γ- and β-globin gene expression. To determine whether previously identified sequences in the
A
γ–δ intergenic region are required for appropriate developmental expression of the human β-globin gene cluster, transgenic mice were generated by transfer of yeast artificial chromosomes containing the entire human β-globin locus. Three different deletions of the
A
γ–δ intergenic region were introduced, including (
i
) deletion of the 750-bp
A
γ 3′ regulatory element (
A
γe), (
ii
) deletion of 3.2 kb upstream of the δ-globin gene encompassing pyrimidine-rich sequences and the recently described intergenic transcript initiation site, and (
iii
) deletion of a 12.5-kb fragment encompassing most of the
A
γ–δ globin intergenic region. Analysis of multiple transgenic lines carrying these deletion constructs demonstrated that the normal stage-specific sequential expression of the ɛ-, γ-, and β-globin genes was preserved, despite deletion of these putative regulatory sequences. These studies suggest that regulatory sequences required for activation and silencing of the human β-globin gene family during ontogeny reside proximally to the genes and immediately 5′ to the human γ- and β-globin genes.
Increasing vitamin C content of plants through enhanced ascorbate recycling
Authors: Chen Zhong , Young Todd E. , Ling Jun , Chang Su-Chih , Gallie Daniel R.
Published: March 2003

Vitamin C (ascorbic acid) is essential to prevent disease associated with connective tissue (e.g., scurvy), improves cardiovascular and immune cell functions, and is used to regenerate α-tocopherol (vitamin E). In contrast to most animals, humans lack the ability to synthesize ascorbic acid as a result of a mutation in the last enzyme required for ascorbate biosynthesis. Vitamin C, therefore, must be obtained from dietary sources and, because it cannot be stored in the body, it must be obtained regularly. Once used, ascorbic acid can be regenerated from its oxidized form in a reaction catalyzed by dehydroascorbate reductase (DHAR). To examine whether overexpression of DHAR in plants would increase the level of ascorbic acid through improved ascorbate recycling, a DHAR cDNA from wheat was isolated and expressed in tobacco and maize, where DHAR expression was increased up to 32- and 100-fold, respectively. The increase in DHAR expression increased foliar and kernel ascorbic acid levels 2- to 4-fold and significantly increased the ascorbate redox state in both tobacco and maize. In addition, the level of glutathione, the reductant used by DHAR, also increased, as did its redox state. These results demonstrate that the vitamin C content of plants can be elevated by increasing expression of the enzyme responsible for recycling ascorbate.
Enhanced insulin sensitivity in mice lacking ganglioside GM3
Authors: Yamashita Tadashi , Hashiramoto Akira , Haluzik Martin , Mizukami Hiroki , Beck Shoshannah , Norton Aaron , Kono Mari , Tsuji Shuichi , Daniotti Jose Luis , Werth Norbert , Sandhoff Roger , Sandhoff Konrad , Proia Richard L.
Published: March 2003

Gangliosides are sialic acid-containing glycosphingolipids that are present on all mammalian plasma membranes where they participate in recognition and signaling activities. We have established mutant mice that lack GM3 synthase (CMP-NeuAc:lactosylceramide α2,3-sialyltransferase; EC 2.4.99.-). These mutant mice were unable to synthesize GM3 ganglioside, a simple and widely distributed glycosphingolipid. The mutant mice were viable and appeared without major abnormalities but showed a heightened sensitivity to insulin. A basis for the increased insulin sensitivity in the mutant mice was found to be enhanced insulin receptor phosphorylation in skeletal muscle. Importantly, the mutant mice were protected from high-fat diet-induced insulin resistance. Our results show that GM3 ganglioside is a negative regulator of insulin signaling, making it a potential therapeutic target in type 2 diabetes.
Small ubiquitin-like modifier conjugation regulates nuclear export of TEL, a putative tumor suppressor
Authors: Wood Lauren D. , Irvin Brenda J. , Nucifora Giuseppina , Luce K. Scott , Hiebert Scott W.
Published: March 2003

Posttranslational modification by small ubiquitin-like modifier (SUMO) conjugation regulates the subnuclear localization of several proteins; however, SUMO modification has not been directly linked to nuclear export. The ETS (E-Twenty-Six) family member TEL (ETV6) is a transcriptional repressor that can inhibit Ras-dependent colony growth in soft agar and induce cellular aggregation of Ras-transformed cells. TEL is frequently disrupted by chromosomal translocations such as the t(12;21), which is associated with nearly one-fourth of pediatric B cell acute lymphoblastic leukemia. In the vast majority of t(12;21)-containing cases, the second allele of

TEL

is deleted, suggesting that inactivation of TEL contributes to the disease. Although TEL functions in the nucleus as a DNA-binding transcriptional repressor, it has also been detected in the cytoplasm. Here we demonstrate that TEL is actively exported from the nucleus in a leptomycin B-sensitive manner. TEL is posttranslationally modified by sumoylation at lysine 99 within a highly conserved domain (the “pointed” domain). Mutation of the sumo-acceptor lysine or mutations within the pointed domain that affect sumoylation impair nuclear export of TEL. Mutation of lysine 99 also results in an increase in TEL transcriptional repression, presumably because of decreased nuclear export. We propose that the ability of TEL to repress transcription and suppress growth is regulated by sumoylation and nuclear export.
Neuroglobin protects the brain from experimental stroke
in
vivo
Authors: Sun Yunjuan , Jin Kunlin , Peel Alyson , Mao Xiao Ou , Xie Lin , Greenberg David A.
Published: March 2003

Neuroglobin (Ngb) is an O
2
-binding protein localized to cerebral neurons of vertebrates, including humans. Its physiological role is unknown but, like hemoglobin, myoglobin, and cytoglobin/histoglobin, it may transport O
2
, detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported recently that hypoxia stimulates transcriptional activation of Ngb in cultured cortical neurons and that antisense inhibition of Ngb expression increases hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to hypoxia. These findings are consistent with a role for Ngb in promoting neuronal survival after hypoxic insults
in vitro
. Here we report that in rats, intracerebroventricular administration of an Ngb antisense, but not sense, oligodeoxynucleotide increases infarct volume and worsens functional neurological outcome, whereas intracerebral administration of a Ngb-expressing adeno-associated virus vector reduces infarct size and improves functional outcome, after focal cerebral ischemia induced by occlusion of the middle cerebral artery. We conclude that Ngb acts as an endogenous neuroprotective factor in focal cerebral ischemia and may therefore represent a target for the development of new treatments for stroke.
Mechanics of DNA packaging in viruses
Authors: Purohit Prashant K. , Kondev Jané , Phillips Rob
Published: March 2003

A new generation of single-molecule experiments has opened up the possibility of reexamining many of the fundamental processes of biochemistry and molecular biology from a unique and quantitative perspective. One technique producing a host of intriguing results is the use of optical tweezers to measure the mechanical forces exerted by molecular motors during key processes such as the transcription of DNA or the packing of a viral genome into its capsid. The objective of the current article is to respond to such measurements on viruses and to use the theory of elasticity and a simple model of charge and hydration forces to derive the force required to pack DNA into a viral capsid as a function of the fraction of the viral genome that has been packed. The results are found to be in excellent accord with recent measurements and complement previous theoretical work. Because the packing of DNA in viral capsids occurs under circumstances of high internal pressure, we also compute how much pressure a capsid can sustain without rupture.
Link between immune response and parasite synchronization in malaria
Authors: Rouzine Igor M. , McKenzie F. Ellis
Published: March 2003

Anti-malaria vaccines and drugs could be greatly improved if we knew which phases of
Plasmodium falciparum
development in red blood cells are major inducers and which are major targets of natural immune responses. This information should focus attention on relevant immunogens and prove useful in developing immune-based therapies. Here we explore the hypothesis that innate immune responses mediate synchronization between the replication cycles of parasites in different red blood cells which is reflected in periodic fevers. Based on a recently developed, rather general mathematical model, we find that periodicity is highly sensitive to the position of both the inducing phase interval and the target phase interval in the parasite replication cycle. In addition, the degree of variability in the length of the replication cycle also strongly affects periodicity. To produce synchronization, the inducing and the target phase intervals must be developmentally distant from each other. We developed a computer program which prompts for information based on measurements of the numbers of erythrocytes in two replication cycle intervals chosen by the researcher, tests our model, and predicts the two phase intervals most critical to the synchronizing immune response. The program can be obtained from the authors.
Potent inhibition of scrapie prion replication in cultured cells by bis-acridines
Authors: May Barnaby C. H. , Fafarman Aaron T. , Hong Septima B. , Rogers Michael , Deady Leslie W. , Prusiner Stanley B. , Cohen Fred E.
Published: March 2003

Prion diseases are characterized by an accumulation of PrP
Sc
, a misfolded isoform of the normal cellular prion protein, PrP
C
. We previously reported the bioactivity of acridine-based compounds against PrP
Sc
replication in scrapie-infected neuroblastoma cells and now report the improved potency of bis-acridine compounds. Bis-acridines are characterized by a dimeric motif, comprising two acridine heterocycles tethered by a linker. A library of bis-(6-chloro-2-methoxy-acridin-9-yl) and bis-(7-chloro-2-methoxy-benzo[
b
][1,5]naphthyridin-10-yl) analogs was synthesized to explore the effect of structurally diverse linkers on PrP
Sc
replication in scrapie-infected neuroblastoma cells. Structure–activity analysis revealed that linker length and structure are important determinants for inhibition of prion replication in cultured scrapied cells. Three bis-acridine analogs, (6-chloro-2-methoxy-acridin-9-yl)-(3-{4-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-piperazin-1-yl}-propyl)-amine,
N
,
N
′-bis-(6-chloro-2-methoxy-acridin-9-yl)-1,8-diamino-3,6-dioxaoctane, and (1-{[4-(6-chloro-2-methoxy-acridin-9-ylamino)-butyl]-[3-(6-chloro-2-methoxy-acridin-9-ylamino)-propyl]-carbamoyl}-ethyl)-carbamic acid
tert
-butyl ester, showed half-maximal inhibition of PrP
Sc
formation at 40, 25, and 30 nM, respectively, and were not cytotoxic to uninfected neuroblastoma cells at concentrations of 500 nM. Our data suggest that bis-acridine analogs may provide a potent alternative to the acridine-based compound quinacrine, which is currently under clinical evaluation for the treatment of prion disease.
Watching proteins fold one molecule at a time
Authors: Rhoades Elizabeth , Gussakovsky Eugene , Haran Gilad
Published: March 2003

Recent theoretical work suggests that protein folding involves an ensemble of pathways on a rugged energy landscape. We provide direct evidence for heterogeneous folding pathways from single-molecule studies, facilitated by a recently developed immobilization technique. Individual fluorophore-labeled molecules of the protein adenylate kinase were trapped within surface-tethered lipid vesicles, thereby allowing spatial restriction without inducing any spurious interactions with the environment, which often occur when using direct surface-linking techniques. The conformational fluctuations of these protein molecules, prepared at the thermodynamic midtransition point, were studied by using fluorescence resonance energy transfer between two specifically attached labels. Folding and unfolding transitions appeared in experimental time traces as correlated steps in donor and acceptor fluorescence intensity. The size of the steps, in fluorescence resonance energy transfer efficiency units, shows a very broad distribution. This distribution peaks at a relatively low value, indicating a preference for small-step motion on the energy landscape. The time scale of the transitions is also distributed, and although many transitions are too fast to be time-resolved here, the slowest ones may take >1 sec to complete. These extremely slow changes during the folding of single molecules highlight the possible importance of correlated, non-Markovian conformational dynamics.
Wireless tele‐operated mechatronic control system for camera platform positioning
Authors: Tlale N.S. , Potgieter J. , Bright G.
Published: March 2003

The skill of the camera operator in controlling the orientation of camera platforms in the film industry is one of the crucial factors in producing movies with good cinematography. Some film footage requires landscapes that make it difficult for the camera operator to efficiently operate the camera platform. Tether connections limit the manner in which the camera platform can be mounted in order to achieve the best scene shooting. This paper reports on the project undertaken by the Mechatronics and Robotics Research Group at Massey University, in conjunction with the New Zealand film industry, on the development of wireless control camera platforms.
Further studies on fabric objective measurement (concentrated loading method)
Authors: Alamdar‐Yazdi A.
Published: March 2003

This paper considers the ability of the concentrated loading method for measuring the basic low stress mechanical properties of heavy weight woven fabrics. Fifty‐three randomly selected woven fabrics were tested and the results show the ability of the method. It also introduces the parameters, which indicate the behavior of the woven fabrics.
A study on the relaxation behavior of fabric's crease recovery angle
Authors: Dong Xia , Zhang Jianchun , Zhang Yan , Yao Mu
Published: March 2003

On the basis of Viscoelasticity Theory of textile materials, the Maxwell's Model, Kalvin Paunting Model and Burger's model were analyzed in the paper. The regression equation of the strain relaxation curve was established and the experiments verify that the crease recovery angle can be predicted by the regression equation of Burger's model. The relaxation behavior of crease recovery angle varying with time was according to the creep‐relaxation equation.
Community participation and public awareness in disaster mitigation
Authors: Newport Jeyanth K. , Jawahar Godfrey G.P.
Published: March 2003

Describes how the Society for National Integration through Rural Development in India involves the local communities when developing disaster mitigation measures. Shows how participation of the community in resource identification, capabilities, coping mechanisms and vulnerability assessment will be more effective in the planning of a sensible and practical system, more suitable for the needs of the community. Covers contingency planning, community preparedness, task forces (comprising active youths in the ratio of one youth for ten families) and response mechanisms.
Malta’s risk minimisation to earthquake, volcanic and tsunami damage
Authors: Camilleri Denis H.
Published: March 2003

The paper defines Malta’s disaster risks parameter. Various data are given on Malta’s earthquake‐related hazards. By referring to mean damage ratios and death rates, earthquake losses are equated as a percentage of the gross domestic product, and the number of casualties and homeless estimated. Being a small island, the need for foreign help in the aftermath of a large disaster is analysed. Because of the present large number of vacant premises available, the amount of material foreign help required is minimized, as households could be evacuated to other regions of the Island. The above risks could further be minimized if Malta adopts strategic preparedness and mitigation management. Retrofitting of the present building stock is necessary, as is actively encouraging the purchase of disaster insurance, together with preparation of planning tools and strategic choices.
REVIEW OF CHAOS COMMUNICATION BY FEEDBACK CONTROL OF SYMBOLIC DYNAMICS
Authors: BOLLT ERIK M.
Published: March 2003

This paper is meant to serve as a tutorial describing the link between symbolic dynamics as a description of a chaotic attractor, and how to use control of chaos to manipulate the corresponding symbolic dynamics to transmit an information bearing signal. We use the Lorenz attractor, in the form of the discrete successive maxima map of the z-variable time-series, as our main example. For the first time, here, we use this oscillator as a chaotic signal carrier. We review the many previously developed issues necessary to create a working control of symbol dynamics system. These include a brief review of the theory of symbol dynamics, and how they arise from the flow of a differential equation. We also discuss the role of the (symbol dynamics) generating partition, the difficulty of finding such partitions, which is an open problem for most dynamical systems, and a newly developed algorithm to find the generating partition which relies just on knowing a large set of periodic orbits. We also discuss the importance of using a generating partition in terms of considering the possibility of using some other arbitrary partition, with discussion of consequences both generally to characterizing the system, and also specifically to communicating on chaotic signal carriers. Also, of practical importance, we review the necessary feedback-control issues to force the flow of a chaotic differential equation to carry a desired message.
INTEGRATING IDENTIFICATION AND QUALITATIVE ANALYSIS FOR THE DYNAMIC MODEL OF A LAGOON
Authors: GARULLI A. , MOCENNI C. , VICINO A. , TESI A.
Published: March 2003

This paper deals with the identification and the qualitative analysis of a dynamic model of a shallow lagoon. The model describes the relations between biotic (phytoplankton, zooplankton) and abiotic (oxygen, nutrients) components of a lagoon. The first step of the paper is to derive estimates for the model parameters through an identification procedure using real data. The second step is to perform a qualitative analysis of the model dynamics, via the introduction of a parameterized reduced order model. The main contribution of the paper is to make an effort in the direction of synergyzing the identification stage with the qualitative analysis of the model dynamics, in order to gain a better understanding of the system behavior and obtain more reliable estimates for the model parameters and exogenous inputs.
ELECTRON TRANSFER REACTIONS COUPLED TO PROTON TRANSLOCATION: CYTOCHROME OXIDASE, PROTON PUMPS, AND BIOLOGICAL ENERGY TRANSDUCTION
Authors: STUCHEBRUKHOV ALEXEI A.
Published: March 2003

Cytochrome oxidase (COX) is the terminal component of electron transport chain of the respiratory system in mitochondria, and one of the key enzymes responsible for energy generation in cells. COX functions as a proton pump that utilizes free energy of oxygen reduction for translocation of protons across the mitochondrion membrane. The proton gradient created in the process is later utilized to drive synthesis of ATP. Although the structure of COX has been recently resolved, the molecular mechanism of proton pumping remains unknown. In this paper, general principles and possible molecular mechanisms of energy transformations in this enzyme will be discussed. The main question is how exactly chemical energy of oxygen reduction and water formation is transformed into a proton gradient; or, how exactly electron transfer reactions are utilized to translocate protons across the mitochondrion membrane against the electrochemical gradient. A key to the solution of this problem is in understanding correlated transport of electrons and protons. Here, theoretical models are discussed for coupled electron and proton transfer reactions in which an electron is tunneling over long distance between two redox cofactors, and a coupled proton is moving along a proton conducting channel in a classical, diffusion-like random walk fashion. Such reactions are typical for COX and other enzymes involved in biological energy transformations.
PHOTOCHEMISTRY OF BUTYROPHENONE AND ITS α-SUBSTITUTED DERIVATIVE: A THEORETICAL EXAMINATION OF A NEW PHOTOCHEMICAL ROUTE TO CYCLOPROPANE GROUP FORMATION
Authors: FANG WEI-HAI , PHILLIPS DAVID LEE
Published: March 2003

The potential energy surfaces of dissociations and isomerizations for butyrophenone and its α-substituted derivative in low-lying electronic states have been studied with use of the CASSCF and DFT methods. A three-surface (S1, T1 and T2) intersection was found in the present work and this plays an important role in the S1 → T1 process for butyrophenone and related aromatic carbonyl compounds. Examination of these results provides some new insights into the mechanistic photochemistry of aromatic ketones. The most probable mechanism leading to formation of a cyclopropane moiety was obtained on the basis of the calculated potential energy surfaces and their intersections. The selection of a suitable α-substituent was found to be a key step for cyclopropanation to occur by photoexcitation of butyrophenone derivatives.
THEORETICAL STUDY OF N2O ADSORPTION AND DECOMPOSITION AT REGULAR AND DEFECT SITES OF MgO (001) SURFACE
Authors: XU YI-JUN , LI JUN-QIAN , ZHANG YONG-FAN
Published: March 2003

The adsorption of N 2 O at regular and defect sites of MgO (001) surface has been studied systematically using cluster models embedded in a large array of point charges by density functional method. The calculated results show that the MgO (001) surface with oxygen vacancies exhibits high catalytic reactivity toward N 2 O adsorptive-decomposition at variance with the regular MgO surface or the surface with magnesium vacancies. Much elongation of O–N bond of N 2 O after adsorption at oxygen vacancy site with O end of N 2 O down indicates that O–N bond has been broken with concurrent production of N 2, leaving a regular site instead of the original oxygen vacancy site (F center). Besides, the MgO (001) surface with magnesium vacancies hardly exhibits catalytic reactivity. It can be concluded that N 2 O dissociation is likely occurred at MgO (001) surface oxygen vacancy sites, which is consistent with the generally accepted viewpoint in the experiment.
COMPUTATIONAL ANALYSIS OF THE INTERACTIONS BETWEEN THE ANGIOGENESIS INHIBITOR PD173074 AND FIBROBLAST GROWTH FACTOR RECEPTOR 1
Authors: TØNDEL KRISTIN , WONG CHUNG F. , MCCAMMON J. A.
Published: March 2003

We have carried out computational sensitivity analysis to analyze the interactions between the inhibitor PD173074 and FGFR1 in order to identify the determinants of their recognition and generate insights into further refining the inhibitor. The analysis has identified the parts of the inhibitor that are already useful for binding, e.g. the part that recognizes the linker connecting the N-terminal and C-terminal lobes of the kinase domain. These parts are profitably kept during a lead optimization process. The analysis has also pointed out regions of the inhibitors that may be useful to modify to improve its binding affinity, e.g. the dimethoxyphenyl ring. Comparative structural analysis of the binding pocket of almost 400 protein kinases also suggests that modifying the dimethoxyphenyl moiety might improve selective binding. Selectivity may be achieved not only by introducing groups to the 3 and 5 positions but also to the 1 and 6 positions. Replacing the tertiary amines by hydrocarbon might also improve binding affinity.
Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide
Authors: Heineke Jörg , Kempf Tibor , Kraft Theresia , Hilfiker Andres , Morawietz Henning , Scheubel Robert J. , Caroni Pico , Lohmann Suzanne M. , Drexler Helmut , Wollert Kai C.
Published: March 2003

Background—

In chronic heart failure, myocardial expression of the inducible isoform of nitric oxide (NO) synthase (NOS2) is enhanced, leading to a sustained production of NO. We postulated that NO modulates expression of genes in cardiac myocytes that may be functionally important in the context of cardiac hypertrophy and failure.

Methods and Results—

As revealed by cDNA expression array analyses, the NO donor SNAP, which has been shown previously to inhibit agonist-induced cardiac myocyte hypertrophy, downregulates expression of the cytoskeleton-associated muscle LIM protein (MLP) in endothelin-1 (ET-1)–stimulated neonatal rat cardiac myocytes. Northern blotting and immunoblotting experiments confirmed this finding and established that SNAP negatively controls MLP mRNA (−49%,
P
<0.01) and protein (−52%,
P
<0.01) abundance in ET-1–treated cardiomyocytes via cGMP-dependent protein kinase and superoxide/peroxynitrite-dependent signaling pathways. Treatment of cardiac myocytes with IL-1β and IFN-γ downregulated MLP expression levels via induction of NOS2. Moreover, expression levels of NOS2 and MLP were inversely correlated in the failing human heart, indicating that NOS2 may regulate MLP abundance in vitro and in vivo. Antisense oligonucleotides were used to explore the functional consequences of reduced MLP expression levels in cardiac myocytes. Like SNAP, antisense downregulation of MLP protein expression (−52%,
P
<0.01) blunted the increases in protein synthesis, cell size, and sarcomere organization in response to ET-1 stimulation. Conversely, overexpression of MLP augmented cell size and sarcomere organization in cardiac myocytes.

Conclusions—

NO negatively controls MLP expression in cardiac myocytes. Because MLP is necessary and sufficient for hypertrophy and sarcomere assembly, MLP downregulation may restrain hypertrophic growth in pathophysiological situations with increased cardiac NO production.
Morning Surge in Blood Pressure as a Predictor of Silent and Clinical Cerebrovascular Disease in Elderly Hypertensives
Authors: Kario Kazuomi , Pickering Thomas G. , Umeda Yuji , Hoshide Satoshi , Hoshide Yoko , Morinari Masato , Murata Mitsunobu , Kuroda Toshio , Schwartz Joseph E. , Shimada Kazuyuki
Published: March 2003

Background—

Cardiovascular events occur most frequently in the morning hours. We prospectively studied the association between the morning blood pressure (BP) surge and stroke in elderly hypertensives.

Methods and Results—

We studied stroke prognosis in 519 older hypertensives in whom ambulatory BP monitoring was performed and silent cerebral infarct was assessed by brain MRI and who were followed up prospectively. The morning BP surge (MS) was calculated as follows: mean systolic BP during the 2 hours after awakening minus mean systolic BP during the 1 hour that included the lowest sleep BP. During an average duration of 41 months (range 1 to 68 months), 44 stroke events occurred. When the patients were divided into 2 groups according to MS, those in the top decile (MS group; MS ≥55 mm Hg, n=53) had a higher baseline prevalence of multiple infarcts (57% versus 33%,
P
=0.001) and a higher stroke incidence (19% versus 7.3%,
P
=0.004) during the follow-up period than the others (non-MS group; MS <55 mm Hg, n=466). After they were matched for age and 24-hour BP, the relative risk of the MS group versus the non-MS group remained significant (relative risk=2.7,
P
=0.04). The MS was associated with stroke events independently of 24-hour BP, nocturnal BP dipping status, and baseline prevalence of silent infarct (
P
=0.008).

Conclusions—

In older hypertensives, a higher morning BP surge is associated with stroke risk independently of ambulatory BP, nocturnal BP falls, and silent infarct. Reduction of the MS could thus be a new therapeutic target for preventing target organ damage and subsequent cardiovascular events in hypertensive patients.
Electron Spin Resonance Characterization of Vascular Xanthine and NAD(P)H Oxidase Activity in Patients With Coronary Artery Disease
Authors: Spiekermann Stephan , Landmesser Ulf , Dikalov Sergey , Bredt Martin , Gamez Graciela , Tatge Helma , Reepschläger Nina , Hornig Burkhard , Drexler Helmut , Harrison David G.
Published: March 2003

Background—

Increased inactivation of nitric oxide by superoxide (O
2
·−
) contributes to endothelial dysfunction in patients with coronary disease (CAD). We therefore characterized the vascular activities of xanthine oxidase and NAD(P)H oxidase, 2 major O
2
·−
-producing enzyme systems, and their relationship with flow-dependent, endothelium-mediated vasodilation (FDD) in patients with CAD.

Methods and Results—

Xanthine- and NAD(P)H-mediated O
2
·−
formation was determined in coronary arteries from 10 patients with CAD and 10 controls by using electron spin resonance spectroscopy. Furthermore, activity of endothelium-bound xanthine oxidase in vivo and FDD of the radial artery were determined in 21 patients with CAD and 10 controls. FDD was measured before and after infusion of the antioxidant vitamin C (25 mg/min i.a.) to determine the portion of FDD inhibited by radicals. In coronary arteries from patients with CAD, xanthine- and NAD(P)H-mediated O
2
·−
formation was increased compared with controls (xanthine: 12±2 versus 7±1 nmol O
2
·−
/μg protein; NADH: 11±1 versus 7±1 nmol O
2
·−
/μg protein; and NADPH: 12±2 versus 9±1 nmol O
2
·−
/μg protein; each
P
<0.05). Endothelium-bound xanthine oxidase activity was increased by >200% in patients with CAD (25±4 versus 9±1 nmol O
2
·−
/μL plasma per min;
P
<0.05) and correlated inversely with FDD (
r
=−0.55;
P
<0.05) and positively with the effect of vitamin C on FDD (
r
=0.54;
P
<0.05).

Conclusions—

The present study represents the first electron spin resonance measurements of xanthine and NAD(P)H oxidase activity in human coronary arteries and supports the concept that increased activities of both enzymes contribute to increased vascular oxidant stress in patients with CAD. Furthermore, the present study suggests that increased xanthine oxidase activity contributes to endothelial dysfunction in patients with CAD and may thereby promote the atherosclerotic process.
Cellular Phospholipid and Cholesterol Efflux in High-Density Lipoprotein Deficiency
Authors: Marcil Michel , Bissonnette Rachel , Vincent Jérôme , Krimbou Larbi , Genest Jacques
Published: March 2003

Background—

Prospective studies have examined the relationship between coronary artery disease and low plasma levels of high-density lipoprotein cholesterol (HDL-C).

Methods and Results—

We investigated the causes of hypoalphalipoproteinemia (HypoA; HDL-C <5th percentile) in 64 subjects (12 women and 52 men). Apolipoprotein AI–mediated cellular cholesterol and phospholipid efflux were measured in fibroblasts from HypoA subjects, 9 controls, 2 patients with Tangier disease, and 5 patients with hyperalphalipoproteinemia. A phospholipid efflux defect was defined as <70% of controls. Mean HDL-C was 0.49±0.21 mmol/L. Cholesterol and phospholipid efflux correlated strongly (
r
=0.72,
P
<0.001). Phospholipid efflux and HDL-C (
r
=0.64,
P
<0.001) correlated in HypoA subjects. However, phospholipid or cholesterol efflux was no longer a determinant of HDL-C levels at higher levels (>≈1.0 mmol/L) of HDL-C. In HypoA subjects, 4 cases of Tangier disease and 6 of familial HDL deficiency (heterozygous Tangier disease) were identified (10 of 64; 16%). In the remaining 54 subjects, mean lipid efflux was not significantly different from controls and subjects with hyperalphalipoproteinemia. A phospholipid efflux defect was identified in 7 additional HypoA subjects, and a cholesterol efflux defect was detected in 11 subjects. In 2 of these subjects, the ABCA1 gene was ruled out as the cause of the efflux defect, while in 3, the low HDL-C trait segregated with the ABCA1 gene locus.

Conclusions—

Lipidation of lipid-poor apolipoprotein AI may not be a major determinant of cholesterol accumulation within more mature HDL particles and increasing cholesterol or phospholipid efflux beyond normal levels may not lead to increase in plasma HDL-C levels. ABCA1 is essential in the initial steps of HDL formation but other plasma events are major modulators of HDL-C levels.
The VIVA Trial
Authors: Henry Timothy D. , Annex Brian H. , McKendall George R. , Azrin Michael A. , Lopez John J. , Giordano Frank J. , Shah P.K. , Willerson James T. , Benza Raymond L. , Berman Daniel S. , Gibson C. Michael , Bajamonde Alex , Rundle Amy Chen , Fine Jennifer , McCluskey Edward R.
Published: March 2003

Background—

Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF.

Methods and Results—

A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng · kg
−1
· min
−1
), or high-dose rhVEGF (50 ng · kg
−1
· min
−1
) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups (placebo, +48 seconds; low dose, +30 seconds; high dose, +30 seconds). Angina class and quality of life were significantly improved within each group, with no difference between groups. By day 120, placebo-treated patients demonstrated reduced benefit in all three measures, with no significant difference compared with low-dose rhVEGF. In contrast, high-dose rhVEGF resulted in significant improvement in angina class (
P
=0.05) and nonsignificant trends in ETT time (
P
=0.15) and angina frequency (
P
=0.09) as compared with placebo.

Conclusions—

rhVEGF seems to be safe and well tolerated. rhVEGF offered no improvement beyond placebo in all measurements by day 60. By day 120, high-dose rhVEGF resulted in significant improvement in angina and favorable trends in ETT time and angina frequency.
E‐Commerce: Sorting Out the Environmental Consequences
Authors: Fichter Klaus
Published: March 2003

The environmental effects of e‐commerce may be described in terms of first‐, second‐, and third‐order effects. Data for these effects are scarce, partly because research on environmental effects of e‐commerce and e‐business is still in its infancy, although it is evolving very rapidly.

Until now, positive environmental consequences of e‐commerce have generally been coincidental. Two crucial questions that must be addressed are (1) How do we improve our understanding and management of the environmental effects of e‐commerce? and (2) Which approaches are best suited to the development of sustainable e‐solutions? Three approaches to developing sustainable e‐commerce solutions are discussed: the extension of environmental performance measurement and management to e‐commerce activities, the use of new cooperative forms of innovation management, and the provision of customer choice. Finally, an outlook on future research demands is presented. The technology itself (information and communication technologies, Internet) does not determine sustainability, but rather its design, use, and regulation does.
Energy Burdens of Conventional Wholesale and Retail Portions of Product Life Cycles
Authors: Norris Gregory A. , Croce Filippo Della , Jolliet Olivier
Published: March 2003

E‐commerce is often cited as offering the potential to reduce wholesale and retail burdens within product life cycles; however its potential impacts upon transport may be positive or negative. But the relative environmental importance of wholesale and retail trade and their intervening transportation links within product life cycles has not been generally characterized. The objective of this research was to assess the upstream (preusage) life‐cycle energy burden shares associated with retail trade and wholesale trade using input‐output life‐cycle assessment (IO LCA) with a special focus on the electronic computers sector.

According to our results, the physical transfers of products within the distribution phase play a minor role in terms of energy consumption compared with wholesaling and retailing. On the other hand, the supply chains of the wholesale and retail trade sectors can lead to energy consumption that is a significant share of the total preconsumer energy consumption for many products. Thus, where e‐commerce circumvents wholesale and/or retail trade, it can have a major impact on total preconsumer energy consumption.

As an example, for the electronic computers sector, retailing and wholesaling as a portion of distribution are responsible for 38% of the total energy consumption from production until purchase (cradle to gate), whereas transportation within the distribution phase corresponds to only 9%. Our analysis of more than 400 commodities in the United States showed that for the large majority of them, retailing and wholesaling account for appreciable shares of the total preconsumer energy burdens. Wholesaling and retailing should be included in LCA, and IO LCA is an effective tool for doing so.
Energy Use in Sales and Distribution via E‐Commerce and Conventional Retail: A Case Study of the Japanese Book Sector
Authors: Williams Eric , Tagami Takashi
Published: March 2003

Energy use associated with sales and distribution via business‐to‐consumer (B2C) e‐commerce versus conventional retail is analyzed for the Japanese book sector. Results indicate that e‐commerce uses considerably more energy per book than conventional retail in dense urban areas, because of additional packaging. In suburban and rural areas, the energy consumption of the two systems is nearly equal because the relative efficiency of courier services compared to personal automobile transport balances out the impact of additional packaging. The main reason e‐commerce does not save energy, even in rural areas, is because of the multipurpose use of automobiles; e‐commerce does consume less energy in the case of single‐purpose shopping trips by automobile. Overall consumption at the national level is nearly the same: 5.6 mega‐joules (MJ) per book for e‐commerce and 5.2 MJ per book for traditional retail. Although this difference is smaller than the uncertainty in the result, the structure of energy use for the two systems is quite distinct, which suggests reprioritization of energy‐efficiency strategies. Important factors influencing the energy efficiency of B2C e‐commerce include packaging, loading factors of courier trucks, number of trips per delivery, and residential energy consumption.
Digital versus Print: Energy Performance in the Selection and Use of Scholarly Journals
Authors: Gard David L. , Keoleian Gregory A.
Published: March 2003

Advances in digital technology and the growth of information networks are revolutionizing human activity. The Internet has been championed as a new tool for environmental improvement. A life‐cycle energy analysis of digital libraries, a growing application of information technology, was conducted to test this premise.

Life‐cycle models were compared for journal collections in digital and traditional formats. The basis for analysis was the amount of information in a typical scientific journal article (∼12 pages), which is equivalent to 0.97 hr of on‐screen reading time. Digital system elements such as servers, routers, laser printers, and computer workstations were modeled. Journal production, delivery, storage, binding, interlibrary loan, and photocopying were examined for the traditional system. Building‐related infrastructure, office paper, and personal transportation of the library patron were analyzed for both cases. In all, the study incorporated nearly 30 model elements, 90 input variables, and numerous fixed parameters.

Five primary scenarios were constructed to consider increasing levels of complexity. Scenario 1 assumes only one reading per article (unit of analysis). Additional scenarios assume 1,000 readings and vary the following: laser printing, photocopying, and personal transportation. Energy consumed by the digital collection ranged between 4.10 and 216 MJ. The traditional system realized burdens from 0.55 to 525 MJ. Four significant effects were uncovered: (1) Energy consumption per unit was highly influenced by the number of readings per article. (2) Networking infrastructure by itself had a relatively small effect on total energy consumed by the digital system. (3) When personal transportation was considered, its effects tended to dominate. (4) The impact of making personal copies varied. Photocopying always increased energy consumption, whereas laser printing actually saved energy when it substituted for on‐screen reading.
Books
Authors: McLaren Jake
Published: March 2003

Book reviewed in this article:

Digital Futures: Living in a Dot‐Com World, edited by James Wilsdon.
Human NK cell development in NOD/SCID mice receiving grafts of cord blood CD34+ cells
Authors: Kalberer Christian P. , Siegler Uwe , Wodnar-Filipowicz Aleksandra
Published: March 2003

Definition of the cytokine environment, which regulates the maturation of human natural killer (NK) cells, has been largely based on in vitro assays because of the lack of suitable animal models. Here we describe conditions leading to the development of human NK cells in NOD/SCID mice receiving grafts of hematopoietic CD34+ precursor cells from cord blood. After 1-week-long in vivo treatment with various combinations of interleukin (IL)–15, flt3 ligand, stem cell factor, IL-2, IL-12, and megakaryocyte growth and differentiation factor, CD56+CD3- cells were detected in bone marrow (BM), spleen, and peripheral blood (PB), comprising 5% to 15% of human CD45+ cells. Human NK cells of NOD/SCID mouse origin closely resembled NK cells from human PB with respect to phenotypic characteristics, interferon (IFN)–γ production, and cytotoxicity against HLA class 1–deficient K562 targets in vitro and antitumor activity against K562 erythroleukemia in vivo. In the absence of growth factor treatment, CD56+ cells were present only at background levels, but CD34+CD7+ and CD34-CD7+ lymphoid precursors with NK cell differentiation potential were detected in BM and spleen of chimeric NOD/SCID mice for up to 5 months after transplantation. Our results demonstrate that limitations in human NK cell development in the murine microenvironment can be overcome by treatment with NK cell growth–promoting human cytokines, resulting in the maturation of IFN-γ–producing cytotoxic NK cells. These studies establish conditions to explore human NK cell development and function in vivo in the NOD/SCID mouse model. (Blood. 2003;102:127-135)
Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation
Authors: Thirukkumaran Chandini M. , Luider Joanne M. , Stewart Douglas A. , Cheng Tina , Lupichuk Sasha M. , Nodwell Michael J. , Russell James A. , Auer Iwona A. , Morris Donald G.
Published: March 2003

Hematologic stem cell rescue after high-dose cytotoxic therapy is extensively used for the treatment of many hematopoietic and solid cancers. Gene marking studies suggest that occult tumor cells within the autograft may contribute to clinical relapse. To date purging of autografts contaminated with cancer cells has been unsuccessful. The selective oncolytic property of reovirus against myriad malignant histologies in in vitro, in vivo, and ex vivo systems has been previously demonstrated. In the present study we have shown that reovirus can successfully purge cancer cells within autografts. Human monocytic and myeloma cell lines as well as enriched ex vivo lymphoma, myeloma, and Waldenström macroglobulinemia patient tumor specimens were used in an experimental purging model. Viability of the cell lines or purified ex vivo tumor cells of diffuse large B-cell lymphoma, chronic lymphocytic leukemia, Waldenström macroglobulinemia, and small lymphocytic lymphoma was significantly reduced after reovirus treatment. Further, [35S]-methionine labeling and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of cellular proteins demonstrated reovirus protein synthesis and disruption of host cell protein synthesis as early as 24 hours. Admixtures of apheresis product with the abovementioned tumor cells and cell lines treated with reovirus showed complete purging of disease. In contrast, reovirus purging of enriched ex vivo multiple myeloma, Burkitt lymphoma, and follicular lymphoma was incomplete. The oncolytic action of reovirus did not affect CD34+ stem cells or their long-term colony-forming assays even after granulocyte colony-stimulating factor (G-CSF) stimulation. Our results indicate the ex vivo use of an unattenuated oncolytic virus as an attractive purging strategy for autologous stem cell transplantations. (Blood. 2003;102:377-387)