bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing thrombin's ability to accommodate a V34F substitution within the factor XIII activation peptide segment (28–41)*
Authors: Isetti G. , Maurer M.C.
Published: March 2004

Abstract:  In blood coagulation, thrombin helps to activate factor XIII (FXIII) by cleaving the activation peptide (AP) at the R37‐G38 peptide bond. The common polymorphism V34L yields a FXIII that is more easily activated than the wild type enzyme. Peptides based on the FXIII (28–41) (28TVELQGVVPRGVNL41) sequence serve as an important model system to evaluate the substrate specificity of thrombin and thus how to regulate FXIII activation. Our previous kinetic and nuclear magnetic resonance (NMR) studies have suggested that the P4–P1 amino acids on this FXIII segment provide key anchors to the thrombin active site surface. Furthermore, the most effective amino acid to have at the P4 position is a leucine. In the current work, a peptide containing V34F was examined to probe the ability to accommodate an aromatic residue at this position. Kinetic parameters for thrombin‐catalyzed hydrolysis of FXIII AP (28–41) V34F are comparable with that of the wild type V34. One‐dimensional proton line‐broadening studies reveal that the 34FVPR37 segment encompassing the P4–P1 positions makes the most contact with the thrombin surface. Two‐dimensional transferred‐nuclear overhauser effect spectroscopy (NOESY) studies indicate that when the peptide is bound to thrombin, the F34 aromatic ring is oriented to promote P4–P2 interactions with P36. This characteristic has been viewed as a hallmark for V34L. An ability to generate this interaction may promote the ability of FXIII AP (28–41) V34F to remain a viable substrate for thrombin.
Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor–coactivator interactions
Authors: Galande A.K. , Bramlett K.S. , Burris T.P. , Wittliff J.L. , Spatola A.F.
Published: March 2004

Abstract:  Cystine, lanthionine, and cystathionine containing cyclic peptides incorporating the signature nuclear receptor (NR) box (LXXLL) motif have been synthesized and the abilities of these peptides to inhibit estrogen receptor (ER)–coactivator interactions have been determined. We found that helicity of these peptides directly correlated with their bioactivity. Cystathionine proved to be a redox‐stable, isosteric replacement for the cystine disulfide. Cystathionine containing peptide 3 showed higher helical character and a lower inhibition constant (Ki, 7 nm) when compared with its cystine counterpart.
The conformation and movement of Na+ channel inactivation gate peptide in linker between domain III and IV during inactivation by NMR spectroscopy and molecular modeling study
Authors: Lou B.‐S. , Lin T.‐H. , Lo C.‐Z.
Published: March 2004

Abstract:  A model peptide that their sequence corresponds to the linker part between domain III and IV of rat brain type IIA Na+ channel has been synthesized for the conformational affect study corresponded to different gated states of Na+ channel. Nuclear magnetic resonance spectra of local anesthetic (LA) diphenyl drugs, such as phenytoin, in presence of a model peptide in both phosphate buffer and phospholipid bicelles (dimyristotl phosphocholine/dihexanoyl phospholcholine), which micelles serve to mimic the peptide–lipid interactions, have been measured to obtain information of the interactions between selected drugs and model peptide. Molecular modeling is performed to help to provide possible conformational information about the polypeptide LIII–IV that may be critical for recognition and signal transduction of inactivated Na+ channel. The voltage‐sensing mechanism of Na+ channel involves the movement of the inactivation particles (Ile, Phe, and Met) in the LIII–IV while binding to S4–S5 intracellular region within DIII and DIV. The movement of LIII–IV making its C‐terminal residues, including Glu1492 and Glu1493, may aligned near and stabilize the LAs bound with their receptors.
Inhibition of β‐amyloid toxicity by short peptides containing N‐methyl amino acids
Authors: Cruz M. , Tusell J.M. , Grillo‐Bosch D. , Albericio F. , Serratosa J. , Rabanal F. , Giralt E.
Published: March 2004

Abstract:  Single N‐methyl amino acid‐containing peptides related to the central hydrophobic region β16–20 (Lys‐Leu‐Val‐Phe‐Phe) of the β‐amyloid protein are able to reduce the cytotoxicity of natural β1–42 in PC12 cell cultures. N‐methyl phenylalanine analogs yield statistically significant increments in cell viability (Student's t‐test < 0.01%) and are nontoxic in the same assay. These promising results indicate that these peptide molecules could be a starting point for the development of potential therapeutic compounds for the treatment of Alzheimer's disease.
WHO and ATPIII proposals for the definition of the metabolic syndrome in patients with Type 2 diabetes
Authors: Marchesini G. , Forlani G. , Cerrelli F. , Manini R. , Natale S. , Baraldi L. , Ermini G. , Savorani G. , Zocchi D. , Melchionda N.
Published: March 2004

Aims  Different criteria have been proposed by the World Health Organization (WHO) and by the Third Report of the National Cholesterol Education Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATPIII) for the diagnosis of the metabolic syndrome. Its identification is of particular importance for coronary risk assessment.

Methods  The prevalence of the metabolic syndrome was determined according to the two different proposals in 1569 consecutive subjects with Type 2 diabetes.

Results  By the WHO proposal, 81% of cases (95% confidence interval, 79–83) were labelled as metabolic syndrome. Microalbuminuria had the highest specificity (99%) and visceral obesity the highest sensitivity (93%). Seventy‐eight per cent of patients (95% CI, 76–80) fulfilled the ATPIII criteria for metabolic syndrome, low HDL‐cholesterol having the highest specificity (95%), elevated blood pressure having the highest sensitivity. According to both proposals, 1113 patients were positive; 183 were concordantly negative, indicative of a fairly good agreement (k statistics, 0.464). Subjects only positive for the WHO proposal were more frequently males, had a lower BMI and a higher arterial pressure. Only subjects identified by the ATPIII proposal had a significantly higher prevalence of previously detected coronary heart disease.

Conclusions  Minimum criteria for the metabolic syndrome are met in most patients with Type 2 diabetes. Correct identification of the syndrome is important for an integrated approach to reduce the high costs and the associated disabilities. The ATPIII proposal more clearly identifies the burden of coronary heart disease associated with the metabolic syndrome.
Clustering of autoimmune disease in parents of siblings from the Type 1 diabetes Warren repository
Authors: Tait K. F. , Marshall T. , Berman J. , Carr‐Smith J. , Rowe B. , Todd J. A. , Bain S. C. , Barnett A. H. , Gough S. C. L.
Published: March 2004

Aims  Autoimmune disorders co‐exist in the same individuals and in families, implying a shared aetiology. The aim of this study was to compare the prevalence of the common autoimmune diseases in the parents of siblings from the Type 1 diabetes Warren repository with the general population.

Methods  Between 1989 and 1996, 505 British families with at least two siblings affected by Type 1 diabetes were recruited. Clinical information was collected regarding the presence of autoimmune disease in the parents and the prevalence of disease in the parents was compared with that expected in the general population.

Results  The prevalence of autoimmune disease in the parents was significantly higher in the repository compared with that expected in the general population [P‐value = 1.98 × 10−5 (female), P‐value = 1.1 × 10−8 (male)]. Type 1 diabetes was recorded in 63/1010 (6.2%) parents with a marked paternal preponderance (9.5 vs. 3%P = 0.002). Other autoimmune diseases affected 27% of parents with diabetes and 13.2% of parents without diabetes (P < 0.01).

Conclusion  These data confirm the importance of family history as a significant risk factor for the development of Type 1 diabetes and support the hypothesis that the common autoimmune diseases share at least some aetiological mechanisms.
The pass‐through of exchange rate changes to the prices of Australian exports of dairy and livestock products
Authors: Swift Robyn
Published: March 2004

Agricultural exports are usually assumed to operate in perfectly competitive international markets, but many are subject to non‐tariff barriers to trade that can affect the degree of pass‐through of exchange rate changes to foreign currency prices. The present study uses multivariate cointegration techniques to examine the effects of exchange rate changes on the prices of Australian exports of milk products, cheese, beef, sheepmeat, and hides and skins. The results indicate that Australian dairy exports operate in competitive markets in which pass‐through is complete, but there is no stable long‐run relationship between exchange rates and prices for any of the other livestock products.
Gendered Rationality? A Genealogical Exploration of the Philosophical and Sociological Conceptions of Rationality, Masculinity and Organization
Authors: Ross‐Smith Anne , Kornberger Martin
Published: March 2004

Although feminist organizational theory frequently refers to the association between rationality and masculinity, this association tends to be stated rather than argued for. This article examines, from a philosophical and sociological perspective, how these two concepts have become genealogically so closely and inseparably intertwined. It proposes that it is the early philosophical and sociological interpretations of reason and rationality that linked masculinity and rationality. To explore the connection between rationality and masculinity that is so fundamental to management and, more broadly, organizational discourse, is the purpose of this article. Commencing with a brief overview of pre‐Cartesian concepts of rationality, the main focus of the article is on modern conceptions of rationality, starting with the philosophy of Descartes. It examines the influence of the ideas of Francis Bacon, Enlightenment interpretations of rationality and the influence of Weberian rationality and subsequent interpretations of this concept of rationality by early organizational theorists. Finally, it demonstrates, via a case study of strategic management, how contemporary organizational discourse continues to reflect many of the assumptions about masculinity and rationality that are deeply embedded in more traditional organizational discourse. The article concludes with a number of suggestions for a way forward for critical gender studies that moves beyond the standard feminist critique of organizational discourse and practice.
Restructuring Flexibility: Case Studies of Part‐Time Female Workers in Six Workplaces
Authors: Jenkins Sarah
Published: March 2004

The article is based on six workplace case studies within a local economy and investigates the reasons behind the different utilization of part‐time workers within these workplaces. The research examines the content and nature of part‐time work in these organizations and the experiences of the part‐time workforce. The findings suggest that we need to distinguish between three types of part‐time workers; core, peak and ancillary. It is argued that such distinctions capture the variegated utilization of part‐time workers and contribute to the debate concerning the integration or marginalization of part‐time staff within workplaces. Furthermore, workplace cultures are an important arena for contextualizing these discussions. It is contended that the different uses of part‐time workers can be explained by different sectoral and organizational contexts but that the nature of part‐time work is also influenced by existing social relations within the workplace, notably with respect to gender, class and age.
‘Accelerated aging’: a primrose path to insight?
Authors: Miller Richard A.
Published: March 2004

Organism envy afflicts most researchers who work on aging in mice; how frustrating it is to see the worm and fly biologists nail down milestone after milestone, citation after citation! Surely genetic trickery can produce mice that age in a comparable jiffy? Alas, our near‐total ignorance of what times the aging process makes it hard to guess what genes to tweak, if indeed aging can be mimicked a presto. Building a case that a given short‐lived mutant ages quickly is a steep and thorny path, requiring more than just plucking a symptom here and there from a list of things that sometimes go wrong in old people or old mice. The hallmark of aging is that a lot goes wrong more or less at the same time, in 2‐year‐old mice, 10‐year‐old dogs and 70‐year‐old people. Finding ways to damage one or two systems in a 6‐week or 6‐month‐old mouse is not too hard to do, but the implications of such studies for improved understanding of aging per se are at best indirect and at worst imaginary and distracting.
Folate deficiency and homocysteine induce toxicity in cultured dorsal root ganglion neurons via cytosolic calcium accumulation
Authors: Tjiattas Lindsay , Ortiz Daniela O. , Dhivant Sirikarnt , Mitton Kerrie , Rogers Eugene , Shea Thomas B.
Published: March 2004

Folate deficiency induces neurotoxicity by multiple routes, including increasing cytosolic calcium and oxidative stress via increasing levels of the neurotoxin homocysteine (HC), and inducing mitochondrial and DNA damage. Because some of these neurotoxic effects overlap with those observed in motor neuron disease, we examined the impact of folate deprivation on dorsal root ganglion (DRG) neurons in culture. Folate deprivation for 2 h increased cytosolic calcium and reactive oxygen species (ROS) and impaired mitochondrial function. Treatment with nimodipine [an L voltage‐sensitive calcium channel (LVSCC) antagonist], MK‐801 (an NMDA channel antagonist) and thapsigarin (an inhibitor of efflux of calcium from internal stores) indicated that folate deprivation initially induced calcium influx via the LVSCC, with subsequent additional calcium derived from NMDA channels and internal stores. These compounds also reduced ROS and mitochondrial degeneration, indicating that calcium influx contributed to these phenomena. Calcium influx was prevented by co‐treatment with 3‐deaza‐adenosine, which inhibits HC formation, indicating that HC mediated increased cytosolic calcium following folate deprivation. Nimodipine, MK‐801 and thapsigargin had similar effects following direct treatment with HC as they did following folate deprivation. These findings support the idea that folate deprivation and HC treatment can compromise the health of DRG neurons by perturbing calcium homeostasis.
Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms
Authors: Lindholm Harri , Löfberg Mervi , Somer Hannu , Näveri Hannu , Sovijärvi Anssi
Published: March 2004

Study objectives:  Muscle is one of the most commonly affected organs in mitochondrial disorders, and the symptoms are often exercise related. The cardiopulmonary exercise test with the determination of lactic acid formation could give supplementary information about the exercise‐induced metabolic stress and compensatory mechanisms used in these disorders. The aim of this study was to evaluate the exercise capacity and lactate kinetics related to exercise in subjects with two genetically characterized mitochondrial disorders (multiple mitochondrial DNA deletions with PEO, MELAS) compared with lactate kinetics in subjects with metabolic myopathy (McArdle's disease) and in the healthy controls.

Design:  The subjects were consecutive, co‐operative patients of Department of Neurology of Helsinki University Hospital. Molecular genetic analyses were used for group classification of the mitochondrial myopathy.

Study subjects:  The study groups consisted of 11 patients with multiple deletions (PEO) and five patients with a point mutation in the mitochondrial DNA (MELAS), four patients with a muscle phosphorylase enzyme deficiency (McArdle's disease) and 13 healthy controls. The clinical disease of the patients was relatively mild.

Measurements and results:  A graded exercise test with ventilatory gas analyses and venous blood lactic acid analyses was performed. The main finding was the prolonged accumulation of blood lactate after the exercise in the PEO and MELAS groups compared with the controls. An overcompensation in ventilation was found in the MELAS and PEO group.

Conclusions:  The blood lactate accumulation after exercise occurs in patients with multiple mitochondrial DNA deletions or MELAS even in patients with only mild exercise intolerance. Cardiopulmonary exercise can be used in the diagnostic process of patients with mitochondrial myopathies.
Influence of chronic hypoxemia on peripheral muscle function and oxidative stress in humans
Authors: Faucher Marion , Steinberg Jean Guillaume , Barbier Dominique , Hug François , Jammes Yves
Published: March 2004

Transient re‐oxygenation of humans suffering from chronic obstructive pulmonary disease (COPD) allows the assessment of the consequences of chronic hypoxemia on peripheral muscle and metabolism apart from the effects of de‐conditioning. The subjects performed maximal voluntary contractions (MVC) of flexor digitorum and vastus lateralis muscles and sustained infra‐maximal contractions. COPD patients repeated the whole challenge during a 50‐min oxygen breathing period and after recovery to baseline hypoxemia. We measured the compound evoked muscle mass action potential (M‐wave) and the medium frequency (MF) of surface electromyography (EMG) power spectrum. Blood lactate (LA) and potassium (K+), erythrocyte‐reduced glutathione (GSH), and plasma thiobarbituric acid reactive substances (TBARS) were also measured. Compared with a control group, COPD patients had lower MVCs, an attenuated decrease in MF during exercise, lower resting level of GSH, no posthandgrip TBARS increase and no GSH consumption. Reoxygenation (1) increased MVCs, (2) accentuated the MF decline and (3) elicited a posthandgrip TBARS increase and GSH consumption. Thus, we conclude that chronic hypoxemia exerts specific muscular effects: a reduced force production, an attenuated ‘muscle wisdom’, and the suppression of the exercise oxidative stress.
Differential effects of peripheral ketamine and lidocaine on skin flux and hyperalgesia induced by intradermal capsaicin in humans
Authors: Gottrup Hanne , Bach Flemming Winther , Jensen Troels Staehelin
Published: March 2004

The capsaicin‐induced flux in the primary and secondary hyperalgesic area after pretreating the capsaicin injection site with local ketamine, lidocaine or saline 10 min prior to injection was examined in this study. Twelve healthy volunteers participated in two randomized, double‐blinded, placebo‐controlled, cross‐over experiments. In the first experiment, the skin on the volar forearm was pretreated with s.c. ketamine or saline, 10 min prior to capsaicin injection. Flux was recorded before and continuously after the injection of capsaicin in the primary and secondary hyperalgesic area. Spontaneous pain, evoked pain and areas of hyperalgesia were measured. In the second experiment, a similar capsaicin test was carried out 10 min after pretreating the skin with s.c. lidocaine or saline. Ketamine reduced flux significantly both in the primary and secondary hyperalgesic area. Lidocaine reduced flux significantly in the primary hyperalgesic area. No effect was observed on flux in the secondary hyperalgesic area. Only lidocaine reduced spontaneous pain, evoked pain and areas of hyperalgesia, whereas ketamine had no effect. Our results suggest that there is no simple and close relation between vascular and sensory reactions to pharmacological manipulation following intradermal capsaicin injection. We propose distinct mechanisms for local lidocaine and ketamine based on the differential effects of local lidocaine and ketamine on flux and pain.
STATISTICAL LIMIT LAWS FOR EQUIVARIANT OBSERVATIONS
Authors: MELBOURNE IAN , NICOL MATTHEW
Published: March 2004

We show that statistical limit laws for ergodic stationary sequences of G-equivariant observations ϕ on a probability space Ω×G are inherited by sequences of observations ϕ(·,g0) on the probability space Ω for each fixed g0. The statistical limit laws we consider are the central limit theorem, weak invariance principle and the law of the iterated logarithm.
STERN–BROCOT PRESSURE AND MULTIFRACTAL SPECTRA IN ERGODIC THEORY OF NUMBERS
Authors: KESSEBÖHMER MARC , STRATMANN BERND O.
Published: March 2004

In this note we apply the general multifractal analysis for growth rates derived in [10], and show that this leads to some new results in ergodic theory and the theory of multifractals of numbers. Namely, we consider Stern–Brocot growth rates and introduce the Stern–Brocot pressure P. We then obtain the results that P is differentiable everywhere and that its Legendre transformation governs the multifractal spectra arising from level sets of Stern–Brocot rates.
Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes
Authors: Shiromani Priyattam J. , Xu Man , Winston Elizabeth M. , Shiromani Samara N. , Gerashchenko Dmitry , Weaver David R.
Published: March 2004

In mammals, sleep is regulated by circadian and homeostatic mechanisms. The circadian component, residing in the suprachiasmatic nucleus (SCN), regulates the timing of sleep, whereas homeostatic factors determine the amount of sleep. It is believed that these two processes regulating sleep are independent because sleep amount is unchanged after SCN lesions. However, because such lesions necessarily damage neuronal connectivity, it is preferable to investigate this question in a genetic model that overcomes the confounding influence of circadian rhythmicity. Mice with disruption of both mouse Period genes ( mPer) 1 and mPer2 have a robust diurnal sleep-wake rhythm in an entrained light-dark cycle but lose rhythmicity in a free-run condition. Here, we examine the role of the mPer genes on the rhythmic and homeostatic regulation of sleep. In entrained conditions, when averaged over the 24-h period, there were no significant differences in waking, slow-wave sleep (SWS), or rapid eye movement (REM) sleep between mPer1, mPer2, mPer3, mPer1-mPer2 double-mutant, and wild-type mice. The mice were then kept awake for 6 h (light period 6–12), and the mPer mutants exhibited increased sleep drive, indicating an intact sleep homeostatic response in the absence of the mPer genes. In free-run conditions (constant darkness), the mPer1-mPer2 double mutants became arrhythmic, but they continued to maintain their sleep levels even after 36 days in free-running conditions. Although mPer1 and mPer2 represent key elements of the molecular clock in the SCN, they are not required for homeostatic regulation of the daily amounts of waking, SWS, or REM sleep.
Mapping Neural Architectures Onto Acoustic Features of Birdsong
Authors: Abarbanel Henry D. I. , Gibb Leif , Mindlin Gabriel B. , Talathi Sachin
Published: March 2004

The motor pathway responsible for the complex vocalizations of songbirds has been extensively characterized, both in terms of intrinsic and synaptic physiology in vitro and in terms of the spatiotemporal patterns of neural activity in vivo. However, the relationship between the neural architecture of the song motor pathway and the acoustic features of birdsong is not well understood. Using a computational model of the song motor pathway and the songbird vocal organ, we investigate the relationship between song production and the neural connectivity of nucleus HVc (used as a proper name) and the robust nucleus of the archistriatum (RA). Drawing on recent experimental observations, our neural model contains a population of sequentially bursting HVc neurons driving the activity of a population of RA neurons. An important focus of our investigations is the contribution of intrinsic circuitry within RA to the acoustic output of the model. We find that the inclusion of inhibitory interneurons in the model can substantially influence the features of song syllables, and we illustrate the potential for subharmonic behavior in RA in response to forcing by HVc neurons. Our results demonstrate the association of specific acoustic features with specific neural connectivities and support the view that intrinsic circuitry within RA may play a critical role in generating the features of birdsong.
Italian Communism and Soviet Terror
Authors: Drake Richard
Published: March 2004

The declassification of materials from the Russian archives has provided a good deal of new evidence about the relationship between the Italian Communist Party (PCI) and the Soviet Union both before and after World War II. Two newly published collections of documents leave no doubt that, contrary to arguments made by supporters of the PCI, the Italian party was in fact strictly subservient to the dictates of Josif Stalin. The documents reveal the unsavory role of the PCI leader, Palmiro Togliatti, in the destruction of large sections of the Italian Communist movement and in the tragic fate of Italian prisoners of war who were held in the Soviet Union during and after World War II. Togliatti's legacy, as these documents make clear, was one of terror and the Stalinization of the PCI.
REVERTER ET SON FILS, DEUX OFFICIERS CATALANS AU SERVICE DES SULTANS DE MARRAKECH
Authors: Clément François
Published: March 2004

Some individuals who decided or had to move from Christian Spain to Muslim Maghrib during the Middle Ages succeeded in having a second start in their new country, whether they converted to Islam or not. As most of these men were soldiers, this study recalls first how Moroccan sovereigns got into the habit of recruiting Christian militia as a kind of personal bodyguard, then it focuses on the careers of Reverter and his son 'Alī. The former was a senior officer of Catalan origin, and he reached a high rank in the Almoravid army, although preserving his Christian faith. The latter, who converted to Islam, loyally served under the Almohad sultan, while never forgetting his roots, as it would seem from his attitude towards the Christian renegades and captives he cooperated with during a mission in Majorca.
THE LANGUAGES OF MEDIEVAL IBERIA AND THEIR RELIGIOUS DIMENSION1
Authors: Gallego María Angeles
Published: March 2004

The aim of this article is to investigate language use as a social phenomenon in the period of eight centuries during which there was a Muslim state in the Iberian peninsula—that is, more exactly, the period comprising 711 C.E. to 1492 C.E., which are the dates of the Muslim arrival and conquest of the peninsula, and the end of the reconquest of the Muslim territory by the Christians, respectively. For this purpose, I will look into the contexts and registers in which the different languages of Medieval Iberia were used, as well as references to linguistic usages that the written sources of this period contain. Religious affiliation will prove to be a decisive factor in the use of different linguistic varieties and, moreover, the values ascribed to each of them.
FINANCING A CAPTIVE'S RANSOM IN LATE MEDIEVAL ARAGON
Authors: Rodriguez Jarbel
Published: March 2004

Capture and Captivity were significant problems in the lands of the medieval Crown of Aragon, due to the ongoing struggle between Muslims and Christians in the Iberian Peninsula. This article addresses the question of how Christian captives and their families raised the large ransoms that were demanded for their release. The raising of a ransom often began with the captives or those acting on their behalf having to beg on the streets for the money. By the late fourteenth century, however, additional options had emerged to help those in need. Consequently, raising the money became a complex process whereby captives depended not only on their own resources and whatever they could beg for, but also whatever aid civic, ecclesiastical, and royal sources could provide.
Towards a Paradigm of Multiparty Negotiation
Authors: Glendon A. Ian , Crump Larry
Published: March 2004

Despite considerable research on multiparty negotiation, no prior attempt has been made to organize and describe knowledge from the various disciplines represented within this field of study. The present article seeks to offer a comprehensive understanding of multiparty negotiation. It establishes a foundation for a multiparty negotiation paradigm by building a coherent multi-disciplinary framework. Development of this framework begins by defining fundamental concepts and identifying essential dynamics that structure the field of multiparty negotiation. This article then describes the building blocks and boundaries of the field. A review of the three most developed multiparty negotiation bodies of literature or domains – international negotiations, public disputes, and organizational and group negotiations – follows. Similarities and differences between the three domains are identified, as are points of theoretical integration. This examination of multiparty negotiation concepts and dynamics, building blocks, boundaries, and domains constitutes a framework that defines multiparty negotiation as a field of practice. The article also establishes a research agenda that will contribute to the development of multiparty negotiation as an area of study.
Multistakeholder Dialogue at the Global Scale
Authors: Susskind Lawrence , Fuller Boyd , Fairman David , Ferenz Michèle
Published: March 2004

Multistakeholder Dialogues (MSDs) are being used as part of many international policy-making efforts. Official and unofficial representatives are being brought together to build relationships, set agendas for future official and unofficial dialogues, and even to generate packages of proposals or recommendations. The authors describe the key challenges that face prospective MSD designers, including: finding the right participants, managing with extremely limited financial resources, providing effective meeting facilitation, and integrating the work of MSDs into existing institutional activities and structures. While there are examples of successful MSDs that contribute to official policymaking, too many multistakeholder dialogues founder because the participants are inadequately prepared, the processes are managed ineffectively, and expectations are unrealistic.
Leadership in Multilateral Negotiation and Domestic Policy: The Netherlands at the Kyoto Protocol Negotiation
Authors: Kanie Norichika
Published: March 2004

This article examines the causal mechanisms through which domestic policies and underlying domestic structural and institutional factors influenced the Netherlands' leadership-taking capability during climate change negotiations leading up to the 1997 Kyoto Protocol. Two causal mechanisms are prominent. One is the importance and necessity of building domestic capacity before the negotiation, and the other is the role of the "power devise" for a middle power to become influential in the negotiation. In this case, a regional organization provided the framework for a middle power to materialise its leadership potential.
Keynes' Attack on the Versailles Treaty: An Early Investigation of the Consequences of Bounded Rationality, Framing, and Cognitive Illusions
Authors: Bottom William
Published: March 2004

The Paris Peace Conference was arguably the most complex negotiation ever undertaken. The principal product of the conference, the Treaty of Versailles, failed to accomplish any of its framers' major goals. Relations between the Allies themselves and the Allies and their defeated enemies seriously deteriorated as a consequence of the negotiations and attempts to implement the treaty. Economic conditions in Germany, the rest of Europe, and eventually the United States declined as well. At the time of the Treaty's publication, John Maynard Keynes and a considerable number of other participants predicted these events, pointing to the negotiators' errors and oversights as a primary cause. The logic of Keynes' argument is re-examined in light of recent research on the psychology of human information processing, judgment and choice. It reveals that his approach is actually very consistent with and anticipates both Simon's conception of bounded rationality and recent work on cognitive heuristics and illusions. Negotiator bias has been studied almost exclusively using simple laboratory settings. The catastrophic lose-lose nature of the Versailles Treaty illustrates the way in which complexity necessitates reliance on simplifying heuristics while propagating and amplifying the impact of the bias that is generated. Evidence from the treaty negotiations and the failed implementation of the treaty suggest some very significant boundary conditions for the application of rational choice models in the business, politics, and international relations contexts. It also demonstrates the need for negotiations researchers to focus more attention on the implementation of agreements and the long-term effects of those agreements on relationships.
Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients
Authors: Au Wing-Yan , Pang Annie , Choy Carolyn , Chim Chor-Sang , Kwong Yok-Lam
Published: March 2004

In Epstein-Barr-virus (EBV)–positive lymphomas in immunocompetent patients, release of EBV DNA from tumor cells into the plasma might be useful for disease monitoring and prognostication. To test this hypothesis, we quantified serially plasma EBV DNA by quantitative polymerase chain reaction in 39 cases of EBV-positive (natural killer [NK] cell, n = 23; T cell, n = 8; B cell, n = 4; Hodgkin, n = 4) lymphomas. As control, EBV DNA was undetectable in 34 cases of EBV-negative lymphomas at diagnosis and during chemotherapy. In all cases of EBV-positive lymphomas, EBV DNA was detectable (105-1010 copies/mL) at diagnosis. It paralleled the clinical course, with EBV DNA becoming undetectable at remission and remaining elevated in refractory disease. On multivariate analysis, high-presentation EBV DNA (> 7.3 × 107 copies/mL) was significantly associated with an inferior overall survival (OS). Subgroup analysis of NK cell lymphomas, the largest cohort in this study, showed that presentation EBV DNA was correlated with disease stage and lactate dehydrogenase. On multivariate analysis, high-presentation EBV DNA (> 6.1 × 107 copies/mL) was significantly associated with an inferior disease-free survival. During treatment, patients with EBV DNA that showed further increases or failed to become undetectable had significantly inferior OS. In EBV-positive lymphomas, plasma EBV DNA is valuable as a tumor biomarker and for prognostication.
An Introduction to the Molecular Mechanisms of Apoptosis
Authors: DELHALLE SYLVIE , DUVOIX ANNELYSE , SCHNEKENBURGER MICHAËL , MORCEAU FRANCK , DICATO MARIO , DIEDERICH MARC
Published: March 2004

Abstract: Apoptosis is a type of cell death that has been observed and studied for more than a century. The process of apoptosis was described as “programmed cell death” in 1964, and the term apoptosis, from a Greek word meaning “to fall away from” and describing the fall of dead leaves from trees in autumn, was only coined in 1972. During the last 30 years, this type of cell death has been extensively investigated and the molecular mechanisms underlying this cell suicide well characterized. Apoptosis is a physiological phenomenon necessary to tissue and body genesis and homeostasis, but defects in its regulation may cause numerous diseases, including cancer. Investigating the mechanisms of apoptosis is thus important to discover new cellular regulators that could be potential targets for new death‐inducing drugs.
Role of p38 MAP Kinase Signal Transduction in Apoptosis and Survival of Renal Epithelial Cells
Authors: KOUL HARI K.
Published: March 2004

Abstract: The p38 MAP kinase signal transduction pathway is activated by various forms of cellular stress. While, in many tissues, activation of p38 MAP kinase is associated with apoptosis, in some tissues p38 activation is critical for survival. Oxalate deposits are associated with several pathological conditions that involve aberrant proliferation and cellular apoptosis. Studies from our laboratory demonstrated that exposure of renal epithelial cells to oxalate and COM‐crystals resulted in activation of the p38 MAP kinase pathway. Moreover, the inhibition of the p38 MAO kinase pathway resulted in the inhibition of oxalate as well as COM‐crystal‐induced reinitiation of the DNA synthesis. These results suggest a critical role for the p38 MAP kinase pathway in pathological conditions associated with cellular proliferation and apoptosis following deposition of calcium oxalate.
Calcium‐Dependent Apoptotic Gene Expression in Cerulein‐Treated AR42J Cells
Authors: YU JI HOON , KIM HYEYOUNG , KIM KYUNG HWAN
Published: March 2004

Abstract: Elevated Ca2+ concentrations within the pancreatic acinar cells represent a risk factor for the development of acute pancreatitis. Apoptosis is an important characteristic of pancreatitis, with induction of apoptotic genes and intraceullar increase of calcium, endonucleases, and protease. The present study, which aims to investigate whether (1) cerulein induces apoptotic gene expression (bax, bid, p53) in pancreatic acinar AR42J cells and (2) cerulein‐induced gene expression is mediated by intracellular Ca2+, monitored the gene expression profile in the cells treated with the Ca2+ chelator BAPTA‐AM. Results showed that cerulein (10−7 M) evoked an initial peak Ca2+ signal; a further Ca2+ signal was induced with second treatment of cerulein. Cerulein‐induced Ca2+ signal could not be detected in the cells treated with the Ca2+ chelator BAPTA‐AM. Cerulein dose‐dependently induced apoptosis, determined by DNA fragmentation and pro‐apoptotic bid expression in AR42J cells. Cerulein induced bid, bax, and p53 mRNA expression, which was inhibited in the cells treated with cerulein and cultured in the presence of BAPTA‐AM. The present results suggest that increase in the free cytosolic Ca2+ may be the upstream event of apoptotic gene (bax, bid, p53) expression, which contribute to cerulein‐induced apoptosis in pancreatic acinar cells.
Effects of Intracellular Calcium on Cell Survival and the MAPK Pathway in a Human Hormone‐Dependent Leukemia Cell Line (TF‐1)
Authors: APÁTI ÁGOTA , JÁNOSSY JUDIT , BRÓZIK ANNA , MAGÓCSI MÁRIA
Published: March 2004

Abstract: Changes in the cytoplasmic calcium concentration ([Ca2+]i) regulate a wide variety of cellular processes. Here we demonstrate that increased [Ca2+]i was able to induce hormone‐independent survival and proliferation, as well as to evoke apoptosis in human myelo‐erythroid GM‐CSF/IL‐3 dependent leukemia cells (TF‐1). Cellular responses induced by elevated [Ca2+]i depended on the duration and amplitude of the calcium‐signal. Moderate or high, but transient, elevation of [Ca2+]i caused a transient, biphasic activation of ERK1/2 and protected cells from hormone withdrawal‐induced apoptosis.1 In contrast, high and long‐lasting elevation of [Ca2+]i led to sustained activation of the ERK1/2 kinases and apoptosis of TF‐1 cells. Our data suggest that a time‐dependent action of the MAPK pathway works as a decision‐point between cell proliferation and apoptosis.
Cytosolic and Endoplasmic Reticulum Ca2+ Concentrations Determine the Extent and the Morphological Type of Apoptosis, Respectively
Authors: CERELLA CLAUDIA , D'ALESSIO MARIA , DE NICOLA MILENA , MAGRINI ANDREA , BERGAMASCHI ANTONIO , GHIBELLI LINA
Published: March 2004

Abstract: During apoptosis, an increase in cytosolic Ca2+ concentration ([Ca2+]c) accompanies the depletion of endoplasmic reticulum (ER). The actual roles of each of the two events in apoptosis are difficult to understand. In this work, we have modulated the basal [Ca2+]c and the thapsigargin (THG)‐dependent reticular flux (i.e., by chelating extracellular Ca2+ or by modulating intracellular Ca2+ by 3‐aminobenzamide [3‐ABA]). We have found that these treatments alter these Ca2+ parameters in a differential way and, accordingly, affect apoptosis differentially. We have found that the increase in [Ca2+]c is related to the extent of apoptosis, whereas the ER depletion affects the apoptotic nuclear morphology by shifting it towards the cleavage mode.
G‐CSF Modulates LPS‐Induced Apoptosis and IL‐8 in Human Microvascular Endothelial Cells
Authors: SCHNEIDER E M. , LORENZ I , MA X , WEISS M
Published: March 2004

Abstract: Microvascular endothelial cells (mECs) circulate at higher numbers in patients with severe sepsis and hemophagocytic syndromes. Although these blood mECs might stem from damaged microvasculature, they are perfectly viable and lead to the establishment of cell lines. Such mECs were cultured in low‐dose human serum pools (0.5%) and MEM‐alpha medium. Antigenic profiling revealed the expression of CD36, factor VIIIa, CD95‐ligand, and CD44, but also CD146. We studied the antioxidative effect of the hematopoietic growth factor G‐CSF1 after in vitro stimulation with LPS from E. coli 0111:B4; the growth factor appeared to exhibit a protective effect on organ function in patients with SIRS. mECs were stimulated with 1 μg/mL of LPS for 24 h and 48 h with and without G‐CSF (3×103 U/mL) preincubation. After 24 h, supernatants of the stimulated mEC were tested for IL‐8 by ELISA, and cells were tested for hemoxygenase‐1 (HO‐1, Hsp32) by immunohistochemistry and flow cytometry using OSA110 (mAb, Stressgene). Stimulation with LPS upregulated IL‐8 by a factor of 2 to 10 in mEC. Preincubation with G‐CSF markedly downregulated the LPS‐induced IL‐8 secretion (20–50%), but IL‐6 production was not affected. Upon 48 h of LPS stimulation, mECs developed massive signs of apoptosis and concomitant caspase 3 activation. Caspase 3 activity induced by LPS (24 h) or by staurosporin (6 h) was found to be dramatically downregulated by the G‐CSF preincubation protocol.
Pro‐Apoptotic and Anti‐Apoptotic Molecules Affecting Pathways of Signal Transduction
Authors: KÉRI G , RÁCZ G , MAGYAR K , ÖRFI L , HORVÁTH A , SCHWAB R , HEGYMEGI B B. , SZENDE B
Published: March 2004

Abstract: Selective inhibition of the “false” proliferative signals via targeting tyrosine kinases resulting in the induction of apoptosis by depletion of the “survival factors” is one of the most studied and widely accepted concepts of modern chemotherapy. We have synthesized a series of potent tyrosine kinase inhibitors and tested these compounds for apoptosis induction. Some of the tyrosine kinase inhibitors caused either apoptotic or cytoplasmic vacuolar cell death in various tumor cell cultures. The somatostatin analogue oligopeptide TT‐232, which indirectly inhibits tyrosine kinases, exerted a dose‐dependent apoptosis‐inducing effect. The tumor growth‐inhibitory effect of TT‐232 and some tyrosine kinase inhibitors has also been proven by in vivo experiments, using human tumor xenografts. On the other hand, a dose‐dependent pro‐ or anti‐apoptotic activity of (−)‐deprenyl has been shown in melanoma cell cultures, the lower doses inhibiting and the higher doses inducing apoptosis. Various metabolites of (−)‐deprenyl are responsible for these actions. The effect of (−)‐deprenyl is connected with depolarization of mitochondrial membranes. The kinase inhibitors act on the growth factor receptor signaling pathways (survival factor pathways) and initiate the caspase cascade. The key enzyme for the action of both pro‐apoptotic and anti‐apoptotic compounds is caspase 3.
Cell Death in Protists without Mitochondria
Authors: CHOSE OLIVIER , SARDE CLAUDE‐OLIVIER , NOËL CHRISTOPHE , GERBOD DELPHINE , JIMENEZ JUAN‐CARLOS , BRENNER CATHERINE , CAPRON MONIQUE , VISCOGLIOSI ERIC , ROSETO ALBERTO
Published: March 2004

Abstract: Some protozoans, such as Trichomonad species, do not possess mitochondria. Most of the time, they harbor another type of membrane‐bounded organelle, called hydrogenosome from its capacity to produce H2. This is the case for the human parasite Trichomonas vaginalis. Some other parasites, such as the protist Giardia lamblia, do not harbor any of these organelles. From this observation arises naturally a naive question: How do cells die when the mitochondrion, the cornerstone of apoptotic process, is absent? Data strongly suggest that the mitochondrion and the hydrogenosome arose from a common ancestral endosymbiont. But hydrogenosomes do not appear to directly substitute for mitochondria in apoptotic functions. Thus, it appears judicious to examine more closely the genome of unicellular cells, which do not harbor mitochondria, and search for new molecules that could participate in the apoptotic process in these microorganisms.
Induction of Apoptosis by Ultrasound Application in Human Malignant Lymphoid Cells
Authors: FIRESTEIN F , ROZENSZAJN L A. , SHEMESH‐DARVISH L , ELIMELECH R , RADNAY J , ROSENSCHEIN U
Published: March 2004

Abstract: In the present study, we have focused on the specific question of whether ultrasound application (ULS) delivered with optimized parameters for cavitation generation can stimulate apoptosis in lymphoid cell lines. Suspended T and B lymphoid cell lines (Jurkat and Raji, respectively) were exposed to low frequency ULS (750 KHz) at an intensity level of 54.6 W/cm2 spatial peak temporal average (SPTA) at focal area, which was found to be the optimal physical parameter to induce apoptosis in these malignant cell lines. Unsonicated cells and cells exposed to γ‐radiation (20 Gy) using 137Cs source were used as control. Apoptosis was evaluated by cell morphology changes, cell‐cycle analysis, and phosphatidylserine exposure. Fraction of cells with low mitochondria membrane potential was observed 1 h after sonication, accompanied by cytochrome c release from mitochondria to the cytosol and caspase‐3 activation. Here we present evidence that ULS exposure with cavitation formation on malignant lymphoid cell lines differs from γ‐radiation and is associated with time‐dependent apoptosis, which is mitochondria‐caspase dependent.
Caspase‐12 and ER‐Stress‐Mediated Apoptosis
Authors: SZEGEZDI EVA , FITZGERALD UNA , SAMALI AFSHIN
Published: March 2004

Abstract: The labyrinth of the endoplasmic reticulum (ER) interweaves the cytosol and connects to the nucleus, mitochondria, and the plasma membrane. In the lumen of the ER, the essential function of lipid synthesis, Ca2+ storage, folding, and maturation of proteins take place. Therefore, the tight regulation and maintenance of ER homeostasis is vital. Disturbance of the Ca2+ homeostasis during hypoxia, or imbalance between the demand and capacity of the protein‐folding apparatus, initiates an adaptive response of the cell, termed the unfolded protein response (UPR, ER stress response). As a result, ER‐localized chaperones are induced, protein synthesis is slowed down, and a protein degrading system is initiated. However, if the ER stress cannot be alleviated, it culminates in apoptosis. This paper reviews the newly outlined signaling pathways of the unfolded protein response and describes the central role of caspase‐12 in the initiation of cell death. The complex role of the ER and its signaling pathways provides a novel angle on apoptosis research and may offer a key to apoptosis‐associated diseases.