bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood Pressure and Stroke
Authors: Lawes Carlene M.M. , Bennett Derrick A. , Feigin Valery L. , Rodgers Anthony
Published: March 2004

Background—

The last few years have seen a considerable increase in the amount of information available concerning blood pressure (BP) and stroke associations. This article provides an overview of published reviews of the effects on stroke seen in trials of BP-lowering drugs and compares these with the results available from cohort studies.

Summary of Review—

We present a review of major overviews of prospective cohort studies and an updated meta-analysis of >40 randomized controlled trials of BP lowering, which included >188 000 participants and approximately 6800 stroke events. Cohort studies now indicate that in the Asia Pacific region as well as in North America and Western Europe, each 10 mm Hg lower systolic BP is associated with a decrease in risk of stroke of approximately one third in subjects aged 60 to 79 years. The association is continuous down to levels of at least 115/75 mm Hg and is consistent across sexes, regions, and stroke subtypes and for fatal and nonfatal events. The proportional association is age dependent but is still strong and positive in those aged 80 years. Data from randomized controlled trials, in which mean age at event was approximately 70 years, indicate that a 10 mm Hg reduction in systolic BP is associated with a reduction in risk of stroke of approximately one third. Per mm Hg systolic BP reduction, the relative benefits for stroke appear similar between agents, by baseline BP levels, and whether or not individuals have a past history of cardiovascular disease. There is, however, evidence of greater benefit with a larger BP reduction.

Conclusions—

The epidemiologically expected benefits of BP lowering for stroke risk reduction are broadly consistent across a range of different population subgroups. There are greater benefits from larger BP reductions, and initiating and maintaining BP reduction for stroke prevention is a more important issue than choice of initial agent.
Interpolation and Extrapolation in Human Behavior and Neural Networks
Authors: Guigon Emmanuel
Published: March 2004

Unlike most artificial systems, the brain is able to face situations that it has not learned or even encountered before. This ability is not in general echoed by the properties of most neural networks. Here, we show that neural computation based on least-square error learning between populations of intensitycoded neurons can explain interpolation and extrapolation capacities of the nervous system in sensorimotor and cognitive tasks. We present simulations for function learning experiments, auditory-visual behavior, and visuomotor transformations. The results suggest that induction in human behavior, be it sensorimotor or cognitive, could arise from a common neural associative mechanism.
Separate Geometric and Non-Geometric Modules for Spatial Reorientation: Evidence from a Lopsided Animal Brain
Authors: Vallortigara Giorgio , Pagni Piero , Sovrano Valeria Anna
Published: March 2004

Research has proved that disoriented children and nonhuman animals can reorient themselves using geometric and nongeometric features of the environment, showing conjoined use of both types of information to different degree depending on species and developmental level. Little is known of the neurobiological bases of these spatial reorientation processes. Here we take advantage of the neuroanatomical peculiarities of the visual system of birds (showing segregation of information between the two sides of the brain to a considerable degree) to investigate the way in which geometric and nongeometric information is encoded and used by the left and right hemispheres. Domestic chicks were trained binocularly in an environment with a distinctive geometry (a rectangular cage) with panels at the corners providing nongeometric cues. Between trials, chicks were passively disoriented to disable dead reckoning. When tested after removal of the panels, lefteyed chicks, but not right-eyed chicks, reoriented using the residual information provided by the geometry of the cage. When tested after removal of geometric information (i.e., in a square-shaped cage), both rightand left-eyed chicks reoriented using the residual nongeometric information provided by the panels. When trained binocularly with only geometric information, at test, left-eyed chicks reoriented better than right-eyed chicks. Finally, when geometric and nongeometric cues provided contradictory information, left-eyed chicks showed more reliance on geometric cues, whereas right-eyed chicks showed more reliance on nongeometric cues. The results suggest separate mechanisms for dealing with spatial reorientation problems, with the right hemisphere taking charge of large-scale geometry of the environment and with both hemispheres taking charge of local, nongeometric cues when available in isolation, but with a predominance of the left hemisphere when competition between geometric and nongeometric information occurs.
Inter- and Intra-hemispheric Processing of Visual Event-related Potentials in the Absence of the Corpus Callosum
Authors: Bayard Sophie , Gosselin Nadia , Robert Manon , Lassonde Maryse
Published: March 2004

Interhemispheric differences of the N100 latency in visual evoked potentials have been used to estimate interhemispheric transfer time (e.g., Saron & Davidson, 1989). Recent work has also suggested that the P300 component could reflect the efficacy of interhemispheric transmission (Polich & Hoffman, 1998). The purpose of the present study was to study the differential role of the corpus callosum (CC) and anterior commissure (AC) in the interhemispheric propagation of these two electrophysiological components. Thus, the amplitude and latency distribution of the N100 and P300 components were analyzed using high-density electrical mapping in a subject with agenesis of CC but preservation of AC, a subject with agenesis of both CC and AC, and 10 neurologically intact control subjects. The task consisted of a modified visual oddball paradigm comprising one frequent and two rare stimuli, one presented on the same and the other on the opposite side of the frequent stimulus. Interhemispheric differences in latency were found for the N100 component in controls. However, in the acallosal subjects, this component was not identifiable in the indirectly stimulated hemisphere. In controls, no interhemispheric differences were observed in the distribution of the P300 latency and amplitude to rare and frequent stimuli. The distribution of the P300 amplitude in the acallosal subject with an AC was identical to that of the controls, whereas in the acallosal subject lacking the AC, the amplitude was greater in the hemisphere receiving the frequent stimuli, regardless of the visual hemifield in which the rare stimuli were presented. In both acallosal subjects, hemispheric differences in the P300 latency were observed, the latencies being shorter in the hemisphere directly stimulated for all categories of stimuli. These results suggest that the interhemispheric transfer of both the N100 and P300 components relies on the integrity of cortical commissures. Possible P300 generator sources are discussed.
Semantic Relevance and Semantic Disorders
Authors: Sartori Giuseppe , Lombardi Luigi
Published: March 2004

Semantic features are of different importance in concept representation. The concept elephant may be more easily identified from the feature  than from the feature . We propose a new model of semantic memory to measure the relevance of semantic features for a concept and use this model to investigate the controversial issue of category specificity. Category-specific patients have an impairment in one domain of knowledge (e.g., living), whereas the other domain (e.g., nonliving) is relatively spared. We show that categories differ in the level of relevance and that, when concepts belonging to living and nonliving categories are equated to this parameter, the category-specific disorder disappears. Our findings suggest that category specificity, as well as other semantic-related effects, may be explained by a semantic memory model in which concepts are represented by semantic features with associated relevance values.
Face Recognition Memory and Configural Processing: A Developmental ERP Study using Upright, Inverted, and Contrast-Reversed Faces
Authors: Itier Roxane J. , Taylor Margot J.
Published: March 2004

The effects of configural changes on faces were investigated in children to determine their role in encoding and recognition processes. Upright, inverted, and contrast-reversed unfamiliar faces were presented in blocks in which one-third of the pictures repeated immediately or after one intervening face. Subjects (8–16 years) responded to repeated faces; eventrelated potentials were recorded throughout the procedure. Recognition improved steadily with age and all components studied showed age effects reflecting differing maturation processes occurring until adulthood. All children were affected by inversion and contrast-reversal, and face-type effects were seen on latencies and amplitudes of early components (P1 and N170), as well as on later frontal amplitudes. The “old-new” repetition effects (larger amplitude for repeated stimuli) were found at frontal sites and were similar across age groups and face types, suggesting a general working memory system comparably involved in all age groups. These data demonstrate that (1) there is quantitative development in face processing, (2) both face encoding and recognition improve with age, but (3) only encoding is affected by configural changes. The data also suggest a gradual tuning of face processing towards the upright orientation.
Erythropoietin regulation of Raf-1 and MEK: evidence for a Ras-independent mechanism
Authors: Chen Changmin , Sytkowski Arthur J.
Published: March 2004

Stimulation of the erythropoietin (EPO) receptor triggers a cascade of signaling events. We reported that EPO upregulates c-myc expression through 2 pathways in BaF3-EpoR cells—a phosphatidylinositol 3-kinase (PI3K) pathway operating on transcriptional initiation and a Raf-1–mitogen-activated protein kinase (MAPK) pathway affecting elongation. We now show that EPO induces phosphorylation of Raf-1 at serine 338 and within the carboxy-terminal domain, resulting in an electrophoretic mobility change (hyperphosphorylation). Importantly, MEK 1 inhibitor PD98059 blocked only the hyperphosphorylation of Raf-1 but not the phosphorylation at serine 338. This inhibition of Raf-1 hyperphosphorylation resulted in increased kinase activity of Raf-1 and increased phosphorylation of MEK, suggesting that the hyperphosphorylation of Raf-1 inhibits its MEK kinase activity. Deletion of the first 184 amino acids of Raf-1, which are involved in its interaction with Ras, had no effect on EPO-induced phosphorylation. Introducing the dominant-negative N17Ras or GAP had no effect on EPO-induced kinase activity of Raf-1 and ELK activation. N17Ras failed to inhibit ELK activation in another cell line—Rauscher murine erythroleukemia— which expresses the EPO receptor endogenously and differentiates in response to the hormone. These results indicate the presence of a Ras-independent mechanism for Raf-1 and MEK activation in these cells.
Selective recognition of fibroblast growth factor-2 by the long pentraxin PTX3 inhibits angiogenesis
Authors: Rusnati Marco , Camozzi Maura , Moroni Emanuela , Bottazzi Barbara , Peri Giuseppe , Indraccolo Stefano , Amadori Alberto , Mantovani Alberto , Presta Marco
Published: March 2004

The long pentraxin PTX3 is a soluble pattern recognition receptor produced by monocytes and endothelial cells that plays a nonredundant role in inflammation. Several pathologic conditions are characterized by local production of both PTX3 and the angiogenic fibroblast growth factor-2 (FGF2). Here, solid-phase binding assays demonstrated that PTX3 binds with high affinity to FGF2 but not to a panel of cytokines and growth factors, including FGF1, FGF4, and FGF8. Accordingly, PTX3 prevented 125I-FGF2 binding to endothelial cell receptors, leading to specific inhibition of FGF2-induced proliferation. PTX3 hampered also the motogenic activity exerted by endogenous FGF2 on a wounded endothelial cell monolayer. Moreover, PTX3 cDNA transduction in FGF2-transformed endothelial cells inhibited their autocrine FGF2-dependent proliferation and morphogenesis in vitro and their capacity to generate vascular lesions when injected in nude mice. Finally, PTX3 suppressed neovascularization triggered by FGF2 in the chick embryo chorioallantoic membrane with no effect on physiologic angiogenesis. In contrast, the short pentraxin C-reactive protein was a poor FGF2 ligand/antagonist. These results establish the selective binding of a member of the pentraxin superfamily to a growth factor. PTX3/FGF2 interaction may modulate angiogenesis in various physiopathologic conditions driven by inflammation, innate immunity, and/or neoplastic transformation.
Dominant factor XI deficiency caused by mutations in the factor XI catalytic domain
Authors: Kravtsov Dmitri V. , Wu Wenman , Meijers Joost C. M. , Sun Mao-Fu , Blinder Morey A. , Dang Thao P. , Wang Hongli , Gailani David
Published: March 2004

The bleeding diathesis associated with hereditary factor XI (fXI) deficiency is prevalent in Ashkenazi Jews, in whom the disorder appears to be an autosomal recessive condition. The homodimeric structure of fXI implies that the product of a single mutant allele could confer disease in a dominant manner through formation of heterodimers with wild-type polypeptide. We studied 2 unrelated patients with fXI levels less than 20% of normal and family histories indicating dominant disease transmission. Both are heterozygous for single amino acid substitutions in the fXI catalytic domain (Gly400Val and Trp569Ser). Neither mutant is secreted by transfected fibroblasts. In cotransfection experiments with a wild-type fXI construct, constructs with mutations common in Ashkenazi Jews (Glu117Stop and Phe283Leu) and a variant with a severe defect in dimer formation (fXI-Gly350Glu) have little effect on wild-type fXI secretion. In contrast, cotransfection with fXI-Gly400Val or fXI-Trp569Ser reduces wild-type secretion about 50%, consistent with a dominant negative effect. Immunoprecipitation of cell lysates confirmed that fXI-Gly400Val forms intracellular dimers. The data support a model in which nonsecretable mutant fXI polypeptides trap wild-type polypeptides within cells through heterodimer formation, resulting in lower plasma fXI levels than in heterozygotes for mutations that cause autosomal recessive fXI deficiency.
Bleeding risks associated with inheritance of the Quebec platelet disorder
Authors: McKay Heather , Derome Francine , Haq M. Anwar , Whittaker Susan , Arnold Emmy , Adam Frédéric , Heddle Nancy M. , Rivard Georges E. , Hayward Catherine P. M.
Published: March 2004

Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder associated with increased urokinase-type plasminogen activator in platelets and α-granule protein degradation. To determine bleeding risks and common manifestations of QPD, a history questionnaire was developed and administered to 127 relatives in a family with QPD. Data entry was done blinded to affected and unaffected status, determined by assays for platelet urokinase-type plasminogen activator (u-PA) and fibrinogen degradation. Odds ratios (ORs), with 95% confidence intervals (CIs), were determined for items queried. Summative bleeding scores for each individual were calculated using items with OR more than 1. Mean ages (34 years; range, 1-89 years) were similar for affected (n = 23) and unaffected (n = 104) family members. Affected individuals had higher mean bleeding scores (P < .0001) and a much higher likelihood (OR > 20) of having bleeding that led to lifestyle changes, bruises that spread lower or as large or larger than an orange or both, joint bleeds, bleeding longer than 24 hours after dental extractions or deep cuts, and received or been recommended other treatments (fibrinolytic inhibitors) for bleeding. Individuals with QPD and exposure(s) to hemostatic challenges had experienced excessive bleeding only when fibrinolytic inhibitors had not been used. These data illustrate that QPD is associated with increased risks of bleeding that can be modified by fibrinolytic inhibitors.
Platelets, protease-activated receptors, and fibrinogen in hematogenous metastasis
Authors: Camerer Eric , Qazi Aisha A. , Duong Daniel N. , Cornelissen Ivo , Advincula Rommel , Coughlin Shaun R.
Published: March 2004

Procoagulant activity on tumor cells can enhance their ability to spread via the circulation to colonize distant organs. Toward defining the relative importance of the main host responses to coagulation for hematogenous metastasis, we examined lung metastases after intravenous injection of melanoma cells in Nf-E2-/- mice, which have virtually no circulating platelets; Par4-/- mice, which have platelets that fail to respond to thrombin; Par1 and Par2-/- mice, which have markedly attenuated endothelial responses to coagulation proteases; and Fib-/- mice, which lack fibrinogen. In a severe combined immunodeficiency (SCID) background, median lung tumor count in Nf-E2-/-, Par4-/-, and Fib-/- mice was 6%, 14%, and 24% of wild type, respectively; total tumor burden was only 4%, 9%, and 3% of wild type, respectively. Similar results were seen in a syngeneic C57BL6 background. By contrast, deficiencies of protease-activated receptor 1 (PAR1) or PAR2 did not provide protection. These results provide strong genetic evidence that platelets play a key role in hematogenous metastasis and contribute to this process by both thrombin-dependent and -independent mechanisms. Importantly, PAR4 heterozygosity conferred some protection against metastasis in this model. Thus even partial attenuation of platelet function may be sufficient to provide benefit. (Blood. 2004;104:397-401)
Benefit and Timing of Second Transplantations in Multiple Myeloma: Clinical Findings and Methodological Limitations in a European Group for Blood and Marrow Transplantation Registry Study
Authors: Morris C. , Iacobelli S. , Brand R. , Bjorkstrand B. , Drake M. , Niederwieser D. , Gahrton G.
Published: March 2004

Purpose

To use European Group for Blood and Marrow Transplantation registry data to assess the benefit and optimal timing of a double-autologous transplantation strategy for patients with myeloma.

Patients and Methods

7,452 transplantation patients described as being either in a multiple graft program (“planned”) or not, were analyzed on an intention-to-treat basis. Subsequent multivariate analyses concentrated on the real occurrence of second transplantation, survival, relapse, and transplant-related mortality.

Results

Although the transplantation rate in the planned group failed to reach 60%, the median survival from transplantation is 60 months for the planned, compared with 51 months for the remainder group. While the hazard ratio of the planned group is 0.89 (95% CI, 0.79 to 1.00; P =.05) before approximately 70 months, this “effect” is reversed after 70 months, with the hazard ratio estimated as 3.01 (95% CI, 1.07 to 8.46; P = .04). A time-dependent multivariate Cox analysis shows that, taking patients without a second transplantation as a reference group, those receiving a second transplantation in first remission (ie, before relapse) show an increased probability of transplant-related mortality, especially if the transplantation is performed more than 12 months after the first, and the reduction of the risk of relapse is less than when the transplantation is performed earlier. Performing a second transplantation after relapse does not seem to prolong survival, though a second transplantation before relapse is associated with a higher probability of mortality.

Conclusion

To improve survival of tandem autologous transplantation in multiple myeloma, the second transplantation should preferably be performed before relapse and within 6 to 12 months of the first transplantation.
Impaired Leptin Expression and Abnormal Response to Fasting in Corticotropin-Releasing Hormone-Deficient Mice
Authors: Jeong Kyeong-Hoon , Sakihara Satoru , Widmaier Eric P. , Majzoub Joseph A.
Published: March 2004

Leptin has been postulated to comprise part of an adipostat, whereby during states of excessive energy storage, elevated levels of the hormone prevent further weight gain by inhibiting appetite. A physiological role for leptin in this regard remains unclear because the presence of excessive food, and therefore the need to restrain overeating under natural conditions, is doubtful. We have previously shown that CRH-deficient (Crh−/−) mice have glucocorticoid insufficiency and lack the fasting-induced increase in glucocorticoid, a hormone important in stimulating leptin synthesis and secretion. We hypothesized that these mice might have low circulating leptin. Indeed, Crh−/− mice exhibited no diurnal variation of leptin, whereas normal littermates showed a clear rhythm, and their leptin levels were lower than their counterparts. A continuous peripheral CRH infusion to Crh−/− mice not only restored corticosterone levels, but it also increased leptin expression to normal. Surprisingly, 36 h of fasting elevated leptin levels in Crh−/− mice, rather than falling as in normal mice. This abnormal leptin change during fasting in Crh−/− mice was corrected by corticosterone replacement. Furthermore, Crh−/− mice lost less body weight during 24 h of fasting and ate less food during refeeding than normal littermates. Taken together, we conclude that glucocorticoid insufficiency in Crh−/− mice results in impaired leptin production as well as an abnormal increase in leptin during fasting, and propose that the fast-induced physiological reduction in leptin may play an important role to stimulate food intake during the recovery from fasting.
Rhythmic Secretion of Prolactin in Rats: Action of Oxytocin Coordinated by Vasoactive Intestinal Polypeptide of Suprachiasmatic Nucleus Origin
Authors: Egli Marcel , Bertram Richard , Sellix Michael T. , Freeman Marc E.
Published: March 2004

Prolactin (PRL) is secreted from lactotrophs of the anterior pituitary gland of rats in a unique pattern in response to uterine cervical stimulation (CS) during mating. Surges of PRL secretion occur in response to relief from hypothalamic dopaminergic inhibition and stimulation by hypothalamic releasing neurohormones. In this study, we characterized the role of oxytocin (OT) in this system and the involvement of vasoactive intestinal polypeptide (VIP) from the suprachiasmatic nucleus (SCN) in controlling OT and PRL secretion of CS rats. The effect of OT on PRL secretion was demonstrated in cultured lactotrophs showing simultaneous enhanced secretion rate and increased intracellular Ca2+. Neurosecretory OT cells of the hypothalamic paraventricular nucleus that express VIP receptors were identified by using immunocytochemical techniques in combination with the retrogradely transported neuronal tracer Fluoro-Gold (iv injected). OT measurements of serial blood samples obtained from ovariectomized (OVX) CS rats displayed a prominent increase at the time of the afternoon PRL peak. The injection of VIP antisense oligonucleotides into the SCN abolished the afternoon increase of OT and PRL in CS-OVX animals. These findings suggest that VIP from the SCN contributes to the regulation of OT and PRL secretion in CS rats. We propose that in CS rats the regulatory mechanism(s) for PRL secretion comprise coordinated action of neuroendocrine dopaminergic and OT cells, both governed by the daily rhythm of VIP-ergic output from the SCN. This hypothesis is illustrated with a mathematical model.
Evolution of neural precursor selection: functional divergence of proneural proteins
Authors: Quan Xiao-Jiang , Denayer Tinneke , Yan Jiekun , Jafar-Nejad Hamed , Philippi Anne , Lichtarge Olivier , Vleminckx Kris , Hassan Bassem A.
Published: March 2004

How conserved pathways are differentially regulated to produce diverse outcomes is a fundamental question of developmental and evolutionary biology. The conserved process of neural precursor cell (NPC) selection by basic helix-loop-helix (bHLH) proneural transcription factors in the peripheral nervous system (PNS) by atonal related proteins (ARPs) presents an excellent model in which to address this issue. Proneural ARPs belong to two highly related groups: the ATONAL (ATO) group and the NEUROGENIN (NGN) group. We used a cross-species approach to demonstrate that the genetic and molecular mechanisms by which ATO proteins and NGN proteins select NPCs are different. Specifically, ATO group genes efficiently induce neurogenesis in Drosophila but very weakly in Xenopus, while the reverse is true for NGN group proteins. This divergence in proneural activity is encoded by three residues in the basic domain of ATO proteins. In NGN proteins,proneural capacity is encoded by the equivalent three residues in the basic domain and a novel motif in the second Helix (H2) domain. Differential interactions with different types of zinc (Zn)-finger proteins mediate the divergence of ATO and NGN activities: Senseless is required for ATO group activity, whereas MyT1 is required for NGN group function. These data suggest an evolutionary divergence in the mechanisms of NPC selection between protostomes and deuterostomes.
Wnt signaling enhances FGF2-triggered lens fiber cell differentiation
Authors: Lyu Jungmook , Joo Choun-Ki
Published: March 2004

Wnt signaling is implicated in many developmental processes, including cell fate changes. Several members of the Wnt family, as well as other molecules involved in Wnt signaling, including Frizzled receptors, LDL-related protein co-receptors, members of the Dishevelled and Dickkopf families, are known to be expressed in the lens during embryonic or postembryonic development. However, the function of Wnt signaling in lens fiber differentiation remains unknown. Here, we show that GSK-3β kinase is inactivated and thatβ-catenin accumulates during the early stages of lens fiber cell differentiation. In an explant culture system, Wnt conditioned medium (CM)induced the accumulation of β-crystallin, a marker of fiber cell differentiation, without changing cell shape. In contrast, epithelial cells stimulated with Wnt after priming with FGF elongated, accumulatedβ-crystallin, aquaporin-0, p57kip2, and altered their expression of cadherins. Treatment with lithium, which stabilizes β-catenin, induced the accumulation of β-crystallin, but explants treated with lithium after FGF priming did not elongate as they did after Wnt application. These results show that Wnts promote the morphological aspects of fiber cell differentiation in a process that requires FGF signaling, but is independent ofβ-catenin. Wnt signaling may play an important role in lens epithelial-to-fiber differentiation.
Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo
Authors: Dunn N. Ray , Vincent Stéphane D. , Oxburgh Leif , Robertson Elizabeth J. , Bikoff Elizabeth K.
Published: March 2004

TGFβ/activin/Nodal receptors activate both Smad2 and Smad3 intracellular effector proteins. The functional activities of these closely related molecules have been extensively studied in cell lines. We show both are expressed in the early mouse embryo from the blastocyst stage onwards and mediate Foxh1-dependent activation of the Nodal autoregulatory enhancer in vitro. Genetic manipulation of their expression ratios reveals that Smad3 contributes essential signals at early post-implantation stages. Thus, loss of Smad3 in the context of one wild-type copy of Smad2 results in impaired production of anterior axial mesendoderm,while selective removal of both Smad2 and Smad3 from the epiblast additionally disrupts specification of axial and paraxial mesodermal derivatives. Finally, we demonstrate that Smad2;Smad3 double homozygous mutants entirely lack mesoderm and fail to gastrulate. Collectively, these results demonstrate that dose-dependent Smad2 and Smad3 signals cooperatively mediate cell fate decisions in the early mouse embryo.
Different spindle checkpoint proteins monitor microtubule attachment and tension at kinetochores inDrosophilacells
Authors: Logarinho Elsa , Bousbaa Hassan , Dias José Miguel , Lopes Carla , Amorim Isabel , Antunes-Martins Ana , Sunkel Claudio E.
Published: March 2004

The spindle assembly checkpoint detects errors in kinetochore attachment to the spindle including insufficient microtubule occupancy and absence of tension across bi-oriented kinetochore pairs. Here, we analyse how the kinetochore localization of the Drosophila spindle checkpoint proteins Bub1, Mad2, Bub3 and BubR1, behave in response to alterations in microtubule binding or tension. To analyse the behaviour in the absence of tension, we treated S2 cells with low doses of taxol to disrupt microtubule dynamics and tension, but not kinetochore-microtubule occupancy. Under these conditions, we found that Mad2 and Bub1 do not accumulate at metaphase kinetochores whereas BubR1 does. Consistently, in mono-oriented chromosomes, both kinetochores accumulate BubR1 whereas Bub1 and Mad2 only localize at the unattached kinetochore. To study the effect of tension we analysed the kinetochore localization of spindle checkpoint proteins in relation to tension-sensitive kinetochore phosphorylation recognised by the 3F3/2 antibody. Using detergent-extracted S2 cells as a system in which kinetochore phosphorylation can be easily manipulated, we observed that BubR1 and Bub3 accumulation at kinetochores is dependent on the presence of phosphorylated 3F3/2 epitopes. However, Bub1 and Mad2 localize at kinetochores regardless of the 3F3/2 phosphorylation state. Altogether, our results suggest that spindle checkpoint proteins sense distinct aspects of kinetochore interaction with the spindle, with Mad2 and Bub1 monitoring microtubule occupancy while BubR1 and Bub3 monitor tension across attached kinetochores.
Formulation and interpretation of the equation of motion on the basis of the energy-momentum method
Authors: Miyazaki Y , Kodama T
Published: March 2004

Numerical solution of the Lagrange equation of motion for geometrically non-linear rigid and flexible dynamics essentially has a risk of numerical instability associated with time integration. Several methods have been proposed, including the energy-momentum method (EMM), that avoid this instability by enforcing the conservation of total energy and momentum. The EMM provides equations of motion that are modified from the d'Alembert-Lagrange equations, ensuring that the solution satisfies the conservation unconditionally. However, there are few studies in the literature that explain the detail of the relationship between the original d'Alembert-Lagrange equations and the modified equations of motion. This paper examines the direct derivation of modified equations of motion from the conservation principles of energy and momentum. The general condition for formulation of the energy momentum conservation algorithm is also shown in this derivation process. The result clarifies the physical meaning of each term in the modified equation of motion.
Development of selection methodologies and procedures of the modal set for the generation of flexible body models for multi-body simulation
Authors: Braccesi C , Cianetti F
Published: March 2004

In this paper, a mode selection method, useful in multi-body analysis and, in particular, in modal model generation of flexible bodies, is shown. This method is based on so-called component mode synthesis and, in particular, on the Craig and Bampton approach. It is able to identify before any multi-body simulations which modes, among the so-called normal modes, could have a high participation factor in model dynamic behaviour. The idea is to evaluate the reaction forces that each normal mode generates on connection points (boundary degrees of freedom). The methodology and the implemented procedure are shown in the paper. The procedure was carried out in a particular simulation environment (finite element and multi-body codes) using routines developed in Fortran language. Lastly, an automotive test case, used to verify the implemented selection method, is shown.
Equations of motion of planar mechanical systems based on particle dynamics and a recursive algorithm
Authors: Attia H A
Published: March 2004

In the present study, the equations of motion for planar mechanical systems that consist of interconnected rigid bodies with common types of kinematic joint are derived on the basis of particle dynamics and a recursive approach. The system of rigid bodies is replaced by a dynamically equivalent constrained system of particles. Then, for the resulting equivalent system of particles, the concepts of linear and angular momenta are used to generate the equations of motion without either introducing any rotational coordinates or distributing the external forces and force couples over the particles. For an open-loop system, the equations of motion are generated recursively along the open chains. For a closed-loop system, the system is transformed to open chains by cutting suitable kinematic joints with the addition of cut-joint kinematic constraints. Examples of multibranch closed-loop systems are chosen to demonstrate the generality and simplicity of the proposed method.
Analytical dynamic analysis of earthquake base-isolation structures using time history modal superposition
Authors: Carneiro J O , de Melo F J Q , Jalali S , Camanho P P
Published: March 2004

This paper analyses a case study of the dynamic behaviour of structures with a base-isolation device support. The objective of the present analysis is to understand why and under what conditions the base-isolation pair is effective in reducing earthquake-induced forces in structures. To this end, a one-storey building with high-damping rubber bearings (HDR) installed between the base building and the foundation was considered. Most isolation systems are non-linear in force-deformation relations, but this behaviour was not considered, since, in the region of typical design rubber shear strain (100 per cent), the rubber shear modulus does not change sharply, and thus the isolator shows approximately a linear behaviour. In order to evaluate the efficiency of the base-isolation system under earthquake motion, linear analysis using a modal superposition technique was carried out on buildings with and without the isolation system under two different strong ground motions, namely the Northridge 1994 and El Centro 1940 earthquakes. It was found from the analysis that the primary reason for effectiveness offered by rubber bearings in reducing earthquake-induced forces in a building is the lengthening of the first natural vibration period. Moreover, the reduction in forces also depends on the type of earthquake motion. However, the maximum accelerations and base shear force were significantly reduced with the insertion of a rubber isolation system, regardless of the ground motion input.
Solid State 31P MAS NMR Detection of Hydrogen-bonded Phosphate Polymer in Calcium–Phosphate Composites
Authors: Onoda Akira , Doi Mototsugu , Takahashi Kazuyuki , Okamura Taka-aki , Yamamoto Hitoshi , Ueyama Norikazu
Published: March 2004

A novel poly(vinyl phosphate) ligand was synthesized as a model of biopolymer ligands containing the OH···O hydrogen bonds and CaHPO4·2H2O (brushite) composites with the polymer ligands were also prepared. Successful detection of the polymer ligand binding to the CaHPO4·2H2O crystals is achieved by 31P MAS NMR with 1 pda (single pulse with decoupling and phase cycling) sequence, which enhances 31P signals of the phosphate polymer having shorter T1 value.
Novel Reversed Chain Modified Oligopeptides via Sequential α-N-Mitsunobu Condensation of a Functionalized C-glycoside
Authors: Turner John J , Sikkema Friso D , Erkelens Kees , Marel Gijs A van der , Overkleeft Herman S , Boom Jacques H van , Overhand Mark
Published: March 2004

The synthesis of a novel reversed chain modified oligopeptide via sequential α-N-Mitsunobu condensation reactions on a C-glycoside with amino acid derived nitrobenzenesulfonamides is described. Structural analysis of the target compound 11 using NMR techniques indicates a folded structure.
Enhanced Two-photon Properties of Tri-branched Styryl Derivatives Based on 1,3,5-Triazine
Authors: Meng Fanshun , Li Bo , Qian Shixiong , Chen Kongchang , Tian He
Published: March 2004

Novel styryl derivatives with triphenylamine as donor and 1,3,5-triazine as acceptor were synthesized and their one- and two-photon properties were investigated. These molecules show large two-photon absorption (TPA) cross sections and strong two-photon fluorescence. TPA cross section is as large as 1.64 × 10−20 cm4/GW for the tri-branched molecule.
Microwave Polyol Synthesis and Characterizations of Carbon-supported Pt and Ru Nanoparticles
Authors: Chen Weixiang , Zhao Jie , Lee Jim Yang , Liu Zhaolin
Published: March 2004

Carbon-supported platinum and ruthenium nanoparticles were synthesized by a microwave-assisted polyol heating process. TEM observations showed that the Pt and Ru particles prepared as such have uniform shapes and sizes, and well dispersed on the carbon surface. The average particle size was 3.1 nm for Pt and 2.9 nm for Ru.
Green Protocol for the Synthesis of vicinal-Halohydrins from Oxiranes Using the [Bmim]PF6/LiX Reagent System
Authors: Yadav J S , Reddy B V S , Reddy Ch Srinivas , Rajasekhar K
Published: March 2004

Epoxides undergo rapid ring-opening with lithium halides in [bmim]PF6 or [bmim]BF4 ionic liquids under mild and neutral conditions to afford the corresponding vic-halohydrins in high to quantitative yields. The epoxides show enhanced reactivity in ionic liquids thereby reducing reaction times and improving the yields significantly. The recovered ionic liquid can be reused in three to four subsequent runs with consistent activity.
Collision-Induced Dissociation of Purine Antiviral Agents: Mechanisms of Ion Formation Using Gas-Phase Hydrogen/Deuterium Exchange and Electrospray Ionization Tandem Mass Spectrometry
Authors: Kamel Amin M. , Munson Burnaby
Published: March 2004

Electrospray ionization (ESI) and collision-induced dissociation (CID) mass spectra were obtained for two purine nucleoside antiviral agents (acycloguanosine and vidarabine) and one purine nucleotide (vidarabine monophosphate) and for the corresponding compounds in which the labile hydrogens were replaced by deuterium gas-phase exchange. The number of labile hydrogens, x, was determined from a comparison of ESI spectra obtained with N2 and with ND3 as the nebulizer gas. CID mass spectra were obtained for [M + H]+ and [M – H]− ions and the exchanged analogs, [M(Dx) + D]+ and [M(Dx) – D]−, produced by ESI using a Sciex API-IIIplus mass spectrometer. Compositions of product ions were determined and mechanisms of decomposition elucidated by comparison of the CID mass spectra of the undeuterated and deuterated species. Protonated purine antiviral agents dissociate through rearrangement decompositions of base-protonated [M + H]+ ions by cleavage of the glycosidic bonds to give the protonated bases with a sugar moiety as the neutral fragment. Cleavage of the same bonds with charge retention on the sugar moiety gives low abundance ions, due to the low proton affinity of the sugar moiety compared with that of the purine base. CID of protonated purine bases [B + H]+ occurs through two major pathways: (1) elimination of NH3 (ND3) and (2) loss of NH2CN (ND2CN). Minor pathways include elimination of HNCO (DNCO), loss of CO and loss of HCN (DCN). Deprotonated acycloguanosine and vidarabine exhibit the deprotonated base [B – H]− as a major fragment from glycosidic bond cleavage and charge delocalization on the base. Deprotonated vidarabine monophosphate, however, shows predominantly phosphate-related product ions. CID of deprotonated guanine shows two principal pathways: (1) elimination of NH3 (ND3) and (2) loss of NH2CN (ND2CN). Minor pathways include elimination of HNCO (DNCO), loss of CO and loss of HCN (DCN). The dissociation reactions of deprotonated adenine, however, proceed by elimination of HCN and elimination of NCHNH (NCHND). The mass spectra of the antiviral agents studied in this paper may be useful in predicting reaction pathways in other heteroaromatic ring decompositions of nucleosides and nucleotides.
Matrix-Assisted Laser Desorption/Ionisation Time-of-Flight Mass Spectrometry. A Comparison of Fragmentation Patterns of Linear Dextran Obtained by In-Source Decay, Post-Source Decay and Collision-Induced Dissociation and the Stability of Linear and Cyclic Glucans Studied by In-Source Decay
Authors: Bashir Sajid , Giannakopulos Anastassios E. , Derrick Peter J. , Critchley Peter , Bottrill Andrew , Padley Henry D.
Published: March 2004

In the first part of this study, fragmentation patterns from a range of dextran oligomers (containing 4–20 anhydroglucose units) were compared using three different methods of analysis coupled with matrix-assisted laser desorption/ionisation (MALDI) mass spectrometry. Collision-induced dissociation (CID), prompt in-source decay (ISD) and post-source decay (PSD) all caused cleavage of the glycosidic bonds. Both CID and, to a lesser extent, ISD caused further cleavage of pyranose rings of the individual sugar residues. There was very little cleavage of pyranose rings detected in the PSD spectrum. Derivatisation of the reducing end-groups of the oligodextrans with 1-phenyl-3-methyl-5-pyrazolone (PMP) restricted cleavage in the MALDI mass spectrometer to the non-reducing end and also enabled the saccharides to be separated by high-performance liquid chromatography (HPLC) so that a single chain length could be examined as a standard. Maltoheptaose was also used as a standard. In the second part of the study, prompt ISD-MALDI mass spectrometry was used to compare the fragmentation of three oligoglucans, viz. dextran, maltodextrin and gamma cyclodextrin, that have different linkages and different secondary structure. The results showed that the degree of fragmentation correlated with the degree of freedom in the saccharide chains in solution as determined by NMR. Dextran, with the most random conformation, was fragmented most whereas there was little evidence of any fragments, not even glycosidic bond breakage, from cyclodextrin, even when the laser power was increased considerably. The fragmentation pattern of maltodextrin was intermediate. The patterns of fragmentation produced by MALDI mass spectrometry, particularly where standards are available to calibrate the spectrum and the energy of the laser is controlled, can be used to predict the type of linkage present.
Determination of Selenium in Human Serum by Liquid Chromatography/Electron Capture Atmospheric Pressure Chemical Ionization Mass Spectrometry after Acid Digestion and Derivatization Using 2,3-Diaminonaphthalene
Authors: Ando Masayuki , Takizawa Megumi , Suwabe Sayuri , Yamato Susumu , Shimada Kenji
Published: March 2004

Analysis of selenium in biological samples is very important and numerous analytical methods for the element have been developed. One of the most convenient and widely used methods for routine determination of serum selenium is a fluorometric method using 2,3-diaminonaphthalene (DAN); however, this method lacks specificity. We observed that 4,5-benzopiazselenol (BPS), a selenium derivative of DAN, is ionized with electron capture in an atmospheric pressure chemical ionization (APCI) interface, and subsequently established a method for determining total human serum selenium by means of liquid chromatography/atmospheric pressure chemical ionization mass spectrometry. All pretreatment procedures were carried out in a single test tube to minimize selenium loss. The recovery of organic or inorganic selenium spiked to human serum was 97–103%. The detection limit of BPS was equivalent to 0.2 ng of selenium and the lower quantitative limit of serum selenium was 10 ng mL−1. The coefficient of variation of standard concentrations in control serum samples was 4.5%. The purity of the observed peak obtained from serum samples was confirmed using the ion cluster technique.
Methylating Peptides to Prevent Adduct Ion Formation Also Directs Cleavage in Collision-Induced Dissociation Mass Spectrometry
Authors: Poon Clement , Kaplan Harvey , Mayer Paul M.
Published: March 2004

We investigated the effect of N-terminal amino group and carboxyl group methylation on peptide analysis by electrospray mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS). Permethylation of the N-terminal amino group and the carboxyl groups can reduce metal ion adducts but does not enhance sensitivity in electrospray as previously observed for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. N-terminal trimethylated peptides exhibit collision-induced dissociation (CID) tandem mass spectra that differ from their unmodified analogs; the results support the mobile proton hypothesis of peptide fragmentation. A permanent positive charge at the N-terminus leads to competition between permanent-charge directed processes and loss of the N-terminal trimethyl amino group. Carboxyl methylation has no effect on fragmentation behavior other than to shift the mass of fragments containing methylated carboxyl groups. Comparison of regular and tandem mass spectra of different methylated peptides allowed probing the location of incomplete methylation, the proton displaced by alkali metal ions and the purity of a mass-selected methylated peptide ion.
The Thermochemistry of Adsorbates on Transition Metal Cluster Ions: Relationship to Bulk-Phase Properties
Authors: Armentrout P.B.
Published: March 2004

In previous work, guided ion beam tandem mass spectrometry has been used to study the reactions of the cluster cations of several transition metals (V, Cr, Fe and Ni) with D2, O2, CO2 and CD4. By examining the kinetic energy dependence of these reactions and interpreting thresholds observed for various reactions, bond energies for D, O, C, CD, CD2 and CD3 can be obtained. The results of these studies are reviewed with an emphasis on the relationship between the thermochemistry obtained from this work with that for adsorbates on bulk-phase metal surfaces. It is found that in cases where quantitative comparison can be made, for example D and O atoms, modest sized clusters bind these species to approximately the same extent as the bulk-phase surface of the same metal. As there is little information available for the molecular fragments investigated here, the cluster bond energies provide some of the first experimental values for such adsorbates on surfaces.