bluuebunny/crossref_metadata_2025 huggingface dataset:
Testosterone, Physical Aggression, Dominance, and Physical Development in Early Adolescence
Authors: Tremblay Richard E. , Schaal Benoist , Boulerice Bernard , Arseneault Louise , Soussignan Robert G. , Paquette Daniel , Laurent Denis
Published: July 2002

The associations among testosterone, physical development, social dominance, and antisocial behaviour during early adolescence were assessed in a sample of boys followed from 6 to 13 years. Saliva testosterone level was positively correlated with height, and uncorrelated with measures of fatness, including the body mass index. Physical aggression and social dominance were not significantly correlated. Regression analyses revealed that testosterone level and body mass additively predicted social dominance, whereas only body mass predicted physical aggression. Thus, early adolescents with high levels of testosterone were more likely to be socially dominant, especially if they had a large body mass. Those who had a large body mass were more likely to be physically aggressive, independently of their testosterone level. The observed pattern of correlations between testosterone, body mass, dominance, and physical aggression offers an interesting example of the complex hormone-physique-behaviour relations at puberty. They support the hypothesis that testosterone level and social dominance are related, and that the association between testosterone level and physical aggression is probably observed in contexts where physical aggression leads to social dominance.
Differential Age Effects on Semantic and Syntactic Priming
Authors: Friederici Angela D. , Schriefers Herbert , Lindenberger Ulman
Published: July 2002

Adult age differences in the processing of semantic and syntactic information during language comprehension were investigated in a lexical decision task in which the target word was preceded by a sentence fragment. Sentence fragment and target were presented visually and made up either a correct or an incorrect sentence containing either a semantic violation (selectional restriction violation) or a syntactic violation (subcategorisation violation). Experiment 1 revealed a differential age effect for the processing of syntactic, but not for the processing of semantic violations. Experiment 2, using visually degraded targets, demonstrated that this differential effect was independent of peripheral processing aspects, such as visual encoding. Experiment 3 including a neutral baseline condition revealed that the differential age effect on syntactic processing was due to controlled rather than to automatic aspects of priming, as it was observed for the cost component, but not for the bene”t component. Experiment 4 revealed that this effect was independent of the timing parameters used for stimulus presentation. It appears that age can have differential effects on specific cognitive domains, such as syntax and semantics. This may be attributable to the amount of controlled processes involved in syntactic and semantic priming.
Norm Development in Outsourcing Relationships
Authors: Kern Thomas , Blois Keith
Published: July 2002

This paper considers the role of norms within networks by describing how BP Exploration outsourced its information technology function – a major business activity. This outsourcing venture led to the formation of a consortium. However, this attempt was found to have failed. It is suggested here that central to the failure of the consortium as an outsourcing arrangement was the issue of ‘norms’.
Language learning and antiracism: some pedagogical challenges
Authors: Starkey Hugh , Osler Audrey
Published: July 2002

It is often argued that the study of a foreign language can influence the attitudes and behaviour of learners. One of the goals of language teaching is to challenge stereotypes and encourage learners to engage with the cultural forms that can be accessed through a new language. Through learning a language it is hoped that learners will draw on their experiences to reflect critically on their own cultures and identities. We set out to examine these claims with respect to an advanced Open University French course for adult speakers of English. This article reports on a documentary analysis of the course materials for a particular unit and of a very small opportunity sample of student work and tutor comments. The unit sets out to provide a positive view of France as a multicultural society. The analysis focuses on the extent to which the materials and the tasks help learners engage with issues of racism, xenophobia, antiracism and human rights. We found that issues of race and racism are not presented in their complexity and that the materials and learning tasks unwittingly tend to reinforce stereotyped views. We suggest that attention should be given to helping students develop skills of intercultural evaluation. This requires an understanding of human rights on the one hand and of the various forms and manifestations of racism and xenophobia on the other. We conclude by proposing some guidelines for course writers and teachers that invite them to include a range of perspectives, including those of minorities. This attention to materials and pedagogy should enable students to engage critically with issues of race, identity and culture as they learn a foreign language.
Induced Expression of Trimerized Intracellular Domains of the Human Tumor Necrosis Factor (TNF) p55 Receptor Elicits TNF Effects
Authors: Vandevoorde Veronique , Haegeman Guy , Fiers Walter
Published: July 2002

The various biological activities of tumor necrosis factor (TNF) are mediated by two receptors, one of 55 kD (TNF-R55) and one of 75 kD (TNF-R75). Although the phenotypic and molecular responses elicited by TNF in different cell types are fairly well characterized, the signaling pathways leading to them are so far only partly understood. To further unravel these processes, we focused on TNF-R55, which is responsible for mediating most of the known TNF effects. Since several studies have demonstrated the importance of receptor clustering and consequently of close association of the intracellular domains for signaling, we addressed the question of whether clustering of the intracellular domains of TNF-R55 (TNF-R55i) needs to occur in structural association with the inner side of the cell membrane, where many signaling mediators are known to reside. Therefore, we investigated whether induced intracellular clustering of only TNF-R55i would be sufficient to initiate and generate a full TNF response, without the need for a full-length receptor molecule or a transmembrane region. Our results provide clear evidence that inducible forced trimerization of either TNF-R55i or only the death domain elicits an efficient TNF response, comprising activation of the nuclear factor κB, induction of interleukin-6, and cell killing.
Localization of Mad2 to Kinetochores Depends on Microtubule Attachment, Not Tension
Authors: Waters Jennifer C. , Chen Rey-Huei , Murray Andrew W. , Salmon E.D.
Published: July 2002

A single unattached kinetochore can delay anaphase onset in mitotic tissue culture cells (Rieder, C.L., A. Schultz, R. Cole, G. Sluder. 1994. J. Cell Biol. 127:1301–1310). Kinetochores in vertebrate cells contain multiple binding sites, and tension is generated at kinetochores after attachment to the plus ends of spindle microtubules. Checkpoint component Mad2 localizes selectively to unattached kinetochores (Chen, R.-H., J.C. Waters, E.D. Salmon, and A.W. Murray. 1996. Science. 274:242–246; Li, Y., and R. Benezra. Science. 274: 246–248) and disappears from kinetochores by late metaphase, when chromosomes are properly attached to the spindle. Here we show that Mad2 is lost from PtK1 cell kinetochores as they accumulate microtubules and re-binds previously attached kinetochores after microtubules are depolymerized with nocodazole. We also show that when kinetochore microtubules in metaphase cells are stabilized with taxol, tension at kinetochores is lost. The phosphoepitope 3f3/2, which has been shown to become dephosphorylated in response to tension at the kinetochore (Nicklas, R.B., S.C. Ward, and G.J. Gorbsky. 1995. J. Cell Biol. 130:929–939), is phosphorylated on all 22 kinetochores after tension is reduced with taxol. In contrast, Mad2 only localized to an average of 2.6 out of the 22 kinetochores in taxol-treated PtK1 cells. Therefore, loss of tension at kinetochores occupied by microtubules is insufficient to induce Mad2 to accumulate on kinetochores, whereas unattached kinetochores consistently bind Mad2. We also found that microinjecting antibodies against Mad2 caused cells arrested with taxol to exit mitosis after ∼12 min, while uninjected cells remained in mitosis for at least 6 h, demonstrating that Mad2 is necessary for maintenance of the taxol-induced mitotic arrest. We conclude that kinetochore microtubule attachment stops the Mad2 interactions at kinetochores which are important for inhibiting anaphase onset.
Apical Membrane Targeting of Nedd4 Is Mediated by an Association of Its C2 Domain with Annexin Xiiib
Authors: Plant Pamela J. , Lafont Frank , Lecat Sandra , Verkade Paul , Simons Kai , Rotin Daniela
Published: July 2002

Nedd4 is a ubiquitin protein ligase (E3) containing a C2 domain, three or four WW domains, and a ubiquitin ligase HECT domain. We have shown previously that the C2 domain of Nedd4 is responsible for its Ca2+-dependent targeting to the plasma membrane, particularly the apical region of epithelial MDCK cells. To investigate this apical preference, we searched for Nedd4-C2 domain-interacting proteins that might be involved in targeting Nedd4 to the apical surface. Using immobilized Nedd4-C2 domain to trap interacting proteins from MDCK cell lysate, we isolated, in the presence of Ca2+, a ∼35–40-kD protein that we identified as annexin XIII using mass spectrometry. Annexin XIII has two known isoforms, a and b, that are apically localized, although XIIIa is also found in the basolateral compartment. In vitro binding and coprecipitation experiments showed that the Nedd4-C2 domain interacts with both annexin XIIIa and b in the presence of Ca2+, and the interaction is direct and optimal at 1 μM Ca2+. Immunofluorescence and immunogold electron microscopy revealed colocalization of Nedd4 and annexin XIIIb in apical carriers and at the apical plasma membrane. Moreover, we show that Nedd4 associates with raft lipid microdomains in a Ca2+-dependent manner, as determined by detergent extraction and floatation assays. These results suggest that the apical membrane localization of Nedd4 is mediated by an association of its C2 domain with the apically targeted annexin XIIIb.
Preservation of Mitochondrial Structure and Function after Bid- or Bax-Mediated Cytochrome c Release
Authors: von Ahsen Oliver , Renken Christian , Perkins Guy , Kluck Ruth M. , Bossy-Wetzel Ella , Newmeyer Donald D.
Published: July 2002

Proapoptotic members of the Bcl-2 protein family, including Bid and Bax, can activate apoptosis by directly interacting with mitochondria to cause cytochrome c translocation from the intermembrane space into the cytoplasm, thereby triggering Apaf-1–mediated caspase activation. Under some circumstances, when caspase activation is blocked, cells can recover from cytochrome c translocation; this suggests that apoptotic mitochondria may not always suffer catastrophic damage arising from the process of cytochrome c release. We now show that recombinant Bid and Bax cause complete cytochrome c loss from isolated mitochondria in vitro, but preserve the ultrastructure and protein import function of mitochondria, which depend on inner membrane polarization. We also demonstrate that, if caspases are inhibited, mitochondrial protein import function is retained in UV-irradiated or staurosporine-treated cells, despite the complete translocation of cytochrome c. Thus, Bid and Bax act only on the outer membrane, and lesions in the inner membrane occurring during apoptosis are shown to be secondary caspase-dependent events.
Asymmetric p38 Activation in Zebrafish
Authors: Fujii Ritsuko , Yamashita Susumu , Hibi Masahiko , Hirano Toshio
Published: July 2002

Cleavage is one of the initial steps of embryogenesis, and is characterized by a series of symmetric and synchronous cell divisions. We showed that p38 MAP kinase (p38) is asymmetrically activated on one side of the blastodisc during the early cleavage period in zebrafish (Danio rerio) embryos. When a dominant negative (DN) form of p38 was uniformly expressed, blastomere cleavage was impaired on one side of the blastodisc, resulting in the formation of blastomeres with a large mass of cytoplasm and an enlarged nucleus on the affected side. The area affected by the DN-p38 expression did not correlate with the initial cleavage plane, but coincided with the side where dharma/bozozok, a dorsal-specific zygotic gene, was expressed (Yamanaka et al. 1998). Furthermore, UV irradiation and removal of the vegetal yolk mass before the first cleavage, both of which inhibit the initiation of the dorsalizing signals, abolished the asymmetric p38 activation. Our findings suggest that asymmetric p38 activation is required for symmetric and synchronous cleavage, and may be regulated by the same machinery that controls the initiation of dorsalizing signals.
The Plastid of Toxoplasma gondii Is Divided by Association with the Centrosomes
Authors: Striepen Boris , Crawford Michael J. , Shaw Michael K. , Tilney Lewis G. , Seeber Frank , Roos David S.
Published: July 2002

Apicomplexan parasites harbor a single nonphotosynthetic plastid, the apicoplast, which is essential for parasite survival. Exploiting Toxoplasma gondii as an accessible system for cell biological analysis and molecular genetic manipulation, we have studied how these parasites ensure that the plastid and its 35-kb circular genome are faithfully segregated during cell division. Parasite organelles were labeled by recombinant expression of fluorescent proteins targeted to the plastid and the nucleus, and time-lapse video microscopy was used to image labeled organelles throughout the cell cycle. Apicoplast division is tightly associated with nuclear and cell division and is characterized by an elongated, dumbbell-shaped intermediate. The plastid genome is divided early in this process, associating with the ends of the elongated organelle. A centrin-specific antibody demonstrates that the ends of dividing apicoplast are closely linked to the centrosomes. Treatment with dinitroaniline herbicides (which disrupt microtubule organization) leads to the formation of multiple spindles and large reticulate plastids studded with centrosomes. The mitotic spindle and the pellicle of the forming daughter cells appear to generate the force required for apicoplast division in Toxoplasma gondii. These observations are discussed in the context of autonomous and FtsZ-dependent division of plastids in plants and algae.
Vacuolar Storage Proteins Are Sorted in the Cis-Cisternae of the Pea Cotyledon Golgi Apparatus
Authors: Hillmer Stefan , Movafeghi Ali , Robinson David G. , Hinz Giselbert
Published: July 2002

Developing pea cotyledons contain functionally different vacuoles, a protein storage vacuole and a lytic vacuole. Lumenal as well as membrane proteins of the protein storage vacuole exit the Golgi apparatus in dense vesicles rather than in clathrin-coated vesicles (CCVs). Although the sorting receptor for vacuolar hydrolases BP-80 is present in CCVs, it is not detectable in dense vesicles. To localize these different vacuolar sorting events in the Golgi, we have compared the distribution of vacuolar storage proteins and of α-TIP, a membrane protein of the protein storage vacuole, with the distribution of the vacuolar sorting receptor BP-80 across the Golgi stack. Analysis of immunogold labeling from cryosections and from high pressure frozen samples has revealed a steep gradient in the distribution of the storage proteins within the Golgi stack. Intense labeling for storage proteins was registered for the cis-cisternae, contrasting with very low labeling for these antigens in the trans-cisternae. The distribution of BP-80 was the reverse, showing a peak in the trans-Golgi network with very low labeling of the cis-cisternae. These results indicate a spatial separation of different vacuolar sorting events in the Golgi apparatus of developing pea cotyledons.
Cyclin-Dependent Kinase Inhibitor P27Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function
Authors: Muraoka Rebecca S. , Lenferink Anne E.G. , Simpson Jean , Brantley Dana M. , Roebuck L. Renee , Yakes F. Michael , Arteaga Carlos L.
Published: July 2002

We have studied the role of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 in postnatal mammary gland morphogenesis. Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation. However, recent evidence about the stabilizing effect of p27 on cyclin D1–Cdk4 complexes suggests that p27 deficiency might recapitulate the hypoplastic mammary phenotype of cyclin D1–deficient animals. These hypotheses were investigated in postnatal p27-deficient (p27−/−), hemizygous (p27+/−), or wild-type (p27+/+) mammary glands. Mammary glands from p27+/− mice displayed increased ductal branching and proliferation with delayed postlactational involution. In contrast, p27−/− mammary glands or wild-type mammary fat pads reconstituted with p27−/− epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate. The association of cyclin D1 with Cdk4, the kinase activity of Cdk4 against pRb in vitro, the nuclear localization of cyclin D1, and the stability of cyclin D1 were all severely impaired in p27−/− mammary epithelial cells compared with p27+/+ and p27+/− mammary epithelial cells. Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D–Cdk4 function in the mammary gland.
Effects of Purified Recombinant Neural and Muscle Agrin on Skeletal Muscle Fibers in Vivo
Authors: Bezakova Gabriela , Helm Johannes P. , Francolini Maura , Lømo Terje
Published: July 2002

Aggregation of acetylcholine receptors (AChRs) in muscle fibers by nerve-derived agrin plays a key role in the formation of neuromuscular junctions. So far, the effects of agrin on muscle fibers have been studied in culture systems, transgenic animals, and in animals injected with agrin–cDNA constructs. We have applied purified recombinant chick neural and muscle agrin to rat soleus muscle in vivo and obtained the following results. Both neural and muscle agrin bind uniformly to the surface of innervated and denervated muscle fibers along their entire length. Neural agrin causes a dose-dependent appearance of AChR aggregates, which persist ≥7 wk after a single application. Muscle agrin does not cluster AChRs and at 10 times the concentration of neural agrin does not reduce binding or AChR-aggregating activity of neural agrin. Electrical muscle activity affects the stability of agrin binding and the number, size, and spatial distribution of the neural agrin–induced AChR aggregates. Injected agrin is recovered from the muscles together with laminin and both proteins coimmunoprecipitate, indicating that agrin binds to laminin in vivo. Thus, the present approach provides a novel, simple, and efficient method for studying the effects of agrin on muscle under controlled conditions in vivo.
Selective Expression of an Interleukin-12 Receptor Component by Human T Helper 1 Cells
Authors: Rogge Lars , Barberis-Maino Luisella , Biffi Mauro , Passini Nadia , Presky David H. , Gubler Ueli , Sinigaglia Francesco
Published: July 2002

Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-γ production and in the generation of IFN–γ–producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL12R) β2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R β2 chain during in vitro T cell differentiation after antigen receptor triggering. The selective expression and regulation of the IL-12R β2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.
Diversification of  T Cell Responses to Carboxy-terminal Determinants within the 65-kD Heat-shock Protein Is Involved in Regulation of Autoimmune Arthritis
Authors: Moudgil Kamal D. , Chang Tammy T. , Eradat Herbert , Chen Audrey M. , Gupta Radhey S. , Brahn Ernest , Sercarz Eli E.
Published: July 2002

The T cell response to the 65-kD mycobacterial heat-shock protein (Bhsp65) has been implicated in the pathogenesis of autoimmune arthritis. Adjuvant arthritis (AA) induced in the Lewis rat (RT-1l) by injection of Mycobacterium tuberculosis serves as an experimental model for human rheumatoid arthritis (RA). However, the immunological basis of regulation of acute AA, or of susceptibility/resistance to AA is not known. We have defined the specificity of the proliferative T cell responses to Bhsp65 during the course of AA in the Lewis rat. During the early phase of the disease (6–9 d after onset of AA), Lewis rats raised T cell responses to many determinants within Bhsp65, spread throughout the molecule. Importantly, in the late phase of the disease (8–10 wk after onset of AA), there was evidence for diversification of the T cell responses toward Bhsp65 carboxy-terminal determinants (BCTD) (namely, 417–431, 441–455, 465–479, 513–527, and 521–535). Moreover, arthritic rats in the late phase of AA also raised vigorous T cell responses to those carboxy-terminal determinants within self(rat) hsp65 (Rhsp65) that correspond in position to the above BCTD. These results suggest that the observed diversification is possibly triggered in vivo by induction of self(Rhsp65)-reactive T cells. Interestingly, another strain of rat, the Wistar Kyoto (WKY/NHsd) rat (RT-1l), with the same major histocompatibility complex class II molecules as the Lewis rat, was found to be resistant to AA. In WKY rats, vigorous responses to the BCTD, to which the Lewis rat responded only in the late phase of AA, were observed very early, 10 d after injection of M. tuberculosis. Strikingly, pretreatment with the peptides comprising the set of BCTD, but not its amino-terminal determinants, provided significant protection to naive Lewis rats from subsequent induction of AA. Thus, T cell responses to the BCTD are involved in regulating inflammatory arthritis in the Lewis rat and in conferring resistance to AA in the WKY rat. These results have important implications in understanding the pathogenesis of RA and in devising new immunotherapeutic strategies for this disease.
Altered Hematopoiesis, Behavior, and Sexual Function in μ Opioid Receptor–deficient Mice
Authors: Tian Mingting , Broxmeyer Hal E. , Fan Yi , Lai Zhennan , Zhang Shengwen , Aronica Susan , Cooper Scott , Bigsby Robert M. , Steinmetz Rosemary , Engle Sandra J. , Mestek Anton , Pollock Jonathan D. , Lehman Michael N. , Jansen Heiko T. , Ying Moyin , Stambrook Peter J. , Tischfield Jay A. , Yu Lei
Published: July 2002

The μ opioid receptor is thought to be the cellular target of opioid narcotics such as morphine and heroin, mediating their effects in both pain relief and euphoria. Its involvement is also implicated in a range of diverse biological processes. Using a mouse model in which the receptor gene was disrupted by targeted homologous recombination, we explored the involvement of this receptor in a number of physiological functions. Mice homozygous for the disrupted gene developed normally, but their motor function was altered. Drug-naive homozygotes displayed reduced locomotor activity, and morphine did not induce changes in locomotor activity observed in wild-type mice. Unexpectedly, lack of a functional receptor resulted in changes in both the host defense system and the reproductive system. We observed increased proliferation of granulocyte-macrophage, erythroid, and multipotential progenitor cells in both bone marrow and spleen, indicating a link between hematopoiesis and the opioid system, both of which are stress-responsive systems. Unexpected changes in sexual function in male homozygotes were also observed, as shown by reduced mating activity, a decrease in sperm count and motility, and smaller litter size. Taken together, these results suggest a novel role of the μ opioid receptor in hematopoiesis and reproductive physiology, in addition to its known involvement in pain relief.
Protective Immunity to Nematode Infection Is Induced by CTLA-4 Blockade
Authors: McCoy Kathy , Camberis Mali , Gros Graham Le
Published: July 2002

The recent observation that neutralization or genetic deletion of the T lymphocyte receptor CTLA-4 allows enhanced T cell reactivity offers new opportunities for immunotherapy against infectious agents. We used a neutralizing antibody to block CTLA-4 interaction with its ligands CD80 and CD86 during infection of mice with the nematode, Nippostrongylus brasiliensis. CTLA-4 blockade greatly enhanced and accelerated the T cell immune response to N. brasiliensis, resulting in a profound reduction in adult worm numbers and early termination of parasite egg production. The ability of CTLA-4 blockade to accelerate primary immune responses to a protective level during an acute infection indicates its potential as an immunotherapeutic tool for dealing with infectious agents.
Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice
Authors: Kägi David , Odermatt Bernhard , Seiler Peter , Zinkernagel Rolf M. , Mak Tak W. , Hengartner Hans
Published: July 2002

To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.
The Sequence Alteration Associated with a Mutational Hotspot in p53 Protects Cells From Lysis by Cytotoxic T Lymphocytes Specific for a Flanking Peptide Epitope
Authors: Theobald Matthias , Ruppert Thomas , Kuckelkorn Ulrike , Hernandez Javier , Häussler Annett , Ferreira Edite Antunes , Liewer Ulrike , Biggs Judith , Levine Arnold J. , Huber Christoph , Koszinowski Ulrich H. , Kloetzel Peter-M. , Sherman Linda A.
Published: July 2002

A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264–272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201–restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.264–272 peptide-specific CTLs. Synthetic 27-mer p53 polypeptides covering the antigenic nonamer region 264–272 of p53 were used as proteasome substrates to investigate whether the R to H mutation at the P1′ position of the COOH terminus of the epitope affects proteasome-mediated processing of the protein. Analysis of the generated products by tandem mass spectrometry and the kinetics of polypeptide processing in conjunction with CTL assays demonstrate that the R to H mutation alters proteasomal processing of the p53 protein by inhibiting proteolytic cleavage between residues 272 and 273. This prevents the release of the natural CTL epitope that spans flanking residues 264–272 as well as a putative precursor peptide. These results demonstrate that mutation of p53 not only leads to malignant transformation but may also, in some instances, affect immune surveillance and should be considered in the design of cancer vaccines.
Liver Damage Preferentially Results from CD8+ T Cells Triggered by High Affinity Peptide Antigens
Authors: Russell Jennifer Q. , Morrissette Gregory J. , Weidner Mark , Vyas Chirag , Aleman-Hoey Deborah , Budd Ralph C.
Published: July 2002

Little is understood of the anatomical fate of activated T lymphocytes and the consequences they have on the tissues into which they migrate. Previous work has suggested that damaged lymphocytes migrate to the liver. This study compares class I versus class II major histocompatibility complex (MHC)–restricted ovalbumin-specific T cell antigen receptor (TCR) transgenic mice to demonstrate that after in vivo activation with antigen the emergence of CD4−CD8−B220+ T cells occurs more frequently from a CD8+ precursor than from CD4+ T cells. Furthermore, this change in phenotype is conferred only by the high affinity native peptide antigen and not by lower affinity peptide variants. After activation of CD8+ cells with only the high affinity peptide, there is also a dramatically increased number of liver lymphocytes with accompanying extensive hepatocyte damage and elevation of serum aspartate transaminase. This was not observed in mice bearing a class II MHC–restricted TCR. The findings show that CD4−CD8−B220+ T cells preferentially derive from a CD8+ precursor after a high intensity TCR signal. After activation, T cells can migrate to the liver and induce hepatocyte damage, and thereby serve as a model of autoimmune hepatitis.
Arterial Inflammation in Mice Lacking the Interleukin 1 Receptor Antagonist Gene
Authors: Nicklin Martin J.H. , Hughes David E. , Barton Jenny L. , Ure Jan M. , Duff Gordon W.
Published: July 2002

Branch points and flexures in the high pressure arterial system have long been recognized as sites of unusually high turbulence and consequent stress in humans are foci for atherosclerotic lesions. We show that mice that are homozygous for a null mutation in the gene encoding an endogenous antiinflammatory cytokine, interleukin 1 receptor antagonist (IL-1ra), develop lethal arterial inflammation involving branch points and flexures of the aorta and its primary and secondary branches. We observe massive transmural infiltration of neutrophils, macrophages, and CD4+ T cells. Animals appear to die from vessel wall collapse, stenosis, and organ infarction or from hemorrhage from ruptured aneurysms. Heterozygotes do not die from arteritis within a year of birth but do develop small lesions, which suggests that a reduced level of IL-1ra is insufficient to fully control inflammation in arteries. Our results demonstrate a surprisingly specific role for IL-1ra in the control of spontaneous inflammation in constitutively stressed artery walls, suggesting that expression of IL-1 is likely to have a significant role in signaling artery wall damage.
Enhanced Peroxynitrite Formation Is Associated with Vascular Aging
Authors: van der Loo Bernd , Labugger Ralf , Skepper Jeremy N. , Bachschmid Markus , Kilo Juliane , Powell Janet M. , Palacios-Callender Miriam , Erusalimsky Jorge D. , Quaschning Thomas , Malinski Tadeusz , Gygi Daniel , Ullrich Volker , Lüscher Thomas F.
Published: July 2002

Vascular aging is mainly characterized by endothelial dysfunction. We found decreased free nitric oxide (NO) levels in aged rat aortas, in conjunction with a sevenfold higher expression and activity of endothelial NO synthase (eNOS). This is shown to be a consequence of age-associated enhanced superoxide (·O2−) production with concomitant quenching of NO by the formation of peroxynitrite leading to nitrotyrosilation of mitochondrial manganese superoxide dismutase (MnSOD), a molecular footprint of increased peroxynitrite levels, which also increased with age. Thus, vascular aging appears to be initiated by augmented ·O2− release, trapping of vasorelaxant NO, and subsequent peroxynitrite formation, followed by the nitration and inhibition of MnSOD. Increased eNOS expression and activity is a compensatory, but eventually futile, mechanism to counter regulate the loss of NO. The ultrastructural distribution of 3-nitrotyrosyl suggests that mitochondrial dysfunction plays a major role in the vascular aging process.
Cd8 Expression up to the Double-Positive CD3Low/Intermediate Stage of Thymic Differentiation Is Sufficient for Development of Peripheral Functional Cytotoxic T Lymphocytes
Authors: Zhang X.-L. , Zhao S. , Borenstein S.H. , Liu Y. , Jayabalasingham B. , Chamberlain J.W.
Published: July 2002

Control of CD8α transcription during development of α/β T cell receptor (TCR) T lymphocytes is mediated by at least two distinct stage-specific cis-acting transcriptional mechanisms (i.e., enhancers). On the CD8α−/−knockout (KO) background, cis-mechanism I and cis-mechanism II together mediate appropriate stage- and sublineage-specific transgenic (Tg) CD8α expression and “rescue” development of peripheral CD8+ single-positive (SP) cytotoxic T lymphocytes (CTLs). In contrast, on the wild-type (WT)/CD8+/+ or CD8α−/−KO backgrounds, a CD8α Tg directed by cis-mechanism I alone is activated during the double negative [DN] to double positive [DP] transition and expressed up to the CD3low/intermediate DP stage but not in more mature DP or SP thymocytes or peripheral T cells. As loss of cis mechanism I activity occurs around the onset of positive selection, it is possible that events associated with TCR/major histocompatibility complex (MHC) interactions and selection are involved in initiating these changes in CD8α transcription. To examine this issue, phenotypic and functional studies were performed for thymocytes and T cells of CD8α−/−KO mice that expressed a CD8α Tg under control of cis-mechanism I only. Despite loss of CD8α expression at the DP CD3low/intermediate stage, increased populations of mature CD3hiCD4−CD8− thymocytes and CD3+CD4−CD8− peripheral T cells were detected. By several criteria, including MHC class I–restricted antigen recognition, these cells have at least partially undergone positive and negative selection. Therefore, initiation of selection and sublineage commitment are determined before loss of cis-mechanism I–mediated control of CD8α transcription. Further, CD8 expression beyond the CD3low/intermediate DP thymic stage is not essential for CTL development in vivo or function.
Molecular Tuning of an EF-Hand-like Calcium Binding Loop
Authors: Drake Steven K. , Zimmer Michael A. , Kundrot Craig , Falke Joseph J.
Published: July 2002

Calcium binding and signaling orchestrate a wide variety of essential cellular functions, many of which employ the EF-hand Ca2+ binding motif. The ion binding parameters of this motif are controlled, in part, by the structure of its Ca2+ binding loop, termed the EF-loop. The EF-loops of different proteins are carefully specialized, or fine-tuned, to yield optimized Ca2+ binding parameters for their unique cellular roles. The present study uses a structurally homologous Ca2+ binding loop, that of the Escherichia coli galactose binding protein, as a model for the EF-loop in studies examining the contribution of the third loop position to intramolecular tuning. 10 different side chains are compared at the third position of the model EF-loop with respect to their effects on protein stability, sugar binding, and metal binding equilibria and kinetics. Substitution of an acidic Asp side chain for the native Asn is found to generate a 6,000-fold increase in the ion selectivity for trivalent over divalent cations, providing strong support for the electrostatic repulsion model of divalent cation charge selectivity. Replacement of Asn by neutral side chains differing in size and shape each alter the ionic size selectivity in a similar manner, supporting a model in which large-ion size selectivity is controlled by complex interactions between multiple side chains rather than by the dimensions of a single coordinating side chain. Finally, the pattern of perturbations generated by side chain substitutions helps to explain the prevalence of Asn and Asp at the third position of natural EF-loops and provides further evidence supporting the unique kinetic tuning role of the gateway side chain at the ninth EF-loop position.
Cotorsion theories and splitters
Authors: Göbel Rüdiger , Shelah Saharon
Published: July 2002

Let

R
R

be a subring of the rationals. We want to investigate self splitting

R
R

-modules

G
G

(that is

Ext
R

⁡
(
G
,
G
)
=
0
)

\operatorname {Ext}_R(G,G) = 0)

. Following Schultz, we call such modules splitters. Free modules and torsion-free cotorsion modules are classical examples of splitters. Are there others? Answering an open problem posed by Schultz, we will show that there are more splitters, in fact we are able to prescribe their endomorphism

R
R

-algebras with a free

R
R

-module structure. As a by-product we are able to solve a problem of Salce, showing that all rational cotorsion theories have enough injectives and enough projectives. This is also basic for answering the flat-cover-conjecture.
Beyond Borcherds Lie algebras and inside
Authors: Berman Stephen , Jurisich Elizabeth , Tan Shaobin
Published: July 2002

We give a definition for a new class of Lie algebras by generators and relations which simultaneously generalize the Borcherds Lie algebras and the Slodowy G.I.M. Lie algebras. After proving these algebras are always subalgebras of Borcherds Lie algebras, as well as some other basic properties, we give a vertex operator representation for a factor of them. We need to develop a highly non-trivial generalization of the square length two cut off theorem of Goddard and Olive to do this.
The nonstationary ideal and the other 𝜎-ideals on 𝜔₁
Authors: Zapletal Jindřich
Published: July 2002

Under Martin’s Maximum every

σ
\sigma

-ideal on

ω

1

\omega _{1}

is a subset of an ideal Rudin-Keisler reducible to a finite Fubini power of the nonstationary ideal restricted to a positive set.
Properties of Anick’s spaces
Authors: Theriault Stephen
Published: July 2002

We prove three useful properties of Anick’s space 

T

2
n
−
1

(

p

r

)

T^{2n-1}(p^{r})

. First, at odd primes a map from

P

2
n

(

p

r

)

P^{2n}(p^{r})

into a homotopy commutative, homotopy associative

H
H

-space

X
X

can be extended to a unique

H
H

-map from

T

2
n
−
1

(

p

r

)

T^{2n-1}(p^{r})

into 

X
X

. Second, at primes larger than 

3
3

,

T

2
n
−
1

(

p

r

)

T^{2n-1}(p^{r})

is itself homotopy commutative and homotopy associative. And third, the first two properties combine to show that the order of the identity map on 

T

2
n
−
1

(

p

r

)

T^{2n-1}(p^{r})

is 

p

r

p^{r}

.
Transfers of Chern classes in BP-cohomology and Chow rings
Authors: Schuster Björn , Yagita Nobuaki
Published: July 2002

The

B

P
∗

BP^*

-module structure of

B

P
∗

(
B
G
)

BP^*(BG)

for extraspecial

2
2

-groups is studied using transfer and Chern classes. These give rise to

p
p

-torsion elements in the kernel of the cycle map from the Chow ring to ordinary cohomology first obtained by Totaro.
Measuring the tameness of almost convex groups
Authors: Hermiller Susan , Meier John
Published: July 2002

A 1-combing for a finitely presented group consists of a continuous family of paths based at the identity and ending at points

x
x

in the 1-skeleton of the Cayley 2-complex associated to the presentation. We define two functions (radial and ball tameness functions) that measure how efficiently a 1-combing moves away from the identity. These functions are geometric in the sense that they are quasi-isometry invariants. We show that a group is almost convex if and only if the radial tameness function is bounded by the identity function; hence almost convex groups, as well as certain generalizations of almost convex groups, are contained in the quasi-isometry class of groups admitting linear radial tameness functions.
Constructing product fibrations by means of a generalization of a theorem of Ganea
Authors: Selick Paul
Published: July 2002

A theorem of Ganea shows that for the principal homotopy fibration

Ω
B
→
F
→
E

\Omega B\to F\to E

induced from a fibration

F
→
E
→
B

F\to E\to B

, there is a product decomposition

Ω
(
E

/

F
)
≈
Ω
B
×
Ω
(
F
∗
Ω
B
)

\Omega (E/F)\approx \Omega B\times \Omega (F*\Omega B)

. We will determine the conditions for a fibration

X
→
Y
→
Z

X\to Y\to Z

to yield a product decomposition

Ω
(
Z

/

Y
)
≈
X
×
Ω
(
X
∗
Y
)

\Omega (Z/Y)\approx X\times \Omega (X*Y)

and generalize it to pushouts. Using this approach we recover some decompositions originally proved by very computational methods. The results are then applied to produce, after localization at an odd prime 

p
p

, homotopy decompositions for

Ω

J

k

(

S

2
n

)

\Omega {J_{k}\left (S^{2n}\right )}

for some 

k
k

which include the cases 

k
=

p

t

k=p^{t}

. The factors of

Ω

J

p

t

(

S

2
n

)

\Omega {J_{p^{t}}\left (S^{2n}\right )}

consist of the homotopy fibre of the attaching map

S

2
n

p

t

−
1

→

J

p

t

−
1

(

S

2
n

)

S^{2np^{t}-1}\to {J_{p^{t}-1}\left (S^{2n}\right )}

for

J

p

t

(

S

2
n

)

{J_{p^{t}}\left (S^{2n}\right )}

and combinations of spaces occurring in the Snaith stable decomposition of

Ω

2

S

2
n
+
1

\Omega ^{2} S^{2n+1}

.
Extensions of codimension one immersions
Authors: Pappas Christian
Published: July 2002

We give a method for constructing all of the extensions of an immersion, and determine the CW structure and diffeomorphism type of each.
A deformation of flat conformal structures
Authors: Izeki Hiroyasu
Published: July 2002

We consider deformations of flat conformal structures from a viewpoint of connected sum decomposition of conformally flat manifolds.
Divisors on Generic Complete Intersections in Projective Space
Authors: Xu Geng
Published: July 2002

Let

V
V

be a generic complete intersection of hypersurfaces of degree

d

1

,

d

2

,
⋯
,

d

m

d_{1}, d_{2}, \cdots , d_{m}

in

n
n

-dimensional projective space. We study the question when a divisor on

V
V

is nonrational or of general type, and give an alternative proof of a result of Ein. We also give some improvement of Ein’s result in the case

d

1

+

d

2

+
⋯
+

d

m

=
n
+
2

d_{1}+d_{2}+\cdots + d_{m}=n+2

.
The stability of foliations of orientable 3-manifolds covered by a product
Authors: Shields Sandra
Published: July 2002

We examine the relationship between codimension one foliations that are covered by a trivial product of hyperplanes and the branched surfaces that can be constructed from them. We present a sufficient condition on a branched surface constructed from a foliation to guarantee that all

C
1

C^1

perturbations of the foliation are covered by a trivial product of hyperplanes. We also show that a branched surface admits a strictly positive weight system if and only if it can be constructed from a fibration over

S
1

S^1

.
Properties of extremal functions for some nonlinear functionals on Dirichlet spaces
Authors: Matheson Alec , Pruss Alexander
Published: July 2002

Let

B

\mathfrak {B}

be the set of holomorphic functions

f
f

on the unit disc

D
D

with

f
(
0
)
=
0

f(0)=0

and Dirichlet integral

(
1

/

π
)

∬

D

|

f
′

|

2

(1/\pi ) \iint _{D} |f’|^{2}

not exceeding one, and let

b

\mathfrak {b}

be the set of complex-valued harmonic functions

f
f

on the unit disc with

f
(
0
)
=
0

f(0)=0

and Dirichlet integral

(
1

/

2
)
(
1

/

π
)

∬

D

|

∇
f

|

2

(1/2)(1/\pi ) \iint _{D} |\nabla f|^{2}

not exceeding one. For a (semi)continuous function

Φ
:
[
0
,
∞
)
→

R

\Phi :[0,\infty ) \to \mathbb {R}

, define the nonlinear functional

Λ

Φ

\Lambda _{\Phi }

on

B

\mathfrak {B}

or

b

\mathfrak {b}

by
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="normal upper Lamda Subscript normal upper Phi Baseline left-parenthesis f right-parenthesis equals StartFraction 1 Over 2 pi EndFraction integral Subscript 0 Superscript 2 pi Baseline normal upper Phi left-parenthesis StartAbsoluteValue f left-parenthesis e Superscript i theta Baseline right-parenthesis EndAbsoluteValue right-parenthesis d theta">

Λ

Φ

(
f
)
=

1

2
π

∫

0

2
π

Φ
(

|

f
(

e

i
θ

)

|

)

d
θ

\Lambda _{\Phi }(f)={\frac {1}{2\pi }} \int _{0}^{2\pi }\Phi (|f(e^{i\theta })|)\,d\theta

. We study the existence and regularity of extremal functions for these functionals, as well as the weak semicontinuity properties of the functionals. We also state a number of open problems.
Multiplication of natural number parameters and equations in a free semigroup
Authors: Makanin Gennady
Published: July 2002

This paper deals with the problem of describing the set

M
M

of all solutions of an equation over a free semigroup

S
S

. The standard way to do this involves the introduction of auxiliary equations containing polynomials in natural number parameters of arbitrarily high degree. Since

S
S

has a solvable word problem,

M
M

must be computable. However,

M
M

cannot necessarily be computed from the standard description of

M
M

. The present paper shows that the only polynomials needed to describe

M
M

are just products of one parameter by a linear combination of some other parameters. The resulting simplification of the standard description of

M
M

clearly can be used to compute

M
M

.
Curvature invariants, differential operators and local homogeneity
Authors: Prüfer Friedbert , Tricerri Franco , Vanhecke Lieven
Published: July 2002

We first prove that a Riemannian manifold

(
M
,
g
)

(M,g)

with globally constant additive Weyl invariants is locally homogeneous. Then we use this result to show that a manifold

(
M
,
g
)

(M,g)

whose Laplacian commutes with all invariant differential operators is a locally homogeneous space.
The boundary of iterates in Euclidean growth models
Authors: Gravner Janko
Published: July 2002

This paper defines a general Euclidean growth model via a translation invariant, monotone and local transformation on Borel subsets of

R

2

\mathbf {R}^2

. The main result gives a geometric condition for the boundary curvature of the iterates to go to 0. Consequences include estimates for the speed of convergence to the asymptotic shape, and a result about survival of Euclidean deterministic forest fires.