bluuebunny/crossref_metadata_2025 huggingface dataset:
Perception of Material from Contact Sounds
Authors: Klatzky Roberta L. , Pai Dinesh K. , Krotkov Eric P.
Published: July 2002

Contact sounds can provide important perceptual cues in virtual environments. We investigated the relation between material perception and variables that govern the synthesis of contact sounds. A shape-invariant, auditory-decay parameter was a powerful determinant of the perceived material of an object. Subjects judged the similarity of synthesized sounds with respect to material (Experiment 1 and 2) or length (Experiment 3). The sounds corresponded to modal frequencies of clamped bars struck at an intermediate point, and they varied in fundamental frequency and frequency-dependent rate of decay. The latter parameter has been proposed as reflecting a shape-invariant material property: damping. Differences between sounds in both decay and frequency affected similarity judgments (magnitude of similarity and judgment duration), with decay playing a substantially larger role. Experiment 2, which varied the initial sound amplitude, showed that decay rate—rather than total energy or sound duration—was the critical factor in determining similarity. Experiment 3 demonstrated that similarity judgments in the first two studies were specific to instructions to judge material. Experiment 4, in which subjects assigned the sounds to one of four material categories, showed an influence of frequency and decay, but confirmed the greater importance of decay. Decay parameters associated with each category were estimated and found to correlate with physical measures of damping. The results support the use of a simplified model of material in virtual auditory environments.
Defense of the Ansatz for Dynamical Hierarchies
Authors: Rasmussen Steen , Baas Nils A. , Mayer Bernd , Nilsson Martin
Published: July 2002

Gross and McMullin [Artificial Life, 7, 355–365] criticize the conclusions of our article on dynamical hierarchies [Artificial Life, 7, 329–353]. In this note we respond to their criticisms. After clarifying our ansatz, we argue that the simulations presented by Gross and McMullin present no evidence against the ansatz, in part because their simulations use a different simulation framework, and in part because their simulations are no less complex than ours. We also clarify why the micelles in our simulations are third-order emergent structures, and why we emphasize realism in our simulation.
Artificial Ears for a Biomimetic Sonarhead: From Multiple Reflectors to Surfaces
Authors: Carmena J. M. , Kämpchen N. , Kim D. , Hallam J. C. T.
Published: July 2002

This work presents an evolutionary approach to pinna design. Narrowband echolocating bats move the pinna to alter the directional sensitivity of their perceptual systems. Adding pinnae to RoBat—a biomimetic sonarhead mounted on a mobile robot—is the goal of this work. After a description of the earlier work on artificial pinnae consisting of multiple reflectors around the transducer, an acoustic model, inspired by a physical model of sound diffraction and reflections in the human concha, is described and revisited as the model to use for evolving complex shapes. A genetic algorithm evolved the shape of the pinnae with respect to desired features of the directivity pattern of the receiver transducers. Some interesting paraboloid shapes for specific echolocating behaviors were evolved, improving performance with respect to the bare transducer's performance.
WHY DID NOAH SEND OUT A RAVEN?
Authors:   Moberly
Published: July 2002

A survey of ancient and modern interpretations of Genesis viii 7 reveals the consistent assumption that the raven must perform the same function as the dove, which makes the presence of the raven puzzling - why two birds? Traditional commentators explain the raven in symbolic and moralizing terms, while modern commentators generally see it as a traditio-historical fragment. It is here proposed that the raven has a different task from that of the dove, in that its flying to and fro above the waters is a symbolic replication of God's action through the ruah (Genesis viii 1) whereby the waters recede. This is related to the concept of imitatio Dei in Priestly thought.
THE DISTRIBUTION OF GROOMING AMONG FEMALE PRIMATES: TESTING HYPOTHESES WITH THE SHANNON-WIENER DIVERSITY INDEX
Authors: Di Bitetti Mario S.
Published: July 2002

The Shannon-Wiener diversity index (H) has been used to characterize grooming relationships among adult female primates. To make comparisons among different groups, the value of H has been divided by the maximum value it can reach for a particular group size. This ratio, the grooming diversity ratio (GDR), has been used to test predictions from hypotheses that may explain the distribution of social relationships among adult female primates. Using grooming data from different primate populations and random computer simulations I show that the mean value of H and GDR are positively affected by the ln of the mean number of grooming bouts recorded per dyad (LnMNBD) and negatively by the coefficient of variation in the frequency of grooming bouts recorded for the females within a group (CV). These two variables reflect the combined effect of sampling effort and the rate of interactions among individuals (and their variance) and should be statistically controlled to make sensible use of H or GDR. After controlling for LnMNBD and CV, I found no significant effect of female group size, the degree of female involvement in inter-group encounters and the patterns of female dispersal on the mean value of GDR. The socioecological model of female social relationships (Sterck et al., 1997) predicts that groups categorized as resident-egalitarian should have higher GDRs than resident-nepotistic ones. I find some support for this prediction when using a data set where some species contributed more than one data point but not when using mean values per species as in the previous analyses. This result may be confounded by a phylogenetic effect: langurs seem to have more diverse relationships than other primates. Data from more species are necessary to corroborate these results and to disentangle the effect of phylogeny from that of the social categories since most monkey groups characterized as resident-egalitarian were langurs.
BEHAVIOUR OF DOMESTIC PIGS IN A VISUAL PERSPECTIVE TAKING TASK
Authors: Held Suzanne , Mendl Michael , Devereux Claire , Byrne Richard
Published: July 2002

Animals with visual perspective taking abilities should differ in their responses to individuals that do and individuals that do not have visual access to some critical event. We investigated whether domestic pigs show behaviour consistent with this ability. Ten subjects were trained to move from a start box into one of four corridors that they had seen a human enter with a bucket for baiting. They received a food reward for choosing the correct corridor. In unrewarded probe tests, the subjects' view of the corridors was blocked, but they could see a 'seeing' companion pig who had visual access to the baiting event, and another, whose view was also blocked, located in start boxes to their left and right. After the companions had been released and entered corridors, the subject was released and which companion it followed was recorded. Eight pigs followed companions less frequently than expected by chance, probably due to specific corridor or centre/side preferences. However, one subject showed no positional bias, and a significant preference for following the 'seeing' companion, consistent with the ability to take another's visual perspective. Our design rules out learning of a correct response during the experiment, by testing subjects in unrewarded probe trials, and by using companions that were equally trained and unaware of the subject's task. However, we cannot rule out the possibility that previously learned contingencies were used to solve the problem. We therefore consider that this apparent visual perspective taking ability does not necessarily imply any ability to understand knowledge states.
SILK MEDIATED DEFENSE BY AN ORB WEB SPIDER AGAINST PREDATORY MUD-DAUBER WASPS
Authors: Blackledge Todd , Wenzel John
Published: July 2002

Stabilimenta are zigzag and spiral designs of seemingly conspicuous silk included at the centers of many spider webs. We examined the association of stabilimenta with the ability of spiders to defend themselves against predatory mud-dauber wasps. We found that Argiope trifasciata (Araneae, Araneidae) were significantly more likely to survive attacks by Chalybion caeruleum and Sceliphron caementarium (Hymenoptera, Sphecidae) when spiders included stabilimenta in webs. This association could not be explained by factors such as differences in sizes or conditions of spiders nor locations of webs. We suggest that stabilimenta may function to delay pursuit of spiders as they drop from webs by physically blocking wasps, camouflaging spiders or distracting attacking wasps. Stabilimenta may function in a role very similar to the retreats built by many other genera of spiders and appear to be an adaptation to reduce the predation pressure faced by spiders that have evolved foraging habits at highly exposed diurnal web sites.
SEXUAL HARASSMENT AS A COST FOR MOLLY FEMALES: BIGGER MALES COST LESS
Authors: Schlupp Ingo , McKnab Ryan , Ryan Michael
Published: July 2002

Females of many species receive male attention that reflects a conflict between the sexes over reproduction. Here we demonstrate that female sailfin mollies (Poecilia latipinna) suffer such a cost via a reduction of their feeding time in the presence of males. Female sailfin mollies spend significantly more time feeding when accompanied by an Amazon molly (P.formosa) or a sailfin molly female than when accompanied by a male sailfin molly. Furthermore, we show that male sexual harassment is size dependent and that small males impose a greater cost on females.
HUNGER SUPPRESSES THE ONSET AND THE FREEZING COMPONENT OF THE ANTIPREDATOR RESPONSE TO CONSPECIFIC SKIN EXTRACT IN PINTADO CATFISH
Authors: Giaquinto Percília , Volpato Gilson
Published: July 2002

Although the skin of an injured conspecific releases alarm substance in some fish species, it has been shown that such damage induces feeding behaviour rather than an alarm reaction under conditions of food scarcity. We studied chemical communication associated with this paradox in a Brazilian catfish, the pintado (Pseudoplatystoma coruscans). In preliminary tests pintado were confirmed to demonstrate an alarm reaction to conspecific skin extract. In the experiment we investigated whether skin extract of pintado induces either alarm response (panic or alert component) or feeding in hungry conspecifics. Fish feed-deprived for eight days and fed control fish were exposed to either conspecific skin extract or distilled water (as a control). Alarm reaction was restricted to the skin extract treatment and occurred in the fish irrespective of their hunger state, but the components of this response were significantly affected by hungry. Fed fish showed a complete alarm reaction (dashing and freezing behaviours). Feed-deprived fish exhibited only part of this biphasic response, the dashing component. We conclude that chemicals from injured fish elicit an alarm reaction, which is partially inhibited by feeding motivation.
INTRA- AND INTERINDIVIDUAL VARIATION IN THE CONTACT CALLS OF SPECTACLED PARROTLETS (FORPUS CONSPICILLATUS)
Authors: Wanker Ralf , Fischer Judith
Published: July 2002

The ability to discriminate individuals or different social classes of individuals is important for the evolution of social behaviour. In animal societies with ample social relationships selection will often favour the capacity to signal and perceive the identity and the membership to a certain social class. Spectacled parrotlets (Forpus conspicillatus, Psittacidae, Psittaciformes) live in a complex system of social relationships throughout their lives and are able to recognize their mates and their siblings on the basis of their contact calls. Here we attempt to identify the acoustic parameters that might be used in individual recognition and recognition of social categories. Therefore we analysed recordings of contact calls with reference to the variation of certain acoustical parameters. There was significant interindividual variation in the peak frequency, maximum frequency, duration, energy, bandwidth and minimum frequency in the contact calls of spectacled parrotlets. Discriminant function analysis has shown individual and social subunit specific calls but also that individuals of different social classes share some calls. From our results we hypothesize that spectacled parrotlets could use at least six acoustical cues in their contact calls that might encode information about the individual, the age class, the pair, the pairing status and the family.
BEHAVIORAL SYNCHRONY IN IBEX GROUPS: EFFECTS OF AGE, SEX AND HABITAT
Authors: Ruckstuhl Kathreen , Neuhaus Peter
Published: July 2002

Synchrony of activities is usually high in foraging groups, possibly to maintain group cohesion. Individuals with different levels of activity budgets, however, may have a hard time synchronizing their behavior to each other without incurring a cost. We predicted that the age and sex structure of a group would affect synchronization levels within a group because of differing individual activity budgets. Individuals in same-sex-age groups were hypothesized to show higher levels of activity synchrony than individuals in mixed sex-age groups. We investigated activity synchrony in adult male, adult female, subadult, and mixed sex-age groups of Alpine ibex - one of the most sexually dimorphic ruminant species. Activity budgets and movement rates were measured to calculate synchrony of activities between group members in June and July 1999. Adult males were more synchronized with group peers than either females or subadults of both sexes. However, while adult males were synchronized in 81% when in bachelor (adult male) groups, they were only synchronized in 65% of the time when in mixed sex-age groups. Adult females were synchronized 61% of their time when in mixed sex-age groups and 69% when in female groups. Individual subadult males displayed higher synchrony when in bachelor or female groups than when in mixed sex-age or subadult mixed-sex groups. Subadult groups and mixed sex-age groups showed the lowest degree of synchrony of all group types. In general, animals in groups of same body-sized individuals were more synchronized with their group members than animals in mixed body-size groups. Two and three year-old males did not adjust their time spent lying to the group but their time spent walking. They also tended to change their time spent grazing and standing according to group type. Among subadults, females spent more time foraging than males but less time lying and standing. There was no difference in time spent walking. Bachelor and subadult groups had the greatest movement rates while female groups were relatively sedentary within escape terrain. Individuals in escape terrain did only marginally synchronize their behavior to each other likely because groups did not move much and synchrony was presumably less important. We conclude that habitat type, group movement rates, and a group's sex-age composition may affect the extent to which an individual will synchronize its activities to the other group members.
THE 'WHINNY' OF SPIDER MONKEYS: INDIVIDUAL RECOGNITION BEFORE SITUATIONAL MEANING
Authors: Teixidor Patricia , Byrne Richard
Published: July 2002

When spider monkeys (Ateles geoffroyi) are dispersed and moving through wooded areas in the dry forest of Santa Rosa National Park in Costa Rica, they give loud calls, whinnies, that can be heard over long distances and appear to be answered with the same call from other monkeys. We examined the circumstances in which this vocalization was emitted and the responses elicited from other group members. A total of 105 h of continuous recordings on emission of whinnies, 113 h of individual focal samples and 291 spectrograms were analyzed from a study group with 15 identified subjects. Whinnies emitted in different circumstances caused different reactions. Whinnies provoked by the sight of an observer were never responded to in any particular way, while those given during resting or feeding sometimes caused an active response of approach or calling. Most strikingly, whinnies given during group movement provoked hearers to approach or call significantly more often than either those given while feeding or resting. Playback experiments found one response, 'scan', to differ according to the original circumstances of emission of the broadcast call: monkeys scanned more in the direction of the sound when hearing feeding rather than group movement whinnies.
DOES THE BEHAVIOUR OF THE NEONATE INFLUENCE THE EXPRESSION OF MATERNAL BEHAVIOUR IN SHEEP?
Authors: Dwyer  , Lawrence
Published: July 2002

Maternal care is provided in response to cues from the offspring. The role of offspring stimuli in determining the quality of maternal care was assessed using the sheep (Ovis aries) as a model. The effects of variation in lamb behaviour on the expression of maternal behaviour in a hill (Scottish Blackface) and a lowland (Suffolk) breed of ewe was examined by embryo transfer of single embryos between the two breeds to give the four possible combinations of ewe and lamb. Labour was significantly shorter for both breeds of ewe when delivering Blackface lambs than Suffolk lambs. Blackface lambs were also significantly more active than the Suffolk lambs in the first 3 days after birth; there was no effect of maternal breed. Despite these differences in both length of labour and lamb activity at birth with lamb breed, the behaviours of the ewe associated with the onset of maternal care (e.g. licking the lamb, allowing the lamb to the udder, absence of aggressive behaviours) were unaffected by the breed of lamb. Suffolk ewes, however, were more likely to show an aversive reaction to their lamb, spent less time licking the lamb and were more likely to move as the lamb approached the udder. There was a significant influence of ewe breed on lamb sucking behaviour. Suffolk ewes received significantly more sucking attempts than Blackface ewes from both breeds of lamb. A higher sucking rate on Suffolk ewes continued over the first 3 days after birth. Other behaviours, such as playing, were specific to lamb breed and not affected by ewe behaviour at this time. These data suggest that offspring behaviour had no effect on the onset of bonding behaviours of the ewe. Neonatal lamb activity was also largely independent of the behaviour of their dam. However, sucking behaviour of the lamb was modified by ewe behaviour and this may affect the strength of the bond between ewe and lamb.
Influence of Chicks and Food Quality on Food Calling in Broody Domestic Hens
Authors: Wauters A.M. , Richard-Yris M.A. , Pierre J.S. , Lunel  , Richard J.P.
Published: July 2002

The aim of this study was to understand the relationship between production of food calls by maternal hens and both food quality and social context. Nineteen broody hens were tested in twenty experiments combining four different food contexts with five social situations in which they could receive different levels of stimuli from their chicks. Results revealed that the food call rates of broody hens were positively correlated with food quality (or motivational state with regard to food). They were also influenced by the caller's social context: presence of chicks, behaviour of chicks and separation from chicks modified food call production. These results are therefore consistent with previous reports on food calling by cockerels.
Evaluation of the energy barrier for dehydration of homoionic (Li, Na, Cs, Mg, Ca, Ba, Alx(OH)yz+ and La)-montmorillonite by a differentiation method
Authors: Zabat M. , Van Damme H.
Published: July 2002

The thermal energy necessary for the removal of molecular water from Li+-, Na+-, Cs+-, Mg2+-, Ca2+-, Ba2+-, Alx(OH)yz+- and La3+-homoionic montmorillonite powders was determined by thermogravimetric analysis under atmospheric pressure. The weight loss curves and their derivatives exhibit one or several features related to the various populations of water molecules. The activation energy for water removal, which is the sum of the adsorption energy and the activation energy for diffusion, was calculated in each case using a simple first-order differentiation method. The results allow the physisorbed water and the water coordinated to the cations to be clearly separated. For the later population and with the exception of the Na-clay, a good correlation was found between the temperatures and activation energies for water removal and the polarizing power of the cations. Comparison with the results of mechanical tests performed on similar samples suggests that the creep of smectite clays is not controlled by mobility of the individual water molecules but by the mobility of the interlayer cations surrounded by their hydration shell.
Preparation of drug-montmorillonite UV-radiation protection compounds by gas-solid adsorption
Authors: del Hoyo C. , Vicente M. A. , Rives V.
Published: July 2002

Ethyl cinnamate/montmorillonite intercalation complexes were obtained by gaseous adsorption of the drug on the clay surface. They were characterized by powder X-ray diffraction, differential thermal and thermogravimetric analyses and by visible-UV and IR spectroscopies. It was found that after 1 day of adsorption, most of the drug enters the interlayer space of the clay by substitution of water molecules, and is removed only after heating at high temperature. In addition, a portion is physisorbed on the external surface of the crystallites, being removed easily below 100°C. The interlayer complex improves the protecting ability of the pure clay or the pure drug against ultraviolet radiation, specially in the so-called ‘C’ range (290–190 nm).
Clays and zeolite authigenesis in sediments from the flank of the Juan de Fuca Ridge
Authors: Buatier M. D. , Karpoff A. M. , Charpentier D.
Published: July 2002

This study focuses on the mineralogical and chemical analysis of sediments overlying basaltic basement through which seawater circulates (ODP Leg 168, flank of the Juan de Fuca Ridge). A SEM and TEM-EDX study of the authigenic clays and zeolites allowed the characterization of the hydrothermal phases and the determination of their mechanism of formation. Silicate authigenesis related to hydrothermal alteration of sediment was observed in the sediment layer just above basement at sites located >30 km from the ridge axis. This sediment alteration is particularly intense at Site 1031 where authigenic formation of Fe-Mg- rich smectites (montmorillonite and saponite) and zeolites occur, linked to the dissolution of biogenic calcite. Vertical advection of basement fluid through the sediment column is required to produce this alteration. This process is still active at Site 1031, based on systematic variations in porewater profiles and temperatures obtained from stable isotopic data on calcium carbonates, and the nature of authigenic minerals.
Primary zoning in pyrochlore group minerals from carbonatites
Authors: Hogarth D. D. , Williams C. T. , Jones P.
Published: July 2002

Pyrochlore group minerals have the general formula A16–xB16O48Z8–y·nH2O, with A mainly Na, Ca, Sr, REE, Th, U; B mainly Nb, Ta, Ti and Z being O, F, OH. In this study, pyrochlore specimens were examined from carbonatites at Argor, Carillon Dam, Chilwa Island, Fen, Lueshe, Oka, Mbeya, Meech Lake and Verity. Primary features include a background with little compositional variation, from core to rim, upon which are commonly superimposed narrow oscillatory zones, parallel to {111}. These zones are usually characterized by high Ta, in many cases coupled with U (here Argor, Meech Lake and Verity specimens), but Chilwa Island and Fen pyrochlores have little Ta and zonation is mainly by enrichment in Ce and Nb. Primary zonation may persist through high-temperature metamorphism (Meech Lake and Verity) and metamictization (Meech Lake). Oscillatory zones were generated by a disequilibrium system that cooled under tranquil conditions, signalling absence of magma turbulence and, in many cases, the end of crystal growth. Some fresh crystals (Oka, Fen) have no oscillatory zones, possibly the product of magma turbulence in space or time. Low-temperature effects may mimic those of primary high temperature and are especially characterized by replacement rims, pyrochlore-inpyrochlore veinlets and low A-ion totals (Carillon Dam, Lueshe, Myeba).
Hypogene violarite of exsolution origin from Mount Keith, Western Australia: field evidence for a stable pentlandite–violarite tie line
Authors: Grguric B. A.
Published: July 2002

In most documented occurrences, violarite (FeNi2S4) occurs as a product of the supergene alteration of primary pentlandite or millerite. Earlier experimental phase relations studies predicted the possible existence of a stable violarite–pentlandite tie line, though there has been little field evidence supporting this hypothesis, and the preferred topology in the Ni-Fe-S system involves a pyrite–millerite tie line. This paper documents the occurrence of violarite-pentlandite±pyrite assemblages which, on the basis of mineral chemistry and textural evidence, appear to be hypogene. Primary cobaltian violarite (with 2.1–13.2 wt.% Co) occurs as lamellae in pentlandite in the MKD5 nickel sulphide orebody at Mount Keith, central Western Australia. These lamellae are interpreted to be of exsolution origin. Cobalt is preferentially partitioned into violarite, resulting in high Ni:Co ratios in the associated pentlandite relative to pentlandite in violarite-free assemblages. Hypogene violarite-millerite±pentlandite assemblages were also noted. In all hypogene assemblages, violarite differs in both textural and mineral chemical characteristics from supergene violarite from the upper portions of the MKD5 orebody. The implications of the assemblages for the known low-temperature phase relations in the Ni-Fe-S-(Co) system are discussed.
REE -Sr-Ba minerals from the Khibina carbonatites, Kola Peninsula, Russia: their mineralogy, paragenesis and evolution
Authors: Zaitsev Anatoly N. , Wall Frances , Le Bas Michael J.
Published: July 2002

Carbonatites from the Khibina Alkaline Massif (360–380 Ma), Kola Peninsula, Russia, contain one of the most diverse assemblages of REE minerals described thus far from carbonatites and provide an excellent opportunity to track the evolution of late-stage carbonatites and their sub-solidus (secondary) changes. Twelve rare earth minerals have been analysed in detail and compared with literature analyses. These minerals include some common to carbonatites (e.g. Ca-rare-earth fluocarbonates and ancylite-(Ce)) plus burbankite and carbocernaite and some very rare Ba,REE fluocarbonates.

Overall the REE patterns change from light rare earth-enriched in the earliest carbonatites to heavy rare earth-enriched in the late carbonate-zeolite veins, an evolution which is thought to reflect the increasing ‘carbohydrothermal’ nature of the rock-forming fluid. Many of the carbonatites have been subject to sub-solidus metasomatic processes whose products include hexagonal prismatic pseudomorphs of ancylite-(Ce) or synchysite-(Ce), strontianite and baryte after burbankite and carbocernaite. The metasomatic processes cause little change in the rare earth patterns and it is thought that they took place soon after emplacement.
Seven new mutations in the nicotinamide adenine dinucleotide reduced–cytochrome b5 reductase gene leading to methemoglobinemia type I
Authors: Dekker Jan , Eppink Michel H. M. , van Zwieten Rob , de Rijk Thea , Remacha Angel F. , Law Lap Kay , Li Albert M. , Cheung Kam Lau , van Berkel Willem J. H. , Roos Dirk
Published: July 2002

Cytochrome b5 reductase (b5R) deficiency manifests itself in 2 distinct ways. In methemoglobinemia type I, the patients only suffer from cyanosis, whereas in type II, the patients suffer in addition from severe mental retardation and neurologic impairment. Biochemical data indicate that this may be due to a difference in mutations, causing enzyme instability in type I and complete enzyme deficiency or enzyme inactivation in type II. We have investigated 7 families with methemoglobulinemia type I and found 7 novel mutations in the b5R gene. Six of these mutations predicted amino acid substitutions at sites not involved in reduced nicotinamide adenine dinucleotide (NADH) or flavin adenine dinucleotide (FAD) binding, as deduced from a 3-dimensional model of human b5R. This model was constructed from comparison with the known 3-dimensional structure of pig b5R. The seventh mutation was a splice site mutation leading to skipping of exon 5 in messenger RNA, present in heterozygous form in a patient together with a missense mutation on the other allele. Eight other amino acid substitutions, previously described to cause methemoglobinemia type I, were also situated in nonessential regions of the enzyme. In contrast, 2 other substitutions, known to cause the type II form of the disease, were found to directly affect the consensus FAD-binding site or indirectly influence NADH binding. Thus, these data support the idea that enzyme inactivation is a cause of the type II disease, whereas enzyme instability may lead to the type I form.
B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function
Authors: Tamura Hideto , Dong Haidong , Zhu Gefeng , Sica Gabriel L. , Flies Dallas B. , Tamada Koji , Chen Lieping
Published: July 2002

B7-H1 is a recently described B7-like molecule that costimulates T-cell growth and cytokine secretion without binding to CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and inducible costimulator (ICOS). In this report, a mouse homologue of human B7-H1 is identified, and its immunologic functions are studied in vitro and in vivo. Mouse B7-H1 shares 69% amino acid homology to the human counterpart. Similar to human B7-H1, mouse B7-H1 can be induced to express on macrophages, T cells, and B cells and to enhance T-cell proliferation and secretion of interleukin-10 (IL-10), interferon-γ, and granulocyte-macrophage colony-stimulating factor but not IL-2 and IL-4. Furthermore, B7-H1 preferentially costimulates CD4+ T cells independently of CD28 and enhances mixed lymphocyte responses to allogeneic antigens. In contrast to B7-1, expression of B7-H1 on murine P815 tumor cells by transfection fails to increase allogeneic and syngeneic cytolytic T-cell responses in vitro and in vivo. Administration of B7-H1Ig fusion protein, however, enhances keyhole limpet hemocyanin– specific T-cell proliferation and 2,4,6-trinitrophenyl–specific immunoglobulin G2a antibody production. The study thus identifies a unique costimulatory pathway that preferentially affects T-helper cell functions.
BCR-ABL down-regulates the DNA repair protein DNA-PKcs
Authors: Deutsch Eric , Dugray Aymeric , AbdulKarim Bassam , Marangoni Elisabetta , Maggiorella Laurence , Vaganay Sabine , M'Kacher Radia , Rasy Setha Douc , Eschwege François , Vainchenker William , Turhan Ali G. , Bourhis Jean
Published: July 2002

This study demonstrates in both stable and inducible BCR-ABL–expressing hematopoietic cells a down-regulation of the major mammalian DNA repair protein DNA-PKcs by BCR-ABL. Similar results were found in BCR-ABL CD34+ cells from patients with chronic myelogenous leukemia (CML). DNA-PKcs down-regulation is a proteasome-dependent degradation that requires tyrosine kinase activity and is associated with a marked DNA repair deficiency along with increased sensitivity to ionizing radiation. The conjunction of a major DNA repair deficiency and a resistance to apoptosis, both induced by BCR-ABL, provides a new mechanism to explain how secondary genetic alterations can accumulate in CML, eventually leading to blast crisis. The down-regulation of DNA-PKcs was reversible in CD34+ CML cells suggesting that this approach might offer a novel and powerful therapeutic strategy in this disease, especially to delay the blast crisis.
βMinor-globin messenger RNA accumulation in reticulocytes governs improved erythropoiesis in β thalassemic mice after erythropoietin complementary DNA electrotransfer in muscles
Authors: Samakoglu Selda , Fattori Elena , Lamartina Stefania , Toniatti Carlo , Stockholm Daniel , Heard Jean Michel , Bohl Delphine
Published: July 2002

Mechanisms governing the induction of effective erythropoiesis in response to erythropoietin (Epo) oversecretion have been investigated in β thalassemic C57Bl/6Hbbth mice. Naked DNA encoding an expression vector for mouse Epo was introduced into skeletal muscles by electrotransfer. A transient increase of serum Epo concentrations with a proportional augmentation of hematocrit values was observed. Various parameters relevant to β thalassemia were surveyed in blood samples taken before treatment, at the peak of Epo secretion, and when the phenotype reverted to anemia. We measured globin messenger RNA (mRNA) levels in reticulocytes by real-time quantitative polymerase chain reaction, globin chain synthesis levels, and several indicators of erythrocyte membrane quality, including bound α chains, bound immunoglobulins, main protein components, and iron compartmentalization. Data indicated that high serum Epo levels primarily affect βminor-globin mRNA accumulation in reticulocytes. Other changes subsequent to intense Epo stimulation, like increased βminor/α-globin chain synthesis ratio, reduced levels of α chains and immunoglobulins bound to membranes, improved spectrin/band 3 ratio, increased red blood cell survival, and improved erythropoiesis appeared as consequences of increased βminor-globin mRNA levels. This conclusion is consistent with models postulating that intense Epo stimulation induces the expansion and differentiation of erythroid progenitors committed to fetal erythropoiesis. Although phenotypic correction was partial in mice, and comparable achievements will probably be more difficult to obtain in humans, naked DNA electrotransfer may provide a safe and low-cost method for reassessing the potentials of Epo as an inducer of fetal erythropoiesis reactivation in patients with β thalassemia.
Systemic circulation of poly(l-lysine)/DNA vectors is influenced by polycation molecular weight and type of DNA: differential circulation in mice and rats and the implications for human gene therapy
Authors: Ward Christopher M. , Read Martin L. , Seymour Leonard W.
Published: July 2002

Effective gene therapy for diseases of the circulation requires vectors capable of systemic delivery. The molecular weight of poly(l-lysine) (pLL) has a significant effect on the circulation of pLL/DNA complexes in mice, with pLL211/DNA complexes displaying up to 20 times greater levels in the blood after 30 minutes compared with pLL20/DNA. It is shown that pLL20/DNA complexes fix mouse complement C3 in vitro, independent of immunoglobulin binding; are less soluble in the blood in vivo; bind erythrocytes; are rapidly removed by the liver, where they associate predominantly with Kupffer cells; and result in a rapid increase in hepatic leukocytes expressing high levels of complement receptor 3 (CR3). The circulation properties of these complexes are also dependent on the type of DNA used, with circular plasmid DNA complexes exhibiting increased circulation compared with linear DNA. PLL211/DNA complexes bind erythrocytes and associate with Kupffer cells but, in contrast, do not fix mouse complement in vitro and are unaffected by the type of DNA used. In rats, both types of complexes produce hematuria and are rapidly removed from the circulation. Correlation of in vivo and in vitro results suggests that the solubility of complexes in physiological saline and species-matched complement fixation and erythrocyte lysis may correlate with systemic circulation. Analysis using human blood in vitro shows no hemolysis, but both types of complexes fix complement and bind IgG, suggesting that pLL/DNA complexes may be rapidly cleared from the human circulation.
Durable engraftment of major histocompatibility complex–incompatible cells after nonmyeloablative conditioning with fludarabine, low-dose total body irradiation, and posttransplantation cyclophosphamide
Authors: Luznik Leo , Jalla Sanju , Engstrom Laura W. , Iannone Robert , Fuchs Ephraim J.
Published: July 2002

Treatment of leukemia by myeloablative conditioning and transplantation of major histocompatibility complex (MHC)–mismatched stem cells is generally avoided because of the high risk of graft rejection or lethal graft-versus-host disease (GVHD). This study shows that MHC-incompatible cells can engraft stably after nonmyeloablative conditioning with immunosuppressive chemotherapy and low-dose total body irradiation (TBI). Long-term mixed hematopoietic chimerism, clonal deletion of donor-reactive T cells, and bidirectional cytotoxic T-cell tolerance were achieved by transplanting MHC-mismatched marrow cells into recipients conditioned with pretransplantation fludarabine or cyclophosphamide (Cy), 50 to 200 cGy TBI on day −1, and Cy 200 mg/kg intraperitoneally on day 3. In this model, long-term donor chimerism was proportional to the dose of TBI or donor marrow cells. Pretransplantation fludarabine and posttransplantation Cy were both required for alloengraftment, but the drugs had additional effects. For example, fludarabine sensitized host stem cells to the toxicity of TBI, because animals conditioned with both agents had higher chimerism than animals conditioned with TBI alone (P < .05). Also, posttransplantation Cy attenuated lethal and nonlethal GVH reactions, because F1 recipients of host-reactive, parental spleen cells survived longer (P < .05) and had lower donor cell chimerism (P < .01) if they received posttransplantation Cy than if they did not. Finally, delayed infusions of donor lymphocytes into mixed chimeras prolonged survival after leukemia challenge (P < .0001) without causing lethal GVHD. These results indicate that stable engraftment of MHC-incompatible cells can be induced after fludarabine-based, nonmyeloablative conditioning and that it serves as a platform for adoptive immunotherapy with donor lymphocyte infusions.
Signaling pathways activated by daunorubicin
Authors: Laurent Guy , Jaffrézou Jean-Pierre
Published: July 2002

The anthracycline daunorubicin is widely used in the treatment of acute nonlymphocytic leukemia. The drug has, of course, been the object of intense basic research, as well as preclinical and clinical study. As reviewed in this article, evidence stemming from this research clearly demonstrates that cell response to daunorubicin is highly regulated by multiple signaling events, including a sphingomyelinase-initiated sphingomyelin-ceramide pathway, mitogen-activated kinase and stress-activated protein/c-Jun N-terminal kinase activation, transcription factors such as nuclear factor κB, as well as the Fas/Fas-ligand system. These pathways are themselves influenced by a number of lipid products (diacylglycerol, sphingosine-1 phosphate, and glucosyl ceramide), reactive oxygen species, oncogenes (such as the tumor suppressor gene p53), protein kinases (protein kinase C and phosphoinositide-3 kinase), and external stimuli (hematopoietic growth factors and the extracellular matrix). In light of the complexity and diversity of these observations, a comprehensive review has been attempted toward the understanding of their individual implication (and regulation) in daunorubicin-induced signaling.
Vascular endothelial growth factor (VEGF) is an autocrine growth factor for VEGF receptor–positive human tumors
Authors: Masood Rizwan , Cai Jie , Zheng Tong , Smith D. Lynne , Hinton David R. , Gill Parkash S.
Published: July 2002

Angiogenesis is required for the progression of tumors from a benign to a malignant phenotype and for metastasis. Malignant tumor cells secrete factors such as vascular endothelial growth factor (VEGF), which bind to their cognate receptors on endothelial cells to induce angiogenesis. Here it is shown that several tumor types express VEGF receptors (VEGFRs) and that inhibition of VEGF (VEGF antisense oligonucleotide AS-3) or VEGFRs (neutralizing antibodies) inhibited the proliferation of these cell lines in vitro. Furthermore, this effect was abrogated by exogenous VEGF. Thus, VEGF is an autocrine growth factor for tumor cell lines that express VEGFRs. A modified form of VEGF AS-3 (AS-3m), in which flanking 4 nucleotides were substituted with 2-O-methylnucleosides (mixed backbone oligonucleotides), retained specificity and was active when given orally or systemically in vitro and in murine tumor models. In VEGFR-2–expressing tumors, VEGF inhibition may have dual functions: direct inhibition of tumor cell growth and inhibition of angiogenesis.
A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts
Authors: Press Oliver W. , Corcoran Melissa , Subbiah Krishnan , Hamlin Don K. , Wilbur D. Scott , Johnson Timothy , Theodore Louis , Yau Eric , Mallett Robert , Meyer Damon L. , Axworthy Don
Published: July 2002

Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to–normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin “pretargeting” approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine–containing “clearing agent” and finally 3 hours later by 111In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional 111In-1F5. Tumor-to–normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional 111In-1F5. Therapy experiments demonstrated that 400 μCi (14.8 MBq) or more of conventional 90Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 μCi (29.6 MBq)90Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing.
ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances
Authors: Camacho Emma , Hernández Luis , Hernández Silvia , Tort Frederic , Bellosillo Beatriz , Beà Silvia , Bosch Francesc , Montserrat Emili , Cardesa Antonio , Fernández Pedro L. , Campo Elias
Published: July 2002

The ataxia–telangiectasia mutated (ATM) gene codifies for a protein critically involved in the cellular response to DNA damage. ATM alterations have been observed in some sporadic lymphoproliferative disorders. The recurrent 11q22-23 deletions found in mantle cell lymphoma (MCL) suggest that ATM could be inactivated in these lymphomas. In this study, ATM gene alterations and protein expression were examined in 20 and 17 MCL tumor specimens, respectively. Previously, these patients had been examined forp53 and p14ARF gene status and analyzed by comparative genomic hybridization. Nine patients had 11q22-23 losses. Eight ATM gene mutations were detected in 7 patients. These alterations were 3 missense mutations in the phosphatidylinositol-3 kinase (PI-3K) domain and 5 truncating mutations, including 3 frameshifts, a nonsense mutation, and a substitution of the initial methionine. All truncating mutations were associated with lack of protein expression. Somatic origin was demonstrated in 3 mutations, whereas one mutation was carried heterozygously in the patient germ line. Chromosomal imbalances were significantly higher in typical MCL with ATM inactivation (7.8 ± 1.3) than in tumors with the wild-type gene (3 ± 1.1) (P = .001). Moreover, tumors with bi-allelic ATM alteration were associated with 3q gains (P = .015) and frequent extranodal involvement (P = .049).ATM gene alterations were not related to the histologic variant of the tumors, p53/p14ARF gene status, survival, or other clinicopathologic features of the patients. These findings indicate that ATM gene mutations in MCL are mainly truncating or missense mutations involving the PI-3K domain, and that may play a role in the pathogenesis of a subset of these tumors with increased numbers of chromosomal imbalances.
Effects of Long-Term Intravenous Ibandronate Therapy on Skeletal-Related Events, Survival, and Bone Resorption Markers in Patients With Advanced Multiple Myeloma
Authors: Menssen Hans D. , Sakalová Adriana , Fontana Aurélie , Herrmann Zuzana , Boewer Christian , Facon Thierry , Lichinitser Michail R. , Singer C.R.J. , Euller-Ziegler Liana , Wetterwald Marc , Fiere Denis , Hrubisko Mikulás , Thiel Eckhard , Delmas Pierre D.
Published: July 2002

PURPOSE: Bisphosphonates have been found to reduce the incidence of skeletal-related events (SREs) in patients with multiple myeloma. This is the first double-blind, randomized, placebo-controlled study to assess the efficacy of ibandronate, a third-generation amino-bisphosphonate, in preventing SREs in advanced-stage multiple myeloma patients.

PATIENTS AND METHODS: Patients with multiple myeloma stage II or III were randomly assigned to receive either ibandronate 2 mg or placebo as a monthly intravenous (IV) bolus injection for 12 to 24 months in addition to conventional chemotherapy. SREs such as peripheral pathologic or vertebral fractures, hypercalcemia, severe bone pain, and bone radiotherapy or surgery were analyzed. Bone-turnover markers were also studied. Finally, post hoc analyses of bone morbidity and survival were performed.

RESULTS: Ninety-nine patients per treatment group were assessable for efficacy analysis. The occurrence of SRE per patient year and the time to first SRE were not significantly different between the two treatment groups. In overall evaluation, no differences were found between the treatment groups regarding bone pain, analgesic drug use, quality of life, and median survival (33.1 v 28.2 months, respectively). Explorative post hoc analyses revealed that ibandronate patients with strongly suppressed bone-turnover markers (≥ 30% and ≥ 50% mean reduction of serum osteocalcin and urinary C-terminal telopeptides) developed significantly less bone morbidity. Ibandronate was tolerated well during as many as 25 therapy cycles.

CONCLUSION: Monthly injections of ibandronate 2 mg IV neither reduced bone morbidity nor prolonged survival in the overall population of stage II/III multiple myeloma patients.