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For rodents, olfaction is essential for locating food, recognizing mates and competitors, avoiding predators, and navigating their environment. It is thought that rodents may have expanded olfactory receptor repertoires in order to specialize in olfactory behavior. Despite being the largest clade of mammals and depending on olfaction relatively little work has documented olfactory repertoires outside of conventional laboratory species. Here we report the olfactory receptor repertoire of the African giant pouched rat (Cricetomys ansorgei), a Muroid rodent distantly related to mice and rats. The African giant pouched rat is notable for its large cortex and olfactory bulbs relative to its body size compared to other sympatric rodents, which suggests anatomical elaboration of olfactory capabilities. We hypothesized that in addition to anatomical elaboration for olfaction, these pouched rats might also have an expanded olfactory receptor repertoire to enable their olfactory behavior. We examined the composition of the olfactory receptor repertoire to better understand how their sensory capabilities have evolved. We identified 1145 intact olfactory genes, and 260 additional pseudogenes within 301 subfamilies from the African giant pouched rat genome. This repertoire is similar to mice and rats in terms of size, pseudogene percentage and number of subfamilies. Analyses of olfactory receptor gene trees revealed that the pouched rat has 6 expansions in different subfamilies compared to mice, rats and squirrels. We identified 81 orthologous genes conserved among 4 rodent species and an additional 147 conserved genes within the Muroid rodents. The orthologous genes shared within Muroidea suggests that there may be a conserved Muroid-specific olfactory receptor repertoire. We also note that the description of this repertoire can serve as a complement to other studies of rodent olfaction, as the pouched rat is an outgroup within Muroidea. Thus, our data suggest that African giant pouched rats are capable of both natural and trained olfactory behaviors with a typical Muriod olfactory receptor repertoire., Competing Interests: The authors have declared they have no competing interests.

In many species, individuals gather information about their environment both through direct experience and through information obtained from others. Social learning, or the acquisition of information from others, can occur both within and between species and may facilitate the rapid spread of antipredator behaviour. Within birds, acoustic signals are frequently used to alert others to the presence of predators, and individuals can quickly learn to associate novel acoustic cues with predation risk. However, few studies have addressed whether such learning occurs only though direct experience or whether it has a social component, nor whether such learning can occur between species. We investigate these questions in two sympatric species of Parids: blue tits ( Cyanistes caeruleus ) and great tits ( Parus major ). Using playbacks of unfamiliar bird vocalizations paired with a predator model in a controlled aviary setting, we find that blue tits can learn to associate a novel sound with predation risk via direct experience, and that antipredator response to the sound can be socially transmitted to heterospecific observers, despite lack of first-hand experience. Our results suggest that social learning of acoustic cues can occur between species. Such interspecific social information transmission may help to mediate the formation of mixed-species aggregations.

Cognitive abilities can vary dramatically among species. The relative importance of social and ecological challenges in shaping cognitive evolution has been the subject of a long-running and recently renewed debate, but little work has sought to understand the selective dynamics underlying the evolution of cognitive abilities. Here, we investigate recent selection related to cognition in the paper wasp Polistes fuscatus -a wasp that has uniquely evolved visual individual recognition abilities. We generate high quality de novo genome assemblies and population genomic resources for multiple species of paper wasps and use a population genomic framework to interrogate the probable mode and tempo of cognitive evolution. Recent, strong, hard selective sweeps in P. fuscatus contain loci annotated with functions in long-term memory formation, mushroom body development, and visual processing, traits which have recently evolved in association with individual recognition. The homologous pathways are not under selection in closely related wasps that lack individual recognition. Indeed, the prevalence of candidate cognition loci within the strongest selective sweeps suggests that the evolution of cognitive abilities has been among the strongest selection pressures in P. fuscatus ' recent evolutionary history. Detailed analyses of selective sweeps containing candidate cognition loci reveal multiple cases of hard selective sweeps within the last few thousand years on de novo mutations, mainly in noncoding regions. These data provide unprecedented insight into some of the processes by which cognition evolves., Competing Interests: The authors declare no competing interest.

Hormones are often major regulators of complex behaviors, such as mating and reproduction. In insects, juvenile hormone (JH) is integral to many components of reproductive physiology and behavior, but its role in female sexual receptivity is not well understood. To investigate the influence of JH on receptivity, we utilized the social wasp Polistes fuscatus. In Polistes, mating behavior is temporally separated from other components of reproduction, which allows for examination of the physiology and behavior of mating, disentangled from fertilization and egg-laying. We reared virgin gynes (reproductive females) in the lab and divided them into four groups, in which gynes received multiple topical treatments of either 20 μg, 10 μg, 5 μg, or 0 μg of the JH analog methoprene. Gynes were then placed in petri dishes with 2 unrelated males and we recorded attempted and successful mating. Additionally, we measured gyne ovarian development and survival in each group. We found that methoprene increased both sexual receptivity and ovarian development, but was associated with a decrease in long-term survival. Receptivity increased linearly as methoprene treatment increased, but the effect of methoprene on ovarian development was independent of dose. These results demonstrate the importance of JH in sexual receptivity and mating behavior. We argue that the relatively understudied Polistes gyne has potential as a model for mating and reproduction, and for the internal and external regulation of this complex behavior., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Scent marks are important mediators of territorial behaviour and sexual selection, especially among mammals. The evolution of compounds used in scent marks has the potential to inform our understanding of signal evolution in relation to social and sexual selection. A major challenge in studies of chemical communication is that the link between semiochemical compounds and genetic changes is often unclear. The major urinary proteins (MUPs) of house mice provide information on sex, status and individual identity. Importantly, MUPs are a direct protein product of genes, providing a clear link between genotype and phenotype. Here, we examine the evolution of urinary protein signals among house mice and relatives by examining the sequences and patterns of mRNA expression of Mup genes related to urinary scent marks. MUP patterns have evolved among mouse species both by gene duplication and variation in expression. Notably, protein scent signals that are male specific in well-studied inbred laboratory strains vary in sex-specificity among species. Our data reveal that individual identity signals in MUPs evolved prior to 0.35 million years ago and have rapidly diversified through recombining a modest number of amino acid variants. Amino acid variants are much more common on the exterior of the protein where they could interact with vomeronasal receptors, suggesting that chemosensory perception may have played a major role in shaping MUP diversity. These data highlight diverse processes and pressures shaping scent signals, and suggest new avenues for using wild mice to probe the evolution of signals and signal processing., (© 2019 John Wiley & Sons Ltd.)

Identifying a common set of genes that mediate host-microbial interactions across populations and species of mammals has broad relevance for human health and animal biology. However, the genetic basis of the gut microbial composition in natural populations remains largely unknown outside of humans. Here, we used wild house mouse populations as a model system to ask three major questions: (a) Does host genetic relatedness explain interindividual variation in gut microbial composition? (b) Do population differences in the microbiota persist in a common environment? (c) What are the host genes associated with microbial richness and the relative abundance of bacterial genera? We found that host genetic distance is a strong predictor of the gut microbial composition as characterized by 16S amplicon sequencing. Using a common garden approach, we then identified differences in microbial composition between populations that persisted in a shared laboratory environment. Finally, we used exome sequencing to associate host genetic variants with microbial diversity and relative abundance of microbial taxa in wild mice. We identified 20 genes that were associated with microbial diversity or abundance including a macrophage-derived cytokine (IL12a) that contained three nonsynonymous mutations. Surprisingly, we found a significant overrepresentation of candidate genes that were previously associated with microbial measurements in humans. The homologous genes that overlapped between wild mice and humans included genes that have been associated with traits related to host immunity and obesity in humans. Gene-bacteria associations identified in both humans and wild mice suggest some commonality to the host genetic determinants of gut microbial composition across mammals., (© 2019 John Wiley & Sons Ltd.)

Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) arise from complex interactions between genetic and environmental factors. Common genetic variants associated with multiple psychiatric disorders suggest that shared genetic architecture could contribute to divergent clinical syndromes. To evaluate shared transcriptional alterations across connected brain regions, Affymetrix microarrays were used to profile postmortem dorsolateral prefrontal cortex (DLPFC), hippocampus, and associative striatum from 19 well-matched tetrads of subjects with SCZ, BD, MDD, or unaffected controls. SCZ subjects showed a substantial burden of differentially expressed genes across all examined brain regions with the greatest effects in hippocampus, whereas BD and MDD showed less robust alterations. Pathway analysis of transcriptional profiles compared across diagnoses demonstrated commonly enriched pathways between all three disorders in hippocampus, significant overlap between SCZ and BD in DLPFC, but no significant overlap of enriched pathways between disorders in striatum. SCZ samples showed increased expression of transcripts associated with inflammation across all brain regions examined, which was not evident in BD or MDD, or in rat brain following chronic dosing with antipsychotic drugs. Several markers of inflammation were confirmed by RT-PCR in hippocampus, including S100A8/9, IL-6, MAFF, APOLD1, IFITM3, and BAG3. A cytokine ELISA panel showed significant increases in IL-2 and IL-12p70 protein content in hippocampal tissue collected from same SCZ subjects when compared to matched control subjects. These data suggest an overlapping subset of dysregulated pathways across psychiatric disorders; however, a widespread increase in inflammation appears to be a specific feature of the SCZ brain and is not likely to be attributable to chronic antipsychotic drug treatment.

Paper wasps (genus Polistes ) are one of the most species-rich genera of social insect. Prior studies have found that male coloration, male colour pattern, territory choice and female caste are potential drivers of intraspecific mate choice in paper wasps. However, there has been no formal assessment of interspecific mate choice in this group; therefore, the mechanism driving diversification in paper wasps remains an open question. In this study, we measured interspecific and intraspecific mating behaviour between two closely related species of paper wasps, Polistes fuscatus and Polistes metricus . These two species have ample opportunity to interbreed because P. fuscatus and P. metricus forage, nest and mate in the same habitats. We tested the strength of reproductive isolation between these species using no-choice and choice mating trials. Our results show strong, symmetric, prezygotic isolation between P. fuscatus and P. metricus . Males discriminated between conspecifics and heterospecifics but attempted to mate with females of the other species in ~10% of heterospecific mating trials. Female wasps were more discriminating than males and probably evaluated species identity and male quality through visual or olfactory cues. We additionally report sexual dimorphism in P. metricus body size.

Cooperative breeding decreases the direct reproductive output of subordinate individuals, but cooperation can be evolutionarily favored when there are challenges or constraints to breeding independently. Environmental factors, including temperature, precipitation, latitude, high seasonality, and environmental harshness have been hypothesized to correlate with the presence of cooperative breeding. However, to test the relationship between cooperation and ecological constraints requires comparative data on the frequency and variation of cooperative breeding across differing environments, ideally replicated across multiple species. Paper wasps are primitively social species, forming colonies composed of reproductively active dominants and foraging subordinates. Adult female wasps, referred to as foundresses, initiate new colonies. Nests can be formed by a single solitary foundress (noncooperative) or by multiple foundress associations (cooperative). Cooperative behavior varies within and among species, making paper wasps species well suited to disentangling ecological correlates of variation in cooperative behavior. This data set reports the frequency and extent of cooperative nest founding for 87 paper wasp species. Data were assembled from more than 170 published sources, previously unpublished field observations, and photographs contributed by citizen scientists to online natural history repositories. The data set includes 25,872 nest observations and reports the cooperative behavioral decisions for 45,297 foundresses. Species names were updated to reflect modern taxonomic revisions. The type of substrate on which the nest was built is also included, when available. A smaller population-level version of this data set found that the presence or absence of cooperative nesting in paper wasps was correlated with temperature stability and environmental harshness, but these variables did not predict the extent of cooperation within species. This expanded data set contains details about individual nests and further increases the power to address the relationship between the environment and the presence and extent of cooperative breeding. Beyond the ecological drivers of cooperation, these high-resolution data will be useful for future studies examining the evolutionary consequences of variation in social behavior. This data set may be used for research or educational purposes provided that this data paper is cited., (© 2018 The Authors. Ecology © 2018 The Ecological Society of America.)

House mice (Mus musculus) arrived in the Americas only recently in association with European colonization (~400-600 generations), but have spread rapidly and show evidence of local adaptation. Here, we take advantage of this genetic model system to investigate the genomic basis of environmental adaptation in house mice. First, we documented clinal patterns of phenotypic variation in 50 wild-caught mice from a latitudinal transect in Eastern North America. Next, we found that progeny of mice from different latitudes, raised in a common laboratory environment, displayed differences in a number of complex traits related to fitness. Consistent with Bergmann's rule, mice from higher latitudes were larger and fatter than mice from lower latitudes. They also built bigger nests and differed in aspects of blood chemistry related to metabolism. Then, combining exomic, genomic, and transcriptomic data, we identified specific candidate genes underlying adaptive variation. In particular, we defined a short list of genes with cis-eQTL that were identified as candidates in exomic and genomic analyses, all of which have known ties to phenotypes that vary among the studied populations. Thus, wild mice and the newly developed strains represent a valuable resource for future study of the links between genetic variation, phenotypic variation, and climate., Competing Interests: The authors have declared that no competing interests exist.

Research on individual recognition often focuses on species-typical recognition abilities rather than assessing intraspecific variation in recognition. As individual recognition is cognitively costly, the capacity for recognition may vary within species. We test how individual face recognition differs between nest-founding queens (foundresses) and workers in Polistes fuscatus paper wasps. Individual recognition mediates dominance interactions among foundresses. Three previously published experiments have shown that foundresses (1) benefit by advertising their identity with distinctive facial patterns that facilitate recognition, (2) have robust memories of individuals, and (3) rapidly learn to distinguish between face images. Like foundresses, workers have variable facial patterns and are capable of individual recognition. However, worker dominance interactions are muted. Therefore, individual recognition may be less important for workers than for foundresses. We find that (1) workers with unique faces receive amounts of aggression similar to those of workers with common faces, indicating that wasps do not benefit from advertising their individual identity with a unique appearance; (2) workers lack robust memories for individuals, as they cannot remember unique conspecifics after a 6-day separation; and (3) workers learn to distinguish between facial images more slowly than foundresses during training. The recognition differences between foundresses and workers are notable because Polistes lack discrete castes; foundresses and workers are morphologically similar, and workers can take over as queens. Overall, social benefits and receiver capacity for individual recognition are surprisingly plastic.

Behaviors are among the most complex phenotypes, making the genetic dissection of behavioral differences extremely challenging. A careful dissection of ontogenetic differences in burrowing behavior between mouse species highlights the importance of integrative approaches to the study of behavioral evolution., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Status epilepticus (SE) is a life-threatening and commonly drug-refractory condition. Novel therapies are needed to rapidly terminate seizures to prevent mortality and morbidity. Monoacylglycerol lipase (MAGL) is the key enzyme responsible for the hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) and a major contributor to the brain pool of arachidonic acid (AA). Inhibiting of monoacylglycerol lipase modulates synaptic activity and neuroinflammation, 2 mediators of excessive neuronal activation underlying seizures. We studied the effect of a potent and selective irreversible MAGL inhibitor, CPD-4645, on SE that was refractory to diazepam, its neuropathologic sequelae, and the mechanism underlying the drug's effects., Methods: Diazepam-resistant SE was induced in adult mice fed with standard or ketogenic diet or in cannabinoid receptor type 1 (CB1) receptor knock-out mice. CPD-4645 (10 mg/kg, subcutaneously) or vehicle was dosed 1 and 7 h after status epilepticus onset in video-electroencephalography (EEG) recorded mice. At the end of SE, mice were examined in the novel object recognition test followed by neuronal cellloss analysis., Results: CPD-4645 maximal plasma and brain concentrations were attained 0.5 h postinjection (half-life = 3.7 h) and elevated brain 2-AG levels by approximately 4-fold. CPD-4645 administered to standard diet-fed mice progressively reduced spike frequency during 3 h postinjection, thereby shortening SE duration by 47%. The drug immediately abrogated SE in ketogenic diet-fed mice. CPD-4645 rescued neuronal cell loss and cognitive deficit and reduced interleukin (IL)-1β and cyclooxygenase 2 (COX-2) brain expression resulting from SE. The CPD-4645 effect on SE was similar in mice lacking CB1 receptors., Significance: MAGL represents a novel therapeutic target for treating status epilepticus and improving its sequelae. CPD-4645 therapeutic effects appear to be predominantly mediated by modulation of neuroinflammation., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Recognition systems play a central role in mediating cooperative behavior among individuals in a population. Despite the importance of discriminating among potential recipients of cooperation, the evolutionary forces that maintain diversity in traits used for kin recognition are poorly understood. Greenbeard-based models of kin recognition in which alleles for cooperative behavior also control recognition of those alleles in potential cooperators suggest that discrimination based on a greenbeard locus leads to positive frequency dependence, eroding diversity at the very genes responsible for recognition. As a result, the phenotypic diversity used for kin recognition has been widely assumed to be cues rather than signals of genetic identity. Diversity in identity cues is maintained by selection on other traits for reasons unrelated to recognition. A major problem with greenbeard-based models is that greenbeard recognition systems are uncommon among animals, which tend to learn kin phenotypes. We develop a simple model showing that learning a kin recognition template is sufficient to increase and maintain diversity in genetic traits used for kin recognition. Thus, our results suggest that phenotypes used for recognition may be true signals of genetic identity. As such, phenotypes are expected to evolve to facilitate recognition. Increased diversity in genetically-based recognition signals is also predicted to initiate a positive feedback loop between recognition efficiency and levels of cooperation. Finally, we discuss how the genetic architecture of recognition traits may influence kin discrimination abilities., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.)

Understanding the developmental and evolutionary processes that generate and maintain variation in natural populations remains a major challenge for modern biology. Populations of Polistes fuscatus paper wasps have highly variable colour patterns that mediate individual recognition. Previous experimental and comparative studies have provided evidence that colour pattern diversity is the result of selection for individuals to advertise their identity. Distinctive identity-signalling phenotypes facilitate recognition, which reduces aggression between familiar individuals in P. fuscatus wasps. Selection for identity signals may increase phenotypic diversity via two distinct modes of selection that have different effects on genetic diversity. Directional selection for increased plasticity would greatly increase phenotypic diversity but decrease genetic diversity at associated loci. Alternatively, heritable identity signals under balancing selection would maintain genetic diversity at associated loci. Here, we assess whether there is heritable variation underlying colour pattern diversity used for facial recognition in a wild population of P. fuscatus wasps. We find that colour patterns are heritable and not Mendelian, suggesting that multiple loci are involved. Additionally, patterns of genetic correlations among traits indicated that many of the loci underlying colour pattern variation are unlinked and independently segregating. Our results support a model where the benefits of being recognizable maintain genetic variation at multiple unlinked loci that code for phenotypic diversity used for recognition.

Recognition of individuals by scent is widespread across animal taxa. Though animals can often discriminate chemical blends based on many compounds, recent work shows that specific protein pheromones are necessary and sufficient for individual recognition via scent marks in mice. The genetic nature of individuality in scent marks (e.g. coding versus regulatory variation) and the evolutionary processes that maintain diversity are poorly understood. The individual signatures in scent marks of house mice are the protein products of a group of highly similar paralogs in the major urinary protein (Mup) gene family. Using the offspring of wild-caught mice, we examine individuality in the major urinary protein (MUP) scent marks at the DNA, RNA and protein levels. We show that individuality arises through a combination of variation at amino acid coding sites and differential transcription of central Mup genes across individuals, and we identify eSNPs in promoters. There is no evidence of post-transcriptional processes influencing phenotypic diversity as transcripts accurately predict the relative abundance of proteins in urine samples. The match between transcripts and urine samples taken six months earlier also emphasizes that the proportional relationships across central MUP isoforms in urine is stable. Balancing selection maintains coding variants at moderate frequencies, though pheromone diversity appears limited by interactions with vomeronasal receptors. We find that differential transcription of the central Mup paralogs within and between individuals significantly increases the individuality of pheromone blends. Balancing selection on gene regulation allows for increased individuality via combinatorial diversity in a limited number of pheromones.

Ecological constraints on independent breeding are recognised as major drivers of cooperative breeding across diverse lineages. How the prevalence and degree of cooperative breeding relates to ecological variation remains unresolved. Using a large data set of cooperative nesting in Polistes wasps we demonstrate that different aspects of cooperative breeding are likely to be driven by different aspects of climate. Whether or not a species forms cooperative groups is associated with greater short-term temperature fluctuations. In contrast, the number of cooperative foundresses increases in more benign environments with warmer, wetter conditions. The same data set reveals that intraspecific responses to climate variation do not mirror genus-wide trends and instead are highly heterogeneous among species. Collectively these data suggest that the ecological drivers that lead to the origin or loss of cooperation are different from those that influence the extent of its expression within populations., (© 2015 John Wiley & Sons Ltd/CNRS.)

Purpose: Oculomotor nerve palsy (ONP) is often the presenting symptom in patients with posterior communicating artery (PCOMM) aneurysms with variable recovery of oculomotor nerve function following treatment. In this study we report the ophthalmologic outcome of 20 patients treated by endovascular coiling for PCOMM aneurysm-induced ONP., Methods: We performed 230 PCOMM aneurysm endovascular coilings between the years 2006 and 2011, of which 20 cases presented with ONP. We recorded the degree of nerve recovery - complete, partial or none - while also documenting other predictive factors, such as degree of pre-intervention nerve deficit, presence of subarachnoid haemorrhage (SAH), size and location of the PCOMM aneurysm and length of follow-up., Results: Of the 20 patients, 9 (45%) presented with complete ONP and 11 (55%) with partial ONP. After an average follow-up period of 16 months, all patients achieved oculomotor nerve recovery; 9 (45%) patients had complete recovery and 11 (55%) patients had partial recovery. Of the 9 patients who presented with complete ONP, 5 (56%) patients made a complete recovery and 4 (44%) made a partial recovery. Of the 11 patients who initially presented with partial ONP, 4 (36%) made a complete recovery and 7 (64%) made a partial recovery. 7 (35%) patients also had a SAH, of whom 3 (43%) made a complete recovery with 4 (57%) making a partial recovery., Conclusions: ONP can occur with PCOMM aneurysm with or without SAH. Endovascular coiling is an effective treatment for ONP due to PCOMM aneurysms., (© The Author(s) 2015.)

Facial recognition plays a key role in human interactions, and there has been great interest in understanding the evolution of human abilities for individual recognition and tracking social relationships. Individual recognition requires sufficient cognitive abilities and phenotypic diversity within a population for discrimination to be possible. Despite the importance of facial recognition in humans, the evolution of facial identity has received little attention. Here we demonstrate that faces evolved to signal individual identity under negative frequency-dependent selection. Faces show elevated phenotypic variation and lower between-trait correlations compared with other traits. Regions surrounding face-associated single nucleotide polymorphisms show elevated diversity consistent with frequency-dependent selection. Genetic variation maintained by identity signalling tends to be shared across populations and, for some loci, predates the origin of Homo sapiens. Studies of human social evolution tend to emphasize cognitive adaptations, but we show that social evolution has shaped patterns of human phenotypic and genetic diversity as well.

To be effective, signals must propagate through the environment and be detected by receivers. As a result, signal form evolves in response to both the constraints imposed by the transmission environment and receiver perceptual abilities. Little work has examined the extent to which signals may act as selective forces on receiver sensory systems to improve the efficacy of communication. If receivers benefit from accurate signal assessment, selection could favour sensory organs that improve discrimination of established signals. Here, we provide evidence that visual resolution coevolves with visual signals in Polistes wasps. Multiple Polistes species have variable facial patterns that function as social signals, whereas other species lack visual signals. Analysis of 19 Polistes species shows that maximum eye facet size is positively associated with both eye size and presence of visual signals. Relatively larger facets within the eye's acute zone improve resolution of small images, such as wasp facial signals. Therefore, sensory systems may evolve to optimize signal assessment. Sensory adaptations to facilitate signal detection may represent an overlooked area of the evolution of animal communication.

Primates are notable for having a rich and detailed understanding of their social environment and there has been great interest in the evolution and function of social knowledge in primates. Indeed, primates have been shown to have impressive understandings of not only other group members but also the complex relationships among them. To be useful, however, social knowledge requires memories from previous encounters and observations about individual traits that are stable. Here, we argue that social systems or traits that make social knowledge more costly or less accurate will favor signals that either supplement or replace social knowledge. Thus, the relationship between signals and social knowledge can be complementary or antagonistic depending on the type of signal. Our goal in this review is to elucidate the relationships between signals and social knowledge in primates. We categorize signals into three types, each with different relationships to social knowledge. (1) Identity signals directly facilitate social knowledge, (2) current-state signals supplement information gained through social knowledge, and (3) badges of status replace social knowledge. Primates rely extensively on identity information, but it remains to be determined to what extent this is based on receiver perception of individual variation or senders using identity signals. Primates frequently utilize current-state signals including signals of intent to augment their interactions with familiar individuals. Badges of status are rare in primates, and the cases where they are used point to a functional and evolutionary trade-off between badges of status and social knowledge. However, the nature of this relationship needs further exploration., (© 2012 Wiley Periodicals, Inc.)

Purpose: Deficiencies in pain knowledge and attitudes among students and health practitioners are well documented. Occupational therapists (OTs) commonly care for patients who present with pain, and their knowledge of the field presumably impacts that care. This study presents the results of testing OT students' pain knowledge in order to assess the effects of embedding pain teaching in a generic master's-level OT course and to determine specific topics that should be addressed to improve upon existing OT curricula., Method: During the academic years 2004 through 2009, 194 OT students were administered a test of pain knowledge and attitudes on the first and last day of a required class which focused on procedural reasoning., Results: The results indicated significant (p < 0.001) improvement in test scores after participation in the class. Whereas only 35% of students met the minimum "adequate" standard for pain knowledge at pre-test, 92% of students met this standard at post-test., Conclusions: The results demonstrate the effectiveness of a course taught by an instructor with pain expertise. In addition, analysis of individual items highlights the need for curricula to address theoretical versus practical understanding of pain, the ever-evolving science of pain, and pervasive biases about specific pain topics., Implications for Rehabilitation: Deficiencies in pain knowledge and attitudes among students and health practitioners are well documented. Occupational therapists (OTs) commonly care for patients who present with pain, and their knowledge of the field presumably impacts that care. The results of this study demonstrate the effectiveness of an OT course taught by an instructor with pain expertise. OT curricula should address pain in special populations (e.g. children and the elderly), acute versus chronic pain, theoretical versus practical understanding of pain, the ever-evolving science of pain, and pervasive biases about specific pain topics (e.g. malingering and opioid addiction).

Progression of meiosis has been traditionally reconstructed from microscopic images collected from fixed cells. However, studies conducted in a number of species, including plants, indicate that this approach has clear shortcomings in accurately portraying the dynamic nature of meiotic processes. Here, we describe two methods to study chromosome dynamics in live meiocytes in maize, a protocol to observe chromosomes during meiotic prophase I and a technique to monitor chromosome segregation in anaphase I and anaphase II. The first method relies on culturing intact maize anthers and observing meiocytes embedded in the anthers with multiphoton excitation (MPE) microscopy. This approach circumvents difficulties in culturing isolated prophase I meiocytes in plants. The second technique uses culturing isolated meiocytes, which is possible with anaphase cells. Both methods can be fairly easily adapted for use in other plant species. We also detail the kinds of time-lapse movies that can be captured and analyzed using this technique, and describe software that can be utilized for analysis of movies chromosome dynamic in live meiocytes.

Social insects provide good models for studying how and why the mechanisms that underlie reproduction vary, as there is dramatic reproductive plasticity within and between species. Here, we test how the effect of juvenile hormone (JH) on fertility covaries with cooperative behavior in workers and nest-founding queens in the primitively eusocial wasp Polistes metricus. P. metricus foundresses and workers appear morphologically similar and both are capable of reproduction, though there is variation in the extent of social cooperation and the probability of reproduction across castes. Do the endocrine mechanisms that mediate reproduction co-vary with cooperative behavior? We found dramatic differences in the effect of JH on fertility across castes. In non-cooperative nest-founding queens, all individuals responded to JH by increasing their fertility. However, in cooperative workers, the effect of JH on fertility varies with body weight; large workers increase their fertility in response to JH while small workers do not. The variation in JH response may be an adaptation to facilitate resource allocation based on the probability of independent reproduction. This work contrasts with previous studies in closely related Polistes dominulus paper wasps, in which both foundresses and workers form cooperative associations and both castes show similar, condition-dependent JH response. The variation in JH responsiveness within and between species suggests that endocrine responsiveness and the factors influencing caste differentiation are surprisingly evolutionarily labile., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Although yield trials for switchgrass (Panicum virgatum L.), a potentially high value biofuel feedstock crop, are currently underway throughout North America, the genetic tools for crop improvement in this species are still in the early stages of development. Identification of high-density molecular markers, such as single nucleotide polymorphisms (SNPs), that are amenable to high-throughput genotyping approaches, is the first step in a quantitative genetics study of this model biofuel crop species. We generated and sequenced expressed sequence tag (EST) libraries from thirteen diverse switchgrass cultivars representing both upland and lowland ecotypes, as well as tetraploid and octoploid genomes. We followed this with reduced genomic library preparation and massively parallel sequencing of the same samples using the Illumina Genome Analyzer technology platform. EST libraries were used to generate unigene clusters and establish a gene-space reference sequence, thus providing a framework for assembly of the short sequence reads. SNPs were identified utilizing these scaffolds. We used a custom software program for alignment and SNP detection and identified over 149,000 SNPs across the 13 short-read sequencing libraries (SRSLs). Approximately 25,000 additional SNPs were identified from the entire EST collection available for the species. This sequencing effort generated data that are suitable for marker development and for estimation of population genetic parameters, such as nucleotide diversity and linkage disequilibrium. Based on these data, we assessed the feasibility of genome wide association mapping and genomic selection applications in switchgrass. Overall, the SNP markers discovered in this study will help facilitate quantitative genetics experiments and greatly enhance breeding efforts that target improvement of key biofuel traits and development of new switchgrass cultivars.

Progression of meiosis has been traditionally reconstructed from microscopic images collected from fixed cells. This approach has clear shortcomings in accurately portraying the dynamics of meiotic processes. Studies conducted in recent years mostly in unicellular fungi have shown that chromosomes in meiotic prophase exhibit dynamic motility that cannot be accurately examined using fixed cell imaging. However, in contrast to yeast, research on meiotic chromosome dynamics in multicellular eukaryotes has been lagging. This was in part because meiocytes in multicellular eukaryotes reside deep within reproductive organs and are often refractory to culturing. Here, we describe a method in which intact, live-plant reproductive organs (anthers) are cultured to enable monitoring chromosome dynamics of meiocytes using multiphoton excitation (MPE) microscopy. The method was developed for use in maize but can be applied to other plant species and adapted for use in other taxa in which meiocytes are embedded in multicellular reproductive structures. MPE microscopy allows visualization of meiocytes embedded within native tissue in planta and thus meiocytes remain intact for the entire imaging procedure. We detail the kinds of time-lapse movies that can be captured and analyzed using this technique and also highlight software packages that can be utilized for analysis of movies chromosome dynamic in live meiocytes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We demonstrate that the evolution of facial recognition in wasps is associated with specialized face-learning abilities. Polistes fuscatus can differentiate among normal wasp face images more rapidly and accurately than nonface images or manipulated faces. A close relative lacking facial recognition, Polistes metricus, however, lacks specialized face learning. Similar specializations for face learning are found in primates and other mammals, although P. fuscatus represents an independent evolution of specialization. Convergence toward face specialization in distant taxa as well as divergence among closely related taxa with different recognition behavior suggests that specialized cognition is surprisingly labile and may be adaptively shaped by species-specific selective pressures such as face recognition.

Individual recognition (IR) requires individuals to uniquely identify their social partners based on phenotypic variation. Because IR is so specific, distinctive phenotypes that stand out from the crowd facilitate efficient recognition. Over time, the benefits of unique appearances are predicted to produce a correlation between IR and phenotypic variation. Here, we test whether there is an association between elevated phenotypic polymorphism and IR in paper wasps. Previous work has shown that Polistes fuscatus use variable colour patterns for IR. We test whether two less variable wasp species, Polistes dominulus and Polistes metricus, are capable of IR. As predicted, neither species is capable of IR, suggesting that highly variable colour patterns are confined to Polistes species with IR. This association suggests that elevated phenotypic variation in taxa with IR may be the result of selection for identity signals rather than neutral processes. Given that IR is widespread among social taxa, selection for identity signalling may be an underappreciated mechanism for the origin and maintenance of polymorphism.

Juveniles should choose social partners on the basis of both current and future utility. Where one sex is philopatric, one expects members of that sex to develop greater and sex-typical social integration with group-mates over the juvenile period. Where a partner's position in a dominance hierarchy is not associated with services it can provide, one would not expect juveniles to choose partners based on rank, nor sex differences in rank-based preferences. We tested these ideas on 39 wild juvenile (3.2-7.4 years) blue monkeys (Cercopithecus mitis stuhlmanni), cercopithecines with strict female philopatry and muted hierarchies. We made focal animal observations over 6 months, and computed observed:expected amounts of proximity time, approaches and grooming given to various social partners. Overall, our results agree with the hypothesis that juvenile blue monkeys target social partners strategically. Spatial proximity, approaches and active grooming showed similar patterns regarding juvenile social preferences. Females were far more sociable than males, groomed more partners, reciprocated grooming more frequently, and preferred-while males avoided-infants as partners. Older juveniles (5-7 years) spent more time than younger juveniles (3-4 years) near others, and older females were especially attracted to infants. Close kin, especially mothers and less consistently adult sisters, were attractive to both male and female juveniles, regardless of age. Both sexes also preferred same-sex juveniles as social partners while avoiding opposite-sex peers. Juveniles of both sexes and ages generally neither preferred nor avoided nonmaternal adult females, but all juveniles avoided adult males. Partner's rank had no consistent effect on juveniles' preference, as expected for a species in which dominance plays a weak role. Juveniles' social preferences likely reflect both future and current benefits, including having tolerant adult kin to protect them against predators and conspecifics, same-sex play partners, and, for females, infants on which to practice mothering skills. Am. J. Primatol. 72:193-205, 2010. (c) 2009 Wiley-Liss, Inc.

The ability of chromosomes to move across the nuclear space is essential for the reorganization of the nucleus that takes place in early meiotic prophase. Chromosome dynamics of prophase I have been studied in budding and fission yeasts, but little is known about this process in higher eukaryotes, where genomes and chromosomes are much larger and meiosis takes a longer time to complete. This knowledge gap has been mainly caused by difficulties in culturing isolated live meiocytes of multicellular eukaryotes. To study the nuclear dynamics during meiotic prophase in maize, we established a system to observe live meiocytes inside intact anthers. We found that maize chromosomes exhibited extremely dynamic and complex motility in zygonema and pachynema. The movement patterns differed dramatically between the two stages. Chromosome movements included rotations of the entire chromatin and movements of individual chromosome segments, which were mostly telomere-led. Chromosome motility was coincident with dynamic deformations of the nuclear envelope. Both, chromosome and nuclear envelope motility depended on actin microfilaments as well as tubulin. The complexity of the nuclear movements implies that several different mechanisms affect chromosome motility in early meiotic prophase in maize. We propose that the vigorous nuclear motility provides a mechanism for homologous loci to find each other during zygonema.

Identifying broad-scale evolutionary processes that maintain phenotypic polymorphisms has been a major goal of modern evolutionary biology. There are numerous mechanisms, such as negative frequency-dependent selection, that may maintain polymorphisms, although it is unknown which mechanisms are prominent in nature. Traits used for individual recognition are strikingly variable and have evolved independently in numerous lineages, providing an excellent model to investigate which factors maintain ecologically relevant phenotypic polymorphisms. Theoretical models suggest that individuals may benefit by advertising their identities with distinctive, recognizable phenotypes. Here, we test the benefits of advertising one's identity with a distinctive phenotype. We manipulated the appearance of Polistes fuscatus paper wasp groups so that three individuals had the same appearance and one individual had a unique, easily recognizable appearance. We found that individuals with distinctive appearances received less aggression than individuals with nondistinctive appearances. Therefore, individuals benefit by advertising their identity with a unique phenotype. Our results provide a potential mechanism through which negative frequency-dependent selection may maintain the polymorphic identity signals in P. fuscatus. Given that recognition is important for many social interactions, selection for distinctive identity signals may be an underappreciated and widespread mechanism underlying the evolution of phenotypic polymorphisms in social taxa.

Background: MMRpro, prediction of mutations in MLH1 and MLH2 (PREMM(1,2)) and MMRpredict are models which were developed to predict the probability that an individual carries a Lynch syndrome-causing mutation. Each model utilizes data from personal and family histories of cancer. To date, no studies have compared these models in a cancer genetics clinic. The purpose of this study was to determine each model's ability to predict the probability of carrying a Lynch syndrome-causing mutation in individuals with a family history of colorectal cancer and to determine their clinical applicability., Methods: We obtained family pedigrees from 81 individuals who presented for Lynch syndrome testing due to a personal and/or family history of cancer. Data from each pedigree were entered into the models and analyzed using SPSS., Results: We found that MMRpredict, PREMM(1,2) and MMRpro showed similar performances with areas under the receiver-operating characteristic curve of 0.731, 0.765 and 0.732, respectively. MMRpro showed the least dispersion of mutation probability estimates with a P value of 0.205, compared with 0.034 for PREMM(1,2) and 0.001 for MMRpredict., Conclusion: We found all three carried out well in a cancer genetics setting, with PREMM(1,2) giving slightly better estimates. There were some significant discrepancies between the models in cases where the proband had endometrial cancer.

Most studies assessing the link between parental discipline and child aggression have focused primarily on discipline as a cause and aggression as an outcome. In addition to the pathway from discipline to aggression, however, aggressive behavior on the part of the child may lead to future use of discipline by the parent. In this study, structural equation modeling was used to assess reciprocal influences over time between a mothers' use of discipline and aggression in children. Data were drawn from the Springfield Child Development Project, a longitudinal study of middle childhood and adolescence, focusing on antecedents of aggression. The original sample consisted of 440 mother-child dyads living in the city of Springfield, MA. Children in the sample were between 7 and 14 years of age at the first data collection period and between 12 and 19 years of age at the final data collection period. Four hypotheses were tested: (1) a mother's use of aggressive discipline predicts an increase in later child aggression, (2) child aggression predicts an increase in later use of aggressive discipline, (3) the use of reasoning predicts a decrease in later child aggression, and (4) child aggression predicts an increase in later use of reasoning. All hypotheses except number 3 were supported to some degree. Results suggest that children's early aggressive behavior leads to an increase in their mothers' use of both reasoning and aggressive discipline; in turn, increased use of aggressive discipline leads to an increase in aggression during both childhood and adolescence., (Copyright 2007 Wiley-Liss, Inc.)

The pharmacological properties of the novel ligand, (2R,3R,4S,5R)-2-(6-amino-2-{[(1S)-2-hydroxy-1-(phenylmethyl)ethyl]amino}-9H-purin-9-yl)-5-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3,4-furandiol (I), at the human adenosine receptors were investigated using Chinese hamster ovary cell lines recombinantly expressing these receptors. Functional studies were performed using a cyclic AMP-coupled reporter gene system. Binding studies were performed using membranes from these cells. The effects of ligand (I) were also determined on functional responses of human neutrophils and eosinophils. Ligand (I) had a high affinity for the adenosine A(2A) receptor (pKi 7.8+/-0.2) and was a potent agonist at this receptor (pEC(50) 9.0+/-0.2). Ligand (I) had a similar affinity for the adenosine A(3) receptor (pKi 7.8+/-0.1) but displayed no agonist activity, acting instead as a competitive antagonist (pA(2) 8.3+/-0.04). Ligand (I) had lower affinity for adenosine A(1) and A(2B) receptors (pKi

The most-critical point of reproductive development in all sexually reproducing species is the transition from mitotic to meiotic cell cycle. Studies in unicellular fungi have indicated that the decision to enter meiosis must be made before the beginning of the premeiotic S phase. Recent data from the mouse suggest that this timing of meiosis initiation is a universal feature shared also by multicellular eukaryotes. In contrast, the signaling cascade that leads to meiosis initiation shows great diversity among species., ((c) 2007 Wiley Periodicals, Inc.)

Phytochromes are the primary red/far-red photoreceptors of higher plants, mediating numerous developmental processes throughout the life cycle, from germination to flowering. In seed plants, phytochromes are encoded by a small gene family with each member performing both distinct and redundant roles in mediating physiological responses to light cues. Studies in both eudicot and monocot species have defined a central role for phytochrome B in mediating responses to light in the control of several agronomically important traits, including plant height, transitions to flowering and axillary branch meristem development. Here we characterize Mutator-induced alleles of PhyB1 and a naturally occurring deletion allele of PhyB2 in Zea mays (maize). Using single and double mutants, we show that the highly similar PhyB1 and PhyB2 genes encode proteins with both overlapping and non-redundant functions that control seedling and mature plant traits. PHYB1 and PHYB2 regulate elongation of sheath and stem tissues of mature plants and contribute to the light-mediated regulation of PhyA and Cab gene transcripts. However, PHYB1 and not PHYB2 contributes significantly to the inhibition of mesocotyl elongation under red light, whereas PHYB2 and to a lesser extent PHYB1 mediate the photoperiod-dependent floral transition. This sub functionalization of PHYB activities in maize has probably occurred since the tetraploidization of maize, and may contribute to flowering time variation in modern-day varieties.

Plants respond to shading through an adaptive syndrome termed shade avoidance. In high-density crop plantings, shade avoidance generally increases extension growth at the expense of yield and can be at odds with the agronomic performance of the crop as a whole. Studies in Arabidopsis are beginning to reveal the essential role phytochromes play in regulating this process and to identify genes underlying the response. In this article, we focus on how phytochrome signaling networks have been targeted in cereal breeding programs in the past and discuss the potential to alter these pathways through breeding and transgenic manipulation to develop crops that perform better under typical high density conditions.

Determining how the human brain differs from nonhuman primate brains is central to understanding human behavioral evolution. There is currently dispute over whether the prefrontal cortex, which mediates evolutionarily interesting behaviors, has increased disproportionately. Using magnetic resonance imaging brain scans from 11 primate species, we measured gray, white and total volumes for both prefrontal and the entire cerebrum on each specimen (n = 46). In relative terms, prefrontal white matter shows the largest difference between human and nonhuman, whereas gray matter shows no significant difference. This suggests that connectional elaboration (as gauged by white matter volume) played a key role in human brain evolution.

To begin the study of phytochrome signaling in maize, we have cloned and characterized the phytochrome gene family from the inbred B73. Through DNA gel blot analysis of maize genomic DNA and BAC library screens, we show that the PhyA, PhyB, and PhyC genes are each duplicated once in the genome of maize. Each gene pair was positioned to homeologous regions of the genome using recombinant inbred mapping populations. These results strongly suggest that the duplication of the phytochrome gene family in maize arose as a consequence of an ancient tetraploidization in the maize ancestral lineage. Furthermore, sequencing of Phy genes directly from BAC clones indicates that there are six functional phytochrome genes in maize. Through Northern gel blot analysis and a semiquantitative reverse transcriptase polymerase chain reaction assay, we determined that all six phytochrome genes are transcribed in several seedling tissues. However, expression from PhyA1, PhyB1, and PhyC1 predominate in all seedling tissues examined. Dark-grown seedlings express higher levels of PhyA and PhyB than do light-grown plants but PhyC genes are expressed at similar levels under light and dark growth conditions. These results are discussed in relation to phytochrome gene regulation in model eudicots and monocots and in light of current genome sequencing efforts in maize.

Objective: This study was designed to demonstrate the presence of adenosine A3 receptors on human peripheral blood eosinophils, and to investigate the effect of A3 receptor stimulation on eosinophil function., Material: Eosinophils from either non-asthmatic or asthmatic donors., Methods: Eosinophils were isolated from peripheral venous blood by discontinuous gradient centrifugation and negative immunoselection. Receptor localisation was investigated by immunoblotting and by immunocytochemistry using a novel antibody specific for the human A3 receptor. Two pharmacological responses were studied: elevation of intracellular calcium in single eosinophils, measured by microfluorimetry, and hydrogen peroxide generation in cell suspensions., Results: The expression of A3 receptors by eosinophils was confirmed using the selective antibody. Addition of the A3 receptor selective agonist, IB-MECA (100 nM), produced increases in intracellular calcium in less than 10% of the eosinophils isolated from non-asthmatic donors. These responses were only partially attenuated with the A3 receptor antagonist, I-ABOPX. IB-MECA (0.001-1000 nM) did not stimulate hydrogen peroxide (H2O2) generation, nor did it enhance fMLP- or C5a-stimulated generation of H2O2. In fact high concentrations of IB-MECA inhibited the generation of H2O2 (when stimulated by fMLP or C5a), an effect probably mediated by A2 receptors. Similar results were obtained using eosinophils from asthmatic donors., Conclusions: Stimulation of adenosine A3 receptors does not appear to be a prime mechanism for free radical generation by human peripheral blood eosinophils.

A series of N6,2-disubstituted adenosine analogues have been synthesized and their functional activity measured against A2a and A1 receptors. Examples of compounds with both a lipophilic N6-substituent and amino-functionalized 2-position were highly active at the A2a receptor on the human neutrophil.

The effectiveness of one particular shrouded tool type in capturing composite dust generated during dry machining operations was tested. The effectiveness of the shrouded tool was measured by comparing exposures during identical operations done by the same workers. The operation was conducted by dividing the time into two equal portions, one using an unshrouded tool and the other with same tool shrouded. The operations included sanding and grinding operations of fibrous glass/epoxy composite materials. Unshrouded short-term exposures ranged from 2.17 mg/m3 to 50.81 mg/m3. There was a significant reduction in exposure using the shroud (paired t-test, p = 0.005). The effect of a shroud on respirable dust exposures was inconclusive, because of the limited amount of respirable dust collected in these short-term samples.

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals. 2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 microg kg[-1] in 5 min and 15 min, and 120 microg kg[-1] in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+/-s.e., n=19) were Emax: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hill factor: 2.2+/-0.2. 4. In another group, given 400 microg kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

Objective: To investigate the effects of adenosine receptor agonists and antagonists on 5-HT release from rat isolated pleural mast cells and on plasma protein extravasation in the skin of conscious rats. In vitro, Methods: Rat isolated pleural mast cells were loaded with [14C] 5-HT, sensitised with mouse monoclonal anti-DNP and then challenged with human serum albumin-DNP. DNP-stimulated 5-HT release from mast cells was determined. In vivo, Methods: Rats, loaded intravenously with [125I] human serum albumin, were injected intradermally with adenosine agonists at sites on the back. 30 min later plasma protein extravasation at each injection site was determined., Results: In isolated mast cells, each adenosine agonist enhanced DNP-induced 5-HT release, N6-(3-iodobenzyl)-5-(N-methyl-carboxamidoadenosine), (IB-MECA), being the most potent agonist. The adenosine A1/A2 antagonist, 8-phenyltheophylline (8-PT), had no effect on the response to IB-MECA. In contrast, 3-(4-amino-iodobenzyl)-8-[4-[[[carboxy]methyl]oxy]phenyl]-1-propylxanthi ne, (I-ABOPX), inhibited (pA2 6.2) the IB-MECA responses. In the skin of conscious rats, intradermal IB-MECA produced a marked plasma protein extravasation (PPE) which was mimicked by N6-2-(4-aminophenyl)-ethyladenosine (APNEA). The PPE produced by IB-MECA was not affected by either 8-PT or CGS15943A, but was virtually abolished by cyproheptadine and in rats pre-treated with Compound 48/80., Conclusions: These results indicate that stimulation of adenosine A3 receptors both enhances degranulation in vitro and directly produces degranulation of rat mast cells in vivo.

This research investigated the efficacy of machine enclosures in reducing employee exposures to metalworking fluid mist. Four hundred fifty-five personal samples from automotive machining and grinding operations collected over six years were divided into three groups based on the type and extent of enclosure and local exhaust ventilation. The sample groups were (1) machining equipment with original equipment manufacturer (OEM) total enclosures and local exhaust ventilation, (2) machining equipment with partial or retrofit enclosures and local exhaust ventilation, and (3) machining equipment with little or no enclosure. The results of the Mann Whitney U test of the three data sets indicated that the employees operating equipment with OEM enclosures had significantly lower exposures than employees operating equipment that had either of the other two control methods. There was no difference between the exposures of operators of equipment with retrofit enclosures compared to operators of equipment without enclosures. The median exposure for operators of equipment with OEM enclosures was 0.21 mg/m3, about half that found with the other two control methods. Each of the data sets was compared to exposure criteria; 100% of the exposures associated with OEM enclosures were below 1.0 mg/m3, and 90% of the exposures were below 0.5 mg/m3. The other two methods were not as effective as OEM in reducing exposure to below these criteria. These results indicate that OEM enclosures provide the most effective control of metalworking fluid mist exposure.

1. The alkylxanthine antagonists, 8-phenyltheophylline (8-PT), 8-p-sulphophenyltheophylline (8-SPT) and 1,3,7-trimethylxanthine (caffeine) produced rightward displacements of contractile concentration-effect curves to 5'-N-ethylcarboxamidoadenosine (NECA) in rat isolated colonic muscularis mucosae (RCMM) with concentration-ratios consistent with adenosine receptor blockade. The non-xanthine antagonist, 9 fluro-2-(2-furyl)-5,6-dihydro [1,2,4] triazo to [1,5-c]-quinazin-imine (CGS15943A) also antagonized contractions to NECA with an affinity (pKB8.1-8.5) consistent with adenosine A1 receptor blockade. 2. In addition to producing rightward shifts of the concentration-response curves, the maximum contractions to 5'-N-ethylcarboxamidoadenosine (NECA) were also markedly increased in the presence of 8-PT (by 83 +/- 16% at 1 microM), 8-SPT (by 37 +/- 7% at 10 microM) and caffeine (by 45 +/- 5% at 100 microM) but were unaffected by CGS15943A (at 0.01 and 0.03 microM). 3. As with NECA, the maximum contractions to the adenosine A1 receptor agonists R-phenylisopropyladenosine (R-PIA) and N-[(1S, trans)-2-hydroxyclopentyl] adenosine (GR79236) were both antagonized and augmented by 8-PT. In addition, the contractions to NECA in the presence of 8-PT (1 microM) were inhibited by nanomolar concentrations of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). 4. The non-selective phosphodiesterase (PDE) inhibitor, 3-isobutyl-1-methylxanthine (1 microM) produced a marked increase in the NECA maximum without producing a rightward shift in the NECA curve, whereas a higher concentration (10 microM) virtually abolished responses. The PDE type III inhibitor,milrinone (1 microM), the type IV inhibitor, rolipram (10 microM), and the type V PDE inhibitor, zaprinast(3 microM), were all without effect on NECA responses in RCMM.5. Partial inhibitions of contractions to NECA were produced by indomethacin (at 3 or 10 micro M) or piroxicam (at 3 microM). Responses to GR79236 were also partially inhibited by indomethacin. In the presence of indomethacin, 8-PT was still able to enhance markedly the maximum contractions obtained to NECA in RCMM.6. The present study has shown that certain alkylxanthine antagonists (but not the non-xanthineCGS15943A) produced a marked augmentation of adenosine Al receptor-mediated contractions inRCMM. The mechanism of this augmentation is, as yet, not known but is unlikely to result from inhibition of PDE. This study has also shown that adenosine Al receptor-induced contractions inRCMM are mediated, in part, via products of the cyclo-oxygenase pathway.

1. The effects of a range of adenosine receptor-selective ligands on body temperature were investigated following intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection in conscious mice. The compounds tested were the non-selective adenosine receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA), the adenosine A1 receptor-selective agonists cyclopentyl-adenosine (CPA), N6-(9R-phenyl-isopropyl)-adenosine (R-PIA) and N-(1S,trans)-[2-hydroxyclopentyl]-adenosine (GR79236), the A2a receptor selective agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxyamidoaden osine (CGS-21680), the A2b receptor agonist N-[(2-methylphenyl)methyl[adenosine (metrifudil) and the A3 receptor agonist N6-(4-aminophenylethyl)adenosine (APNEA). 2. NECA (0.01-1 microgram, i.c.v.), all of the A1-selective agonists (0.01-1 microgram, i.c.v.) and APNEA (0.1-3 micrograms i.c.v.) produced profound and dose-related hypothermia and sedation. However, CGS-21680 (0.1-10 micrograms i.c.v.) and metrifudil (0.01-1 microgram i.c.v.), produced only mild hypothermia at the highest doses tested. 3. The hypothermic response to the A1 receptor-selective agonists, GR79236 and R-PIA was dose-dependently antagonized by peripheral administration of either the non-selective adenosine receptor antagonist, 8-phenyltheophylline (8-PT, approximately 40 and 30 fold rightward shifts of the dose-response curves respectively at 10 mg kg-1, i.p.), or the adenosine A1 receptor-selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, approximately 20 fold shift of the GR79236 dose-response curve at 1 mg kg-1, i.p.). The hypothermic response to APNEA was similarly dose-dependently antagonized by the A1 receptor-selective antagonist, DPCPX (5 fold shift at 0.1 mg kg-1, i.p.). 4.8(p-Sulphophenyl)theophylline (8-SPT, 10 and 30 mg kg-1, i.p.), a non-selective adenosine receptorantagonist that penetrates the blood brain barrier poorly, produced only modest antagonism (approximately 2 fold shift at 30 mg kg-1, i.p.) of the hypothermic response to GR79236.5. These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine A1 receptors, which are probably located in the CNS.