Concluding conversation: decentring science diplomacy.

Gordon Barrett (GB): Research Associate, Centre for the History of Science, Technology and Medicine, University of Manchester, UK (special issue co-editor).

Decentring histories of science diplomacy: cases from Asia.

This special issue brings together a diverse set of cases from Asia with the aim of decentring established historical narratives about science diplomacy. With a critical perspective bringing together the bodies of literature in the fields of the History of Science, Technology and Medicine (STM) and critical Asian Studies, we argue that these cases foreground a geopolitical history with multiple forms of sovereignty - often contested ones - and a range of political institutions and actors that enables us to revisit science diplomacy as a means for understanding the relationship between science and international affairs. In doing so, the articles in this issue consciously eschew the normative 'centring' of superpowers or Western imperial powers as the primary actors, focusing instead on the agency and subjectivity of actors within Asia, many of whom were prominent in their respective local contexts. Additionally, we argue that the cases presented here, which examine issues from across science, technology, medicine and the environment, collectively demonstrate the further need for the 'science' in 'science diplomacy' to be interpreted more broadly, incorporating as it does many aspects of human engagement with the material world.

Picturing Chinese science: wartime photographs in Joseph Needham's science diplomacy.

Joseph Needham occupies a central position in the historical narrative underpinning the most influential practitioner-derived definition of 'science diplomacy'. The brief biographical sketch produced by the Royal Society and the American Association for the Advancement of Science sets Needham's activities in the Second World War as an exemplar of a science diplomacy. This article critically reconsiders Needham's wartime activities, shedding light on the roles played by photographs in those diplomatic activities and his onward dissemination of them as part of his self-fashioning. Images were important to the British biochemist, and he was an avid amateur photographer himself, amassing a unique collection of hundreds of images relating to science, technology and medicine in wartime China during his time working as director of the Sino-British Science Co-operation Office. These included ones produced by China's Nationalist Party-led government, and by the Chinese Communist Party. Focusing on these photographs, this article examines the way Joseph Needham used his experiences to underpin claims to authority which, together with the breadth of his networks, enabled him to establish himself as an international interlocutor. All three aspects formed essential parts of his science diplomacy.

Assessing the safety of cosmetic chemicals: Consideration of a flux decision tree to predict dermally delivered systemic dose for comparison with oral TTC (Threshold of Toxicological Concern).

Threshold of Toxicological Concern (TTC) aids assessment of human health risks from exposure to low levels of chemicals when toxicity data are limited. The objective here was to explore the potential refinement of exposure for applying the oral TTC to chemicals found in cosmetic products, for which there are limited dermal absorption data. A decision tree was constructed to estimate the dermally absorbed amount of chemical, based on typical skin exposure scenarios. Dermal absorption was calculated using an established predictive algorithm to derive the maximum skin flux adjusted to the actual 'dose' applied. The predicted systemic availability (assuming no local metabolism), can then be ranked against the oral TTC for the relevant structural class. The predictive approach has been evaluated by deriving the experimental/prediction ratio for systemic availability for 22 cosmetic chemical exposure scenarios. These emphasise that estimation of skin penetration may be challenging for penetration enhancing formulations, short application times with incomplete rinse-off, or significant metabolism. While there were a few exceptions, the experiment-to-prediction ratios mostly fell within a factor of 10 of the ideal value of 1. It can be concluded therefore, that the approach is fit-for-purpose when used as a screening and prioritisation tool.

Illustrative case using the RISK21 roadmap and matrix: prioritization for evaluation of chemicals found in drinking water.

The HESI-led RISK21 effort has developed a framework supporting the use of twenty-first century technology in obtaining and using information for chemical risk assessment. This framework represents a problem formulation-based, exposure-driven, tiered data acquisition approach that leads to an informed decision on human health safety to be made when sufficient evidence is available. It provides a transparent and consistent approach to evaluate information in order to maximize the ability of assessments to inform decisions and to optimize the use of resources. To demonstrate the application of the framework's roadmap and matrix, this case study evaluates a large number of chemicals that could be present in drinking water. The focus is to prioritize which of these should be considered for human health risk as individual contaminants. The example evaluates 20 potential drinking water contaminants, using the tiered RISK21 approach in combination with graphical representation of information at each step, using the RISK21 matrix. Utilizing the framework, 11 of the 20 chemicals were assigned low priority based on available exposure data alone, which demonstrated that exposure was extremely low. The remaining nine chemicals were further evaluated, using refined estimates of toxicity based on readily available data, with three deemed high priority for further evaluation. In the present case study, it was determined that the greatest value of additional information would be from improved exposure models and not from additional hazard characterization.

Coordination of glioblastoma cell motility by PKCι.

BACKGROUND: Glioblastoma is one of the deadliest forms of cancer, in part because of its highly invasive nature. The tumor suppressor PTEN is frequently mutated in glioblastoma and is known to contribute to the invasive phenotype. However the downstream events that promote invasion are not fully understood. PTEN loss leads to activation of the atypical protein kinase C, PKCι. We have previously shown that PKCι is required for glioblastoma cell invasion, primarily by enhancing cell motility. Here we have used time-lapse videomicroscopy to more precisely define the role of PKCι in glioblastoma. RESULTS: Glioblastoma cells in which PKCι was either depleted by shRNA or inhibited pharmacologically were unable to coordinate the formation of a single leading edge lamellipod. Instead, some cells generated multiple small, short-lived protrusions while others generated a diffuse leading edge that formed around the entire circumference of the cell. Confocal microscopy showed that this behavior was associated with altered behavior of the cytoskeletal protein Lgl, which is known to be inactivated by PKCι phosphorylation. Lgl in control cells localized to the lamellipod leading edge and did not associate with its binding partner non-muscle myosin II, consistent with it being in an inactive state. In PKCι-depleted cells, Lgl was concentrated at multiple sites at the periphery of the cell and remained in association with non-muscle myosin II. Videomicroscopy also identified a novel role for PKCι in the cell cycle. Cells in which PKCι was either depleted by shRNA or inhibited pharmacologically entered mitosis normally, but showed marked delays in completing mitosis. CONCLUSIONS: PKCι promotes glioblastoma motility by coordinating the formation of a single leading edge lamellipod and has a role in remodeling the cytoskeleton at the lamellipod leading edge, promoting the dissociation of Lgl from non-muscle myosin II. In addition PKCι is required for the transition of glioblastoma cells through mitosis. PKCι therefore has a role in both glioblastoma invasion and proliferation, two key aspects in the malignant nature of this disease.

Lovastatin enhances gefitinib activity in glioblastoma cells irrespective of EGFRvIII and PTEN status.

The epidermal growth factor receptor (EGFR) is commonly amplified and mutated in glioblastoma, making it a compelling therapeutic target. Recent reports have demonstrated clinical activity of the EGFR inhibitors gefitinib and erlotinib in a subset of glioblastoma patients. Co-expression of EGFRvIII, a constitutively active mutant receptor expressed in 50% of tumours, and PTEN, an inhibitor of PI3K activity, by glioblastoma cells is associated with clinical response to these EGFR kinase inhibitors. PTEN loss and resulting increased PI3K pathway activity appears to act as a resistance factor. A critical therapeutic challenge is to identify agents that enhance the anti-cancer effects of these agents and promote responsiveness to EGFR kinase inhibitors in a broader spectrum of glioblastoma patients. For example, combining gefitinib with inhibitors of the PI3K/AKT pathway show enhanced cytotoxicity in glioblastoma derived cell lines. Here, we show that targeting HMG-CoA reductase with lovastatin, that can affect the activity of multiple cell signaling pathways, significantly enhanced the sensitivity of glioblastoma cells to the EGFR kinase inhibitor gefitinib in the five cell lines tested. In an isogenic model system, U87MG glioblastoma cells expressing EGFRvIII and PTEN in relevant combinations, we show that combined gefitinib and lovastatin treatments induce potent synergistic cytotoxicity irrespective of EGFRvIII and PTEN status. These studies demonstrate the potential of lovastatin to augment the cytotoxic effects of gefitinib and provide a rationale for combined statin/EGFR targeted therapies in glioblastoma patients.

Regulation of sexual behaviour in male macaques by sex steroid modulation of the serotonergic system.

The view that androgen action is the primary impetus underlying male-typical behaviour has been irrevocably altered by the profound perturbations in social and sexual behaviour observed in recent models of oestrogen insufficiency in male mice. Evidence is also accumulating for an involvement of oestrogens in the modulation of neural systems that are thought to play important roles in male reproductive functioning. Specifically, the serotonergic system is implicated in diverse autonomic functions, most or all of which are sensitive to oestradiol as well. Although their interaction domains have yet to be examined in male primates, roles have been established for both oestrogen and serotonin in the regulation of male sexual behaviour. We used a blinded, sham-treated and self-controlled, randomized, multitreatment cross-over design to test the hypothesis that male sexual behaviour is regulated by oestrogen modulation of the serotonergic system in intact male Japanese macaques. Regression analysis revealed that oestradiol and whole blood tryptophan, but not testosterone or 5alpha-dihydrotestosterone, had additive, independent effects on male potentia over a range of hormone concentrations, whereas androgens were confirmed to be the primary determinants of sexual motivation. We suggest that modulation of the serotonergic system by 'female hormones' may be fundamental to the regulation of male mating success in higher primates. This might also explain, at least in part, why significant correlations between steroid hormones and male copulatory behaviour have traditionally proven so elusive in this order, thereby warranting a re-evaluation of the current notion that male sexual behaviour has been emancipated from activational hormonal control in higher primates.

Differences in the endocrine and behavioral profiles during the peripartum period in macaques.

The present investigation aims to assess the changes in both social interaction and sex steroids excreted in feces of group-living Japanese macaques and rhesus monkeys. By comparing profiles of estrone conjugates (E1C) and pregnanediol-glucuronide (PdG) with the behavioral propensities of two closely related species living in similar environments, we could test the hypothesis that the social behavior of pregnant females shows significant hormonally mediated changes during the late prepartum and early postpartum period. We found a general tendency to withdraw from social life across pregnancy in both species. These behavioral changes were paralleled by endocrine profiles showing a slight prepartum increase in E1C during the last week in the rhesus group, whereas the increase was more marked and continuous in the Japanese macaque group. PdG increased slightly in rhesus macaques, whereas in Japanese macaques the fluctuations were not significant. Postpartum, both hormones dropped to low levels in both species, with no significant variation therein. Consequent to these changes, the E1C/PdG ratio increased significantly in late pregnancy only in the Japanese macaque group. Overall, these results show significant differences in the social behavior and endocrine profiles of two closely related species, thus complementing previous findings and indicating species-specific characteristics of the association between changes in affiliative behaviors and hormonal fluctuations. In particular, the shift between grooming performed and self-grooming, which showed the closest association with variations in the E1C/PdG ratio, could represent a reliable indicator of the change in the internal status of pregnant females, and is probably functional to infant survival.

Peripartum sex steroid changes and maternal style in rhesus and Japanese macaques.

The subtle and complex relationships between the sequential maturation of the endocrine systems during pregnancy and parturition, and the hormonal role in activating the central nervous system to express maternal behavior in primates, are far from being completely understood. Recent studies on the association between sex steroids and maternal behavior have yielded conflicting results in this group. Here we use a comparative approach to assess the correlation between changes in the peripartum endocrine profiles and maternal styles in two closely related macaque species, housed in analogous environments. We included in this study the first seven Japanese macaque and seven rhesus macaque mother-infant pairs born during the birth season of 2001 at the Primate Research Institute, Kyoto University, Japan. We observed each pair 3h/week (six weekly 30-min observation sessions) during the first 12 weeks of lactation. We collected fecal samples twice a week from each mother, starting 4 weeks before parturition and ending 4 weeks after parturition. We tested the hypothesis that neuroendocrine changes during pregnancy and lactation might specifically contribute to the regulation and timing of infant rejection. Despite their biological similarities, we observed a clear difference in maternal style between the two groups concerning rejection rates: rhesus macaque mothers rejected their infants earlier and more frequently throughout the whole 12 weeks of study. On the other hand, protectiveness showed similar patterns and values in the two groups, and maternal warmth was significantly higher in the rhesus group, but it followed a similar pattern over time. We also confirmed an association between maternal rejection and excreted estrogen, but not excreted progesterone, for Japanese macaques. This association was not apparent for the rhesus macaques. This result, coupled with the observation that rhesus mothers are more rejecting than Japanese macaque mothers, tends to support our hypothesis. As a group, rhesus macaques are less inhibited in the rejection of their infants, and this is paralleled by a less marked change in the primacy of estrogen in the last phase of pregnancy. On the contrary, the Japanese group is characterized by higher levels of E(1)C and the E(1)C/PdG ratio. Therefore, according to our hypothesis, their tendency to increase the rejection rate may be suppressed through a feedback loop that enhances maternal motivation and results in a more tolerant outcome toward the infant.

Peripartum cortisol levels and mother-infant interactions in Japanese macaques.

As evidence accumulates regarding the influence of hormones and stress-related conditions on maternal behavior, it becomes critical to better understand the relationship between physiological stress and the ability to cope with infants. Eight Japanese macaque females were observed 3 hr per week during the first 12 weeks after parturition; fecal samples were collected twice a week from each mother, starting 4 weeks before parturition and ending 4 weeks after parturition. Time spent in contact, maternal responsiveness, latency of response, and maternal rejection were measured and correlated with peripartum excreted cortisol and estradiol metabolite levels. Two indices of peripartum hormonal status were also tested against behavior: the postpartum stress index, and the postpartum cortisol/prepartum estradiol ratio (F/E). Postpartum cortisol levels showed a positive correlation with maternal rejection. The cortisol/estradiol ratio was positively correlated with rejection and latency of response, and negatively correlated with maternal responsiveness. Prepartum cortisol levels and the postpartum stress index did not correlate with any aspect of maternal behavior. Our findings suggest that hypothalamic-pituitary-adrenal (HPA) axis activity per se is not enough to predict the quality of interaction between mother and infant. Only when cortisol is high relative to estradiol could it be symptomatic of a possible negative feedback response involving stress, adrenal activity, and the ability of mothers to cope with the additional problems imposed by newborns.

Endocrine correlates of rank, reproduction, and female-directed aggression in male Japanese macaques (Macaca fuscata).

Fecal testosterone and cortisol levels in six wild male Japanese macaques (Macaca fuscata), three of high rank and three of low, were analyzed to investigate the hormonal correlates of rank, reproduction, and female-directed aggression. The study encompassed the 6-month mating season, from October 1999 to March 2000, during which time 251 fecal samples and approximately 550 h of behavioral data were collected. Dominant males were not found to differ from subordinate males in overall rates of aggressive or copulatory behavior. Likewise, testosterone excretion, which peaked in the early part of the mating season and declined gradually thereafter, did not differ significantly by rank. High-ranking males, however, were observed to excrete significantly higher levels of cortisol than low-ranking males, suggesting that dominance may carry costs. The two hormones were found to be inversely correlated in the two most dominant males, but independent in all others. Rate of noncontact aggression was significantly correlated with testosterone, while no significant relationships were observed between testosterone and contact aggression nor any aspect of copulatory behavior. These data further support the contention that social subordinance and stress are not inexorably linked, as well as suggest that elevated glucocorticoid concentrations in high-ranking males may reflect increased metabolic costs associated with dominant male reproductive strategy.

Fecal testosterone immunoreactivity as a non-invasive index of functional testosterone dynamics in male Japanese macaques (Macaca fuscata).

Validation of a simple method for the extraction and quantification of testosterone (T) from the excreta of male Japanese macaques (Macaca fuscata) is presented. Radioimmunoassay of paired fecal and serum samples collected from four intact sexually mature males during the breeding season provided profiles that were significantly correlated when samples were offset by approximately 48 hr. Additionally, no significant differences were observed in the pattern of temporal variation of T levels in serum and feces. Two castrated males were injected with radioinert T, and the patterns of excretion were observed by analysis of serial fecal and urine samples. Approximately 48 hr after the steroid was administered, a significant peak in the average fecal T levels was apparent. The injection event was also registered in the urine of both males, although qualitative differences were observed. These data suggest that measures of fecal T provide a reliable and non-invasive means of assessing gonadal function in this species. As the analysis of hormone levels in feces allows for frequent, stress-free sampling with minimal disruption, this method should be preferred in long-term or in situ applications requiring endocrine monitoring.