Human platelet activation by Escherichia coli: roles for FcγRIIA and integrin αIIbβ3

Gram-negative Escherichia coli cause diseases such as sepsis and hemolytic uremic syndrome in which thrombotic disorders can be found. Direct platelet–bacterium interactions might contribute to some of these conditions; however, mechanisms of human platelet activation by E. coli leading to thrombus formation are poorly understood. While the IgG receptor FcγRIIA has a key role in platelet response to various Gram-positive species, its role in activation to Gram-negative bacteria is poorly defined. This study aimed to investigate the molecular mechanisms of human platelet activation by E. coli, including the potential role of FcγRIIA. Using light-transmission aggregometry, measurements of ATP release and tyrosine-phosphorylation, we investigated the ability of two E. coli clinical isolates to activate platelets in plasma, in the presence or absence of specific receptors and signaling inhibitors. Aggregation assays with washed platelets supplemented with IgGs were performed to evaluate the requirement of this plasma component in activation. We found a critical role for the immune receptor FcγRIIA, αIIbβ3, and Src and Syk tyrosine kinases in platelet activation in response to E. coli. IgG and αIIbβ3 engagement was required for FcγRIIA activation. Moreover, feedback mediators adenosine 5’-diphosphate (ADP) and thromboxane A₂ (TxA₂) were essential for platelet aggregation. These findings suggest that human platelet responses to E. coli isolates are similar to those induced by Gram-positive organisms. Our observations support the existence of a central FcγRIIA-mediated pathway by which human platelets respond to both Gram-negative and Gram-positive bacteria

The actin binding proteins cortactin and HS1 are dispensable for platelet actin nodule and megakaryocyte podosome formation

A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage. These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation. No effect on tail bleeding time or in thrombosis models was observed. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets

Innovative multi-material tool use in the pant-hoot display of a chimpanzee

‘Pant-hoot displays’ are a species-typical, multi-modal communicative behaviour in chimpanzees in which pant-hoot vocalisations are combined with varied behavioural displays. In both captivity and the wild, individuals commonly incorporate striking or throwing elements of their environment into these displays. In this case study, we present five videos of an unenculturated, captive, adult male chimpanzee combining a large rubber feeding tub with excelsior (wood wool) in a multi-step process, which was then integrated into the subject’s pant-hoot displays as a percussive tool or ‘instrument’. During the construction process, the subject demonstrated an understanding of the relevant properties of these materials, ‘repairing’ the tub to be a more functional drum when necessary. We supplement these videos with a survey of care staff from the study site for additional detail and context. Although care must be taken in generalising data from a single individual, the behaviour reported here hints at three intriguing features of chimpanzee communicative cognition: (1) it suggests a degree of voluntary control over vocal production, (2) it is a so-far unique example of compound tool innovation and use in communicative behaviour and (3) it may represent an example of forward planning in communicative behaviour. Each of these would represent hitherto undocumented dimensions of flexibility in chimpanzee communication, mapping fertile ground for future research

Chimpanzees prioritise social information over pre-existing behaviours in a group context but not in dyads

Funding: John Templeton Foundation (US) (40128).How animal communities arrive at homogeneous behavioural preferences is a central question for studies of cultural evolution. Here, we investigated whether chimpanzees (Pan troglodytes) would relinquish a pre-existing behaviour to adopt an alternative demonstrated by an overwhelming majority of group mates; in other words, whether chimpanzees behave in a conformist manner. In each of five groups of chimpanzees (N = 37), one individual was trained on one method of opening a two-action puzzle box to obtain food, while the remaining individuals learned the alternative method. Over 5 h of open access to the apparatus in a group context, it was found that 4/5 ‘minority’ individuals explored the majority method and three of these used this new method in the majority of trials. Those that switched did so after observing only a small subset of their group, thereby not matching conventional definitions of conformity. In a further ‘Dyad’ condition, six pairs of chimpanzees were trained on alternative methods and then given access to the task together. Only one of these individuals ever switched method. The number of observations that individuals in the minority and Dyad individuals made of their untrained method was not found to influence whether or not they themselves switched to use it. In a final ‘Asocial’ condition, individuals (N = 10) did not receive social information and did not deviate from their first-learned method. We argue that these results demonstrate an important influence of social context upon prioritisation of social information over pre-existing methods, which can result in group homogeneity of behaviour.Publisher PDFPeer reviewe

Plasmas and Controlled Nuclear Fusion

Contains reports on two research projects.U. S. Atomic Energy Commission (Contract AT(11-1)-3070

The gravitational S-matrix

We investigate the hypothesized existence of an S-matrix for gravity, and some of its expected general properties. We first discuss basic questions regarding existence of such a matrix, including those of infrared divergences and description of asymptotic states. Distinct scattering behavior occurs in the Born, eikonal, and strong gravity regimes, and we describe aspects of both the partial wave and momentum space amplitudes, and their analytic properties, from these regimes. Classically the strong gravity region would be dominated by formation of black holes, and we assume its unitary quantum dynamics is described by corresponding resonances. Masslessness limits some powerful methods and results that apply to massive theories, though a continuation path implying crossing symmetry plausibly still exists. Physical properties of gravity suggest nonpolynomial amplitudes, although crossing and causality constrain (with modest assumptions) this nonpolynomial behavior, particularly requiring a polynomial bound in complex s at fixed physical momentum transfer. We explore the hypothesis that such behavior corresponds to a nonlocality intrinsic to gravity, but consistent with unitarity, analyticity, crossing, and causality.Comment: 46 pages, 10 figure

Chimpanzees demonstrate individual differences in social information use

Studies of transmission biases in social learning have greatly informed our understanding of how behaviour patterns may diffuse through animal populations, yet within-species inter-individual variation in social information use has received little attention and remains poorly understood. We have addressed this question by examining individual performances across multiple experiments with the same population of primates. We compiled a dataset spanning 16 social learning studies (26 experimental conditions) carried out at the same study site over a 12-year period, incorporating a total of 167 chimpanzees. We applied a binary scoring system to code each participant’s performance in each study according to whether they demonstrated evidence of using social information from conspecifics to solve the experimental task or not (Social Information Score—‘SIS’). Bayesian binomial mixed effects models were then used to estimate the extent to which individual differences influenced SIS, together with any effects of sex, rearing history, age, prior involvement in research and task type on SIS. An estimate of repeatability found that approximately half of the variance in SIS was accounted for by individual identity, indicating that individual differences play a critical role in the social learning behaviour of chimpanzees. According to the model that best fit the data, females were, depending on their rearing history, 15–24% more likely to use social information to solve experimental tasks than males. However, there was no strong evidence of an effect of age or research experience, and pedigree records indicated that SIS was not a strongly heritable trait. Our study offers a novel, transferable method for the study of individual differences in social learning

Impact of preoperative therapy on patterns of recurrence in pancreatic cancer

AbstractBackgroundA theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence.MethodsMedical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan–Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis.ResultsPreoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease-free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis.ConclusionsPreoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection

Nonadjacent dependency processing in monkeys, apes and humans

The ability to track syntactic relationships between words, particularly over distances (“nonadjacent dependencies”), is a critical faculty underpinning human language, although its evolutionary origins remain poorly understood. While some monkey species are reported to process auditory nonadjacent dependencies, comparative data from apes are missing, complicating inferences regarding shared ancestry. Here, we examined nonadjacent dependency processing in common marmosets, chimpanzees, and humans using “artificial grammars”: strings of arbitrary acoustic stimuli composed of adjacent (nonhumans) or nonadjacent (all species) dependencies. Individuals from each species (i) generalized the grammars to novel stimuli and (ii) detected grammatical violations, indicating that they processed the dependencies between constituent elements. Furthermore, there was no difference between marmosets and chimpanzees in their sensitivity to nonadjacent dependencies. These notable similarities between monkeys, apes, and humans indicate that nonadjacent dependency processing, a crucial cognitive facilitator of language, is an ancestral trait that evolved at least ~40 million years before language itself

Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αiIbβ3, and platelet factor 4

Bacterial adhesion to platelets is mediated via a range of strain-specific bacterial surface proteins that bind to a variety of platelet receptors. It is unclear how these interactions lead to platelet activation. We demonstrate a critical role for the immune receptor FcγRIIA, αIIbβ3, and Src and Syk tyrosine kinases in platelet activation by Staphylococcus aureus, Streptococcus sanguinis, Streptococcus gordonii, Streptococcus oralis, and Streptococcus pneumoniae. FcγRIIA activation is dependent on immunoglobulin G (IgG) and αIIbβ3 engagement. Moreover, feedback agonists adenosine 59-diphosphate and thromboxane A2 aremandatory for platelet aggregation. Additionally, platelet factor 4 (PF4) binds to bacteria and reduces the lag time for aggregation, and gray platelet syndromea-granule-deficient platelets do not aggregate to 4 of 5 bacterial strains. We propose that FcγRIIA-mediated activation is a common response mechanism used against a wide range of bacteria, and that release of secondary mediators and PF4 serve as a positive feedback mechanism for activation through an IgG-dependent pathway. © 2014 by The American Society of Hematology