Stereotype research emphasizes systematic processes over seemingly arbitrary contents, but content also may prove systematic. On the basis of stereotypes' intergroup functions, the stereotype content model hypothesizes that (a) 2 primary dimensions are competence and warmth, (b) frequent mixed clusters combine high warmth with low competence (paternalistic) or high competence with low warmth (envious), and (c) distinct emotions (pity, envy, admiration, contempt) differentiate the 4 competence-warmth combinations. Stereotypically, (d) status predicts high competence, and competition predicts low warmth. Nine varied samples rated gender, ethnicity, race, class, age, and disability out-groups. Contrary to antipathy models, 2 dimensions mattered, and many stereotypes were mixed, either pitying (low competence, high warmth subordinates) or envying (high competence, low warmth competitors). Stereotypically, status predicted competence, and competition predicted low warmth.

Hyper–inflammatory responses can lead to a variety of diseases including sepsis1. We now report that extracellular histones released in response to inflammatory challenge contribute to endothelial dysfunction, organ failure and death during sepsis. They can be targeted pharmacologically by antibody to histone or by activated protein C (APC). Antibody to histone reduced the mortality of mice in lipopolysaccharide (LPS), tumor necrosis factor (TNF) or cecal ligation and puncture models of sepsis. Extracellular histones are cytotoxic toward endothelium in vitro and are lethal in mice. In vivo, histone administration resulted in neutrophil margination, vacuolated endothelium, intra–alveolar hemorrhage and macro and microvascular thrombosis. Histone was detected in the circulation of baboons challenged with E. coli and the increase in histone levels accompanied the onset of renal dysfunction. APC cleaves histones and reduces their cytotoxicity. Co–infusion of APC with E. coli in baboons or histones in mice prevented lethality. Blockade of protein C activation exacerbated sublethal LPS challenge into lethality which was reversed by antibody to histone. We conclude that extracellular histones are potential molecular targets for therapeutics for sepsis and other inflammatory diseases.

We previously reported that extracellular histones are major mediators of death in sepsis. Infusion of extracellular histones leads to increased cytokine levels. Histones activate TLR 2 and 4 in a process that is enhanced by binding to DNA. Activation of TLR4 is responsible for the histone dependent increase in cytokine levels. To study the impact of histone release on pathology we used two models: a concanavalin A (ConA) triggered activation of T cells to mimic sterile inflammation and acetaminophen (APAP), to model drug induced tissue toxicity. Histones were released in both models and anti-histone antibodies were protective. TLR 2 or TLR 4 null mice were also protected. These studies imply that histone release contributes to death in inflammatory injury and in chemical induced cellular injury, both of which are mediated in part through the toll-like receptors.

Synaptotagmin-1 and -2 are known Ca(2+) sensors for fast synchronous neurotransmitter release, but the potential Ca(2+)-sensor functions of other synaptotagmins in release remain uncharacterized. We now show that besides synaptotagmin-1 and -2, only synaptotagmin-9 (also called synaptotagmin-5) mediates fast Ca(2+) triggering of release. Release induced by the three different synaptotagmin Ca(2+) sensors exhibits distinct kinetics and apparent Ca(2+) sensitivities, suggesting that the synaptotagmin isoform expressed by a neuron determines the release properties of its synapses. Conditional knockout mice producing GFP-tagged synaptotagmin-9 revealed that synaptotagmin-9 is primarily expressed in the limbic system and striatum. Acute deletion of synaptotagmin-9 in striatal neurons severely impaired fast synchronous release without changing the size of the readily-releasable vesicle pool. These data show that in mammalian brain, only synaptotagmin-1, -2, and -9 function as Ca(2+) sensors for fast release, and that these synaptotagmins are differentially expressed to confer distinct release properties onto synapses formed by defined subsets of neurons.

Spontaneous ‘mini’ release occurs at all synapses, but its nature remains enigmatic. Here, we show that in murine cortical neurons, >95% of spontaneous release is induced by Ca2+-binding to synaptotagmin-1, the Ca2+-sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release use the same Ca2+-dependent release mechanism. As a consequence, synaptotagmin-1 mutations that alter its Ca2+-affinity alter spontaneous and evoked release correspondingly. Paradoxically, synaptotagmin-1 deletions (as opposed to point mutations) massively increase spontaneous release. This increased spontaneous release remains Ca2+-dependent, but is activated at lower Ca2+-concentrations, and with a lower Ca2+-cooperativity, than synaptotagmin-driven spontaneous release. Thus, in addition to serving as Ca2+-sensor for spontaneous and evoked release, synaptotagmin-1 clamps a second, more sensitive Ca2+-sensor for spontaneous release which resembles the Ca2+-sensor for evoked asynchronous release. Viewed together, these data suggest that synaptotagmin-1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.

Sterile inflammatory insults are known to activate innate immunity and propagate organ damage through the recognition of extracellular Damage Associated Molecular Pattern (DAMP) molecules. Although DAMPs, such as endogenous DNA and nuclear High Mobility Group Box 1, have been shown to be critical in sterile inflammation, the role of nuclear histone proteins has not yet been investigated. We report that endogenous histones function as DAMPs following ischemic injury through the pattern recognition receptor Toll-Like Receptor 9 (TLR9) to initiate inflammation. Using an in vivo model of hepatic ischemia/reperfusion (I/R) injury, we show that levels of circulating histones are significantly higher after I/R, and that histone neutralization significantly protects against injury. Injection of exogenous histones exacerbates I/R injury through cytotoxic effects mediated by TLR9 and MyD88. In addition, histone administration increases TLR9 activation, while neither TLR9 nor MyD88 mutant mice respond to exogenous histones. Furthermore, we demonstrate in vitro that extracellular histones enhance DNA-mediated TLR9 activation in immune cells through a direct interaction. Conclusions these novel findings reveal that histones represent a new class of DAMP molecules and they serve as a crucial link between initial damage and activation of innate immunity during sterile inflammation.

Histones enhance plasma thrombin generation by reducing TM-dependent protein C activation. This mechanism might contribute to microvascular thrombosis induced by histones in vivo at sites of organ failure or severe inflammation.

Research has demonstrated that certain genotypes are expressed in different forms, depending on input from the social environment. To examine sensitivity to cultural norms regarding emotional support seeking as a type of social environment, we explored the behavioral expression of oxytocin receptor polymorphism (OXTR) rs53576, a gene previously related to socio-emotional sensitivity. Seeking emotional support in times of distress is normative in American culture but not in Korean culture. Consequently, we predicted a three-way interaction of culture, distress, and OXTR genotype on emotional support seeking. Korean and American participants (n = 274) completed assessments of psychological distress and emotional support seeking and were genotyped for OXTR. We found the predicted three-way interaction: among distressed American participants, those with the GG/AG genotypes reported seeking more emotional social support, compared with those with the AA genotype, whereas Korean participants did not differ significantly by genotype; under conditions of low distress, OXTR groups did not differ significantly in either cultural group. These findings suggest that OXTR rs53576 is sensitive to input from the social environment, specifically cultural norms regarding emotional social support seeking. These findings also indicate that psychological distress and culture are important moderators that shape behavioral outcomes associated with OXTR genotypes.genetics | social support | psychological distress | stress coping | gene-by-culture interaction