Little is known about the neurobiological pathways through which testosterone promotes aggression or about the people in whom this effect is observed. Using a psychopharmacogenetic approach, we found ...that testosterone increases aggression in men (N = 308) with select personality profiles and that these effects are further enhanced among those with fewer cytosine-adenine-guanine (CAG) repeats in exon 1 of the androgen receptor (AR) gene, a polymorphism associated with increased AR efficiency. Testosterone’s effects were rapid (~30 min after administration) and mediated, in part, by subjective reward associated with aggression. Testosterone thus appears to promote human aggression through an AR-related mechanism and to have stronger effects in men with the select personality profiles because it more strongly upregulates the subjective pleasure they derive from aggression. Given other evidence that testosterone regulates reward through dopaminergic pathways, and that the sensitivity of such pathways is enhanced among individuals with the personality profiles we identified, our findings may also implicate dopaminergic processes in testosterone’s heterogeneous effects on aggression.
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) ...as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
We present the results of an investigation into the biographies, letters, and archives of approximately 50 well-known figures in Western intellectual and artistic history in the post-Enlightenment ...era. In this article, in the interest of space, we have limited our remarks to the biographies and partners of Virginia Woolf, Frida Kahlo, Max Weber, Edna St. Vincent Millay, William Moulton Marston, Erwin Schrodinger, and Victor Hugo. While some of these non-monogamous relationships are well known, some of the evidence of their existence has been ignored, misrecognized, or intentionally obscured. The results of this survey demonstrate that contemporary patterns of non-monogamies are deeply rooted in historical precedence. Our hope is that by outlining some of the themes in our historical findings we can help modern researchers better interpret their own quantitative and qualitative research. Additionally, we look particularly closely at relationships between metamours. A great deal of previous psychological and sexological research has focused on competitive behavior in sex and relationships, particularly competition between rivals. However, relatively little attention has been given to collaborative (or symbiotic) behavior. Our research has located a wealth of examples of metamours supporting one another in material, social, and psychological ways throughout their lives. Furthermore, we suggest that while our existing societal and social-scientific norms primarily focus on competitive sexual behaviors, much can be learnt from historically documented practices of consensual non-monogamy. These practices—however flawed—point to potentially emancipatory ways of living, loving and building relationships, families, and communities—as some contemporary research has demonstrated. Moreover, a future world might benefit from a turn to far more collaborative relationships—and such behavior is well within the realm of possibility.
The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals ...given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and-in high risk men-reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.
The increasing sophistication and prevalence of digital archives, alongside "archival turns" in a number of different disciplines, has meant increasing engagement with archives (digital and ...otherwise) in a variety of new ways. Most notably, this has meant significant interest in the archival field by digital humanists. However, archivists have been far less engaged in the other direction.1 The latest book in the University of Minnesota Press's Debates in the Digital Humanities series, Bodies of Information: Intersectional Feminism and Digital Humanities, is a superb example of the former. The editors are Dr. Elizabeth M. Losh, associate professor of English and American studies at the College of William and Mary, whose work focuses on rhetoric, feminism, digital humanities, and electronic literature; and Dr. Jacqueline Wernimont, Distinguished Chair of Digital Humanities and Social Engagement at Dartmouth College Library and associate professor of women's, gender, and sexuality studies, who previously published on histories of media and technology and how they intersect and interact with archives and historiography.
ABSTRACT
The goal of this paper is to report and discuss findings from an analysis of 14 qualitative semi‐structured interviews with historians and historical researchers on how cataloging systems ...commonly used in cultural heritage institutions such as libraries label and describe works dealing with the history of Indigenous Peoples of North America. These interviews are a subset of a larger project that interviewed 39 creators about their catalog record. In asking authors to evaluate their work's catalog record, this study utilized a novel method and theoretical framework, and therefore was able to derive several recommendations for future research and practice.
Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an ...international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD).
We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations.
In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients.
In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.
Diphtheria is a potentially fatal respiratory disease caused by toxigenic Corynebacterium diphtheriae. Although resistance to erythromycin has been recognized, β-lactam resistance in toxigenic ...diphtheria has not been described. Here, we report a case of fatal respiratory diphtheria caused by toxigenic C. diphtheriae resistant to penicillin and all other β-lactam antibiotics, and describe a novel mechanism of inducible carbapenem resistance associated with the acquisition of a mobile resistance element.
Long-read whole-genome sequencing was performed using Pacific Biosciences Single Molecule Real-Time sequencing to determine the genome sequence of C. diphtheriae BQ11 and the mechanism of β-lactam resistance. To investigate the phenotypic inducibility of meropenem resistance, short-read sequencing was performed using an Illumina NextSeq500 sequencer on the strain both with and without exposure to meropenem.
BQ11 demonstrated high-level resistance to penicillin (benzylpenicillin minimum inhibitory concentration MIC ≥ 256 μg/ml), β-lactam/β-lactamase inhibitors and cephalosporins (amoxicillin/clavulanic acid MIC ≥ 256 μg/mL; ceftriaxone MIC ≥ 8 μg/L). Genomic analysis of BQ11 identified acquisition of a novel transposon carrying the penicillin-binding protein (PBP) Pbp2c, responsible for resistance to penicillin and cephalosporins. When strain BQ11 was exposed to meropenem, selective pressure drove amplification of the transposon in a tandem array and led to a corresponding change from a low-level to a high-level meropenem-resistant phenotype.
We have identified a novel mechanism of inducible antibiotic resistance whereby isolates that appear to be carbapenem susceptible on initial testing can develop in vivo resistance to carbapenems with repeated exposure. This phenomenon could have significant implications for the treatment of C. diphtheriae infection, and may lead to clinical failure.
Like other animals, humans are sensitive to facial cues of threat. Recent evidence suggests that we use this information to dynamically calibrate competitive decision-making over resources, ceding ...more to high-threat individuals (who appear more willing/able to retaliate) and keeping more from low-threat individuals. Little is known, however, about the biological factors that support such threat assessment and decision-making systems. In a pre-registered, double-blind, placebo-controlled, cross-over testosterone administration study ( n = 118 men), we show for the first time that testosterone reduces the effects of threat on decision-making: participants ceded more resources to high-threat (versus low-threat) individuals (replicating the 'threat premium'), but this effect was blunted by testosterone, which selectively reduced the amount of resources ceded to those highest in threat. Thus, our findings suggest that testosterone influences competitive decision-making by recalibrating the integration of threat into the decision-making process.
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