Exclusion from social relationships is a painful experience that may threaten an individual’s status and dominance. The steroid hormone testosterone, which fluctuates rapidly in response to such ...threats, may be implicated in subsequent behavioral action (e.g., aggressive or prosocial responses) that aims to protect or enhance one’s status after exclusion. Past research, however, indicates that the link between acute changes in testosterone and behavior depend on context-relevant individual dispositions. In the context of social exclusion, an individual’s level of shame proneness—characterized by a tendency to experience shame and to react submissively—is theoretically relevant to the testosterone-induced aggression relationship but has yet to be examined empirically. Here, men (n = 167) were randomly assigned to be socially included or excluded in the virtual ball-tossing game, Cyberball, after which aggressive behavior was examined using the Point Subtraction Aggression Paradigm (PSAP). Testosterone reactivity was measured via salivary hormone samples collected pre- and post-game. Moderated multiple regression analyses were run to examine the extent to which testosterone reactivity and shame proneness moderated the effect of Cyberball condition on aggression. Results revealed a significant two-way interaction between Cyberball condition and testosterone reactivity, as well as a three-way interaction including shame proneness. For individuals low in shame proneness, exclusion was associated with higher post-cyberball aggression among those who experienced a rise in testosterone but was associated with lower post-cyberball aggression among those who experienced a decrease in testosterone. For individuals high in shame proneness, however, exclusion did not meaningfully affect aggressive responses, regardless of whether they experienced an increase or decrease in testosterone. These findings extend our understanding of the moderating roles of context and disposition on the neuroendocrinology of aggression in social interaction
•Testosterone-aggression relationship has been shown to be dependent on moderators.•Shame proneness is associated with behavioral withdrawal and submission.•Testosterone predicts aggression in excluded participants low in shame proneness.•No association with aggression in participants high in shame proneness.•High shame proneness may motivate submission regardless of testosterone reactivity.
BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent ...and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid β lowering in nonclinical animal models. Similar potent and persistent amyloid β lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
According to the amyloid cascade hypothesis, cerebral deposition of amyloid-β peptide (Aβ) is critical for Alzheimer's disease (AD) pathogenesis. Aβ generation is initiated when β-secretase (BACE1) ...cleaves the amyloid precursor protein. For more than a decade, BACE1 has been a prime target for designing drugs to prevent or treat AD. However, development of such agents has turned out to be extremely challenging, with major hurdles in cell penetration, oral bioavailability/metabolic clearance, and brain access. Using a fragment-based chemistry strategy, we have generated LY2811376 (S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-1,3thiazin-2-ylamine, the first orally available non-peptidic BACE1 inhibitor that produces profound Aβ-lowering effects in animals. The biomarker changes obtained in preclinical animal models translate into man at doses of LY2811376 that were safe and well tolerated in healthy volunteers. Prominent and long-lasting Aβ reductions in lumbar CSF were measured after oral dosing of 30 or 90 mg of LY2811376. This represents the first translation of BACE1-driven biomarker changes in CNS from preclinical animal models to man. Because of toxicology findings identified in longer-term preclinical studies, this compound is no longer progressing in clinical development. However, BACE1 remains a viable target because the adverse effects reported here were recapitulated in LY2811376-treated BACE1 KO mice and thus are unrelated to BACE1 inhibition. The magnitude and duration of central Aβ reduction obtainable with BACE1 inhibition positions this protease as a tractable small-molecule target through which to test the amyloid hypothesis in man.
This paper originated from a collaborative effort between an academic and archivist and a cataloger to address the issues around the LCSH heading “Social disabilities.” In it, we examine various ...aspects and consequences resulting from the ways that galleries, libraries, archives, museums, and special collections (GLAMS) organize knowledge about disability and disabled users. We do this primarily through the lens of documentary analysis of cataloging and classification systems as this process, elsewhere called “the power to name” (Olson, 2002), as it is the basis for the operation of GLAMS. First, we will provide an outline and contextual information about the Library of Congress Subject Headings (LCSH), the largest and most influential subject heading vocabulary system in the world. Next, we will examine the discourse around disability in library and information science via the results of a literature review. Next, we will examine the history, transformations, use, and meaning behind the LCSH heading “Social disabilities,” as an example of breakdown in terminology. Finally, and unique to the literature, we will propose an alternative hierarchy of terms for the Persons hierarchy in LCSH and discuss other methods that catalogers may use for organizing holdings about disability.
This paper examines the addition of "asexuality" to the Library of Congress Subject Headings as a case study from which to examine the critical cataloging movement. Beginning with a review of some of ...the theoretical and practical issues around subject access for minoritized and marginalized sexualities, this paper then contextualizes, historicizes, and introduces the critical cataloging movement to the literature, situating it within a larger and longer history of radical cataloging. It will define critical cataloging as a social justice-oriented style of radical cataloging that places an emphasis on radical empathy, outreach work, and recognizes the importance of information maintenance and care. This paper introduces the concept of "catalogic warrant" to characterize the process of "reading" the catalog to examine the harm or benefit of terms on users and the wider library community.
The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). ...The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.
Triple pnictogen bonding refers to the ability of a pnictogen atom to engage in three simultaneous pnictogen bonds (PnBs) to a complementary partner through a single pnictogen atom. This ...supramolecular strategy was recently introduced as a unique facet of pnictogen bonding as compared to other named supramolecular interactions. Here, the ability of bismuth to participate in this phenomenon is demonstrated using Bi((NC9H7)3CH3). The study reveals that Bi engages in stronger PnBs than the analogous Sb system. The results have been contrasted with Bi systems that form strong coordination bonds, and analysis of the electron density along the bond path reveals key differences. The solution behavior of these newly synthesized supramolecules were studied by PFGSE NMR spectroscopy and they are found to remain intact in solution. Molecular design strategies that allow for triple pnictogen bonding should find use in the fields of molecular recognition and crystal engineering.
The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer’s disease drug target owing to its critical role in the production of amyloid-beta. We have previously ...reported the clinical development of LY2811376 and LY2886721. LY2811376 advanced to Phase I before development was terminated due to nonclinical retinal toxicity. LY2886721 advanced to Phase II, but development was halted due to abnormally elevated liver enzymes. Herein, we report the discovery and clinical development of LY3202626, a highly potent, CNS-penetrant, and low-dose BACE inhibitor, which successfully addressed these key development challenges.
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