The natural stilbenoid (-)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7, and B.1.351 variants

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID- 19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 mM, in contrast to an IC50 of 28.3 mM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVDG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC50s], 10.2 to 23.4 mM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC50s, 1.0 to 7.3 mM). Notably, (-)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern

Parkin Ubiquitination of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson\u27s disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does not affect tumor cell proliferation, cell cycle transitions, or apoptosis. Expression of a Parkin Ub-resistant K2 Lys581Ala/Lys582Ala double mutant is sufficient to restore membrane lamellipodia dynamics, correct mitochondrial fusion/fission, and preserve single-cell migration and invasion. In a 3D model of mammary gland developmental morphogenesis, impaired K2 Ub drives multiple oncogenic traits of EMT, increased cell proliferation, reduced apoptosis, and disrupted basal-apical polarity. Therefore, deregulated K2 is a potent oncogene, and its Ub by Parkin enables mitochondria-associated metastasis suppression

Can Sophie's Choice Be Adequately Captured by Cold Computation of Minimizing Losses? An fMRI Study of Vital Loss Decisions

The vast majority of decision-making research is performed under the assumption of the value maximizing principle. This principle implies that when making decisions, individuals try to optimize outcomes on the basis of cold mathematical equations. However, decisions are emotion-laden rather than cool and analytic when they tap into life-threatening considerations. Using functional magnetic resonance imaging (fMRI), this study investigated the neural mechanisms underlying vital loss decisions. Participants were asked to make a forced choice between two losses across three conditions: both losses are trivial (trivial-trivial), both losses are vital (vital-vital), or one loss is trivial and the other is vital (vital-trivial). Our results revealed that the amygdala was more active and correlated positively with self-reported negative emotion associated with choice during vital-vital loss decisions, when compared to trivial-trivial loss decisions. The rostral anterior cingulate cortex was also more active and correlated positively with self-reported difficulty of choice during vital-vital loss decisions. Compared to the activity observed during trivial-trivial loss decisions, the orbitofrontal cortex and ventral striatum were more active and correlated positively with self-reported positive emotion of choice during vital-trivial loss decisions. Our findings suggest that vital loss decisions involve emotions and cannot be adequately captured by cold computation of minimizing losses. This research will shed light on how people make vital loss decisions

The physical properties of slash pine semi-chemical kraft pulp and of its fully chlorited component

Ph.D

Accounting for time preference in management decisions: an application to invasive species

Managers of invasive species seek to prevent and mitigate their impact, which vary in the time horizon over which they are realized. Likewise, stakeholders vary in the time horizons they consider relevant. Agricultural impacts might reasonably be considered over two or three decades, although ecologists typically consider environmental impacts over much longer time frames. Although time preference plays a critical role in decision making, it has largely been ignored in multicriteria analyses. In this study, we examine how time has been treated in previous decision analyses of invasive species management, focusing on the differences between multicriteria and economic cost-benefit analyses. We then outline a method for incorporating time preference information into multicriteria decision analyses to ensure that criteria weights remain a faithful representation of the decision maker's preferences. To illustrate how time preference can be elicited for invasive species problems involving both monetary and nonmonetary consequences, we describe a small empirical study we conducted with a small group of experts and managers. By outlining a way to consider time preference information in multicriteria analyses of invasive species management, we hope to facilitate better decision making that is reflective of the decision maker's true preferences

A detection model of college withdrawal A detection model of college withdrawal

a b s t r a c t Many students during their college careers consider withdrawing from their respective college or university. Understanding why some students decide to withdraw yet others persist has implications for both the well being of students as well as for institutes of higher education. The present study develops a model of the decision to withdraw drawing on theories of voluntary employee turnover from organizational psychology and signal detection theory from the cognitive sciences. The model posits that precipitating events or shocks (e.g., changes in tuition) lead students to consider withdrawing from the university. If the evidence surpasses a criterion then the student decides to withdraw. The model was used to identify shocks students were sensitive to and to test hypotheses about the underlying decision process. The theoretical implications of this model in terms of understanding and predicting student withdrawal decisions and voluntary employee turnover decisions are discussed. Ó 2010 Elsevier Inc. All rights reserved. A detection model of college withdrawal An unavoidable fact in higher education is that some students persist in obtaining a degree, while others withdraw. The National Center for Education Statistics reported that only 57% of bachelor's or equivalent degree-seekers that began college in 2001 had within 6 years graduated from that same college. This overall completion rate is qualified by a number of dimensions. Females have a greater completion rate than males (60% vs. 54%). Completion rates also differ by race and ethnicity, with Asian/Pacific Islanders having the highest rate and American Indian/Alaskan natives the lowest (66% and 40%, respectively; Knapp, Most descriptive level explanations of student retention are structural in nature. They focus on how academic, social-psychological, and environmental factors, predict intermediate attitudes such as different levels of satisfaction and perceptions of poor fit with the university setting, which in turn predict college turnover Formal cognitive models Before going further we should clarify what a formal cognitive model is and why it is important in theory development. A formal cognitive model uses mathematical or computer language to specify how basic cognitive processes give rise to a phenomenon of interest Formal cognitive models also differ in important ways from other models often used in psychology. By formally specifying a theory in mathematical language the model can synthesize the process and/or system in an observable and testable form. In other words, one can use the model to see how the process works (or does not work) to produce the behavior of interest (e.g., a decision). One can also then add or subtract features to the model (e.g., variability) or change parameter values within the model and then 0749-5978/$ -see front matter

A detection model of college withdrawal

Many students during their college careers consider withdrawing from their respective college or university. Understanding why some students decide to withdraw yet others persist has implications for both the well being of students as well as for institutes of higher education. The present study develops a model of the decision to withdraw drawing on theories of voluntary employee turnover from organizational psychology and signal detection theory from the cognitive sciences. The model posits that precipitating events or shocks (e.g., changes in tuition) lead students to consider withdrawing from the university. If the evidence surpasses a criterion then the student decides to withdraw. The model was used to identify shocks students were sensitive to and to test hypotheses about the underlying decision process. The theoretical implications of this model in terms of understanding and predicting student withdrawal decisions and voluntary employee turnover decisions are discussed.College withdrawal Signal detection theory Shocks Turnover Quit