EVL and MIM/MTSS1 regulate actin cytoskeletal remodeling to promote dendritic filopodia in neurons.

Dendritic spines are the postsynaptic compartment of a neuronal synapse and are critical for synaptic connectivity and plasticity. A developmental precursor to dendritic spines, dendritic filopodia (DF), facilitate synapse formation by sampling the environment for suitable axon partners during neurodevelopment and learning. Despite the significance of the actin cytoskeleton in driving these dynamic protrusions, the actin elongation factors involved are not well characterized. We identified the Ena/VASP protein EVL as uniquely required for the morphogenesis and dynamics of DF. Using a combination of genetic and optogenetic manipulations, we demonstrated that EVL promotes protrusive motility through membrane-direct actin polymerization at DF tips. EVL forms a complex at nascent protrusions and DF tips with MIM/MTSS1, an I-BAR protein important for the initiation of DF. We proposed a model in which EVL cooperates with MIM to coalesce and elongate branched actin filaments, establishing the dynamic lamellipodia-like architecture of DF.

Getting unstuck: The effects of growth mindsets about the self and job on happiness at work.

Past research on growth mindsets has focused on the benefits of viewing the self as flexible rather than fixed. We propose that employees can make more substantial agentic changes to their work experiences if they also hold growth mindsets about their job designs. We introduce the concept of dual-growth mindset-viewing both the self and job as malleable-and examine its impact on employee happiness over time. We hypothesize that fostering a dual-growth mindset yields relatively durable gains in happiness, while fostering a growth mindset about either the self or job is insufficient for sustainable increases in happiness. We tested these predictions using two experimental studies: a field quasi-experiment in a Fortune 500 technology company and a controlled experiment with employees in a variety of organizations and occupations. Across the two experiments, fostering dual-growth mindset yielded gains in self-reported and observer-rated happiness that lasted at least 6 months. Fostering growth mindsets about either the self or job alone did not generate lasting increases in happiness. Supplementary mediation analyses suggest dual-growth mindsets boosted happiness by enabling employees to plan more substantial job crafting. Our research suggests that durable gains in happiness at work depend on holding flexible mindsets about the job, not only the self. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Social Motivation at Work: The Organizational Psychology of Effort for, Against, and with Others.

Although a great deal of effort in tasks, projects, and jobs is fueled by our interactions and relationships, psychologists have often overlooked the social forces that shape work motivation. In this review, we examine new developments in research on the interpersonal dynamics that enable and constrain proactivity, persistence, performance, and productivity. The first section examines the impact of competition on work motivation, including the roles of rivalries, favorite versus underdog expectations, and status strivings. The second section focuses on when and how prosocial motivation can drive people to work harder, smarter, safer, and more collaboratively, as well as on the antecedents and collective consequences of this desire to benefit others. The third section centers on motivation in collaborations, emphasizing contagion, social proximity, friendship, and the motivation to lead. Together, these literatures suggest that although rivalries and friendships are double-edged swords, the twin goals to compete and contribute can be harnessed constructively.

Molecular drivers of tumor progression in microsatellite stable APC mutation-negative colorectal cancers.

The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut-) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut- and APC mutation-positive (APCmut+) microsatellite stable CRCs. Transcriptionally, APCmut- CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut- CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APCmut- CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways.

Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning.

While the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo. Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.

Generating Ensembles of Gene Regulatory Networks to Assess Robustness of Disease Modules.

The use of biological networks such as protein-protein interaction and transcriptional regulatory networks is becoming an integral part of genomics research. However, these networks are not static, and during phenotypic transitions like disease onset, they can acquire new "communities" (or highly interacting groups) of genes that carry out cellular processes. Disease communities can be detected by maximizing a modularity-based score, but since biological systems and network inference algorithms are inherently noisy, it remains a challenge to determine whether these changes represent real cellular responses or whether they appeared by random chance. Here, we introduce Constrained Random Alteration of Network Edges (CRANE), a method for randomizing networks with fixed node strengths. CRANE can be used to generate a null distribution of gene regulatory networks that can in turn be used to rank the most significant changes in candidate disease communities. Compared to other approaches, such as consensus clustering or commonly used generative models, CRANE emulates biologically realistic networks and recovers simulated disease modules with higher accuracy. When applied to breast and ovarian cancer networks, CRANE improves the identification of cancer-relevant GO terms while reducing the signal from non-specific housekeeping processes.

Interrogating Mutant Allele Expression via Customized Reference Genomes to Define Influential Cancer Mutations.

Genetic alterations are essential for cancer initiation and progression. However, differentiating mutations that drive the tumor phenotype from mutations that do not affect tumor fitness remains a fundamental challenge in cancer biology. To better understand the impact of a given mutation within cancer, RNA-sequencing data was used to categorize mutations based on their allelic expression. For this purpose, we developed the MAXX (Mutation Allelic Expression Extractor) software, which is highly effective at delineating the allelic expression of both single nucleotide variants and small insertions and deletions. Results from MAXX demonstrated that mutations can be separated into three groups based on their expression of the mutant allele, lack of expression from both alleles, or expression of only the wild-type allele. By taking into consideration the allelic expression patterns of genes that are mutated in PDAC, it was possible to increase the sensitivity of widely used driver mutation detection methods, as well as identify subtypes that have prognostic significance and are associated with sensitivity to select classes of therapeutic agents in cell culture. Thus, differentiating mutations based on their mutant allele expression via MAXX represents a means to parse somatic variants in tumor genomes, helping to elucidate a gene's respective role in cancer.

The mixed effects of online diversity training.

We present results from a large (n = 3,016) field experiment at a global organization testing whether a brief science-based online diversity training can change attitudes and behaviors toward women in the workplace. Our preregistered field experiment included an active placebo control and measured participants' attitudes and real workplace decisions up to 20 weeks postintervention. Among groups whose average untreated attitudes-whereas still supportive of women-were relatively less supportive of women than other groups, our diversity training successfully produced attitude change but not behavior change. On the other hand, our diversity training successfully generated some behavior change among groups whose average untreated attitudes were already strongly supportive of women before training. This paper extends our knowledge about the pathways to attitude and behavior change in the context of bias reduction. However, the results suggest that the one-off diversity trainings that are commonplace in organizations are unlikely to be stand-alone solutions for promoting equality in the workplace, particularly given their limited efficacy among those groups whose behaviors policymakers are most eager to influence.

Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due to any established mechanism or published biomarker. Rather, there is a KRAS-dependent rapid adaptive response that leads to the upregulation of cyclin proteins, which participate in functional complexes to mediate resistance. In vivo, the degree of response is associated with the suppression of a gene expression signature that is strongly prognostic in pancreatic cancer. Resistance is associated with an adaptive gene expression signature that is common to multiple kinase inhibitors, but is attenuated with MTOR inhibitors. Combination treatment with MTOR and CDK4/6 inhibitors had potent activity across a large number of patient-derived models of PDAC underscoring the potential clinical efficacy.

Hale and Hearty Policies: How Psychological Science Can Create and Maintain Healthy Habits.

Strategies are needed to ensure that the U.S. Government meets its goals for improving the health of the nation (e.g., Healthy People 2020). To date, progress toward these goals has been undermined by a set of discernible challenges: People lack sufficient motivation, they frequently fail to translate healthy intentions into action, their efforts are undermined by the persistence of prior unhealthy habits, and they have considerable difficulty maintaining new healthy patterns of behavior. Guided by advances in psychological science, we provide innovative, evidence-based policies that address each of these challenges and, if implemented, will enhance people's ability to create and maintain healthy behavioral practices.

Convincing Yourself to Care About Others: An Intervention for Enhancing Benevolence Values.

To study value change, this research presents an intervention with multiple exercises designed to instigate change through both effortful and automatic routes. Aiming to increase the importance attributed to benevolence values, which reflect the motivation to help and care for others, the intervention combines three mechanisms for value change (self-persuasion, consistency-maintenance, and priming). In three experiments, 142 undergraduates (67% male, ages 19-26) participated in an intervention emphasizing the importance of either helping others (benevolence condition) or recognizing flexibility in personality (control condition). We measured the importance of benevolence values before and after the task. In Experiment 1, the intervention increased U.S. participants' benevolence values. In Experiment 2, we replicated these effects in a different culture (Israel) and also showed that by enhancing benevolence values, the intervention increased participants' willingness to volunteer to help others. Experiment 3 showed that the increases in the importance of benevolence values lasted at least 4 weeks. Our results provide evidence that value change does not require fictitious feedback or information about social norms, but can occur through a 30-min intervention that evokes both effortful and automatic processes.

When in doubt, seize the day? Security values, prosocial values, and proactivity under ambiguity.

Researchers have suggested that both ambiguity and values play important roles in shaping employees' proactive behaviors, but have not theoretically or empirically integrated these factors. Drawing on theories of situational strength and values, we propose that ambiguity constitutes a weak situation that strengthens the relationship between the content of employees' values and their proactivity. A field study of 204 employees and their direct supervisors in a water treatment plant provided support for this contingency perspective. Ambiguity moderated the relationship between employees' security and prosocial values and supervisor ratings of proactivity. Under high ambiguity, security values predicted lower proactivity, whereas prosocial values predicted higher proactivity. Under low ambiguity, values were not associated with proactivity. We replicated these findings in a laboratory experiment with 232 participants in which we measured proactivity objectively as initiative taken to correct errors: Participants with strong security values were less proactive, and participants with strong prosocial values were more proactive, but only when performance expectations were ambiguous. We discuss theoretical implications for research on proactivity, values, and ambiguity and uncertainty.

Rethinking the extraverted sales ideal: the ambivert advantage.

Despite the widespread assumption that extraverts are the most productive salespeople, research has shown weak and conflicting relationships between extraversion and sales performance. In light of these puzzling results, I propose that the relationship between extraversion and sales performance is not linear but curvilinear: Ambiverts achieve greater sales productivity than extraverts or introverts do. Because they naturally engage in a flexible pattern of talking and listening, ambiverts are likely to express sufficient assertiveness and enthusiasm to persuade and close a sale but are more inclined to listen to customers' interests and less vulnerable to appearing too excited or overconfident. A study of 340 outbound-call-center representatives supported the predicted inverted-U-shaped relationship between extraversion and sales revenue. This research presents a fresh perspective on the personality traits that facilitate successful influence and offers novel insights for people in choosing jobs and for organizations in hiring and training employees.

In the company of givers and takers.

Employees make decisions every day about whether to contribute to others--and their willingness to help is crucial to group and organizational effectiveness. But in a competitive, often zero-sum, world of work, generosity can be a dangerous path. How can leaders foster it without cutting into productivity, undermining fairness, and allowing employees to become doormats? The key, explains Wharton's Adam Grant, is to help givers reach a more nuanced understanding of what generosity is and is not. They'll be better positioned for sustainable giving when they can distinguish generosity from three attributes that often travel with it: timidity, availability, and empathy. Givers can overcome timidity, Grant says, by learning to act as agents--using "relational accounts" to advocate for others while negotiating for themselves. They can set boundaries on when, how, and whom to help. And they can strive to be perspective takers, not just empathizers, gathering knowledge about others that can lead to more-productive allocations of time that will benefit the organization as a whole.

Beneficiary or benefactor: are people more prosocial when they reflect on receiving or giving?

Research shows that reflecting on benefits received can make people happier, but it is unclear whether or not such reflection makes them more helpful. Receiving benefits can promote prosocial behavior through reciprocity and positive affect, but these effects are often relationship-specific, short-lived, and complicated by ambivalent reactions. We propose that prosocial behavior is more likely when people reflect on being a benefactor to others, rather than a beneficiary. The experience of giving benefits may encourage prosocial behavior by increasing the salience and strength of one's identity as a capable, caring contributor. In field and laboratory experiments, we found that participants who reflected about giving benefits voluntarily contributed more time to their university, and were more likely to donate money to natural-disaster victims, than were participants who reflected about receiving benefits. When it comes to reflection, giving may be more powerful than receiving as a driver of prosocial behavior.

It's not all about me: motivating hand hygiene among health care professionals by focusing on patients.

Diseases often spread in hospitals because health care professionals fail to wash their hands. Research suggests that to increase health and safety behaviors, it is important to highlight the personal consequences for the actor. However, because people (and health care professionals in particular) tend to be overconfident about personal immunity, the most effective messages about hand hygiene may be those that highlight its consequences for other people. In two field experiments in a hospital, we compared the effectiveness of signs about hand hygiene that emphasized personal safety ("Hand hygiene prevents you from catching diseases") or patient safety ("Hand hygiene prevents patients from catching diseases"). We assessed hand hygiene by measuring the amount of soap and hand-sanitizing gel used from dispensers (Experiment 1) and conducting covert, independent observations of health care professionals' hand-hygiene behaviors (Experiment 2). Results showed that changing a single word in messages motivated meaningful changes in behavior: The hand hygiene of health care professionals increased significantly when they were reminded of the implications for patients but not when they were reminded of the implications for themselves.

Too Much of a Good Thing: The Challenge and Opportunity of the Inverted U.

Aristotle proposed that to achieve happiness and success, people should cultivate virtues at mean or intermediate levels between deficiencies and excesses. In stark contrast to this assertion that virtues have costs at high levels, a wealth of psychological research has focused on demonstrating the well-being and performance benefits of positive traits, states, and experiences. This focus has obscured the prevalence and importance of nonmonotonic inverted-U-shaped effects, whereby positive phenomena reach inflection points at which their effects turn negative. We trace the evidence for nonmonotonic effects in psychology and provide recommendations for conceptual and empirical progress. We conclude that for psychology in general and positive psychology in particular, Aristotle's idea of the mean may serve as a useful guide for developing both a descriptive and a prescriptive account of happiness and success.

A little thanks goes a long way: Explaining why gratitude expressions motivate prosocial behavior.

Although research has established that receiving expressions of gratitude increases prosocial behavior, little is known about the psychological mechanisms that mediate this effect. We propose that gratitude expressions can enhance prosocial behavior through both agentic and communal mechanisms, such that when helpers are thanked for their efforts, they experience stronger feelings of self-efficacy and social worth, which motivate them to engage in prosocial behavior. In Experiments 1 and 2, receiving a brief written expression of gratitude motivated helpers to assist both the beneficiary who expressed gratitude and a different beneficiary. These effects of gratitude expressions were mediated by perceptions of social worth and not by self-efficacy or affect. In Experiment 3, we constructively replicated these effects in a field experiment: A manager's gratitude expression increased the number of calls made by university fundraisers, which was mediated by social worth but not self-efficacy. In Experiment 4, a different measure of social worth mediated the effects of an interpersonal gratitude expression. Our results support the communal perspective rather than the agentic perspective: Gratitude expressions increase prosocial behavior by enabling individuals to feel socially valued.