Antagonism of the brain P2X7 ion channel attenuates repeated social defeat induced microglia reactivity, monocyte recruitment and anxiety-like behavior in male mice.

Chronic stress is linked to increased anxiety. Repeated social defeat (RSD) in mice causes anxiety that is dependent on activated neurons, reactive microglia, and accumulation of monocytes in the brain. This response requires interactions between the immune system and central nervous system (CNS). Neuronal activation within threat appraisal regions is a key response to RSD, however, it is unclear how microglia become activated. One potential explanation is that microglia express a purinergic non-selective ligand gated adenosine-triphosphate (ATP) receptor 7 (P2X7). Activation of P2X7 promotes the release of chemokines and cytokines, and recruitment of monocytes to the brain. Thus, the purpose of this study was to determine if a novel P2X7 antagonist blocked neuronal and microglia interactions and the corresponding anxiety following RSD. Male mice were administered (i.p.) a P2X7 antagonist, JNJ-54471300, prior to each cycle of RSD. Fourteen hours after RSD, behavioral deficits including social avoidance and anxiety-like were determined. Moreover, several immune parameters were assessed. RSD caused neuronal activation in stress-responsive regions, monocyte production and release, splenomegaly, and social avoidance. These parameters were unaffected by P2X7 antagonism. RSD-associated proportional area of Iba-1+ microglia, monocyte accumulation in the brain, IL-1ß mRNA expression in enriched myeloid cells, plasma IL-6, and anxiety-like behavior were ameliorated by P2X7 antagonism. Gene expression analysis in the hippocampus and amygdala showed regional specific responses to RSD and some were reversed with P2X7 antagonism. Overall, blocking P2X7 activation attenuated RSD-induced microglia reactivity with corresponding reduction in neuroinflammation, monocyte accumulation, and anxiety-like behavior in male mice.

Should social scientists be distanced from or engaged with the people they study?

This commentary focuses on two important contrasts in the behavioral sciences: (i) default versus nondefault study populations, where default samples have been used disproportionately (for psychology, the default is undergraduates at major research universities), and (ii) the adoption of a distant versus close (engaged) attitude toward study samples. Previous research has shown a strong correlation between these contrasts, where default samples and distant perspectives are the norm. Distancing is sometimes seen as necessary for objectivity, and an engaged orientation is sometimes criticized as biased, advocacy research, especially if the researcher shares a social group membership with the study population (e.g., a black male researcher studying black male students). The lack of diversity in study samples has been paralleled by a lack of diversity in the researchers themselves. The salience of default samples and distancing in prior research creates potential (and presumed) risk factors for engaged research with nondefault samples. However, a distant perspective poses risks as well, and particularly so for research with nondefault populations. We suggest that engaged research can usefully encourage attention to the study context and taking the perspective of study samples, both of which are good research practices. More broadly, we argue that social and educational sciences need skepticism, interestedness, and engagement, not distancing. Fostering an engaged perspective in research may also foster a more diverse population of social scientists.

Repeated social defeat in female mice induces anxiety-like behavior associated with enhanced myelopoiesis and increased monocyte accumulation in the brain.

Anxiety and mood disorders affect both men and women. The majority of experimental models of stress, however, are completed using only male animals. For repeated social defeat (RSD), a rodent model, this is due to the inherent difficulty in eliciting male aggression toward female mice. To address this limitation, a recent study showed that a DREADD-based activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) was effective in inducing aggressive behavior in male mice towards females in a social defeat paradigm. Therefore, the goal of this study was to determine if this modified version of RSD in females elicited behavioral, physiological, and immune responses similar to those reported in males. Here, we show that female mice subjected to RSD with the male DREADD aggressor developed anxiety-like behavior and social avoidance. These behavioral alterations coincided with enhanced neuronal and microglial activation in threat-appraisal regions of the brain. Moreover, stressed female mice had an enhanced peripheral immune response characterized by increased myelopoiesis, release of myeloid cells into circulation, and monocyte accumulation in the spleen and brain. These results are consistent with previously reported findings that male mice exposed to RSD exhibited increased fear and threat appraisal responses, enhanced myelopoiesis, myeloid cell release and trafficking, and anxiety-like behavior. These findings validate that RSD is a relevant model to study stress responses in female mice.

Thinking Cap Plus Thinking Zap: tDCS of Frontopolar Cortex Improves Creative Analogical Reasoning and Facilitates Conscious Augmentation of State Creativity in Verb Generation.

Recent neuroimaging evidence indicates neural mechanisms that support transient improvements in creative performance (augmented state creativity) in response to cognitive interventions (creativity cueing). Separately, neural interventions via tDCS show encouraging potential for modulating neuronal function during creative performance. If cognitive and neural interventions are separately effective, can they be combined? Does state creativity augmentation represent "real" creativity, or do interventions simply yield divergence by diminishing meaningfulness/appropriateness? Can augmenting state creativity bolster creative reasoning that supports innovation, particularly analogical reasoning? To address these questions, we combined tDCS with creativity cueing. Testing a regionally specific hypothesis from neuroimaging, high-definition tDCS-targeted frontopolar cortex activity recently shown to predict state creativity augmentation. In a novel analogy finding task, participants under tDCS formulated substantially more creative analogical connections in a large matrix search space (creativity indexed via latent semantic analysis). Critically, increased analogical creativity was not due to diminished accuracy in discerning valid analogies, indicating "real" creativity rather than inappropriate divergence. A simpler relational creativity paradigm (modified verb generation) revealed a tDCS-by-cue interaction; tDCS further enhanced creativity cue-related increases in semantic distance. Findings point to the potential of noninvasive neuromodulation to enhance creative relational cognition, including augmentation of the deliberate effort to formulate connections between distant concepts.

Sex differences in verbal working memory performance emerge at very high loads of common neuroimaging tasks.

Working memory (WM) supports a broad range of intelligent cognition and has been the subject of rich cognitive and neural characterization. However, the highest ranges of WM have not been fully characterized, especially for verbal information. Tasks developed to test multiple levels of WM demand (load) currently predominate brain-based WM research. These tasks are typically used at loads that allow most healthy participants to perform well, which facilitates neuroimaging data collection. Critically, however, high performance at lower loads may obscure differences that emerge at higher loads. A key question not yet addressed at high loads concerns the effect of sex. Thoroughgoing investigation of high-load verbal WM is thus timely to test for potential hidden effects, and to provide behavioral context for effects of sex observed in WM-related brain structure and function. We tested 111 young adults, matched on genotype for the WM-associated COMT-Val108/158Met polymorphism, on three classic WM tasks using verbal information. Each task was tested at four WM loads, including higher loads than those used in previous studies of sex differences. All tasks loaded on a single factor, enabling comparison of verbal WM ability at a construct level. Results indicated sex effects at high loads across tasks and within each task, such that males had higher accuracy, even among groups that were matched for performance at lower loads.

Gender identity importance in cisgender and gender diverse adolescents in the US and Canada.

Transgender adolescents often categorize themselves in the same way that cisgender adolescents do-that is, as girls/women and boys/men. Potential differences in the extent to which these self-categorizations matter to transgender and cisgender adolescents, however, have yet to be explored, as has the relative importance transgender adolescents place on their gender compared to their transgender self-categorization. In the current study, we explored self-reported identity importance in a sample of 392 primarily White (70%) and multiracial/ethnic (20%) 12-18-year-old (M = 15.02) binary transgender (n = 130), binary cisgender (n = 236), and nonbinary (n = 26) adolescents in the United States and Canada. Results revealed that binary transgender adolescents considered their gender self-categorization to be more important to them than both binary cisgender and nonbinary adolescents did. Most binary transgender adolescents rated their gender self-categorization as maximally important to them. Additionally, transgender adolescents considered their gender self-categorization to be more important to them than their transgender self-categorization (that is, their identification with the label "transgender"). These findings demonstrate that the identities that are often denied to binary transgender adolescents may be the very identities that are most important to them. Results also suggest that gender diverse adolescents with different gender identities may differ in the importance they place on these identities.

The Pandemic and the "Perpetual Foreigner": How Threats Posed by the COVID-19 Pandemic Relate to Stereotyping of Asian Americans.

We examined the "othering" of Asian Americans in the context of the COVID-19 pandemic. Given past evidence that pathogen-related threat perceptions can exacerbate intergroup biases, as well as salient public narratives blaming the Chinese for the pandemic, we assessed whether individuals experiencing a greater sense of threat during the pandemic were more likely to apply the "perpetual foreigner" stereotype to Asian Americans. Over a seven-week period, we recruited 1,323 White Americans to complete a measure of the perceived Americanness of Asian, Black, and White targets. Asian targets were consistently perceived as less American than White targets, across variations in subjective health threat and regional case counts. The direct and indirect connections of political ideology to the observed patterns were examined, revealing that White participants who blamed China for the pandemic were more likely to apply the perpetual foreigner stereotype to Asian Americans. These results indicate that the othering of Asian Americans is pervasive among White Americans and that variables related to social conditions surrounding the COVID-19 pandemic can predict the potency of this association.

Gender Identity 5 Years After Social Transition.

BACKGROUND AND OBJECTIVES: Concerns about early childhood social transitions among transgender youth include that these youth may later change their gender identification (ie, retransition), a process that could be distressing. The current study aimed to provide the first estimate of retransitioning and to report the current gender identities of youth an average of 5 years after their initial social transitions. METHODS: The current study examined the rate of retransition and current gender identities of 317 initially transgender youth (208 transgender girls, 109 transgender boys; M = 8.1 years at start of study) participating in a longitudinal study, the Trans Youth Project. Data were reported by youth and their parents through in-person or online visits or via e-mail or phone correspondence. RESULTS: We found that an average of 5 years after their initial social transition, 7.3% of youth had retransitioned at least once. At the end of this period, most youth identified as binary transgender youth (94%), including 1.3% who retransitioned to another identity before returning to their binary transgender identity. A total of 2.5% of youth identified as cisgender and 3.5% as nonbinary. Later cisgender identities were more common among youth whose initial social transition occurred before age 6 years; their retransitions often occurred before age 10 years. CONCLUSIONS: These results suggest that retransitions are infrequent. More commonly, transgender youth who socially transitioned at early ages continued to identify that way. Nonetheless, understanding retransitions is crucial for clinicians and families to help make retransitions as smooth as possible for youth.

An Online experiment during the 2020 US-Iran crisis shows that exposure to common enemies can increase political polarization.

A longstanding theory indicates that the threat of a common enemy can mitigate conflict between members of rival groups. We tested this hypothesis in a pre-registered experiment where 1670 Republicans and Democrats in the United States were asked to complete an online social learning task with a bot that was labeled as a member of the opposing party. Prior to this task, we exposed respondents to primes about (a) a common enemy (involving Iran and Russia); (b) a patriotic event; or (c) a neutral, apolitical prime. Though we observed no significant differences in the behavior of Democrats as a result of priming, we found that Republicans-and particularly those with very strong conservative views-were significantly less likely to learn from Democrats when primed about a common enemy. Because our study was in the field during the 2020 Iran Crisis, we were able to further evaluate this finding via a natural experiment-Republicans who participated in our study after the crisis were even less influenced by the beliefs of Democrats than those Republicans who participated before this event. These findings indicate common enemies may not reduce inter-group conflict in highly polarized societies, and contribute to a growing number of studies that find evidence of asymmetric political polarization in the United States. We conclude by discussing the implications of these findings for research in social psychology, political conflict, and the rapidly expanding field of computational social science.

Analogical mapping across sensory modalities and evidence for a general analogy factor.

Analogy is a central component of human cognition. Analogical "mapping" of similarities between pieces of information present in our experiences supports cognitive and social development, classroom learning, and creative insights and innovation. To date, analogical mapping has primarily been studied within separate modalities of information (e.g., verbal analogies between words, visuo-spatial analogies between objects). However, human experience, in development and adulthood, includes highly variegated information (e.g., words, sounds, objects) received via multiple sensory and information-processing pathways (e.g., visual vs. auditory pathways). Whereas cross-modal correspondences (e.g., between pitch and height) have been observed, the correspondences were between individual items, rather than between relations. Thus, analogical mapping (characterized by second-order relations between relations) has not been directly tested as a basis for cross-modal correspondence. Here, we devised novel cross-modality analogical stimuli (lines-to-sounds, lines-to-words, words-to-sounds) that explicated second-order comparisons between relations. In four samples across three studies-participants demonstrated well-above-chance identification of cross-modal second-order relations, providing robust evidence of analogy across modalities. Further, performance across all analogy types was explained by a single factor, indicating a modality-general analogical ability (i.e., an "analo-g" factor). Analo-g explained performance over-and-above fluid intelligence as well as verbal and spatial abilities, though a stronger relationship to verbal than visuo-spatial ability emerged, consistent with verbal/semantic contributions to analogy. The present data suggests novel questions about our ability to find/learn second-order relations among the diverse information sources that populate human experience, and about cross-modal human and AI analogical mapping in developmental, educational, and creative contexts.

Unique brain endothelial profiles activated by social stress promote cell adhesion, prostaglandin E2 signaling, hypothalamic-pituitary-adrenal axis modulation, and anxiety.

Chronic stress may precipitate psychiatric disorders including anxiety. We reported that Repeated Social Defeat (RSD) in mice increased accumulation of inflammatory monocytes within the brain vasculature, which corresponded with increased interleukin (IL)-1 Receptor 1-mediated activation of endothelia, and augmented anxiety-like behavior. One unknown, however, is the role of immune-activated endothelia in regulating the physiological and behavioral responses to social stress. Thus, we sought to determine the RNA profile of activated endothelia and delineate the pathways by which these endothelia communicate within the brain to influence key responses to social stress. First, endothelial-specific RiboTag mice were exposed to RSD and brain endothelial mRNA profiles from the whole brain and prefrontal cortex were determined using RNAseq. RSD increased expression of cell adhesion molecules (Icam1), inflammatory genes (Lrg1, Lcn2, Ackr1, Il1r1), and cyclooxygenase-2 (Ptgs2/COX-2). In studies with IL-1R1KO mice, there was clear dependence on IL-1R1 on endothelia-associated transcripts including Lrg1, Icam1, Lcn2. Moreover, prostaglandin (PG)E2 was increased in the brain after RSD and Ptgs2 was localized to endothelia, especially within the hypothalamus. Next, a selective COX-2 inhibitor, Celecoxib (CCB), was used with social stress. RSD increased PGE2 in the brain and this was abrogated by CCB. Moreover, CCB reduced RSD-induced Hypothalamic-Pituitary-Adrenal (HPA) axis activation with attenuation of hypothalamic paraventricular neuron activation, hypothalamic Crh expression, and corticosterone in circulation. Production, release, and accumulation of inflammatory monocytes after RSD was COX-2 independent. Nonetheless, CCB blocked anxiety-like behavior in response to RSD. Collectively, social stress stimulated specific endothelia RNA profiles associated with increased cell adhesion, IL-1 and prostaglandin signaling, HPA axis activation, and anxiety.

IL-1 Receptor-1 on Vglut2 + neurons in the hippocampus is critical for neuronal and behavioral sensitization after repeated social stress.

Myriad findings connect stress and inflammation to mood disorders. Social defeat in mice promotes the convergence of neuronal, central inflammatory (microglia), and peripheral immune (monocytes) pathways causing anxiety, social avoidance, and "stress-sensitization." Stress-sensitization results in augmented inflammation and the recurrence of anxiety after re-exposure to social stress. Different cell compartments, including neurons, may be uniquely sensitized by social defeat-induced interleukin-1 (IL-1) signaling. Therefore, the aim of this study was to determine if glutamatergic neuronal IL-1 receptor signaling was essential in promoting stress-sensitization after social defeat. Here, wild-type (IL-1R1+/+) mice and mice with IL-1 receptor-1 deleted selectively in glutamatergic neurons (Vglut2-IL-1R1-/-) were stress-sensitized by social defeat (6-cycles) and then exposed to acute defeat (1-cycle) at day 30. Acute defeat-induced neuronal activation (ΔFosB and phospo-CREB) in the hippocampus of stress-sensitized mice was dependent on neuronal IL-1R1. Moreover, acute defeat-induced social withdrawal and working memory impairment in stress-sensitized mice were also dependent on neuronal IL-1R1. To address region and time dependency, an AAV2-IL-1 receptor antagonist construct was administered into the hippocampus after sensitization, but prior to acute defeat at day 30. Although stress-sensitized mice had increased hippocampal pCREB and decreased working memory after stress re-exposure, these events were not influenced by AAV2-IL-1 receptor antagonist. Hippocampal ΔFosB induction and corresponding social withdrawal in stress-sensitized mice after stress re-exposure were prevented by the AAV2-IL-1 receptor antagonist. Collectively, IL-1 signaling in glutamatergic neurons of the hippocampus was essential in neuronal-sensitization after social defeat and the recall of social withdrawal.

Gender essentialism and the mental representation of transgender women and men: A multimethod investigation of stereotype content.

The growing visibility of transgender women and men in the US challenges a dominant cultural model of gender in which dichotomous sex assigned at birth gives rise to dichotomous gender identity in adulthood. How are these groups - verbally marked as atypical relative to their cisgender counterparts - stereotyped? Moreover, how do gender essentialist beliefs predict the content of such stereotypes? Across four studies with diverse methods of stereotype measurement, we assessed characteristics that cisgender people associate with transgender women and men, comparing these to their stereotypes of cisgender women and men. In our final study, we directly assessed how cisgender people mentally position transgender groups relative to cisgender groups. Across these studies, transgender categories were characterized in less positive ways than cisgender ones, and there was as a lower level of consensus about transgender than cisgender stereotypes. On average, transgender groups were de-gendered relative to cisgender groups, such that transgender women and men were not strongly differentiated on traditionally-gendered stereotype dimensions. Finally, we showed that participants higher in gender essentialism (relative to participants lower in gender essentialism) evaluated cisgender groups more positively and were more likely to stereotype transgender groups based on their sex assigned at birth.

A method for campus-wide SARS-CoV-2 surveillance at a large public university.

The systematic screening of asymptomatic and pre-symptomatic individuals is a powerful tool for controlling community transmission of infectious disease on college campuses. Faced with a paucity of testing in the beginning of the COVID-19 pandemic, many universities developed molecular diagnostic laboratories focused on SARS-CoV-2 diagnostic testing on campus and in their broader communities. We established the UC Santa Cruz Molecular Diagnostic Lab in early April 2020 and began testing clinical samples just five weeks later. Using a clinically-validated laboratory developed test (LDT) that avoided supply chain constraints, an automated sample pooling and processing workflow, and a custom laboratory information management system (LIMS), we expanded testing from a handful of clinical samples per day to thousands per day with the testing capacity to screen our entire campus population twice per week. In this report we describe the technical, logistical, and regulatory processes that enabled our pop-up lab to scale testing and reporting capacity to thousands of tests per day.

Implicit pattern learning predicts individual differences in belief in God in the United States and Afghanistan.

Most humans believe in a god, but many do not. Differences in belief have profound societal impacts. Anthropological accounts implicate bottom-up perceptual processes in shaping religious belief, suggesting that individual differences in these processes may help explain variation in belief. Here, in findings replicated across socio-religiously disparate samples studied in the U.S. and Afghanistan, implicit learning of patterns/order within visuospatial sequences (IL-pat) in a strongly bottom-up paradigm predict 1) stronger belief in an intervening/ordering god, and 2) increased strength-of-belief from childhood to adulthood, controlling for explicit learning and parental belief. Consistent with research implicating IL-pat as a basis of intuition, and intuition as a basis of belief, mediation models support a hypothesized effect pathway whereby IL-pat leads to intuitions of order which, in turn, lead to belief in ordering gods. The universality and variability of human IL-pat may thus contribute to the global presence and variability of religious belief.

Subjective functional outcomes in oropharyngeal cancer treated with induction chemotherapy using the MD Anderson Symptom Inventory (MDASI).

OBJECTIVES: Evaluate the use of induction chemotherapy (IC) in oropharyngeal cancer (OPC) and its impact on subjective functional outcomes using a validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) survey tool. METHODS: A single institution retrospective review of OPC patients who received IC, including reasons given for using IC, regimens employed, responses, and patient-reported outcomes (PRO). The latter included pain, distress, dysphagia, xerostomia, and feeding tube placement and dependency. PRO's were assessed using the validated MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) conducted at baseline, during treatment, and at six-month follow up. RESULTS: One hundred and twenty-five patients were evaluable. They were more likely to have large primary and/or bulky or low neck nodal disease as a reason for IC. A taxane-containing regimen was most common. Primary tumor response was seen in 83.2% and the nodal response in 81.6%. Pain and xerostomia improved with IC, dysphagia was not adversely affected with IC. These symptoms all increased with consolidation chemoradiotherapy (CRT) but returned to baseline by 6 months post treatment. Feeding tube placement did not increase with IC but did with CRT, most patients were no longer feeding tube dependent at 6 months. CONCLUSION: This retrospective review of subjective functional outcomes, especially swallowing and feeding tube dependency, using the MDASI survey tool in 125 oropharyngeal cancer patients with large primary tumors and/or bulky adenopathy treated predominantly with platinum-taxane based induction chemotherapy showed that such outcomes were not adversely impacted. While not standard, such approach may be beneficial in such patients. LEVEL OF EVIDENCE: 2.

Cancer-Related Acute Pain: A Systematic Review of Evidence-Based Interventions for Putting Evidence Into Practice.

BACKGROUND: Identifying and implementing evidence-based interventions for cancer-related acute pain can decrease adverse effects and improve quality of life. 
. OBJECTIVES: This article presents current evidence supporting interventions to reduce cancer-related acute pain. 
. METHODS: PubMed and CINAHL® databases were searched to identify studies addressing interventions to manage acute pain in patients with cancer. The interventions are categorized according to the Putting Evidence Into Practice classification schema.
. FINDINGS: Interventions that are recommended for practice in the management of acute pain include epidural analgesia and local anesthetic infusions. Interventions likely to be effective include pharmacologic interventions, such as gabapentin and intraspinal analgesia, and nonpharmacologic interventions, such as music therapy. Methodologically stronger clinical trials of new and existing therapies are needed to provide clinicians with accurate resources for managing cancer-related acute pain.

Social analogical reasoning in school-aged children with autism spectrum disorder and typically developing peers.

Analogical reasoning is an important mechanism for social cognition in typically developing children, and recent evidence suggests that some forms of analogical reasoning may be preserved in autism spectrum disorder. An unanswered question is whether children with autism spectrum disorder can apply analogical reasoning to social information. In all, 92 children with autism spectrum disorder completed a social content analogical reasoning task presented via photographs of real-world social interactions. Autism spectrum disorder participants exhibited performance that was well above chance and was not significantly worse than age- and intelligence quotient-matched typically developing children. Investigating the relationship of social content analogical reasoning performance to age in this cross-sectional dataset indicated similar developmental trajectories in the autism spectrum disorder and typically developing children groups. These findings provide new support for intact analogical reasoning in autism spectrum disorder and have theoretical implications for analogy as a metacognitive skill that may be at least partially dissociable from general deficits in processing social content. As an initial study of social analogical reasoning in children with autism spectrum disorder, this study focused on a basic research question with limited ecological validity. Evidence that children with autism spectrum disorder can apply analogical reasoning ability to social content may have long-range applied implications for exploring how this capacity might be channeled to improve social cognition in daily life.

Is less really more: Does a prefrontal efficiency genotype actually confer better performance when working memory becomes difficult?

Perhaps the most widely studied effect to emerge from the combination of neuroimaging and human genetics is the association of the COMT-Val(108/158)Met polymorphism with prefrontal activity during working memory. COMT-Val is a putative risk factor in schizophrenia, which is characterized by disordered prefrontal function. Work in healthy populations has sought to characterize mechanisms by which the valine (Val) allele may lead to disadvantaged prefrontal cognition. Lower activity in methionine (Met) carriers has been interpreted as advantageous neural efficiency. Notably, however, studies reporting COMT effects on neural efficiency have generally not reported working memory performance effects. Those studies have employed relatively low/easy working memory loads. Higher loads are known to elicit individual differences in working memory performance that are not visible at lower loads. If COMT-Met confers greater neural efficiency when working memory is easy, a reasonable prediction is that Met carriers will be better able to cope with increasing demand for neural resources when working memory becomes difficult. To our knowledge, this prediction has thus far gone untested. Here, we tested performance on three working memory tasks. Performance on each task was measured at multiple levels of load/difficulty, including loads more demanding than those used in prior studies. We found no genotype-by-load interactions or main effects of COMT genotype on accuracy or reaction time. Indeed, even testing for performance differences at each load of each task failed to find a single significant effect of COMT genotype. Thus, even if COMT genotype has the effects on prefrontal efficiency that prior work has suggested, such effects may not directly impact high-load working memory ability. The present findings accord with previous evidence that behavioral effects of COMT are small or nonexistent and, more broadly, with a growing consensus that substantial effects on phenotype will not emerge from candidate gene studies.

Anticancer RuII and RhIII Piano-Stool Complexes that are Histone Deacetylase Inhibitors.

The first examples of RuII and RhIII piano-stool complex histone deacetylase (HDAC) inhibitors are presented. The novel complexes have antiproliferative activity against H460 non-small-cell lung carcinoma cells that is comparable to the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). Strong evidence for HDAC inhibition as a primary mechanism of action is provided. The complexes reported here represent an important step towards the design of highly active and selective HDAC inhibitors.