Psilocybin Facilitates Fear Extinction: Importance of Dose, Context, and Serotonin Receptors.

A variety of classic psychedelics and MDMA have been shown to enhance fear extinction in rodent models. This has translational significance because a standard treatment for post-traumatic stress disorder (PTSD) is prolonged exposure therapy. However, few studies have investigated psilocybin's potential effect on fear learning paradigms. More specifically, the extents to which dose, timing of administration, and serotonin receptors may influence psilocybin's effect on fear extinction are not understood. In this study, we used a delay fear conditioning paradigm to determine the effects of psilocybin on fear extinction, extinction retention, and fear renewal in male and female mice. Psilocybin robustly enhances fear extinction when given acutely prior to testing for all doses tested. Psilocybin also exerts long-term effects to elevate extinction retention and suppress fear renewal in a novel context, although these changes were sensitive to dose. Analysis of sex differences showed that females may respond to a narrower range of doses than males. Administration of psilocybin prior to fear learning or immediately after extinction yielded no change in behavior, indicating that concurrent extinction experience is necessary for the drug's effects. Cotreatment with a 5-HT2A receptor antagonist blocked psilocybin's effects for extinction, extinction retention, and fear renewal, whereas 5-HT1A receptor antagonism attenuated only the effect on fear renewal. Collectively, these results highlight dose, context, and serotonin receptors as crucial factors in psilocybin's ability to facilitate fear extinction. The study provides preclinical evidence to support investigating psilocybin as a pharmacological adjunct for extinction-based therapy for PTSD.

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

BACKGROUND: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. METHODS: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. RESULTS: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. CONCLUSIONS: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.

Does No Mean No? Situational and Dispositional Factors Influence Emerging Adult Men's Intentions to Use Assault Tactics in Response to Women's Sexual Refusal During Hookups.

Hookups can result in sexual assault when men do not listen to requests from women to stop. It is thus important to identify factors that influence men's decisions to override direct refusals in these situations. Presently, we administered first-person vignettes depicting a prototypical hookup wherein the woman refuses the man's attempt to escalate intimacy. Using a national sample of emerging adult men (N = 420), we found that they on average did not completely rule out coercive or forcible tactics, but those elevated on rape myth acceptance, hypermasculinity, and psychopathy were uniquely at risk of assault when controlling for several other traits known to correlate with rape. Participants also reported being likelier to use coercive sexual practices when refusals occurred at higher levels of sexual intimacy already attained. Notably, diagnostic analyses revealed that a subset of men had a disproportionate influence on the regression estimates, and that these men were not only elevated across a range of assault-relevant traits, but also endorsed higher likelihoods of using coercion and force in the face of female sexual refusal. Although removal of these cases did not substantively alter the results, exploratory analyses revealed that these individuals responded differently to situational factors in ways that suggested sexual opportunism. Theoretical and practical implications of these findings are discussed.

ScreenDMT reveals DiHOMEs are replicably inversely associated with BMI and stimulate adipocyte calcium influx.

Activating brown adipose tissue (BAT) improves systemic metabolism, making it a promising target for metabolic syndrome. BAT is activated by 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME), which we previously identified to be inversely associated with BMI and which directly improves metabolism in multiple tissues. Here we profile plasma lipidomics from 83 people and test which lipids' association with BMI replicates in a concordant direction using our novel tool ScreenDMT, whose power and validity we demonstrate via mathematical proofs and simulations. We find that the linoleic acid diols 12,13-diHOME and 9,10-diHOME are both replicably inversely associated with BMI and mechanistically activate calcium influx in mouse brown and white adipocytes in vitro, which implicates this signaling pathway and 9,10-diHOME as candidate therapeutic targets. ScreenDMT can be applied to test directional mediation, directional replication, and qualitative interactions, such as identifying biomarkers whose association is shared (replication) or opposite (qualitative interaction) across diverse populations.

Decoding the decline: unveiling drivers of sarcopenia.

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.

Flavonols improve tomato pollen thermotolerance during germination and tube elongation by maintaining ROS homeostasis.

Elevated temperatures impair pollen performance and reproductive success, resulting in lower crop yields. The tomato (Solanum lycopersicum) anthocyanin reduced (are) mutant harbors a mutation in FLAVANONE 3-HYDROXYLASE (F3H), resulting in impaired flavonol antioxidant biosynthesis. The are mutant has reduced pollen performance and seed set relative to the VF36 parental line, phenotypes that are accentuated at elevated temperatures. Transformation of are with the wild-type F3H gene, or chemical complementation with flavonols, prevented temperature-dependent reactive oxygen species (ROS) accumulation in pollen and restored the reduced viability, germination, and tube elongation of are to VF36 levels. Overexpression of F3H in VF36 prevented temperature-driven ROS increases and impaired pollen performance, revealing that flavonol biosynthesis promotes thermotolerance. Although stigmas of are had reduced flavonol and elevated ROS levels, the growth of are pollen tubes was similarly impaired in both are and VF36 pistils. RNA-seq was performed at optimal and stress temperatures in are, VF36, and the F3H overexpression line at multiple timepoints across pollen tube elongation. The number of differentially expressed genes increased over time under elevated temperatures in all genotypes, with the greatest number in are. These findings suggest potential agricultural interventions to combat the negative effects of heat-induced ROS in pollen that lead to reproductive failure.

Using formative process evaluation to improve program implementation and accessibility of competitive group-based physical activity in the TEAM-PA trial.

BACKGROUND: This study demonstrates how formative process evaluation was used to assess implementation and improve dose and fidelity in the Together Everyone Achieves More Physical Activity (TEAM-PA) randomized controlled trial. TEAM-PA uses a randomized group cohort design to evaluate the efficacy of a group-based intervention for increasing physical activity among African American women. METHODS: Intervention groups met for 10 weeks and were co-led by female African American facilitators, with intervention sessions consisting of group feedback, a health curriculum, group-based physical activity games, and group-based goal-setting. Drawing from a multi-theoretical framework, the intervention targeted social affiliation using collaborative and competitive group strategies, including essential elements focused on group-based behavioral skills, peer-to-peer positive communication, collectivism, optimal challenge, social facilitation, and peer to peer challenges. Formative process evaluation was used to monitor reach, dose, and fidelity, and implement feedback and solutions. RESULTS: Across two cohorts, four groups (n = 54) were randomized to the TEAM-PA intervention. On average 84.8% of participants attended each week, which exceeded the a priori criteria. Results from the systematic observations indicated that on average 93% of the dose items were completed in each session and adequate levels of fidelity were achieved at both the facilitator and group-levels. Participants were compliant with wearing the FitBits (6.73 ± 0.42 days/week) and most participants successfully contributed to meeting the group-based goals. The use of open-ended items also revealed the need for additional modifications to the group-based PA games, including allowing for individuals to take breaks, incorporating a broader range of exercises, minimizing activities that required bending/reaching down without assistance, and providing facilitators with additional training for implementing the games. Initial evidence suggests that these changes were successful in increasing participants' comprehension of the games from Cohort 1 (M = 1.83, SD = 0.71) to Cohort 2 (M = 3.33, SD = 0.69). CONCLUSION: Findings from this study demonstrated high levels of reach, dose, and fidelity, while also highlighting strategies for implementing competitive group-based PA games that are accessible across physical fitness levels. Formative process evaluation, including open-ended items and collaborative brainstorming, holds tremendous potential for improving future interventions. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (# NCT05519696) on August 22, 2022 prior to the enrollment of the first participant on September 12, 2022 ( https://clinicaltrials.gov/study/NCT05519696?term=NCT05519696&rank=1 ).

Enantioselective Nickel-Catalyzed α-Spirocyclization of Lactones.

Herein we report a strategy for the enantioselective synthesis of spirocycles containing all-carbon quaternary centers via nickel-catalyzed intramolecular addition of lactone enolates to aryl nitriles. The established lactone α-spirocyclization efficiently and enantioselectively forges 5-, 6-, and 7-membered rings, performing best in the synthesis of 7-membered rings (up to 90% ee). This discovery represents an expansion of the synthetic toolkit for enantioselective spirocyclization, providing access to chiral, pharmaceutically relevant spirocyclic products.

Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade.

Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.

Molecular mimicry in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.

Central mechanisms of emesis: A role for GDF15.

BACKGROUND: Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life-threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α-like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity. PURPOSE: This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy-induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome.

Leveraging and learning from the long COVID experience: Translating telerehabilitation into practice.

BACKGROUND: Telerehabilitation, or the delivery of rehabilitation services through telehealth platforms, has existed since the late 1990 s. Telerehabilitation was characterized by unprecedented, exponential growth at the beginning of the novel coronavirus-2019 (COVID-19) pandemic. Medical systems sought to reduce the likelihood of disease transmission by using telerehabilitation to limit physical proximity during routine care. This dramatic change in how medical care was delivered forced many professions to adapt processes and practices. Following the change, debates sparked regarding the best path to move forward for the betterment of patients, clinicians, systems, and society. Long COVID has emerged as a complex chronic health condition arising from COVID-19. The unique needs and dynamic disease process of Long COVID has incentivized medical systems to create equitable ways for patients to safely access interdisciplinary care. OBJECTIVES: The purpose of this commentary is to describe what medical systems must consider when deploying high-quality telerehabilitation to deliver rehabilitation through asynchronous (e.g., text, portal) and synchronous modalities (e.g., phone or video). We highlight lessons learned to help guide decision-makers on key actions to support their patients and clinicians. METHODS: Not applicable. RESULTS: Not applicable. CONCLUSIONS: Key action steps from our lessons learned may be used to address complex chronic health conditions such as Long COVID and prepare for future challenges that may disrupt medical systems.

Transitional Palliative Care for Family Caregivers: Outcomes from a Randomized Controlled Trial.

CONTEXT: Patients receiving inpatient palliative care often face physical and psychological uncertainties during transitions out of the hospital. Family caregivers often take on responsibilities to ensure patient safety, quality of care, and extend palliative care principles, but often without support or training, potentially compromising their health and well-being. OBJECTIVES: This study tested an eight-week intervention using video visits between palliative care nurse interventionists and caregivers to assess changes in caregiver outcomes and patient quality of life. METHODS: This randomized controlled trial, conducted from 2018 to 2022, enrolled adult caregivers in rural or medically underserved areas in Minnesota, Wisconsin, and Iowa. Eligible caregivers included those caring for patients who received inpatient palliative care and transitioned out of the hospital. The intervention group received teaching, guidance, and counseling from a palliative care nurse before and for eight weeks after hospital discharge. The control group received monthly phone calls but no intervention. Caregiver outcomes included changes in depression, burden, and quality of life, and patient quality of life, as reported by the caregiver. RESULTS: Of those consented, 183 completed the intervention, and 184 completed the control arm; 158 participants had complete baseline and eight-week data. In unadjusted analyses, the intervention group and their care recipients showed statistically significant improvements in quality of life compared to the control group. Improvements persisted in adjusted analyses, and depression significantly improved. No differences in caregiver burden were observed. CONCLUSION: Addressing rural caregivers' needs during transitions in care can enhance caregiver outcomes and improve patient quality of life.

How peer status and ability track shape behavioral disengagement over the transition from primary to secondary school.

The transition from primary to secondary school is often associated with an increase in behavioral disengagement, which undermines students' academic development. Prior studies examined the average development of behavioral disengagement across school transitions. This study examined how students' peer status in primary school and ability track in secondary school relate to trajectories of behavioral disengagement. We followed n = 1564 students who transitioned to secondary school across three time points: February/March, and May/June in students' final year of primary school and January/February, roughly 6 months after students transited to secondary school. Latent Growth Curve Analyses showed that on average, behavioral disengagement increased, but this increase mostly occurred before transitioning to secondary school. Peer status and track related to students' initial levels of behavioral disengagement, but not to their development in behavioral disengagement over the transition. Specifically, students who were viewed as more popular by peers, and students who ended up in the lowest track showed more behavioral disengagement in primary school, whereas students who were more accepted by peers were less disengaged in primary school.

Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.

A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.

NADPH oxidase in B cells and macrophages protects against murine lupus by regulation of TLR7.

Loss of NADPH oxidase (NOX2) exacerbates systemic lupus erythematosus (SLE) in mice and humans, but the mechanisms underlying this effect remain unclear. To identify the cell lineages in which NOX2 deficiency drives SLE, we employed conditional knockout (KO) and chimera approaches to delete Cybb in several hematopoietic cell lineages of MRL.Faslpr lupus-prone mice. Deletion of Cybb in macrophages/monocytes exacerbated lupus nephritis, though not to the degree observed in the Cybb global KOs. Unexpectedly, the absence of Cybb in B cells resulted in profound glomerulonephritis and interstitial nephritis, rivaling that seen with global deletion. Further, we identified that NOX2 is a key regulator of TLR7, a driver of SLE pathology, both globally and specifically in B cells. This is mediated in part through suppression of TLR7-mediated NF-kB signaling in B cells. Thus, NOX2's immunomodulatory effect in SLE is orchestrated not only by its function in the myeloid compartment, but through a pivotal role in B cells by selectively inhibiting TLR7 signaling.

Sex-based differences in hematological values after normalization to body mass or fat-free mass in adults matched for aerobic fitness.

Blood properties influence aerobic exercise performance. While vascular volumes and hemoglobin mass (Hbmass) are elevated in trained individuals, evidence of sex differences in vascular volumes is equivocal due to inadequate matching of aerobic fitness between males and females. This cross-sectional study aimed to compare hematological values normalized to body mass (BM) and fat-free mass (FFM) between males (n=45) and females (n=34) matched for aerobic fitness (V̇O2max) normalized to FFM (mL∙kg FFM-1∙min-1). Data included body composition measured by dual-energy x-ray absorptiometry (DXA), V̇O2max from an incremental test, and hematological values derived from a CO rebreathe test. Fat mass was unrelated to blood volume (BV; R2 = 0.02, p=0.26) and Hbmass (R2=0.03, p=0.16), while FFM was the strongest predictor of both (R2=0.75 and R2=0.83, respectively, P<0.001). Females exhibited higher FFM-normalized BV (+4%, P<0.05) and plasma volume (PV) (+14%, P<0.001) and lower red blood cell volume (RBCV) (-8%, P<0.001) and Hbmass (-8%, P<0.001) compared to males. Positive correlations between aerobic fitness and relative Hbmass and BV were observed in both sexes when normalized to BM and FFM (0.48

Mercury concentrations in Seaside Sparrows and Marsh Rice Rats differ across the Mississippi River Estuary.

Mercury (Hg) concentrations and their associated toxicological effects in terrestrial ecosystems of the Gulf of Mexico are largely unknown. Compounding this uncertainty, a large input of organic matter from the 2010 Deepwater Horizon oil spill may have altered Hg cycling and bioaccumulation dynamics. To test this idea, we quantified blood concentrations of total mercury (THg) in Seaside Sparrows (Ammospiza maritima) and Marsh Rice Rats (Oryzomys palustris) in marshes west and east of the Mississippi River in 2015 and 2016. We also tested for a difference in THg concentrations between oiled and non-oiled sites. To address the potential confounding effect of diet variation on Hg transfer, we used stable nitrogen (δ15N) and carbon (δ13C) isotope values as proxies of trophic position and the source of primary production, respectively. Our results revealed that five to six years after the spill, THg concentrations were not higher in sites oiled by the spill compared to non-oiled sites. In both species, THg was higher at sites east of the Mississippi River compared to control and oiled sites, located west. In Seaside Sparrows but not in Marsh Rice Rats, THg increased with δ15N values, suggesting Hg trophic biomagnification. Overall, even in sites with the most elevated THg, concentrations were generally low. In Seaside Sparrows, THg concentrations were also lower than previously reported in this and other closely related passerines, with only 7% of tested birds exceeding the lowest observed effect concentration associated with toxic effects across bird species (0.2 µg/g ww). The factors associated with geographic heterogeneity in Hg exposure remain uncertain. Clarification could inform risk assessment and future restoration and management actions in a region facing vast anthropogenic changes.

Precision feedback: A conceptual model.

Introduction: When performance data are provided as feedback to healthcare professionals, they may use it to significantly improve care quality. However, the question of how to provide effective feedback remains unanswered, as decades of evidence have produced a consistent pattern of effects-with wide variation. From a coaching perspective, feedback is often based on a learner's objectives and goals. Furthermore, when coaches provide feedback, it is ideally informed by their understanding of the learner's needs and motivation. We anticipate that a "coaching"-informed approach to feedback may improve its effectiveness in two ways. First, by aligning feedback with healthcare professionals' chosen goals and objectives, and second, by enabling large-scale feedback systems to use new types of data to learn what kind of performance information is motivating in general. Our objective is to propose a conceptual model of precision feedback to support these anticipated enhancements to feedback interventions. Methods: We iteratively represented models of feedback's influence from theories of motivation and behavior change, visualization, and human-computer interaction. Through cycles of discussion and reflection, application to clinical examples, and software development, we implemented and refined the models in a software application to generate precision feedback messages from performance data for anesthesia providers. Results: We propose that precision feedback is feedback that is prioritized according to its motivational potential for a specific recipient. We identified three factors that influence motivational potential: (1) the motivating information in a recipient's performance data, (2) the surprisingness of the motivating information, and (3) a recipient's preferences for motivating information and its visual display. Conclusions: We propose a model of precision feedback that is aligned with leading theories of feedback interventions to support learning about the success of feedback interventions. We plan to evaluate this model in a randomized controlled trial of a precision feedback system that enhances feedback emails to anesthesia providers.