Reducing Preoperative Caregiver Anxiety With Virtual Reality: A Pragmatic, Randomized Controlled Study.

Pediatric patients and their caregivers often experience perioperative anxiety. Interventions reduce caregiver anxiety improve cooperation and contribute to an improved patient experience. This study seeks to evaluate the efficacy of virtual reality (VR)-assisted mindfulness on perioperative caregiver anxiety. Participants were randomized into a standard of care (SOC) group, which included snacks but no technology-based distractions, or a VR group, which included snacks and a VR-guided meditation. Caregiver anxiety was measured before and after the intervention using the Visual Analogue Scale for Anxiety (VAS-A). Secondary aims explored participants' baseline anxiety with the State-Trait Anxiety Inventory (STAI). VR group participants completed a satisfaction survey. Linear regression models of VAS-A and STAI were used to compare group differences. Satisfaction survey results were reported with descriptive statistics. 26 participants were included, with 12 randomized to the SOC group and 14 to the VR group. VAS-A scores in the VR group were lower than those in the SOC group (p = .002). The STAI found no change in participants' state of anxiety in the SOC group (p = .7108), compared to a significant reduction (p = .014) in the VR group when controlling for anxiety traits. 12 of 14 caregivers in the VR group expressed satisfaction or strong satisfaction. This study supports the implementation of VR mindfulness as a method to reduce caregiver anxiety. VR use in the pediatric healthcare setting is safe and inexpensive, and the intervention had a high degree of participant satisfaction.

Structural insights into the mechanism of leptin receptor activation.

Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

A new visual design language for biological structures in a cell.

As part of a project to build a spatiotemporal model of the pancreatic ß-cell, we are creating an immersive experience called "World in a Cell" that can be used to integrate and create new educational tools. To do this, we have developed a new visual design language that uses tetrahedral building blocks to express the structural features of biological molecules and organelles in crowded cellular environments. The tetrahedral language enables more efficient animation and user interaction in an immersive environment.

Enhanced T cell effector activity by targeting the Mediator kinase module.

T cells are the major arm of the immune system responsible for controlling and regressing cancers. To identify genes limiting T cell function, we conducted genome-wide CRISPR knockout screens in human chimeric antigen receptor (CAR) T cells. Top hits were MED12 and CCNC, components of the Mediator kinase module. Targeted MED12 deletion enhanced antitumor activity and sustained the effector phenotype in CAR- and T cell receptor-engineered T cells, and inhibition of CDK8/19 kinase activity increased expansion of nonengineered T cells. MED12-deficient T cells manifested increased core Meditator chromatin occupancy at transcriptionally active enhancers-most notably for STAT and AP-1 transcription factors-and increased IL2RA expression and interleukin-2 sensitivity. These results implicate Mediator in T cell effector programming and identify the kinase module as a target for enhancing potency of antitumor T cell responses.

Determination of the melanocortin-4 receptor structure identifies Ca2+ as a cofactor for ligand binding.

The melanocortin-4 receptor (MC4R) is involved in energy homeostasis and is an important drug target for syndromic obesity. We report the structure of the antagonist SHU9119-bound human MC4R at 2.8-angstrom resolution. Ca2+ is identified as a cofactor that is complexed with residues from both the receptor and peptide ligand. Extracellular Ca2+ increases the affinity and potency of the endogenous agonist α-melanocyte-stimulating hormone at the MC4R by 37- and 600-fold, respectively. The ability of the MC4R crystallized construct to couple to ion channel Kir7.1, while lacking cyclic adenosine monophosphate stimulation, highlights a heterotrimeric GTP-binding protein (G protein)-independent mechanism for this signaling modality. MC4R is revealed as a structurally divergent G protein-coupled receptor (GPCR), with more similarity to lipidic GPCRs than to the homologous peptidic GPCRs.