Discovery of Highly Selective Inhibitors of Microtubule-Associated Serine/Threonine Kinase-like (MASTL).

By virtue of its role in cellular proliferation, microtubule-associated serine/threonine kinase-like (MASTL) represents a novel target and a first-in-class (FIC) opportunity to provide a new impactful therapeutic agent to oncology patients. Herein, we describe a hit-to-lead optimization effort that resulted in the delivery of two highly selective MASTL inhibitors. Key strategies leveraged to enable this work included structure-based drug design (SBDD), analysis of lipophilic efficiency (LipE) and novel synthesis.

Usability Testing Via Simulation: Optimizing the NEAR4PEM Preintubation Checklist With a Human Factors Approach.

Objectives: To inform development of a preintubation checklist for pediatric emergency departments via multicenter usability testing of a prototype checklist.

Methods: This was a prospective, mixed methods study across 7 sites in the National Emergency Airway Registry for Pediatric Emergency Medicine (NEAR4PEM) collaborative. Pediatric emergency medicine attending physicians and senior fellows at each site were first oriented to a checklist prototype, including content previously identified using a modified Delphi approach.

Increasing equity in science requires better ethics training: A course by trainees, for trainees.

Despite the profound impacts of scientific research, few scientists have received the necessary training to productively discuss the ethical and societal implications of their work. To address this critical gap, we-a group of predominantly human genetics trainees-developed a course on genetics, ethics, and society. We intend for this course to serve as a template for other institutions and scientific disciplines.

Educational Strategies in Pediatric Trauma Resuscitation Across Disciplines: A Scoping Review.

Introduction: Trauma is the leading cause of death and disability in children. Differences in mechanism, injury pattern, severity, and physiology in this population distinguish pediatric trauma patients from adults. Educational techniques including simulation and didactics may improve pediatric readiness in this setting.

Use of pediatric trauma simulations to facilitate exposure to pediatric trauma resuscitations during training.

Background: Pediatric traumas are often high-acuity but are low-frequency compared to adult trauma activations. This is reflected in the relatively limited experience with these events during training. Although some principles of trauma resuscitation are similar between adults and children, there are also important differences in physiology, injury patterns, and presentation.

Discovery of a highly potent, selective, orally bioavailable inhibitor of KAT6A/B histone acetyltransferases with efficacy against KAT6A-high ER+ breast cancer.

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer.

A National Comparison of Volume and Acuity for Adult and Pediatric Trauma: A Trauma Quality Improvement Program Cohort Study.

Introduction: Most injured children receive trauma care outside of a pediatric trauma center. Differences in physiology, dosing, and injury pattern limit extrapolation of adult trauma principles to pediatrics. We compare US trauma center experience with pediatric and adult trauma resuscitation.

GPCR Signaling Measurement and Drug Profiling with an Automated Live-Cell Microscopy System.

A major limitation of time-lapse microscopy combined with fluorescent biosensors, a powerful tool for quantifying spatiotemporal dynamics of signaling in single living cells, is low-experimental throughput. To overcome this limitation, we created a highly customizable, MATLAB-based platform: flexible automated liquid-handling combined microscope (FALCOscope) that coordinates an OpenTrons liquid handler and a fluorescence microscope to automate drug treatments, fluorescence imaging, and single-cell analysis. To test the feasibility of the FALCOscope, we quantified G protein-coupled receptor (GPCR)-stimulated Protein Kinase A activity and cAMP responses to GPCR agonists and antagonists.

Use of a Structured Observation Tool to Promote Medical Student Engagement in Trauma Resuscitations.

Objective: We describe a novel approach to promoting medical student learning and engagement during trauma resuscitation with implementation of a structured observation and debriefing tool.

Design: In the context of a multifaceted quality improvement effort in our emergency room, we implemented a structured trauma observation tool (SOT) for medical students based on ATLS trauma guidelines. The SOT reflects the American College of Surgeons and Association for Surgical Education (ACS/ASE) trauma evaluation module for medical students.

Multiple causal variants underlie genetic associations in humans.

Associations between genetic variation and traits are often in noncoding regions with strong linkage disequilibrium (LD), where a single causal variant is assumed to underlie the association. We applied a massively parallel reporter assay (MPRA) to functionally evaluate genetic variants in high, local LD for independent cis-expression quantitative trait loci (eQTL). We found that 17.

Transgenic Drosophila lines for LexA-dependent gene and growth regulation.

Conditional expression of short hairpin RNAs with binary genetic systems is an indispensable tool for studying gene function. Addressing mechanisms underlying cell-cell communication in vivo benefits from simultaneous use of 2 independent gene expression systems. To complement the abundance of existing Gal4/UAS-based resources in Drosophila, we and others have developed LexA/LexAop-based genetic tools.

Peer Consultation: An Enriching Necessity Rather Than a Luxury for Psychologists During and Beyond the Pandemic.

The pandemic increased professional and personal demands on psychologists, resulting in higher levels of burnout and clinician isolation (Aafjes-van Doorn et al., 2020; Shklarski et al., 2021).

Evaluating a longitudinal point-of-care-ultrasound (POCUS) curriculum for pediatric residents.

Background: POCUS is a growing field in medical education, and an imaging modality ideal for children given the lack of ionizing radiation, ease of use, and good tolerability. A 2019 literature review revealed that no US pediatric residency programs integrated obligatory POCUS curricula. Our objective was to provide a formalized POCUS curriculum over multiple years, and to retrospectively assess improvement in resident skills and comfort.

Patient Satisfaction with and Use of Telemental Health Services in the Perinatal Period: a Survey Study.

We aimed to assess patients' utilization of and satisfaction with telemental health (TMH) in the perinatal period. We hypothesized that satisfaction with TMH would be at least equal to, if not greater than, with in-person appointments. We conducted a cross-sectional survey between March 2018-June 2019 to evaluate patient satisfaction with and use of TMH services in the perinatal period.

Spatially compartmentalized phase regulation of a Ca-cAMP-PKA oscillatory circuit.

Signaling networks are spatiotemporally organized to sense diverse inputs, process information, and carry out specific cellular tasks. In β cells, Ca, cyclic adenosine monophosphate (cAMP), and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback. Here, we describe a mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca.

Pediatric Sepsis in Community Emergency Care Settings: Guideline Concordance and Outcomes.

Objectives: Bundled pediatric sepsis care has been associated with improved outcomes in tertiary pediatric emergency departments. Sepsis care at nontertiary sites where most children seek emergency care is not well described. We sought to describe the rate of guideline-concordant care, and we hypothesized that guideline-concordant care in community pediatric emergency care settings would be associated with decreased hospital length of stay (LOS).

Transcriptomic signatures across human tissues identify functional rare genetic variation.

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs.

Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance.

Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity.

Real-world outcomes of melanoma surveillance using the MoleMap NZ telemedicine platform.

Background: MoleMap NZ is a novel New Zealand-based store-and-forward telemedicine service to detect melanoma. It uses expert review of total body photography and close-up and dermoscopic images of skin lesions that are suspicious for malignancy.

Objective: The purpose of this study was to assess the effectiveness of MoleMap NZ as a melanoma early detection program.

Colony entropy-Allocation of goods in ant colonies.

Allocation of goods is a key feature in defining the connection between the individual and the collective scale in any society. Both the process by which goods are to be distributed, and the resulting allocation to the members of the society may affect the success of the population as a whole. One of the most striking natural examples of a highly successful cooperative society is the ant colony which often acts as a single superorganism.

AKAP95 Organizes a Nuclear Microdomain to Control Local cAMP for Regulating Nuclear PKA.

Contrary to the classic model of protein kinase A (PKA) residing outside of the nucleus, we identify a nuclear signaling complex that consists of AKAP95, PKA, and PDE4D5 and show that it forms a functional cyclic AMP (cAMP) signaling microdomain. Locally generated cAMP can accumulate within the vicinity of this complex; however, when cAMP is generated at the plasma membrane, PDE4 serves as a local sink and PDE3 as a barrier to prevent accumulation of cAMP within the microdomain as a means of controlling activation of tethered nuclear PKA.

Genetically Encoded Fluorescent Biosensors Illuminate the Spatiotemporal Regulation of Signaling Networks.

Cellular signaling networks are the foundation which determines the fate and function of cells as they respond to various cues and stimuli. The discovery of fluorescent proteins over 25 years ago enabled the development of a diverse array of genetically encodable fluorescent biosensors that are capable of measuring the spatiotemporal dynamics of signal transduction pathways in live cells. In an effort to encapsulate the breadth over which fluorescent biosensors have expanded, we endeavored to assemble a comprehensive list of published engineered biosensors, and we discuss many of the molecular designs utilized in their development.