Joe B. Blumer

Developing high‐quality pharmacology multiple‐choice questions (MCQs) is challenging in large part due to continually evolving therapeutic guidelines and the complex integration of basic science and clinical medicine in this subject area. Large language models (LLMs) like ChatGPT‐4 have repeatedly demonstrated proficiency in answering medical licensing exam questions, prompting interest in their use for generating high stakes exam‐style questions. This study evaluates the performance of ChatGPT‐4o in generating USMLE‐style pharmacology questions based on American Society for Pharmacology and Experimental Therapeutics/Association of Medical School Pharmacology Chairs (ASPET/AMSPC) knowledge objectives and assesses the impact of retrieval‐augmented generation (RAG) on question accuracy and quality. Using standardized prompts, 50 questions (25 RAG and 25 non‐RAG) were generated and subsequently evaluated by expert reviewers. Results showed higher accuracy for non‐RAG questions (88.0% vs. 69.2%), though the difference was not statistically significant. No significant differences were observed in other quality dimensions. These findings suggest that sophisticated LLMs can generate high‐quality pharmacology questions efficiently without RAG, though human oversight remains crucial.

The American Society for Pharmacology and Experimental Therapeutics (ASPET) held its annual meeting at the Experimental Biology 2022 conference in Philadelphia, PA on April 2–5, 2022. The authors provide a synopsis and discussion of each of the four sessions presented at the meeting under the ASPET Division for Pharmacology Education (DPE).

Expectations for physicians are rapidly changing, as is the environment in which they will practice. In response, preclerkship medical education curricula are adapting to meet these demands, often by reducing the time for foundational sciences. This descriptive study compares preclerkship pharmacology education curricular practices from seven allopathic medical schools across the United States. We compare factors and practices that affect how pharmacology is integrated into the undergraduate medical education curriculum, including teaching techniques, resources, time allocated to pharmacology teaching, and assessment strategies. We use data from seven medical schools in the United States, along with results from a literature survey, to inform the strengths and weaknesses of various approaches and to raise important questions that can guide future research regarding integration of foundational sciences in medical school and health professions’ curricula. In this comparative study, we found that there is significant heterogeneity in the number of hours dedicated to pharmacology in the preclerkship curriculum, whereas there was concordance in the use of active learning pedagogies for content delivery. Applying the ICAP (Interactive, Constructive, Active, Passive) Framework for cognitive engagement, our data showed that pharmacology was presented using more highly engaging pedagogies during sessions that are integrated with other foundational sciences. These findings can serve as a model that can be applied beyond pharmacology to other foundational sciences such as genetics, pathology, microbiology, biochemistry, etc.

A grounded knowledge of pharmacology is essential for healthcare providers to improve the quality of patients’ lives, avoid medical errors, and circumvent potentially dangerous drug–drug interactions. One of the greatest tools to achieve this foundational knowledge of pharmacology is the dedicated pharmacology educators who teach in health sciences programs. Too often, the pharmacology educators responsible for teaching this material are left siloed at their own institutions with little room for dialog and collaboration. As scientists, we know that it is through dialog and collaboration that ideas grow, are refined, and improve. More collaborative work is needed to identify and describe best practices for pharmacology education in health sciences programs. While evidence‐based, outcomes‐focused studies are the optimum standard for this work, there is also a place for descriptive studies and innovative reports.

Macrophages exist as innate immune subsets that exhibit phenotypic heterogeneity and functional plasticity. Their phenotypes are dictated by inputs from the tissue microenvironment. G-protein–coupled receptors are essential in transducing signals from the microenvironment, and heterotrimeric Gα signaling links these receptors to downstream effectors. Several Gα_i-coupled G-protein–coupled receptors have been implicated in macrophage polarization. In this study, we use genetically modified mice to investigate the role of Gα_i2 on inflammasome activity and macrophage polarization. We report that Gα_i2 in murine bone marrow–derived macrophages (BMDMs) regulates IL-1β release after activation of the NLRP3, AIM2, and NLRC4 inflammasomes. We show this regulation stems from the biased polarity of Gα_i2 deficient (Gnai2^−/−) and RGS-insensitive Gα_i2 (Gnai2^G184S/G184S) BMDMs. We determined that although Gnai2^G184S/G184S BMDMs (excess Gα_i2 signaling) have a tendency toward classically activated proinflammatory (M1) phenotype, Gnai2^−/− BMDMs (Gα_i2 deficient) are biased toward alternatively activated anti-inflammatory (M2) phenotype. Finally, we find that Gα_i2-deficient macrophages have increased Akt activation and IFN-β production but defects in ERK1/2 and STAT3 activation after LPS stimulation. Gα_i2-deficient macrophages also exhibit increased STAT6 activation after IL-4 stimulation. In summary, our data indicates that excess Gα_i2 signaling promotes an M1 macrophage phenotype, whereas Gα_i2 signaling deficiency promotes an M2 phenotype. Understanding Gα_i2-mediated effects on macrophage polarization may bring to light insights regarding disease pathogenesis and the reprogramming of macrophages for the development of novel therapeutics.

Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gαi-GDP free of Gβγ. We previously demonstrated that the AGS4-Gαi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gαi module to the receptor analogous to canonical Gαβγ heterotrimer. We have demonstrated that the AGS4-Gαi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gαi module in the regulation of leukocyte function.

Many intracellular pathogens cause disease by subverting macrophage innate immune defense mechanisms. Intracellular pathogens actively avoid delivery to or directly target lysosomes, the major intracellular degradative organelle. In this article, we demonstrate that activator of G-protein signaling 3 (AGS3), an LPS-inducible protein in macrophages, affects both lysosomal biogenesis and activity. AGS3 binds the Gi family of G proteins via its G-protein regulatory (GoLoco) motif, stabilizing the Gα subunit in its GDP-bound conformation. Elevated AGS3 levels in macrophages limited the activity of the mammalian target of rapamycin pathway, a sensor of cellular nutritional status. This triggered the nuclear translocation of transcription factor EB, a known activator of lysosomal gene transcription. In contrast, AGS3-deficient macrophages had increased mammalian target of rapamycin activity, reduced transcription factor EB activity, and a lower lysosomal mass. High levels of AGS3 in macrophages enhanced their resistance to infection by Burkholderia cenocepacia J2315, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus, whereas AGS3-deficient macrophages were more susceptible. We conclude that LPS priming increases AGS3 levels, which enhances lysosomal function and increases the capacity of macrophages to eliminate intracellular pathogens.