Faculty Bibliography

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) use in children is rapidly expanding, though in contrast to adults, morphologic data on dermatologic adverse events (AEs) in pediatric patients remain sparse, underscoring the need for further focused investigation. We review and synthesize the existing literature on dermatologic AEs of GLP-1 RAs in children in comparison to adults, to summarize current evidence, identify knowledge gaps, and highlight areas for future research. Available reports suggest that rash, urticaria, and alopecia may occur with greater frequency in children on injectable GLP-1 RAs compared with adults, while facial lipodystrophy has been more often described in adults. However, pediatric dermatologic AE data are not as robust as adult data, reducing the ability for direct comparisons. Based on this initial investigation, dermatologic AEs of GLP-1 RAs are seemingly under-described in children and may have important differences compared with adult dermatologic AEs.

Members of the Mammalian Cell Entry (MCE) superfamily interact with other proteins to form diverse architectures for the transport of hydrophobic molecules across the cell envelope in Gram-negative bacteria. Some of these trans-envelope MCE protein complexes include a PqiC-like outer membrane (OM) lipoprotein component. The best-studied member of this group of OM lipoproteins is E. coli PqiC, from the PqiABC system, which can form an octameric ring. How PqiC-like lipoproteins interact with their MCE protein binding partners to facilitate transport is not well understood. Here we report the cryo-electron microscopy structures of Pseudomonas aeruginosa PA3214, a homolog of PqiC, in the context of the full MCE transport PA3211-PA3214 system. Our structure provides insight into the biological assembly of the lipoprotein and interactions with its binding partner, MCE protein PA3213. We utilize deep mutational scanning to identify functionally important sites in E. coli PqiC in an unbiased manner. Through phenotypic and biochemical experiments, we characterize the interactions of the lipoproteins PqiC and PA3214 with their associated MCE proteins PqiB and PA3213, thus providing a model for how some MCE proteins employ a C-terminal peptide to mediate key interactions with their cognate lipoproteins at the OM.

Temporal patterning is an evolutionarily conserved mechanism to produce neuronal and glial diversity from common cells of origin during neurodevelopment. This process is controlled by a series of temporal transcription factors that are transiently expressed and drive the sequential production of specific progeny subtypes. Intermediate neural progenitors (INPs) and optic lobe neural stem cells (OL NSCs) share striking similarities in temporal factor expression despite divergent cells of origin. Tailless (Tll) is a terminal temporal factor in the visual system, in OL NSCs. Tll expression coincides with the termination of neurogenesis and onset of gliogenesis. Here, we report that Tll also acts as a terminal factor in INPs, demonstrating functional conservation. Tll expression is activated by the preceding temporal factor, Scarecrow, and represses odd-paired and hamlet. tll also plays a partial role in promoting gliogenesis in gliogenic NSCs. We performed genome-wide binding analysis of Tll in the OL NSCs and INPs by Targeted DamID, revealing both conserved and divergent targets, reflecting differences in regulatory outcomes. We show that temporal patterning mechanisms are conserved between different brain regions, whilst facilitating lineage-specific outputs.

The divalent anion sodium symporter (DASS) family mediates the uptake of Krebs cycle intermediates and sulfate and influences adiposity, insulin resistance, and metabolism in mammals. While Na⁺:substrate stoichiometry is known for several DASS transporters, the location of key Na⁺-binding sites remains elusive; important information for understanding the mechanism. In VcINDY, a bacterial DASS protein, we visualized a nonprotein cryo-electron microscopy (cryo-EM) density in the middle of the transport domain. Its size and coordination suggest that it may represent either a third Na⁺ ion or a structural water molecule. Using a combination of in vitro binding and transport assays, cryo-EM structural determination, and molecular dynamic simulations, we show that the density is not a Na⁺ ion. Instead, the data indicate that the density likely represents a structural water molecule critical for transport domain integrity. Sequence and structural similarities suggest this feature may be conserved across human DASS transporters such as NaCT and NaDC3.

The divalent anion sodium symporter (DASS) family mediates the uptake of Krebs cycle intermediates and sulfate and influences adiposity, insulin resistance, and metabolism in mammals. While Na⁺:substrate stoichiometry is known for several DASS transporters, the location of key Na⁺-binding sites remains elusive; important information for understanding the mechanism. In VcINDY, a bacterial DASS protein, we visualized a nonprotein cryo-electron microscopy (cryo-EM) density in the middle of the transport domain. Its size and coordination suggest that it may represent either a third Na⁺ ion or a structural water molecule. Using a combination of in vitro binding and transport assays, cryo-EM structural determination, and molecular dynamic simulations, we show that the density is not a Na⁺ ion. Instead, the data indicate that the density likely represents a structural water molecule critical for transport domain integrity. Sequence and structural similarities suggest this feature may be conserved across human DASS transporters such as NaCT and NaDC3.

BACKGROUND/UNASSIGNED:Obesity is associated with a loss of anti-inflammatory regulatory T cells (Tregs) in adipose tissue (AT), resulting in systemic inflammation. The adipocyte is a central modulator of CD4+T-cell subpopulations via antigen presentation through the MHCII (major histocompatibility complex class II). However, the role of adipocyte-induced AT inflammation due to changes in AT Tregs in obesity-related complications, such as atherosclerosis and metabolic-dysfunction-associated fatty liver disease (MAFLD), remains unknown. METHODS/UNASSIGNED:mice fed a Western high-fat diet for 12 weeks. We used 1-year-old mice because, unlike young mice, they develop markedly accelerated atherosclerosis like humans. RESULTS/UNASSIGNED:) ingesting a Western high-fat diet, had no effect on disease progression. CONCLUSIONS/UNASSIGNED:These results suggest that AT immunosuppressive T cells play a pivotal role in regulating both atherosclerosis development and liver fat accumulation in obesity.

Alopecia areata (AA) is an autoimmune hair disease with variable presentations necessitating individualized, stepwise management given patient age, extent of involvement, comorbidities, and treatment tolerability. Historically, severity was defined by percentage of scalp hair loss using the Severity of Alopecia Tool (SALT), with SALT≥50 defining severe disease and systemic therapy eligibility. Recently, severity assessment has expanded beyond scalp involvement with the AA Scale for Clinical Use (AASc), incorporating eyebrow/eyelash involvement, psychosocial impairment, and treatment response to better capture disease burden. First-line therapy for mild-to-moderate AA (SALT<50) includes topical or intralesional corticosteroids, often with topical or oral minoxidil. Observation may be appropriate in select cases given potential for spontaneous regrowth. FDA approval of oral Janus kinase inhibitors (JAKis) for severe AA (SALT≥50) has changed the therapeutic landscape. Selection among baricitinib, ritlecitinib, and deuruxolitinib is guided by patient age, safety considerations, comorbidities, laboratory monitoring, and insurance coverage. Switching between JAKis may still be beneficial after nonresponse to one agent. Adjunctive and alternative therapies include topical immunotherapy, systemic immunosuppressants, emerging biologic/targeted therapies, and procedural modalities, such as platelet-rich plasma, laser- and light-based therapies, and microneedling. This review synthesizes current evidence on AA treatment and offers a practical, contemporary framework for AA management.

BACKGROUND:Penetrating trauma disproportionately affects young patients, yet many survivors cannot be discharged directly home and instead require post-acute care. Identifying these patients early could expedite rehabilitation referral and discharge planning, but no validated tool predicts non-home discharge in penetrating trauma. We developed and internally validated the Penetrating Injury Risk of Non-home Discharge (PIRD) score. METHODS:Using the National Trauma Data Bank (NTDB) Trauma Quality Improvement Program Participant Use Files (2019-2024), we selected adult patients (≥18 years) with penetrating trauma who survived to discharge. The outcome was non-home discharge to post-acute care (e.g., skilled nursing or inpatient rehabilitation) versus home. The cohort was split 2:1 into derivation and validation sets, stratified by outcome. Candidate predictors available early in the hospital course (demographics, insurance, mechanism, emergency-department physiology, the Injury Severity Score [ISS], body-region injury, transport, and comorbidities) underwent univariate screening, collinearity assessment, and backward-stepwise multivariable logistic regression. Unlike the orthopedic FORD score, ISS was retained because penetrating trauma is a high-severity, mortality-driven population. Coefficients were converted to integer points, scaled 0-10. RESULTS:Among 302,399 patients, 21,186 (7.0%) had non-home discharge. The 40-predictor model was led by spinal-cord injury, critical injury severity (ISS ≥25), advanced age, and severe traumatic brain injury, whereas stab mechanism and private-vehicle arrival lowered the odds. Validation discrimination was strong (area under the receiver operating characteristic curve [AUROC] 0.866, 95% confidence interval 0.861-0.871) with excellent calibration (Brier 0.046, calibration slope 1.00), exceeding the GTOS-II, TRIAGES, FORD, and DEPARTS scores (all p < 0.001). Non-home discharge rose from 0.7% (low risk) to 37.5% (high risk); at a score ≥4, sensitivity was 86.0% and negative predictive value 98.5%. CONCLUSION/CONCLUSIONS:Derived from variables available early in care, the PIRD score accurately predicts post-acute care discharge in adult penetrating trauma and outperforms existing severity scores, supporting timely discharge planning and resource allocation.

The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa-the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13⁺ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell-cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease.

Cryo-electron tomography (cryo-ET) has emerged as a transformative technique for visualizing the native ultrastructure of eukaryotic parasites, from proteins to cellular architecture. Recent technical advances in sample preparation, data collection, and computational analysis have enabled unprecedented insights into structural cell biology of medically important pathogens including Toxoplasma gondii, Plasmodium falciparum, Trypanosoma brucei and Trypanosoma cruzi, Cryptosporidium parvum, and Microsporidia. This review highlights the range of resolutions and cellular structures accessible by cryo-ET, and the kinds of biological insights that may be obtained, using eukaryotic parasites as case studies. Lower-resolution data (20-30 Å) provide structural information on organelles, whole-cells, and cell-cell interactions, while at the higher-resolution end, near-atomic structures can be resolved in situ using subtomogram averaging, typically for large, abundant particles such as ribosomes. Combined with orthogonal techniques, cryo-ET is a powerful tool for studying the structural cell biology of parasites.