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Endothelial Cell Expression of STING Gain-of-Function Mutation Delays the Resolution of UVB-induced Skin Injury [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Gain-of-function mutations in STimulator of INterferon Genes (STING) cause STING-Associated Vasculopathy with Onset in Infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, non-healing ulcers. Mice expressing the most common SAVI-associated variant STING (VM) recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low dose of ultraviolet B (UVB) irradiation, which induces only transient skin inflammation in wild-type (WT) mice, causes severe and progressive skin injury in VM mice. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with WT bone marrow, demonstrating that STING expression in non-hematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis identified endothelial cells expressing STING as the primary driver of the cutaneous phenotype. Flow cytometry and bulk RNA sequencing showed that VM mice exhibited reduced early skin infiltration of macrophages and dendritic cells after UVB exposure. These findings establish a critical link between endothelial STING activation, impaired recruitment of skin myeloid cells, and defective resolution of acute inflammation, offering new insights into the pathogenesis of SAVI-associated skin disease.No embarg
Genetic and Dietary Mechanisms of Neuroprotection Against TIR-1/SARM1-Induced Degeneration
No full textNeurodegeneration causes loss of cognitive, sensory, and motor abilities for which there is a critical lack of therapeutic approaches. Understanding the genetic and cellular mechanisms that regulate degeneration is crucial to developing effective therapies. In my early dissertation work, we found that the Caenorhabditis elegans homolog of dSarm/SARM1, TIR-1, functions within injured GABA motor axons to promote axon degeneration and, surprisingly, inhibit axon regeneration. We then found that 1) TIR-1 regulates the two seemingly opposite responses to injury by interacting with distinct genetic pathways on either side of injury and 2) overexpression of TIR-1 induces chronic degeneration in the absence of injury. Our findings add to our mechanistic understanding of regeneration and degeneration and reveal a powerful model for identifying conserved neurodegenerative mechanisms.
Emerging evidence establishes that the microbiome influences the onset and progression of neurodegenerative diseases. The well-characterized nervous system and ability to exist on uni-bacterial diets make C. elegans a highly tractable model to dissect specific gut-brain interactions. I used our TIR-1 degeneration model to ask whether and how bacterial diets and their metabolites suppress axon degeneration. Feeding individual bacterial species to C. elegans revealed Comamonas aquatica protects axons from degenerating. Detailed genetic analyses, imaging, and metabolomics led me to 1) identify vitamin B12 as the neuroprotective metabolite provided by Comamonas and 2) find B12 regulates neuroprotection by enabling methionine synthase activity and lowering toxic homocysteine levels. My findings identify neuroprotective bacteria and reveal mechanisms by which they are protective, providing a greater understanding of ‘gut-brain’ interactions.Neuroscience2 years2027-09-1
Structural Analysis of Inhibitor Binding to the Feline Enteric Coronavirus (FECV) Main Protease
Full text linkCoronaviruses include various strains that reside in natural animal reservoirs, with zoonotic transmission posing risks to both domesticated animals and human health. Recent efforts to address coronavirus infections have focused on developing inhibitors targeting the main protease (M), some of which exhibit potential broad-spectrum efficacy. This study presents crystal structures of four clinically relevant inhibitors-GC376, PF-00835231, nirmatrelvir, and ibuzatrelvir-bound to M from the feline coronavirus strain FECV-UU23. Structural analysis identified distinct FECV-specific features within the active site where these inhibitors bind and revealed S4 loop as a susceptible structural region essential for the enhanced binding of inhibitors in UU23 M. We therefore propose to incorporate sterically constrained, functionally tailored heterocyclic moieties at the P3 site of known inhibitors which can optimally engage Q187, P188, and S189 residues of the S4 loop. The findings presented enhance understanding of inhibitor specificity and reinforce the promise of these inhibitor scaffolds for developing antivirals against feline coronavirus strains, with possible applications in broad-spectrum coronavirus therapy.No embarg
Expanding the Therapeutic Reach of Chimeric Antigen Receptor T-Cells and Bispecific T-Cell Engagers Across Solid Tumors
No full textThe introduction of T-cell-based therapeutics in hematologic malignancies has led to improvements in outcomes for patients with acute leukemia, lymphoma, and multiple myeloma. To date, the Food and Drug Administration (FDA) has approved seven chimeric antigen receptor-T (CAR-T) cell therapies and seven bispecific T-cell engagers (BiTEs) across a variety of hematologic malignancies; however, the extension of CAR-T therapies and BiTEs to the solid tumor arena has been somewhat limited. In this review, we discuss the landmark data that led to the commercialization of four novel FDA-approved T-cell-based therapeutics in solid malignancies, including tarlatamab for small cell lung cancer, afamitresgene autoleucel for synovial sarcoma, lifileucel for metastatic melanoma, and tebentafusp for metastatic uveal melanoma. We discuss the targetable antigen landscape of CAR-T therapies and BiTEs under investigation in solid malignancies. We explore the translational potential for various CARs under active investigation, including human epidermal growth factor receptor 2-directed CARs in breast cancer, prostate stem cell antigen-directed CARs for prostate cancer, epidermal growth factor receptor (EGFR)-IL13Ra2 and EGFR-vIII CARs for glioblastoma, and GD2-directed CARs for neuroblastoma. We glean from lessons learned for existing CAR-T therapies and BiTEs for hematologic malignancies and emphasize solutions toward facilitating the clinical rollout of T-cell-based therapies in solid tumors, including scalability to meet the growing needs of clinical oncology. Some solutions include addressing on-target, off-tumor toxicity; improving the manufacturing of CARs; optimizing the tissue-specific tumor microenvironment by combating immune desert tumors; and discovering natural tumor neoantigens and non-self-epitopes generated by tumor-specific mutations. These concepts can help provide transformative benefits for patients with solid malignancies in the coming years.No embarg
Developing Gene Therapies for the Treatment of Pediatric Nervous System Tumors
No full textCentral and Peripheral Nervous System (CNS/PNS) tumors in the pediatric population represent diseases with complex physiologic and societal burdens. CNS tumors are the greatest cause of pediatric cancer related death, and PNS tumors have lifelong symptomatic burdens. We focus on Diffuse Intrinsic Pontine Glioma (DIPG) and Neurofibromatosis Type-I (NF1). Both have few successful therapies and none are curative. However, both have pathognomonic mutations, H3F3A and NF1 respectively, which drive disease development. We developed gene therapies for these diseases through modulation of their pathognomonic genes.
For DIPG, we developed a siRNA-based therapy for H3K27M oncohistone knockdown, hypothesizing that allele-specific knockdown would result in tumor stasis or regression. We successfully developed compounds which cause knockdown of the mutant H3K27M mRNA. However, this knockdown does not impact mutant H3K27M protein expression nor broader cellular changes.
For NF1, we developed a trans-splicing therapeutic to correct the first and final third of the mutant NF1 mRNA while NF1 mRNA production is maintained under endogenous regulation. We performed library-based screening to identify functional trans-splicing moieties. Unguided trans-splicing did not occur at appreciable rates. Re-designing the system with Cas13 guidance resulted in successful trans-splicing at a molecular level, but efficiency was minimal.
In summary, we investigated novel gene therapy methodologies for DIPG and NF1 that have therapeutic potential in ideal circumstances, however inherent disease specific challenges prevent expanding their use. Further refinement of these technologies and greater understanding of the disease context surrounding their function is required for successful therapeutic development to improve the lives of patients.MD/PhD2 years2027-06-0
Post-traumatic stress and genetic interactions affect tobacco and alcohol use after trauma: findings from a multi-ancestry cohort
Full text linkTobacco smoking and drinking alcohol are common substance use behaviors influenced by both genetic risk and environmental exposures. Traumatic events are highly prevalent, affecting about 70% of people in their lifetime. After trauma, it is unclear what role post-traumatic stress disorder (PTSD) symptoms play in substance use behaviors when accounting for this genetic risk. We used data from the Advancing Understanding of RecOvery afteR traumA (AURORA), which included 2973 participants recruited at emergency departments (EDs) within 72 h of a traumatic event and followed over time. We measured PTSD symptoms via PTSD Checklist for the DSM-5. Tobacco and alcohol consumption as frequency, quantity, and quantity-frequency in the past 30 days. We generated polygenic risk scores with continuous shrinkage for cross-ancestry estimation (PRS-CSx). We tested for main effects between PRS-CSx scores and interactions with PTSD using quasipoisson regression, with week 8 PTSD symptoms and month 6 substance use behaviors after the traumatic event. Tobacco PRS-CSx score increased the risk of tobacco use by 14% (95% CI: 1.01, 1.29, p = 0.03), and alcohol PRS-CSx score did not demonstrate consistent associations in the whole cohort (IRR: 1.08, 95% CI: 0.97, 1.19, p = 0.16). When stratified by ancestry group, both tobacco (IRR: 1.36, 95% CI: 1.14, 1.61, p < 0.001) and alcohol (IRR: 1.24, 95% CI: 1.07, 1.44, p = 0.005) PRS-CSx scores were associated with their respective outcomes in the European ancestry subcohort. Participants with lower genetic risk had stronger associations between re-experiencing symptoms and tobacco use, while participants with higher genetic risk demonstrated weaker association between re-experiencing symptoms and tobacco use. A similar pattern was observed for negative alterations in cognition/mood (NACM) symptoms-participants with lower PRS-CSx scores had stronger associations between NACM symptoms with tobacco use, compared to participants with higher PRS-CSx scores. These interactions were both statistically significant, suggesting an antagonistic effect between PRS-CSx scores and PTSD symptoms on tobacco use.No embarg
Global Transcriptomic Changes Across Multiple Isogenic C9orf72 ALS Patient iPSC Derived Neurons
No full textHexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), yet the mechanisms underlying selective neuronal vulnerability remain unclear. A major challenge in identifying consistent transcriptomic changes across C9orf72 patient-derived neuron lines has been heterogeneous differentiations, lack of isogenic controls and low sequencing depth. To overcome these challenges, we generated homogeneous cortical neuron (iCNs) cultures from multiple isogenic C9orf72 patient iPSCs pairs and performed RNA deep sequencing. We identified robust and reproducible gene expression and splicing alterations in pathways related to cytoskeletal organization, extracellular matrix adhesion and synaptic signaling. Notably, we observed exon 30 skipping in the cytoskeletal regulator Filamin B (FLNB), leading to the loss of its hinge domain. This was accompanied by altered FLNB localization, disrupted actin crosslinking and impaired mechano-transduction pathways. These findings reveal convergent transcriptomic and functional disruptions across multiple isogenic C9orf72 patient derived iCNs offering new insights into ALS/FTD pathogenesis.
Building on these findings, we tested the cytoskeletal- microtubule-stabilizing agent Paclitaxel (Taxol) for its therapeutic potential in C9orf72 iCNs. In one patient line, Taxol improved neurite density, supporting the functional relevance of cytoskeletal dysregulation. However, bulk RNA sequencing in additional patient lines revealed minimal transcriptomic rescue, suggesting Taxol may act downstream of transcription or has variable effects across patient backgrounds.
Altogether, this study establishes an isogenic iPSC-based neuronal platform that integrates transcriptomic and functional analysis to uncover reproducible disease mechanisms and further evaluate candidate therapeutic strategies for ALS/FTD.Neuroscience6 months2026-05-1
Assessing Critical Care Delivery Using National-Level ICU Registry Data
No full textObjective: The specialty of critical care in the United States currently lacks a single, broad, unified database. We conducted a scoping review of existing established national ICU databases, describing national and international patterns of critical care delivery.
Data sources: A systematic literature search was undertaken using MEDLINE, Embase, and Web of Science search engines.
Study selection: Projects describing national critical care delivery (including any subspecialty) published in any language were included. Titles, abstracts, and full-text manuscripts were reviewed in duplicate for inclusion.
Data extraction: National database characteristics were collected, including the number and subspecialty of ICUs, the inaugural year, data entry methodology, the number of episodes of care included, and captured clinical data elements.
Data synthesis: Of 24,003 abstracts screened, 185 manuscripts were eligible for inclusion. Thirty countries were identified as having established national ICU registries: Argentina, Australia/New Zealand, Austria, Belgium, Brazil, Canada, Denmark, Ecuador, Finland, Germany, Iceland, India, Ireland, Italy, Japan, Kenya, Malaysia, Mexico, Nepal, Netherlands, Norway, Pakistan, Paraguay, Spain, Sri Lanka, Sweden, Switzerland, United Kingdom, United States and Uruguay. Data entry commonly incorporates a combination of automated data abstraction from electronic healthcare systems and manual data entry, followed by independent validation. Frequently recorded variables include patient demographics; admission vital signs and laboratory data; comorbidities; admission source and diagnoses; ICU diagnoses, treatments, and complications; illness severity scores; and clinically relevant outcomes including discharge disposition, functional status, lengths of stay, and mortality.
Conclusions: Insights and experience gained from the study of mature national ICU registries may be used to guide an equivalent U.S. multidisciplinary program aimed at benchmarking, needs assessment, quality improvement, and research facilitation.No embarg
Environment scan of generative AI infrastructure for clinical and translational science
Full text linkThis study reports a comprehensive environmental scan of the generative AI (GenAI) infrastructure in the national network for clinical and translational science across 36 institutions supported by the CTSA Program led by the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) at the United States. Key findings indicate a diverse range of institutional strategies, with most organizations in the experimental phase of GenAI deployment. The results underscore the need for a more coordinated approach to GenAI governance, emphasizing collaboration among senior leaders, clinicians, information technology staff, and researchers. Our analysis reveals that 53% of institutions identified data security as a primary concern, followed by lack of clinician trust (50%) and AI bias (44%), which must be addressed to ensure the ethical and effective implementation of GenAI technologies.No embarg
Parental liver disease mortality is associated with unfavorable outcomes in patients with alcohol-associated hepatitis
Full text linkBackground: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown.
Methods: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome.
Results: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]).
Conclusions: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.No embarg