MSTPublications: October 2024
NeuroimaGene: an R package for assessing the neurological correlates of genetically regulated gene expression.
Bledsoe X, Gamazon ER.
BMC Bioinformatics. 2024 Oct 8;25(1):325. doi: 10.1186/s12859-024-05936-x.
Background: We present the NeuroimaGene resource as an R package designed to assist researchers in identifying genes and neurologic features relevant to psychiatric and neurological health. While recent studies have identified hundreds of genes as potential components of pathophysiology in neurologic and psychiatric disease, interpreting the physiological consequences of this variation is challenging. The integration of neuroimaging data with molecular findings is a step toward addressing this challenge. In addition to sharing associations with both molecular variation and clinical phenotypes, neuroimaging features are intrinsically informative of cognitive processes. NeuroimaGene provides a tool to understand how disease-associated genes relate to the intermediate structure of the brain.
Results: We created NeuroimaGene, a user-friendly, open access R package now available for public use. Its primary function is to identify neuroimaging derived brain features that are impacted by genetically regulated expression of user-provided genes or gene sets. This resource can be used to (1) characterize individual genes or gene sets as relevant to the structure and function of the brain, (2) identify the region(s) of the brain or body in which expression of target gene(s) is neurologically relevant, (3) impute the brain features most impacted by user-defined gene sets such as those produced by cohort level gene association studies, and (4) generate publication level, modifiable visual plots of significant findings. We demonstrate the utility of the resource by identifying neurologic correlates of stroke-associated genes derived from pre-existing analyses.
Conclusions: Integrating neurologic data as an intermediate phenotype in the pathway from genes to brain-based diagnostic phenotypes increases the interpretability of molecular studies and enriches our understanding of disease pathophysiology. The NeuroimaGene R package is designed to assist in this process and is publicly available for use.
Elevated Hemoglobin A1c and the Risk of Developing ARDS in Two Cohort Studies.
Bogart AM, Lopez CR, Obeidalla SN, Wang C, Willmore A, Jauregui A, Kangelaris KN, Hendrickson C, Gomez A, Liu KD, Matthay MA, Shaver CM, Bastarache JA, Calfee CS, Kerchberger VE, Ware LB.
CHEST Crit Care. 2024 Sep;2(3):100082. doi: 10.1016/j.chstcc.2024.100082. Epub 2024 May 15.
Background: Only a subset of patients at risk for ARDS go on to develop it, and the contribution of preexisting comorbidities (eg, diabetes) to ARDS risk is not well understood. Prior studies of the association between diabetes and ARDS have yielded conflicting results.
Research question: Does assessing ARDS risk based on hemoglobin A1c (HbA1c) as a marker of long-term blood glucose levels, rather than a charted diagnosis of diabetes, clarify the relationship between diabetes and ARDS?
Study design and methods: Using data from two prospective observational cohorts of critically ill adults (Validating Acute Lung Injury Biomarkers for Diagnosis [VALID] and Early Assessment of Renal and Lung Injury [EARLI]), we analyzed the association between clinical HbA1c category and development of ARDS in patients with a risk factor for ARDS and at least one clinical HbA1c measurement within the 180 days prior through 14 days after enrollment.
Results: A total of 599 patients in VALID and 276 in EARLI met inclusion criteria, of whom 164 and 58 developed ARDS, respectively. Patients with a charted diagnosis of diabetes were not shown to be more likely to develop ARDS (VALID: 24.6% ARDS in those categorized as nondiabetic vs 30.0% in those categorized as diabetic, P = .14; EARLI: 19.6% vs 22.8%, respectively; P = .55). However, in VALID, patients categorized as diabetic with inadequate glycemic control based on their HbA1c had an increased risk of developing ARDS compared with those with nondiabetic HbA1c (20.9% vs 34.0%, respectively; P = .0073), a finding that persisted in multivariable analysis (OR for those categorized as diabetic with inadequate glycemic control vs those categorized as nondiabetic range HbA1c, 1.25; 95% CI, 1.01-1.57). These findings were not reproduced in the smaller EARLI cohort, but were appreciated when the cohorts were combined for analysis.
Interpretation: Elevated HbA1c may be associated with risk of developing ARDS, independent of clinical diagnosis of diabetes, but prospective validation is needed. If confirmed, these findings suggest that inadequate glycemic control could be an unrecognized risk factor for ARDS.
Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
Chowdhury NU, Cephus JY, Henriquez Pilier E, Wolf MM, Madden MZ, Kuehnle SN, McKernan KE, Jennings EQ, Arner EN, Heintzman DR, Chi C, Sugiura A, Stier MT, Voss K, Ye X, Scales KL, Krystofiak ES, Gandhi VD, Guzy RD, Cahill KN, Sperling AI, Peebles RS Jr, Rathmell JC, Newcomb DC.
J Clin Invest. 2024 Oct 1:e177242. doi: 10.1172/JCI177242. Online ahead of print.
Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
Elevated Body Mass Index Is Associated With Rotator Cuff Disease: A Systematic Review and Meta-analysis.
Herzberg SD, Garriga GA, Jain NB, Giri A.
Arthrosc Sports Med Rehabil. 2024 May 31;6(4):100953. doi: 10.1016/j.asmr.2024.100953. eCollection 2024 Aug.
Purpose: To analyze the literature regarding obesity, body mass index (BMI), and rotator cuff disease (RCD).
Methods: In this Systematic Review and Meta-analysis, we queried PubMed, Embase, Cochrane, Cumulative Index to Nursing & Allied Health, and Science Direct using key words (August 25, 2023). Analytic observational studies (cohort, case-control, and cross-sectional studies) with more than 30 participants per comparison group, evaluating the association between obesity and rotator cuff pathology, were eligible for inclusion. Meta-analysis was performed to quantitatively summarize associations between BMI and RCD to report odds ratios and corresponding 95% confidence intervals (CIs) for regression-based models and BMI mean differences between cases and controls. Risk Of Bias In Non-randomised Studies – of Interventions tool was used to evaluate risk of bias across all studies in the systematic review.
Results: After full-text review of 248 articles, 27 presented data on obesity and RCD, and 17 qualified for meta-analysis. Individuals with RCD were 1.21 times (95% CI 1.10-1.34) as likely to be overweight and 1.44 times (95% CI 1.32-1.59) as likely to have obesity compared with those without RCD. Each 5-unit increase in BMI was associated with 35% greater odds of having rotator cuff tear (95% CI 1.06-1.71). In-depth assessment for risk of bias shows quality of studies varies greatly and highlights outcome heterogeneity, lack of temporality, confounding and selection bias as major concerns for individual studies.
Conclusions: In this study, we found a positive association between elevated BMI and RCD.
Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.
McBride MA, Caja KR, Patil TK, Owen AM, Luan L, Bohannon JK, Hernandez A, Stothers CL, Trenary IA, Rahim M, Young JD, Calcutt MW, Stephens VR, Davis X, Oliver MA, Hao D, Si C, McRae M, Nguyen KK, Davis NS, Wang J, Patil NK, Sherwood ER.
J Leukoc Biol. 2024 Oct 1:qiae198. doi: 10.1093/jleuko/qiae198. Online ahead of print.
Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory. We observed that priming of wild type (WT) mice with MPLA potently facilitated accumulation of the TCA cycle metabolite itaconate at sites of infection and enhanced microbial clearance. Augmentation of itaconate accumulation and microbial clearance was ablated in immune responsive gene 1 (Irg1) -deficient mice. We further observed that MPLA potently induces expression of Irg1 and accumulation of itaconate in macrophages. Compared to WT macrophages, the ability of Irg1-deficient macrophages to kill Pseudomonas aeruginosa was impaired. We further observed that itaconate is directly antimicrobial against P. aeruginosa at pH 5, which is characteristic of the phagolysosome, and is facilitated by reactive oxygen species. MPLA-induced augmentation of glycolysis, oxidative phosphorylation and accumulation of the TCA cycle metabolites succinate and malate was decreased in Irg1 KO macrophages compared to WT controls. RNA sequencing revealed suppressed transcription of genes associated with phagolysosome function and increased expression of genes associated with cytokine production and chemotaxis in Irg1 deficient macrophages. This study identifies a contribution of itaconate to MPLA-induced augmentation of innate antimicrobial immunity via facilitation of microbial killing as well as impact on metabolic and transcriptional adaptations.
Variance quantitative trait loci reveal gene-gene interactions which alter blood traits.
Pershad Y, Poisner H, Corty RW, Hellwege JN, Bick AG.
medRxiv [Preprint]. 2024 Sep 19:2024.09.18.24313883. doi: 10.1101/2024.09.18.24313883.
Gene-gene (GxG) interactions play an important role in human genetics, potentially explaining part of the “missing heritability” of polygenic traits and the variable expressivity of monogenic traits. Many GxG interactions have been identified in model organisms through experimental breeding studies, but they have been difficult to identify in human populations. To address this challenge, we applied two complementary variance QTL (vQTL)-based approaches to identify GxG interactions that contribute to human blood traits and blood-related disease risk. First, we used the previously validated genome-wide scale test for each trait in ~450,000 people in the UK Biobank and identified 4 vQTLs. Genome-wide GxG interaction testing of these vQTLs enabled discovery of novel interactions between (1) CCL24 and CCL26 for eosinophil count and plasma CCL24 and CCL26 protein levels and (2) HLA-DQA1 and HLA-DQB1 for lymphocyte count and risk of celiac disease, both of which replicated in ~140,000 NIH All of Us and ~70,000 Vanderbilt BioVU participants. Second, we used a biologically informed approach to search for vQTL in disease-relevant genes. This approach identified (1) a known interaction for hemoglobin between two pathogenic variants in HFE which cause hereditary hemochromatosis and alters risk of cirrhosis and (2) a novel interaction between the JAK2 46/1 haplotype and a variant on chromosome 14 which modifies platelet count, JAK2 V617F clonal hematopoiesis, and risk of polycythemia vera. This work identifies novel disease-relevant GxG interactions and demonstrates the utility of vQTL-based approaches in identifying GxG interactions relevant to human health at scale.
Biofunctionalized gelatin hydrogels support development and maturation of iPSC-derived cortical organoids.
Kjar A, Haschert MR, Zepeda JC, Simmons AJ, Yates A, Chavarria D, Fernandez M, Robertson G, Abdulrahman AM, Kim H, Marguerite NT, Moen RK, Drake LE, Curry CW, O’Grady BJ, Gama V, Lau KS, Grueter B, Brunger JM, Lippmann ES.
Cell Rep. 2024 Oct 17;43(11):114874. doi: 10.1016/j.celrep.2024.114874. Online ahead of print.
Cardiomyocyte-derived circulating extracellular vesicles allow a non-invasive liquid biopsy of myocardium in health and disease.
Spanos M, Gokulnath P, Li G, Hutchins E, Meechoovet B, Sheng Q, Chatterjee E, Sharma R, Carnel-Amar N, Lin C, Azzam C, Ghaeli I, Amancherla KV, Victorino JF, Garcia-Mansfield K, Pfeffer R, Sahu P, Lindman BR, Elmariah S, Gamazon ER, Betti MJ, Bledsoe X, Lance ML, Absi T, Su YR, Do N, Contreras MG, Varrias D, Kladas M, Radulovic M, Tsiachris D, Spanos A, Tsioufis K, Ellinor PT, Tucker NR, Januzzi JL, Pirrotte P, Jovanovic-Talisman T, Van Keuren-Jensen K, Shah R, Das S.
medRxiv [Preprint]. 2024 Sep 22:2024.09.19.24314009. doi: 10.1101/2024.09.19.24314009.
Language-model-based patient embedding using electronic health records facilitates phenotyping, disease forecasting, and progression analysis.
Xian S, Grabowska ME, Kullo IJ, Luo Y, Smoller JW, Wei WQ, Jarvik G, Mooney S, Crosslin D.
Res Sq [Preprint]. 2024 Sep 23:rs.3.rs-4708839. doi: 10.21203/rs.3.rs-4708839/v1.
The IBEX Knowledge-Base: Achieving more together with open science.
Radtke AJ, Anidi I, Arakkal L, Arroyo-Mejias A, Beuschel RT, Börner K, Chu CJ, Clark B, Clatworthy MR, Colautti J, Croteau J, Denha S, Dever R, Dutra WO, Fritzsche S, Fullam S, Gerner MY, Gola A, Gollob KJ, Hernandez JM, Hor JL, Ichise H, Jing Z, Jonigk D, Kandov E, Kastenmüller W, Koenig JFE, Kothurkar A, Kreins AY, Lamborn I, Lin Y, Luciano Pereira Morais K, Lunich A, Luz JCS, MacDonald RB, Makranz C, Maltez VI, Moriaty RV, Ocampo-Godinez JM, Olyntho VM, Padhan K, Remmert K, Richoz N, Schrom EC, Shang W, Shi L, Shih RM, Speranza E, Stierli S, Teichmann SA, Veres TZ, Vierhout M, Wachter BT, Wade-Vallance AK, Williams M, Zangger N, Germain RN, Yaniv Z.
ArXiv [Preprint]. 2024 Jul 26:arXiv:2407.19059v1. Preprint.
Induction, amplification, and propagation of diabetic retinopathy-associated inflammatory cytokines between human retinal microvascular endothelial and Müller cells and in the mouse retina.
Padovani-Claudio DA, Morales MS, Smith TE, Ontko CD, Namburu NS, Palmer SA, Jhala MG, Ramos CJ, Capozzi ME, McCollum GW, Penn JS.
Cell Signal. 2024 Oct 9;124:111454. doi: 10.1016/j.cellsig.2024.111454. Online ahead of print.
Disruption of mitochondrial electron transport impairs urinary concentration via AMPK-dependent suppression of aquaporin-2.
Carty JS, Bessho R, Zuchowski Y, Trapani JB, Davidoff O, Kobayashi H, Roland JT, Watts JA, Terker AS, Bock F, Arroyo JP, Haase VH.
JCI Insight. 2024 Oct 3:e182087. doi: 10.1172/jci.insight.182087. Online ahead of print.
The Suicide Assessment Kit-Modified Interview: Development and preliminary validation of a modified clinical interview for the assessment of suicidal thoughts and behavior in autistic adults.
Hedley D, Williams ZJ, Deady M, Batterham PJ, Bury SM, Brown CM, Robinson J, Trollor JN, Uljarević M, Stokes MA.
Autism. 2024 Oct 19:13623613241289493. doi: 10.1177/13623613241289493. Online ahead of print.
The missing clinical guidance: a scoping review of care for autistic transgender and gender-diverse people.
Bo L, van der Miesen AIR, Klomp SE, Williams ZJ, Szatmari P, Lai MC.
EClinicalMedicine. 2024 Sep 27;76:102849. doi: 10.1016/j.eclinm.2024.102849. eCollection 2024 Oct. Review.