MSTPublications: April 2025
Genome-wide meta-analysis identifies novel risk loci for uterine fibroids within and across multiple ancestry groups.
Kim J, Williams A, Noh H, Jasper EA, Jones SH, Jaworski JA, Shuey MM, Ruiz-Narváez EA, Wise LA, Palmer JR, Connolly J, Keaton JM, Denny JC, Khan A, Abbass MA, Rasmussen-Torvik LJ, Kottyan LC, Madhivanan P, Krupp K, Wei WQ, Edwards TL, Velez Edwards DR, Hellwege JN.
Nat Commun. 2025 Mar 6;16(1):2273. doi: 10.1038/s41467-025-57483-5.
PMID: 40050615 Free PMC article.
Abstract
Uterine leiomyomata or fibroids are highly heritable, common, and benign tumors of the uterus with poorly understood etiology. Previous GWAS have reported 72 associated genes but included limited numbers of non-European individuals. Here, we identify 11 novel genes associated with fibroids across multi-ancestry and ancestry-stratified GWAS analyses. We replicate a known fibroid GWAS gene in African ancestry individuals and estimate the SNP-based heritability of fibroids in African ancestry populations as 15.9%. Using genetically predicted gene expression and colocalization analyses, we identify 46 novel genes associated with fibroids. These genes are significantly enriched in cancer, cell death and survival, reproductive system disease, and cellular growth and proliferation networks. We also find that increased predicted expression of HEATR3 in uterine tissue is associated with fibroids across ancestry strata. Overall, we report genetic variants associated with fibroids coupled with functional and gene pathway enrichment analyses.
Single-cell map of innate-like lymphocyte response to Francisella tularensis infection reveals interleukin-17-dependent protection by MAIT cells.
Okoye GD, Kumar A, Ghanbari F, Chowdhury NU, Wu L, Newcomb DC, Van Kaer L, Algood HMS, Joyce S.
iScience. 2025 Jan 16;28(3):111810. doi: 10.1016/j.isci.2025.111810. eCollection 2025 Mar 21.
PMID: 40160424 Free PMC article.
Abstract
Early immune dynamics during the initiation of fatal tularemia caused by Francisella tularensis infection remain unknown. Unto that end, we generated a transcriptomic map at single-cell resolution of the innate-like lymphocyte responses to F. tularensis live vaccine strain (LVS) infection of mice. We found that both interferon-γ (IFN-γ)-producing type 1 and interleukin-17 (IL-17)-producing type 3 innate-like lymphocytes expanded in the infected lungs. Natural killer (NK) and NKT cells drove the type 1 response, whereas mucosal-associated invariant T (MAIT) and γδ T cells drove the type 3 response. Furthermore, tularemia-like disease resistant NKT cell-deficient, Cd1d -/- mice accumulated more MAIT1 cells, MAIT17 cells, and cells with a hybrid phenotype between MAIT1 and MAIT17 cells than wild-type mice. Critically, adoptive transfer of LVS-activated MAIT cells from Cd1d -/- mice, which were enriched in MAIT17 cells, was sufficient to protect LVS-susceptible, immunodeficient RAG2 -/- mice from severe LVS infection-inflicted pathology. Collectively, our findings position MAIT cells as potential mediators of IL-17-dependent protection from pulmonary tularemia-like disease.
Keywords: Cell biology; Immunology; Microbiology.
Adenosine A2A Receptors Link Astrocytic α1-Adrenergic Signaling to Wake-Promoting Dopamine Neurons.
Petersen N, McCann KE, Stavarache MA, Kim LY, Weinshenker D, Winder DG.
Biol Psychiatry. 2025 May 1;97(9):915-928. doi: 10.1016/j.biopsych.2024.09.030. Epub 2024 Oct 16.
PMID: 39419462
Abstract
Background: Sleep and arousal disorders are common, but the underlying physiology of wakefulness is not fully understood. The locus coeruleus promotes arousal via α1-adrenergic receptor (α1AR)-driven recruitment of wake-promoting dopamine neurons in the ventral periaqueductal gray (vPAGDA neurons). α1AR expression is enriched on vPAG astrocytes, and chemogenetic activation of astrocytic Gq signaling promotes wakefulness. Astrocytes can release extracellular gliotransmitters, such as ATP and adenosine, but the mechanism underlying how vPAG astrocytic α1ARs influence sleep/wake behavior and vPAGDA neuron physiology is unknown.
Methods: In this study, we utilized genetic manipulations with ex vivo calcium imaging in vPAGDA neurons and astrocytes, patch-clamp electrophysiology, and behavioral experiments in mice to test our hypothesis that astrocytic α1ARs mediate noradrenergic modulation of wake-promoting vPAGDA neurons via adenosine signaling.
Results: Activation of α1ARs with phenylephrine increased calcium transients in vPAGDA neurons and vPAG astrocytes and increased vPAGDA neuron excitability ex vivo. Chemogenetic Gq-DREADD (designer receptor exclusively activated by designer drugs) activation of vPAG astrocytes similarly increased vPAGDA neuron calcium activity and intrinsic excitability. Conversely, short hairpin RNA knockdown of vPAG astrocytic α1ARs reduced the excitatory effect of phenylephrine on vPAGDA neurons and blunted arousal during the wake phase. Pharmacological blockade of adenosine A2A receptors precluded the α1AR-induced increase in vPAGDA calcium activity and excitability in brain slices, as well as the wake-promoting effects of vPAG α1AR activation in vivo.
Conclusions: We have identified a crucial role for vPAG astrocytic α1ARs in sustaining arousal through heightened excitability and activity of vPAGDA neurons mediated by local A2A receptors.
Keywords: Adenosine A(2A) receptor; Arousal; Astrocytes; Dopamine neurons; Norepinephrine; Sleep-wake regulation; Ventral periaqueductal gray; α(1)-adrenergic receptor.
CFTR negatively reprograms Th2 cell responses and CFTR potentiation restrains allergic airway inflammation.
Rusznak M, Thomas CM, Zhang J, Toki S, Zhou W, Abney M, Yanda DM, Norlander AE, Hodges CA, Newcomb DC, Kaplan MH, Peebles RS Jr, Cook DP.
JCI Insight. 2025 Mar 25:e191098. doi: 10.1172/jci.insight.191098. Online ahead of print.
PMID: 40131363 Free article.
Abstract
Type 2 inflammatory diseases are common in cystic fibrosis (CF) including asthma, sinusitis, and allergic bronchopulmonary aspergillosis. CD4+ T helper 2 (Th2) cells promote these diseases through secretion of IL-4, IL-5, and IL-13. Whether the cystic fibrosis transmembrane conductance regulator (CFTR), the mutated protein in CF, has a direct effect on Th2 development is unknown. Using murine models of CFTR deficiency and human CD4+ T cells, we show CD4+ T cells expressed Cftr transcript and CFTR protein following activation. Loss of T cell CFTR expression increased Th2 cytokine production compared to control cells. Mice with CFTR-deficient T cells developed increased allergic airway disease to Alternaria alternata extract compared to control mice. Culture of CFTR-deficient Th2 cells demonstrated increased IL-4Rα expression and increased sensitivity to IL-4 with greater induction of GATA3 and IL-13 compared to control Th2 cell cultures. The CFTR potentiator ivacaftor reduced allergic inflammation and type 2 cytokine secretion in bronchoalveolar lavage of “humanized” CFTR mice following Alternaria alternata extract challenge and decreased Th2 development in human T cell culture. Together, these data support a direct role of CFTR in regulating T cell sensitivity to IL-4 and demonstrate a potential CFTR-specific therapeutic strategy for Th2 cell-mediated allergic disease.
Keywords: Adaptive immunity; Immunology; Inflammation; Pulmonology; T cell development; Th2 response.
Mitochondrial fatty acid synthesis and MECR regulate CD4+ T cell function and oxidative metabolism.
Steiner KK, Young AC, Patterson AR, Sugiura A, Watson MJ, Preston SEJ, Zhelonkin A, Jennings EQ, Chi C, Heintzman DR, Pahnke AP, Toudji YT, Hatem Z, Madden MZ, Arner EN, Sewell AE, Blount AK, Okparaugo R, Fallman E, Krystofiak ES, Sheldon RD, Gibson-Corley KN, Voss K, Nowinski SM, Jones RG, Mogilenko DA, Rathmell JC.
J Immunol. 2025 Apr 9:vkaf034. doi: 10.1093/jimmun/vkaf034. Online ahead of print.
PMID: 40204636
TET2-loss enhances immediate and time-resolved interferon-γ signaling responses across myeloid differentiation.
Jenkins MT, Chu YE, Franceski AM, Potts CR, Dubin R, Dickerson KM, Lee SC, Lu R, Welner RS, Ferrell PB.
Exp Hematol. 2025 Apr;144:104727. doi: 10.1016/j.exphem.2025.104727. Epub 2025 Jan 22.
PMID: 39855457
Surgical targeting of lateralized 18F-fluorodeoxyglucose positron emission tomography hypometabolism relates to long-term epilepsy surgery outcomes.
Sainburg LE, Hoang J, Doss DJ, Berry V, Roche A, Lagrange AH, Peterson TE, Smith GT, Englot DJ, Morgan VL.
Epilepsia. 2025 Apr 9. doi: 10.1111/epi.18402. Online ahead of print.
PMID: 40202811
2024 Physician-Scientist Trainee Diversity Summit conference proceedings.
Weng J, Tang CY, Enriquez KT, Guin RN, Christophers B, Soto Albrecht YE, Amusin DB, Rupert DD, Cooper Byas P.
J Clin Transl Sci. 2025 Feb 11;9(1):e49. doi: 10.1017/cts.2025.24. eCollection 2025.
PMID: 40201649 Free PMC article.
Beyond Phecodes: leveraging PheMAP to identify patients lacking diagnosis codes in electronic health records.
Yan C, Grabowska ME, Thakkar R, Dickson AL, Embí PJ, Feng Q, Denny JC, Kerchberger VE, Malin BA, Wei WQ.
J Am Med Inform Assoc. 2025 Mar 29:ocaf055. doi: 10.1093/jamia/ocaf055. Online ahead of print.
PMID: 40156924
Application of an Externally Developed Algorithm to Identify Research Cases and Controls from EHR Data: Trials and Triumphs.
Garduno-Rapp NE, Herzberg S, Ong HH, Kao C, Lehmann CU, Gangireddy S, Jain NB, Giri A.
Appl Clin Inform. 2025 Mar;16(2):314-326. doi: 10.1055/a-2524-5216. Epub 2025 Jan 24.
PMID: 39855267 Free PMC article.
Lung rehabilitation using xenogeneic cross-circulation does not lead to hyperacute rejection in a human lung transplantation model.
Tracy KM, Harris TR, Petrovic M, Cortelli M, Tucker W, François S, Shishido Y, Simon V, Petree B, Johnson CA Jr, Wu WK, Cardwell NL, Simonds E, Adesanya TT, Fortier AK, Raietparvar K, Landstreet SR, Wickersham N, O’Neill JD, Poland J, Shah AS, DeVries S, Crannell C, Marboe CC, Ukita R, Demarest CT, Shaver CM, Bacchetta M.
J Heart Lung Transplant. 2025 Mar 20:S1053-2498(25)01837-6. doi: 10.1016/j.healun.2025.02.1696. Online ahead of print.
PMID: 40120998 Free article.
Save a trip: Clinical outcomes of cardiac allografts recovered by local surgeons compared to recipient center surgeons.
Ahmad A, Harris TR, Williams A, DeBose-Scarlett A, Kamal R, Adjei EA, Siddiqi HK, Wang CC, Petrovic M, Keck CD, Scholl SR, Shah AS, Bommareddi S, Lima B, Trahanas JM.
JHLT Open. 2025 Jan 22;7:100217. doi: 10.1016/j.jhlto.2025.100217. eCollection 2025 Feb.
PMID: 40144840 Free PMC article.
Ten hour donor heart ischemic time with 10ºC static storage.
Tucker W, Patel Y, Petrovic M, Schwartz C, Petree B, Devries S, Lima B, Trahanas J, Bacchetta M, Shah A, Bommareddi S.
JHLT Open. 2024 Oct 13;7:100163. doi: 10.1016/j.jhlto.2024.100163. eCollection 2025 Feb.
PMID: 40144816 Free PMC article.
10 degree C static storage of porcine donation after circulatory death livers improves biliary viability and mitigates ischemia-reperfusion injury.
Tracy KM, Shishido Y, Petrovic M, Murphy A, Adesanya T, Fortier AK, Harris TR, Cortelli M, Tucker WD, François SA, Petree B, Raietparvar K, Simon V, Johnson CA Jr, Simonds E, Poland J, Glomp GA, Crannell C, Liang J, Marshall A, Hinton A Jr, Shaver CM, Demarest CT, Ukita R, Shah AS, Rizzari M, Montenovo M, Rauf MA, McReynolds M, Bacchetta M.
Am J Transplant. 2025 Mar 20:S1600-6135(25)00147-9. doi: 10.1016/j.ajt.2025.03.018. Online ahead of print.
PMID: 40120647 Free article.
The Social Validity of Behavioral Interventions: Seeking Input from Autistic Adults.
Baiden KMP, Williams ZJ, Schuck RK, Dwyer P, Wang M.
J Autism Dev Disord. 2025 Apr;55(4):1172-1186. doi: 10.1007/s10803-024-06297-3. Epub 2024 Mar 12.
PMID: 38470531 Free PMC article.