Skip to main content

MSTPublications: May 2022

Posted by on Tuesday, May 31, 2022 in New Publications .

MTG16 regulates colonic epithelial differentiation, colitis, and tumorigenesis by repressing E protein transcription factors.
Brown RE, Jacobse J, Anant SA, Blunt KM, Chen B, Vega PN, Jones CT, Pilat JM, Revetta F, Gorby AH, Stengel KR, Choksi YA, Palin K, Piazuelo MB, Washington MK, Lau KS, Goettel JA, Hiebert SW, Short SP, Williams CS.
JCI Insight. 2022 May 23;7(10):e153045. doi: 10.1172/jci.insight.153045. PMID: 35503250 

Aberrant epithelial differentiation and regeneration contribute to colon pathologies, including inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Myeloid translocation gene 16 (MTG16, also known as CBFA2T3) is a transcriptional corepressor expressed in the colonic epithelium. MTG16 deficiency in mice exacerbates colitis and increases tumor burden in CAC, though the underlying mechanisms remain unclear. Here, we identified MTG16 as a central mediator of epithelial differentiation, promoting goblet and restraining enteroendocrine cell development in homeostasis and enabling regeneration following dextran sulfate sodium-induced (DSS-induced) colitis. Transcriptomic analyses implicated increased Ephrussi box-binding transcription factor (E protein) activity in MTG16-deficient colon crypts. Using a mouse model with a point mutation that attenuates MTG16:E protein interactions (Mtg16P209T), we showed that MTG16 exerts control over colonic epithelial differentiation and regeneration by repressing E protein-mediated transcription. Mimicking murine colitis, MTG16 expression was increased in biopsies from patients with active IBD compared with unaffected controls. Finally, uncoupling MTG16:E protein interactions partially phenocopied the enhanced tumorigenicity of Mtg16-/- colon in the azoxymethane/DSS-induced model of CAC, indicating that MTG16 protects from tumorigenesis through additional mechanisms. Collectively, our results demonstrate that MTG16, via its repression of E protein targets, is a key regulator of cell fate decisions during colon homeostasis, colitis, and cancer.


Human Monoclonal Antibodies to Escherichia coli Outer Membrane Protein A Porin Domain Cause Aggregation but Do Not Alter In Vivo Bacterial Burdens in a Murine Sepsis Model.
Fowler BD, Kose N, Reidy JX, Handal LS, Skaar EP, Crowe JE Jr.
Infect Immun. 2022 May 18:e0017622. doi: 10.1128/iai.00176-22. Online ahead of print.

Escherichia coli is one of the most frequent human pathogens, increasingly exhibits antimicrobial resistance, and has complex interactions with the host immune system. E. coli exposure or infection can result in the generation of antibodies specific for outer membrane protein A (OmpA), a multifunctional porin. We identified four OmpA-specific naturally occurring antibodies from healthy human donor B cells and assessed their interactions with E. coli and OmpA. These antibodies are highly specific for OmpA, exhibiting no cross-reactivity to a strain lacking ompA and retaining binding to both laboratory and clinical isolates of E. coli in enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assays. One monoclonal antibody (Mab), designated ECOL-11, is specific for the extracellular N-terminal porin domain of OmpA and induces growth phase-specific bacterial aggregation. This aggregation is not induced by the fragment antigen binding (Fab) form of the MAb, suggesting the importance of bivalency for this aggregating activity. ECOL-11 decreases adhesion and phagocytosis of E. coli by RAW 264.7 macrophage-like cells, possibly by inhibiting the adhesion functions of OmpA. Despite this in vitro phenotype, organ E. coli burdens were not altered by antibody prophylaxis in a murine model of lethal E. coli septic shock. Our findings support the importance of OmpA at the host-pathogen interface and begin to explore the implications and utility of E. coli-specific antibodies in human hosts.


Vascular alterations impede fragile tolerance to pregnancy in type 1 diabetes.
McNew KL, Abraham A, Sack DE, Smart CD, Pettway YD, Falk AC, Lister RL, Faucon AB, Bejan CA, Capra JA, Aronoff DM, Boyd KL, Moore DJ.
F S Sci. 2022 May;3(2):148-158. doi: 10.1016/j.xfss.2022.02.001. Epub 2022 Feb 5.

Objective: To determine the impact of autoimmunity in the absence of glycemic alterations on pregnancy in type 1 diabetes (T1D).
Design: Because nonobese diabetic (NOD) mice experience autoimmunity before the onset of hyperglycemia, we studied pregnancy outcomes in prediabetic NOD mice using flow cytometry and enzyme-linked immunosorbent assays. Once we determined that adverse events in pregnancy occurred in euglycemic mice, we performed an exploratory study using electronic health records to better understand pregnancy complications in humans with T1D and normal hemoglobin A1c levels.
Setting: University Medical Center.
Patient(s)/animal(s): Nonobese diabetic mice and electronic health records from Vanderbilt University Medical Center.
Intervention(s): Nonobese diabetic mice were administered 200 μg of an anti-interleukin 6 (IL-6) antibody every other day starting on day 5 of gestation.
Main outcome measure(s): Changes in the number of abnormal and reabsorbed pups in NOD mice and odds of vascular complications in pregnancy in T1D in relation to A1c.
Result(s): Prediabetic NOD mice had increased adverse pregnancy outcomes compared with nonautoimmune mice; blockade of IL-6, which was secreted by endothelial cells, decreased the number of reabsorbed and abnormal fetuses. Similarly, vascular complications were increased in pregnant patients with T1D across all A1c values.
Conclusion(s): The vascular secretion of IL-6 drives adverse pregnancy outcomes in prediabetic NOD mice. Pregnant patients with T1D have increased vascular complications even with normal hemoglobin A1cs, indicating a potential effect of autoimmunity on the placental vasculature.


Incomplete Hippocampal Inversion: A Neurodevelopmental Mechanism for Hippocampal Shape Deformation in Schizophrenia.
Roeske MJ, Lyu I, McHugo M, Blackford JU, Woodward ND, Heckers S.
Biol Psychiatry. 2022 Feb 23:S0006-3223(22)01041-1. doi: 10.1016/j.biopsych.2022.02.954. Online ahead of print.

Background: Shape analyses of patients with schizophrenia have revealed bilateral deformations of the anterolateral hippocampus, primarily localized to the CA1 subfield. Incomplete hippocampal inversion (IHI), an anatomical variant of the human hippocampus resulting from an arrest during neurodevelopment, is more prevalent and severe in patients with schizophrenia. We hypothesized that IHI would affect the shape of the hippocampus and contribute to hippocampal shape differences in schizophrenia.
Methods: We studied 199 patients with schizophrenia and 161 healthy control participants with structural magnetic resonance imaging to measure the prevalence and severity of IHI. High-fidelity hippocampal surface reconstructions were generated with the SPHARM-PDM toolkit. We used general linear models in SurfStat to test for group shape differences, the impact of IHI on hippocampal shape variation, and whether IHI contributes to hippocampal shape abnormalities in schizophrenia.
Results: Not including IHI as a main effect in our between-group comparison replicated well-established hippocampal shape differences in patients with schizophrenia localized to the CA1 subfield in the anterolateral hippocampus. Shape differences were also observed near the uncus and hippocampal tail. IHI was associated with outward displacements of the dorsal and ventral surfaces of the hippocampus and inward displacements of the medial and lateral surfaces. Including IHI as a main effect in our between-group comparison eliminated the bilateral shape differences in the CA1 subfield. Shape differences in the uncus persisted after including IHI.
Conclusions: IHI impacts hippocampal shape. Our results suggest IHI as a neurodevelopmental mechanism for the well-known shape differences, particularly in the CA1 subfield, in schizophrenia.


Couples-based interventions and postpartum contraceptive uptake: A systematic review.
Sack DE, Peetluk LS, Audet CM.
Contraception. 2022 May 14:S0010-7824(22)00131-7. doi: 10.1016/j.contraception.2022.05.001. Online ahead of print.

Objective: Systematically review the existing evidence about couples-based interventions and postpartum contraceptive uptake and generate recommendations for future research.
Data sources: PubMed, Web of Science, PsycINFO, Embase, and CINAHL through June 7, 2021.
Study selection and data extraction: Studies with a couples-based intervention assessing postpartum contraceptive uptake. Two independent reviewers screened studies, extracted data, and assessed risk of bias with RoB-2 (Cochrane Risk of Bias 2) for randomized and ROBINS-I (Risk of Bias in Non-Randomized Studies – Interventions) for observational studies. Data were synthesized in tables, figures, and a narrative review.
Results: A total of 925 papers were identified, 66 underwent full text review, and 17 articles, which included 18 studies – 16 randomized, 2 observational – were included. The lack of intervention and outcome homogeneity precluded meta-analysis and isolating the effect of partner involvement. Four studies were partner-required, where partner involvement was a required component of the intervention, and 14 were partner-optional. Unadjusted risk differences ranged from 0.01 to 0.51 in favor of couples-based interventions increasing postpartum contraceptive uptake versus standard of care. Bias assessment of the 16 randomized studies classified 8, 3, and 5 studies as at a high, some concern, and low risk of bias. Common sources of bias included intervention non-adherence and missing outcome data. One observational study was at a high and the other at a low risk of bias.
Conclusions: Future studies that assess couples-based interventions must clearly define and measure how partners are involved in the intervention and assess how intervention adherence impacts postpartum contraceptive uptake.


Gram-negative bacteria act as a reservoir for aminoglycoside antibiotics that interact with host factors to enhance bacterial killing in a mouse model of pneumonia | FEMS Microbes | Oxford Academic
Wijers CDM, Pham L, Douglass MV, Skaar EP, Palmer LD, Noto MJ.
FEMS Microbes, 2022;, xtac016,

In vitro exposure of multiple Gram-negative bacteria to an aminoglycoside (AG) antibiotic has previously been demonstrated to result in bacterial alterations that interact with host factors to suppress Gram-negative pneumonia. However, the mechanisms resulting in suppression are not known. Here, the hypothesis that Gram-negative bacteria bind and retain AGs, which are introduced into the lung and interact with host defenses to affect bacterial killing, was tested. Following in vitro exposure of one of several, pathogenic Gram-negative bacteria to the AG antibiotics kanamycin or gentamicin, AGs were detected in bacterial cell pellets (up to 208 μg/mL). Using inhibitors of AG binding and internalization, the bacterial outer membrane was implicated as the predominant kanamycin and gentamicin reservoir. Following intranasal administration of gentamicin-bound bacteria or gentamicin solution at the time of infection with live, AG-naïve bacteria, gentamicin was detected in the lungs of infected mice (up to 8 μg/g). Co-inoculation with gentamicin-bound bacteria resulted in killing of AG-naïve bacteria by up to 3-log10, mirroring the effects of intranasal gentamicin treatment. In vitro killing of AG-naïve bacteria mediated by kanamycin-bound bacteria required the presence of detergents or pulmonary surfactant, suggesting that increased bacterial killing inside the murine lung is facilitated by the detergent component of pulmonary surfactant. These findings demonstrate that Gram-negative bacteria bind and retain AGs that can interact with host-derived pulmonary surfactant to enhance bacterial killing in the lung. This may help explain why AGs appear to have unique efficacy in the lung and might expand their clinical utility.


Feasibility of SARS-CoV-2 Antibody Testing in Remote Outpatient Trials.

Lofgren SM, Okafor EC, Colette AA, Pastick KA, Skipper CP, Pullen MF, Nicol MR, Bold TD, Bangdiwala AS, Engen NW, Collins LB, Williams DA, Axelrod ML, Thielen BK, Hullsiek KH, Boulware DR, Rajasingham R.
Open Forum Infect Dis. 2021 Oct 6;8(11):ofab506. doi: 10.1093/ofid/ofab506. eCollection 2021 Nov.

Highly motile cells are metabolically responsive to collagen density.
Zanotelli MR, Zhang J, Ortiz I, Wang W, Chada NC, Reinhart-King CA.
Proc Natl Acad Sci U S A. 2022 May 3;119(18):e2114672119. doi: 10.1073/pnas.2114672119. Epub 2022 Apr 26.

Comparison of supratentorial meningioma resection outcomes by dural reconstruction technique.
Chotai S, Tang AR, McDermott JR, Guidry BS, Grisham CJ, Yengo-Kahn AM, Morone PJ, Thompson RC, Chambless LB.
J Neurosurg. 2022 May 27:1-8. doi: 10.3171/2022.4.JNS22290. Online ahead of print.

Measures of Intracranial Injury Size Do Not Improve Clinical Decision Making for Children With Mild Traumatic Brain Injuries and Intracranial Injuries.
Greenberg JK, Olsen MA, Johnson GW, Ahluwalia R, Hill M, Hale AT, Belal A, Baygani S, Foraker RE, Carpenter CR, Ackerman LL, Noje C, Jackson EM, Burns E, Sayama CM, Selden NR, Vachhrajani S, Shannon CN, Kuppermann N, Limbrick DD Jr.
Neurosurgery. 2022 Jun 1;90(6):691-699. doi: 10.1227/neu.0000000000001895. Epub 2022 Mar 16.

Aging and white matter microstructure and macrostructure: a longitudinal multi-site diffusion MRI study of 1218 participants.
Schilling KG, Archer D, Yeh FC, Rheault F, Cai LY, Hansen C, Yang Q, Ramdass K, Shafer AT, Resnick SM, Pechman KR, Gifford KA, Hohman TJ, Jefferson A, Anderson AW, Kang H, Landman BA.
Brain Struct Funct. 2022 May 23. doi: 10.1007/s00429-022-02503-z. Online ahead of print.

The Paramedian Forehead Flap: A Retrospective Clinical Model for Understanding the Connection Between Supraorbital and Supratrochlear Nerve Pathology and Headaches.
Niklinska EB, Colazo JM, Patrinely JR Jr, Drolet BC, Kassis SA.
Plast Surg (Oakv). 2022 May;30(2):102-107. doi: 10.1177/22925503211007234. Epub 2021 Apr 27.

Patient-specific severity of von Willebrand factor degradation identifies patients with a left ventricular assist device at high risk for bleeding.
Hennessy-Strahs S, Kang J, Krause E, Dowling RD, Rame JE, Bartoli CR.
J Thorac Cardiovasc Surg. 2022 Mar 30:S0022-5223(22)00360-9. doi: 10.1016/j.jtcvs.2022.03.018. Online ahead of print.

Stimulating TAM-mediated anti-tumor immunity with mannose-decorated nanoparticles in ovarian cancer.
Glass EB, Hoover AA, Bullock KK, Madden MZ, Reinfeld BI, Harris W, Parker D, Hufnagel DH, Crispens MA, Khabele D, Rathmell WK, Rathmell JC, Wilson AJ, Giorgio TD, Yull FE.
BMC Cancer. 2022 May 6;22(1):497. doi: 10.1186/s12885-022-09612-2.

Clinical insights into pulmonary hypertension in chronic obstructive pulmonary disease.
Cook DP, Xu M, Martucci VL, Annis JS, Aldrich MC, Hemnes AR, Brittain EL.
Pulm Circ. 2022 Jan 3;12(1):e12006. doi: 10.1002/pul2.12006. eCollection 2022 Jan.

Mortality Among Patients With Early-Onset Atrial Fibrillation and Rare Variants in Cardiomyopathy and Arrhythmia Genes.
Yoneda ZT, Anderson KC, Ye F, Quintana JA, O’Neill MJ, Sims RA, Sun L, Glazer AM, Davogustto G, El-Harasis M, Laws JL, Saldivar BN, Crawford DM, Stricker T, Wells Q, Darbar D, Michaud GF, Stevenson LW, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB.
JAMA Cardiol. 2022 May 11. doi: 10.1001/jamacardio.2022.0810. Online ahead of print.

Isolevuglandins disrupt PU.1 mediated C1q expression and promote autoimmunity and hypertension in systemic lupus erythematosus.
Patrick DM, de la Visitación N, Krishnan J, Chen W, Ormseth MJ, Stein CM, Davies SS, Amarnath V, Crofford LJ, Williams JM, Zhao S, Smart CD, Dikalov S, Dikalova A, Xiao L, Van Beusecum JP, Ao M, Fogo AB, Kirabo A, Harrison DG.
JCI Insight. 2022 May 24:e136678. doi: 10.1172/jci.insight.136678. Online ahead of print.

Liraglutide increases islet Ca2+ oscillation frequency and insulin secretion by activating hyperpolarization-activated nucleotide-gated channels.
Zaborska KE, Jordan KL, Thorson AS, Dadi PK, Schaub CM, Nakhe AY, Dickerson MT, Lynch JC, Weiss AJ, Dobson JR, Jacobson DA.
Diabetes Obes Metab. 2022 May 11. doi: 10.1111/dom.14747. Online ahead of print.