MSTPublications: March 2018
Congratulations to all of our MSTP students on their successful publications! Take a look at the great work our students are doing.
First Author Original Research:
α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.
Brissova M*, Haliyur R*, Saunders D*, Shrestha S*, Dai C, Blodgett DM, Bottino R, Campbell-Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC.
Cell Rep. 2018 Mar 6;22(10):2667-2676. doi: 10.1016/j.celrep.2018.02.032.
Read more about this publication in the VUMC Reporter!
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β cells in the pancreas. Recent observations have challenged the long held concept that all β cells are eventually destroyed in type 1 diabetes (T1D). Indeed, many T1D patients produce small amounts of C-peptide long after disease onset but develop an inadequate α cell glucagon response to changes in blood glucose following T1D diagnosis, which contributes to poor glucose control in patients. The molecular features of these β and α cells in the T1D pancreas were largely unknown due to the difficulty of comprehensive investigation. Using a novel approach to study the pancreas and isolated pancreatic islets from individuals with T1D, we show that the remaining β cells, while few in number, appeared to maintain several aspects of regulated insulin secretion. However, we found that the T1D α cells have impaired glucagon secretion and altered gene expression. When we transplanted T1D islets into a non-autoimmune, normoglycemic environment, we found that T1D α cell identity factors improved suggesting interventions could be developed to recover α cell gene expression and glucagon secretion in T1D. Our results provide a new explanation for the disordered counter-regulatory response of glucagon in T1Ds. (By Rachana Haliyur, G4)
The TRiC chaperonin controls reovirus replication through outer-capsid folding.
Knowlton JJ, Fernández de Castro I, Ashbrook AW, Gestaut DR, Zamora PF, Bauer JA, Forrest JC, Frydman J, Risco C, Dermody TS.
Nat Microbiol. 2018 Mar 12. doi: 10.1038/s41564-018-0122-x. [Epub ahead of print]
As intracellular parasites, viruses hijack components of the cell to accomplish each step in a replication cycle. For years our lab has been interested in identifying these host proteins and exploring the molecular mechanisms by which these proteins aid viral replication. Our goal has been to expand an understanding of the basic biology underlying viral infections. To this end, we have studied mammalian orthoreovirus (reovirus) infection of eukaryotic cells. Recent advances in robotics, liquid handling, and high-content imaging enabled us to develop a two-step RNAi-based screen to identify host proteins required for late steps in viral replication. After completing the screen, we were struck by the identification of numerous subunits of the TRiC chaperonin as top candidates. TRiC is required for life and functions in the eukaryotic cytoplasm to fold a subset (~10%) of cellular proteins, most notably actin and tubulin. Based on the known function of TRiC, we hypothesized that this chaperonin engages in the folding or assembly of one or more of the viral polypeptides. A series of co-immunoprecipitation experiments profiling the TRiC interactome in infected cells revealed that TRiC specifically interacts with the reovirus σ3 major outer-capsid protein. We took advantage of the rabbit reticulocyte-based in vitro translation system and purified recombinant human TRiC to demonstrate that TRiC is necessary and sufficient to fold the σ3 protein into its native state. In addition, we discovered that TRiC folds σ3 into a conformation capable of assembling into the mature reovirus outer capsid. Finally, we discovered that homologous capsid components of evolutionary disparate Reoviridae viruses also form a complex with TRiC, pointing towards a conserved mechanism of capsid folding. This work establishes a new function for TRiC in viral replication and provides rationale for the development of TRiC inhibitors as potential broad-spectrum antiviral therapeutics. (By Jon Knowlton, G4)
Clinical Use of Cerebrovascular Compliance Imaging to Evaluate Revascularization in Patients With Moyamoya.
Watchmaker JM, Frederick BD, Fusco MR, Davis LT, Juttukonda MR, Lants SK, Kirshner HS, Donahue MJ.
Neurosurgery. 2018 Mar 8. doi: 10.1093/neuros/nyx635. [Epub ahead of print]
Surgical revascularization is often performed in patients with moyamoya, however routine tools for efficacy evaluation are underdeveloped. The gold standard is digital subtraction angiography (DSA); however, DSA requires ionizing radiation and procedural risk, and therefore is suboptimal for routine surveillance of parenchymal health. In collaboration with Neurosurgery (Fusco) and Neuroradiology (Davis), we aimed to determine whether parenchymal vascular compliance measures obtained noninvasively using magnetic resonance imaging (MRI) provide surrogates to revascularization success by comparing measures with DSA before and after surgical revascularization. We evaluated multiple metrics of tissue health with cerebrovascular reactivity (CVR)-weighted imaging, including metrics of absolute tissue compliance as well as measures that indicate microvascular response time. Overall, we found that improvement in parenchymal compliance measures post-revascularization, primarily attributed to reductions in microvascular response time, is concurrent with collateral formation visualized on DSA, and may be useful for longitudinal monitoring of surgical outcomes. (By Jenny Watchmaker, M3)
Co-authorships, Clinical Studies, and Reviews:
Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space.
Veri AO, Miao Z, Shapiro RS, Tebbji F, O'Meara TR, Kim SH, Colazo J, Tan K, Vyas VK, Whiteway M, Robbins N, Wong KH, Cowen LE.
PLoS Genet. 2018 Mar 28;14(3):e1007270. doi: 10.1371/journal.pgen.1007270. eCollection 2018 Mar.
Predictors of post-discharge seizures in children with traumatic brain injury.
Hale AT, Pekala K, Theobald B, Kelly K, Wolf M, Wellons JC, Le T, Shannon CN.
Childs Nerv Syst. 2018 Mar 21. doi: 10.1007/s00381-018-3779-9. [Epub ahead of print]
Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis.
Hudson BH, Hale AT, Irving RP, Li S, York JD.
Proc Natl Acad Sci U S A. 2018 Mar 5. pii: 201715302. doi: 10.1073/pnas.1715302115. [Epub ahead of print]
The Scope of Extra-Professional Caregiving Challenges Among Early Career Faculty: Findings From a University Medical Center.
Hartmann KE, Sundermann AC, Helton R, Bird H, Wood A.
Acad Med. 2018 Mar 27. doi: 10.1097/ACM.0000000000002229. [Epub ahead of print]
Protein Phosphatase 2A in the Regulation of Wnt Signaling, Stem Cells, and Cancer.
Thompson JJ, Williams CS.
Genes (Basel). 2018 Feb 26;9(3). pii: E121. doi: 10.3390/genes9030121. Review.
APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway.
Saito-Diaz K, Benchabane H, Tiwari A, Tian A, Li B, Thompson JJ, Hyde AS, Sawyer LM, Jodoin JN, Santos E, Lee LA, Coffey RJ, Beauchamp RD, Williams CS, Kenworthy AK, Robbins DJ, Ahmed Y, Lee E.
Dev Cell. 2018 Mar 12;44(5):566-581.e8. doi: 10.1016/j.devcel.2018.02.013.
Are prophylactic antibiotics necessary prior to transarterial chemoembolization for hepatocellular carcinoma in patients with native biliary anatomy?
Watchmaker JM, Lipnik AJ, Fritsche MR, Baker JC, Mouli SK, Geevarghese S, Banovac F, Omary RA, Brown DB.
J Surg Oncol. 2018 Mar 7. doi: 10.1002/jso.24993. [Epub ahead of print]
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