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‘Best Research Papers’ highlight innovative biomedical research

University of Iowa Carver College of Medicine leaders have launched a new initiative this fall to call attention to impactful and innovative research articles by the college’s faculty and staff.

The “Best Research Paper Awards” were given to Carver College of Medicine faculty who served as authors on articles published in peer-reviewed journals over the past year. Awards were presented in three categories: basic, clinical, and educational research.

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Best Basic Research Paper
Best Clinical Research Paper
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Best Educational Research Paper

“Despite all the challenges brought by COVID-19, progress on research and discovery here in the Carver College of Medicine the past 18 months has been remarkably strong,” says Brooks Jackson, MD, vice president for medical affairs and the Tyrone D. Artz Dean. “Many of our investigators published papers that helped advance a number of fields.”

Rob Piper, PhD, professor of molecular physiology and biophysics and the college’s associate dean for research, led a team of Carver College of Medicine faculty and staff to select this year’s “Best Paper” award recipients.

“We surveyed numerous published articles to identify some of the most impactful and influential,” Piper says. “It was rewarding to see the breadth and quality of published works by our research teams.”

Here are this year’s “Best Research Paper Award” winners:

Basic research

FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Senior author

Matthew Potthoff, PhD, associate professor, Department of Neuroscience and Pharmacology

Lead author

Sharon Jensen-Cody, Graduate Program in Molecular Medicine

Citation

Jensen-Cody SO, Flippo KH, Claflin KE, Yavuz Y, Sapouckey SA, Walters GC, Usachev YM, Atasoy D, Gillum MP, Potthoff MJ. FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake. Cell Metab. 2020 Aug 4;32(2):273-286.e6. doi: 10.1016/j.cmet.2020.06.008. Epub 2020 Jul 7. PMID: 32640184; PMCID: PMC7734879

Description

Jensen-Cody, Potthoff and colleagues detail the neural pathways whereby fibroblast growth factor 21 produced in the liver can signal to the brain to reduce appetite for carbohydrates. Published in Cell Metabolism, this study leverages single-cell transcriptomics and cell-specific knockouts of FGF21 receptors in subsets of neurons to find regions in the hypothalamus that respond to FGF21 that go on to modulate sugar consumption. These studies uncover an important homeostatic metabolic regulatory pathway while also creating an experimental paradigm for finding other brain regions that respond to FGF21.

Clinical research

Cystic Fibrosis Carriers are at Increased Risk for a Wide Range of Cystic Fibrosis-Related Conditions

Senior author

Philip Polgreen, MD, MPH, professor, Department of Internal Medicine, Division of Infectious Diseases

Lead author

Aaron Miller, PhD, research assistant professor, Department of Internal Medicine, Division of Infectious Diseases

Citation

Miller AC, Comellas AP, Hornick DB, Stoltz DA, Cavanaugh JE, Gerke AK, Welsh MJ, Zabner J, Polgreen PM. Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions. Proc Natl Acad Sci U S A. 2020 Jan 21;117(3):1621-1627. doi: 10.1073/pnas.1914912117. Epub 2019 Dec 27. PMID: 31882447; PMCID: PMC6983448

Description

Miller, Polgreen, and others investigate whether people who are carriers of cystic fibrosis are at greater risk for developing health conditions that mirror those by patients with cystic fibrosis, a condition manifested when two autosomal recessive genes for CFTR are inherited. In an expansive informatics analysis using health insurance claims data, the team reports that there is indeed an increased risk for CF-related conditions for carriers of recessive CFTR alleles. The authors conclude that while the risk to individual CF carriers is low, the fact that there are 10 million carriers in the U.S. alone may make such morbidity substantial overall and motivate broader genetic testing.

Educational research

Responding to Patient-Initiated Verbal Sexual Harassment: Outcomes of a Pilot Training for Ophthalmologists

Senior author

Erin Shriver, MD, FACS, clinical professor, Department of Ophthalmology and Visual Sciences

Lead author

Lauren Hock, MD, former resident physician, Department of Ophthalmology and Visual Sciences

Citation

Hock LE, Scruggs BA, Barlow PB, Oetting TA, Abràmoff MD, Shriver EM. Responding to Patient-Initiated Verbal Sexual Harassment: Outcomes of a Pilot Training for Ophthalmologists. J Acad Ophthalmol. 2020 Jul;12(2):e175-e180. doi: 10.1055/s-0040-1717062. Epub 2020 Oct 10. PMID: 33796813; PMCID: PMC8011573

Description

Hock, Shriver, and colleagues used a survey study to assess effective ways for faculty, residents, fellows, and students to respond to incidents of sexual harassment from patients. This is a pressing problem that has prompted the American Medical Association and the National Academies of Sciences, Engineering, and Medicine to push for improved training and preparation for dealing with workplace harassment. The study finds that brief workshops focused on building skills to deal with this problem greatly improved the ability of health providers to respond to verbal sexual harassment by patients. While the investigators conclude this type of training helps, additional measures such as explicit support from department leadership and practicing modes of bystander intervention would strongly complement these efforts.

Additional research papers of note:

NTS Catecholamine Neurons Mediate Hypoglycemic Hunger via Medial Hypothalamic Feeding Pathways

Deniz Atasoy, PhDSenior author

Deniz Atasoy, PhD, assistant professor, Department of Neuroscience and Pharmacology

Lead author

Iltan Aklan, Graduate Program in Pharmacology

Citation

Aklan I, Sayar Atasoy N, Yavuz Y, Ates T, Coban I, Koksalar F, Filiz G, Topcu IC, Oncul M, Dilsiz P, Cebecioglu U, Alp MI, Yilmaz B, Davis DR, Hajdukiewicz K, Saito K, Konopka W, Cui H, Atasoy D. NTS Catecholamine Neurons Mediate Hypoglycemic Hunger via Medial Hypothalamic Feeding Pathways. Cell Metab. 2020 Feb 4;31(2):313-326.e5. doi: 10.1016/j.cmet.2019.11.016. Epub 2019 Dec 12. PMID: 31839488

Description

Aklan, Atasoy, and others describe a neuronal pathway connecting brainstem neurons that sense low glucose levels to areas of the hypothalamus that control feeding behavior. This pathway may be impaired in patients with diabetes, and its discovery may provide new targets for improved glycemic regulation.

RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors

Dawn Quelle, PhDSenior author

Dawn Quelle, PhD, professor, Department of Neuroscience and Pharmacology

Lead author

Jordan Kohlmeyer, Graduate Program in Molecular Medicine

Citation

Kohlmeyer JL, Kaemmer CA, Pulliam C, Maharjan CK, Samayoa AM, Major HJ, Cornick KE, Knepper-Adrian V, Khanna R, Sieren JC, Leidinger MR, Meyerholz DK, Zamba KD, Weimer JM, Dodd RD, Darbro BW, Tanas MR, Quelle DE. RABL6A Is an Essential Driver of MPNSTs that Negatively Regulates the RB1 Pathway and Sensitizes Tumor Cells to CDK4/6 Inhibitors. Clin Cancer Res. 2020 Jun 15;26(12):2997-3011. doi: 10.1158/1078-0432.CCR-19-2706. Epub 2020 Feb 21. PMID: 32086342; PMCID: PMC7299809

Description

Kohlmeyer, Quelle, and colleagues conducted a clinical research study on the mechanisms behind treating malignant peripheral nerve sheath tumors with inhibitors of cyclin-dependent kinases that regulate cell division. Using both RNA sequencing data from patient tumors as well as experimental manipulation of RABL6A, a signaling protein that also regulates tumor suppressors, the study authors report that RAB6LA is an important driver of tumor pathogenesis and works partly by inhibiting retinoblastoma tumor suppressor (RB1). Their findings suggest that combination therapies that also target RB1 might effectively treat MPNSTs (malignant peripheral nerve sheath tumors) as well as other RABL6A-driven tumors.

Reliability and Validity of Performance Evaluations of Pain Medicine Clinical Faculty by Residents and Fellows Using a Supervision Scale

Brad Hindman, MDSenior author

Brad Hindman, MD, professor, Department of Anesthesia

Lead author

Franklin Dexter, MD, PhD, FASA, professor, Department of Anesthesia

Citation

Dexter F, Hadlandsmyth K, Pearson ACS, Hindman BJ. Reliability and Validity of Performance Evaluations of Pain Medicine Clinical Faculty by Residents and Fellows Using a Supervision Scale. Anesth Analg. 2020 Sep;131(3):909-916. doi: 10.1213/ANE.0000000000004779. PMID: 32332292

Description

Dexter, Hindman, and others evaluated whether a clinical supervisory scale could effectively evaluate the competence of pain medicine clinicians with hospital privileges. The researchers evaluated a nine-item scale for measuring the quality of individual faculty member’s supervision of resident physicians and fellows when they provide clinical care in operating rooms—one-on-one, paired for a day. The findings show that the scale has excellent internal consistency and reliability, making it appropriate for the mandatory annual and semi-annual evaluation of pain medicine clinical faculty required at multiple organizations in the United States. In the current study, the team generalizes to chronic pain clinics—a practice location with broad applicability to many other medical specialties, combining patient evaluation, counseling, and brief interventional and diagnostic procedures.

The Unfolded Protein Response Regulates Hepatic Autophagy by sXBP1-Mediated Activation of TFEB

Ling Yang, MDSenior author

Ling Yang, MD, associate professor, Department of Anatomy and Cell Biology

Lead author

Zeyuan Zhang, Graduate Program in Cell and Developmental Biology

Citation

Zhang Z, Qian Q, Li M, Shao F, Ding WX, Lira VA, Chen SX, Sebag SC, Hotamisligil GS, Cao H, Yang L. The unfolded protein response regulates hepatic autophagy by sXBP1-mediated activation of TFEB. Autophagy. 2021 Aug;17(8):1841-1855. doi: 10.1080/15548627.2020.1788889. Epub 2020 Jul 15. PMID: 32597296; PMCID: PMC8386593

Description

Zhang, Yang and others demonstrate that that sXBP1, a transcription factor activated by ER (endoplasmic reticulum) stress, regulates hepatic autophagy and lysosome biogenesis. Using mouse Xbp1 and Tfeb loss-of-function and gain-of-function models of diet-induced obesity, they demonstrate that Xbp1 suppresses the transcription of Tfeb to inhibit autophagy. Human hepatic samples confirmed that Xbp1 occupancy of the Tfeb promoter is reduced in fatty livers. Collectively, these data indicate that sXBP1-Tfeb signaling integrates organelle stress responses to protect against obesity-associated metabolic dysfunction.

Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes

Val Sheffield, MDSenior author

Val Sheffield, MD, professor, Department of Pediatrics

Lead author

Calvin Carter, PhD, postdoctoral research scholar, Department of Pediatrics

Citation

Carter CS, Huang SC, Searby CC, Cassaidy B, Miller MJ, Grzesik WJ, Piorczynski TB, Pak TK, Walsh SA, Acevedo M, Zhang Q, Mapuskar KA, Milne GL, Hinton AO Jr, Guo DF, Weiss R, Bradberry K, Taylor EB, Rauckhorst AJ, Dick DW, Akurathi V, Falls-Hubert KC, Wagner BA, Carter WA, Wang K, Norris AW, Rahmouni K, Buettner GR, Hansen JM, Spitz DR, Abel ED, Sheffield VC. Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes. Cell Metab. 2020 Oct 6;32(4):561-574.e7. doi: 10.1016/j.cmet.2020.09.012. Erratum in: Cell Metab. 2020 Dec 1;32(6):1076. PMID: 33027675; PMCID: PMC7819711

Description

Carter, Sheffield, and colleagues describe a provocative study showing that diabetic animals living within static electromagnetic fields had improved glycemia and lower oxidative stress, suggesting that the beneficial effects experienced are due to systemic changes in the redox environment that sensitizes the body toinsulin.

Infection-Induced Plasmablasts are a Nutrient Sink that Impairs Humoral Immunity to Malaria

Noah Butler, PhDSenior author

Noah Butler, PhD, associate professor, Department of Microbiology and Immunology

Lead author

Rahul Vijay, PhD, former graduate student, Department of Microbiology and Immunology

Citation

Vijay R, Guthmiller JJ, Sturtz AJ, Surette FA, Rogers KJ, Sompallae RR, Li F, Pope RL, Chan JA, de Labastida Rivera F, Andrew D, Webb L, Maury WJ, Xue HH, Engwerda CR, McCarthy JS, Boyle MJ, Butler NS. Infection-induced plasmablasts are a nutrient sink that impairs humoral immunity to malaria. Nat Immunol. 2020 Jul;21(7):790-801. doi: 10.1038/s41590-020-0678-5. Epub 2020 May 18. PMID: 32424361; PMCID: PMC7316608.

Description

Germinal centers contain B cells and follicular helper T (TFH) cells that promote genesis of B cells, which can secrete antibodies with enhanced affinity for a given pathogen. Work from Vijay, Butler, and others shows that one of the limiting nutrients germinal center B cells experience during a response to malaria infection is glutamine. These studies offer new therapeutic possibilities to augment immune response against malaria and to promote longer-lived protection against severe disease.

Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass

Mohamed Mokadem, MDSenior author

Mohamed Mokadem, MD, assistant professor, Department of Internal Medicine – Gastroenterology and Hepatology

Lead author

Yuanchao Ye, PhD, former postdoctoral trainee, Department of Neuroscience and Pharmacology

Citation

Ye Y, Abu El Haija M, Morgan DA, Guo D, Song Y, Frank A, Tian L, Riedl RA, Burnett CML, Gao Z, Zhu Z, Shahi SK, Zarei K, Couvelard A, Poté N, Ribeiro-Parenti L, Bado A, Noureddine L, Bellizzi A, Kievit P, Mangalam AK, Zingman LV, Le Gall M, Grobe JL, Kaplan LM, Clegg D, Rahmouni K, Mokadem M. Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass. Cell Rep. 2020 Oct 27;33(4):108270. doi: 10.1016/j.celrep.2020.108270. PMID: 33113371; PMCID: PMC7660289

Description

Ye, Mokadem, and others studied how gastric bypass surgery affects the regulation of metabolism. It had been known that gastric bypass surgery reduced food intake and also increased energy expenditure. The researchers show that the elevated resting metabolism is mostly localized to visceral fat and that this was under the control of the endocannabinoid system, in particular endocannabinoid receptor (CB1) in non-CNS peripheral tissues.

Smooth Muscle Cell-Specific Fibronectin-EDA Mediates Phenotypic Switching and Neointimal Hyperplasia

Anil Chauhan, MTech, PhDSenior author

Anil Chauhan, MTech, PhD, professor, Department of Internal Medicine – Hematology, Oncology, and Blood and Marrow Transplantation

Lead author

Manish Jain, PhD, former postdoctoral trainee, Department of Internal Medicine

Citation

Jain M, Dhanesha N, Doddapattar P, Chorawala MR, Nayak MK, Cornelissen A, Guo L, Finn AV, Lentz SR, Chauhan AK. Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia. J Clin Invest. 2020 Jan 2;130(1):295-314. doi: 10.1172/JCI124708. PMID: 31763999; PMCID: PMC6934199

Description

A splice variant of the extracellular matrix protein fibronectin (Fn) is produced by smooth muscle cells after vascular injury. Jain, Chauhan, and colleagues examined this protein for its potential role in the heart, where the success of stent implants can be limited because of too much proliferation of the extracellular matrix. Using both mouse models and patient samples, they were able to conclude that Fn-EDA (fibronectin containing extra domain A) controls the behavior of smooth muscle cells and promotes deleterious post-intervention, pathological, vascular remodeling.