ItemAuthor Correction: Generation of the organotypic kidney structure by integrating pluripotent stem cell-derived renal stroma(Springer Nature, 2023-04-04) Tanigawa, Shunsuke; Tanaka, Etsuko; Miike, Koichiro; Ohmori, Tomoko; Inoue, Daisuke; Cai, Chen-Leng; Taguchi, Atsuhiro; Kobayashi, Akio; Nishinakamura, Ryuichi; Pediatrics, School of MedicineCorrection to: Nature Communications 10.1038/s41467-022-28226-7, published online 01 February 2022 ItemAsparagine starvation suppresses histone demethylation through iron depletion(Elsevier, 2023-03-16) Jiang, Jie; Srivastava, Sankalp; Liu, Sheng; Seim, Gretchen; Claude, Rodney; Zhong, Minghua; Cao, Sha; Davé, Utpal; Kapur, Reuben; Mosley, Amber L.; Zhang, Chi; Wan, Jun; Fan, Jing; Zhang, Ji; Pediatrics, School of MedicineIntracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation. ItemAn Epidemic Zika Virus Isolate Drives Enhanced T Follicular Helper Cell and B Cell-Mediated Immunity(The American Association of Immunologists, 2022) Pardy, Ryan D.; Gentile, Maria E.; Carter, Alexandria M.; Condotta, Stephanie A.; King, Irah L.; Richer, Martin J.; Microbiology and Immunology, School of MedicineZika virus (ZIKV) is a mosquito-borne pathogen that recently caused a series of increasingly severe outbreaks. We previously demonstrated that, compared with a pre-epidemic isolate (ZIKVCDN), a Brazilian ZIKV isolate (ZIKVBR) possesses a novel capacity to suppress host immunity, resulting in delayed viral clearance. However, whether ZIKVBR modulates CD4 T cell responses remains unknown. In this study, we show that, in comparison with ZIKVCDN infection, CD4 T cells are less polarized to the Th1 subtype following ZIKVBR challenge in mice. In contrast, we observed an enhanced accumulation of T follicular helper cells 10, 14, and 21 d postinfection with ZIKVBR This response correlated with an enhanced germinal center B cell response and robust production of higher avidity-neutralizing Abs following ZIKVBR infection. Taken together, our data suggest that contemporary ZIKV strains have evolved to differentially induce CD4 T cell, B cell, and Ab responses and this could provide a model to further define the signals required for T follicular helper cell development. ItemCOVID-Associated Cast-Forming Cholangiopathy: A Commentary on Disease Mechanism, Treatment, and Prognosis(Dove Press, 2023-03-28) Sarkis, Yara; Saleem, Nasir; Vuppalanchi, Raj; Gromski, Mark; Medicine, School of MedicineThe complete impact of COVID-19 infection continues to develop since the onset of the COVID-19 pandemic. COVID-19 cholangiopathy has been recently described in a subset of patients who recovered from severe COVID-19 infection. The most common phenotype of patients suffering from COVID-19 cholangiopathy had severe infection requiring a stay in the intensive care unit, mechanical ventilation and vasopressor medications. Patients with COVID-cholangiopathy present with severe and prolonged cholestatic liver injury. In cases where biliary cast formation is identified, we defined the entity as “COVID-19 cast-forming cholangiopathy”. This subset of COVID-19 cholangiopathy is not well understood and there are no standardized diagnosis or management to this date. The reported clinical outcomes are variable, from resolution of symptoms and liver test abnormalities to liver transplant and death. In this commentary, we discuss the proposed pathophysiology, diagnosis, management, and prognosis of this disease. ItemPreparation and Characterization of IL-22 mRNA-loaded Lipid Nanoparticles(Bio-Protocol, 2023-04-05) Alghoul, Zahra; Sung, Junsik; Wu, Kenji; Alpini, Gianfranco; Glaser, Shannon; Yang, Chunhua; Merlin, Didier; Medicine, School of MedicineInterleukin-22 (IL-22) has been demonstrated as a critical regulator of epithelial homeostasis and repair; it showed an anti-inflammatory effect against ulcerative colitis. Local microinjection of IL-22 cDNA vector has been shown to be effective in treating ulcerative colitis in mouse models. However, microinjection comes with multiple technical challenges for routine colon-targeted drug delivery. In contrast, oral administration can get around these challenges and provide comparable efficacy. We showed in previous studies that oral administration of new lipid nanoparticles (nLNP)-encapsulated IL-22 mRNA targets the colon region and efficiently ameliorates colitis. This protocol describes the details of preparing and characterizing the nLNP-encapsulated IL-22 mRNA using three major lipids that mimic the natural ginger-derived nanoparticles. It provides an nLNP platform that can be used to orally deliver other types of nucleic acids to the colon. ItemDefective BVES-mediated feedback control of cAMP in muscular dystrophy(Springer Nature, 2023-03-30) Li, Haiwen; Wang, Peipei; Zhang, Chen; Zuo, Yuanbojiao; Zhou, Yuan; Han, Renzhi; Pediatrics, School of MedicineBiological processes incorporate feedback mechanisms to enable positive and/or negative regulation. cAMP is an important second messenger involved in many aspects of muscle biology. However, the feedback mechanisms for the cAMP signaling control in skeletal muscle are largely unknown. Here we show that blood vessel epicardial substance (BVES) is a negative regulator of adenylyl cyclase 9 (ADCY9)-mediated cAMP signaling involved in maintaining muscle mass and function. BVES deletion in mice reduces muscle mass and impairs muscle performance, whereas virally delivered BVES expressed in Bves-deficient skeletal muscle reverses these defects. BVES interacts with and negatively regulates ADCY9’s activity. Disruption of BVES-mediated control of cAMP signaling leads to an increased protein kinase A (PKA) signaling cascade, thereby promoting FoxO-mediated ubiquitin proteasome degradation and autophagy initiation. Our study reveals that BVES functions as a negative feedback regulator of ADCY9-cAMP signaling in skeletal muscle, playing an important role in maintaining muscle homeostasis. ItemSuccess of implementation of a systemwide point-of-care ultrasound privileging program for emergency medicine faculty(Wiley, 2022-04-01) Kennedy, Sarah K.; Ferre, Robinson M.; Rood, Loren K.; Nti, Benjamin; Ehrman, Robert R.; Brenner, Daniel; Rutz, Matt A.; Zahn, Greg S.; Herbert, Audrey G.; Russell, Frances M.; Emergency Medicine, School of MedicineObjectives: Point-of-care ultrasound (POCUS) is widely used in the emergency department (ED). Not all practicing emergency physicians received POCUS training during residency, leaving a training gap that is reflected in POCUS privileging. The purpose of this study was to evaluate the success of meeting privileging criteria as well as associated factors, following implementation of a basic POCUS training and privileging program within a large emergency medicine department. Methods: We implemented a POCUS training and privileging program, based on national guidelines, for faculty physicians who worked at one of the following EDs staffed by the same emergency medicine department: a pediatric tertiary site, two tertiary academic sites, and seven community sites. POCUS examinations included aorta, cardiac, first-trimester obstetrics (OB), and extended focused assessment with sonography in trauma. Pediatric emergency medicine faculty were taught soft tissue and thoracic US instead of aorta and OB. Completion of the program required 16 h of didactics, ≥25 quality-assured US examinations by examination type, and passing a series of knowledge-based examinations. Descriptive statistics were calculated. Associations between physician characteristics and successfully becoming privileged in POCUS were modeled using Firth's logistic regression. Results: A total of 176 faculty physicians were eligible. A total of 145 (82.4%) achieved basic POCUS privileging during the study period. Different pathways were used including 86 (48.9%) practice-based, nine (5.1%) fellowship-based, and 82 (46.9%) residency-based. POCUS privileging was lower for those working in a community versus academic setting (odds ratio 0.3, 95% confidence interval 0.1-0.9). A greater number of scans completed prior to the privileging program was associated with greater success. Conclusions: Implementation of a POCUS training and privileging program can be successful in a large emergency medicine department that staffs hospitals in a large-scale health care system composed of both academic and community sites. Faculty physicians with at least some prior exposure to POCUS were more successful. ItemChronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook(Shared Science Publishers, 2023-02-13) Chan, Shing Fai; Vora, Keyur; Dharmakumar, Rohan; Medicine, School of MedicineMyocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI. ItemClosing the gender gap in medicine: the impact of a simulation-based confidence and negotiation course for women in graduate medical education(BMC, 2023-04-14) Bona, Anna; Ahmed, Rami; Falvo, Lauren; Welch, Julie; Heniff, Melanie; Cooper, Dylan; Sarmiento, Elisa; Hobgood, Cherri; Emergency Medicine, School of MedicineBackground: Currently, 75-80% of the medical workforce worldwide consists of women. Yet, women comprise 21% of full professors and less than 20% of department chairs and medical school deans. Identified causes of gender disparities are multifactorial including work-life responsibilities, gender discrimination, sexual harassment, bias, lack of confidence, gender differences in negotiation and leadership emergence, and lack of mentorship, networking, and/or sponsorship. A promising intervention for the advancement of women faculty is the implementation of Career Development Programs (CDPs). Women physician CDP participants were shown to be promoted in rank at the same rate as men by year five, and more likely to remain in academics after eight years compared to both men and women counterparts. The objective of this pilot study is to investigate the effectiveness of a novel, simulation-based, single-day CDP curriculum for upper-level women physician trainees to teach communication skills identified as contributing to medicine's gender advancement gap. Methods: This was a pilot, pre/post study performed in a simulation center implementing a curriculum developed to educate women physicians on 5 identified communication skills recognized to potentially reduce the gender gap. Pre- and post-intervention assessments included confidence surveys, cognitive questionnaires, and performance action checklists for five workplace scenarios. Assessment data were analyzed using scored medians and descriptive statistics, applying Wilcoxon test estimation to compare pre- versus post-curriculum intervention scores, with p < 0.05 considered statistically significant. Results: Eleven residents and fellows participated in the curriculum. Confidence, knowledge, and performance improved significantly after completion of the program. Pre-confidence: 28 (19.0-31.0); Post-confidence: 41 (35.0-47.0); p < 0.0001. Pre-knowledge: 9.0 (6.0-11.00); Post knowledge: 13.0 (11.0-15.0); p < 0.0001. Pre-performance: 35.0 (16.0-52.0); Post-performance: 46.0 (37-53.00); p < 0.0001. Conclusion: Overall, this study demonstrated the successful creation of a novel, condensed CDP curriculum based on 5 identified communication skills needed for women physician trainees. The post-curriculum assessment demonstrated improved confidence, knowledge, and performance. Ideally, all women medical trainees would have access to convenient, accessible, and affordable courses teaching these crucial communication skills to prepare them for careers in medicine to strive to reduce the gender gap. ItemWhite matter integrity is associated with cognition and amyloid burden in older adult Koreans along the Alzheimer's disease continuum(medRxiv, 2023-04-06) Hirschfeld, Lauren Rose; Deardorff, Rachael; Chumin, Evgeny J.; Wu, Yu-Chien; McDonald, Brenna C.; Cao, Sha; Risacher, Shannon L.; Yi, Dahyun; Byun, Min Soo; Lee, Jun-Young; Kim, Yu Kyeong; Kang, Koung Mi; Sohn, Chul-Ho; Nho, Kwangsik; Saykin, Andrew J.; Lee, Dong Young; KBASE Research Group; Radiology and Imaging Sciences, School of MedicineBackground: White matter (WM) microstructural changes in the hippocampal cingulum bundle (CBH) in Alzheimer's disease (AD) have been described in cohorts of largely European ancestry but are lacking in other populations. Methods: We assessed the relationship between CBH WM integrity and cognition or amyloid burden in 505 Korean older adults aged ≥55 years, including 276 cognitively normal older adults (CN), 142 mild cognitive impairment (MCI), and 87 AD, recruited as part of the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's disease (KBASE) at Seoul National University. Results: Compared to CN, AD and MCI subjects showed decreased WM integrity in the bilateral CBH. Cognition, mood, and higher amyloid burden were also associated with poorer WM integrity in the CBH. Conclusion: These findings are consistent with patterns of WM microstructural damage previously reported in non-Hispanic White (NHW) MCI/AD cohorts, reinforcing existing evidence from predominantly NHW cohort studies.