Digital Commons Network^™

Research Hotspots And Trends Of Microrna In Periodontology And Dental Implantology: A Bibliometric Analysis, Kang Gao, Yiping Dou, Menghao Lv, Yihui Zhu, Sitong Hu, Pan Ma

Faculty, Staff and Student Publications

BACKGROUND: Periodontal disease is a leading cause of tooth loss, and microRNA (miRNA) has been shown to regulate various biological processes. This study aimed to quantitatively analyze the literature related to miRNA in periodontology and dental implantology and summarize the research hotspots and trends in this field.

METHODS: Literature records from 1985 to 2020 were obtained from the Web of Science Core Collection database. After manual selection, the data was used for cooperative network analysis, keyword co-occurrence analysis, and reference co-citation analysis and visualized by CiteSpace.

RESULTS: A total of 287 papers were analyzed between 2007 and 2020, and more …

Lymphatic Dissemination And Axillary Web Syndrome In Primary Cutaneous Tuberculosis Secondary To Needlestick Injury, Alexandre E Malek, Caroline E Fife, John C Rasmussen, Ron J Karni, John R Morrow, Audrey Wanger, Eva M Sevick-Muraca, Luis Ostrosky-Zeichner

Faculty, Staff and Student Publications

Cutaneous tuberculosis secondary to skin inoculation of Mycobacterium tuberculosis is uncommon but it can occur in the health care settings. Herein, we report an unusual case of primary cutaneous tuberculosis of the thumb following a needlestick injury. The infection progressed with a necrotic granuloma, lymphatic dysfunction as visualized by near-infrared fluorescence lymphatic imaging, and the development of an axillary web syndrome.

High Burden Of Subclinical And Cardiovascular Disease Risk In Adults With Metabolically Healthy Obesity: The Atherosclerosis Risk In Communities (Aric) Study, Yvonne Commodore-Mensah, Mariana Lazo, Olive Tang, Justin B Echouffo-Tcheugui, Chiadi E Ndumele, Vijay Nambi, Dan Wang, Christie Ballantyne, Elizabeth Selvin

Faculty, Staff and Students Publications

OBJECTIVE: It is controversial whether adults who are obese but "metabolically healthy" have cardiovascular disease (CVD) risk comparable with that of normal-weight adults. High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of myocardial damage, is useful in characterizing subclinical CVD. We categorized obesity phenotypes and studied their associations with subclinical and clinical CVD and CVD subtypes, including heart failure (HF).

RESEARCH DESIGN AND METHODS: We conducted cross-sectional and prospective analyses of 9,477 adults in the Atherosclerosis Risk in Communities (ARIC) study. We used the Adult Treatment Panel III criteria and BMI to define obesity phenotypes as follows: metabolically healthy normal weight, …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Faculty, Staff and Student Publications

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Crosstalk Between Beta-Adrenergic And Insulin Signaling Mediates Mechanistic Target Of Rapamycin Hyperactivation In Liver Of High-Fat Diet-Fed Male Mice, Sadia Ashraf, Nadia Ashraf, Gizem Yilmaz, Romain Harmancey

Faculty, Staff and Student Publications

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on …

Magnetic Resonance Biomarkers In Radiation Oncology: The Report Of Aapm Task Group 294, Kiaran P Mcgee, Ken-Pin Hwang, Daniel C Sullivan, John Kurhanewicz, Yanle Hu, Jihong Wang, Wen Li, Josef Debbins, Eric Paulson, Jeffrey R Olsen, Chia-Ho Hua, Lizette Warner, Daniel Ma, Eduardo Moros, Neelam Tyagi, Caroline Chung

Faculty, Staff and Student Publications

A magnetic resonance (MR) biologic marker (biomarker) is a measurable quantitative characteristic that is an indicator of normal biological and pathogenetic processes or a response to therapeutic intervention derived from the MR imaging process. There is significant potential for MR biomarkers to facilitate personalized approaches to cancer care through more precise disease targeting by quantifying normal versus pathologic tissue function as well as toxicity to both radiation and chemotherapy. Both of which have the potential to increase the therapeutic ratio and provide earlier, more accurate monitoring of treatment response. The ongoing integration of MR into routine clinical radiation therapy (RT) …

Socio-Demographic And Trauma-Related Predictors Of Ptsd Within 8 Weeks Of A Motor Vehicle Collision In The Aurora Study, Ronald C Kessler, Kerry J Ressler, Stacey L House, Francesca L Beaudoin, Xinming An, Jennifer S Stevens, Donglin Zeng, Thomas C Neylan, Sarah D Linnstaedt, Laura T Germine, Paul I Musey, Phyllis L Hendry, Sophia Sheikh, Alan B Storrow, Christopher W Jones, Brittany E Punches, Elizabeth M Datner, Kamran Mohiuddin, Nina T Gentile, Meghan E Mcgrath, Sanne J Van Rooij, Lauren A Hudak, John P Haran, David A Peak, Robert M Domeier, Claire Pearson, Leon D Sanchez, Niels K Rathlev, William F Peacock, Steven E Bruce, Mark W Miller, Jutta Joormann, Deanna M Barch, Diego A Pizzagalli, John F Sheridan, Jordan W Smoller, Thaddeus W W Pace, Steven E Harte, James M Elliott, Nathaniel G Harnett, Lauren A M Lebois, Irving Hwang, Nancy A Sampson, Karestan C Koenen, Samuel A Mclean

Faculty, Staff and Students Publications

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively …

Factors Associated With Access To And Receipt Of Liver Transplantation In Veterans With End-Stage Liver Disease, Fasiha Kanwal, Ruben Hernaez, Yan Liu, Thomas J Taylor, Abbas Rana, Jennifer R Kramer, Aanand D Naik, Donna Smith, Tamar Taddei, Steven M Asch

Faculty, Staff and Students Publications

IMPORTANCE: Organ scarcity means few patients with advanced liver disease undergo a transplant, making equitable distribution all the more crucial. Disparities may arise at any stage in the complex process leading up to this curative therapy.

OBJECTIVE: To examine the rate of and factors associated with referral, wait-listing, and receipt of liver allografts.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used linked data from comprehensive electronic medical records and the United Network of Organ Sharing. Adult patients with cirrhosis and a Model for End-Stage Liver Disease with addition of sodium score of at least 15 points between October 1, …

Intermittent Hypoxia And Effects On Early Learning/Memory: Exploring The Hippocampal Cellular Effects Of Pediatric Obstructive Sleep Apnea, Arvind Chandrakantan, Adam C Adler, Mehmet Tohsun, Farrah Kheradamand, Russell S Ray, Steven Roth

Faculty, Staff and Students Publications

This review provides an update on the neurocognitive phenotype of pediatric obstructive sleep apnea (OSA). Pediatric OSA is associated with neurocognitive deficits involving memory, learning, and executive functioning. Adenotonsillectomy (AT) is presently accepted as the first-line surgical treatment for pediatric OSA, but the executive function deficits do not resolve postsurgery, and the timeline for recovery remains unknown. This finding suggests that pediatric OSA potentially causes irreversible damage to multiple areas of the brain. The focus of this review is the hippocampus, 1 of the 2 major sites of postnatal neurogenesis, where new neurons are formed and integrated into existing circuitry …

Administrative Coding In Electronic Health Care Record-Based Research Of Nafld: An Expert Panel Consensus Statement, Hannes Hagström, Leon A Adams, Alina M Allen, Christopher D Byrne, Yoosoo Chang, Henning Grønbaek, Mona Ismail, Peter Jepsen, Fasiha Kanwal, Jennifer Kramer, Jeffrey V Lazarus, Michelle T Long, Rohit Loomba, Philip N Newsome, Ian A Rowe, Seungho Ryu, Jörn M Schattenberg, Marina Serper, Nick Sheron, Tracey G Simon, Elliot B Tapper, Sarah Wild, Vincent Wai-Sun Wong, Yusuf Yilmaz, Shira Zelber-Sagi, Fredrik Åberg

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Electronic health record (EHR)-based research allows the capture of large amounts of data, which is necessary in NAFLD, where the risk of clinical liver outcomes is generally low. The lack of consensus on which International Classification of Diseases (ICD) codes should be used as exposures and outcomes limits comparability and generalizability of results across studies. We aimed to establish consensus among a panel of experts on ICD codes that could become the reference standard and provide guidance around common methodological issues.

APPROACH AND RESULTS: Researchers with an interest in EHR-based NAFLD research were invited to collectively define …

Central And Peripheral Arterial Diseases In Chronic Kidney Disease: Conclusions From A Kidney Disease: Improving Global Outcomes (Kdigo) Controversies Conference, Kirsten L Johansen, Pranav S Garimella, Caitlin W Hicks, Philip A Kalra, Dearbhla M Kelly, Sven Martens, Kunihiro Matsushita, Pantelis Sarafidis, Manish M Sood, Charles A Herzog, Michael Cheung, Michel Jadoul, Wolfgang C Winkelmayer, Holger Reinecke, Conference Participants

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) affects about 10% of all populations worldwide, with about 2 million people requiring dialysis. Although patients with CKD are at high risk of cardiovascular disease and events, they are often underrepresented or excluded in clinical trials, leading to important knowledge gaps about how to treat these patients. KDIGO (Kidney Disease: Improving Global Outcomes) convened the fourth clinical Controversies Conference on the heart, kidney and vasculature in Dublin, Ireland, in February 2020, entitled Central and Peripheral Arterial Diseases in Chronic Kidney Disease. A global panel of multidisciplinary experts from the fields of nephrology, cardiology, neurology, surgery, radiology, …

Sex-Related Disparities In Cardiovascular Health Care Among Patients With Premature Atherosclerotic Cardiovascular Disease, Michelle T Lee, Dhruv Mahtta, David J Ramsey, Jing Liu, Arunima Misra, Khurram Nasir, Zainab Samad, Dipti Itchhaporia, Safi U Khan, Richard S Schofield, Christie M Ballantyne, Laura A Petersen, Salim S Virani

Faculty, Staff and Students Publications

IMPORTANCE: There is a paucity of data regarding secondary prevention care disparities in women with premature and extremely premature atherosclerotic cardiovascular disease (ASCVD), defined as an ASCVD event at 55 years or younger and 40 years or younger, respectively.

OBJECTIVE: To evaluate sex-based differences in antiplatelet agents, any statin, high-intensity statin (HIS) therapy, and statin adherence in patients with premature and extremely premature ASCVD.

DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional, multicenter, nationwide VA health care system-based study with patients enrolled in the Veterans With Premature Atherosclerosis (VITAL) registry. The study assessed patients who had at least 1 primary …

Cd8+ T Cells Inhibit Metastasis And Cxcl4 Regulates Its Function, Robiya Joseph, Rama Soundararajan, Suhas Vasaikar, Fei Yang, Kendra L Allton, Lin Tian, Petra Den Hollander, Sevinj Isgandarova, Monika Haemmerle, Barbara Mino, Tieling Zhou, Crystal Shin, Melisa Martinez-Paniagua, Aysegul A Sahin, Jaime Rodriguez-Canales, Juri Gelovani, Jeffrey T Chang, Ghanashyam Acharya, Anil K Sood, Ignacio I Wistuba, Don L Gibbons, Luisa M Solis, Michelle C Barton, Navin Varadarajan, Jeffrey M Rosen, Xiang H Zhang, Sendurai A Mani

Faculty, Staff and Students Publications

Background

The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival.

Methods

We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as …

Habitual Sleep Duration And The Colonic Mucosa-Associated Gut Microbiota In Humans-A Pilot Study, Ritwick Agrawal, Nadim J Ajami, Sonal Malhotra, Liang Chen, Donna L White, Amir Sharafkhaneh, Kristi L Hoffman, David Y Graham, Hashem B El-Serag, Joseph F Petrosino, Li Jiao

Faculty, Staff and Students Publications

We examined the association between the colonic adherent microbiota and nocturnal sleep duration in humans. In a cross-sectional study, 63 polyp-free adults underwent a colonoscopy and donated 206 mucosal biopsies. The gut microbiota was profiled using the 16S rRNA gene sequencing targeting the V4 region. The sequence reads were processed using UPARSE and DADA2, respectively. Lifestyle factors, including sleep habits, were obtained using an interviewer-administered questionnaire. We categorized the participants into short sleepers (<6 h per night; n = 16) and normal sleepers (6–8 h per night; n = 47) based on self-reported data. Differences in bacterial biodiversity and the taxonomic relative abundance …

Barbadin Potentiates Long-Term Effects Of Lorcaserin On Pomc Neurons And Weight Loss, Yang He, Hailan Liu, Na Yin, Yongjie Yang, Chunmei Wang, Meng Yu, Hesong Liu, Chen Liang, Julia Wang, Longlong Tu, Nan Zhang, Lina Wang, Yanlin He, Makoto Fukuda, Qi Wu, Zheng Sun, Qingchun Tong, Yong Xu

Children’s Nutrition Research Center Staff Publications

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT_2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel β-arrestin/β2-adaptin inhibitor, can prevent 5-HT_2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, …

Gene Therapy Knockdown Of Hippo Signaling Induces Cardiomyocyte Renewal In Pigs After Myocardial Infarction, Shijie Liu, Ke Li, Leonardo Wagner Florencio, Li Tang, Todd R Heallen, John P Leach, Yidan Wang, Francisco Grisanti, James T Willerson, Emerson C Perin, Sui Zhang, James F Martin

Faculty, Staff and Students Publications

Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav …

Restoration Of The Molecular Clock Is Tumor Suppressive In Neuroblastoma, Myrthala Moreno-Smith, Giorgio Milazzo, Ling Tao, Baharan Fekry, Bokai Zhu, Mahmoud A Mohammad, Simone Di Giacomo, Roshan Borkar, Karthik Reddy Kami Reddy, Mario Capasso, Sanjeev A Vasudevan, Pavel Sumazin, John Hicks, Nagireddy Putluri, Giovanni Perini, Kristin Eckel-Mahan, Thomas P Burris, Eveline Barbieri

Children’s Nutrition Research Center Staff Publications

MYCN activation is a hallmark of advanced neuroblastoma (NB) and a known master regulator of metabolic reprogramming, favoring NB adaptation to its microenvironment. We found that the expression of the main regulators of the molecular clock loops is profoundly disrupted in MYCN-amplified NB patients, and this disruption independently predicts poor clinical outcome. MYCN induces the expression of clock repressors and downregulates the one of clock activators by directly binding to their promoters. Ultimately, MYCN attenuates the molecular clock by suppressing BMAL1 expression and oscillation, thereby promoting cell survival. Reestablishment of the activity of the clock activator RORα via its genetic …

Left Ventricular Recovery With Explantation Of Continuous-Flow Left Ventricular Assist Device After 5 Years Of Support, Andre Critsinelis, Chitaru Kurihara, Masashi Kawabori, Tadahisa Sugiura, Andrew B Civitello, Jeffrey A Morgan

Faculty, Staff and Students Publications

Mechanical circulatory support may result in sufficient myocardial recovery to allow for explantation of the left ventricular assist device (LVAD). The duration of support associated with left ventricular recovery has generally been 6-12 months. In this report, we present a patient in whom the left ventricle recovered after 5 years of support with a LVAD. Our report demonstrates that long-term monitoring for left ventricular recovery is prudent and may allow for late device explantation.

Fructose Causes Liver Damage, Polyploidy, And Dysplasia In The Setting Of Short Telomeres And P53 Loss, Christopher Chronowski, Viktor Akhanov, Doug Chan, Andre Catic, Milton Finegold, Ergün Sahin

Faculty, Staff and Students Publications

Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease. We find that telomere shortening in telomerase knockout mice (TKO) imparts a pronounced susceptibility to fructose as reflected in the activation of p53, …

The Aric (Atherosclerosis Risk In Communities) Study: Jacc Focus Seminar 3/8, Jacqueline D Wright, Aaron R Folsom, Josef Coresh, A Richey Sharrett, David Couper, Lynne E Wagenknecht, Thomas H Mosley, Christie M Ballantyne, Eric A Boerwinkle, Wayne D Rosamond, Gerardo Heiss

Faculty, Staff and Student Publications

ARIC (Atherosclerosis Risk In Communities) initiated community-based surveillance in 1987 for myocardial infarction and coronary heart disease (CHD) incidence and mortality and created a prospective cohort of 15,792 Black and White adults ages 45 to 64 years. The primary aims were to improve understanding of the decline in CHD mortality and identify determinants of subclinical atherosclerosis and CHD in Black and White middle-age adults. ARIC has examined areas including health disparities, genomics, heart failure, and prevention, producing more than 2,300 publications. Results have had strong clinical impact and demonstrate the importance of population-based research in the spectrum of biomedical research …

Genetic Variation And Recurrent Haplotypes On Chromosome 6q23-25 Risk Locus In Familial Lung Cancer, Anthony M Musolf, Claire L Simpson, Bilal A Moiz, Claudio W Pikielny, Candace D Middlebrooks, Diptasri Mandal, Mariza De Andrade, Michael D Cole, Colette Gaba, Ping Yang, Ming You, Yafang Li, Elena Y Kupert, Marshall W Anderson, Ann G Schwartz, Susan M Pinney, Christopher I Amos, Joan E Bailey-Wilson

Faculty, Staff and Students Publications

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 …

Development And Validation Of Machine Learning-Based Race-Specific Models To Predict 10-Year Risk Of Heart Failure: A Multicohort Analysis, Matthew W Segar, Byron C Jaeger, Kershaw V Patel, Vijay Nambi, Chiadi E Ndumele, Adolfo Correa, Javed Butler, Alvin Chandra, Colby Ayers, Shreya Rao, Alana A Lewis, Laura M Raffield, Carlos J Rodriguez, Erin D Michos, Christie M Ballantyne, Michael E Hall, Robert J Mentz, James A De Lemos, Ambarish Pandey

Faculty, Staff and Students Publications

BACKGROUND: Heart failure (HF) risk and the underlying risk factors vary by race. Traditional models for HF risk prediction treat race as a covariate in risk prediction and do not account for significant parameters such as cardiac biomarkers. Machine learning (ML) may offer advantages over traditional modeling techniques to develop race-specific HF risk prediction models and to elucidate important contributors of HF development across races.

METHODS: We performed a retrospective analysis of 4 large, community cohort studies (ARIC [Atherosclerosis Risk in Communities], DHS [Dallas Heart Study], JHS [Jackson Heart Study], and MESA [Multi-Ethnic Study of Atherosclerosis]) with adjudicated HF events. …

Dietary Patterns And Hepatocellular Carcinoma Risk Among Us Adults, Iman Moussa, Rena S Day, Ruosha Li, Xianglin L Du, Ahmed O Kaseb, Prasun K Jalal, Carrie Daniel-Macdougall, Rikita I Hatia, Ahmed Abdelhakeem, Asif Rashid, Yun Shin Chun, Donghui Li, Manal M Hassan

Faculty, Staff and Student Publications

The objective of this study was to assess the association between dietary patterns and risk of hepatocellular carcinoma (HCC) among US adults in a hospital-based case-control study. We analyzed data from 641 cases and 1002 controls recruited at The University of Texas MD Anderson Cancer Center during 2001-2018. Cases were patients with a pathologically or radiologically confirmed new diagnosis of HCC; controls were cancer-free spouses of patients with cancers other than gastrointestinal, lung, liver, or head and neck cancer. Cases and controls were frequency-matched by age and sex. Dietary patterns were identified by principal component analysis. Odds ratios (ORs) and …

Targeting The Apoa1 Locus For Liver-Directed Gene Therapy, Marco De Giorgi, Ang Li, Ayrea Hurley, Mercedes Barzi, Alexandria M Doerfler, Nikitha A Cherayil, Harrison E Smith, Jonathan D Brown, Charles Y Lin, Karl-Dimiter Bissig, Gang Bao, William R Lagor

Faculty, Staff and Students Publications

Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent and broadly applicable while minimizing risks of off-target integration. In the liver, the Albumin (Alb) locus is currently the only well-characterized site for promoterless transgene insertion. Here, we target the Apoa1 locus with adeno-associated viral (AAV) delivery of CRISPR-Cas9 and achieve rates of 6% to 16% of targeted hepatocytes, with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic …

Deciphering An Agrp-Serotoninergic Neural Circuit In Distinct Control Of Energy Metabolism From Feeding, Yong Han, Guobin Xia, Dollada Srisai, Fantao Meng, Yanlin He, Yali Ran, Yang He, Monica Farias, Giang Hoang, István Tóth, Marcelo O Dietrich, Miao-Hsueh Chen, Yong Xu, Qi Wu

Children’s Nutrition Research Center Staff Publications

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4RdlDRN neurons …

Subchronic Tolerance Trials Of Graded Oral Supplementation With Phenylalanine Or Serine In Healthy Adults, Naoki Miura, Hideki Matsumoto, Luc Cynober, Patrick J Stover, Rajavel Elango, Motoni Kadowaki, Dennis M Bier, Miro Smriga

Children’s Nutrition Research Center Staff Publications

Phenylalanine and serine are amino acids used in dietary supplements and nutritional products consumed by healthy consumers; however, the safe level of phenylalanine or serine supplementation is unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral phenylalanine and oral serine. Healthy male adults (n = 60, 38.2 ± 1.8y) completed graded dosages of either phenylalanine or serine supplement (3, 6, 9 and 12 g/d) for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, …

Rap1 In The Vmh Regulates Glucose Homeostasis, Kentaro Kaneko, Hsiao-Yun Lin, Yukiko Fu, Pradip K Saha, Ana B De La Puente-Gomez, Yong Xu, Kousaku Ohinata, Peter Chen, Alexei Morozov, Makoto Fukuda

Faculty, Staff and Students Publications

The hypothalamus is a critical regulator of glucose metabolism and is capable of correcting diabetes conditions independently of an effect on energy balance. The small GTPase Rap1 in the forebrain is implicated in high-fat diet-induced (HFD-induced) obesity and glucose imbalance. Here, we report that increasing Rap1 activity selectively in the medial hypothalamus elevated blood glucose without increasing the body weight of HFD-fed mice. In contrast, decreasing hypothalamic Rap1 activity protected mice from diet-induced hyperglycemia but did not prevent weight gain. The remarkable glycemic effect of Rap1 was reproduced when Rap1 was specifically deleted in steroidogenic factor-1-positive (SF-1-positive) neurons in the …

Evidence-Based Approach To Early Outpatient Treatment Of Sars-Cov-2 (Covid-19) Infection, J Drew Payne, Kimberly Sims, Cynthia Peacock, Tanis Welch, Ruth E Berggren

Faculty, Staff and Students Publications

Misinformation and promotion of well-intended but disproved therapies for COVID-19 have plagued evidence-based shared decision-making throughout the COVID-19 pandemic. In times of crisis, clinicians may feel that their strong inclination to prescribe potentially harmful, unproven therapies on behalf of their patients is supported by beneficence. Clinicians should mindfully identify and avoid commission bias during this pandemic, especially as more data have accumulated to assist with clinically sound decision-making. We describe a more evidence-based approach to treatment of early outpatient COVID-19, stressing the availability of Food and Drug Administration emergency use authorization therapies and considering plausibly beneficial, nonprescription supplements that are …

Clinical Characterization Of Pediatric Gastroparesis Using A Four-Hour Gastric Emptying Scintigraphy Standard, Sharon Wolfson, Zoe Wilhelm, Antone R Opekun, Robert Orth, Robert J Shulman, Bruno P Chumpitazi

Children’s Nutrition Research Center Staff Publications

Objectives: Four-hour gastric emptying scintigraphy (GES) is the recommended method to identify both adult and childhood gastroparesis (GP). Previous pediatric studies have, however, not used this standard. We sought to determine the characteristics and outcomes of children versus adolescents with GP using the 4-hour GES evaluation.

Methods: We performed a retrospective chart review of pediatric patients diagnosed with GP by 4-hour GES (>10% retention at 4 hours). Demographics, body mass index, GP-related symptoms, comorbidities, etiologies, therapies (eg, medications), healthcare utilization, and response to therapy were captured systematically. Symptoms were compared from the initial versus last gastroenterology visit. Outcomes were …

Defining Vdr Expression In The Brain Using A Novel Vdrcre Mouse, Hailan Liu, Yang He, Jessie Beck, Silvania Da Silva Teixeira, Keisha Harrison, Yong Xu, Stephanie Sisley

Children’s Nutrition Research Center Staff Publications

Vitamin D action has been linked to several diseases regulated by the brain including obesity, diabetes, autism, and Parkinson’s. However, the location of the vitamin D receptor (VDR) in the brain is not clear due to conflicting reports. We found that two antibodies previously published as specific in peripheral tissues are not specific in the brain. We thus created a new knockin mouse with cre recombinase expression under the control of the endogenous VDR promoter (VDRCre). We demonstrated that the cre activity in the VDRCre mouse brain (as reported by a cre-dependent tdTomato expression) is highly overlapping with endogenous VDR …