Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Knockdown Of Ketohexokinase Versus Inhibition Of Its Kinase Activity Exert Divergent Effects On Fructose Metabolism, Se-Hyung Park, Taghreed Fadhul, Lindsey R. Conroy, Harrison A. Clarke, Ramon Sun, Kristina Wallenius, Jeremie Boucher, Gavin O'Mahony, Alessandro Boianelli, Marie Persson, Sunhee Jung, Cholsoon Jang, Analia S. Loria, Genesee J. Martinez, Zachary A. Kipp, Evelyn A. Bates, Terry D. Hinds Jr., Senad Divanovic, Samir Softic

Markey Cancer Center Faculty Publications

Excessive fructose intake is a risk factor for the development of obesity and its complications. Targeting ketohexokinase (KHK), the first enzyme of fructose metabolism, has been investigated for the management of metabolic dysfunction–associated steatotic liver disease (MASLD). We compared the effects of systemic, small molecule inhibitor of KHK enzymatic activity with hepatocyte-specific, N-acetylgalactosamine siRNA–mediated knockdown of KHK in mice on an HFD. We measured KHK enzymatic activity, extensively quantified glycogen accumulation, performed RNA-Seq analysis, and enumerated hepatic metabolites using mass spectrometry. Both KHK siRNA and KHK inhibitor led to an improvement in liver steatosis; however, via substantially different mechanisms, KHK …

Inhibition Of Hepatic Oxalate Overproduction Ameliorates Metabolic Dysfunction-Associated Steatohepatitis, Sandeep Das, Alexandra C Finney, Sumit Kumar Anand, Sumati Rohilla, Yuhao Liu, Nilesh Pandey, Alia Ghrayeb, Dhananjay Kumar, Kelley Nunez, Zhipeng Liu, Fabio Arias, Ying Zhao, Brenna H Pearson-Gallion, M Peyton Mckinney, Koral S E Richard, Jose A Gomez-Vidal, Chowdhury S Abdullah, Elizabeth D Cockerham, Joseph Eniafe, Andrew D Yurochko, Tarek Magdy, Christopher B Pattillo, Christopher G Kevil, Babak Razani, Md Shenuarin Bhuiyan, Erin H Seeley, Gretchen E Galliano, Bo Wei, Lin Tan, Iqbal Mahmud, Ida Surakka, Minerva T Garcia-Barrio, Philip L Lorenzi, Eyal Gottlieb, Eduardo Salido, Jifeng Zhang, A Wayne Orr, Wanqing Liu, Monica Diaz-Gavilan, Y Eugene Chen, Nirav Dhanesha, Paul T Thevenot, Ari J Cohen, Arif Yurdagul, Oren Rom

Faculty, Staff and Student Publications

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid β-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In …

Hormone Replacement Therapy And Risk Of Pancreatic Cancer In Postmenopausal Women: Evidence From The Us National Inpatient Sample 2008–2018, Lei Liu, Xinyu Wang, Dekai Guo, Ruirui Ma, Haibing Gong, Congjun Wang

Faculty, Staff and Student Publications

BACKGROUND: Pancreatic cancer is a serious, usually fatal disease and one of the most aggressive malignancies. Research into whether hormone replacement therapy (HRT) might protect against pancreatic cancer has yielded mixed results. This study aimed to investigate the potential association between HRT and the risk of pancreatic cancer in postmenopausal women.

METHODS: This population-based, retrospective study extracted data from the US National Inpatient Sample (NIS) 2008-2018. Hospitalized females aged ≥55 years were eligible for inclusion. Associations between HRT, other study variables, and pancreatic cancer diagnosis were determined using univariate and multivariable regression analyses.

RESULTS: After 1:4 matching by age, data …

Dense And Persistent Odor Representations In The Olfactory Bulb Of Awake Mice, Delaram Pirhayati, Cameron L Smith, Ryan Kroeger, Saket Navlakha, Paul Pfaffinger, Jacob Reimer, Benjamin R Arenkiel, Ankit Patel, Elizabeth H Moss

Children’s Nutrition Research Center Staff Publications

Recording and analysis of neural activity are often biased toward detecting sparse subsets of highly active neurons, masking important signals carried in low-magnitude and variable responses. To investigate the contribution of seemingly noisy activity to odor encoding, we used mesoscale calcium imaging from mice of both sexes to record odor responses from the dorsal surface of bilateral olfactory bulbs (OBs). The outer layer of the mouse OB is comprised of dendrites organized into discrete "glomeruli," which are defined by odor receptor-specific sensory neuron input. We extracted activity from a large population of glomeruli and used logistic regression to classify odors …

A Bayesian Semi-Parametric Scalar-On-Function Regression With Measurement Error Using Instrumental Variables, Roger S Zoh, Yuanyuan Luan, Lan Xue, David B Allison, Carmen D Tekwe

Children’s Nutrition Research Center Staff Publications

Wearable devices such as the ActiGraph are now commonly used in research to monitor or track physical activity. This trend corresponds with the growing need to assess the relationships between physical activity and health outcomes, such as obesity, accurately. Device-based physical activity measures are best treated as functions when assessing their associations with scalar-valued outcomes such as body mass index. Scalar-on-function regression (SoFR) is a suitable regression model in this setting. Most estimation approaches in SoFR assume that the measurement error in functional covariates is white noise. Violating this assumption can lead to underestimating model parameters. There are limited approaches …

The De Winter Pattern In A Single Precordial Lead Caused By High-Grade Stenosis Of The Proximal Left Anterior Descending Artery With Plaque Rupture: A Case Report, Zhizhou Song, Yuehong Huo, Qi Wu, Xinjian Yu, Youdong Yang, Zejun Meng, Xia Li

Children’s Nutrition Research Center Staff Publications

The de Winter electrocardiogram (ECG) pattern indicates severe stenosis or occlusion of the left anterior descending artery (LAD). We present a 72-year-old female with 1.5-h chest pain. Angiography and optical coherence tomography (OCT) revealed 90 % LAD stenosis with plaque rupture, but no ST-segment elevation in the precordial leads. The de Winter pattern, characterized by upsloping ST-segment depression in V1-V6, appeared only in lead V2. Following successful percutaneous coronary intervention (PCI), the de Winter pattern disappeared. This case underscores the significance of the de Winter pattern in one precordial lead, necessitating prompt angiography and PCI for improved patient outcomes.

A Qualitative Study Of The Knowledge Of Metabolic Syndrome, Attitudes About Lifestyle Modifications, And Preferences For Lifestyle Interventions Among Patients With Cancer And Metabolic Syndrome, Isabel Martinez Leal, Ashwathy B Pillai, Jessica T Foreman, Kimberly W Siu, Natalia I Heredia, Carmen P Escalante, Ellen F Manzullo, Aimee J Christie, Tamara E Lacourt, Zayd Adnan Razouki, Jessica P Hwang

Faculty, Staff and Student Publications

Metabolic syndrome is a group of disorders-hypertension, dyslipidemia, obesity, and insulin resistance-that together increase the risk of coronary heart disease, stroke, and diabetes. Although ~60% of cancer patients have metabolic syndrome, which increases their risk of mortality, oncology providers lack clear guidance about its management. The development of metabolic syndrome lifestyle interventions requires a better understanding of these patients' knowledge, attitudes, and intervention preferences in order to inform management. During 2022-2023, 19 adult cancer patients with metabolic syndrome engaged in semistructured interviews focused on metabolic syndrome and lifestyle interventions. Interviews were analyzed using hybrid thematic analysis involving deductive and inductive …

Small Gtp-Binding Protein Gdp Dissociation Stimulator Influences Cisplatin-Induced Acute Kidney Injury Via Perk-Dependent Er Stress, Yuxue Yang, Ting Xiong, Ti Wang, Xiwei Chen, Ziwei Ma, Bangyun Zuo, Dong Ning, Ruilong Song, Xuesong Liu, Daxin Wang

Children’s Nutrition Research Center Staff Publications

Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK …

Not Feeling The Heat? Effects Of Dietary Protein On Satiation And Satiety In Mice Are Not Due To Its Impact On Body Temperature, Jazmin Osorio M, Sharon E Mitchell, Catherine Hambly, David B Allison, John R Speakman

Children’s Nutrition Research Center Staff Publications

Dietary protein modulates food intake (FI) via unclear mechanism(s). One possibility is that higher protein leads to greater post-ingestive heat production (Specific dynamic action: SDA) leading to earlier meal termination (increased satiation), and inhibition of further intake (increased satiety). The influence of dietary protein on feeding behaviour in C57BL/6J mice was tested using an automated FI monitoring system (BioDAQ), simultaneous to body temperature (Tb). Total FI, inter meal intervals (IMI, satiety) and meal size (MS, satiation) were related to changes in Tb after consuming low (5%, LP), moderate (15%, MP) and high (30%, HP) protein diets. Diets were tested over …

Lifr Regulates Cholesterol-Driven Bidirectional Hepatocyte-Neutrophil Cross-Talk To Promote Liver Regeneration, Yalan Deng, Zilong Zhao, Marisela Sheldon, Yang Zhao, Hongqi Teng, Consuelo Martinez, Jie Zhang, Chunru Lin, Yutong Sun, Fan Yao, Michael A Curran, Hao Zhu, Li Ma

Faculty, Staff and Student Publications

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 …

Mechanistic Insights Into Metabolic Function Of Dynamin-Related Protein 1, Xin Li, Katherine Pham, Jazmin Ysaguirre, Iqbal Mahmud, Lin Tan, Bo Wei, Long J Shao, Maryam Elizondo, Rabie Habib, Fathima Elizondo, Hiromi Sesaki, Philip L Lorenzi, Kai Sun

Faculty, Staff and Student Publications

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue-specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, …

Metabolic Cell Death In Cancer: Ferroptosis, Cuproptosis, Disulfidptosis, And Beyond, Chao Mao, Min Wang, Li Zhuang, Boyi Gan

Faculty, Staff and Student Publications

Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

Natural Killer Cell Effector Function Is Critical For Host Defense Against Alcohol-Associated Bacterial Pneumonia, Daniel Villageliu, Kelly C. Cunningham, Deandra R. Smith, Daren L. Knoell, Mason Mandolfo, Todd A. Wyatt, Derrick R. Samuelson

Food for Health: Publications

Alcohol use is an independent risk factor for the development of bacterial pneumonia due, in part, to impaired mucus-facilitated clearance, macrophage phagocytosis, and recruitment of neutrophils. Alcohol consumption is also known to reduce peripheral natural killer (NK) cell numbers and compromise NK cell cytolytic activity, especially NK cells with a mature phenotype. However, the role of innate lymphocytes, such as NK cells during host defense against alcohol-associated bacterial pneumonia is essentially unknown. We have previously shown that indole supplementation mitigates increases in pulmonary bacterial burden and improves pulmonary NK cell recruitment in alcohol-fed mice, which were dependent on aryl hydrocarbon …

Analysis Of Serum Exosome Metabolites Identifies Potential Biomarkers For Human Hepatocellular Carcinoma, Tingting Zhao, Yan Liang, Xiaolan Zhen, Hong Wang, Li Song, Didi Xing, Hui Li

Faculty, Staff and Student Publications

Currently, the clinical cure rate for primary liver cancer remains low. Effective screening and early diagnosis of hepatocellular carcinoma (HCC) remain clinical challenges. Exosomes are intimately associated with tumor development and their contents have the potential to serve as highly sensitive tumor-specific markers. A comprehensive untargeted metabolomics study was conducted using exosome samples extracted from the serum of 48 subjects (36 HCC patients and 12 healthy controls) via a commercial kit. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) strategy was used to identify the metabolic compounds. A total of 18 differential metabolites were identified using the non-targeted metabolomics approach of UPLC-QTOF-MS/MS. …

Factors Associated With Elevated Sars-Cov-2 Immune Response In Children And Adolescents, Sarah E Messiah, Rhiana Abbas, Emma Bergqvist, Harold W Kohl, Michael D Swartz, Yashar Talebi, Rachit Sabharwal, Haoting Han, Melissa A Valerio-Shewmaker, Stacia M Desantis, Ashraf Yaseen, Henal A Gandhi, Ximena Flandes Amavisca, Jessica A Ross, Lindsay N Padilla, Michael O Gonzalez, Leqing Wu, Mark A Silberman, David Lakey, Jennifer A Shuford, Stephen J Pont, Eric Boerwinkle

Faculty, Staff and Student Publications

BACKGROUND: Understanding the distinct immunologic responses to SARS-CoV-2 infection among pediatric populations is pivotal in navigating the COVID-19 pandemic and informing future public health strategies. This study aimed to identify factors associated with heightened antibody responses in children and adolescents to identify potential unique immune dynamics in this population.

METHODS: Data collected between July and December 2023 from the Texas Coronavirus Antibody REsponse Survey (Texas CARES), a statewide prospective population-based antibody survey among 1-to-19-year-old participants, were analyzed. Each participant had the following data available for analysis: (1) Roche Elecsys® Anti-SARS-CoV-2 Immunoassay for Nucleocapsid protein antibodies (Roche N-test), (2) qualitative and …

Translational Potential Of Mouse Models Of Human Metabolic Disease, I Sadaf Farooqi, Yong Xu

Children’s Nutrition Research Center Staff Publications

Obesity causes significant morbidity and mortality globally. Research in the last three decades has delivered a step-change in our understanding of the fundamental mechanisms that regulate energy homeostasis, building on foundational discoveries in mouse models of metabolic disease. However, not all findings made in rodents have translated to humans, hampering drug discovery in this field. Here, we review how studies in mice and humans have informed our current framework for understanding energy homeostasis, discuss their challenges and limitations, and offer a perspective on how human studies may play an increasingly important role in the discovery of disease mechanisms and identification …

Individually Randomized Trial Mislabeled As A Cluster-Randomized Trial Comment On: “Effectiveness Of Wearable Technology To Optimize Youth Soccer Players’ Off-Training Behaviour And Training Responses: A Cluster-Randomized Trial”, Jean Michel R S Leite, Jasmine Jamshidi-Naeini, Colby J Vorland, Lilian Golzarri-Arroyo, David B Allison

Children’s Nutrition Research Center Staff Publications

No abstract provided.

Comparative Toxicological Assessment Of 2 Bisphenols Using A Systems Approach: Evaluation Of The Behavioral And Transcriptomic Responses Of Danio Rerio To Bisphenol A And Tetrabromobisphenol A, Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Jessica Nixon, Susanne Penny, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis

Faculty, Staff and Student Publications

The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, …

Autophagic Signaling Promotes Systems-Wide Remodeling In Skeletal Muscle Upon Oncometabolic Stress By D2-Hg, Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel Mcnavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt

Faculty, Staff and Student Publications

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in …

The F Plasmid Conjutome: The Repertoire Of E Coli Proteins Translocated Through An F-Encoded Type Iv Secretion System, Abu Amar M Al Mamun, Kimberley Kissoon, Yang Grace Li, Erin Hancock, Peter J Christie

Faculty, Staff and Student Publications

Bacterial conjugation systems pose a major threat to human health through their widespread dissemination of mobile genetic elements (MGEs) carrying cargoes of antibiotic resistance genes. Using the Cre Recombinase Assay for Translocation (CRAfT), we recently reported that the IncFV pED208 conjugation system also translocates at least 16 plasmid-encoded proteins to recipient bacteria. Here, we deployed a high-throughput CRAfT screen to identify the repertoire of chromosomally encoded protein substrates of the pED208 system. We identified 32 substrates encoded by the Escherichia coli W3110 genome with functions associated with (i) DNA/nucleotide metabolism, (ii) stress tolerance/physiology, (iii) transcriptional regulation, or (iv) toxin inhibition. …

The Significant Role Of Amino Acid Metabolic Reprogramming In Cancer, Xiaohong Liu, Bo Ren, Jie Ren, Minzhi Gu, Lei You, Yupei Zhao

Faculty, Staff and Student Publications

Amino acid metabolism plays a pivotal role in tumor microenvironment, influencing various aspects of cancer progression. The metabolic reprogramming of amino acids in tumor cells is intricately linked to protein synthesis, nucleotide synthesis, modulation of signaling pathways, regulation of tumor cell metabolism, maintenance of oxidative stress homeostasis, and epigenetic modifications. Furthermore, the dysregulation of amino acid metabolism also impacts tumor microenvironment and tumor immunity. Amino acids can act as signaling molecules that modulate immune cell function and immune tolerance within the tumor microenvironment, reshaping the anti-tumor immune response and promoting immune evasion by cancer cells. Moreover, amino acid metabolism can …

Social Marketing And The Challenges Of Participant Recruitment, Tom Baranowski, Teresia M O'Connor, John A Jimenez-Garcia, Kavita Radhakrishnan, Elva M Arrendondo, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

Recruitment of research participants often has not obtained a desired sample size, thereby becoming a major problem inhibiting investigators' ability to adequately test the specified hypotheses. Social marketing with its four Ps, originally developed by the business world to sell products and adapted for public health initiatives, is proposed as a dynamic comprehensive conceptual framework to apply marketing principles and practices to enhance participant recruitment. Applying a social marketing approach to research recruitment would require initial investigation to understand the motivations of the target audience in regard to research participation, and continued research throughout the main project to adapt the …

Clinical Metabolomics Investigation Of Rheumatoid Arthritis Patients Receiving Ayurvedic Whole System Intervention, Sanjeev Rastogi, Ankita Verma, Rimjhim Trivedi, Anuj Shukla, Dinesh Kumar

Faculty, Staff and Student Publications

BACKGROUND: Arthritis is a common clinical condition seen in Ayurveda clinics. Clinical trials have reported Ayurvedic interventions to be of benefits in many arthritic conditions including Rheumatoid Arthritis (RA). No mechanistic details however are available about how such interventions on their own or as a combination of whole system Ayurveda might be working.

OBJECTIVE: The study aims to evaluate simultaneously the clinical outcome of Ayurveda whole system (AWS) intervention in RA patients and identifying the serum metabolic signatures which could be useful for diagnosing the disease and monitoring treatment response.

MATERIAL AND METHODS: RA patients (n = 37) simultaneously diagnosed …

Urban-Rural Disparities In Food Insecurity And Weight Status Among Children In The United States, Jayna M Dave, Tzuan A Chen, Alexandra N Castro, Mamie A White, Elizabeth A Onugha, Sloane Zimmerman, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

Place of residence (urban versus rural) is a contextual determinant of health that has received less attention in the food insecurity literature. The purpose of this study was to assess the urban–rural disparity in the prevalence of food insecurity and weight status among US children. Using data from the National Health and Nutrition Examination Survey (NHANES) 2013–2016 with three age groups of children (2–5, 6–11, and 12–17 years old), the associations of weight status and child and household food security status by urban–rural residence were examined using Rao–Scott Chi-square tests. Statistical significance was set at p < 0.05. Children living in urban areas were significantly more likely to experience household food insecurity (29.15%) compared to their rural counterparts (19.10%), among those aged 6–11 years. The associations between children’s weight status and child and household food security status were significant for children living in urban areas overall and different age groups but not for children living in rural areas. These trends were more pronounced in older age groups. Given the link between food insecurity and higher obesity rates, particularly among urban children, this study highlights the importance of incorporating food security interventions into future obesity prevention programs.

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Dose-Dependent Effects Of Dnmt3a In An Inducible Murine Model Of Krasg12d-Driven Leukemia, Jason H Rogers, Allison Rosen, Jaime M Reyes, Shamika Ketkar, Shannon E Conneely, Rohit Gupta, Luibin Yang, Matthew B Miller, Geraldo Medrano, Rogelio Aguilar, Nneka Uchenda, Margaret A Goodell, Rachel E Rau

Children’s Nutrition Research Center Staff Publications

DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ER^T2 murine model systems to study the effects of constitutively active Kras^G12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of …

Outcomes Of The Emdataresource Cryo-Em Ligand Modeling Challenge, Catherine L Lawson, Andriy Kryshtafovych, Grigore D Pintilie, Stephen K Burley, Jiří Černý, Vincent B Chen, Paul Emsley, Alberto Gobbi, Andrzej Joachimiak, Sigrid Noreng, Michael G Prisant, Randy J Read, Jane S Richardson, Alexis L Rohou, Bohdan Schneider, Benjamin D Sellers, Chenghua Shao, Elizabeth Sourial, Chris I Williams, Christopher J Williams, Ying Yang, Venkat Abbaraju, Pavel V Afonine, Matthew L Baker, Paul S Bond, Tom L Blundell, Tom Burnley, Arthur Campbell, Renzhi Cao, Jianlin Cheng, Grzegorz Chojnowski, K D Cowtan, Frank Dimaio, Reza Esmaeeli, Nabin Giri, Helmut Grubmüller, Soon Wen Hoh, Jie Hou, Corey F Hryc, Carola Hunte, Maxim Igaev, Agnel P Joseph, Wei-Chun Kao, Daisuke Kihara, Dilip Kumar, Lijun Lang, Sean Lin, Sai R Maddhuri Venkata Subramaniya, Sumit Mittal, Arup Mondal, Nigel W Moriarty, Andrew Muenks, Garib N Murshudov, Robert A Nicholls, Mateusz Olek, Colin M Palmer, Alberto Perez, Emmi Pohjolainen, Karunakar R Pothula, Christopher N Rowley, Daipayan Sarkar, Luisa U Schäfer, Christopher J Schlicksup, Gunnar F Schröder, Mrinal Shekhar, Dong Si, Abhishek Singharoy, Oleg V Sobolev, Genki Terashi, Andrea C Vaiana, Sundeep C Vedithi, Jacob Verburgt, Xiao Wang, Rangana Warshamanage, Martyn D Winn, Simone Weyand, Keitaro Yamashita, Minglei Zhao, Michael F Schmid, Helen M Berman, Wah Chiu

Children’s Nutrition Research Center Staff Publications

The EMDataResource Ligand Model Challenge aimed to assess the reliability and reproducibility of modeling ligands bound to protein and protein-nucleic acid complexes in cryogenic electron microscopy (cryo-EM) maps determined at near-atomic (1.9-2.5 Å) resolution. Three published maps were selected as targets: Escherichia coli beta-galactosidase with inhibitor, SARS-CoV-2 virus RNA-dependent RNA polymerase with covalently bound nucleotide analog and SARS-CoV-2 virus ion channel ORF3a with bound lipid. Sixty-one models were submitted from 17 independent research groups, each with supporting workflow details. The quality of submitted ligand models and surrounding atoms were analyzed by visual inspection and quantification of local map quality, model-to-map …

Association Of Candidate Single-Nucleotide Polymorphism Genotypes With Plasma And Skin Carotenoid Concentrations In Adults Provided A Lycopene-Rich Juice, Anna C Norman, Daniel G Palmer, Nancy E Moran, James N Roemmich, Shanon L Casperson

Children’s Nutrition Research Center Staff Publications

Background: Carotenoids are fat-soluble phytochemicals with biological roles, including ultraviolet protective functions in skin. Spectroscopic skin carotenoid measurements can also serve as a noninvasive biomarker for carotenoid consumption. Single-nucleotide polymorphisms (SNPs) in metabolic genes are associated with human plasma carotenoid concentrations; however, their relationships with skin carotenoid concentrations are unknown.

Objectives: The objective of this study was to determine the relationship between 13 candidate SNPs with skin and plasma carotenoid concentrations before and after a carotenoid-rich tomato juice intervention.

Methods: In this randomized, controlled trial, participants (n = 80) were provided with lycopene-rich vegetable juice providing low (13.1 mg), medium …

Personal Light Exposure Patterns And Incidence Of Type 2 Diabetes: Analysis Of 13 Million Hours Of Light Sensor Data And 670,000 Person-Years Of Prospective Observation, Daniel P Windred, Angus C Burns, Martin K Rutter, Chris Ho Ching Yeung, Jacqueline M Lane, Qian Xiao, Richa Saxena, Sean W Cain, Andrew J K Phillips

Faculty, Staff and Student Publications

BACKGROUND: Light at night disrupts circadian rhythms, and circadian disruption is a risk factor for type 2 diabetes. Whether personal light exposure predicts diabetes risk has not been demonstrated in a large prospective cohort. We therefore assessed whether personal light exposure patterns predicted risk of incident type 2 diabetes in UK Biobank participants, using ∼13 million hours of light sensor data.

METHODS: Participants (N = 84,790, age (M ± SD) = 62.3 ± 7.9 years, 58% female) wore light sensors for one week, recording day and night light exposure. Circadian amplitude and phase were modeled from weekly light data. Incident …

Cholesterol-Dependent Lxr Transcription Factor Activity Represses Pronociceptive Effects Of Estrogen In Sensory Neurons And Pain Induced By Myelin Basic Protein Fragments, Swathi K Hullugundi, Jennifer Dolkas, Andrei V Chernov, Tony L Yaksh, Kelly A Eddinger, Mila Angert, Glaucilene Ferreira Catroli, Alex Y Strongin, Patrick M Dougherty, Yan Li, Oswal Quehenberger, Aaron Armando, Veronica I Shubayev

Faculty, Staff and Student Publications

BACKGROUND: A bioactive myelin basic protein (MBP) fragment, comprising MBP

METHODS: In male and female normal and post-CCI rat sciatic nerves, we assessed: (i) cholesterol precursor and metabolite levels by lipidomics; (ii) MBP

RESULTS: CCI regulated LXRα ligand and receptor levels in nerves of both sexes, with cholesterol precursors, desmosterol and 7-DHC, and oxysterol elevated in females relative to males. MBP

CONCLUSION: The injury-released bioactive MBP fragments induce pronociceptive changes by selective inactivation of nuclear transcription factors, including LXRα. By Ncoa1 sequestration, bioactive MBP fragments render LXRα function to counteract pronociceptive activity of estrogen/ESR1 in sensory neurons. This effect of …