Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Comparison Of Percentile Tables And Algorithm-Based Calculators For Classification Of Blood Pressures In Children And Adolescents With Obesity: A Secondary Analysis Of A Clinical Trial, William J Pitts, Tami L Cave, Alana Cavadino, Roman J Shypailo, Sarah E Maessen, Paul L Hofman, William Wong, Yvonne C Anderson

Faculty, Staff and Students Publications

AIM: Obesity as a major risk factor for childhood hypertension necessitates careful blood pressure (BP) monitoring of those affected. This study aimed to compare BP classification in a cohort of children affected by obesity using tables versus digital calculations in two sets of guidelines.

METHODS: This study was a secondary analysis of data collected from a randomised clinical trial of a multidisciplinary life-style assessment and intervention program. Baseline data from 237 children with a body mass index >99th percentile or >91st percentile with weight-related comorbidities and available BP measurements were analysed. We assessed agreement between tables and algorithms in classification …

Prospective Evaluation Of The Fungitell® (1-->3) Beta-D-Glucan Assay As A Diagnostic Tool For Invasive Fungal Disease In Pediatric Allogeneic Hematopoietic Cell Transplantation: A Report From The Children’S Oncology Group, William R Otto, Christopher C Dvorak, Craig L K Boge, Luis Ostrosky-Zeichner, Adam J Esbenshade, Michael L Nieder, Sarah Alexander, William J Steinbach, Ha Dang, Doojduen Villaluna, Lu Chen, Micah Skeens, Theoklis E Zaoutis, Lillian Sung, Brian T Fisher

Faculty, Staff and Student Publications

BACKGROUND: Invasive fungal disease (IFD) is a major source of morbidity and mortality for hematopoietic cell transplant (HCT) recipients. Non-invasive biomarkers, such as the beta-D-glucan assay, may improve the diagnosis of IFD. The objective was to define the utility of surveillance testing using Fungitell® beta-D-glucan (BDG) assay in children receiving antifungal prophylaxis in the immediate post-HCT period.

METHODS: Weekly surveillance blood testing with the Fungitell® BDG assay was performed during the early post-HCT period in the context of a randomized trial of children, adolescents, and young adults undergoing allogeneic HCT allocated to triazole or caspofungin prophylaxis. Positivity was defined at …

Serial Recombineering Cloning To Build Selectable And Tagged Genomic P[Acman] Bac Clones For Selection Transgenesis And Functional Gene Analysis Using Drosophila Melanogaste, Koen J T Venken, Nick Matinyan, Yezabel Gonzalez, Herman A Dierick

Faculty, Staff and Students Publications

Transgenes with genomic DNA fragments that encompass genes of interest are the gold standard for complementing null alleles in rescue experiments in the fruit fly Drosophila melanogaster. Of particular interest are genomic DNA clones available as bacterial artificial chromosomes (BACs) or fosmids from publicly available genomic DNA libraries. Genes contained within BAC and fosmid clones can be easily modified by recombineering cloning to insert peptide or protein tags to localize, visualize, or manipulate gene products, and to create point mutations or deletions for structure-function analysis of the inserted genes. However, since transgenesis efficiency is inversely correlated with transgene size, obtaining …

Differential Transcriptional Alterations In Detoxification Genes In Parkinson’S Disease In Egypt, Nourhan Shebl

Theses and Dissertations

PD is the most common motor neurodegenerative disease worldwide. The underlying cause of PD is still unknow, owingthis to the complexity of the disease. Often, genetics and environmental factors are collaborating in the initiation of the disease. Despite the diversity of its genetical and environmental profiles, the Egyptian population is one of the mostunderrepresented population in terms of PD research. In this study, we investigated PD through various perspectives tohighlight the complexity of the disease in Egypt, taking into consideration the diversity of the Egyptian population. We recruited PD patients and reference controls from 4 governorates: Cairo, Giza, Alexandria, and …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Interfering With Lipid Metabolism Through Targeting Ces1 Sensitizes Hepatocellular Carcinoma For Chemotherapy, Gang Li, Xin Li, Iqbal Mahmud, Jazmin Ysaguirre, Baharan Fekry, Shuyue Wang, Bo Wei, Kristin L Eckel-Mahan, Philip L Lorenzi, Richard Lehner, Kai Sun

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC) is the most common lethal form of liver cancer. Apart from surgical removal and transplantation, other treatments have not yet been well established for patients with HCC. In this study, we found that carboxylesterase 1 (CES1) is expressed at various levels in HCC. We further revealed that blockage of CES1 by pharmacological and genetical approaches leads to altered lipid profiles that are directly linked to impaired mitochondrial function. Mechanistically, lipidomic analyses indicated that lipid signaling molecules, including polyunsaturated fatty acids (PUFAs), which activate PPARα/γ, were dramatically reduced upon CES1 inhibition. As a result, the expression of SCD, …

Brain Nuclear Receptors And Cardiovascular Function, Mengjie Wang, Yongjie Yang, Yong Xu

Faculty, Staff and Students Publications

Brain-heart interaction has raised up increasing attentions. Nuclear receptors (NRs) are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of cardiovascular diseases (CVDs), including hypertension, heart failure, atherosclerosis, etc. In this review, we will elaborate recent findings that have established the physiological relevance of brain NRs in the context of cardiovascular function. In addition, we will discuss the currently available evidence regarding the distinct neuronal populations that respond to brain NRs in the cardiovascular control. These findings suggest connections between cardiac control and brain dynamics through NR signaling, which …

Hypoxia Truncates And Constitutively Activates The Key Cholesterol Synthesis Enzyme Squalene Monooxygenase, Hudson W Coates, Isabelle M Capell-Hattam, Ellen M Olzomer, Ximing Du, Rhonda Farrell, Hongyuan Yang, Frances L Byrne, Andrew J Brown

Faculty, Staff and Student Publications

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates …

Pgc-1Α Senses The Cbc Of Pre-Mrna To Dictate The Fate Of Promoter-Proximally Paused Rnapii, Xavier Rambout, Hana Cho, Roméo Blanc, Qing Lyu, Joseph M Miano, Joe V Chakkalakal, Geoffrey M Nelson, Hari K Yalamanchili, Karen Adelman, Lynne E Maquat

Children’s Nutrition Research Center Staff Publications

PGC-1α is well established as a metazoan transcriptional coactivator of cellular adaptation in response to stress. However, the mechanisms by which PGC-1α activates gene transcription are incompletely understood. Here, we report that PGC-1α serves as a scaffold protein that physically and functionally connects the DNA-binding protein estrogen-related receptor α (ERRα), cap-binding protein 80 (CBP80), and Mediator to overcome promoter-proximal pausing of RNAPII and transcriptionally activate stress-response genes. We show that PGC-1α promotes pausing release in a two-arm mechanism (1) by recruiting the positive transcription elongation factor b (P-TEFb) and (2) by outcompeting the premature transcription termination complex Integrator. Using mice …

Association Of Omega 3 Polyunsaturated Fatty Acids With Incident Chronic Kidney Disease: Pooled Analysis Of 19 Cohorts, Kwok Leung Ong, Matti Marklund, Liping Huang, Kerry-Anne Rye, Nicholas Hui, Xiong-Fei Pan, Casey M Rebholz, Hyunju Kim, Lyn M Steffen, Anniek C Van Westing, Johanna M Geleijnse, Ellen K Hoogeveen, Yun-Yu Chen, Kuo-Liong Chien, Amanda M Fretts, Rozenn N Lemaitre, Fumiaki Imamura, Nita G Forouhi, Nicholas J Wareham, Anna Birukov, Susanne Jäger, Olga Kuxhaus, Matthias B Schulze, Vanessa Derenji De Mello, Jaakko Tuomilehto, Matti Uusitupa, Jaana Lindström, Nathan Tintle, William S Harris, Keisuke Yamasaki, Yoichiro Hirakawa, Toshiharu Ninomiya, Toshiko Tanaka, Luigi Ferrucci, Stefania Bandinelli, Jyrki K Virtanen, Ari Voutilainen, Tharusha Jayasena, Anbupalam Thalamuthu, Anne Poljak, Sonia Bustamante, Perminder S Sachdev, Mackenzie K Senn, Stephen S Rich, Michael Y Tsai, Alexis C Wood, Markku Laakso, Maria Lankinen, Xiaowei Yang, Liang Sun, Huaixing Li, Xu Lin, Christoph Nowak, Johan Ärnlöv, Ulf Risérus, Lars Lind, Mélanie Le Goff, Cécilia Samieri, Catherine Helmer, Frank Qian, Renata Micha, Adrienne Tin, Anna Köttgen, Ian H De Boer, David S Siscovick, Dariush Mozaffarian, Jason Hy Wu

Faculty, Staff and Students Publications

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were …

Noninvasive Reflection Spectroscopy Measurement Of Skin Carotenoid Score In Infants Is Feasible And Reliable, Nancy E Moran, Jocelyn Chang, Rachel Stroh, Yusuf Zaidi, Noor Hason, Salma Musaad, Teresia O'Connor

Children’s Nutrition Research Center Staff Publications

Background: Skin carotenoid measurement by reflection spectroscopy (RS) offers a noninvasive biomarker of carotenoid intake, but feasibility, reliability, and validity are not established in infants.

Objectives: In this study we aimed to determine the feasibility and reliability of 4-mo-old infant skin carotenoid score (SCS) measurement and its correlation with total carotenoid intake and plasma concentrations.

Methods: SCSs were measured in a prospective, observational study with a modified, portable RS device at the index finger and heel of the foot in 4-mo-olds (n = 21). Infant plasma, human milk, and formula carotenoid concentrations were measured by HPLC-photodiode array, and carotenoid intake …

Only One Cluster Per Condition Is An Invalid Design For A Cluster Randomized Trial And Should Be Re-Labeled A Quasi-Experimental Study Response To: “Effect Of Behavioral Activation On Time And Frequency Domain Heart Rate Variability In Older Adults With Subthreshold Depression: A Cluster Randomized Controlled Trial In Thailand”, Yasaman Jamshidi-Naeini, Lilian Golzarri-Arroyo, Abu Bakkar Siddique, Colby J Vorland, David B Allison

Children’s Nutrition Research Center Staff Publications

Ayudhaya et al. examined the effect of Behavioral Activation on daily step count and heart rate variability among older adults with depression in a study labeled a cluster randomized controlled trial (cRCT). However, only one cluster was assigned to either of the study conditions. Such a design would have zero degrees of freedom for inferential testing, because the variation due to cluster membership cannot be estimated apart from the variation due to treatment assignment. Thus, the intervention effect is completely confounded with the cluster effect. The study should be labeled a quasi-experimental study, not a cRCT. Accordingly, the numerical results …

Sgc-Camkk2-1: A Chemical Probe For Camkk2, Carrow Wells, Yi Liang, Thomas L Pulliam, Chenchu Lin, Dominik Awad, Benjamin Eduful, Sean O'Byrne, Mohammad Anwar Hossain, Carolina Moura Costa Catta-Preta, Priscila Zonzini Ramos, Opher Gileadi, Carina Gileadi, Rafael M Couñago, Brittany Stork, Christopher G Langendorf, Kevin Nay, Jonathan S Oakhill, Debarati Mukherjee, Luigi Racioppi, Anthony R Means, Brian York, Donald P Mcdonnell, John W Scott, Daniel E Frigo, David H Drewry

Faculty, Staff and Student Publications

The serine/threonine protein kinase calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays critical roles in a range of biological processes. Despite its importance, only a handful of inhibitors of CAMKK2 have been disclosed. Having a selective small molecule tool to interrogate this kinase will help demonstrate that CAMKK2 inhibition can be therapeutically beneficial. Herein, we disclose SGC-CAMKK2-1, a selective chemical probe that targets CAMKK2.

Obesity Is Associated With Altered Tumor Metabolism In Metastatic Melanoma, Andrew W Hahn, Ashley V Menk, Dayana B Rivadeneira, Ryan C Augustin, Mingchu Xu, Jun Li, Xiaogang Wu, Aditya K Mishra, Tuba N Gide, Camelia Quek, Yan Zang, Christine N Spencer, Alexander M Menzies, Carrie R Daniel, Courtney W Hudgens, Theodore Nowicki, Lauren E Haydu, M A Wadud Khan, Vancheswaran Gopalakrishnan, Elizabeth M Burton, Jared Malke, Julie M Simon, Chantale Bernatchez, Nagireddy Putluri, Scott E Woodman, Y N Vashisht Gopal, Renato Guerrieri, Grant M Fischer, Jian Wang, Khalida M Wani, John F Thompson, Jeffrey E Lee, Patrick Hwu, Nadim Ajami, Jeffrey E Gershenwald, Georgina V Long, Richard A Scolyer, Michael T Tetzlaff, Alexander J Lazar, Dirk Schadendorf, Jennifer A Wargo, John M Kirkwood, Ralph J Deberardinis, Han Liang, Andrew Futreal, Jianhua Zhang, James S Wilmott, Weiyi Peng, Michael A Davies, Greg M Delgoffe, Yana G Najjar, Jennifer L Mcquade

Faculty, Staff and Student Publications

PURPOSE: Overweight/obese (OW/OB) patients with metastatic melanoma unexpectedly have improved outcomes with immune checkpoint inhibitors (ICI) and BRAF-targeted therapies. The mechanism(s) underlying this association remain unclear, thus we assessed the integrated molecular, metabolic, and immune profile of tumors, as well as gut microbiome features, for associations with patient body mass index (BMI).

EXPERIMENTAL DESIGN: Associations between BMI [normal (NL < 25) or OW/OB (BMI ≥ 25)] and tumor or microbiome characteristics were examined in specimens from 782 patients with metastatic melanoma across 7 cohorts. DNA associations were evaluated in The Cancer Genome Atlas cohort. RNA sequencing from 4 cohorts (n = 357) was batch corrected and gene set enrichment analysis (GSEA) by BMI category was performed. Metabolic profiling was conducted in a subset of patients (x = 36) by LC/MS, and in flow-sorted melanoma tumor cells (x = 37) and patient-derived melanoma cell lines (x = 17) using the Seahorse XF assay. Gut microbiome features were examined in an independent cohort (n = 371).

RESULTS: DNA mutations and copy number variations were not associated with BMI. GSEA demonstrated that tumors from OW/OB patients were metabolically quiescent, with downregulation of oxidative phosphorylation and multiple other metabolic pathways. Direct metabolite analysis and functional metabolic profiling confirmed decreased …

Increased Camkk2 Expression Is An Adaptive Response That Maintains The Fitness Of Tumor-Infiltrating Natural Killer Cells, Patrick K Juras, Luigi Racioppi, Debarati Mukherjee, Sandeep Artham, Xia Gao, Laura Akullian D'Agostino, Ching-Yi Chang, Donald P Mcdonnell

Faculty, Staff and Students Publications

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a key regulator of energy homeostasis in several cell types. Expression of this enzyme in tumor cells promotes proliferation and migration, and expression in tumor-associated immune cells facilitates M2 macrophage polarization and the development of myeloid-derived suppressor cells. Thus, there has been interest in developing CaMKK2 inhibitors as potential anticancer therapeutics. One impediment to clinical development of these agents is that the roles of CaMKK2 in other cellular compartments within the tumor immune microenvironment remain to be established. We report herein that CaMKK2 is expressed at low basal levels in natural killer (NK) …

Adolescence, Alcohol, And Astrocytes: The Impact Of Adolescent Alcohol Use On Astrocyte-Synaptic Interactions, Structure, Function, And Behavior, Christopher Douglas Walker

Theses, Dissertations and Capstones

Alcohol is the third leading cause of preventable death in the United States and has substantial social and economic burdens. Excessive alcohol consumption in the form of binge drinking is highly prevalent among adolescents and emerging adults. Binge drinking is a form of excessive drinking, defined as consuming enough alcohol on a single occasion to result in blood alcohol concentrations above 0.08%. Approximately 55% of full-time college students aged 18- 22 years old have reported consuming alcohol in a binge manner. Furthermore, studies have shown that approximately 20% of college students meet the criteria for an alcohol use disorder (AUD). …

Effect Of Stretch And Release On Myofascial Stem Cell Function In Vitro: A Putative Model To Understand The Molecular Benefits Of The Myofascial Release (Mfr) Technique, Ben Smith, Shahn Notta, Debasis Mondal

Research Day

Despite the beneficial effects of osteopathic manipulative techniques (OMT), there is a lack of in vitro models to understand the molecular mechanisms associated with these time-tested therapies. The Myofascial Release (MFR) technique is a non-invasive approach that involves passive stretching, hold and release, of the soft tissue to achieve myofascial homeostasis. Tissue-resident mesenchymal stem cells (MSC) can regulate the myofascial microenvironment by altering their secreted factors following stretch and release. Therefore, we initiated studies to develop an in vitro model to investigate the possible effects of stretch and release on MSC function, i.e. proliferation and differentiation capabilities, and changes in …

Characterizing Cellular Injury And Inflammation With Aldob-/-Mouse Model Of Mafld, Andy Rashid

All Master's Theses

Metabolic-associated fatty liver disease (MAFLD) affects 1 in 3 people in the US and is a healthcare burden on the order of billions of dollars. MAFLD is characterized by pathological lipid accumulation in the liver, excess production of triglycerides and cholesterol, and export of LDL particles that raise serum lipid levels. These metabolic perturbations can lead to the development of liver fibrosis, chronic inflammation, and insulin resistance. Diagnosing MAFLD prior to fibrosis is crucial for successful intervention and prevention of advanced liver disease and other metabolic complications. Fructose-1Phospahte (F1P) accumulation from fructose overconsumption can drive hepatic lipogenesis and MAFLD progression. …

The Effects Of Sex On Zebrafish Bone Metabolism, Simon Bagatto

Williams Honors College, Honors Research Projects

I investigated the effects of diet and sex on zebrafish bone metabolism. Zebrafish were subjected to either a high-calorie or low-calorie diet over a five-week period. After this diet, zebrafish scales were used to measure alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) enzyme activity with a fluorescent substrate. The enzyme activities were markers of the osteoblasts (ALP) and the osteoclasts (TRAP). These data were compared among sex and diet of the zebrafish using a repeated measures ANOVA statistical test. I also measured the number of resorption lacunae per scale (another indicator of osteoclast activity). The results showed higher TRAP …