Biochemical Phenomena, Metabolism, and Nutrition Commons^™

A Computational Pipeline To Infer Alternative Poly-Adenylation From 3′ Sequencing Data, Hari Krishna Yalamanchili, Nathan D Elrod, Madeline K Jensen, Ping Ji, Ai Lin, Eric J Wagner, Zhandong Liu

Children’s Nutrition Research Center Staff Publications

An increasing number of investigations have established alternative polyadenylation (APA) as a key mechanism of gene regulation through altering the length of 3' untranslated region (UTR) and generating distinct mRNA termini. Further, appreciation for the significance of APA in disease contexts propelled the development of several 3' sequencing techniques. While these RNA sequencing technologies have advanced APA analysis, the intrinsic limitation of 3' read coverage and lack of appropriate computational tools constrain precise mapping and quantification of polyadenylation sites. Notably, Poly(A)-ClickSeq (PAC-seq) overcomes limiting factors such as poly(A) enrichment and 3' linker ligation steps using click-chemistry. Here we provide an …

On The Joint Role Of Non-Hispanic Black Race/Ethnicity And Weight Status In Predicting Postmenopausal Weight Gain, Christopher N Ford, Shine Chang, Alexis C Wood, Joann E Manson, David O Garcia, Helena Laroche, Chloe E Bird, Mara Z Vitolins

Children’s Nutrition Research Center Staff Publications

Objectives: To determine how baseline weight status contributes to differences in postmenopausal weight gain among non-Hispanic Blacks (NHBs) and non-Hispanic Whites (NHWs).

Methods: Data were included from 70,750 NHW and NHB postmenopausal women from the Women's Health Initiative Observational Study (WHI OS). Body Mass Index (BMI) at baseline was used to classify women as having normal weight, overweight, obese class I, obese class II or obese class III. Cox proportional hazards was used to estimate the hazard of a 10% or more increase in weight from baseline.

Results: In both crude and adjusted models, NHBs were more likely to experience …

Gut Microbiota Profiles Of Young South Indian Children: Child Sex-Specific Relations With Growth, Nirupama Shivakumar, Ambily Sivadas, Sarita Devi, Farook Jahoor, John Mclaughlin, Craig P Smith, Anura V Kurpad, Arpita Mukhopadhyay

Children’s Nutrition Research Center Staff Publications

Gut microbiota has been implicated as a modifier of childhood growth. Here, 16S rRNA sequencing-based fecal microbiota profiles of 18-24 month old Indian children were evaluated (n = 41), in relation to their anthropometric parameters, intestinal permeability, body composition and total energy expenditure. Pathway analyses were conducted to assess microbial functions related to stunting, underweight and wasting. The fecal microbiota was enriched in Prevotella 9, Bifidobacterium and Escherichia-Shigella. Weight, weight-for-age Z-scores (WAZ) and weight-for-length Z-scores (WLZ), along with age, acted as covariates of microbiota variation specifically in boys (n = 23). Bifidobacterium longum subsp longum abundance was positively associated with …

Probiotic Vsl#3 Treatment Reduces Colonic Permeability And Abdominal Pain Symptoms In Patients With Irritable Bowel Syndrome, Prapaporn Boonma, Jordan M Shapiro, Emily B Hollister, Shyam Badu, Qinglong Wu, Erica M Weidler, Bincy P Abraham, Sridevi Devaraj, Ruth Ann Luna, James Versalovic, Margaret M Heitkemper, Tor C Savidge, Robert J Shulman

Children’s Nutrition Research Center Staff Publications

Background: Little is known regarding the clinical impact of treatment and treatment duration of probiotic VSL#3 on gut and microbiome function in irritable bowel syndrome (IBS). As part of a safety trial, we assessed the effect of VSL#3 treatment duration on abdominal pain, stooling, gut permeability, microbiome composition and function.

Methods: Adults with IBS were randomized into an open label trial to receive the probiotic VSL#3 for 4 or 8 weeks. Adverse events, abdominal pain, and stooling patterns were recorded daily. Gut permeability, fecal bile acid levels, and microbiome composition were profiled at baseline and after treatment.

Results: Fifteen subjects …

Assessment Of The Gut Bacterial Microbiome And Metabolome Of Girls And Women With Rett Syndrome, Santosh Thapa, Alamelu Venkatachalam, Nabeel Khan, Mohammed Naqvi, Miriam Balderas, Jessica K Runge, Anthony Haag, Kathleen M Hoch, Daniel G Glaze, Ruth Ann Luna, Kathleen J Motil

Children’s Nutrition Research Center Staff Publications

Background: Gastrointestinal problems affect the health and quality of life of individuals with Rett syndrome (RTT) and pose a medical hardship for their caregivers. We hypothesized that the variability in the RTT phenotype contributes to the dysbiosis of the gut microbiome and metabolome in RTT, predisposing these individuals to gastrointestinal dysfunction.

Objectives: We characterized the gut bacterial microbiome and metabolome in girls and young women with RTT (n = 44) and unaffected controls (n = 21), and examined the relation between the composition of the microbiome and variations in the RTT phenotype.

Methods: Demographics and clinical information, including growth and …

The Role Of Vascular Endothelial Growth Factor In Leukemia Trafficking, Shaw Powell

Theses and Dissertations--Medical Sciences

Vascular endothelial growth factor (VEGF) is a signaling protein involved in inducing and regulating endothelial cell proliferation and function (Duffy et al 2000). VEGF is also involved in cancer progression, as it induces vascular permeability and promotes angiogenesis to tumor laden areas, giving cancer cells critical oxygen and nutrients (Hoeppner et al.,2012. Studies indicate VEGF prevents lymphoblast apoptosis, which may contribute to leukemia formation and enable the proliferation of leukemic cells (Duffy et al 2000). Ongoing research seeks to further examine VEGF in leukemia, using a rag2:GFP-Myc expressing transgenic zebrafish as the animal model of T-cell Acute Lymphoblastic Leukemia (T-ALL). …

Mitochondrial Aspects Of Neuronal Pathology In Triple-Transgenic Alzheimer’S Disease Mice, John Zachary Cavendish

Graduate Theses, Dissertations, and Problem Reports (ETD)

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and consistent …

Neural Stem Cell Metabolic Changes In The Presence Of Interferon-Gamma, Dylan Mckibben

Williams Honors College, Honors Research Projects

Spinal cord injury results in significant disability and health care costs due to an inability of the mature central nervous system to regenerate. One potential therapy would be implantation of neural stem cells to the injury site and stimulation of their differentiation to mature neurons. Previous work has shown that the cytokine interferon-gamma can promote this process; however, the signaling pathways induced in neural stem cells have not been well-defined. This proposal examines neural stem cell metabolic responses to signaling induced by interferon-gamma. Two questions will be answered: i) What specific metabolic pathway is activated to guide neural stem cell …

Tph2 In The Dorsal Raphe Nuclei Regulates Energy Balance In A Sex-Dependent Manner, Hailan Liu, Chunmei Wang, Meng Yu, Yongjie Yang, Yang He, Hesong Liu, Chen Liang, Longlong Tu, Nan Zhang, Lina Wang, Julia Wang, Feng Liu, Fang Hu, Yong Xu

Children’s Nutrition Research Center Staff Publications

AbstractCentral 5-hydroxytryptamine (5-HT), which is primarily synthesized by tryptophan hydroxylase 2 (TPH2) in the dorsal Raphe nuclei (DRN), plays a pivotal role in the regulation of food intake and body weight. However, the physiological functions of TPH2 on energy balance have not been consistently demonstrated. Here we systematically investigated the effects of TPH2 on energy homeostasis in adult male and female mice. We found that the DRN harbors a similar amount of TPH2+ cells in control male and female mice. Adult-onset TPH2 deletion in the DRN promotes hyperphagia and body weight gain only in male mice, but not in female …

Pre-Clinical Advancements In Biomarkers, Tools, And Therapeutics For A Metabolic Neurodegenerative Disease, Zoë Simmons

Theses and Dissertations--Molecular and Cellular Biochemistry

Glycogen is the storage form of glucose and a highly important substrate for cellular metabolism. Characterization of the enzymes and mechanisms of glycogen metabolism began over 70 years ago and over the last 20 years, a previously unknown protein called laforin has emerged as an important contributor to glycogen metabolism homeostasis. Multiple labs demonstrated that laforin is a glycogen phosphatase and mutations in the gene encoding laforin cause the formation of aberrant glycogen-like aggregates called Lafora bodies (LBs). LBs are cytoplasmic, water-insoluble aggregates that drive neurodegeneration and early death in Lafora disease (LD) patients. The direct relationship between mutated laforin, …

Thyroid Storm In A Patient With Covid-19, Angela N Rao, Ruaa Y Al-Ward, Ruchi Gaba

Faculty, Staff and Students Publications

OBJECTIVE: A thyroid storm is a severe exacerbation of thyrotoxicosis that can cause significant morbidity and mortality. The emergence of the novel coronavirus (SARS-CoV-2) that originated in Wuhan, China, has become a worldwide pandemic. We present the first documented case of thyroid storm (as defined by the Burch-Wartofsky criteria) in a patient with COVID-19.

METHODS: Laboratory and diagnostic studies, including thyroid function tests, thyroid antibody testing, SARS-CoV-2 nasopharyngeal polymerase chain reaction testing, and thyroid ultrasound were performed.

RESULTS: A 25-year-old woman presented to the hospital with dry cough, dyspnea, palpitations, weight loss, diarrhea, and anxiety. Physical examination revealed exophthalmos with …

The E3 Ligase Traf4 Promotes Igf Signaling By Mediating Atypical Ubiquitination Of Irs-1, Wenjuan Yu, Ramesh Singh, Zhao Wang, Bert W O'Malley, Ping Yi

Faculty, Staff and Students Publications

Insulin-like growth factor (IGF) is a potent mitogen that activates the IGF receptor (IGFR)/insulin receptor substrate (IRS) axis, thus stimulating growth in normal cells and uncontrolled cell proliferation in cancer. Posttranslational modifications of IRS such as ubiquitination tightly control IGF signaling, and we previously identified IRS-1 as a potential substrate for the E3 ubiquitin ligase TRAF4 using an unbiased screen. Here we provide evidence that TRAF4-mediated ubiquitination of IRS-1 is physiologically relevant and crucial for IGF signal transduction. Through site-directed mutagenesis we found that TRAF4 promotes an atypical K29-linked ubiquitination at the C-terminal end of IRS-1. Its depletion abolishes AKT …

Enhancing Glucose Metabolism Via Gluconeogenesis Is Therapeutic In A Zebrafish Model Of Dravet Syndrome, Rajeswari Banerji, Christopher Huynh, Francisco Figueroa, Matthew T Dinday, Scott C Baraban, Manisha Patel

Faculty, Staff and Students Publications

Energy-producing pathways are novel therapeutic targets for the treatment of neurodevelopmental disorders. Here, we focussed on correcting metabolic defects in a catastrophic paediatric epilepsy, Dravet syndrome which is caused by mutations in sodium channel NaV1.1 gene, SCN1A. We utilized a translatable zebrafish model of Dravet syndrome (scn1lab) which exhibits key characteristics of patients with Dravet syndrome and shows metabolic deficits accompanied by down-regulation of gluconeogenesis genes, pck1 and pck2. Using a metabolism-based small library screen, we identified compounds that increased gluconeogenesis via up-regulation of pck1 gene expression in scn1lab larvae. Treatment with PK11195, a pck1 activator …

Long Noncoding Rnas And Their Therapeutic Promise In Diabetic Nephropathy, Juan D Coellar, Jianyin Long, Farhad R Danesh

Faculty, Staff and Students Publications

Recent advances in large-scale RNA sequencing and genome-wide profiling projects have unraveled a heterogeneous group of RNAs, collectively known as long noncoding RNAs (lncRNAs), which play central roles in many diverse biological processes. Importantly, an association between aberrant expression of lncRNAs and diverse human pathologies has been reported, including in a variety of kidney diseases. These observations have raised the possibility that lncRNAs may represent unexploited potential therapeutic targets for kidney diseases. Several important questions regarding the functionality of lncRNAs and their impact in kidney diseases, however, remain to be carefully addressed. Here, we provide an overview of the main …