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Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin 2017 University of Michigan Medical Center

Nrg4 Promotes Fuel Oxidation And A Healthy Adipokine Profile To Ameliorate Diet-Induced Metabolic Disorders, Zhimin Chen, Guo-Xiao Wang, Sara L. Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D. Lopaschuk, Jason K. Kim, Jiandie D. Lin

UMass Metabolic Network Publications

OBJECTIVE: Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and ...


The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers 2017 University of Louisville

The Dlk1-Meg3 Locus In Malignant Cells Of Proposed Primordial Germ Cell Origins., Zachariah Payne Sellers

Electronic Theses and Dissertations

Primordial germ cells (PGCs) are hypothesized to deposit hematopoietic stem cells (HSCs) along their migration route through the embryo during the early stages of embryogenesis. PGCs also undergo global chromatin remodeling, including the erasure and reestablishment of genomic imprints, during this migration. While PGCs do not spontaneously form teratomas, their malignant development into germ cell tumors (GCTs) in vivo is often accompanied by the retention of hypomethylation at the IGF2-H19 imprinting control differentially methylated region (DMR). Previous studies in bimaternal embryos determined that proper genomic imprinting at two paternally imprinted loci was necessary for their growth and development: Igf2-H19 and ...


Jnks Function As Cdk4-Activating Kinases By Phosphorylating Cdk4 And P21, B. Colleoni, S. Paternot, J. M. Pita, X. Bisteau, K. Coulonval, Roger J. Davis, E. Raspe, P. P. Roger 2017 Université Libre de Bruxelles, Belgium

Jnks Function As Cdk4-Activating Kinases By Phosphorylating Cdk4 And P21, B. Colleoni, S. Paternot, J. M. Pita, X. Bisteau, K. Coulonval, Roger J. Davis, E. Raspe, P. P. Roger

Open Access Articles

Cyclin D-CDK4/6 are the first cyclin-dependent kinase (CDK) complexes to be activated by mitogenic/oncogenic pathways. They have a central role in the cell multiplication decision and in its deregulation in cancer cells. We identified T172 phosphorylation of CDK4 rather than cyclin D accumulation as the distinctly regulated step determining CDK4 activation. This finding challenges the view that the only identified metazoan CDK-activating kinase, cyclin H-CDK7-Mat1 (CAK), which is constitutively active, is responsible for the activating phosphorylation of all cell cycle CDKs. We previously showed that T172 phosphorylation of CDK4 is conditioned by an adjacent proline (P173), which is ...


Real-Time Sensing Of Single-Ligand Delivery With Nanoaperture-Integrated Microfluidic Devices, W. Elliott Martin, Ning Ge, Bernadeta R. Srijanto, Emily Furnish, C. Patrick Collier, Christine A. Trinkle, Christopher I. Richards 2017 University of Kentucky

Real-Time Sensing Of Single-Ligand Delivery With Nanoaperture-Integrated Microfluidic Devices, W. Elliott Martin, Ning Ge, Bernadeta R. Srijanto, Emily Furnish, C. Patrick Collier, Christine A. Trinkle, Christopher I. Richards

Chemistry Faculty Publications

The measurement of biological events on the surface of live cells at the single-molecule level is complicated by several factors including high protein densities that are incompatible with single-molecule imaging, cellular autofluorescence, and protein mobility on the cell surface. Here, we fabricated a device composed of an array of nanoscale apertures coupled with a microfluidic delivery system to quantify single-ligand interactions with proteins on the cell surface. We cultured live cells directly on the device and isolated individual epidermal growth factor receptors (EGFRs) in the apertures while delivering fluorescently labeled epidermal growth factor. We observed single ligands binding to EGFRs ...


Crystal Structure Of Apobec3a Bound To Single-Stranded Dna Reveals Structural Basis For Cytidine Deamination And Specificity, Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffer 2017 University of Massachusetts Medical School

Crystal Structure Of Apobec3a Bound To Single-Stranded Dna Reveals Structural Basis For Cytidine Deamination And Specificity, Takahide Kouno, Tania V. Silvas, Brendan J. Hilbert, Shivender Shandilya, Markus-Frederik Bohn, Brian A. Kelch, William E. Royer, Mohan Somasundaran, Nese Kurt Yilmaz, Hiroshi Matsuo, Celia A. Schiffer

Celia A. Schiffer

Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active ...


Testing The Independence Hypothesis Of Accepted Mutations For Pairs Of Adjacent Amino Acids In Protein Sequences, Jyotsna Ramanan, Peter Revesz 2017 University of Nebraska-Lincoln

Testing The Independence Hypothesis Of Accepted Mutations For Pairs Of Adjacent Amino Acids In Protein Sequences, Jyotsna Ramanan, Peter Revesz

CSE Journal Articles

Evolutionary studies usually assume that the genetic mutations are independent of each other. However, that does not imply that the observed mutations are independent of each other because it is possible that when a nucleotide is mutated, then it may be biologically beneficial if an adjacent nucleotide mutates too. With a number of decoded genes currently available in various genome libraries and online databases, it is now possible to have a large-scale computer-based study to test whether the independence assumption holds for pairs of adjacent amino acids. Hence the independence question also arises for pairs of adjacent amino acids within ...


Joint Analysis Of Left Ventricular Expression And Circulating Plasma Levels Of Omentin After Myocardial Ischemia, Louis A. Saddic, Sarah M. Nicoloro, Olga T. Gupta, Michael P. Czech, Joshua Gorham, Stanton K. Shernan, Christine E. Seidman, Jon G. Seidman, Sary F. Aranki, Simon C. Body, Timothy P. Fitzgibbons, Jochen D. Muehlschlegel 2017 University of California Los Angeles

Joint Analysis Of Left Ventricular Expression And Circulating Plasma Levels Of Omentin After Myocardial Ischemia, Louis A. Saddic, Sarah M. Nicoloro, Olga T. Gupta, Michael P. Czech, Joshua Gorham, Stanton K. Shernan, Christine E. Seidman, Jon G. Seidman, Sary F. Aranki, Simon C. Body, Timothy P. Fitzgibbons, Jochen D. Muehlschlegel

UMass Metabolic Network Publications

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia.

METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled ...


Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl 2017 University of Nebraska Medical Center

Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl

Theses & Dissertations

Endocytic trafficking is not only an essential process for the maintenance of cellular homeostasis but also plays a vital role in regulating diverse cellular processes such as signaling, migration and cell division. The C-terminal Eps 15 Homology Domain proteins (EHD1-4) play pivotal roles in regulating distinct steps of endocytic trafficking. Among the EHDs, EHD2 is disparate both in terms of sequence homology (70%) and its subcellular localization at the caveolae. The crystal structure of EHD2 has been solved and it contains an unstructured loop consisting of two proline-phenylalanine (PF) motifs: KPFRKLNPF. However, the other paralogs EHD1, EHD3 ...


Rational Drug Design Directed At Blocking The Initial Signaling Events In Lipopolysaccharide-Induced Sepsis., Christopher A. Tipton 2017 University of Missouri - St. Louis

Rational Drug Design Directed At Blocking The Initial Signaling Events In Lipopolysaccharide-Induced Sepsis., Christopher A. Tipton

Theses

Systemic Inflammatory Response Syndrome (SIRS) is classified as an immune system response to an infectious state. If left untreated, SIRS leads to sepsis, septic shock, end-organ dysfunction, and death. As a patient progresses through these stages, associations of acute respiratory distress, disseminated intravascular coagulation, and acute renal failure persist, resulting in millions of deaths annually. Lipopolysaccharide (LPS), a bacterial endotoxin, is released into the blood stream, triggering SIRS. LPS is found in the outer cell-wall of Gram-negative bacteria and is responsible for initiation of a devastating cytokine storm. One of the regions of LPS, lipid A, is a polyacylated glucosamine ...


Hypothalamic Ampk-Er Stress-Jnk1 Axis Mediates The Central Actions Of Thyroid Hormones On Energy Balance, Noelia Martinez-Sanchez, Roger J. Davis, Miguel Lopez 2017 University of Santiago de Compostela

Hypothalamic Ampk-Er Stress-Jnk1 Axis Mediates The Central Actions Of Thyroid Hormones On Energy Balance, Noelia Martinez-Sanchez, Roger J. Davis, Miguel Lopez

UMass Metabolic Network Publications

Thyroid hormones (THs) act in the brain to modulate energy balance. We show that central triiodothyronine (T3) regulates de novo lipogenesis in liver and lipid oxidation in brown adipose tissue (BAT) through the parasympathetic (PSNS) and sympathetic nervous system (SNS), respectively. Central T3 promotes hepatic lipogenesis with parallel stimulation of the thermogenic program in BAT. The action of T3 depends on AMP-activated protein kinase (AMPK)-induced regulation of two signaling pathways in the ventromedial nucleus of the hypothalamus (VMH): decreased ceramide-induced endoplasmic reticulum (ER) stress, which promotes BAT thermogenesis, and increased c-Jun N-terminal kinase (JNK) activation, which controls hepatic lipid ...


The Chondrocyte Channelome: A Novel Ion Channel Candidate In The Pathogenesis Of Pectus Deformities, Anthony J. Asmar 2017 Old Dominion University

The Chondrocyte Channelome: A Novel Ion Channel Candidate In The Pathogenesis Of Pectus Deformities, Anthony J. Asmar

Biological Sciences Theses & Dissertations

Costal cartilage is a type of rod-like hyaline cartilage connecting the ribs to the sternum. The chest wall deformities pectus excavatum (PE) and pectus carinatum (PC) involve displacement of the sternum causing a depression or protrusion of the chest. There is little knowledge about costal cartilage and pectus deformities with much of its understanding based on assumptions from articular cartilage. Chondrocytes are subjected to a constantly changing environment with fluctuations in pH and osmolarity. Ion channels detect these changes and in turn regulate proliferation, differentiation, and extracellular matrix production. Using ion channel qPCR arrays, we produced expression profiles for normal ...


Efficient Heterocyclisation By (Di)Terpene Synthases, S. Mafu, K. C. Potter, M. L. Hillwig, S. Schulte, J. Criswell, R. J. Peters 2017 Iowa State University

Efficient Heterocyclisation By (Di)Terpene Synthases, S. Mafu, K. C. Potter, M. L. Hillwig, S. Schulte, J. Criswell, R. J. Peters

Reuben J. Peters

While cyclic ether forming terpene synthases are known, the basis for such heterocyclisation is unclear. Here it is reported that numerous (di)terpene synthases, particularly including the ancestral ent-kaurene synthase, efficiently produce isomers of manoyl oxide from the stereochemically appropriate substrate. Accordingly, such heterocyclisation is easily accomplished by terpene synthases. Indeed, the use of single residue changes to induce production of the appropriate substrate in the upstream active site leads to efficient bifunctional enzymes producing isomers of manoyl oxide, representing novel enzymatic activity.


Blocking Deprotonation With Retention Of Aromaticity In A Plant Ent-Copalyl Diphosphate Synthase Leads To Product Rearrangement, Kevin C. Potter, Jiachen Zi, Young J. Hong, Samuel Schulte, Brandi Malchow, Dean J. Tantillo, Reuben J. Peters 2017 Iowa State University

Blocking Deprotonation With Retention Of Aromaticity In A Plant Ent-Copalyl Diphosphate Synthase Leads To Product Rearrangement, Kevin C. Potter, Jiachen Zi, Young J. Hong, Samuel Schulte, Brandi Malchow, Dean J. Tantillo, Reuben J. Peters

Reuben J. Peters

Biosynthesis of the labdane-related diterpenoids, a large superfamily of over 7,000 natural products, is characterized by the use of class II diterpene cyclases.[1] The vast majority of these biocatalysts are exclusively found in plants, stemming from repeated evolutionary diversification of the ent-copalyl diphosphate synthase (CPS) required for gibberellin phytohormone biosynthesis – i.e., via gene duplication and neofunctionalization.[2] As implied by this evolutionary scenario, these enzymes must exhibit catalytic plasticity that enables new products to readily arise. Consistent with this hypothesis, we have shown that substitution of smaller residues for the catalytic base group can lead to the ...


A Single Residue Switch Converts Abietadiene Synthase Into A Pimaradiene Specific Cyclase, P. Ross Wilderman, Reuben J. Peters 2017 Iowa State University

A Single Residue Switch Converts Abietadiene Synthase Into A Pimaradiene Specific Cyclase, P. Ross Wilderman, Reuben J. Peters

Reuben J. Peters

Terpene synthases often catalyze complex cyclization reactions that typically represent the committed step in particular biosynthetic pathways, leading to great interest in their enzymatic mechanisms. We have recently demonstrated that substitution of a specific Ile with Thr was sufficient to “short circuit” the complex cyclization reaction normally catalyzed by ent-kaurene synthases to instead produce ent-pimaradiene. Here we report that the complex cyclization/rearrangement reaction catalyzed by abietadiene synthase can be similarly cut short to produce pimaradienes by an analogous Ser for Ala change, albeit with a slight shift in active site location to accommodate the difference in substrate stereochemistry. This ...


Strand-Specific Libraries For High Throughput Rna Sequencing (Rna-Seq) Prepared Without Poly(A) Selection, Zhao Zhang, William E. Theurkauf, Zhiping Weng, Phillip D. Zamore 2017 University of Massachusetts Medical School

Strand-Specific Libraries For High Throughput Rna Sequencing (Rna-Seq) Prepared Without Poly(A) Selection, Zhao Zhang, William E. Theurkauf, Zhiping Weng, Phillip D. Zamore

Zhao Zhang

BACKGROUND: High throughput DNA sequencing technology has enabled quantification of all the RNAs in a cell or tissue, a method widely known as RNA sequencing (RNA-Seq). However, non-coding RNAs such as rRNA are highly abundant and can consume >70% of sequencing reads. A common approach is to extract only polyadenylated mRNA; however, such approaches are blind to RNAs with short or no poly(A) tails, leading to an incomplete view of the transcriptome. Another challenge of preparing RNA-Seq libraries is to preserve the strand information of the RNAs. DESIGN: Here, we describe a procedure for preparing RNA-Seq libraries from 1 ...


Mixing Considerations In Stirred Tank Bioreactors When Using Fluid Property Altering Microorganisms, Enes Kadic, Theodore J. Heindel 2017 Iowa State University

Mixing Considerations In Stirred Tank Bioreactors When Using Fluid Property Altering Microorganisms, Enes Kadic, Theodore J. Heindel

Theodore J. Heindel

Stirred tank reactors are one of the standard reactors in the chemical industry and have been widely implemented for biological applications. They are used with viscous liquids, slurries, very low gas flow rates, and large liquid volumes. Stirred tank bioreactors are popular because a well-mixed state, required or preferred for numerous biological processes, is usually achieved in such situations; however, many production processes using microorganisms tend to experience fluid property alterations, which significantly impact mixing, operational parameters, and process results. The most troubling issues occur when a fluid gradually undergoes a viscosity change and/or slowly exhibits non-Newtonian behavior due ...


Investigating The Phylogenetic Range Of Gibberellin Biosynthesis In Bacteria, Raimund Nagel, Reuben J. Peters 2017 Iowa State University

Investigating The Phylogenetic Range Of Gibberellin Biosynthesis In Bacteria, Raimund Nagel, Reuben J. Peters

Reuben J. Peters

Certain plant-associated microbes can produce gibberellin (GA) phytohormones, as first described for the rice fungal pathogen Gibberella fujikuroi and, more recently, for bacteria, including several rhizobia and the rice bacterial pathogen Xanthomonas oryzae pv. oryzicola. The relevant enzymes are encoded by a biosynthetic operon that exhibits both a greater phylogenetic range and scattered distribution among plant-associated bacteria. Here, the phylogenetic distribution of this operon was investigated. To demonstrate conserved functionality, the enzymes encoded by the disparate operon from X. translucens pv. translucens, along with those from the most divergent example, found in Erwinia tracheiphila, were biochemically characterized. In both of ...


Edaxadiene: A New Bioactive Diterpene From Mycobacterium Tuberculosis, Francis M. Mann, Meimei Xu, Xiaoming Chen, D. Bruce Fulton, David G. Russell, Reuben J. Peters 2017 Iowa State University

Edaxadiene: A New Bioactive Diterpene From Mycobacterium Tuberculosis, Francis M. Mann, Meimei Xu, Xiaoming Chen, D. Bruce Fulton, David G. Russell, Reuben J. Peters

Reuben J. Peters

Mycobacterium tuberculosis remains a widespread and devastating human pathogen. Presented here is the characterization of an atypical class I diterpene cyclase from M. tuberculosis that catalyzes an unusual cyclization reaction in converting the known M. tuberculosis metabolite halimadienyl diphosphate to a further cyclized novel diterpene, which we have termed edaxadiene, as it directly inhibits maturation of the phagosomal compartment in which the bacterium is taken up during infection.


Increasing Diterpene Yield With A Modular Metabolic Engineering System In E. Coli: Comparison Of Mev And Mep Isoprenoid Precursor Pathway Engineering, Dana Morrone, Luke Lowry, Mara K. Determan, David M. Hershey, Meimei Xu, Reuben J. Peters 2017 Iowa State University

Increasing Diterpene Yield With A Modular Metabolic Engineering System In E. Coli: Comparison Of Mev And Mep Isoprenoid Precursor Pathway Engineering, Dana Morrone, Luke Lowry, Mara K. Determan, David M. Hershey, Meimei Xu, Reuben J. Peters

Reuben J. Peters

Engineering biosynthetic pathways in heterologous microbial host organisms offers an elegant approach to pathway elucidation via the incorporation of putative biosynthetic enzymes and characterization of resulting novel metabolites. Our previous work in Escherichia coli demonstrated the feasibility of a facile modular approach to engineering the production of labdane-related diterpene (20 carbon) natural products. However, yield was limited (<0.1 mg/L), presumably due to reliance on endogenous production of the isoprenoid precursors dimethylallyl diphosphate and isopentenyl diphosphate. Here, we report incorporation of either a heterologous mevalonate pathway (MEV) or enhancement of the endogenous methyl erythritol phosphate pathway (MEP) with our modular metabolic engineering system. With MEP pathway enhancement, it was found that pyruvate supplementation of rich media and simultaneous overexpression of three genes (idi, dxs, and dxr) resulted in the greatest increase in diterpene yield, indicating distributed metabolic control within this pathway. Incorporation of a heterologous MEV pathway in bioreactor grown cultures resulted in significantly higher yields than MEP pathway enhancement. We have established suitable growth conditions for diterpene production levels ranging from 10 to >100 mg/L of E. coli culture. These amounts are sufficient for nuclear magnetic resonance analyses, enabling characterization of enzymatic products and hence, pathway elucidation. Furthermore, these results represent an up to >1,000-fold improvement in diterpene production from our facile, modular platform ...


Safety And Potential Efficacy Of Gemfibrozil As A Supportive Treatment For Children With Late Infantile Neuronal Ceroid Lipofuscinosis And Other Lipid Storage Disorders., Kyeongsoon Kim, Hynda K Kleinman, Hahn-Jun Lee, Kalipada Pahan 2017 George Washington University

Safety And Potential Efficacy Of Gemfibrozil As A Supportive Treatment For Children With Late Infantile Neuronal Ceroid Lipofuscinosis And Other Lipid Storage Disorders., Kyeongsoon Kim, Hynda K Kleinman, Hahn-Jun Lee, Kalipada Pahan

Biochemistry and Molecular Medicine Faculty Publications

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more ...


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