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Results: 1 to 10 of 183

Publication Record


Hydrodynamic Renal Pelvis Injection for Non-viral Expression of Proteins in the Kidney.
Woodard LE, Welch RC, Williams FM, Luo W, Cheng J, Wilson MH
(2018) J Vis Exp :
MeSH Terms: Animals, DNA, Hydrodynamics, Injections, Kidney, Kidney Pelvis, Male, Mice, Plasmids, Protein Biosynthesis, Transfection, Transgenes
Show Abstract · Added March 14, 2018
Hydrodynamic injection creates a local, high-pressure environment to transfect various tissues with plasmid DNA and other substances. Hydrodynamic tail vein injection, for example, is a well-established method by which the liver can be transfected. This manuscript describes an application of hydrodynamic principles by injection of the mouse kidney directly with plasmid DNA for kidney-specific gene expression. Mice are anesthetized and the kidney is exposed by a flank incision followed by a fast injection of a plasmid DNA-containing solution directly into the renal pelvis. The needle is kept in place for ten seconds and the incision site is sutured. The following day, live animal imaging, Western blot, or immunohistochemistry may be used to assay gene expression, or other assays suited to the transgene of choice are used for detection of the protein of interest. Published methods to prolong gene expression include transposon-mediated transgene integration and cyclophosphamide treatment to inhibit the immune response to the transgene.
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2 Members
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12 MeSH Terms
High Dose Omega-3 Fatty Acid Administration and Skeletal Muscle Protein Turnover in Maintenance Hemodialysis Patients.
Deger SM, Hung AM, Ellis CD, Booker C, Bian A, Chen G, Abumrad NN, Ikizler TA
(2016) Clin J Am Soc Nephrol 11: 1227-35
MeSH Terms: Adult, Aged, Amino Acids, Blood Glucose, C-Reactive Protein, Dietary Supplements, Double-Blind Method, Fatty Acids, Omega-3, Female, Forearm, Humans, Inflammation, Insulin Resistance, Male, Middle Aged, Muscle Proteins, Muscle, Skeletal, Protein Biosynthesis, Renal Dialysis, Renal Insufficiency, Chronic
Show Abstract · Added July 1, 2016
BACKGROUND AND OBJECTIVES - Protein energy wasting and systemic inflammation are prevalent in maintenance hemodialysis (MHD) patients. Omega-3 (ω-3) fatty acids have anti-inflammatory properties and have been shown to improve protein homeostasis. We hypothesized that administration of high-dose (2.9 g/d) ω-3 would be associated with decreased muscle protein breakdown in MHD patients with systemic inflammation.
DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS - This is a substudy from a randomized, placebo-controlled study (NCT00655525). Patients were recruited between September 2008 and June 2011. Primary inclusion criteria included signs of chronic inflammation (average C-reactive protein of ≥5 mg/L over three consecutive measurements), lack of active infectious or inflammatory disease, no hospitalization within 1 month prior to the study, and not receiving steroids (>5 mg/d) and/or immunosuppressive agents. The primary outcomes were forearm muscle and whole body protein breakdown and synthesis before and after the intervention. The patients received ω-3 (n=11) versus placebo (n=9) for 12 weeks. Analysis of covariance was used to compare outcome variables at 12 weeks. Models were adjusted for a propensity score that was derived from age, sex, race, baseline high sensitivity C-reactive protein, diabetes mellitus, and fat mass because the groups were not balanced for several characteristics.
RESULTS - Compared with placebo, ω-3 supplementation was significantly associated with decreased muscle protein breakdown at 12 weeks (-31, [interquartile range, -98--13] versus 26 [interquartile range, 13-87] µg/100 ml per min; P=0.01), which remained significant after multivariate adjustment (-46, [95% confidence interval, -102 to -1] µg/100 ml per min). ω-3 Supplementation resulted in decreased forearm muscle protein synthesis while the rate in the placebo group increased; however, there is no longer a statistically significant difference in skeletal muscle protein synthesis or in net protein balance after multivariate adjustment. There was no statistically significant effect of ω-3 supplementation on whole body protein synthesis or breakdown.
CONCLUSIONS - High-dose ω-3 supplementation over 12 weeks in MHD patients with systemic inflammation was associated with attenuation of forearm muscle protein breakdown but did not influence skeletal muscle protein synthesis, skeletal muscle net protein balance or any component of the whole-body protein balance. These results should be interpreted cautiously given the imbalance in the two groups and the short duration of the intervention.
Copyright © 2016 by the American Society of Nephrology.
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2 Members
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20 MeSH Terms
Ubiquilin-mediated Small Molecule Inhibition of Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling.
Coffey RT, Shi Y, Long MJ, Marr MT, Hedstrom L
(2016) J Biol Chem 291: 5221-33
MeSH Terms: Adaptor Proteins, Signal Transducing, Arginine, Carbamates, Cell Line, Tumor, Cell Proliferation, Enzyme Inhibitors, HEK293 Cells, Humans, Mechanistic Target of Rapamycin Complex 1, Multiprotein Complexes, Phosphoproteins, Phosphorylation, Protein Binding, Protein Biosynthesis, Protein Processing, Post-Translational, Ribosomal Protein S6 Kinases, Signal Transduction, TOR Serine-Threonine Kinases, Ubiquitins
Show Abstract · Added May 9, 2016
Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism, growth, and proliferation. mTORC1 has been implicated in many diseases such as cancer, diabetes, and neurodegeneration, and is a target to prolong lifespan. Here we report a small molecule inhibitor (Cbz-B3A) of mTORC1 signaling. Cbz-B3A inhibits the phosphorylation of eIF4E-binding protein 1 (4EBP1) and blocks 68% of translation. In contrast, rapamycin preferentially inhibits the phosphorylation of p70(S6k) and blocks 35% of translation. Cbz-B3A does not appear to bind directly to mTORC1, but instead binds to ubiquilins 1, 2, and 4. Knockdown of ubiquilin 2, but not ubiquilins 1 and 4, decreases the phosphorylation of 4EBP1, suggesting that ubiquilin 2 activates mTORC1. The knockdown of ubiquilins 2 and 4 decreases the effect of Cbz-B3A on 4EBP1 phosphorylation. Cbz-B3A slows cellular growth of some human leukemia cell lines, but is not cytotoxic. Thus Cbz-B3A exemplifies a novel strategy to inhibit mTORC1 signaling that might be exploited for treating many human diseases. We propose that Cbz-B3A reveals a previously unappreciated regulatory pathway coordinating cytosolic protein quality control and mTORC1 signaling.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
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1 Members
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19 MeSH Terms
Cytoplasmic hGle1A regulates stress granules by modulation of translation.
Aditi , Folkmann AW, Wente SR
(2015) Mol Biol Cell 26: 1476-90
MeSH Terms: Cell Line, Cytoplasmic Granules, Down-Regulation, Humans, Nucleocytoplasmic Transport Proteins, Protein Biosynthesis, Protein Isoforms, Stress, Physiological
Show Abstract · Added February 15, 2016
When eukaryotic cells respond to stress, gene expression pathways change to selectively export and translate subsets of mRNAs. Translationally repressed mRNAs accumulate in cytoplasmic foci known as stress granules (SGs). SGs are in dynamic equilibrium with the translational machinery, but mechanisms controlling this are unclear. Gle1 is required for DEAD-box protein function during mRNA export and translation. We document that human Gle1 (hGle1) is a critical regulator of translation during stress. hGle1 is recruited to SGs, and hGLE1 small interfering RNA-mediated knockdown perturbs SG assembly, resulting in increased numbers of smaller SGs. The rate of SG disassembly is also delayed. Furthermore, SG hGle1-depletion defects correlate with translation perturbations, and the hGle1 role in SGs is independent of mRNA export. Interestingly, we observe isoform-specific roles for hGle1 in which SG function requires hGle1A, whereas mRNA export requires hGle1B. We find that the SG defects in hGle1-depleted cells are rescued by puromycin or DDX3 expression. Together with recent links of hGLE1 mutations in amyotrophic lateral sclerosis patients, these results uncover a paradigm for hGle1A modulating the balance between translation and SGs during stress and disease.
© 2015 Aditi et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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1 Members
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8 MeSH Terms
CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling.
Palubinsky AM, Stankowski JN, Kale AC, Codreanu SG, Singer RJ, Liebler DC, Stanwood GD, McLaughlin B
(2015) Antioxid Redox Signal 23: 535-49
MeSH Terms: Animals, Autophagy, Cell Hypoxia, Cells, Cultured, Glucose, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Dynamics, Neurons, Oxidation-Reduction, Protein Biosynthesis, Rats, Sprague-Dawley, Signal Transduction, Stress, Physiological, Ubiquitin-Protein Ligases
Show Abstract · Added January 26, 2015
AIMS - Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation.
RESULTS - We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTEN-inducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin-avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen-glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66(shc). Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis.
INNOVATION - CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD.
CONCLUSIONS - CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD.
1 Communities
3 Members
0 Resources
17 MeSH Terms
Metabolic compensation and circadian resilience in prokaryotic cyanobacteria.
Johnson CH, Egli M
(2014) Annu Rev Biochem 83: 221-47
MeSH Terms: Bacterial Proteins, Circadian Clocks, Circadian Rhythm, Circadian Rhythm Signaling Peptides and Proteins, Cyanobacteria, Feedback, Physiological, Gene Expression Regulation, Bacterial, Homeostasis, Protein Biosynthesis, Protein Processing, Post-Translational, Temperature, Transcription, Genetic
Show Abstract · Added June 26, 2014
For a biological oscillator to function as a circadian pacemaker that confers a fitness advantage, its timing functions must be stable in response to environmental and metabolic fluctuations. One such stability enhancer, temperature compensation, has long been a defining characteristic of these timekeepers. However, an accurate biological timekeeper must also resist changes in metabolism, and this review suggests that temperature compensation is actually a subset of a larger phenomenon, namely metabolic compensation, which maintains the frequency of circadian oscillators in response to a host of factors that impinge on metabolism and would otherwise destabilize these clocks. The circadian system of prokaryotic cyanobacteria is an illustrative model because it is composed of transcriptional and nontranscriptional oscillators that are coupled to promote resilience. Moreover, the cyanobacterial circadian program regulates gene activity and metabolic pathways, and it can be manipulated to improve the expression of bioproducts that have practical value.
0 Communities
1 Members
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12 MeSH Terms
One hundred million adenosine-to-inosine RNA editing sites: hearing through the noise.
Ulbricht RJ, Emeson RB
(2014) Bioessays 36: 730-5
MeSH Terms: Adenosine, Alu Elements, Animals, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Inosine, Protein Biosynthesis, RNA Editing, Sequence Analysis, RNA
Show Abstract · Added January 20, 2015
The most recent work toward compiling a comprehensive database of adenosine-to-inosine RNA editing events suggests that the potential for RNA editing is much more pervasive than previously thought; indeed, it is manifest in more than 100 million potential editing events located primarily within Alu repeat elements of the human transcriptome. Pairs of inverted Alu repeats are found in a substantial number of human genes, and when transcribed, they form long double-stranded RNA structures that serve as optimal substrates for RNA editing enzymes. A small subset of edited Alu elements has been shown to exhibit diverse functional roles in the regulation of alternative splicing, miRNA repression, and cis-regulation of distant RNA editing sites. The low level of editing for the remaining majority may be non-functional, yet their persistence in the primate genome provides enhanced genomic flexibility that may be required for adaptive evolution.
© 2014 WILEY Periodicals, Inc.
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1 Members
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10 MeSH Terms
Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy.
Non AL, Binder AM, Kubzansky LD, Michels KB
(2014) Epigenetics 9: 964-72
MeSH Terms: Antidepressive Agents, Anxiety, Case-Control Studies, Cell Division, Cohort Studies, CpG Islands, DNA Methylation, Depression, Female, Fetal Blood, Gene Expression Regulation, Gene Ontology, Genome, Human, Humans, Infant, Newborn, Male, Pregnancy, Pregnancy Complications, Prenatal Exposure Delayed Effects, Protein Biosynthesis, Serotonin Uptake Inhibitors
Show Abstract · Added January 20, 2015
Despite the high prevalence of depression, anxiety, and use of antidepressant medications during pregnancy, there is much uncertainty around the impact of high levels of distress or antidepressant medications on the developing fetus. These intrauterine exposures may lead to epigenetic alterations to the DNA during this vulnerable time of fetal development, which may have important lifetime health consequences. In this study we investigated patterns of genome-wide DNA methylation using the Illumina Infinium Human Methylation450 BeadChip in the umbilical cord blood of neonates exposed to non-medicated maternal depression or anxiety (n = 13), or selective serotonin reuptake inhibitors (SSRIs) during pregnancy (n = 22), relative to unexposed neonates (n = 23). We identified 42 CpG sites with significantly different DNA methylation levels in neonates exposed to non-medicated depression or anxiety relative to controls. CpG site methylation was not significantly different in neonates exposed to SSRIs relative to the controls, after adjusting for multiple comparisons. In neonates exposed either to non-medicated maternal depression or SSRIs, the vast majority of CpG sites displayed lower DNA methylation relative to the controls, but differences were very small. A gene ontology analysis suggests significant clustering of the top genes associated with non-medicated maternal depression/anxiety, related to regulation of transcription, translation, and cell division processes (e.g., negative regulation of translation in response to oxidative stress, regulation of mRNA export from the nucleus, regulation of stem cell division). While the functional consequences of these findings are yet to be determined, these small DNA methylation differences may suggest a possible role for epigenetic processes in the development of neonates exposed to non-medicated maternal depression/anxiety.
0 Communities
1 Members
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21 MeSH Terms
Two Arabidopsis loci encode novel eukaryotic initiation factor 4E isoforms that are functionally distinct from the conserved plant eukaryotic initiation factor 4E.
Patrick RM, Mayberry LK, Choy G, Woodard LE, Liu JS, White A, Mullen RA, Tanavin TM, Latz CA, Browning KS
(2014) Plant Physiol 164: 1820-30
MeSH Terms: Amino Acid Sequence, Arabidopsis, Arabidopsis Proteins, Biological Assay, Computer Simulation, Conserved Sequence, Electrophoresis, Polyacrylamide Gel, Eukaryotic Initiation Factor-4E, Eukaryotic Initiation Factor-4G, Genetic Complementation Test, Genetic Loci, Guanosine, Molecular Sequence Data, Phylogeny, Protein Binding, Protein Biosynthesis, Protein Isoforms, Saccharomyces cerevisiae, Self-Fertilization
Show Abstract · Added December 8, 2017
Canonical translation initiation in eukaryotes begins with the Eukaryotic Initiation Factor 4F (eIF4F) complex, made up of eIF4E, which recognizes the 7-methylguanosine cap of messenger RNA, and eIF4G, which serves as a scaffold to recruit other translation initiation factors that ultimately assemble the 80S ribosome. Many eukaryotes have secondary EIF4E genes with divergent properties. The model plant Arabidopsis (Arabidopsis thaliana) encodes two such genes in tandem loci on chromosome 1, EIF4E1B (At1g29550) and EIF4E1C (At1g29590). This work identifies EIF4E1B/EIF4E1C-type genes as a Brassicaceae-specific diverged form of EIF4E. There is little evidence for EIF4E1C gene expression; however, the EIF4E1B gene appears to be expressed at low levels in most tissues, though microarray and RNA Sequencing data support enrichment in reproductive tissue. Purified recombinant eIF4E1b and eIF4E1c proteins retain cap-binding ability and form functional complexes in vitro with eIF4G. The eIF4E1b/eIF4E1c-type proteins support translation in yeast (Saccharomyces cerevisiae) but promote translation initiation in vitro at a lower rate compared with eIF4E. Findings from surface plasmon resonance studies indicate that eIF4E1b and eIF4E1c are unlikely to bind eIF4G in vivo when in competition with eIF4E. This study concludes that eIF4E1b/eIF4E1c-type proteins, although bona fide cap-binding proteins, have divergent properties and, based on apparent limited tissue distribution in Arabidopsis, should be considered functionally distinct from the canonical plant eIF4E involved in translation initiation.
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1 Members
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19 MeSH Terms
The RNA-binding protein Fus directs translation of localized mRNAs in APC-RNP granules.
Yasuda K, Zhang H, Loiselle D, Haystead T, Macara IG, Mili S
(2013) J Cell Biol 203: 737-46
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Cytoplasmic Granules, Mice, NIH 3T3 Cells, Protein Biosynthesis, RNA, Messenger, RNA-Binding Protein FUS, Ribonucleoproteins
Show Abstract · Added March 20, 2014
RNA localization pathways direct numerous mRNAs to distinct subcellular regions and affect many physiological processes. In one such pathway the tumor-suppressor protein adenomatous polyposis coli (APC) targets RNAs to cell protrusions, forming APC-containing ribonucleoprotein complexes (APC-RNPs). Here, we show that APC-RNPs associate with the RNA-binding protein Fus/TLS (fused in sarcoma/translocated in liposarcoma). Fus is not required for APC-RNP localization but is required for efficient translation of associated transcripts. Labeling of newly synthesized proteins revealed that Fus promotes translation preferentially within protrusions. Mutations in Fus cause amyotrophic lateral sclerosis (ALS) and the mutant protein forms inclusions that appear to correspond to stress granules. We show that overexpression or mutation of Fus results in formation of granules, which preferentially recruit APC-RNPs. Remarkably, these granules are not translationally silent. Instead, APC-RNP transcripts are translated within cytoplasmic Fus granules. These results unexpectedly show that translation can occur within stress-like granules. Importantly, they identify a new local function for cytoplasmic Fus with implications for ALS pathology.
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1 Members
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9 MeSH Terms