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Gastroesophageal Reflux Induces Protein Adducts in the Esophagus.
Caspa Gokulan R, Adcock JM, Zagol-Ikapitte I, Mernaugh R, Williams P, Washington KM, Boutaud O, Oates JA, Dikalov SI, Zaika AI
(2019) Cell Mol Gastroenterol Hepatol 7: 480-482.e7
MeSH Terms: Acetylcysteine, Animals, Benzylamines, Bile Acids and Salts, Cell Line, Cyclic N-Oxides, Esophagus, Gastroesophageal Reflux, Humans, Lipids, Mice, Spin Labels, Tumor Suppressor Protein p53
Added March 26, 2019
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13 MeSH Terms
Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G
(2019) Dev Cell 48: 49-63.e7
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Lineage, Endocrine Cells, Homeodomain Proteins, Insulin-Secreting Cells, Islets of Langerhans, Mice, Nerve Tissue Proteins, Organogenesis, Pancreas, Transcription Factors
Show Abstract · Added February 6, 2019
In the developing pancreas, transient Neurog3-expressing progenitors give rise to four major islet cell types: α, β, δ, and γ; when and how the Neurog3 cells choose cell fate is unknown. Using single-cell RNA-seq, trajectory analysis, and combinatorial lineage tracing, we showed here that the Neurog3 cells co-expressing Myt1 (i.e., Myt1Neurog3) were biased toward β cell fate, while those not simultaneously expressing Myt1 (Myt1Neurog3) favored α fate. Myt1 manipulation only marginally affected α versus β cell specification, suggesting Myt1 as a marker but not determinant for islet-cell-type specification. The Myt1Neurog3 cells displayed higher Dnmt1 expression and enhancer methylation at Arx, an α-fate-promoting gene. Inhibiting Dnmts in pancreatic progenitors promoted α cell specification, while Dnmt1 overexpression or Arx enhancer hypermethylation favored β cell production. Moreover, the pancreatic progenitors contained distinct Arx enhancer methylation states without transcriptionally definable sub-populations, a phenotype independent of Neurog3 activity. These data suggest that Neurog3-independent methylation on fate-determining gene enhancers specifies distinct endocrine-cell programs.
Published by Elsevier Inc.
1 Communities
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13 MeSH Terms
Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.
Egnatchik RA, Leamy AK, Sacco SA, Cheah YE, Shiota M, Young JD
(2019) J Biol Chem 294: 3081-3090
MeSH Terms: Animals, Aspartate Aminotransferases, Cell Death, Cell Line, Citric Acid Cycle, Extracellular Space, Glutamine, Hepatocytes, Ketoglutaric Acids, Male, Oxidative Stress, Oxygen, Palmitates, Rats, Rats, Sprague-Dawley
Show Abstract · Added March 28, 2019
Hepatocyte lipotoxicity is characterized by aberrant mitochondrial metabolism, which predisposes cells to oxidative stress and apoptosis. Previously, we reported that translocation of calcium from the endoplasmic reticulum to mitochondria of palmitate-treated hepatocytes activates anaplerotic flux from glutamine to α-ketoglutarate (αKG), which subsequently enters the citric acid cycle (CAC) for oxidation. We hypothesized that increased glutamine anaplerosis fuels elevations in CAC flux and oxidative stress following palmitate treatment. To test this hypothesis, primary rat hepatocytes or immortalized H4IIEC3 rat hepatoma cells were treated with lipotoxic levels of palmitate while modulating anaplerotic pathways leading to αKG. We found that culture media supplemented with glutamine, glutamate, or dimethyl-αKG increased palmitate lipotoxicity compared with media that lacked these anaplerotic substrates. Knockdown of glutamate-oxaloacetate transaminase activity significantly reduced the lipotoxic effects of palmitate, whereas knockdown of glutamate dehydrogenase (Glud1) had no effect on palmitate lipotoxicity. C flux analysis of H4IIEC3 cells co-treated with palmitate and the pan-transaminase inhibitor aminooxyacetic acid confirmed that reductions in lipotoxic markers were associated with decreases in anaplerosis, CAC flux, and oxygen consumption. Taken together, these results demonstrate that lipotoxic palmitate treatments enhance anaplerosis in cultured rat hepatocytes, causing a shift to aberrant transaminase metabolism that fuels CAC dysregulation and oxidative stress.
© 2019 Egnatchik et al.
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15 MeSH Terms
Muscle-specific stress fibers give rise to sarcomeres in cardiomyocytes.
Fenix AM, Neininger AC, Taneja N, Hyde K, Visetsouk MR, Garde RJ, Liu B, Nixon BR, Manalo AE, Becker JR, Crawley SW, Bader DM, Tyska MJ, Liu Q, Gutzman JH, Burnette DT
(2018) Elife 7:
MeSH Terms: Actin Cytoskeleton, Actins, Cell Line, Cell Line, Tumor, HeLa Cells, Humans, Microfilament Proteins, Microscopy, Confocal, Molecular Motor Proteins, Muscle Fibers, Skeletal, Myocytes, Cardiac, Myosin Heavy Chains, Nonmuscle Myosin Type IIB, RNA Interference, Sarcomeres, Stress Fibers
Show Abstract · Added March 27, 2019
The sarcomere is the contractile unit within cardiomyocytes driving heart muscle contraction. We sought to test the mechanisms regulating actin and myosin filament assembly during sarcomere formation. Therefore, we developed an assay using human cardiomyocytes to monitor sarcomere assembly. We report a population of muscle stress fibers, similar to actin arcs in non-muscle cells, which are essential sarcomere precursors. We show sarcomeric actin filaments arise directly from muscle stress fibers. This requires formins (e.g., FHOD3), non-muscle myosin IIA and non-muscle myosin IIB. Furthermore, we show short cardiac myosin II filaments grow to form ~1.5 μm long filaments that then 'stitch' together to form the stack of filaments at the core of the sarcomere (i.e., the A-band). A-band assembly is dependent on the proper organization of actin filaments and, as such, is also dependent on FHOD3 and myosin IIB. We use this experimental paradigm to present evidence for a unifying model of sarcomere assembly.
© 2018, Fenix et al.
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16 MeSH Terms
A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions.
Goo L, Debbink K, Kose N, Sapparapu G, Doyle MP, Wessel AW, Richner JM, Burgomaster KE, Larman BC, Dowd KA, Diamond MS, Crowe JE, Pierson TC
(2019) Nat Microbiol 4: 71-77
MeSH Terms: Aedes, Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Cell Line, Cercopithecus aethiops, HEK293 Cells, Humans, Male, Mice, Mice, Inbred C57BL, Protein Domains, Vero Cells, Viral Envelope Proteins, West Nile Fever, West Nile Virus Vaccines, West Nile virus
Show Abstract · Added March 31, 2019
West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions.
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18 MeSH Terms
Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection.
Kinchen VJ, Zahid MN, Flyak AI, Soliman MG, Learn GH, Wang S, Davidson E, Doranz BJ, Ray SC, Cox AL, Crowe JE, Bjorkman PJ, Shaw GM, Bailey JR
(2018) Cell Host Microbe 24: 717-730.e5
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibody Specificity, Base Sequence, Binding Sites, Cell Line, Cricetulus, Epitopes, Female, HEK293 Cells, HIV-1, Hepacivirus, Hepatitis C, Hepatitis C Antibodies, Humans, Immunologic Memory, Male, Models, Molecular, Mutagenesis, Site-Directed, Viral Envelope Proteins, Viral Load
Show Abstract · Added March 31, 2019
The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable.
Copyright © 2018 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Activated CaMKII Binds to the mGlu Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.
Marks CR, Shonesy BC, Wang X, Stephenson JR, Niswender CM, Colbran RJ
(2018) Mol Pharmacol 94: 1352-1362
MeSH Terms: Animals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calmodulin, Cell Line, Cell Membrane, Female, HEK293 Cells, Humans, Immunoprecipitation, Male, Mice, Mice, Knockout, Protein Binding, Receptor, Metabotropic Glutamate 5, Signal Transduction
Show Abstract · Added November 8, 2018
Ca/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu is present in CaMKII complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu directly interacts with purified Thr286-autophosphorylated (activated) CaMKII However, the binding of CaMKII to this CTD fragment is reduced by the addition of excess Ca/calmodulin or by additional CaMKII autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKII is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKII with full-length mGlu expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKII with mGlu in heterologous cells. First, cell-surface biotinylation studies showed that CaMKII increases the surface expression of mGlu Second, using Ca fluorimetry and single-cell Ca imaging, we found that CaMKII reduces the initial peak of mGlu-mediated Ca mobilization by about 25% while doubling the relative duration of the Ca signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.
Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.
1 Communities
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16 MeSH Terms
Photostable, hydrophilic, and near infrared quaterrylene-based dyes for photoacoustic imaging.
Yu J, Pin S, Lin X, Su M, Bai M, Kim K
(2018) Mater Sci Eng C Mater Biol Appl 93: 1012-1019
MeSH Terms: Cell Line, Tumor, Contrast Media, Dendrimers, Fluorescent Dyes, Humans, Infrared Rays, Optical Imaging, Photoacoustic Techniques
Show Abstract · Added April 2, 2019
Novel near-infrared contrast agents based on the quaterrylene structure were strategically developed and tested for high photo-stability. Both a dendrimeric quaterrylene molecule, QR-G2-COOH, and a small molecule cationic quaterrylene dye, QR-4PyC4, remain optically stable and continue to generate a competitive photoacoustic response when irradiated by short near-infrared laser pulses for a relatively long time in an in-vitro cell study, unlike indocyanine green that rapidly decreases photoacoustic signal amplitude. The small molecule dye, QR-4PyC4 exhibits not only significantly higher cellular uptake rate than QR-G2-COOH and indocyanine green, but also low toxicity at a concentration of up to 10 μM. The dendrimeric dye, QR-G2-COOH that has surface functional groups available for conjugation with targeting and therapeutic agents shows the highest photoacoustic amplitude with high optical stability. Therefore, QR-4PyC4 can be a promising universal, sensitive and reliable photoacoustic contrast agent and QR-G2-COOH has great potential as a nano-platform with stable photoacoustic imaging capability.
Copyright © 2018 Elsevier B.V. All rights reserved.
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MeSH Terms
CRISPR/Cas9 engineering of a KIM-1 reporter human proximal tubule cell line.
Veach RA, Wilson MH
(2018) PLoS One 13: e0204487
MeSH Terms: Acute Kidney Injury, CRISPR-Cas Systems, Cell Line, Cisplatin, Gene Knock-In Techniques, Gene Targeting, Genes, Reporter, Genetic Engineering, Glucose, Green Fluorescent Proteins, Hepatitis A Virus Cellular Receptor 1, Homologous Recombination, Humans, Kidney Tubules, Proximal, Luciferases, Up-Regulation
Show Abstract · Added December 13, 2018
We used the CRISPR/Cas9 system to knock-in reporter transgenes at the kidney injury molecule-1 (KIM-1) locus and isolated human proximal tubule cell (HK-2) clones. PCR verified targeted knock-in of the luciferase and eGFP reporter at the KIM-1 locus. HK-2-KIM-1 reporter cells responded to various stimuli including hypoxia, cisplatin, and high glucose, indicative of upregulation of KIM-1 expression. We attempted using CRISPR/Cas9 to also engineer the KIM-1 reporter in telomerase-immortalized human RPTEC cells. However, these cells demonstrated an inability to undergo homologous recombination at the target locus. KIM-1-reporter human proximal tubular cells could be valuable tools in drug discovery for molecules inhibiting kidney injury. Additionally, our gene targeting strategy could be used in other cell lines to evaluate the biology of KIM-1 in vitro or in vivo.
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16 MeSH Terms
Combined CB2 receptor agonist and photodynamic therapy synergistically inhibit tumor growth in triple negative breast cancer.
Zhang J, Zhang S, Liu Y, Su M, Ling X, Liu F, Ge Y, Bai M
(2018) Photodiagnosis Photodyn Ther 24: 185-191
MeSH Terms: Acetamides, Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Combined Modality Therapy, Female, Gene Expression Regulation, Neoplastic, Humans, Indoles, Mice, Neoplasm Recurrence, Local, Phenyl Ethers, Photochemotherapy, Photosensitizing Agents, Quality of Life, Receptor, Cannabinoid, CB2, Receptors, GABA, Singlet Oxygen, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because it is more aggressive, diagnosed at later stage and more likely to develop local and systemic recurrence. Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life. Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC. This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CBR, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CBR agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth. This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CBR agonists for cancer.
Copyright © 2018 Elsevier B.V. All rights reserved.
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22 MeSH Terms