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infection damages colonic stem cells via TcdB, impairing epithelial repair and recovery from disease.
Mileto SJ, Jardé T, Childress KO, Jensen JL, Rogers AP, Kerr G, Hutton ML, Sheedlo MJ, Bloch SC, Shupe JA, Horvay K, Flores T, Engel R, Wilkins S, McMurrick PJ, Lacy DB, Abud HE, Lyras D
(2020) Proc Natl Acad Sci U S A 117: 8064-8073
MeSH Terms: Animals, Bacterial Proteins, Bacterial Toxins, Cells, Cultured, Clostridium Infections, Clostridium difficile, Colon, Disease Models, Animal, Female, Frizzled Receptors, Humans, Intestinal Mucosa, Mice, Organoids, Primary Cell Culture, Recombinant Proteins, Stem Cells
Show Abstract · Added March 24, 2020
Gastrointestinal infections often induce epithelial damage that must be repaired for optimal gut function. While intestinal stem cells are critical for this regeneration process [R. C. van der Wath, B. S. Gardiner, A. W. Burgess, D. W. Smith, 8, e73204 (2013); S. Kozar , 13, 626-633 (2013)], how they are impacted by enteric infections remains poorly defined. Here, we investigate infection-mediated damage to the colonic stem cell compartment and how this affects epithelial repair and recovery from infection. Using the pathogen we show that infection disrupts murine intestinal cellular organization and integrity deep into the epithelium, to expose the otherwise protected stem cell compartment, in a TcdB-mediated process. Exposure and susceptibility of colonic stem cells to intoxication compromises their function during infection, which diminishes their ability to repair the injured epithelium, shown by altered stem cell signaling and a reduction in the growth of colonic organoids from stem cells isolated from infected mice. We also show, using both mouse and human colonic organoids, that TcdB from epidemic ribotype 027 strains does not require Frizzled 1/2/7 binding to elicit this dysfunctional stem cell state. This stem cell dysfunction induces a significant delay in recovery and repair of the intestinal epithelium of up to 2 wk post the infection peak. Our results uncover a mechanism by which an enteric pathogen subverts repair processes by targeting stem cells during infection and preventing epithelial regeneration, which prolongs epithelial barrier impairment and creates an environment in which disease recurrence is likely.
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17 MeSH Terms
Probing biophysical sequence constraints within the transmembrane domains of rhodopsin by deep mutational scanning.
Penn WD, McKee AG, Kuntz CP, Woods H, Nash V, Gruenhagen TC, Roushar FJ, Chandak M, Hemmerich C, Rusch DB, Meiler J, Schlebach JP
(2020) Sci Adv 6: eaay7505
MeSH Terms: Cell Membrane, Gene Expression, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Lipid Bilayers, Models, Molecular, Mutation, Protein Domains, Protein Folding, Protein Structure, Secondary, Recombinant Proteins, Rhodopsin, Solubility, Thermodynamics
Show Abstract · Added March 21, 2020
Membrane proteins must balance the sequence constraints associated with folding and function against the hydrophobicity required for solvation within the bilayer. We recently found the expression and maturation of rhodopsin are limited by the hydrophobicity of its seventh transmembrane domain (TM7), which contains polar residues that are essential for function. On the basis of these observations, we hypothesized that rhodopsin's expression should be less tolerant of mutations in TM7 relative to those within hydrophobic TM domains. To test this hypothesis, we used deep mutational scanning to compare the effects of 808 missense mutations on the plasma membrane expression of rhodopsin in HEK293T cells. Our results confirm that a higher proportion of mutations within TM7 (37%) decrease rhodopsin's plasma membrane expression relative to those within a hydrophobic TM domain (TM2, 25%). These results in conjunction with an evolutionary analysis suggest solvation energetics likely restricts the evolutionary sequence space of polar TM domains.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
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15 MeSH Terms
Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment.
Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS
(2019) Appl Microbiol Biotechnol 103: 6711-6723
MeSH Terms: Acyltransferases, Animals, Anti-Bacterial Agents, Anti-Obesity Agents, Arabidopsis, Diet, High-Fat, Disease Models, Animal, Escherichia coli, Humans, Metabolic Engineering, Mice, Obesity, Phosphatidylethanolamines, Plant Proteins, Probiotics, Recombinant Proteins, Treatment Outcome
Show Abstract · Added July 17, 2019
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.
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17 MeSH Terms
Crystal structure of the SH3 domain of human Lyn non-receptor tyrosine kinase.
Berndt S, Gurevich VV, Iverson TM
(2019) PLoS One 14: e0215140
MeSH Terms: Crystallography, X-Ray, Humans, Mutation, Neoplasms, Protein Structure, Tertiary, Recombinant Proteins, src Homology Domains, src-Family Kinases
Show Abstract · Added March 18, 2020
Lyn kinase (Lck/Yes related novel protein tyrosine kinase) belongs to the family of Src-related non-receptor tyrosine kinases. Consistent with physiological roles in cell growth and proliferation, aberrant function of Lyn is associated with various forms of cancer, including leukemia, breast cancer and melanoma. Here, we determine a 1.3 Å resolution crystal structure of the polyproline-binding SH3 regulatory domain of human Lyn kinase, which adopts a five-stranded β-barrel fold. Mapping of cancer-associated point mutations onto this structure reveals that these amino acid substitutions are distributed throughout the SH3 domain and may affect Lyn kinase function distinctly.
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Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains.
Turner HL, Pallesen J, Lang S, Bangaru S, Urata S, Li S, Cottrell CA, Bowman CA, Crowe JE, Wilson IA, Ward AB
(2019) PLoS Biol 17: e3000139
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Neutralizing, Antibody Specificity, Baculoviridae, Binding Sites, Cloning, Molecular, Cryoelectron Microscopy, Gene Expression, Hemagglutinin Glycoproteins, Influenza Virus, Hydrogen Bonding, Immunoglobulin Fab Fragments, Influenza A virus, Molecular Docking Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Recombinant Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Sf9 Cells, Spodoptera
Show Abstract · Added March 31, 2019
Seasonal influenza virus infections can cause significant morbidity and mortality, but the threat from the emergence of a new pandemic influenza strain might have potentially even more devastating consequences. As such, there is intense interest in isolating and characterizing potent neutralizing antibodies that target the hemagglutinin (HA) viral surface glycoprotein. Here, we use cryo-electron microscopy (cryoEM) to decipher the mechanism of action of a potent HA head-directed monoclonal antibody (mAb) bound to an influenza H7 HA. The epitope of the antibody is not solvent accessible in the compact, prefusion conformation that typifies all HA structures to date. Instead, the antibody binds between HA head protomers to an epitope that must be partly or transiently exposed in the prefusion conformation. The "breathing" of the HA protomers is implied by the exposure of this epitope, which is consistent with metastability of class I fusion proteins. This structure likely therefore represents an early structural intermediate in the viral fusion process. Understanding the extent of transient exposure of conserved neutralizing epitopes also may lead to new opportunities to combat influenza that have not been appreciated previously.
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23 MeSH Terms
In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model.
Patel A, Park DH, Davis CW, Smith TRF, Leung A, Tierney K, Bryan A, Davidson E, Yu X, Racine T, Reed C, Gorman ME, Wise MC, Elliott STC, Esquivel R, Yan J, Chen J, Muthumani K, Doranz BJ, Saphire EO, Crowe JE, Broderick KE, Kobinger GP, He S, Qiu X, Kobasa D, Humeau L, Sardesai NY, Ahmed R, Weiner DB
(2018) Cell Rep 25: 1982-1993.e4
MeSH Terms: Animals, Antibodies, Monoclonal, DNA, Disease Models, Animal, Ebolavirus, Epitope Mapping, Epitopes, Female, Glycoproteins, HEK293 Cells, Hemorrhagic Fever, Ebola, Humans, Mice, Inbred BALB C, Muscles, Mutagenesis, Recombinant Proteins
Show Abstract · Added March 31, 2019
Synthetically engineered DNA-encoded monoclonal antibodies (DMAbs) are an in vivo platform for evaluation and delivery of human mAb to control against infectious disease. Here, we engineer DMAbs encoding potent anti-Zaire ebolavirus (EBOV) glycoprotein (GP) mAbs isolated from Ebola virus disease survivors. We demonstrate the development of a human IgG1 DMAb platform for in vivo EBOV-GP mAb delivery and evaluation in a mouse model. Using this approach, we show that DMAb-11 and DMAb-34 exhibit functional and molecular profiles comparable to recombinant mAb, have a wide window of expression, and provide rapid protection against lethal mouse-adapted EBOV challenge. The DMAb platform represents a simple, rapid, and reproducible approach for evaluating the activity of mAb during clinical development. DMAbs have the potential to be a mAb delivery system, which may be advantageous for protection against highly pathogenic infectious diseases, like EBOV, in resource-limited and other challenging settings.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Localized low-dose rhBMP-2 is effective at promoting bone regeneration in mandibular segmental defects.
Carlisle P, Guda T, Silliman DT, Burdette AJ, Talley AD, Alvarez R, Tucker D, Hale RG, Guelcher SA, BrownBaer PR
(2019) J Biomed Mater Res B Appl Biomater 107: 1491-1503
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Bone Regeneration, Calcium Phosphates, Drug Delivery Systems, Durapatite, Humans, Mandible, Mandibular Injuries, Recombinant Proteins, Swine, Swine, Miniature, Tomography, X-Ray Computed
Show Abstract · Added March 20, 2020
At least 26% of recent battlefield injuries are to the craniomaxillofacial (CMF) region. Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used to treat CMF open fractures, but several complications have been associated with its use. This study tested the efficacy and safety of a lower (30% recommended) dose of rhBMP-2 to treat mandibular fractures. rhBMP-2 delivered via a polyurethane (PUR) and hydroxyapatite/β-tricalcium phosphate (Mastergraft®) scaffold was evaluated in a 2 cm segmental mandibular defect in minipigs. Bone regeneration was analyzed at 4, 8, and 12 weeks postsurgery using clinical computed tomography (CT) and rhBMP-2, and inflammatory marker concentrations were analyzed in serum and surgery-site drain effluent. CT scans revealed that pigs treated with PUR-Mastergraft® + rhBMP-2 had complete bone bridging, while the negative control group showed incomplete bone-bridging (n = 6). Volumetric analysis of regenerated bone showed that the PUR-Mastergraft® + rhBMP-2 treatment generated significantly more bone than control by 4 weeks, a trend that continued through 12 weeks. Variations in inflammatory analytes were detected in drain effluent samples and saliva but not in serum, suggesting a localized healing response. Importantly, the rhBMP-2 group did not exhibit an excessive increase in inflammatory analytes compared to control. Treatment with low-dose rhBMP-2 increases bone regeneration capacity in pigs with mandibular continuity defects and restores bone quality. Negative complications from rhBMP-2, such as excessive inflammatory analyte levels, were not observed. Together, these results suggest that treatment with low-dose rhBMP-2 is efficacious and may improve safety when treating CMF open fractures. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1491-1503, 2019.
© 2018 Wiley Periodicals, Inc.
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13 MeSH Terms
Injectable, compression-resistant polymer/ceramic composite bone grafts promote lateral ridge augmentation without protective mesh in a canine model.
Talley AD, Boller LA, Kalpakci KN, Shimko DA, Cochran DL, Guelcher SA
(2018) Clin Oral Implants Res 29: 592-602
MeSH Terms: Alveolar Process, Alveolar Ridge Augmentation, Animals, Bone Morphogenetic Protein 2, Bone Transplantation, Ceramics, Dental Materials, Dogs, Male, Polymers, Rabbits, Recombinant Proteins, X-Ray Microtomography
Show Abstract · Added March 20, 2020
OBJECTIVE - The objective of this study was to test the hypothesis that a compression-resistant bone graft augmented with recombinant human morphogenetic protein-2 (rhBMP-2) will promote lateral ridge augmentation without the use of protective mesh in a canine model.
MATERIALS & METHODS - Compression-resistant (CR) bone grafts were evaluated in a canine model of lateral ridge augmentation. Bilateral, right trapezoidal prism-shaped defects (13-14 mm long × 8-9 mm wide × 3-4 mm deep at the base) in 13 hounds (two defects per hound) were treated with one of four groups: (i) absorbable collagen sponge + 400 μg rhBMP-2/ml (ACS, clinical control) protected by titanium mesh, (ii) CR without rhBMP-2 (CR, negative control), (iii) CR + 200 μg rhBMP-2 (CR-L), or (iv) CR + 400 μg rhBMP-2 (CR-H). All animals were euthanized after 16 weeks. Ridge height and width and new bone formation were assessed by μCT, histology, and histomorphometry. The release kinetics of rhBMP-2 from CR bone grafts in vitro and in vivo in a femoral condyle defect model in rabbits was also evaluated.
RESULTS - All four bone grafts promoted new bone formation (11-31.6 volume%) in the lateral ridge defects. For CR grafts, ridge height and width increased in a dose-responsive manner with increasing rhBMP-2 concentration. Ridge height and width measured for CR-H without the use of protective mesh was comparable to that measured for ACS with a protective mesh.
CONCLUSIONS - At the same dose of rhBMP-2, an injectable, compression-resistant bone graft resulted in a comparable volume of new bone formation with the clinical control (ACS). These findings highlight the potential of compression-resistant bone grafts without the use of protective mesh for lateral ridge augmentation.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA in New-Onset Type 1 Diabetes.
Haller MJ, Schatz DA, Skyler JS, Krischer JP, Bundy BN, Miller JL, Atkinson MA, Becker DJ, Baidal D, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Herold KC, Marks JB, Moran A, Rodriguez H, Russell W, Wilson DM, Greenbaum CJ, Type 1 Diabetes TrialNet ATG-GCSF Study Group
(2018) Diabetes Care 41: 1917-1925
MeSH Terms: Adolescent, Adult, Antilymphocyte Serum, C-Peptide, Child, Cytoprotection, Diabetes Mellitus, Type 1, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Glycated Hemoglobin A, Granulocyte Colony-Stimulating Factor, Humans, Insulin-Secreting Cells, Male, Pilot Projects, Polyethylene Glycols, Recombinant Proteins, Young Adult
Show Abstract · Added May 2, 2019
OBJECTIVE - A pilot study suggested that combination therapy with low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte colony-stimulating factor (GCSF) preserves C-peptide in established type 1 diabetes (T1D) (duration 4 months to 2 years). We hypothesized that ) low-dose ATG/GCSF or ) low-dose ATG alone would slow the decline of β-cell function in patients with new-onset T1D (duration <100 days).
RESEARCH DESIGN AND METHODS - A three-arm, randomized, double-masked, placebo-controlled trial was performed by the Type 1 Diabetes TrialNet Study Group in 89 subjects: 29 subjects randomized to ATG (2.5 mg/kg intravenously) followed by pegylated GCSF (6 mg subcutaneously every 2 weeks for 6 doses), 29 to ATG alone (2.5 mg/kg), and 31 to placebo. The primary end point was mean area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test 1 year after initiation of therapy. Significance was defined as one-sided value < 0.025.
RESULTS - The 1-year mean AUC C-peptide was significantly higher in subjects treated with ATG (0.646 nmol/L) versus placebo (0.406 nmol/L) ( = 0.0003) but not in those treated with ATG/GCSF (0.528 nmol/L) versus placebo ( = 0.031). HbA was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF, = 0.002 and 0.011, respectively.
CONCLUSIONS - Low-dose ATG slowed decline of C-peptide and reduced HbA in new-onset T1D. Addition of GCSF did not enhance C-peptide preservation afforded by low-dose ATG. Future studies should be considered to determine whether low-dose ATG alone or in combination with other agents may prevent or delay the onset of the disease.
© 2018 by the American Diabetes Association.
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A senataxin-associated exonuclease SAN1 is required for resistance to DNA interstrand cross-links.
Andrews AM, McCartney HJ, Errington TM, D'Andrea AD, Macara IG
(2018) Nat Commun 9: 2592
MeSH Terms: Animals, DNA Damage, DNA Helicases, DNA Repair, Enzyme Assays, Exodeoxyribonucleases, Fanconi Anemia Complementation Group D2 Protein, Female, Fibroblasts, Gene Knockdown Techniques, Gene Knockout Techniques, HEK293 Cells, HeLa Cells, Humans, Male, Mice, Mice, Knockout, RNA Helicases, RNA, Small Interfering, Recombinant Proteins, Signal Transduction, Trans-Activators
Show Abstract · Added August 17, 2020
Interstrand DNA cross-links (ICLs) block both replication and transcription, and are commonly repaired by the Fanconi anemia (FA) pathway. However, FA-independent repair mechanisms of ICLs remain poorly understood. Here we report a previously uncharacterized protein, SAN1, as a 5' exonuclease that acts independently of the FA pathway in response to ICLs. Deletion of SAN1 in HeLa cells and mouse embryonic fibroblasts causes sensitivity to ICLs, which is prevented by re-expression of wild type but not nuclease-dead SAN1. SAN1 deletion causes DNA damage and radial chromosome formation following treatment with Mitomycin C, phenocopying defects in the FA pathway. However, SAN1 deletion is not epistatic with FANCD2, a core FA pathway component. Unexpectedly, SAN1 binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops. SAN1-SETX binding is increased by ICLs, and is required to prevent cross-link sensitivity. We propose that SAN1 functions with SETX in a pathway necessary for resistance to ICLs.
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