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UFGI Publications Round-Up Week 10/03/2016

Genome-wide association study identifies pharmacogenomic loci linked with specific antihypertensive drug treatment and new-onset diabetes.

Author information: Chang SW1, McDonough CW1, Gong Y1, Johnson TA2, Tsunoda T2,3, Gamazon ER4, Perera MA5, Takahashi A6, Tanaka T7, Kubo M8, Pepine CJ9, Johnson JA1,9, Cooper-DeHoff RM1,9.

1Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida,Gainesville, FL, USA.
2Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
3Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
4Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
5Department of Medicine, University of Chicago, Chicago, IL, USA.
6Laboratory for Statistical Analysis, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
7Laboratory for Cardiovascular Diseases, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
8Laboratory for Genotyping Development, SNP Research Center, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
9Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Journal: The Pharmacogenomics Journal

Date of e-pub: September 2016

Abstract: We conducted a discovery genome-wide association study with expression quantitative trait loci (eQTL) annotation of new-onset diabetes (NOD) among European Americans, who were exposed to a calcium channel blocker-based strategy (CCB strategy) or a β-blocker-based strategy (β-blocker strategy) in the INternational VErapamil SR Trandolapril STudy. Replication of the top signal from the SNP*treatment interaction analysis was attempted in Hispanic and African Americans, and a joint meta-analysis was performed (total 334 NOD cases and 806 matched controls). PLEKHH2 rs11124945 at 2p21 interacted with antihypertensive exposure for NOD (meta-analysis P=5.3 × 108). rs11124945 G allele carriers had lower odds for NOD when exposed to the β-blocker strategy compared with the CCB strategy (Odds ratio OR=0.38(0.24-0.60), P=4.0 × 105), whereas A/A homozygotes exposed to the β-blocker strategy had increased odds for NOD compared with the CCB strategy (OR=2.02(1.39-2.92), P=2.0 × 104). eQTL annotation of the 2p21 locus provides functional support for regulating gene expression.

 

 

Anti-Thymocyte Globulin + G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders with Established Type 1 Diabetes.

Author information: Haller MJ1, Gitelman SE2, Gottlieb PA3, Michels AW3, Perry DJ4, Schultz AR4, Hulme MA5, Shuster JJ6, Zou B7, Wasserfall CH4, Posgai A4, Mathews CE4,Brusko TM4, Atkinson MA8, Schatz DA9.

1Department of Pediatrics, University of Florida, Gainesville, FL; hallemj@peds.ufl.edu.
2Department of Pediatrics, UCSF, San Francisco, CA;
3Department of Pediatrics and Medicine, University of Colorado, Denver, CO;
4Departments of Pathology, Immunology, and Laboratory Medicine.
5Biomedical Engineering.
6Health Outcomes and Policy, and.
7Biostatistics, University of Florida, Gainesville, FL.
8Department of Pediatrics, University of Florida, Gainesville, FL; Departments of Pathology, Immunology, and Laboratory Medicine.
9Department of Pediatrics, University of Florida, Gainesville, FL;

Journal: Diabetes

Date of e-pub: September 2016

Abstract: Low-dose anti-thymocyte globulin (ATG) + pegylated granulocyte-colony stimulating factor (G-CSF) preserves beta cell function for at least 12-months in type 1 diabetes (T1D). Herein, we describe metabolic and immunologic parameters 24-months following treatment. Patients with established T1D (duration 4-24 months) were randomized to ATG and peg-G-CSF (N=17) or placebo (N=8). Primary outcomes included AUC C-peptide following mixed-meal tolerance test (MMTT) and flow cytometry. “Responders” (12-month C-peptide ≥ baseline), “Super-responders” (24-month C-peptide ≥ baseline), and “Non-responders” (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24-months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49nmol/L/min) versus placebo (0.29nmol/L/min). ATG+G-CSF-treated subjects demonstrated reduced CD4+ T-cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ T-effector memory cells (Tem), CD4+PD-1+ T-central memory cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T-cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24-months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK, and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunologic responders was identified. A phase-II study of ATG+G-CSF in new-onset T1D patients is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.

 

 

Immortalization of human normal and NF1 neurofibroma Schwann cells.

Author information: Li H1, Chang LJ1, Neubauer DR2, Muir DF2,3,4, Wallace MR1,4,5.

1Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
2Department of Pediatrics, Child Health Research Institute, University of Florida College of Medicine, Gainesville, FL, USA.
3Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.
4University of Florida Health Cancer Center, University of Florida, Gainesville, FL, USA.
5University of Florida Genetics Institute, University of Florida, Gainesville, FL, USA.

Journal: Laboratory Investigation: A Journal of Technical Methods and Pathology

Date of e-pub: September 2016

Abstract: Neurofibromas, which are benign Schwann cell tumors, are the hallmark feature in the autosomal dominant condition neurofibromatosis 1 (NF1) and are associated with biallelic loss of NF1 gene function. There is a need for effective therapies for neurofibromas, particularly the larger, plexiform neurofibromas. Tissue culture is an important tool for research. However, it is difficult to derive enriched human Schwann cell cultures, and most enter replicative senescence after 6-10 passages, impeding cell-based research in NF1. Through exogenous expression of human telomerase reverse transcriptase and murine cyclin-dependent kinase (mCdk4), normal (NF1 wild-type), neurofibroma-derived Schwann cells heterozygous for NF1 mutation, and neurofibroma-derived Schwann cells homozygous for NF1 mutation were immortalized, including some matched samples from the same NF1 patient. Initial experiments employed retroviral vectors, while subsequent work utilized lentiviral vectors carrying these genes because of improved efficiency. Expression of both transgenes was required for immortalization. Molecular and immunohistochemical analysis indicated that these cell lines are of Schwann cell lineage and have a range of phenotypes, many of which are consistent with their primary cultures. This is the first report of immortalization and detailed characterization of multiple human NF1 normal nerve and neurofibroma-derived Schwann cell lines, which will be highly useful research tools to study NF1 and other Schwann tumor biology and conditions.

 

 

Aptamers against Cells Overexpressing Glypican 3 from Expanded Genetic Systems Combined with Cell Engineering and Laboratory Evolution.

Author information: Zhang L1,2, Yang Z3, Le Trinh T4, Teng IT1, Wang S1, Bradley KM3, Hoshika S3, Wu Q4, Cansiz S1, Rowold DJ3, McLendon C3, Kim MS3, Wu Y1,2, Cui C1, Liu Y1, Hou W1, Stewart K1, Wan S1, Liu C5, Benner SA6, Tan W7,8.

1Departments of Chemistry, Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface, UF Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL, 32611, USA.
2Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, 410082, China.
3Foundation for Applied Molecular Evolution, Firebird Biomolecular Sciences LLC, 13709 Progress Boulevard, Alachua, FL, 32615, USA.
4Department of Pathology, Immunology, and Laboratory Medicine, Gainesville, FL, 32611, USA.
5Department of Pathology, Immunology, and Laboratory Medicine, Gainesville, FL, 32611, USA. liu@pathology.ufl.edu.
6Foundation for Applied Molecular Evolution, Firebird Biomolecular Sciences LLC, 13709 Progress Boulevard, Alachua, FL, 32615, USA. sbenner@ffame.org.
7Departments of Chemistry, Physiology and Functional Genomics, Center for Research at the Bio/Nano Interface, UF Health Cancer Center, UF Genetics Institute and McKnight Brain Institute, University of Florida, Gainesville, FL, 32611, USA. tan@chem.ufl.edu.
8Molecular Science and Biomedicine Laboratory, State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, Collaborative Innovation Center for Chemistry and Molecular Medicine, Hunan University, Changsha, 410082, China. tan@chem.ufl.edu.

Journal: Angewandte Chemie (International Edition)

Date of e-pub: September 2016

Abstract: Laboratory in vitro evolution (LIVE) might deliver DNA aptamers that bind proteins expressed on the surface of cells. In this work, we used cell engineering to place glypican 3 (GPC3), a possible marker for liver cancer theranostics, on the surface of a liver cell line. Libraries were then built from a six-letter genetic alphabet containing the standard nucleobases and two added nucleobases (2-amino-8H-imidazo[1,2-a][1,3,5]triazin-4-one and 6-amino-5-nitropyridin-2-one), Watson-Crick complements from an artificially expanded genetic information system (AEGIS). With counterselection against non-engineered cells, eight AEGIS-containing aptamers were recovered. Five bound selectively to GPC3-overexpressing cells. This selection-counterselection scheme had acceptable statistics, notwithstanding the possibility that cells engineered to overexpress GPC3 might also express different off-target proteins. This is the first example of such a combination.

 

 

Broadening Participation of Women and Underrepresented Minorities in STEM through a Hybrid Online Transfer Program.

Author information: Drew JC1, Galindo-Gonzalez S2, Ardissone AN3, Triplett EW3.

1Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611 jdrew@ufl.edu.
2Agricultural and Education and Communications, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611.
3Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL 32611.

Journal: CBE Life Sciences Education

Date of e-pub: September 2016

Abstract: The Microbiology and Cell Science (MCS) Department at the University of Florida (UF) developed a new model of a 2 + 2 program that uses a hybrid online approach to bring its science, technology, engineering, and mathematics (STEM) curriculum to students. In this paradigm, 2-year graduates transfer as online students into the Distance Education in MCS (DE MCS) bachelor of science program. The program has broadened access to STEM with a steadily increasing enrollment that does not draw students away from existing on-campus programs. Notably, half of the DE MCS students are from underrepresented minority (URM) backgrounds and two-thirds are women, which represents a greater level of diversity than the corresponding on-campus cohort and the entire university. Additionally, the DE MCS cohort has comparable retention and academic performance compared with the on-campus transfer cohort. Of those who have earned a BS through the DE MCS program, 71% are women and 61% are URM. Overall, these data demonstrate that the hybrid online approach is successful in increasing diversity and provides another viable route in the myriad of STEM pathways. As the first of its kind in a STEM field, the DE MCS program serves as a model for programs seeking to broaden their reach.

 

 

Conservation of context-dependent splicing activity in distant Muscleblind homologs.

Author information: Oddo JC1, Saxena T2, McConnell OL2, Berglund JA3, Wang ET4.

1Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
3Center for Neurogenetics, University of Florida, Gainesville, FL 32610, USA Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA Department of Chemistry and Biochemistry and Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
4Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA eric.t.wang@ufl.edu.

Journal: Nucleic Acids Research

Date of e-pub: August 2016

Abstract: The Muscleblind (MBL) protein family is a deeply conserved family of RNA binding proteins that regulate alternative splicing, alternative polyadenylation, RNA stability and RNA localization. Their inactivation due to sequestration by expanded CUG repeats causes symptoms in the neuromuscular disease myotonic dystrophy. MBL zinc fingers are the most highly conserved portion of these proteins, and directly interact with RNA. We identified putative MBL homologs in Ciona intestinalis and Trichoplax adhaerens, and investigated their ability, as well as that of MBL homologs from human/mouse, fly and worm, to regulate alternative splicing. We found that all homologs can regulate alternative splicing in mouse cells, with some regulating over 100 events. The cis-elements through which each homolog exerts its splicing activities are likely to be highly similar to mammalian Muscleblind-like proteins (MBNLs), as suggested by motif analyses and the ability of expanded CUG repeats to inactivate homolog-mediated splicing. While regulation of specific target exons by MBL/MBNL has not been broadly conserved across these species, genes enriched for MBL/MBNL binding sites in their introns may play roles in cell adhesion, ion transport and axon guidance, among other biological pathways, suggesting a specific, conserved role for these proteins across a broad range of metazoan species.

 

 

Transcriptomic and physiological changes in Eastern Mosquitofish (Gambusia holbrooki) after exposure to progestins and anti-progestagens.

Author information: Brockmeier EK1, Scott PD2, Denslow ND3, Leusch FD2.

1Department of Physiological Sciences, Center for Environmental and Human Toxicology, University of Florida, PO Box 110885, Gainesville, FL32611, USA. Electronic address: e.k.brockmeier@liv.ac.uk.
2Smart Water Research Centre, Australian Rivers Institute, Griffith School of Environment, Griffith University, Southport, Qld 4222, Australia.
3Department of Physiological Sciences, Center for Environmental and Human Toxicology, University of Florida, PO Box 110885, Gainesville, FL32611, USA.

Journal: Aquatic Toxicology

Date of e-pub: August 2016

Abstract: Endocrine active compounds (EACs) remain an important group of chemicals that require additional evaluation to determine their environmental impacts. While estrogens and androgens were previously demonstrated to impact organisms during environmental exposures, progestagens have recently been shown to have strong impacts on aquatic organisms. To gain an understanding of the impacts of these types of chemicals on aquatic species, experiments evaluating the mechanisms of action of progestagen exposure were conducted with the Eastern Mosquitofish (Gambusia holbrooki). The objective of this study was to conduct hepatic microarray analysis of male and female G. holbrooki exposed to progestins and anti-progestagens. In addition, we evaluated the ability of levonorgestrel, a synthetic progesterone (progestin), to induce anal fin elongation and to determine how anal fin growth is modulated during co-exposures with progesterone and androgen receptor antagonists. Gene expression analyses were conducted on male and female G. holbrooki exposed for 48h to the agonist levonorgestrel, the antagonist mifepristone, or a mixture of the two chemicals. Microarray analysis revealed that mifepristone does not act as an anti-progestagen in G. holbrooki in liver tissues, and that levonorgestrel elicits strong effects on the processes of embryo development and lipid transport. Levonorgestrel was also demonstrated to induce male secondary sexual characteristic formation in females, and co-exposure of either an androgen or levonorgestrel in the presence of the anti-androgen flutamide prevented anal fin elongation. These results provide indications as to the potential impacts of progestins, including non-target effects such as secondary sexual characteristic formation, and demonstrate the importance of this class of chemicals on aquatic organisms.

 

 

Co-Infection with Zika and Dengue-2 Viruses in a Traveler Returning from Haiti, 2016: Clinical Presentation and Genetic Analysis.

Author information: Iovine N1, Lednicky J2, Cherabuddi K3, Crooke H4, White SK4, Loeb JC4, Cella E5, Ciccozzi M5, Salemi M6, Morris JG Jr7.

1Division of Infectious Diseases, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610 Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610 Nicole.Iovine@medicine.ufl.edu.
2Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610 Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610.
3Division of Infectious Diseases, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
4Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL 32610.
5Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610 Department of Pathology, Immunology and Laboratory Sciences, College of Medicine, University of Florida, Gainesville, FL 32610 Department of Infectious Parasitic and Immunomediated Diseases, Reference Centre on Phylogeny, Molecular Epidemiology and Microbial Evolution (FEMEM)/Epidemiology Unit, Istituto Superiore di Sanita, Rome, Italy.
6Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610 Department of Pathology, Immunology and Laboratory Sciences, College of Medicine, University of Florida, Gainesville, FL 32610.
7Division of Infectious Diseases, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610 Emerging Pathogens Institute, University of Florida, Gainesville, FL 32610.

Journal: Clinical Infectious Diseases

Date of e-pub: September 2016

Abstract: Zika virus and Dengue virus serotype 2 were isolated from a patient with travel to Haiti who developed fever, rash, arthralgias and conjunctivitis. The infecting ZIKV was related to Venezuelan and Brazilian strains but evolved along a lineage originating from strains isolated in 2014 in the same region of Haiti.

 

 

Distinct and overlapping DNMT1 interactions with multiple transcription factors in erythroid cells: Evidence for co-repressor functions.

Author information: Papageorgiou DN1, Karkoulia E1, Amaral-Psarris A1, Burda P2, Kolodziej K3, Demmers J4, Bungert J5, Stopka T6, Strouboulis J7.

1Division of Molecular Oncology, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece.
2Institute of Hematology and Blood Transfusion, Prague, Czech Republic; Department of Pathological Physiology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.
3Department of Cell Biology, Erasmus Medical Center, Rotterdam, The Netherlands.
4Proteomics Center, Erasmus Medical Center, Rotterdam, The Netherlands.
5Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL, USA.
6Biocev, 1st Medical Faculty, Charles University, Prague, Czech Republic.
7Division of Molecular Oncology, Biomedical Sciences Research Center “Alexander Fleming”, Vari, Greece. Electronic address: john_strouboulis@imbb.forth.gr.

Journal: Biochimica et biophysica acta

Date of e-pub: September 2016

Abstract: DNMT1 is the maintenance DNA methyltransferase shown to be essential for embryonic development and cellular growth and differentiation in many somatic tissues in mammals. Increasing evidence has also suggested a role for DNMT1 in repressing gene expression through interactions with specific transcription factors. Previously, we identified DNMT1 as an interacting partner of the TR2/TR4 nuclear receptor heterodimer in erythroid cells, implicated in the developmental silencing of fetal β-type globin genes in the adult stage of human erythropoiesis. Here, we extended this work by using a biotinylation tagging approach to characterize DNMT1 protein complexes in mouse erythroleukemic cells. We identified novel DNMT1 interactions with several hematopoietic transcription factors with essential roles in erythroid differentiation, including GATA1, GFI-1b and FOG-1. We provide evidence for DNMT1 forming distinct protein subcomplexes with specific transcription factors and propose the existence of a “core” DNMT1 complex with the transcription factors ZBP-89 and ZNF143, which is also present in non-hematopoietic cells. Furthermore, we identified the short (17a.a.) PCNA Binding Domain (PBD) located near the N-terminus of DNMT1 as being necessary for mediating interactions with the transcription factors described herein. Lastly, we provide evidence for DNMT1 serving as a co-repressor of ZBP-89 and GATA1 acting through upstream regulatory elements of the PU.1 and GATA1 gene loci.

 

 

Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin.

Author information: Biswas M, Rogers GL, Sherman A, Byrne BJ, Markusic DM, Jiang H, Herzog RW1.

1Roland W. Herzog, PhD, University of Florida, Cancer and Genetics Research Complex, 2033 Mowry Road, Gainesville, FL 32610, USA, Tel.: +1 352 273 8113, Fax: +1 352 273 8342, E-mail: rherzog@ufl.edu.

Journal: Thrombosis and Haemostasis

Date of e-pub: September 2016

Abstract: Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses. Additionally, it extensively characterises the role of the IgG backbone in B cell depletion by anti-CD20 antibodies. For this, inhibitors were generated in BALB/c-HA mice by weekly IV injection of FVIII. Subsequently, anti-mCD20 (18B12) with IgG2a or IgG1 backbone was injected IV in two doses three weeks apart and B cell depletion and recovery was characterised. Rapamycin was administered orally 3x/week (for 1 month) while continuing FVIII injections. Altering the IgG backbone of anti-mCD20 from IgG2a to IgG1 reduced overall depletion of B cells (including memory B cells), and marginal zone, B-10, and B-1b cells were specifically unaffected. While neither antibody was effective alone, in combination with rapamycin, anti-mCD20 IgG2a but not IgG1 was able to reverse inhibitors in HA mice. This regimen was particularly effective for starting titres of ~10 BU. Although IgG1 anti-mCD20 spared potentially tolerogenic B cell subsets, IgG2a directed sustained hyporesponsiveness when administered in conjunction with rapamycin. This regimen represents a promising treatment for inhibitor reversal in HA, as both of these compounds have been extensively used in human patients.

 

 

DeaD contributes to Pseudomonas aeruginosa virulence in a mouse acute pneumonia model.

Author information: Tan H1, Zhang L1, Zhao Q2, Chen R1, Liu C1, Weng Y1, Peng Q1, Bai F3, Cheng Z1, Jin S4, Wu W1, Jin Y5.

1State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, 300071, China.
2College of Life Sciences, Nankai University, Tianjin, 300071, China.
3State Key Laboratory of Medicinal Chemical Biology, College of Pharmacyand Life Sciences, and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, China.
4Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, U.S.A.
5State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin, 300071, China yxjin@nankai.edu.cn.

Journal: FEMS Microbiology Letters

Date of e-pub: September 2016

Abstract: DExD/H box RNA helicases play essential roles in various biological processes in prokaryotes and eukaryotes. By screening Pseudomonas aeruginosa strains with mutations in various DExD/H box helicase genes, we identified that deaD was required for bacterial cytotoxicity and virulence in a mouse acute pneumonia model. Compared to a wild-type strain and its complementation strain, the deaD mutant induced less production of pro-inflammatory cytokines, neutrophil infiltration and lung damage during infection. We further found that the RNA helicase activity of DeaD was required for the expression of type III secretion system (T3SS) genes. Overexpression of ExsA, a master activator of the T3SS, restored the expression of T3SS genes as well as the virulence of the deaD mutant, suggesting that the attenuated virulence of the deaD mutant was mainly due to the defective T3SS. Overall, our results reveal a role of DeaD in the virulence of P. aeruginosa.

 

 

Regulation of BZR1 in fruit ripening revealed by iTRAQ proteomics analysis.

Author information: Liu L1,2, Liu H1, Li S1, Zhang X1, Zhang M1, Zhu N2, Dufresne CP3, Chen S2,4, Wang Q1,5.

1Key Laboratory of Horticultural Plant Growth, Development and Quality improvement, Ministry of Agriculture, Department of Horticulture, Zhejiang University, Hangzhou 310058, P.R. China.
2Department of Biology, Genetics Institute, University of Florida, Gainesville, FL 32610, USA.
3Thermo Fisher Scientific, West Palm Beach, Florida 33407, USA.
4Proteomics and Mass Spectrometry, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32610, USA.
5Zhejiang Provincial Key Laboratory of Horticultural Plant Integrative Biology, Department of Horticulture, Zhejiang University, Hangzhou 310058, China.

Journal: Science Reports

Date of e-pub: September 2016

Abstract: Fruit ripening is a complex and genetically programmed process. Brassinosteroids (BRs) play an essential role in plant growth and development, including fruit ripening. As a central component of BR signaling, the transcription factor BZR1 is involved in fruit development in tomato. However, the transcriptional network through which BZR1 regulates fruit ripening is mostly unknown. In this study, we use isobaric tags for relative and absolute quantitation (iTRAQ) labeling technology to explore important proteins regulated by BZR1 in two independent tomato transgenic lines over-expressing BZR1-1D at four ripening stages, identifying 411 differentially expressed proteins. These proteins were implicated in light reaction, plant hormone pathways and cell-wall-related metabolism, etc. The ‘light reaction’ metabolic pathway was identified as a markedly enhanced pathway by BZR1 during tomato fruit ripening. The protein level of a probable 2-oxoglutarate-dependent dioxygenase 2-ODD2, involved in gibberellin biosynthesis was significantly increased at all four developmental and ripening stages. The results reveal molecular links between BR signaling pathway and downstream components involved in multiple ripening-associated events during tomato fruit ripening, which will provide new insights into the molecular mechanisms underlying tomato ripening regulatory networks, and be potential in understanding BR-regulated fruit ripening.

 

 

Arabidopsis TH2 Encodes the Orphan Enzyme Thiamin Monophosphate Phosphatase.

Author information: Mimura M1, Zallot R1, Niehaus TD2, Hasnain G1, Gidda SK3, Nguyen TN3, Anderson EM3, Mullen RT4, Brown G5, Yakunin AF5, de Crécy-Lagard V6, Gregory JF1, McCarty DR7, Hanson AD8.

1University of Florida CITY: Gainesville STATE: Florida United States Of America [US].
2University of Florida CITY: Gainesville STATE: Florida POSTAL_CODE: 32611 United States Of America [US].
3University of Guelph CITY: Guelph STATE: Ontario Canada [CA].
4University of Guelph CITY: Guelph STATE: Ontario POSTAL_CODE: N1G 2W1 Canada [CA].
5University of Toronto CITY: Toronto STATE: Ontario Canada [CA].
6University of Florida CITY: Gainesville STATE: FL United States Of America [US].
7University of Florida, IFAS CITY: Gainesville STATE: Florida POSTAL_CODE: 32611-0690 United States Of America [US].
8University of Florida CITY: Gainesville STATE: Florida POSTAL_CODE: 32611-0690 United States Of America [US] adha@ufl.edu.

Journal: The Plant Cell

Date of e-pub: September 2016

Abstract: To synthesize the cofactor thiamin diphosphate (ThDP), plants must first hydrolyze thiamin monophosphate (ThMP) to thiamin, but dedicated enzymes for this hydrolysis step were unknown and widely doubted to exist. The classical thiamin-requiring th2-1 mutation in Arabidopsis was shown to reduce ThDP levels by half and to increase ThMP levels five-fold, implying that the THIAMIN REQUIRING 2 (TH2) gene product could be a dedicated ThMP phosphatase. Genomic and transcriptomic data indicated that TH2 corresponds to At5g32470, encoding a HAD (haloacid dehalogenase) family phosphatase fused to a TenA (thiamin salvage) family protein. Like the th2-1 mutant, an insertional mutant of At5g32470 accumulated ThMP, and the thiamin requirement of the th2-1 mutant was complemented by wild-type At5g32470. Complementation tests in Escherichia coli and enzyme assays with recombinant proteins confirmed that At5g32470 and its Zea mays (maize) orthologs GRMZM2G148896 and GRMZM2G078283 are ThMP-selective phosphatases whose activity resides in the HAD domain, and that the At5g32470 TenA domain has the expected thiamin salvage activity. In vitro and in vivo experiments showed that alternative translation start sites direct the At5g32470 protein to the cytosol and potentially also to mitochondria. Our findings establish that plants have a dedicated ThMP phosphatase and indicate that modest (50%) ThDP depletion can produce severe deficiency symptoms.

 

 

Irisin Inhibits Atherosclerosis by Promoting Endothelial Proliferation Through microRNA126-5p.

Author information: Zhang Y1, Song H1, Zhang Y1, Wu F1, Mu Q1, Jiang M1, Wang F1, Zhang W1, Li L1, Shao L1, Li S2, Yang L2, Zhang M3, Wu Q4, Tang D5.

1Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China.
2Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL.
3The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital of Shandong University, Jinan, China.
4Department of Anatomy, School of Medicine Shandong University, Jinan, China.
5Center for Gene Therapy and Immunotherapy, The Second Hospital of Shandong University, Jinan, China tangdq@sdu.edu.cn.

Journal: Journal of the American Heart Association

Date of e-pub: September 2016

Abstract: Irisin is a newly discovered myokine that has been considered a promising candidate for the treatment of cardiovascular disease through improving endothelial function. However, little is known about the role of irisin in the progression of atherosclerosis.

We used a carotid partial ligation model of apolipoprotein E-deficient mice fed on a high-cholesterol diet to test the anti-atherosclerosis effect of irisin. Irisin treatment significantly suppressed carotid neointima formation. It was associated with increased endothelial cell proliferation. In addition, irisin promoted human umbilical vein endothelial cell survival via upregulating microRNA126-5p expression through the ERK signaling pathway. Inhibition of microRNA126-5p using the microRNA126-5p inhibitor abolished the prosurvival effect. The same results were demonstrated in vivo as the expression of microRNA126-5p noticeably increased in ligated carotid artery after irisin treatment. Furthermore, in vivo blockade of microRNA126-5p expression using the antagomir abolished the inhibitory effects of irisin on neointima formation, lesional lipid deposition, macrophage area, and the pro-proliferation effects on endothelial cells.

Taken together, our study demonstrates that irisin significantly reduces atherosclerosis in apolipoprotein E-deficient mice via promoting endothelial cell proliferation through microRNA126-5p, which may have a direct therapeutic effect on atherosclerotic diseases.

 

 

Comparison of Blood Pressure Control Rates Among Recommended Drug Selection Strategies for Initial Therapy of Hypertension.

Author information: Gharaibeh KA1, Turner ST2, Hamadah AM2, Chapman AB3, Cooper-Dehoff RM4, Johnson JA4, Gums JG4, Bailey KR5, Schwartz GL2.

1Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA; kamelgharaibeh@yahoo.com.
2Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA;
3Section of Nephrology, University of Chicago, Chicago, IL, USA;
4College of Pharmacy, University of Florida, Gainesville, FL, USA;
5Divisions of Biostatistics and Biomedical Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

Journal: American Journal of Hypertension

Date of e-pub: June 2016

Abstract: Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies.

We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites <50 years) or (iii) a PRA based strategy: HCTZ for suppressed PRA (<0.6ng/ml/h) and atenolol for non-suppressed PRA (≥0.6ng/ml/h) despite age or race. Hypertension was confirmed prior to treatment with HCTZ (148 blacks and 218 whites) or with atenolol (146 blacks and 221 whites).

In the overall sample, using clinic blood pressure (BP) response, the renin-based strategy was associated with the greatest control rate (48.9% vs. 40.8% with the age and race-based strategy (P = 0.0004) and 31.7% with the TD for all strategy (P < 0.0001)). The findings were similar using home or by 24-hour ambulatory BP responses and within each racial subgroup.

A strategy for selection of initial antihypertensive drug therapy based on PRA was associated with greater BP control rates compared to a thiazide-for-all or an age and race-based strategy.

 

 

Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis.

Author information: Hackeng WM1, Brosens LA1, Poruk KE2, Noë M1, Hosoda W3, Poling JS3, Rizzo A3, Campbell-Thompson M4, Atkinson MA5, Konukiewitz B6, Klöppel G6,Heaphy CM3, Meeker AK3, Wood LD7.

1Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands.
2Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
3Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
4Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
5Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
6Department of Pathology, Technical University Munich, 81675 Munich, Germany.
7Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu.

Journal: Human Pathology

Date of e-pub: June 2016

Abstract: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.

 

 

Comparison of brain activation patterns during executive function tasks in hoarding disorder and non-hoarding OCD.

Author information: Hough CM1, Luks TL2, Lai K1, Vigil O1, Guillory S3, Nongpiur A4, Fekri SM1, Kupferman E1, Mathalon DH3, Mathews CA5.

1Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA.
2Department of Radiology and Biomedical Imaging, University of California, San Francisco, USA.
3Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA; Department of Psychiatry, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.
4Department of Psychiatry, University of Florida, Gainesville, FL, USA; Department of Psychiatry, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), Shillong, Meghalaya, India.
5Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, USA; Department of Psychiatry, University of Florida, Gainesville, FL, USA. Electronic address: carolmathews@ufl.edu.

Journal: Psychiatry Research

Date of e-pub: July 2016

Abstract: We examined differences in regional brain activation during tests of executive function in individuals with Hoarding Disorder (HD), Obsessive Compulsive Disorder (OCD), and healthy controls (HC) using functional magnetic resonance imaging (fMRI). Participants completed computerized versions of the Stroop and Go/No-Go task. We found that during the conflict monitoring and response inhibition condition in the Go/No-Go task, individuals with HD had significantly greater activity than controls in the anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC). HD also exhibited significantly greater right DLPFC activity than OCD. We also observed significant differences in activity between HD and HC and between HD and OCD in regions (ACC, anterior insula, orbitofrontal cortex, and striatum) involved in evaluating stimulus-response-reward associations, or the personal and task-relevant value of stimuli and behavioral responses to stimuli. These results support the hypothesis that individuals with HD have difficulty deciding on the value or task relevance of stimuli, and may perceive an abnormally high risk of negative feedback for difficult or erroneous cognitive behavior.

 

 

Characterization of intravitreally delivered capsid mutant AAV2-Cre vector to induce tissue-specific mutations in murine retinal ganglion cells.

Author information: Langouet-Astrie CJ1, Yang Z2, Polisetti SM1, Welsbie DS3, Hauswirth WW4, Zack DJ5, Merbs SL3, Enke RA6.

1Department of Biology, 951 Carrier Drive, MSC 7801, James Madison University, Harrisonburg, VA, 22807, USA.
2Department of Surgery, University of California San Diego, 4150 Regents Park Row, La Jolla, CA, 92037, USA.
3Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA.
4Department of Ophthalmology, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
5Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA; Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA; Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA; Institute de la Vision, Université Pierre et Marie Curie, 17 Rue Moreau, Paris, 75012, France.
6Department of Biology, 951 Carrier Drive, MSC 7801, James Madison University, Harrisonburg, VA, 22807, USA; Center for Genome & Metagenome Studies, 951 Carrier Drive, MSC 7801, James Madison University, Harrisonburg, VA, 22807, USA. Electronic address: enkera@jmu.edu.

Journal: Experimental Eye Research

Date of e-pub: July 2016

Abstract: Targeted expression of Cre recombinase in murine retinal ganglion cells (RGCs) by viral vector is an effective strategy for creating tissue-specific gene knockouts for investigation of genetic contribution to RGC degeneration associated with optic neuropathies. Here we characterize dosage, efficacy and toxicity for sufficient intravitreal delivery of a capsid mutant Adeno-associated virus 2 (AAV2) vector encoding Cre recombinase. Wild type and Rosa26 (R26) LacZ mice were intravitreally injected with capsid mutant AAV2 viral vectors. Murine eyes were harvested at intervals ranging from 2 weeks to 15 weeks post-injection and were assayed for viral transduction, transgene expression and RGC survival. 10(9) vector genomes (vg) were sufficient for effective in vivo targeting of murine ganglion cell layer (GCL) retinal neurons. Transgene expression was observed as early as 2 weeks post-injection of viral vectors and persisted to 11 weeks. Early expression of Cre had no significant effect on RGC survival, while significant RGC loss was detected beginning 5 weeks post-injection. Early expression of viral Cre recombinase was robust, well-tolerated and predominantly found in GCL neurons suggesting this strategy can be effective in short-term RGC-specific mutation studies in experimental glaucoma models such as optic nerve crush and transection experiments. RGC degeneration with Cre expression for more than 4 weeks suggests that Cre toxicity is a limiting factor for targeted mutation strategies in RGCs.

 

Why Sexually Selected Weapons Are Not Ornaments.

Author information: McCullough EL1, Miller CW2, Emlen DJ3.

1Centre for Evolutionary Biology, The University of Western Australia, Crawley, WA 6009, Australia. Electronic address: mccullough.e@gmail.com.
2Entomology and Nematology Department, University of Florida, Gainesville, FL 32611, USA.
3Division of Biological Sciences, The University of Montana, Missoula, MN 59812, USA.

Journal: Trends in Ecology & Evolution

Date of e-pub: July 2016

Abstract: The elaboration and diversification of sexually selected weapons remain poorly understood. We argue that progress in this topic has been hindered by a strong bias in sexual selection research, and a tendency for weapons to be conflated with ornaments used in mate choice. Here, we outline how male-male competition and female choice are distinct mechanisms of sexual selection, and why weapons and ornaments are fundamentally different types of traits. We call for research on the factors contributing to weapon divergence, the potential for male-male competition to drive speciation, and the specific use of weapons in the context of direct fights versus displays. Given that weapons are first and foremost fighting structures, biomechanical approaches are an especially promising direction for understanding weapon design.

 

 

Generation and characterization of anti-Adeno-associated virus serotype 8 (AAV8) and anti-AAV9 monoclonal antibodies.

Author information: Tseng YS1, Vliet KV1, Rao L2, McKenna R1, Byrne BJ3, Asokan A2, Agbandje-McKenna M4.

1Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
2Department of Genetics and The Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
3Department Molecular Genetics and Microbiology, and Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL, USA.
4Department of Biochemistry and Molecular Biology, Center for Structural Biology, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: mckenna@ufl.edu.

Journal: Journal of Virological Methods

Date of e-pub: July 2016

Abstract: Adeno-associated viruses (AAVs) are promising viral vectors for therapeutic gene delivery, and the approval of an AAV1 vector for the treatment of lipoprotein lipase deficiency has heralded a new and exciting era for this system. However, preclinical and clinical studies show that neutralization from pre-existing antibodies is detrimental for medical application and this hurdle must be overcome before full clinical realization can be achieved. Thus the binding sites for capsid antibodies must be identified and eliminated through capsid engineering. Towards this goal and to recapitulate patient polyclonal responses, a panel of six new mouse monoclonal antibodies (MAbs) has been generated against AAV8 and AAV9 capsids, two vectors being developed for therapeutic application. Native (capsid) dot blot assays confirmed the specificity of these antibodies for their parental serotypes, with the exception of one MAb, HL2372, selected to cross-react against both capsids. Furthermore, in vitro assays showed that these MAbs are capable of neutralizing virus infection. These MAbs will be utilized for structural mapping of antigenic footprints on their respective capsids to inform development of the next generation of rAAV vectors capable of evading antibody neutralization while retaining parental tropism.

 

 

Rhizobacterial Community Structures Associated with Native Plants Grown in Chilean Extreme Environments.

Author information: Jorquera MA1, Maruyama F2, Ogram AV3, Navarrete OU4, Lagos LM5, Inostroza NG4, Acuña JJ4, Rilling JI5, de La Luz Mora M4.

1Center of Plant, Soil Interaction, and Natural Resources Biotechnology, Scientific and Technological Bioresource Nucleus, Ave. Francisco Salazar, 01145, Temuco, Chile. milko.jorquera@ufrontera.cl.
2Section of Microbiology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
3Soil and Water Science Department, University of Florida, 2181 McCarty Hall, PO Box 110290, Gainesville, FL, 32611, USA.
4Center of Plant, Soil Interaction, and Natural Resources Biotechnology, Scientific and Technological Bioresource Nucleus, Ave. Francisco Salazar, 01145, Temuco, Chile.
5Programa de Doctorado en Ciencias de Recursos Naturales, Universidad de La Frontera, Ave. Francisco Salazar, 01145, Temuco, Chile.

Journal: Microbial Ecology

Date of e-pub: July 2016

Abstract: Chile is topographically and climatically diverse, with a wide array of diverse undisturbed ecosystems that include native plants that are highly adapted to local conditions. However, our understanding of the diversity, activity, and role of rhizobacteria associated with natural vegetation in undisturbed Chilean extreme ecosystems is very poor. In the present study, the combination of denaturing gradient gel electrophoresis and 454-pyrosequencing approaches was used to describe the rhizobacterial community structures of native plants grown in three representative Chilean extreme environments: Atacama Desert (ATA), Andes Mountains (AND), and Antarctic (ANT). Both molecular approaches revealed the presence of Proteobacteria, Bacteroidetes, and Actinobacteria as the dominant phyla in the rhizospheres of native plants. Lower numbers of operational taxonomic units (OTUs) were observed in rhizosphere soils from ATA compared with AND and ANT. Both approaches also showed differences in rhizobacterial community structures between extreme environments and between plant species. The differences among plant species grown in the same environment were attributed to the higher relative abundance of classes Gammaproteobacteria and Alphaproteobacteria. However, further studies are needed to determine which environmental factors regulate the structures of rhizobacterial communities, and how (or if) specific bacterial groups may contribute to the growth and survival of native plants in each Chilean extreme environments.

 

 

An injectable capillary-like microstructured alginate hydrogel improves left ventricular function after myocardial infarction in rats.

Author information: Rocca DG1, Willenberg BJ2, Qi Y1, Simmons CS3, Rubiano A3, Ferreira LF4, Huo T5, Petersen JW1, Ruchaya PJ6, Wate PS2, Wise EA7, Handberg EM1,Cogle CR7, Batich CD2, Byrne BJ8, Pepine CJ9.

1Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
2Department of Materials Science and Engineering, College of Engineering, University of Florida, Gainesville, FL, USA.
3Department of Mechanical and Aerospace Engineering, College of Engineering, University of Florida, Gainesville, FL, USA.
4Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, Gainesville, FL, USA.
5Division of Biostatistics, Department of Epidemiology and Health Policy Research, College of Medicine, University of Florida, Gainesville, FL, USA.
6Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL, USA.
7Division of Hematology & Oncology, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
8Division of Cellular and Molecular Therapy, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.
9Division of Cardiovascular Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. Electronic address: carl.pepine@medicine.ufl.edu.

Journal: International Journal of Cardiology

Date of e-pub: June 2016

Abstract: A new post-myocardial infarction (MI) therapy is injection of high-water-content polymeric biomaterial gels (hydrogels) into damaged myocardium to modulate cardiac negative remodeling and preserve heart function.

We investigated the therapeutic potential of a novel gelatinized alginate hydrogel with a unique microstructure of uniform capillary-like channels (termed Capgel). Shortly (48h) after induced anterior MI, Sprague Dawley rats received intramyocardial injection of Capgel directly into the antero-septal wall at the infarct border zone (n=12) or no injection (n=10, controls). Echocardiograms were performed at 48h (week 0) and 4weeks (week 4) to evaluate left ventricular function.

Echocardiograms showed 27% improvement of left ventricular systolic function over time with gel injection: fractional shortening increased from 26±3% at week 0 to 33±2% at week 4 (p=0.001). Capgel was present at the injection site after 4weeks, but was minimal at 8weeks. The remaining gel was heavily populated by CD68(+) macrophages with CD206(+) clusters and blood vessels. An in vitro experiment was performed to assess Angiotensin-(1-7) released from Capgel. Angiotensin-(1-7) was released from the Capgel in a sustained manner for 90days.

Use of Capgel, a degradable, bioactive hydrogel composed of gelatinized capillary-alginate gel, appears safe for intramyocardial injection, is associated with improved left ventricular function after MI in rats, and may provide a long-term supply of Angiotensin-(1-7).

NOTE: These abstracts were retrieved from the U.S. National Library of Medicine website managed in collaboration with the U.S. National Library of Medicine 

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