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3.
Nat Commun ; 13(1): 5555, 2022 09 22.
Article in English | MEDLINE | ID: mdl-36138009

ABSTRACT

Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases.


Subject(s)
Cicatrix , Protein-Lysine 6-Oxidase , Animals , Cicatrix/drug therapy , Collagen , Fibrosis , Mice , Skin , Swine
4.
Biotechnol Bioeng ; 119(1): 48-58, 2022 01.
Article in English | MEDLINE | ID: mdl-34585736

ABSTRACT

Manufacturing has been the key factor limiting rollout of vaccination during the COVID-19 pandemic, requiring rapid development and large-scale implementation of novel manufacturing technologies. ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS-CoV-2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large-scale production. We discuss the process economics and the "distributed manufacturing" approach we have taken to provide the vaccine at globally-relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID-19 vaccine supply at low cost.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , ChAdOx1 nCoV-19 , Drug Industry/methods , Vaccine Development , Animals , Escherichia coli , Geography , HEK293 Cells , Humans , Pan troglodytes , SARS-CoV-2 , Technology, Pharmaceutical , Vaccination/instrumentation
5.
Ophthalmic Plast Reconstr Surg ; 37(5): 462-464, 2021.
Article in English | MEDLINE | ID: mdl-33481535

ABSTRACT

PURPOSE: The use of antibiotic prophylaxis for the prevention of infection in nonoperative orbital fractures is controversial, with limited high-quality evidence and inconsistent recommendations in the current scientific literature. Our primary study objective was to identify the prophylactic antibiotic prescribing pattern at our institution for nonoperative orbital fractures and to determine the effect of antibiotic prophylaxis. METHODS: We retrospectively reviewed 16 years of data from a single institution on patients with acute traumatic fractures of the orbital floor or medial orbital wall. Prophylactic administration of antibiotics and complication rates were evaluated, and complication rates and patient characteristics analyzed. RESULTS: Of 154 patients with nonoperative orbital fractures, 17 patients (group 1) received IV or oral antibiotics and 137 patients (group 2) did not. No patient in either group had documented infectious orbital complications following their orbital injury. Patients receiving antibiotics were more likely to have a concurrent periorbital laceration (58.8% ± 11.9% vs. 28.5% ± 3.9%; P = 0.01). CONCLUSION: We present the largest cohort yet reported of patients managed without antibiotic prophylaxis for nonoperative orbital fractures, with no infectious complications identified. Currently there is no evidence of utility to prophylactic antibiotics in the setting of nonoperative traumatic orbital fractures. Rather than prescribing antibiotics, we recommend clinicians educate patients on return precautions and offer close follow up for the rare, but potentially severe infectious complications of orbital trauma.


Subject(s)
Antibiotic Prophylaxis , Orbital Fractures , Anti-Bacterial Agents/therapeutic use , Cohort Studies , Humans , Orbital Fractures/complications , Retrospective Studies
6.
Methods Mol Biol ; 1944: 79-93, 2019.
Article in English | MEDLINE | ID: mdl-30840236

ABSTRACT

All tissues contain an extracellular matrix (ECM) which is constantly and dynamically remodeled, either in physiological or pathological processes, such as fibrosis or cancer. One of the key contributors in the establishment of a fibrotic state is the abnormal deposition of extracellular matrix and cross-linked proteins, in particular collagen, leading to tissue stiffening and disruption of organ function. The precise and sensitive measurement of these cross-links by LC-MS/MS is a very powerful tool for providing a quantitative and qualitative analysis of fibrosis and is a key requirement in the study of this state, as well as in the development of drugs for this unmet clinical need.


Subject(s)
Chromatography, Liquid/methods , Collagen/metabolism , Cross-Linking Reagents/chemistry , Skin/metabolism , Tandem Mass Spectrometry/methods , Collagen/analysis , Collagen/chemistry , Humans
7.
J Med Chem ; 62(5): 2447-2465, 2019 03 14.
Article in English | MEDLINE | ID: mdl-30779566

ABSTRACT

A series of imidazo[1,2- b]pyridazin-8-amine kinase inhibitors were discovered to allosterically inhibit the endoribonuclease function of the dual kinase-endoribonuclease inositol-requiring enzyme 1α (IRE1α), a key component of the unfolded protein response in mammalian cells and a potential drug target in multiple human diseases. Inhibitor optimization gave compounds with high kinome selectivity that prevented endoplasmic reticulum stress-induced IRE1α oligomerization and phosphorylation, and inhibited endoribonuclease activity in human cells. X-ray crystallography showed the inhibitors to bind to a previously unreported and unusually disordered conformation of the IRE1α kinase domain that would be incompatible with back-to-back dimerization of the IRE1α protein and activation of the endoribonuclease function. These findings increase the repertoire of known IRE1α protein conformations and can guide the discovery of highly selective ligands for the IRE1α kinase site that allosterically inhibit the endoribonuclease.


Subject(s)
Endoribonucleases/antagonists & inhibitors , Endoribonucleases/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Allosteric Regulation , Biopolymers/metabolism , Crystallography, X-Ray , Dimerization , Endoplasmic Reticulum Stress/drug effects , Endoribonucleases/chemistry , HEK293 Cells , Humans , Phosphorylation , Protein Conformation , Protein Kinase Inhibitors/metabolism , Protein Serine-Threonine Kinases/chemistry
8.
J Cell Mol Med ; 23(3): 1759-1770, 2019 03.
Article in English | MEDLINE | ID: mdl-30536539

ABSTRACT

Fibrosis is characterized by the excessive deposition of extracellular matrix and crosslinked proteins, in particular collagen and elastin, leading to tissue stiffening and disrupted organ function. Lysyl oxidases are key players during this process, as they initiate collagen crosslinking through the oxidation of the ε-amino group of lysine or hydroxylysine on collagen side-chains, which subsequently dimerize to form immature, or trimerize to form mature, collagen crosslinks. The role of LOXL2 in fibrosis and cancer is well documented, however the specific enzymatic function of LOXL2 and LOXL3 during disease is less clear. Herein, we describe the development of PXS-5153A, a novel mechanism based, fast-acting, dual LOXL2/LOXL3 inhibitor, which was used to interrogate the role of these enzymes in models of collagen crosslinking and fibrosis. PXS-5153A dose-dependently reduced LOXL2-mediated collagen oxidation and collagen crosslinking in vitro. In two liver fibrosis models, carbon tetrachloride or streptozotocin/high fat diet-induced, PXS-5153A reduced disease severity and improved liver function by diminishing collagen content and collagen crosslinks. In myocardial infarction, PXS-5153A improved cardiac output. Taken together these results demonstrate that, due to their crucial role in collagen crosslinking, inhibition of the enzymatic activities of LOXL2/LOXL3 represents an innovative therapeutic approach for the treatment of fibrosis.


Subject(s)
Amino Acid Oxidoreductases/antagonists & inhibitors , Collagen/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Fibrosis/prevention & control , Myocardial Infarction/prevention & control , Non-alcoholic Fatty Liver Disease/prevention & control , Animals , Carbon Tetrachloride/toxicity , Collagen/drug effects , Collagen/metabolism , Cross-Linking Reagents/chemistry , Elastin/antagonists & inhibitors , Elastin/drug effects , Elastin/metabolism , Extracellular Matrix/drug effects , Fibrosis/chemically induced , Fibrosis/enzymology , Fibrosis/pathology , Male , Mice , Mice, Inbred C57BL , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Non-alcoholic Fatty Liver Disease/enzymology , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Rats , Rats, Wistar
9.
Proc Natl Acad Sci U S A ; 114(45): 12051-12056, 2017 11 07.
Article in English | MEDLINE | ID: mdl-29078392

ABSTRACT

Unlike their descendants, mitochondria and plastids, bacteria do not have dedicated protein import systems. However, paradoxically, import of protein bacteriocins, the mechanisms of which are poorly understood, underpins competition among pathogenic and commensal bacteria alike. Here, using X-ray crystallography, isothermal titration calorimetry, confocal fluorescence microscopy, and in vivo photoactivatable cross-linking of stalled translocation intermediates, we demonstrate how the iron transporter FpvAI in the opportunistic pathogen Pseudomonas aeruginosa is hijacked to translocate the bacteriocin pyocin S2 (pyoS2) across the outer membrane (OM). FpvAI is a TonB-dependent transporter (TBDT) that actively imports the small siderophore ferripyoverdine (Fe-Pvd) by coupling to the proton motive force (PMF) via the inner membrane (IM) protein TonB1. The crystal structure of the N-terminal domain of pyoS2 (pyoS2NTD) bound to FpvAI (Kd = 240 pM) reveals that the pyocin mimics Fe-Pvd, inducing the same conformational changes in the receptor. Mimicry leads to fluorescently labeled pyoS2NTD being imported into FpvAI-expressing P. aeruginosa cells by a process analogous to that used by bona fide TBDT ligands. PyoS2NTD induces unfolding by TonB1 of a force-labile portion of the plug domain that normally occludes the central channel of FpvAI. The pyocin is then dragged through this narrow channel following delivery of its own TonB1-binding epitope to the periplasm. Hence, energized nutrient transporters in bacteria also serve as rudimentary protein import systems, which, in the case of FpvAI, results in a protein antibiotic 60-fold bigger than the transporter's natural substrate being translocated across the OM.


Subject(s)
Anti-Bacterial Agents/metabolism , Bacterial Outer Membrane Proteins/metabolism , Biological Transport/physiology , Iron/metabolism , Bacteriocins/metabolism , Crystallography, X-Ray/methods , Membrane Transport Proteins/metabolism , Periplasm/metabolism , Protein Transport/physiology , Pseudomonas aeruginosa/metabolism , Siderophores/metabolism
10.
Biochem J ; 473(18): 2799-812, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27402794

ABSTRACT

Protein antibiotics (bacteriocins) are a large and diverse family of multidomain toxins that kill specific Gram-negative bacteria during intraspecies competition for resources. Our understanding of the mechanism of import of such potent toxins has increased significantly in recent years, especially with the reporting of several structures of bacteriocin domains. Less well understood is the structural biochemistry of intact bacteriocins and how these compare across bacterial species. Here, we focus on endonuclease (DNase) bacteriocins that target the genomes of Escherichia coli and Pseudomonas aeruginosa, known as E-type colicins and S-type pyocins, respectively, bound to their specific immunity (Im) proteins. First, we report the 3.2 Šstructure of the DNase colicin ColE9 in complex with its ultra-high affinity Im protein, Im9. In contrast with Im3, which when bound to the ribonuclease domain of the homologous colicin ColE3 makes contact with the translocation (T) domain of the toxin, we find that Im9 makes no such contact and only interactions with the ColE9 cytotoxic domain are observed. Second, we report small-angle X-ray scattering data for two S-type DNase pyocins, S2 and AP41, into which are fitted recently determined X-ray structures for isolated domains. We find that DNase pyocins and colicins are both highly elongated molecules, even though the order of their constituent domains differs. We discuss the implications of these architectural similarities and differences in the context of the translocation mechanism of protein antibiotics through the cell envelope of Gram-negative bacteria.


Subject(s)
Anti-Bacterial Agents/chemistry , Endonucleases/chemistry , Amino Acid Sequence , Biophysics , Protein Conformation , Sequence Homology, Amino Acid
11.
J Mol Biol ; 427(17): 2852-66, 2015 Aug 28.
Article in English | MEDLINE | ID: mdl-26215615

ABSTRACT

How ultra-high-affinity protein-protein interactions retain high specificity is still poorly understood. The interaction between colicin DNase domains and their inhibitory immunity (Im) proteins is an ultra-high-affinity interaction that is essential for the neutralisation of endogenous DNase catalytic activity and for protection against exogenous DNase bacteriocins. The colicin DNase-Im interaction is a model system for the study of high-affinity protein-protein interactions. However, despite the fact that closely related colicin-like bacteriocins are widely produced by Gram-negative bacteria, this interaction has only been studied using colicins from Escherichia coli. In this work, we present the first crystal structures of two pyocin DNase-Im complexes from Pseudomonas aeruginosa, pyocin S2 DNase-ImS2 and pyocin AP41 DNase-ImAP41. These structures represent divergent DNase-Im subfamilies and are important in extending our understanding of protein-protein interactions for this important class of high-affinity protein complex. A key finding of this work is that mutations within the immunity protein binding energy hotspot, helix III, are tolerated by complementary substitutions at the DNase-Immunity protein binding interface. Im helix III is strictly conserved in colicins where an Asp forms polar interactions with the DNase backbone. ImAP41 contains an Asp-to-Gly substitution in helix III and our structures show the role of a co-evolved substitution where Pro in DNase loop 4 occupies the volume vacated and removes the unfulfilled hydrogen bond. We observe the co-evolved mutations in other DNase-Immunity pairs that appear to underpin the split of this family into two distinct groups.


Subject(s)
Multiprotein Complexes/ultrastructure , Pseudomonas aeruginosa/metabolism , Pyocins/metabolism , Amino Acid Sequence , Base Sequence , Colicins/metabolism , Crystallography, X-Ray , Deoxyribonucleases/metabolism , Deoxyribonucleases/ultrastructure , Molecular Sequence Data , Multiprotein Complexes/genetics , Multiprotein Complexes/metabolism , Mutation , Phylogeny , Protein Binding , Protein Interaction Mapping , Protein Structure, Tertiary/genetics , Pseudomonas aeruginosa/genetics , Sequence Analysis, DNA
12.
Oncotarget ; 6(15): 13019-35, 2015 May 30.
Article in English | MEDLINE | ID: mdl-25968568

ABSTRACT

IRE1 transduces the unfolded protein response by splicing XBP1 through its C-terminal cytoplasmic kinase-RNase region. IRE1 autophosphorylation is coupled to RNase activity through formation of a back-to-back dimer, although the conservation of the underlying molecular mechanism is not clear from existing structures. We have crystallized human IRE1 in a back-to-back conformation only previously seen for the yeast homologue. In our structure the kinase domain appears primed for catalysis but the RNase domains are disengaged. Structure-function analysis reveals that IRE1 is autoinhibited through a Tyr-down mechanism related to that found in the unrelated Ser/Thr protein kinase Nek7. We have developed a compound that potently inhibits human IRE1 kinase activity while stimulating XBP1 splicing. A crystal structure of the inhibitor bound to IRE1 shows an increased ordering of the kinase activation loop. The structures of hIRE in apo and ligand-bound forms are consistent with a previously proposed model of IRE1 regulation in which formation of a back-to-back dimer coupled to adoption of a kinase-active conformation drive RNase activation. The structures provide opportunities for structure-guided design of IRE1 inhibitors.


Subject(s)
Endoribonucleases/chemistry , Endoribonucleases/metabolism , Protein Serine-Threonine Kinases/chemistry , Protein Serine-Threonine Kinases/metabolism , Drug Discovery , Endoribonucleases/antagonists & inhibitors , Endoribonucleases/genetics , Humans , Ligands , Models, Molecular , Phosphorylation , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Multimerization , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Ribonucleases/genetics , Ribonucleases/metabolism , Structure-Activity Relationship , Transfection
13.
PeerJ ; 2: e305, 2014.
Article in English | MEDLINE | ID: mdl-24688880

ABSTRACT

The eukaryotic polypyrimidine tract binding protein (PTB) serves primarily as a regulator of alternative splicing of messenger RNA, but is also co-opted to other roles such as RNA localisation and translation initiation from internal ribosome entry sites. The neuronal paralogue of PTB (nPTB) is 75% identical in amino acid sequence with PTB. Although the two proteins have broadly similar RNA binding specificities and effects on RNA splicing, differential expression of PTB and nPTB can lead to the generation of alternatively spliced mRNAs. RNA binding by PTB and nPTB is mediated by four RNA recognition motifs (RRMs). We present here the crystal and solution structures of the C-terminal domain of nPTB (nPTB34) which contains RRMs 3 and 4. As expected the structures are similar to each other and to the solution structure of the equivalent fragment from PTB (PTB34). The result confirms that, as found for PTB, RRMs 3 and 4 of nPTB interact with one another to form a stable unit that presents the RNA-binding surfaces of the component RRMs on opposite sides that face away from each other. The major differences between PTB34 and nPTB34 arise from amino acid side chain substitutions on the exposed ß-sheet surfaces and adjoining loops of each RRM, which are likely to modulate interactions with RNA.

14.
J Med Chem ; 56(22): 9122-35, 2013 Nov 27.
Article in English | MEDLINE | ID: mdl-24195668

ABSTRACT

Aurora-A differs from Aurora-B/C at three positions in the ATP-binding pocket (L215, T217, and R220). Exploiting these differences, crystal structures of ligand-Aurora protein interactions formed the basis of a design principle for imidazo[4,5-b]pyridine-derived Aurora-A-selective inhibitors. Guided by a computational modeling approach, appropriate C7-imidazo[4,5-b]pyridine derivatization led to the discovery of highly selective inhibitors, such as compound 28c, of Aurora-A over Aurora-B. In HCT116 human colon carcinoma cells, 28c and 40f inhibited the Aurora-A L215R and R220K mutants with IC50 values similar to those seen for the Aurora-A wild type. However, the Aurora-A T217E mutant was significantly less sensitive to inhibition by 28c and 40f compared to the Aurora-A wild type, suggesting that the T217 residue plays a critical role in governing the observed isoform selectivity for Aurora-A inhibition. These compounds are useful small-molecule chemical tools to further explore the function of Aurora-A in cells.


Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Drug Design , Imidazoles/chemistry , Imidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Aurora Kinase A/chemistry , Aurora Kinase A/metabolism , Aurora Kinase B/chemistry , Aurora Kinase B/metabolism , Catalytic Domain , Drug Stability , HCT116 Cells , Humans , Imidazoles/metabolism , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Isoenzymes/metabolism , Male , Mice , Molecular Docking Simulation , Protein Kinase Inhibitors/metabolism , Substrate Specificity
15.
Biochem Soc Trans ; 40(4): 815-20, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22817740

ABSTRACT

PTB (polypyrimidine tract-binding protein) is an abundant and widely expressed RNA-binding protein with four RRM (RNA recognition motif) domains. PTB is involved in numerous post-transcriptional steps in gene expression in both the nucleus and cytoplasm, but has been best characterized as a regulatory repressor of some ASEs (alternative splicing events), and as an activator of translation driven by IRESs (internal ribosome entry segments). We have used a variety of approaches to characterize the activities of PTB and its molecular interactions with RNA substrates and protein partners. Using splice-sensitive microarrays we found that PTB acts not only as a splicing repressor but also as an activator, and that these two activities are determined by the location at which PTB binds relative to target exons. We have identified minimal splicing repressor and activator domains, and have determined high resolution structures of the second RRM domain of PTB binding to peptide motifs from the co-repressor protein Raver1. Using single-molecule techniques we have determined the stoichiometry of PTB binding to a regulated splicing substrate in whole nuclear extracts. Finally, we have used tethered hydroxyl radical probing to determine the locations on viral IRESs at which each of the four RRM domains bind. We are now combining tethered probing with single molecule analyses to gain a detailed understanding of how PTB interacts with pre-mRNA substrates to effect either repression or activation of splicing.


Subject(s)
Polypyrimidine Tract-Binding Protein/metabolism , Alternative Splicing/genetics , Animals , Exons/genetics , Humans , Polypyrimidine Tract-Binding Protein/genetics , RNA/genetics , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism
16.
Structure ; 19(12): 1816-25, 2011 Dec 07.
Article in English | MEDLINE | ID: mdl-22153504

ABSTRACT

The polypyrimidine tract-binding protein (PTB) is an important regulator of alternative splicing. PTB-regulated splicing of α-tropomyosin is enhanced by Raver1, a protein with four PTB-Raver1 interacting motifs (PRIs) that bind to the helical face of the second RNA recognition motif (RRM2) in PTB. We present the crystal structures of RRM2 in complex with PRI3 and PRI4 from Raver1, which--along with structure-based mutagenesis--reveal the molecular basis of their differential binding. High-affinity binding by Raver1 PRI3 involves shape-matched apolar contacts complemented by specific hydrogen bonds, a new variant of an established mode of peptide-RRM interaction. Our results refine the sequence of the PRI motif and place important structural constraints on functional models of PTB-Raver1 interactions. Our analysis indicates that the observed Raver1-PTB interaction is a general mode of binding that applies to Raver1 complexes with PTB paralogues such as nPTB and to complexes of Raver2 with PTB.


Subject(s)
Alternative Splicing , Carrier Proteins/chemistry , Nuclear Proteins/chemistry , Polypyrimidine Tract-Binding Protein/chemistry , Amino Acid Sequence , Binding Sites , Carrier Proteins/metabolism , HeLa Cells , Humans , Hydrogen Bonding , Molecular Sequence Data , Nuclear Proteins/metabolism , Polypyrimidine Tract-Binding Protein/metabolism , RNA/chemistry , RNA/metabolism , Ribonucleoproteins , Transfection
17.
Invest Ophthalmol Vis Sci ; 49(11): 4837-43, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18658091

ABSTRACT

PURPOSE: To investigate the cellular effects of mitomycin C (MMC) treatment on corneal endothelial (CE) cells at clinically relevant applications and dosages. METHODS: Radial and posterior diffusion of MMC was determined by an Escherichia coli growth inhibition bioassay. A modified version of the comet assay (single cell gel electrophoresis) was used to detect DNA cross-linking. Immunostaining detected the nuclear phosphorylated histone variant H2AX (gamma-H2AX) indicating DNA double-strand breaks. Apoptosis in MMC-treated cells was detected with annexin V staining. RESULTS: Topical application of 0.02% MMC to intact goat globes resulted in MMC in the CE at 0.37 microg/mL and produced a significant increase in CE DNA cross-linking with as little as 6 seconds of topical MMC treatment. DNA cross-linking was also demonstrated in cultured CE cells by using MMC exposures similar to those detected in CE of intact eyes. Such MMC treatment of CE produced elevated and persistent gamma-H2AX-positive cells indicative of DNA double-strand breaks. Similarly, there was an increase in the proportion of apoptotic CE cells, evidenced by positive annexin V staining. CONCLUSIONS: The results demonstrate that exposure to MMC at times and concentrations commonly used in refractive surgery produces cross-linking of corneal endothelial DNA, persistent DNA damage, and endothelial death via apoptosis. Current practices of MMC application during refractive surgeries may increase the potential for long-term and permanent deleterious effects on the health of the corneal endothelium.


Subject(s)
Apoptosis/genetics , DNA Breaks, Double-Stranded/drug effects , DNA Damage/drug effects , Endothelium, Corneal/pathology , Mitomycin/administration & dosage , Animals , Annexin A5/metabolism , Cell Count , Cells, Cultured , Comet Assay , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelium, Corneal/drug effects , Endothelium, Corneal/metabolism , Goats , Histones/metabolism , Mitomycin/pharmacokinetics , Nucleic Acid Synthesis Inhibitors/administration & dosage , Nucleic Acid Synthesis Inhibitors/pharmacokinetics , Ophthalmic Solutions , Phosphoproteins , Phosphorylation/drug effects , Postoperative Complications/prevention & control
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