Structural Conversions of Synthetic and Protein-Bound Iron-Sulfur Clusters.

Synthetic iron-sulfur clusters of general formulation [FemSqLl]z with core atoms Fe and S and terminal ligands L constitute a family of molecular clusters with remarkably diverse geometrical and electronic structures. Several structure types are also found in proteins. The large majority of research on these clusters has involved elucidation of physical properties. Here, we direct attention to reactivity in the form of cluster conversions in which the FemSq cores of reactants are transformed to new structures, usually of different nuclearity, in overall reactions such as self-assembly and fragment condensation and dissociation. An extensive body of core conversions, many of which have not been recognized as such, are presented including those in biological systems. All structural core types are depicted, and all core conversions are diagrammatically summarized. Clusters containing the cubane-type Fe4S4 core play a central role in conversion chemistry. The core conversion concept tends to reinforce the description of iron-sulfur cores as modular units subject to various covalent bond interactions that lead to different structures.

PRESUMED PANUVEITIS FOLLOWING COVID-19 VACCINATION IN A PATIENT WITH GRANULOMATOUS TATTOO INFLAMMATION.

PURPOSE: To report a case of panuveitis that developed following COVID-19 vaccination in a patient with a recent history of granulomatous tattoo inflammation. METHODS: Case report. RESULTS: A 25-year-old woman with a recent history of biopsy-proven granulomatous tattoo inflammation developed bilateral eye pain and blurred vision 1 week following her second mRNA-1273 COVID-19 vaccination (Moderna, Inc, Cambridge, MA). Examination revealed bilateral panuveitis. Workup for infectious etiologies and sarcoidosis was negative. The intraocular inflammation initially resolved with systemic prednisone therapy but then recurred following tapering, requiring the initiation of mycophenolate mofetil. CONCLUSION: A case of panuveitis that developed following a COVID-19 vaccination in a patient with a recent history of tattoo inflammation is reported. The temporal relationship between the vaccine and the development of uveitis in this patient may be coincidental and should be interpreted with caution, but multiple vaccines have been associated with uveitis, presumably as a result of their generalized stimulation of the immune system. It is believed that this case of tattoo-associated uveitis may have been exacerbated by the generalized inflammatory effect of COVID-19 vaccination.

Formation, spectroscopic characterization, and solution stability of an [Fe4S4]2+ cluster derived from ß-cyclodextrin dithiolate.

The formation and solution properties, including stability in mixed aqueous-Me(2)SO media, have been investigated for an [Fe(4)S(4)](2+) cluster derived from ß-cyclodextrin (CD) dithiolate. Clusters of the type [Fe(4)S(4)(SAr)(4)](2-) (Ar = Ph, C(6)H(4)-3-F) are generated in Me(2)SO by redox reactions of [Fe(4)S(4)(SEt)(4)](2-) with 2 equiv of ArSSAr. An analogous reaction with the intramolecular disulfide of 6(A),6(D)-(3-NHCOC(6)H(4)-1-SH)(2)-6(A),6(D)-dideoxy-ß-cyclodextrin (14), whose synthesis is described, affords a completely substituted cluster formulated as [Fe(4)S(4){ß-CD-(1,3-NHCOC(6)H(4)S)(2)}(2)](2-) (15). Ligand binding is indicated by a circular dichroism spectrum and also by UV-visible and isotropically shifted (1)H NMR spectra and redox behavior convincingly similar to [Fe(4)S(4)(SPh)(4)](2-). One formulation of 15 is a single cluster to which two dithiolates are bound, each in bidentate coordination. With there being no proven precedent for this binding mode, we show that the cluster [Fe(4)S(4)(S(2)-m-xyl)(2)](2-) is a single cubane whose m-xylyldithiolate ligands are bound in a bidentate arrangement. This same structure type was proposed for a cluster formulated as [Fe(4)S(4){ß-CD-(1,3-SC(6)H(4)S)(2)}(2)](2-) (16; Kuroda et al. J. Am. Chem. Soc.1988, 110, 4049-4050) and reported to be water-stable. Clusters 15 and 16 are derived from similar ligands differing only in the spacer group between the thiolate binding site and the CD platform. In our search for clusters stable in aqueous or organic-aqueous mixed solvents that are potential candidates for the reconstitution of scaffold proteins implicated in cluster biogenesis, 15 is the most stable cluster that we have thus far encountered under anaerobic conditions in the absence of added ligand.

Cubane-type Fe4S4 clusters with chiral thiolate ligation: formation by ligand substitution, detection of intermediates by 1H NMR, and solid state structures including spontaneous resolution upon crystallization.

Cubane-type clusters [Fe(4)S(4)(SR*)(4)](2-) containing chiral thiolate ligands with R* = CH(Me)Ph (1), CH(2)CH(Me)Et (2), and CH(2)CH(OH)CH(2)OH (3) have been prepared by ligand substitution in the reaction systems [Fe(4)S(4)(SEt)(4)]/R*SH (1-3, acetonitrile) and [Fe(4)S(4)Cl(4)](2-)/NaSR*(3, Me(2)SO). Reactions with successive equivalents of thiol or thiolate generate the species [Fe(4)S(4)L(4-n)(SR*)(n)](2-) (L = SEt, Cl) with n = 1-4. Clusters 1 and 2 were prepared with racemic thiols leading to the possible formation of one enantiomeric pair (n = 1) and seven diastereomers and their enantiomers (n = 2-4). Reactions were monitored by isotropically shifted (1)H NMR spectra in acetonitrile or Me(2)SO. In systems affording 1 and 2 as final products, individual mixed-ligand species could not be detected. However, crystallization of (Et(4)N)(2)[1] afforded 1-[SS(RS)(RS)] in which two sites are disordered because of occupancy of R and S ligands. Similarly, (Et(4)N)(2)[2] led to 2-[SSSS], a consequence of spontaneous resolution upon crystallization. The clusters 3-[RRRR] and 3-[SSSS] were obtained from enantiomerically pure thiols. Successive reactions lead to detection of species with n = 1-4 by appearance of four pairs of diastereotopic SCH(2) signals in both acetonitrile and Me(2)SO reaction systems. Identical spectra were obtained with racemic, R-(-), and S-(+) thiols, indicating that ligand-ligand interactions are too weak to allow detection of diastereomers (e.g., [SSSS] vs [SSRR]). The stability of 3 in Me(2)SO/H(2)O media is described.

Stabilization of 3:1 site-differentiated cubane-type clusters in the [Fe(4)S(4)](1+) core oxidation state by tertiary phosphine ligation: synthesis, core structural diversity, and S = 1/2 ground states.

An extensive series of 3:1 site-differentiated cubane-type clusters [Fe(4)S(4)(PPr(i)(3))(3)L] (L = Cl(-), Br(-), I(-), RO(-), RS(-), RSe(-)) has been prepared in 40-80% yield by two methods: ligand substitution of [Fe(4)S(4)(PPr(i)(3))(4)](1+) in tetrahydrofuran (THF)/acetonitrile by reaction with monoanions, and reductive cleavage of ligand substrates (RSSR, RSeSeR, I(2)) by the all-ferrous clusters [Fe(8)S(8)(PPr(i)(3))(6)]/[Fe(16)S(16)(PPr(i)(3))(8)] in THF. These neutral clusters are stable and do not undergo ligand redistribution reactions involving charged species in benzene and THF solutions. X-ray structural studies confirm the cubane stereochemistry but with substantial and variable distortions of the [Fe(4)S(4)](1+) core from idealized cubic core geometry. Based on Fe-S bond lengths, seven clusters were found to have compressed tetragonal distortions (4 short and 8 long bonds), and the remaining seven display other types of distortions with different combinations of long, short, and intermediate bond lengths. These results further emphasize the facile deformabililty of this core oxidation state previously observed in [Fe(4)S(4)(SR)(4)](3-) clusters. The Fe(2.25+) mean oxidation state was demonstrated from (57)Fe isomer shifts, and the appearance of two quadrupole doublets arises from the spin-coupled |9/2,4,1/2> state. The S = 1/2 ground state was further supported by electron paramagnetic resonance spectra and magnetic susceptibility data.

Illumination with ultraviolet or visible light induces chemical changes in the water-soluble manganese complex, [Mn(4)O(6)(bpea)(4)]Br(4).

We measured the photosensitivity of an artificial tetranuclear oxo-Mn(IV) complex, [Mn(4)O(6)(bpea)(4)]Br(4), which has an adamantane-shaped {Mn(4)O(6)}(4+) core. Illumination caused changes in the absorption spectrum of the compound consistent with a one-electron reduction in the compound. Bromide appears to be the most probable electron donor in the reaction system. Chemical modification of the cluster appears to destabilize it, predisposing it to reductive degradation. UV light was more efficient than visible light in causing the changes. The data support the suggestion that the natural oxygen-evolving Mn complex is photosensitive and can oxidize components of the oxygen-evolving complex in its excited state causing photoinhibition, and that photostability is an important issue in designing Mn complexes for artificial photosynthesis. Furthermore, light-induced oxidation of bromide by [Mn(4)O(6)(bpea)(4)](4+) may suggest that oxidation of chloride is involved in natural water splitting or has been involved during the evolution of the water-splitting enzyme.

Visual outcomes and incidence of recurrent vitreous hemorrhage after vitrectomy in diabetic eyes pretreated with bevacizumab (avastin).

PURPOSE: To evaluate the safety and effect of bevacizumab pretreatment on the incidence of recurrent vitreous hemorrhage and visual acuity after vitrectomy for proliferative diabetic retinopathy. METHODS: This was a consecutive, retrospective, and comparative cohort study. Patients undergoing vitrectomy from September 2006 through November 2007 at the Emory Eye Center for complications of proliferative diabetic retinopathy were identified and reviewed. A total of 33 eyes pretreated with bevacizumab and 104 untreated eyes were observed for postoperative vitreous hemorrhage and final visual acuity. RESULTS: Patients in the bevacizumab group were significantly younger than those in the untreated group (average age, 46.4 vs. 58.4 years) and were more likely to have 20-gauge instrumentation (58% vs. 36%). An average of 9.6 days passed between injection and surgery. Early (4-6 weeks) rebleed rates were 15% versus 13% in the bevacizumab and untreated groups, respectively, and not statistically different. Preoperative (7/200 vs. count finger at 4'), 1-month postoperative (20/200(-3) vs. 20/150), and 3-month postoperative visual acuity (20/100(-3) vs. 20/100(+2)) were not statistically different between groups. No statistical difference was found in rebleed rates regarding the gauge of vitrectomy. CONCLUSION: Bevacizumab pretreatment for diabetic vitrectomy was not associated with any observed complications but did not influence rates of postoperative vitreous hemorrhage or final visual acuity in this retrospective series. The overall incidence of postoperative early vitreous hemorrhage in this series was 13% and seems lower than historically reported rates.

Macular hole formation, spontaneous closure, and recurrence in a previously vitrectomized eye.

PURPOSE: To report a case of recurrent idiopathic macular hole after spontaneous closure in a previously vitrectomized eye. DESIGN: Case report. METHODS: A 69-year-old woman who had had vitrectomy for vitreous hemorrhage seven years earlier presented with decreased visual acuity and a macular hole. The hole spontaneously resolved within four months. One year later, the macular hole reopened. Internal limiting membrane peeling was performed, resulting in return of visual acuity. Optical coherence tomography (OCT) was obtained during all visits. RESULTS: Initial OCT revealed a macular hole with perifoveal cystoid degeneration and bridging elements. At subsequent visits, OCT showed resolution of the cystoid degeneration. The preoperative OCT demonstrates recurrence of the macular hole with similar perifoveal abnormalities. CONCLUSIONS: After vitrectomy, anteroposterior vitreofoveal traction associated with most macular hole formation does not apply. OCT demonstrates foveal structure and forces coincident with hole formation and resolution. Dynamic interaction between tensile and degenerative forces, and proliferative and reparative glial elements, may lead to hole remodeling.

Histopathologic examination of conjunctival tophi in gouty arthritis.

PURPOSE: To report a case of conjunctival tophi in a 59-year-old woman with gouty arthritis. DESIGN: Observational case report. METHODS: A 59-year-old woman with a 25-year history of severe gouty arthritis presented with bilateral chalky white conjunctival deposits. Conjunctival biopsies were obtained, and light and electron microscopy studies were performed. RESULTS: Light microscopy confirmed multiple gouty tophi. Transmission electron microscopy revealed intracytoplasmic crystalline deposits within histiocytes. Extracellular aggregates of the crystalline deposits were enclosed by membranous material. CONCLUSIONS: Conjunctival crystals may aid in identifying undiagnosed patients. In addition to conjunctival tophi, patients may also have uveitis, corneal crystals, and band keratopathy.

Tissue differential microarray analysis of dexamethasone induction reveals potential mechanisms of steroid glaucoma.

PURPOSE: To identify myocilin (TIGR/MYOC) properties that are specific to the human trabecular meshwork (HTM). To search for genes highly expressed in dexamethasone (DEX)-induced HTM cells that are barely expressed or absent in DEX-induced cells from other tissues. METHODS: TIGR/MYOC induction by DEX (10(-7) M for 8-10 days) was analyzed by Northern and Western blot analyses in HTM, human umbilical vein endothelial cells, HeLa cells, and human embryonic skeletal muscle cells and optic nerve head (ONH) astrocytes at confluence. Processing and secretion were analyzed after the cells were infected with adenoviruses overexpressing wild-type and mutant forms of TIGR/MYOC. Affymetrix U95Av2 GeneChips (n = 6) and software were used to compare paired expression profiles of HTM, HTM-DEX, ONH astrocytes, and ONH astrocytes-DEX. Identification of HTM-DEX-specific genes (compared with ONH astrocytes-DEX) was performed by selecting genes with the highest fold change values (>/=20). Genes with fold change values of four or more were matched with loci linked to glaucoma, by using gene databases. RESULTS: TIGR/MYOC induction by DEX occurred only in HTM cells. Secretory and glycosylation characteristics remained the same across cell types. Expression profile analysis revealed multiple genes differentially upregulated in HTM-DEX including, in addition to TIGR/MYOC, a serine protease inhibitor (alpha1-antichymotrypsin), a neuroprotective factor (pigment epithelium-derived factor), an antiangiogenesis factor (cornea-derived transcript 6), and a prostaglandin synthase (prostaglandin D(2) synthase). Fifteen of the 249 genes with fold change values of four or more mapped to glaucoma-linked loci. CONCLUSIONS: The induction of TIGR/MYOC by DEX is HTM-specific, whereas its secretory and glycosylation characteristics are ubiquitous. The known functions of HTM-DEX-specific genes reveal the presence of protective and damaging mechanisms for regulation of IOP during DEX treatment. Besides TIGR/MYOC, other HTM-DEX-specific genes may be good candidates for linkage to glaucoma.

Studies of iron(II) and iron(III) complexes with fac-N2O, cis-N2O2 and N2O3 donor ligands: models for the 2-His 1-carboxylate motif of non-heme iron monooxygenases.

Enzymes in the oxygen-activating class of mononuclear non-heme iron oxygenases (MNOs) contain a highly conserved iron center facially ligated by two histidine nitrogen atoms and one carboxylate oxygen atom that leave one face of the metal center (three binding sites) open for coordination to cofactor, substrate, and/or dioxygen. A comparative family of [Fe(II/III)(N(2)O(n))(L)(4-n))](±x), n = 1-3, L = solvent or Cl(-), model complexes, based on a ligand series that supports a facially ligated N,N,O core that is then modified to contain either one or two additional carboxylate chelate arms, has been structurally and spectroscopically characterized. EPR studies demonstrate that the high-spin d(5) Fe(III)g = 4.3 signal becomes more symmetrical as the number of carboxylate ligands decreases across the series Fe(N(2)O(3)), Fe(N(2)O(2)), and Fe(N(2)O(1)), reflecting an increase in the E/D strain of these complexes as the number of exchangeable/solvent coordination sites increases, paralleling the enhanced distribution of electronic structures that contribute to the spectral line shape. The observed systematic variations in the Fe(II)-Fe(III) oxidation-reduction potentials illustrate the fundamental influence of differential carboxylate ligation. The trend towards lower reduction potential for the iron center across the [Fe(III)(N(2)O(1))Cl(3)](-), [Fe(III)(N(2)O(2))Cl(2)](-) and [Fe(III)(N(2)O(3))Cl](-) series is consistent with replacement of the chloride anions with the more strongly donating anionic O-donor carboxylate ligands that are expected to stabilize the oxidized ferric state. This electrochemical trend parallels the observed dioxygen sensitivity of the three ferrous complexes (Fe(II)(N(2)O(1)) < Fe(II)(N(2)O(2)) < Fe(II)(N(2)O(3))), which form µ-oxo bridged ferric species upon exposure to air or oxygen atom donor (OAD) molecules. The observed oxygen sensitivity is particularly interesting and discussed in the context of α-ketoglutarate-dependent MNO enzyme mechanisms.

Stabilities of cubane type [Fe4S4(SR)4](2-) clusters in partially aqueous media.

The stability of cubane-type [Fe4S4(SR)4](2-) clusters in mixed organic/aqueous solvents was examined as an initial step in the development of stable water-soluble cluster compounds possibly suitable for reconstitution of scaffold proteins in protein biosynthesis. The research involves primarily spectrophotometric assessment of stability in 20-80% Me2SO/aqueous media (v/v), from which it was found that conventional clusters tend to be stable for up to 12h in 60% Me2SO but are much less stable at higher aqueous content. α-Cyclodextrin mono- and dithioesters and thiols were prepared as ligand precursors for cluster binding, which was demonstrated by spectroscopic methods. A potentially bidentate cyclodextrin dithiolate was found to be relatively effective for cluster stabilization in 40% Me2SO, suggesting (together with earlier results) that other exceptionally large thiolate ligands may promote cluster stability in aqueous media.

Topical ketorolac in vitreoretinal surgery: a prospective, randomized, placebo-controlled, double-masked trial.

OBJECTIVE: To evaluate the effects of topical ketorolac in patients undergoing vitreoretinal surgery. METHODS: One hundred nine patients undergoing vitrectomies were randomized to receive either topical ketorolac tromethamine, 0.4%, or placebo. Patients were instructed to begin taking the study medication 3 days preoperatively (4 times daily) and to continue taking it 4 weeks postoperatively. MAIN OUTCOME MEASURES: Intraoperative pupil diameter, postoperative day 1 pain and inflammation, 1-month postoperative retinal thickness, and preoperative and 1-month postoperative best-corrected visual acuities. RESULTS: The difference in mean pupil diameters between patients using ketorolac and those taking placebo was 0.06 mm (P = .39). Patients taking ketorolac and those taking placebo had mean pain scores (scale, 1-10) of 0.24 (SD, 0.6) and 1.06 (SD, 2) (P = .03) and mean inflammation grades (grade, 0-4) of 0.59 (SD, 0.7) and 1.16 (SD, 0.9) (P < .001), respectively. Ketorolac reduced central subfield thickness by 8%, but this was not statistically significant. At 1 month, mean visual acuities improved to 0.40 logMAR units (mean Snellen, 20/50; SD, 0.28 logMAR units) in the ketorolac group from 0.83 logMAR units (20/150(+2); SD, 0.60 logMAR units) at baseline and to 0.67 logMAR units (20/100(+1); SD, 0.46 logMAR units) in the placebo group from 0.92 logMAR units (20/150(-2); SD, 0.62 logMAR units) at baseline (P = .001). CONCLUSIONS: Topical ketorolac was well tolerated and safe, reduced postoperative pain and inflammation, and improved visual recovery in this prospective, double-masked trial. APPLICATION TO CLINICAL PRACTICE: Topical ketorolac may benefit patients undergoing vitreoretinal surgery. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00576329.