Morphological characteristics of eyes with neovascular age-related macular degeneration and good long-term visual outcomes after anti-VEGF therapy.

PURPOSE: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy. METHODS: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands. RESULTS: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 µm) compared with the intermediate (86.25 µm) or good (97.92 µm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 µm) compared with eyes with intermediate vision (64.37 µm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 µm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001). CONCLUSION: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment.

Chirality transmission in macromolecular domains.

Chiral communications exist in secondary structures of foldamers and copolymers via a network of noncovalent interactions within effective intermolecular force (IMF) range. It is not known whether long-range chiral communication exists between macromolecular tertiary structures such as peptide coiled-coils beyond the IMF distance. Harnessing the high sensitivity of single-molecule force spectroscopy, we investigate the chiral interaction between covalently linked DNA duplexes and peptide coiled-coils by evaluating the binding of a diastereomeric pair of three DNA-peptide conjugates. We find that right-handed DNA triple helices well accommodate peptide triple coiled-coils of the same handedness, but not with the left-handed coiled-coil stereoisomers. This chiral communication is effective in a range (<4.5 nm) far beyond canonical IMF distance. Small-angle X-ray scattering and molecular dynamics simulation indicate that the interdomain linkers are tightly packed via hydrophobic interactions, which likely sustains the chirality transmission between DNA and peptide domains. Our findings establish that long-range chiral transmission occurs in tertiary macromolecular domains, explaining the presence of homochiral pairing of superhelices in proteins.

Chalcogen Bond Mediated Enhancement of Cooperative Ion-Pair Recognition.

A series of heteroditopic receptors containing halogen bond (XB) and unprecedented chalcogen bond (ChB) donors integrated into a 3,5-bis-triazole pyridine structure covalently linked to benzo-15-crown-5 ether motifs exhibit remarkable cooperative recognition of halide anions. Multi-nuclear 1 H, 13 C, 125 Te and 19 F NMR, ion pair binding investigations reveal sodium cation-benzo-crown ether binding dramatically enhances the recognition of bromide and iodide halide anions, with the chalcogen bonding heteroditopic receptor notably displaying the largest enhancement of halide binding strength of over two hundred-fold, in comparison to the halogen bonding and hydrogen bonding heteroditopic receptor analogues. DFT calculations suggest crown ether sodium cation complexation induces a polarisation of the sigma hole of ChB and XB heteroditopic receptor donors as a significant contribution to the origin of the unique cooperativity exhibited by these systems.

Extranodal Rosai-Dorfman of the Pancreas Presents with Bilateral Granulomatous Anterior Uveitis.

BACKGROUND/AIMS: To report a case of a 65-year-old female who presented with bilateral anterior granulomatous uveitis, which led to the diagnosis of Rosai-Dorfman Disease (RDD) and the discovery of an associated pancreatic mass. METHODS: This is a retrospective case report of a single patient. RESULTS: A 65-year-old African American Female received a full workup for bilateral anterior granulomatous uveitis and was found to have a pancreatic mass on imaging. Biopsy of this mass was diagnostic for RDD, a rare proliferative histiocytic disorder, which classically presents with painless cervical lymphadenopathy, leukocytosis, and hypergammaglobulinemia. CONCLUSION: Although rare, ocular involvement, including eyelid and orbital masses, and anterior uveitis, can herald the development of other systemic manifestations or RDD and can aid in the diagnosis of this systemic disease.

Therapeutic potential of curcumin in major retinal pathologies.

PURPOSE: The retina is continually exposed to free radicals from its rich blood supply, numerous mitochondria, and photons of light which strike its surface. Most pathological processes that take place in the retina, such as inflammation, cell apoptosis, or angiogenesis, can hence involve free radicals directly or indirectly.  Since inflammatory and oxidative stress pathways underlie retinal pathology, compounds that address these factors are therefore natural choices for treatment. This review article summarizes and provides commentary on curcumin's therapeutic potential use in ophthalmology with principal focus on retinal dosorders. METHODS: Curcumin (diferuloylmethane) is a compound of the Indian spice turmeric (Curcuma longa) that has been found to be efficacious in preventing and treating a number of inflammatory diseases and neoplastic processes. Curcumin exerts anti-inflammatory, anti-tumor, antioxidant, and VEGF inhibition properties through modulation of numerous biochemical mediators. This makes curcumin particularly effective in retinal disorders. RESULTS: Curcumin has found a role in slowing, and in some cases even reversing, age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, proliferative vitreoretinopathy, and retinal cancers. CONCLUSIONS: However, studies on curcumin's efficacy have been limited mostly to animal studies. Moreover, the biomedical potential of curcumin is not easy to use, given its low solubility and oral bioavailability-more attention therefore has been given to nanoparticles and liposomes.

Enzyme-free synthesis of cyclic single-stranded DNA constructs containing a single triazole, amide or phosphoramidate backbone linkage and their use as templates for rolling circle amplification and nanoflower formation.

Cyclic oligonucleotides are valuable targets with a broad range of potential applications spanning molecular biology and nanotechnology. Of particular importance is their role as templates in the rolling circle amplification (RCA) reaction. We describe three different chemical cyclisation methods for the preparation of single-stranded cyclic DNA constructs. These chemical cyclisation reactions are cheaper to carry out than the enzymatic reaction, and more amenable to preparative scale purification and characterisation of the cyclic product. They can also be performed under denaturing conditions and are therefore particularly valuable for cyclic DNA templates that contain secondary structures. The resulting single-stranded cyclic DNA constructs contain a single non-canonical backbone linkage at the ligation point (triazole, amide or phosphoramidate). They were compared to unmodified cyclic DNA in rolling circle amplification reactions using φ-29 and Bst 2.0 DNA polymerase enzymes. The cyclic templates containing a phosphoramidate linkage were particularly well tolerated by φ-29 polymerase, consistently performing as well in RCA as the unmodified DNA controls. Moreover, these phosphoramidate-modified cyclic constructs can be readily produced in oligonucleotide synthesis facilities from commercially available precursors. Phosphoramidate ligation therefore holds promise as a practical, scalable method for the synthesis of fully biocompatible cyclic RCA templates. The triazole-modified cyclic templates generally gave lower and more variable yields of RCA products, a significant proportion of which were double-stranded, while the performances of the templates containing an amide linkage lie in between those of the phosphoramidate- and triazole-containing templates.

A Bis-Triazacyclononane Tris-Pyridyl N9 -Azacryptand "Beer Can" Receptor for Complexation of Alkali Metal and Lead(II) Cations.

A new bis-triazacyclononane tris-pyridyl N9 -azacryptand ligand is prepared via a convenient one-pot [2+3] condensation reaction between triazacyclononane and 2,6-bis(bromomethyl) pyridine in the presence of M2 CO3 (M=Li, Na, K). The proton, lithium, sodium, potassium and lead(II) complexes of the ligand are characterised in the solid state. Preliminary solution-phase competition experiments indicate that the cryptand ligand preferentially binds lead(II) in the presence of sodium, calcium, potassium and zinc cations in methanol solution.

Copper(ii)-directed synthesis of neutral heteroditopic [2]rotaxane ion-pair host systems incorporating hydrogen and halogen bonding anion binding cavities.

Neutral heteroditopic [2]rotaxane ion-pair host systems were synthesised via a Cu(ii) directed passive metal template strategy. Each rotaxane contains discrete, axle-separated interlocked binding sites for a guest anion and a transition metal countercation. The anion binding sites are composed of convergent X-H (X = C, N) hydrogen bond donor groups, or mixed X-H and C-I hydrogen and halogen bond donor groups, whereas an equivalent three-dimensional array of amine, pyridine and carbonyl oxygen donor groups comprise the transition metal binding site. 1H NMR titrations experiments in CDCl3/CD3OD or CDCl3/CD3OD/D2O solvent mixtures reveal that the heteroditopic [2]rotaxane host systems are capable of cooperative anion recognition in the presence of a co-bound Zn(ii) cation.

Active metal template synthesis of a neutral indolocarbazole-containing [2]rotaxane host system for selective oxoanion recognition.

An active metal template strategy was used to synthesise a neutral indolocarbazole containing [2]rotaxane anion host system. 1H NMR anion binding investigations reveal that the [2]rotaxane recognises a range of monoanions in acetone-d5 : D2O 95 : 5 with an unusual interlocked host selectivity for acetate and dihydrogenphosphate oxoanions over halides. The rotaxane displays an overall selectivity for the sulfate dianion, favouring a 2 : 1 host : guest binding stoichiometry at low sulfate concentration and a 1 : 1 stoichiometry in the presence of excess sulfate. Fluorescence titration demonstrates that the [2]rotaxane is also capable of sensing guest anions via significant changes in its emission spectrum.

Neutral iodotriazole foldamers as tetradentate halogen bonding anion receptors.

Neutral tetradentate halogen bond donor foldamers were synthesised and exhibit enhanced anion affinities over their hydrogen bonding analogues, displaying iodide selectivity over lighter halide, carboxylate and dihydrogen phosphate anions. A foldamer with a chiral (S)-binaphthol motif was demonstrated to distinguish between enantiomers of chiral anions.

Halogen bonding anion recognition.

A halogen bond is an attractive non-covalent interaction between an electrophilic region in a covalently bonded halogen atom and a Lewis base. While these interactions have long been exploited as a tool in crystal engineering their powerful ability to direct supramolecular self-assembly and molecular recognition processes in solution has, until recently, been overlooked. During the last decade however an ever-increasing number of studies on solution-phase halogen-bond-mediated anion recognition processes has emerged. This Feature Article summarises advancements which have been made thus far in this rapidly developing research area. We survey the use of iodoperfluoroarene, haloimidazolium and halotriazole/triazolium halogen-bond-donor motifs in anion receptor design, before providing an account of our research into the application of mechanically interlocked rotaxane and catenane frameworks as halogen bonding anion host systems.

Chloride-Anion-Templated Synthesis of a Strapped-Porphyrin-Containing Catenane Host System.

The synthesis, structure and anion-recognition properties of a new strapped-porphyrin-containing [2]catenane anion host system are described. The assembly of the catenane is directed by discrete chloride anion templation acting in synergy with secondary aromatic donor-acceptor and coordinative pyridine-zinc interactions. The [2]catenane incorporates a three-dimensional, hydrogen-bond-donating anion-binding pocket; solid-state structural analysis of the catenane⋅chloride complex reveals that the chloride anion is encapsulated within the catenane's interlocked binding cavity through six convergent CH⋅⋅⋅⋅Cl and NH⋅⋅⋅Cl hydrogen-bonding interactions and solution-phase (1) H NMR titration experiments demonstrate that this complementary hydrogen-bonding arrangement facilitates the selective recognition of chloride over larger halide anions in DMSO solution.

Ligation driven (19)F relaxation enhancement in self-assembled Ln(III) complexes.

Strong bidentate ligation between a fluorinated isophthalate and binuclear lanthanide-DO3A species yields a new class of (19)F NMR agent with very high nuclear relaxation rates at physiologically-relevant pH.

Evidence for halogen bond covalency in acyclic and interlocked halogen-bonding receptor anion recognition.

The synthesis and anion binding properties of novel halogen-bonding (XB) bis-iodotriazole-pyridinium-containing acyclic and [2]catenane anion host systems are described. The XB acyclic receptor displays selectivity for acetate over halides with enhanced anion recognition properties compared to the analogous hydrogen-bonding (HB) acyclic receptor. A reversal in halide selectivity is observed in the XB [2]catenane, in comparison to the acyclic XB receptor, due to the interlocked host's unique three-dimensional binding cavity, and no binding is observed for oxoanions. Notable halide anion association constant values determined for the [2]catenane in competitive organic-aqueous solvent mixtures demonstrate considerable enhancement of anion recognition as compared to the HB catenane analogue. X-ray crystallographic analysis of a series of halide catenane complexes reveal strong XB interactions in the solid state. These interactions were studied using Cl and Br K-edge X-ray Absorption Spectroscopy (XAS) indicating intense pre-edge features characteristic of charge transfer from the halide to its bonding partner (σ(AX←X(-))(*) ← X1s), and providing a direct measure of the degree of covalency in the halogen bond(s). The data reveal that the degree of covalency is similar to that which is observed in transition metal coordinate covalent bonds. These results are supported by DFT results, which correlate well with the experimental data.

Self-assembly between dicarboxylate ions and binuclear europium complexes: moving to water-pH dependence and effects of buffers.

Binuclear lanthanide complexes consisting of two lanthanide binding domains in kinetically stable DO3A binding pockets linked by a 3-functionalized meta-xylyl bridge form stable 1:1 adducts with isophthalate and dinicotinate in water. The influence of buffer, pH and ligand structure on the binding of dinicotinate has been investigated.

Porphyrin-functionalised rotaxanes for anion recognition.

The synthesis and anion-recognition properties of two new porphyrin-functionalised [2]rotaxane host molecules are described. The rotaxane compounds are prepared via a chloride-anion-templated clipping strategy. (1)H NMR titration experiments demonstrate that the rotaxane host systems exhibit high binding affinities and general selectivities for chloride anions in DMSO-d(6) or CDCl(3)/CD(3)OD solvent systems. UV-visible and fluorescence spectroscopy experiments reveal that the rotaxane receptors are ineffective as optical anion sensors. However, both receptors are shown to be capable of detecting chloride anions electrochemically via cathodic shifts in the porphyrin P/P(+) redox couples.

Interlocked host anion recognition by an indolocarbazole-containing [2]rotaxane.

The design, synthesis, structure, and anion-binding properties of the first indolocarbazole-containing interlocked structure are described. The novel [2]rotaxane molecular structure incorporates a neutral indolocarbazole-containing axle component which is encircled by a tetracationic macrocycle functionalized with an isophthalamide anion recognition motif. (1)H NMR and UV-visible spectroscopies and X-ray crystallography demonstrated the importance of pi-donor-acceptor, CH...pi, and electrostatic interactions in the assembly of pseudorotaxanes between the electron-deficient tetracationic macrocycle and a series of pi-electron-rich indolocarbazole derivatives. Subsequent urethane stoppering of one of these complexes afforded a [2]rotaxane, which was shown by (1)H NMR spectroscopic titration experiments to exhibit enhanced chloride and bromide anion recognition compared to its non-interlocked components. Computational molecular dynamics simulations provide further insight into the mechanism and structural nature of the anion recognition process, confirming it to involve cooperative hydrogen-bond donation from both macrocycle and indolocarbazole components of the rotaxane. The observed selectivity of the [2]rotaxane for chloride is interpreted in terms of its unique interlocked binding cavity, defined by the macrocycle isophthalamide and indolocarbazole N-H protons, which is complementary in size and shape to this halide guest.

Anion templated formation of pseudorotaxane and rotaxane monolayers on gold from neutral components.

The surface covalent attachment of indolocarbazole axles enables anion templation to be exploited in the formation of pseudorotaxane assemblies via the threading of neutral isophthalamide macrocycles from solution. The anion selectivity of this templating process can be monitored by a number of surface spectroscopic methods and shows subtle differences compared to the same process in solution. Though the fluxional and disordered nature of ethylene glycol extended axle adlayers prohibits detectable threading on the surface, rotaxane monolayers can be generated by a preassociation of the components and templating anion in solution. The threaded macrocycles therein can subsequently be released and detected by mass spectrometry by reductive stripping of the axle.

Sulfate anion templation of a neutral pseudorotaxane assembly using an indolocarbazole threading component.

The first example of anion templated pseudorotaxane formation between two neutral components in solution and in surface assembled monolayers is described.