Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies.

Purpose: Intravitreal delivery of therapeutic transgenes to the retina via engineered viral vectors can provide sustained local concentrations of therapeutic proteins and thus potentially reduce the treatment burden and improve long-term vision outcomes for patients with neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy.

Methods: We performed directed evolution in nonhuman primates (NHP) to invent an adeno-associated viral (AAV) variant (R100) with the capacity to cross vitreoretinal barriers and transduce all regions and layers of the retina following intravitreal injection. We then engineered 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA sequence that inhibits expression of VEGF-C.

Meniscus-assisted solution printing of large-grained perovskite films for high-efficiency solar cells.

Control over morphology and crystallinity of metal halide perovskite films is of key importance to enable high-performance optoelectronics. However, this remains particularly challenging for solution-printed devices due to the complex crystallization kinetics of semiconductor materials within dynamic flow of inks. Here we report a simple yet effective meniscus-assisted solution printing (MASP) strategy to yield large-grained dense perovskite film with good crystallization and preferred orientation.

Carrier dynamics and the role of surface defects: Designing a photocatalyst for gas-phase CO2 reduction.

InO(OH) nanoparticles have been shown to function as an effective gas-phase photocatalyst for the reduction of CO to CO via the reverse water-gas shift reaction. Their photocatalytic activity is strongly correlated to the number of oxygen vacancy and hydroxide defects present in the system. To better understand how such defects interact with photogenerated electrons and holes in these materials, we have studied the relaxation dynamics of InO(OH) nanoparticles with varying concentration of defects using two different excitation energies corresponding to above-band-gap (318-nm) and near-band-gap (405-nm) excitations.

Spatial Separation of Charge Carriers in In2O3-x(OH)y Nanocrystal Superstructures for Enhanced Gas-Phase Photocatalytic Activity.

The development of strategies for increasing the lifetime of photoexcited charge carriers in nanostructured metal oxide semiconductors is important for enhancing their photocatalytic activity. Intensive efforts have been made in tailoring the properties of the nanostructured photocatalysts through different ways, mainly including band-structure engineering, doping, catalyst-support interaction, and loading cocatalysts. In liquid-phase photocatalytic dye degradation and water splitting, it was recently found that nanocrystal superstructure based semiconductors exhibited improved spatial separation of photoexcited charge carriers and enhanced photocatalytic performance.

Photoexcited Surface Frustrated Lewis Pairs for Heterogeneous Photocatalytic CO2 Reduction.

In this study we investigated, theoretically and experimentally, the unique photoactive behavior of pristine and defected indium oxide surfaces providing fundamental insights into their excited state properties as well as an explanation for the experimentally observed enhanced activity of defected indium oxide surfaces for the gas-phase reverse water gas shift reaction, CO2 + H2 + hν→ CO + H2O in the light compared to the dark. To this end, a detailed excited-state study of pristine and defected forms of indium oxide (In2O3, In2O3-x, In2O3(OH)y and In2O3-x(OH)y) surfaces was performed using time dependent density functional theory (TDDFT) calculations, the results of which were supported experimentally by transient absorption spectroscopy and photoconductivity measurements. It was found that the surface frustrated Lewis pairs (FLPs) created by a Lewis acidic coordinately unsaturated surface indium site proximal to an oxygen vacancy and a Lewis basic surface hydroxide site in In2O3-x(OH)y become more acidic and basic and hence more active in the ES compared to the GS.

Electronic and vibrational dynamics of hollow au nanocages embedded in cu2 o shells.

We have synthesized hollow Au nanocages embedded within thick porous shells of cuprous oxide (Cu2 O). The shell causes a significant redshift of the localized surface plasmon resonance of Au into the near-IR. Electron-phonon coupling in the Au nanocage is 3-6 times faster in the core-shell structure due to the higher thermal conductivity of Cu2 O compared to water.

Self-assembled nanostructured photoanodes with staggered bandgap for efficient solar energy conversion.

Vertically oriented Ta-W-O nanotube array films were fabricated via the anodization of Ta-W alloy foils in HF-containing electrolytes. HF concentration is a key parameter in achieving well-adhered nanotube array structure. X-ray photoelectron spectroscopy (XPS) and diffuse reflectance measurements confirm the staggered band-alignment between Ta2O5 and WO3, which facilitates the separation of charge carriers.

Energy-transfer efficiency in Eu-doped ZnO thin films: the effects of oxidative annealing on the dynamics and the intermediate defect states.

We have studied ultrafast dynamics in thin films of Eu-doped zinc oxide (ZnO), prepared by radio-frequency sputtering onto sapphire substrates. Following UV excitation of ZnO, a red emission is observed. Postdeposition annealing in an oxygen atmosphere improves the crystallinity and emission intensity of the films, which are highly sensitive to the dopant concentration.

Different Methods of Increasing the Mechanical Strength of Gold Nanocages.

Using the ultrafast coherent modulation of the surface plasmon band intensity with the totally symmetric lattice vibration of gold nanocages, we were able to determine and use their frequencies as a measure of the cage's mechanical stability. The presence of an inner "stiff" transition-metal nanoshell with a higher value of the elastic modulus is found to increase the frequency of the lattice vibration of the outer soft gold nanoshell. This could also explain the observed increase in both the gold lattice vibrational frequency as well as the lattice vibration relaxation time in the Au-Pt and Au-Pd double-shell nanocages.

Role of solvent-oxygen ion pairs in photooxidation of CdSe nanocrystal quantum dots.

Understanding the mechanisms for photodegradation of nanocrystal quantum dots is an important step toward their application in real-world technologies. A usual assumption is that photochemical modifications in nanocrystals, such as their photooxidation, are triggered by absorption of a photon in the dot itself. Here, we demonstrate that, contrary to this commonly accepted picture, nanocrystal oxidation can be initiated by photoexcitation of solvent-oxygen ion pairs that relax to produce singlet oxygen, which then reacts with the nanocrystals.

Tailoring plasmonic and electrostatic field effects to maximize solar energy conversion by bacteriorhodopsin, the other natural photosynthetic system.

We have explored the plasmonic field enhancement of current production from bacteriorhodopsin (bR) by maximizing the blue light effect, where the influx of blue photons absorbed by the long-lived M intermediate drastically shortens the time scale of the bR photocycle, leading to current enhancement. To this end, we used three approaches in our solution-based cell: (1) We improved the charge carrier separation in solution through the use of a proton-selective Nafion membrane. (2) We maximized the plasmonic surface field effects by selecting the capping polymer with minimum surface field screening and best nanoparticle stability.

Effect of organic passivation on photoinduced electron transfer across the quantum dot/TiO2 interface.

We report a study of the internal quantum efficiency (IQE) of CdSe quantum-dot (QD)-sensitized solar cells prepared by direct adsorption of pre-synthesized QDs, passivated with either tri-n-octylphosphine oxide (TOPO) or n-butylamine (BA), onto a nanocrystalline TiO(2) film.

Development and validation of an improved inducer-regulator protein complex in the pBRES-regulated expression system.

Widespread adaptation of small molecule-regulated expression systems requires the development of selective inducer molecules that do not have any significant side effects on the endogenous receptors from which the regulated expression system is derived. Here we report the identification and in vitro validation of a novel inducer-receptor pair for the single-plasmid regulated expression system termed pBRES, which contains the ligand-binding domain from the human progesterone receptor (hPR). A small molecule inducer, BLX-913, has been identified as having a 30-fold lower IC(50) for the human progesterone receptor than mifepristone (MFP), the previously best characterized inducer for pBRES.

Temperature-dependent femtosecond photoinduced desorption in CO/Pd(111).

The desorption of CO from a Pd(111) surface following absorption of 120 fs pulses of 780 nm light occurs on two distinct and well-separated time scales. Two-pulse correlation measurements show a fast subpicosecond decay followed by a slower, approximately 40 ps decay. Simulations based on the two-temperature model of electron and phonon heat baths within the substrate, and an empirical friction model to treat coupling to the adsorbate, support the assignment of the desorption mechanism as an electron-mediated process.

Adsorption-state-dependent subpicosecond photoinduced desorption dynamics.

Femtosecond laser excitation has been used to initiate desorption of molecular oxygen from the (111) surface of Pd and to study the adsorption-state dependence of the substrate-adsorbate coupling. The relative populations of the two chemical states, peroxo (O2(2-)) and superoxo (O2-), were varied by changing the total coverage. Two-pulse correlation measurements exhibit a dominant 400 fs response and a slower 10 ps decay that are relatively independent of the initial O2 coverage.

Development and validation of a robust and versatile one-plasmid regulated gene expression system.

We have developed a one-plasmid regulated gene expression system, pBRES, based on a mifepristone (MFP)-inducible two-plasmid system. The various expression elements of the pBRES system (promoters, 5' and 3' untranslated regions (UTRs), introns, target gene, and polyA sequences) are bounded by restriction enzyme sites so that each module can be conveniently replaced by alternate DNA elements in order to tailor the system for particular tissues, organs, or conditions. There are four possible orientations of the two expression units relative to each other, and insertion of a variety of expression elements and target genes into the four different orientations revealed orientation- and gene-dependent effects on induced and uninduced levels of gene expression.

Mx1 and IP-10: biomarkers to measure IFN-beta activity in mice following gene-based delivery.

Recombinant interferon-beta (IFN-beta) protein is used successfully for the treatment of multiple sclerosis (MS). Gene therapy might be an alternative approach to overcome drawbacks occurring with IFN-beta protein therapy. A critical issue in developing a new approach is detection of biologically active IFN-beta in preclinical models.

Ultrafast electron dynamics at metal interfaces: intraband relaxation of image state electrons as friction.

Two-photon photoemission of image potential states above monolayers of p-xylene/Ag(111) shows that electrons with different momenta have very different rise and decay rates as a function of parallel momentum. The dynamics are due to energy and momentum loss (intraband relaxation), which we model as a stochastic process isomorphic to the overdamped motion of a harmonic oscillator. The method extracts a friction coefficient from the data which can be explained by electron-electron scattering in a formalism based on the Lindhard dielectric function.

Gene-based delivery of IFN-beta is efficacious in a murine model of experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) is a model of central nervous system (CNS) inflammation that follows immunization with certain CNS antigens. The course and clinical manifestations of EAE are similar to those of multiple sclerosis (MS) in humans; therefore, EAE has become an accepted animal model to study MS. The purpose of this study was to demonstrate that systemic expression of murine interferon-beta (IFN-beta) (MuIFN-beta), following intramuscular (i.

Determination of band curvatures by angle-resolved two-photon photoemission in thin films of C60 on Ag(111).

The thickness-dependent interfacial band structure was determined for thin films of C(60) on Ag(111) by angle-resolved two-photon photoemission spectroscopy. Dispersions of molecular-orbital derived bands (HOMO, LUMO+1, and LUMO+2) were acquired, and limits were placed on their possible effective masses. A group theoretic approach is also incorporated to further understand the properties of these states.

Measurement and dynamics of the spatial distribution of an electron localized at a metal-dielectric interface.

The ability of time- and angle-resolved two-photon photoemission to estimate the size distribution of electron localization in the plane of a metal-adsorbate interface is discussed. It is shown that the width of angular distribution of the photoelectric current is inversely proportional to the electron localization size within the most common approximations in the description of image potential states. The localization of the n=1 image potential state for two monolayers of butyronitrile on Ag(111) is used as an example.