500 W peak power cavity dumped 2 µm GaSb-based VECSEL.

A single transverse mode high-pulse-energy vertical-external-cavity surface-emitting laser (VECSEL) was developed. The GaSb-based VECSEL emits at a wavelength of 2.04 µm with a peak power exceeding 500 W while maintaining good beam quality. The cavity employs a Pockels cell combined with a low-loss thin film polarizer to selectively dump the intracavity energy into a 10 ns pulse. The laser has promise for incoherent LIDAR, materials processing, gas sensing, and nonlinear optics.

Mid-infrared supercontinuum generation from 1.6 to >11 µm using concatenated step-index fluoride and chalcogenide fibers.

We demonstrate an all-fiber supercontinuum source that generates a continuous spectrum from 1.6 µm to >11 µm with 417 mW on-time average power at 33% duty cycle. By utilizing a master oscillator power amplifier pump with three amplification stages and concatenating solid core ZBLAN, arsenic sulfide, and arsenic selenide fibers, we shift 1550 nm light to ∼4.5 µm, ∼6.5 µm, and >11 µm, respectively. With 69 mW past 7.5 µm, this source provides both high power and broad spectral expansion, while outputting a single fundamental mode.

Generation of near-diffraction-limited, high-power supercontinuum from 1.57 µm to 12 µm with cascaded fluoride and chalcogenide fibers.

We generate a supercontinuum (SC) spectrum ranging from 1.57 µm to 12 µm (20 dB bandwidth) with a soft glass fiber cascade consisting of ZrF4-BaF2-LaF3-AlF3-NaF fiber, As2S3 fiber, and As2Se3 fiber pumped by a nanosecond thulium master oscillator power amplifier system. The highest on-time average power generated is 417 mW at 33% duty cycle. We observe a near-diffraction-limit beam quality across the wavelength range from 3 µm to 12 µm, even though the As2Se3 fiber is multimode below 12 µm. Our study also shows that parameters of the As2Se3 fiber, such as numerical aperture, core size, and core/cladding composition, have significant effects on the long wavelength edge of the generated SC spectrum. Our results suggest that the high numerical aperture of 0.76 and low-loss As2Se3/GeAs2Se5 core/cladding material all contribute to broad SC generation in the long-wave infrared spectral region. Also, among our results, 10 µm core diameter selenide fiber yields the best spectral expansion, while the 12 µm core diameter selenide fiber yields the highest output power.

Melanopsin-driven increases in maintained activity enhance thalamic visual response reliability across a simulated dawn.

Twice a day, at dawn and dusk, we experience gradual but very high amplitude changes in background light intensity (irradiance). Although we perceive the associated change in environmental brightness, the representation of such very slow alterations in irradiance by the early visual system has been little studied. Here, we addressed this deficit by recording electrophysiological activity in the mouse dorsal lateral geniculate nucleus under exposure to a simulated dawn. As irradiance increased we found a widespread enhancement in baseline firing that extended to units with ON as well as OFF responses to fast luminance increments. This change in baseline firing was equally apparent when the slow irradiance ramp appeared alone or when a variety of higher-frequency artificial or natural visual stimuli were superimposed upon it. Using a combination of conventional knockout, chemogenetic, and receptor-silent substitution manipulations, we continued to show that, over higher irradiances, this increase in firing originates with inner-retinal melanopsin photoreception. At the single-unit level, irradiance-dependent increases in baseline firing were strongly correlated with improvements in the amplitude of responses to higher-frequency visual stimuli. This in turn results in an up to threefold increase in single-trial reliability of fast visual responses. In this way, our data indicate that melanopsin drives a generalized increase in dorsal lateral geniculate nucleus excitability as dawn progresses that both conveys information about changing background light intensity and increases the signal:noise for fast visual responses.

Meclofenamic acid improves the signal to noise ratio for visual responses produced by ectopic expression of human rod opsin.

PURPOSE: Retinal dystrophy through outer photoreceptor cell death affects 1 in 2,500 people worldwide with severe impairment of vision in advanced stages of the disease. Optogenetic strategies to restore visual function to animal models of retinal degeneration by introducing photopigments to neurons spared degeneration in the inner retina have been explored, with variable degrees of success. It has recently been shown that the non-steroidal anti-inflammatory and non-selective gap-junction blocker meclofenamic acid (MFA) can enhance the visual responses produced by an optogenetic actuator (channelrhodopsin) expressed in retinal ganglion cells (RGCs) in the degenerate retina. Here, we set out to determine whether MFA could also enhance photoreception by another optogenetic strategy in which ectopic human rod opsin is expressed in ON bipolar cells. METHODS: We used in vitro multielectrode array (MEA) recordings to characterize the light responses of RGCs in the rd1 mouse model of advanced retinal degeneration following intravitreal injection of an adenoassociated virus (AAV2) driving the expression of human rod opsin under a minimal grm6 promoter active in ON bipolar cells. RESULTS: We found treated retinas were light responsive over five decades of irradiance (from 1011 to 1015 photons/cm2/s) with individual RGCs covering up to four decades. Application of MFA reduced the spontaneous firing rate of the visually responsive neurons under light- and dark-adapted conditions. The change in the firing rate produced by the 2 s light pulses was increased across all intensities following MFA treatment, and there was a concomitant increase in the signal to noise ratio for the visual response. Restored light responses were abolished by agents inhibiting glutamatergic or gamma-aminobutyric acid (GABA)ergic signaling in the MFA-treated preparation. CONCLUSIONS: These results confirm the potential of MFA to inhibit spontaneous activity and enhance the signal to noise ratio of visual responses in optogenetic therapies to restore sight.

High peak power cavity dumping semiconductor lasers.

We report on the development of a nanosecond pulsed kW-class optically pumped InGaAs semiconductor laser emitting around 1020 nm, which is suitable for applications such as incoherent laser radar, nonlinear optics, and materials processing. Using an intracavity Pockels cell to cavity-dump VECSELs, we are able to access large pulse energies by storing energy in the optical cavity rather than in the gain medium. We demonstrate peak powers >1 kW and 3 µJ pulses, show the pulse length is equivalent to the photon round-trip time, and show that the wavelength can be tuned within the gain bandwidth of the semiconductor gain.

Tunable type II intracavity difference frequency generation at 5.4 µm in a two chip vertical external cavity surface emitting laser.

We report on the generation and experimental demonstration of intracavity type II difference frequency generation in a two chip InGaAs/GaAs vertical external cavity surface emitting laser. The presented two chip cavity provides two orthogonally polarized, independently tunable, high-intensity lasing modes with emissions around 970 and 1170 nm. A silver thiogallate nonlinear crystal is inserted in the common collinear folded region of the cavity to generate output in the mid-IR spectral band. The independent tunability of each fundamental color allows for more than 100 nm of tuning around a 5.4 µm difference frequency generated signal with a CW output power in excess of 5 mW.

Materials Innovations for Quantum Technology Acceleration: A Perspective.

A broad perspective of quantum technology state of the art is provided and critical stumbling blocks for quantum technology development are identified. Innovations in demonstrating and understanding electron entanglement phenomena using bulk and low-dimensional materials and structures are summarized. Correlated photon-pair generation via processes such as nonlinear optics is discussed. Application of qubits to current and future high-impact quantum technology development is presented. Approaches for realizing unique qubit features for large-scale encrypted communication, sensing, computing, and other technologies are still evolving; thus, materials innovation is crucially important. A perspective on materials modeling approaches for quantum technology acceleration that incorporate physics-based AI/ML, integrated with quantum metrology is discussed.

Gain coupling of class A semiconductor lasers.

We report on the development of a gain-coupled class A semiconductor laser for dual-wavelength generation via optical switching. A vertical external cavity surface emitting laser (VECSEL) structure is used, because it provides a flexible platform for high-power, high-brightness output in the near-IR and visible ranges. For the first time (to our knowledge), two VECSEL cavities sharing a common gain region are studied. Because the cavities are in competition for common carriers, birefringent filters in the external cavity control the laser cavity thresholds; this configuration demonstrates the possibility of switching between the two cavities, which can operate at different wavelengths. However, in this Letter we also show, numerically and experimentally, that with the consideration of spontaneous emission, it is possible to maintain simultaneous lasing in each cavity at a different wavelength.

Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice.

Viral gene delivery is showing great promise for treating retinal disease. Although subretinal vector delivery has mainly been used to date, intravitreal delivery has potential advantages if low retinal transduction efficiency can be overcome. To this end, we investigated the effects of co-injection of glycosaminoglycan-degrading enzymes, singly or in combination, with AAV2 as a method of increasing retinal transduction. Experiments using healthy mice demonstrated that these enzymes enhance retinal transduction. We found that heparinase III produced the greatest individual effect, and this was enhanced further by combination with hyaluronan lyase. In addition, this optimized AAV2-enzyme combination led to a marked improvement in transduction in retinas with advanced retinal degeneration compared with AAV2 alone. Safety studies measuring retinal function by flash electroretinography indicated that retinal function was unaffected in the acute period and at least 12 months after enzyme treatment, whereas pupillometry confirmed that retinal ganglion cell activity was unaffected. Retinal morphology was not altered by the enzyme injection. Collectively these data confirm the efficacy and safety of this intravitreal approach in enhancing retinal transduction efficiency by AAV in rodents. Translating this method into other species, such as non-human primates, or for clinical applications will have challenges and require further studies.

Non-immunoglobulin scaffold proteins: Precision tools for studying protein-protein interactions in cancer.

Cancer is frequently characterised by dysregulation of the cellular signalling processes that govern proliferation, survival and attachment. Understanding such dysregulation continues to present a challenge given the importance of protein-protein interactions in intracellular processes. Exploring this protein-protein interactome requires novel tools capable of discriminating between highly homologous proteins, individual domains and post-translational modifications. This review examines the potential of scaffold-based binding proteins to fulfil these requirements. It also explores protein-protein interactions in the context of intracellular signalling pathways and cancer, and demonstrates the uses of scaffold proteins as functional moderators, biosensors and imaging reagents. This review also highlights the timeliness and potential to develop international consortia to develop and validate highly specific "proteome" scaffold-based binding protein reagents with the ultimate aim of developing screening tools for studying the interactome.

Melanopsin Contributions to the Representation of Images in the Early Visual System.

Melanopsin photoreception enhances retinal responses to variations in ambient light (irradiance) and drives non-image-forming visual reflexes such as circadian entrainment [1-6]. Melanopsin signals also reach brain regions responsible for form vision [7-9], but melanopsin's contribution, if any, to encoding visual images remains unclear. We addressed this deficit using principles of receptor silent substitution to present images in which visibility for melanopsin versus rods+cones was independently modulated, and we recorded evoked responses in the mouse dorsal lateral geniculate nucleus (dLGN; thalamic relay for cortical vision). Approximately 20% of dLGN units responded to patterns visible only to melanopsin, revealing that melanopsin signals alone can convey spatial information. Spatial receptive fields (RFs) mapped using melanopsin-isolating stimuli had ON centers with diameters ∼13°. Melanopsin and rod+cone responses differed in the temporal domain, and responses to slow changes in radiance (<0.9 Hz) and stationary images were deficient when stimuli were rendered invisible for melanopsin. We employed these data to devise and test a mathematical model of melanopsin's involvement in form vision and applied it, along with further experimental recordings, to explore melanopsin signals under simulated active view of natural scenes. Our findings reveal that melanopsin enhances the thalamic representation of scenes containing local correlations in radiance, compensating for the high temporal frequency bias of cone vision and the negative correlation between magnitude and frequency for changes in direction of view. Together, these data reveal a distinct melanopsin contribution to encoding visual images, predicting that, under natural view, melanopsin augments the early visual system's ability to encode patterns over moderate spatial scales.

Modulation of Fast Narrowband Oscillations in the Mouse Retina and dLGN According to Background Light Intensity.

Background light intensity (irradiance) substantially impacts the visual code in the early visual system at synaptic and single-neuron levels, but its influence on population activity is largely unexplored. We show that fast narrowband oscillations, an important feature of population activity, systematically increase in amplitude as a function of irradiance in both anesthetized and awake, freely moving mice and at the level of the retina and dorsal lateral geniculate nucleus (dLGN). Narrowband coherence increases with irradiance across large areas of the dLGN, but especially for neighboring units. The spectral sensitivity of these effects and their substantial reduction in melanopsin knockout animals indicate a contribution from inner retinal photoreceptors. At bright backgrounds, narrowband coherence allows pooling of single-unit responses to become a viable strategy for enhancing visual signals within its frequency range.

Rods progressively escape saturation to drive visual responses in daylight conditions.

Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses.

Affimer proteins are versatile and renewable affinity reagents.

Molecular recognition reagents are key tools for understanding biological processes and are used universally by scientists to study protein expression, localisation and interactions. Antibodies remain the most widely used of such reagents and many show excellent performance, although some are poorly characterised or have stability or batch variability issues, supporting the use of alternative binding proteins as complementary reagents for many applications. Here we report on the use of Affimer proteins as research reagents. We selected 12 diverse molecular targets for Affimer selection to exemplify their use in common molecular and cellular applications including the (a) selection against various target molecules; (b) modulation of protein function in vitro and in vivo; (c) labelling of tumour antigens in mouse models; and (d) use in affinity fluorescence and super-resolution microscopy. This work shows that Affimer proteins, as is the case for other alternative binding scaffolds, represent complementary affinity reagents to antibodies for various molecular and cell biology applications.

Restoration of Vision with Ectopic Expression of Human Rod Opsin.

Many retinal dystrophies result in photoreceptor loss, but the inner retinal neurons can survive, making them potentially amenable to emerging optogenetic therapies. Here, we show that ectopically expressed human rod opsin, driven by either a non-selective or ON-bipolar cell-specific promoter, can function outside native photoreceptors and restore visual function in a mouse model of advanced retinal degeneration. Electrophysiological recordings from retinal explants and the visual thalamus revealed changes in firing (increases and decreases) induced by simple light pulses, luminance increases, and naturalistic movies in treated mice. These responses could be elicited at light intensities within the physiological range and substantially below those required by other optogenetic strategies. Mice with rod opsin expression driven by the ON-bipolar specific promoter displayed behavioral responses to increases in luminance, flicker, coarse spatial patterns, and elements of a natural movie at levels of contrast and illuminance (≈50-100 lux) typical of natural indoor environments. These data reveal that virally mediated ectopic expression of human rod opsin can restore vision under natural viewing conditions and at moderate light intensities. Given the inherent advantages in employing a human protein, the simplicity of this intervention, and the quality of vision restored, we suggest that rod opsin merits consideration as an optogenetic actuator for treating patients with advanced retinal degeneration.

Melanopsin-based brightness discrimination in mice and humans.

Photoreception in the mammalian retina is not restricted to rods and cones but extends to a small number of intrinsically photoreceptive retinal ganglion cells (ipRGCs), expressing the photopigment melanopsin. ipRGCs are known to support various accessory visual functions including circadian photoentrainment and pupillary reflexes. However, despite anatomical and physiological evidence that they contribute to the thalamocortical visual projection, no aspect of visual discrimination has been shown to rely upon ipRGCs. Based on their currently known roles, we hypothesized that ipRGCs may contribute to distinguishing brightness. This percept is related to an object's luminance-a photometric measure of light intensity relevant for cone photoreceptors. However, the perceived brightness of different sources is not always predicted by their respective luminance. Here, we used parallel behavioral and electrophysiological experiments to first show that melanopsin contributes to brightness discrimination in both retinally degenerate and fully sighted mice. We continued to use comparable paradigms in psychophysical experiments to provide evidence for a similar role in healthy human subjects. These data represent the first direct evidence that an aspect of visual discrimination in normally sighted subjects can be supported by inner retinal photoreceptors.

Multichip vertical-external-cavity surface-emitting lasers: a coherent power scaling scheme.

We propose an efficient coherent power scaling scheme, the multichip vertical-external-cavity surface-emitting laser (VECSEL), in which the waste heat generated in the active region is distributed on multi-VECSEL chips such that the pump level at the thermal rollover is significantly increased. The advantages of this laser are discussed, and the development and demonstration of a two-chip VECSEL operating around 970 nm with over 19 W of output power is presented.

Analysis of high-reflectivity metal-dielectric mirrors for edge-emitting lasers.

A metal-dielectric mirror is shown as a simple solution for high-reflectivity coatings on cleaved-facet edge-emitting lasers, as well as a means to provide wavelength stabilization and spectral filtering. We show, through the use of a simple SiO2/Ti/Au coating, reflectivities better than 90% and a 25% reduction in the 30-dB linewidth of the output spectrum. Wavelength filtering and varying reflectivities are described as the result of multiple reflections and a coupled-cavity effect.