Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy.

Genetically encoded voltage indicators are emerging tools for monitoring voltage dynamics with cell-type specificity. However, current indicators enable a narrow range of applications due to poor performance under two-photon microscopy, a method of choice for deep-tissue recording. To improve indicators, we developed a multiparameter high-throughput platform to optimize voltage indicators for two-photon microscopy. Using this system, we identified JEDI-2P, an indicator that is faster, brighter, and more sensitive and photostable than its predecessors. We demonstrate that JEDI-2P can report light-evoked responses in axonal termini of Drosophila interneurons and the dendrites and somata of amacrine cells of isolated mouse retina. JEDI-2P can also optically record the voltage dynamics of individual cortical neurons in awake behaving mice for more than 30 min using both resonant-scanning and ULoVE random-access microscopy. Finally, ULoVE recording of JEDI-2P can robustly detect spikes at depths exceeding 400 µm and report voltage correlations in pairs of neurons.

Ultrafast Two-Photon Imaging of a High-Gain Voltage Indicator in Awake Behaving Mice.

Optical interrogation of voltage in deep brain locations with cellular resolution would be immensely useful for understanding how neuronal circuits process information. Here, we report ASAP3, a genetically encoded voltage indicator with 51% fluorescence modulation by physiological voltages, submillisecond activation kinetics, and full responsivity under two-photon excitation. We also introduce an ultrafast local volume excitation (ULoVE) method for kilohertz-rate two-photon sampling in vivo with increased stability and sensitivity. Combining a soma-targeted ASAP3 variant and ULoVE, we show single-trial tracking of spikes and subthreshold events for minutes in deep locations, with subcellular resolution and with repeated sampling over days. In the visual cortex, we use soma-targeted ASAP3 to illustrate cell-type-dependent subthreshold modulation by locomotion. Thus, ASAP3 and ULoVE enable high-speed optical recording of electrical activity in genetically defined neurons at deep locations during awake behavior.

Solvent Suppression in Pure Shift NMR.

Intense solvent signals in 1H solution-state NMR experiments typically cause severe distortion of spectra and mask nearby solute signals. It is often infeasible or undesirable to replace a solvent with its perdeuterated form, for example, when analyzing formulations in situ, when exchangeable protons are present, or for practical reasons. Solvent signal suppression techniques are therefore required. WATERGATE methods are well-known to provide good solvent suppression while enabling retention of signals undergoing chemical exchange with the solvent signal. Spectra of mixtures, such as pharmaceutical formulations, are often complicated by signal overlap, high dynamic range, the narrow spectral width of 1H NMR, and signal multiplicity. Here, we show that by combining WATERGATE solvent suppression with pure shift NMR, ultrahigh-resolution 1H NMR spectra can be acquired while suppressing intense solvent signals and retaining exchangeable 1H signals. The new method is demonstrated in the analysis of cyanocobalamin, a vitamin B12 supplement, and of an eye-drop formulation of atropine.

Octave-spanning supercontinuum generation in a CMOS-compatible thin Si3N4 waveguide coated with highly nonlinear TeO2.

Supercontinuum generation (SCG) is an important nonlinear optical process enabling broadband light sources for many applications, for which silicon nitride (Si3N4) has emerged as a leading on-chip platform. To achieve suitable group velocity dispersion and high confinement for broadband SCG the Si3N4 waveguide layer used is typically thick (>∼700 nm), which can lead to high stress and cracks unless specialized processing steps are used. Here, we report on efficient octave-spanning SCG in a thinner moderate-confinement 400-nm Si3N4 platform using a highly nonlinear tellurium oxide (TeO2) coating. An octave supercontinuum spanning from 0.89 to 2.11 µm is achieved at a low peak power of 258 W using a 100-fs laser centered at 1565 nm. Our numerical simulations agree well with the experimental results giving a nonlinear parameter of 2.5 ± 0.5 W-1m-1, an increase by a factor of 2.5, when coating the Si3N4 waveguide with a TeO2 film. This work demonstrates highly efficient SCG via effective dispersion engineering and an enhanced nonlinearity in CMOS-compatible hybrid TeO2-Si3N4 waveguides and a promising route to monolithically integrated nonlinear, linear, and active functionalities on a single silicon photonic chip.

Synthetic Control of the Defect Structure and Hierarchical Extra-Large-/Small-Pore Microporosity in Aluminosilicate Zeolite SWY.

The SWY-type aluminosilicate zeolite, STA-30, has been synthesized via different routes to understand its defect chemistry and solid acidity. The synthetic parameters varied were the gel aging, the Al source, and the organic structure directing agent. All syntheses give crystalline materials with similar Si/Al ratios (6-7) that are stable in the activated K,H-form and closely similar by powder X-ray diffraction. However, they exhibit major differences in the crystal morphology and in their intracrystalline porosity and silanol concentrations. The diDABCO-C82+ (1,1'-(octane-1,8-diyl)bis(1,4-diazabicyclo[2.2.2]octan)-1-ium)-templated STA-30 samples (but not those templated by bisquinuclidinium octane, diQuin-C82+) possess hierarchical microporosity, consisting of noncrystallographic extra-large micropores (13 Å) that connect with the characteristic swy and gme cages of the SWY structure. This results in pore volumes up to 30% greater than those measured in activated diQuin-C8_STA-30 as well as higher concentrations of silanols and fewer Brønsted acid sites (BASs). The hierarchical porosity is demonstrated by isopentane adsorption and the FTIR of adsorbed pyridine, which shows that up to 77% of the BASs are accessible (remarkable for a zeolite that has a small-pore crystal structure). A structural model of single can/d6r column vacancies is proposed for the extra-large micropores, which is revealed unambiguously by high-resolution scanning transmission electron microscopy. STA-30 can therefore be prepared as a hierarchically porous zeolite via direct synthesis. The additional noncrystallographic porosity and, subsequently, the amount of SiOHs in the zeolites can be enhanced or strongly reduced by the choice of crystallization conditions.

Silicon-thulium hybrid microdisk lasers with low threshold and wide emission wavelength range.

We demonstrate low-threshold and wide emission wavelength range hybrid-integrated silicon-thulium microdisk lasers based on a pulley-coupled design. The resonators are fabricated on a silicon-on-insulator platform using a standard foundry process and the gain medium is deposited using a straightforward, low-temperature post-processing step. We show lasing in 40- and 60-µm diameter microdisks with up to 2.6 mW double-sided output power and bidirectional slope efficiencies of up to 13.4% with respect to 1620 nm pump power launched to the bus waveguides. We observe thresholds less than 1 mW versus on-chip pump power and both single-mode and multimode laser emission spanning across wavelengths from 1825 to 1939nm. These low threshold lasers with emissions over a > 100 nm range open the door to monolithic silicon photonic integrated circuits with broadband optical gain and highly compact and efficient light sources in the emerging ∼1.8-2.0 µm wavelength band.

A gene-level methylome-wide association analysis identifies novel Alzheimer's disease genes.

MOTIVATION: Transcriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer's disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD. RESULTS: We develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods. AVAILABILITY: Software: https://github.com/ChongWuLab/CMO. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Application of the TDFA window in true optical time delay systems.

Recent advances in silicon photonic components operating in the thulium-doped fiber amplifier (TDFA) wavelength regime around 2-µm have shown that these wavelengths hold great promise for on-chip photonic systems. Here we present our work on characterizing a Mach-Zehnder interferometer coupled silicon photonic ring resonator operating in the TDFA window for optical time delay applications. We describe the optical transmission and variable time delay properties of the resonator, including a detailed characterization and comparison of the directional coupler and Mach-Zehnder interferometer base components at both 1930 and 1550 nm wavelengths. The results show tuning of a ring from a 190-ps peak time delay at a resonant extinction ratio of 5.1-dB to a 560-ps peak time delay at an extinction ratio of 11.0-dB, in good agreement with optical models of the device. These results demonstrate significant promise towards the future application of TDFA band devices in optical time delay systems.

Thulium-doped tellurium oxide waveguide amplifier with 7.6 dB net gain on a silicon nitride chip: publisher's note.

This publisher's note contains corrections to Opt. Lett.44, 5788 (2019)OPLEDP0146-959210.1364/OL.44.005788.

Erbium-ytterbium co-doped aluminium oxide waveguide amplifiers fabricated by reactive co-sputtering and wet chemical etching.

We report on the fabrication and optical characterization of erbium-ytterbium co-doped aluminum oxide (Al2O3:Er3+:Yb3+) waveguides using low-cost, low-temperature deposition and etching steps. We deposited Al2O3:Er3+:Yb3+ films using reactive co-sputtering, with Er3+ and Yb3+ ion concentrations ranging from 1.4-1.6 × 1020 and 0.9-2.1 × 1020 ions/cm3, respectively. We etched ridge waveguides in 85% pure phosphoric acid at 60°C, allowing for structures with minimal polarization sensitivity and acceptable bend radius suitable for optical amplifiers and avoiding alternative etching chemistries which use hazardous gases. Scanning-electron-microscopy (SEM) and profilometry were used to assess the etch depth, sidewall roughness, and facet profile of the waveguides. The Al2O3:Er3+:Yb3+ films exhibit a background loss as low as 0.2 ± 0.1 dB/cm and the waveguide loss after structuring is determined to be 0.5 ± 0.3 dB/cm at 1640 nm. Internal net gain of 4.3 ± 0.9 dB is demonstrated at 1533 nm for a 3.0 cm long waveguide when pumped at 970 nm. The material system is promising moving forward for compact Er-Yb co-doped waveguide amplifiers and lasers on a low-cost silicon wafer-scale platform.

Subwavelength grating metamaterial waveguides functionalized with tellurium oxide cladding.

We report on the design, fabrication and characterization of subwavelength grating metamaterial waveguides coated with tellurium oxide. The structures are first fabricated using a standard CMOS compatible process on a silicon-on-insulator platform. Amorphous tellurium oxide top cladding material is then deposited via post-process RF magnetron sputtering. The photonic bandstructure is controlled by adjustment of the device geometry, opening a wide range of operating regimes, including subwavelength propagation, slow light and the photonic bandgap, for various wavelength bands within the 1550 nm telecommunications window. Propagation loss of 1.0 ± 0.1 dB/mm is reported for the tellurium oxide-cladded device, compared to 1.5 ± 0.1 dB/mm propagation loss reported for the silicon dioxide-cladded reference structure. This is the first time that a high-index (n > 2) oxide cladding has been demonstrated for subwavelength grating metamaterial waveguides, thus introducing a new material platform for on-chip integrated optics.

Low-loss TeO2-coated Si3N4 waveguides for application in photonic integrated circuits.

We report on high-quality tellurium oxide waveguides integrated on a low-loss silicon nitride wafer-scale platform. The waveguides consist of silicon nitride strip features, which are fabricated using a standard foundry process and a tellurium oxide coating layer that is deposited in a single post-processing step. We show that by adjusting the Si3N4 strip height and width and TeO2 layer thickness, a small mode area, small bend radius and high optical intensity overlap with the TeO2 can be obtained. We investigate transmission at 635, 980, 1310, 1550 and 2000 nm wavelengths in paperclip waveguide structures and obtain low propagation losses down to 0.6 dB/cm at 2000 nm. These results illustrate the potential for compact linear, nonlinear and active tellurite glass devices in silicon nitride photonic integrated circuits operating from the visible to mid-infrared.

Thulium-doped tellurium oxide waveguide amplifier with 7.6 dB net gain on a silicon nitride chip.

We report on thulium-doped waveguide amplifiers integrated on a low-loss silicon nitride platform. The amplifier structure consists of a thulium-doped tellurium oxide thin film coated on a silicon nitride strip waveguide on silicon. We determine a waveguide background loss of 0.7 dB/cm at 1479 nm based on the quality factor measured in microring resonators. Gain measurements were carried out in straight and 6.7-cm-long s-bend waveguides realized on a 2.2-cm-long chip. We measure internal net gain over the wavelength range 1860-2000 nm under 1620 nm pumping and up to 7.6 dB total gain at 1870 nm, corresponding to 1.1 dB/cm. These results are promising for the realization of highly compact thulium-doped amplifiers in the emerging 2 µm band for silicon-based photonic microsystems.

High-Q tellurium-oxide-coated silicon nitride microring resonators.

We report on tellurium-oxide (TeO2)-coated silicon nitride microring resonators with internal quality factors up to 7.3×105, corresponding to 0.5 dB/cm waveguide loss, at wavelengths around 1550 nm. The microring resonators are fabricated using a silicon nitride foundry process followed by TeO2 coating deposition in a single post-processing step. The silicon nitride strip height of 0.2 µm enables a small microring bending radius, while the TeO2 coating thickness of 0.33 µm results in a large modal overlap with the TeO2 layer. These results are a promising step towards realizing compact and high-performance linear, nonlinear, and rare-earth-doped active integrated photonic devices with this platform.

Optically pumped rare-earth-doped Al2O3 distributed-feedback lasers on silicon [Invited].

This paper reviews recent progress in the field of optically pumped rare-earth-doped channel waveguide lasers, with a focus on operation utilizing distributed-feedback resonators on silicon wafers. Rare-earth-doped amorphous aluminum oxide thin films have been deposited onto silicon wafers by RF reactive co-sputtering from metallic Al and rare-earth targets, the spectroscopy and optical gain of Er3+, Yb3+, Nd3+, and Tm3+ ions has been investigated, and the near-infrared laser transitions near 1 µm in Yb3+, 1.5 µm in Er3+, and 2 µm in Tm3+ and Ho3+ have been demonstrated. Output power between a few µW and hundreds of mW have been achieved in different waveguide geometries, and ultranarrow-linewidth laser operation has been demonstrated.

Broadband 2-µm emission on silicon chips: monolithically integrated Holmium lasers.

Laser sources in the mid-infrared are of great interest due to their wide applications in detection, sensing, communication and medicine. Silicon photonics is a promising technology which enables these laser devices to be fabricated in a standard CMOS foundry, with the advantages of reliability, compactness, low cost and large-scale production. In this paper, we demonstrate a holmium-doped distributed feedback laser monolithically integrated on a silicon photonics platform. The Al2O3:Ho3+ glass is used as gain medium, which provides broadband emission around 2 µm. By varying the distributed feedback grating period and Al2O3:Ho3+ gain layer thickness, we show single mode laser emission at wavelengths ranging from 2.02 to 2.10 µm. Using a 1950 nm pump, we measure a maximum output power of 15 mW, a slope efficiency of 2.3% and a side-mode suppression ratio in excess of 50 dB. The introduction of a scalable monolithic light source emitting at > 2 µm is a significant step for silicon photonic microsystems operating in this highly promising wavelength region.

High-Q-factor Al2O3 micro-trench cavities integrated with silicon nitride waveguides on silicon.

We report on the design and performance of high-Q integrated optical micro-trench cavities on silicon. The microcavities are co-integrated with silicon nitride bus waveguides and fabricated using wafer-scale silicon-photonics-compatible processing steps. The amorphous aluminum oxide resonator material is deposited via sputtering in a single straightforward post-processing step. We examine the theoretical and experimental optical properties of the aluminum oxide micro-trench cavities for different bend radii, film thicknesses and near-infrared wavelengths and demonstrate experimental Q factors of > 106. We propose that this high-Q micro-trench cavity design can be applied to incorporate a wide variety of novel microcavity materials, including rare-earth-doped films for microlasers, into wafer-scale silicon photonics platforms.

Stabilising sleep for patients admitted at acute crisis to a psychiatric hospital (OWLS): an assessor-blind pilot randomised controlled trial.

BACKGROUND: When patients are admitted onto psychiatric wards, sleep problems are highly prevalent. We carried out the first trial testing a psychological sleep treatment at acute admission (Oxford Ward sLeep Solution, OWLS). METHODS: This assessor-blind parallel-group pilot trial randomised patients to receive sleep treatment at acute crisis [STAC, plus standard care (SC)], or SC alone (1 : 1). STAC included cognitive-behavioural therapy (CBT) for insomnia, sleep monitoring and light/dark exposure for circadian entrainment, delivered over 2 weeks. Assessments took place at 0, 2, 4 and 12 weeks. Feasibility outcomes assessed recruitment, retention of participants and uptake of the therapy. Primary efficacy outcomes were the Insomnia Severity Index and Warwick-Edinburgh Mental Wellbeing Scale at week 2. Analyses were intention-to-treat, estimating treatment effect with 95% confidence intervals. RESULTS: Between October 2015 and July 2016, 40 participants were recruited (from 43 assessed eligible). All participants offered STAC completed treatment (mean sessions received = 8.6, s.d. = 1.5). All participants completed the primary end point. Compared with SC, STAC led to large effect size (ES) reductions in insomnia at week 2 (adjusted mean difference -4.6, 95% CI -7.7 to -1.4, ES -0.9), a small improvement in psychological wellbeing (adjusted mean difference 3.7, 95% CI -2.8 to 10.1, ES 0.3) and patients were discharged 8.5 days earlier. One patient in the STAC group had an adverse event, unrelated to participation. CONCLUSIONS: In this challenging environment for research, the trial was feasible. Therapy uptake was high. STAC may be a highly effective treatment for sleep disturbance on wards with potential wider benefits on wellbeing and admission length.

A Tellurium Oxide Microcavity Resonator Sensor Integrated On-Chip with a Silicon Waveguide.

We report on thermal and evanescent field sensing from a tellurium oxide optical microcavity resonator on a silicon photonics platform. The on-chip resonator structure is fabricated using silicon-photonics-compatible processing steps and consists of a silicon-on-insulator waveguide next to a circular trench that is coated in a tellurium oxide film. We characterize the device's sensitivity by both changing the temperature and coating water over the chip and measuring the corresponding shift in the cavity resonance wavelength for different tellurium oxide film thicknesses. We obtain a thermal sensitivity of up to 47 pm/°C and a limit of detection of 2.2 × 10-3 RIU for a device with an evanescent field sensitivity of 10.6 nm/RIU. These results demonstrate a promising approach to integrating tellurium oxide and other novel microcavity materials into silicon microphotonic circuits for new sensing applications.

Adapted CBT to Stabilize Sleep on Psychiatric Wards: a Transdiagnostic Treatment Approach.

BACKGROUND: Almost all patients admitted at acute crisis to a psychiatric ward experience clinically significant symptoms of insomnia. Ward environments pose challenges to both sleep and the delivery of therapy. Despite this, there is no description of how to adapt cognitive behavioural therapy (CBT) for insomnia to overcome these challenges. AIMS: (i) To describe the key insomnia presentations observed in the Oxford Ward Sleep Solution (OWLS) trial and (ii) outline key adaptations aimed to increase accessibility and hence effectiveness of CBT for insomnia for a ward setting. METHODS: Trial therapists collaboratively agreed the key insomnia presentations and therapy adaptations based on their individual reflective logs used during the trial. RESULTS: Three key insomnia presentations are outlined. These are used to illustrate the application of 10 CBT for insomnia therapy adaptations. These include use of sleep monitoring watches to engage patients in treatment, stabilizing circadian rhythms, reducing the impact of night-time observations and managing discharge as a sleep challenge. CONCLUSIONS: Whilst inpatient wards bring challenges for sleep and therapy delivery, creative adaptations can increase the accessibility of evidence based CBT for insomnia techniques. This therapy has proven popular with patients.