Patterned photostimulation via visible-wavelength photonic probes for deep brain optogenetics

Optogenetic methods developed over the past decade enable unprecedented optical activation and silencing of specific neuronal cell types. However, light scattering in neural tissue precludes illuminating areas deep within the brain via free-space optics; this has impeded employing optogenetics universally. Here, we report an approach surmounting this significant limitation. We realize implantable, ultranarrow, silicon-based photonic probes enabling the delivery of complex illumination patterns deep within brain tissue. Our approach combines methods from integrated nanophotonics and microelectromechanical systems, to yield photonic probes that are robust, scalable, and readily producible en masse. Their minute cross sections minimize tissue displacement upon probe implantation. We functionally validate one probe design in vivo with mice expressing channelrhodopsin-2. Highly local optogenetic neural activation is demonstrated by recording the induced response—both by extracellular electrical recordings in the hippocampus and by two-photon functional imaging in the cortex of mice coexpressing GCaMP6

Update to the Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) protocol: statistical analysis plan for a prospective, multicenter, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial.

BACKGROUND: Observational research suggests that combined therapy with Vitamin C, thiamine and hydrocortisone may reduce mortality in patients with septic shock. METHODS AND DESIGN: The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) trial is a multicenter, double-blind, adaptive sample size, randomized, placebo-controlled trial designed to test the efficacy of combination therapy with vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) given every 6 h for up to 16 doses in patients with respiratory or circulatory dysfunction (or both) resulting from sepsis. The primary outcome is ventilator- and vasopressor-free days with mortality as the key secondary outcome. Recruitment began in August 2018 and is ongoing; 501 participants have been enrolled to date, with a planned maximum sample size of 2000. The Data and Safety Monitoring Board reviewed interim results at N = 200, 300, 400 and 500, and has recommended continuing recruitment. The next interim analysis will occur when N = 1000. This update presents the statistical analysis plan. Specifically, we provide definitions for key treatment and outcome variables, and for intent-to-treat, per-protocol, and safety analysis datasets. We describe the planned descriptive analyses, the main analysis of the primary end point, our approach to secondary and exploratory analyses, and handling of missing data. Our goal is to provide enough detail that our approach could be replicated by an independent study group, thereby enhancing the transparency of the study. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03509350. Registered on 26 April 2018

Genome assemblies across the diverse evolutionary spectrum of Leishmania protozoan parasites

We report the high-quality draft assemblies and gene annotations for 13 species and/or strains of the protozoan parasite gener

Nanophotonic Neural Probes for in vivo Light Sheet Imaging

We present implantable silicon neural probes with nanophotonic waveguide routing networks and grating emitters for light sheet imaging. Fluorescein beam profiles, fluorescent bead imaging, and fluorescence brain imaging in vivo are presented

Nanophotonic Neural Probes for in vivo Light Sheet Imaging

We present implantable silicon neural probes with nanophotonic waveguide routing networks and grating emitters for light sheet imaging. Fluorescein beam profiles, fluorescent bead imaging, and fluorescence brain imaging in vivo are presented

Beam-Steering Nanophotonic Phased-Array Neural Probes

We demonstrate the first implantable nanophotonic neural probes with integrated silicon nitride phased arrays. Coherent beam-steering is achieved in brain tissue by wavelength tuning. Beam profiles, optogenetic stimulation, and functional imaging are validated in vitro

CMB Observations with a Compact Heterogeneous 150 GHz Interferometer in Chile

We report on the design, first observing season, and analysis of data from a new prototype millimeter-wave interferometer, MINT. MINT consists of four 145 GHz SIS mixers operating in double-sideband mode in a compact heterogeneous configuration. The signal band is subdivided by a monolithic channelizer, after which the correlations between antennas are performed digitally. The typical receiver sensitivity in a 2 GHz band is 1.4 mK sqrt(s). MINT observed the cosmic microwave background (CMB) from the Chilean Altiplano. The site has a median nighttime atmospheric temperature of 9 K at zenith (exclusive of the CMB). Observations of Mars, Jupiter, and a telescope-mounted calibration source establish the system's phase and magnitude stability. MINT is the first CMB-dedicated interferometer to operate above 50 GHz. The same type of system can be used to probe the Sunyaev-Zel'dovich effect in galaxy clusters near the SZ null at 217 GHz. We present an analysis of sideband-separated, digitally sampled data recorded by the array. Based on 215 hours of data taken in late 2001, we set an upper limit on the CMB anisotropy in a band of width Delta ell=700 around ell=1540 of delta T < 105 microK (95% conf). Increased sensitivity can be achieved with more integration time, greater bandwidth, and more elements.Comment: 12 pages, 4 figures. v2: Final ApJS version; rewritten analysis section made more clea

Patterned photostimulation via visible-wavelength photonic probes for deep brain optogenetics

Optogenetic methods developed over the past decade enable unprecedented optical activation and silencing of specific neuronal cell types. However, light scattering in neural tissue precludes illuminating areas deep within the brain via free-space optics; this has impeded employing optogenetics universally. Here, we report an approach surmounting this significant limitation. We realize implantable, ultranarrow, silicon-based photonic probes enabling the delivery of complex illumination patterns deep within brain tissue. Our approach combines methods from integrated nanophotonics and microelectromechanical systems, to yield photonic probes that are robust, scalable, and readily producible en masse. Their minute cross sections minimize tissue displacement upon probe implantation. We functionally validate one probe design in vivo with mice expressing channelrhodopsin-2. Highly local optogenetic neural activation is demonstrated by recording the induced response—both by extracellular electrical recordings in the hippocampus and by two-photon functional imaging in the cortex of mice coexpressing GCaMP6

Implantable photonic neural probes for light-sheet fluorescence brain imaging

Significance: Light-sheet fluorescence microscopy (LSFM) is a powerful technique for highspeed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, in vitro, and in vivo mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses <16 μm for propagation distances up to 300 μm in free space. Imaging areas were as large as ≈240 μm × 490 μm in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals

Implantable photonic neural probes for light-sheet fluorescence brain imaging

Significance: Light-sheet fluorescence microscopy is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. Here, we demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200 mm diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed and in vitro mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses < 16 μm for propagation distances up to 300 μm in free space. Imaging areas were as large as ≈ 240 μm x 490 μm in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of light-sheet fluorescence microscopy for deep brain imaging and experiments in freely-moving animals