The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general.</p

Impact of electrical contacts design and materials on the stability of Ti superconducting transition shape

The South Pole Telescope SPT-3G camera utilizes Ti/Au transition edge sensors (TESs). A key requirement for these sensors is reproducibility and long-term stability of the superconducting (SC) transitions. Here, we discuss the impact of electrical contacts design and materials on the shape of the SC transitions. Using scanning electron microscope, atomic force microscope, and optical differential interference contrast microscopy, we observed the presence of unexpected defects of morphological nature on the titanium surface and their evolution in time in proximity to Nb contacts. We found direct correlation between the variations of the morphology and the SC transition shape. Experiments with different diffusion barriers between TES and Nb leads were performed to clarify the origin of this problem. We have demonstrated that the reproducibility of superconducting transitions can be significantly improved by preventing diffusion processes in the TES–leads contact areas

Performance and characterization of the SPT-3G digital frequency-domain multiplexed readout system using an improved noise and crosstalk model

The third-generation South Pole Telescope camera (SPT-3G) improves upon its predecessor (SPTpol) by an order of magnitude increase in detectors on the focal plane. The technology used to read out and control these detectors, digital frequency-domain multiplexing (DfMUX), is conceptually the same as used for SPTpol, but extended to accommodate more detectors. A nearly 5× expansion in the readout operating bandwidth has enabled the use of this large focal plane, and SPT-3G performance meets the forecasting targets relevant to its science objectives. However, the electrical dynamics of the higher-bandwidth readout differ from predictions based on models of the SPTpol system due to the higher frequencies used and parasitic impedances associated with new cryogenic electronic architecture. To address this, we present an updated derivation for electrical crosstalk in higher-bandwidth DfMUX systems and identify two previously uncharacterized contributions to readout noise, which become dominant at high bias frequency. The updated crosstalk and noise models successfully describe the measured crosstalk and readout noise performance of SPT-3G. These results also suggest specific changes to warm electronics component values, wire-harness properties, and SQUID parameters, to improve the readout system for future experiments using DfMUX, such as the LiteBIRD space telescope

An ancient conserved role for prion protein in learning and memory

The misfolding of cellular prion protein (PrPC) to form PrP Scrapie (PrPSc) is an exemplar of toxic gain-of-function mechanisms inducing propagated protein misfolding and progressive devastating neurodegeneration. Despite this, PrPC function in the brain is also reduced and subverted during prion disease progression; thus understanding the normal function of PrPC in healthy brains is key. Disrupting PrPC in mice has led to a myriad of controversial functions that sometimes map onto disease symptoms, including a proposed role in memory or learning. Intriguingly, PrPC interaction with amyloid beta (Aβ) oligomers at synapses has also linked its function to Alzheimer's disease and dementia in recent years. We set out to test the involvement of PrPC in memory using a disparate animal model, the zebrafish. Here we document an age-dependent memory decline in prp2−/− zebrafish, pointing to a conserved and ancient role of PrPC in memory. Specifically, we found that aged (3-year-old) prp2−/− fish performed poorly in an object recognition task relative to age-matched prp2+/+ fish or 1-year-old prp2−/− fish. Further, using a novel object approach (NOA) test, we found that aged (3-year-old) prp2−/− fish approached the novel object more than either age-matched prp2+/+ fish or 1-year-old prp2−/− fish, but did not have decreased anxiety when we tested them in a novel tank diving test. Taken together, the results of the NOA and novel tank diving tests suggest an altered cognitive appraisal of the novel object in the 3-year-old prp2−/− fish. The learning paradigm established here enables a path forward to study PrPC interactions of relevance to Alzheimer's disease and prion diseases, and to screen for candidate therapeutics for these diseases. The findings underpin a need to consider the relative contributions of loss- versus gain-of-function of PrPC during Alzheimer's and prion diseases, and have implications upon the prospects of several promising therapeutic strategies

Progressive Photoreceptor Dysfunction and Age-Related Macular Degeneration-Like Features in rp1l1 Mutant Zebrafish

Photoreceptor disease results in irreparable vision loss and blindness, which has a dramatic impact on quality of life. Pathogenic mutations in RP1L1 lead to photoreceptor degenerations such as occult macular dystrophy and retinitis pigmentosa. RP1L1 is a component of the photoreceptor axoneme, the backbone structure of the photoreceptor&rsquo;s light-sensing outer segment. We generated an rp1l1 zebrafish mutant using CRISPR/Cas9 genome editing. Mutant animals had progressive photoreceptor functional defects as determined by electrophysiological assessment. Optical coherence tomography showed gaps in the photoreceptor layer, disrupted photoreceptor mosaics, and thinner retinas. Mutant retinas had disorganized photoreceptor outer segments and lipid-rich subretinal drusenoid deposits between the photoreceptors and retinal pigment epithelium. Our mutant is a novel model of RP1L1-associated photoreceptor disease and the first zebrafish model of photoreceptor degeneration with reported subretinal drusenoid deposits, a feature of age-related macular degeneration

Large arrays of dual-polarized multichroic TES detectors for CMB measurements with the SPT-3G receiver

Detectors for cosmic microwave background (CMB) experiments are now essentially background limited, so a straightforward alternative to improve sensitivity is to increase the number of detectors. Large arrays of multichroic pixels constitute an economical approach to increasing the number of detectors within a given focal plane area. Here, we present the fabrication of large arrays of dual-polarized multichroic transition-edge-sensor (TES) bolometers for the South Pole Telescope third-generation CMB receiver (SPT-3G). The complete SPT-3G receiver will have 2690 pixels, each with six detectors, allowing for individual measurement of three spectral bands (centered at 95 GHz, 150 GHz and 220 GHz) in two orthogonal polarizations. In total, the SPT-3G focal plane will have 16140 detectors. Each pixel is comprised of a broad-band sinuous antenna coupled to a niobium microstrip transmission line. In-line filters are used to define the different band-passes before the millimeter-wavelength signal is fed to the respective Ti/Au TES sensors. Detectors are read out using a 64x frequency domain multiplexing (fMux) scheme. The microfabrication of the SPT-3G detector arrays involves a total of 18 processes, including 13 lithography steps. Together with the fabrication process, the effect of processing on the Ti/Au TES’s Tc is discussed. In addition, detectors fabricated with Ti/Au TES films with Tc between 400 mK 560 mK are presented and their thermal characteristics are evaluated. Optical characterization of the arrays is presented as well, indicating that the response of the detectors is in good agreement with the design values for all three spectral bands (95 GHz, 150 GHz, and 220 GHz). The measured optical efficiency of the detectors is between 0.3 and 0.8. Results discussed here are extracted from a batch of research of development wafers used to develop the baseline process for the fabrication of the arrays of detectors to be deployed with the SPT-3G receiver. Results from these research and development wafers have been incorporated into the fabrication process to get the baseline fabrication process presented here. SPT-3G is scheduled to deploy to the South Pole Telescope in late 2016

Characterization and performance of the second-year SPT-3G focal plane

The third-generation instrument for the 10-meter South Pole Telescope, SPT-3G, was first installed in January 2017. In addition to completely new cryostats, secondary telescope optics, and readout electronics, the number of detectors in the focal plane has increased by an order of magnitude from previous instruments to ~16,000. The SPT-3G focal plane consists of ten detector modules, each with an array of 269 trichroic, polarization-sensitive pixels on a six-inch silicon wafer. Within each pixel is a broadband, dual-polarization sinuous antenna; the signal from each orthogonal linear polarization is divided into three frequency bands centered at 95, 150, and 220 GHz by in-line lumped element filters and transmitted via superconducting microstrip to Ti/Au transition-edge sensor (TES) bolometers. Properties of the TES film, microstrip filters, and bolometer island must be tightly controlled to achieve optimal performance. For the second year of SPT-3G operation, we have replaced all ten wafers in the focal plane with new detector arrays tuned to increase mapping speed and improve overall performance. Here we discuss the TES superconducting transition temperature and normal resistance, detector saturation power, bandpasses, optical efficiency, and full array yield for the 2018 focal plane

First M87 Event Horizon Telescope Results. II. Array and Instrumentation

The Event Horizon Telescope (EHT) is a very long baseline interferometry (VLBI) array that comprises millimeter- and submillimeter-wavelength telescopes separated by distances comparable to the diameter of the Earth. At a nominal operating wavelength of similar to 1.3 mm, EHT angular resolution (lambda/D) is similar to 25 mu as, which is sufficient to resolve nearby supermassive black hole candidates on spatial and temporal scales that correspond to their event horizons. With this capability, the EHT scientific goals are to probe general relativistic effects in the strong-field regime and to study accretion and relativistic jet formation near the black hole boundary. In this Letter we describe the system design of the EHT, detail the technology and instrumentation that enable observations, and provide measures of its performance. Meeting the EHT science objectives has required several key developments that have facilitated the robust extension of the VLBI technique to EHT observing wavelengths and the production of instrumentation that can be deployed on a heterogeneous array of existing telescopes and facilities. To meet sensitivity requirements, high-bandwidth digital systems were developed that process data at rates of 64. gigabit s(-1), exceeding those of currently operating cm-wavelength VLBI arrays by more than an order of magnitude. Associated improvements include the development of phasing systems at array facilities, new receiver installation at several sites, and the deployment of hydrogen maser frequency standards to ensure coherent data capture across the array. These efforts led to the coordination and execution of the first Global EHT observations in 2017 April, and to event-horizon-scale imaging of the supermassive black hole candidate in M87

Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution

3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3 mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable gamma -ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array (ALMA), at an angular resolution of similar to 20 mu as (at a redshift of z=0.536 this corresponds to similar to 0.13 pc similar to 1700 Schwarzschild radii with a black hole mass M-BH=8x10(8) M-circle dot). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation. We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across different imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI &quot;core&quot;. This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet. We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of similar to 15 c and similar to 20 c (similar to 1.3 and similar to 1.7 mu as day(-1), respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3 mm core and the outer jet. The intrinsic brightness temperature of the jet components are less than or similar to 10(10) K, a magnitude or more lower than typical values seen at &gt;= 7 mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths