Gamma-D crystallin gene (CRYGD) mutation causes autosomal dominant congenital cerulean cataracts

Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction theta=0) was obtained for marker D2S2208 near the g-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts

Magnetic field dependence of the internal quality factor and noise performance of lumped-element kinetic inductance detectors

We present a technique for increasing the internal quality factor of kinetic inductance detectors (KIDs) by nulling ambient magnetic fields with a properly applied magnetic field. The KIDs used in this study are made from thin-film aluminum, they are mounted inside a light-tight package made from bulk aluminum, and they are operated near $150 \, \mathrm{mK}$. Since the thin-film aluminum has a slightly elevated critical temperature ($T_\mathrm{c} = 1.4 \, \mathrm{K}$), it therefore transitions before the package ($T_\mathrm{c} = 1.2 \, \mathrm{K}$), which also serves as a magnetic shield. On cooldown, ambient magnetic fields as small as approximately $30 \, \mathrm{\mu T}$ can produce vortices in the thin-film aluminum as it transitions because the bulk aluminum package has not yet transitioned and therefore is not yet shielding. These vortices become trapped inside the aluminum package below $1.2 \, \mathrm{K}$ and ultimately produce low internal quality factors in the thin-film superconducting resonators. We show that by controlling the strength of the magnetic field present when the thin film transitions, we can control the internal quality factor of the resonators. We also compare the noise performance with and without vortices present, and find no evidence for excess noise beyond the increase in amplifier noise, which is expected with increasing loss.Comment: 5 pages, 4 figure

Percolation and phase behavior in cellulose nanocrystal suspensions from nonlinear rheological analysis

We examine the influence of surface charge on the percolation, gel-point and phase behavior of cellulose nanocrystal (CNC) suspensions in relation to their nonlinear rheological material response. Desulfation decreases CNC surface charge density which leads to an increase in attractive forces between CNCs. Therefore, by considering sulfated and desulfated CNC suspensions, we are comparing CNC systems that differ in their percolation and gel-point concentrations relative to their phase transition concentrations. The results show that independently of whether the gel-point (linear viscoelasticity, LVE) occurs at the biphasic - liquid crystalline transition (sulfated CNC) or at the isotropic - quasi-biphasic transition (desulfated CNC), the nonlinear behavior appears to mark the existence of a weakly percolated network at lower concentrations. Above this percolation threshold, nonlinear material parameters are sensitive to the phase and gelation behavior as determined in static (phase) and LVE conditions (gel-point). However, the change in material response in nonlinear conditions can occur at higher concentrations than identified through polarized optical microscopy, suggesting that the nonlinear deformations could distort the suspensions microstructure such that for example a liquid crystalline phase (static) suspension could show microstructural dynamics similar to a biphasic system

GABAA receptors can initiate the formation of functional inhibitory GABAergic synapses.

The mechanisms that underlie the selection of an inhibitory GABAergic axon's postsynaptic targets and the formation of the first contacts are currently unknown. To determine whether expression of GABAA receptors (GABAA Rs) themselves - the essential functional postsynaptic components of GABAergic synapses - can be sufficient to initiate formation of synaptic contacts, a novel co-culture system was devised. In this system, the presynaptic GABAergic axons originated from embryonic rat basal ganglia medium spiny neurones, whereas their most prevalent postsynaptic targets, i.e. α1/β2/γ2-GABAA Rs, were expressed constitutively in a stably transfected human embryonic kidney 293 (HEK293) cell line. The first synapse-like contacts in these co-cultures were detected by colocalization of presynaptic and postsynaptic markers within 2 h. The number of contacts reached a plateau at 24 h. These contacts were stable, as assessed by live cell imaging; they were active, as determined by uptake of a fluorescently labelled synaptotagmin vesicle-luminal domain-specific antibody; and they supported spontaneous and action potential-driven postsynaptic GABAergic currents. Ultrastructural analysis confirmed the presence of characteristics typical of active synapses. Synapse formation was not observed with control or N-methyl-d-aspartate receptor-expressing HEK293 cells. A prominent increase in synapse formation and strength was observed when neuroligin-2 was co-expressed with GABAA Rs, suggesting a cooperative relationship between these proteins. Thus, in addition to fulfilling an essential functional role, postsynaptic GABAA Rs can promote the adhesion of inhibitory axons and the development of functional synapses

Double deletion of Panx1 and Panx3 affects skin and bone but not hearing

Pannexins (Panxs), large-pore channel forming glycoproteins, are expressed in a wide variety of tissues including the skin, bone, and cochlea. To date, the use of single knock-out mouse models of both Panx1 and Panx3 have demonstrated their roles in skin development, bone formation, and auditory phenotypes. Due to sequence homology between Panx1 and Panx3, when one Panx is ablated from germline, the other may be upregulated in a compensatory mechanism to maintain tissue homeostasis and function. To evaluate the roles of Panx1 and Panx3 in the skin, bone, and cochlea, we created the first Panx1/Panx3 double knock-out mouse model (dKO). These mice had smaller litters and reduced body weight compared to wildtype controls. The dKO dorsal skin had decreased epidermal and dermal area as well as decreased hypodermal area in neonatal but not in older mice. In addition, mouse skull shape and size were altered, and long bone length was decreased in neonatal dKO mice. Finally, auditory tests revealed that dKO mice did not exhibit hearing loss and were even slightly protected against noise-induced hearing damage at mid-frequency regions. Taken together, our findings suggest that Panx1 and Panx3 are important at early stages of development in the skin and bone but may be redundant in the auditory system. Key messages Panx double KO mice had smaller litters and reduced body weight. dKO skin had decreased epidermal and dermal area in neonatal mice. Skull shape and size changed plus long bone length decreased in neonatal dKO mice. dKO had no hearing loss and were slightly protected against noise-induced damage

Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics.

Amyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO). Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, APLP2-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the APP-KO photoreceptor ribbon synapses and bipolar cells were intact. The APLP2-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the APLP2-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including CACNA1F, GRM6, TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, VSX1 and OTX2. These findings demonstrate that APLP2 couples retina development and synaptic genes and present the first evidence that APLP2 expression may be linked to synaptic disease

High quality factor manganese-doped aluminum lumped-element kinetic inductance detectors sensitive to frequencies below 100 GHz

Aluminum lumped-element kinetic inductance detectors (LEKIDs) sensitive to millimeter-wave photons have been shown to exhibit high quality factors, making them highly sensitive and multiplexable. The superconducting gap of aluminum limits aluminum LEKIDs to photon frequencies above 100 GHz. Manganese-doped aluminum (Al-Mn) has a tunable critical temperature and could therefore be an attractive material for LEKIDs sensitive to frequencies below 100 GHz if the internal quality factor remains sufficiently high when manganese is added to the film. To investigate, we measured some of the key properties of Al-Mn LEKIDs. A prototype eight-element LEKID array was fabricated using a 40 nm thick film of Al-Mn deposited on a 500 µm thick high-resistivity, float-zone silicon substrate. The manganese content was 900 ppm, the measured Tc = 694 ± 1mK, and the resonance frequencies were near 150 MHz. Using measurements of the forward scattering parameter S21 at various bath temperatures between 65 and 250 mK, we determined that the Al-Mn LEKIDs we fabricated have internal quality factors greater than 2 × 105 , which is high enough for millimeter-wave astrophysical observations. In the dark conditions under which these devices were measured, the fractional frequency noise spectrum shows a shallow slope that depends on bath temperature and probe tone amplitude, which could be two-level system noise. The anticipated white photon noise should dominate this level of low-frequency noise when the detectors are illuminated with millimeter-waves in future measurements. The LEKIDs responded to light pulses from a 1550 nm light-emitting diode, and we used these light pulses to determine that the quasiparticle lifetime is 60 µs

Spectral Distortions of the CMB as a Probe of Inflation, Recombination, Structure Formation and Particle Physics

Following the pioneering observations with COBE in the early 1990s, studies of the cosmic microwave background (CMB) have focused on temperature and polarization anisotropies. CMB spectral distortions - tiny departures of the CMB energy spectrum from that of a perfect blackbody - provide a second, independent probe of fundamental physics, with a reach deep into the primordial Universe. The theoretical foundation of spectral distortions has seen major advances in recent years, which highlight the immense potential of this emerging field. Spectral distortions probe a fundamental property of the Universe - its thermal history - thereby providing additional insight into processes within the cosmological standard model (CSM) as well as new physics beyond. Spectral distortions are an important tool for understanding inflation and the nature of dark matter. They shed new light on the physics of recombination and reionization, both prominent stages in the evolution of our Universe, and furnish critical information on baryonic feedback processes, in addition to probing primordial correlation functions at scales inaccessible to other tracers. In principle the range of signals is vast: many orders of magnitude of discovery space could be explored by detailed observations of the CMB energy spectrum. Several CSM signals are predicted and provide clear experimental targets, some of which are already observable with present-day technology. Confirmation of these signals would extend the reach of the CSM by orders of magnitude in physical scale as the Universe evolves from the initial stages to its present form. The absence of these signals would pose a huge theoretical challenge, immediately pointing to new physics.Comment: Astro2020 Science White Paper, 5 pages text, 13 pages in total, 3 Figures, minor update to reference

Photon noise from chaotic and coherent millimeter-wave sources measured with horn-coupled, aluminum lumped-element kinetic inductance detectors

We report photon-noise limited performance of horn-coupled, aluminum lumped-element kinetic inductance detectors at millimeter wavelengths. The detectors are illuminated by a millimeter-wave source that uses an active multiplier chain to produce radiation between 140 and 160 GHz. We feed the multiplier with either amplified broadband noise or a continuous-wave tone from a microwave signal generator. We demonstrate that the detector response over a 40 dB range of source power is well-described by a simple model that considers the number of quasiparticles. The detector noise-equivalent power (NEP) is dominated by photonnoise when the absorbed power is greater than approximately 1 pW, which corresponds to NEP ≈ 2×10^(−17) W Hz^(−1/2), referenced to absorbed power. At higher source power levels, we observe the relationships between noise and power expected from the photon statistics of the source signal: NEP∝P for broadband (chaotic) illumination and NEP∝P^(1/2) for continuous-wave (coherent) illumination