Comparison of Phenotypes between Different vangl2vangl2 Mutants Demonstrates Dominant Effects of the LooptailLooptail Mutation during Hair Cell Development

Experiments utilizing the $Looptail$ mutant mouse, which harbors a missense mutation in the $vangl2$ gene, have been essential for studies of planar polarity and linking the function of the core planar cell polarity proteins to other developmental signals. Originally described as having dominant phenotypic traits, the molecular interactions underlying the $Looptail$ mutant phenotype are unclear because Vangl2 protein levels are significantly reduced or absent from mutant tissues. Here we introduce a $vangl2$ knockout mouse and directly compare the severity of the knockout and $Looptail$ mutant phenotypes by intercrossing the two lines and assaying the planar polarity of inner ear hair cells. Overall the $vangl2$ knockout phenotype is milder than the phenotype of compound mutants carrying both the $Looptail$ and $vangl2$ knockout alleles. In compound mutants a greater number of hair cells are affected and changes in the orientation of individual hair cells are greater when quantified. We further demonstrate in a heterologous cell system that the protein encoded by the Looptail mutation $(Vangl2^{S464N})$ disrupts delivery of Vangl1 and Vangl2 proteins to the cell surface as a result of oligomer formation between Vangl1 and $Vangl2^{S464N}$, or Vangl2 and $Vangl2^{S464N}$, coupled to the intracellular retention of $Vangl2^{S464N}$. As a result, Vangl1 protein is missing from the apical cell surface of vestibular hair cells in $Looptail$ mutants, but is retained at the apical cell surface of hair cells in $vangl2$ knockouts. Similarly the distribution of Prickle-like2, a putative Vangl2 interacting protein, is differentially affected in the two mutant lines. In summary, we provide evidence for a direct physical interaction between Vangl1 and Vangl2 through a combination of in vitro and in vivo approaches and propose that this interaction underlies the dominant phenotypic traits associated with the $Looptail$ mutation

Characterization of Cracks in Oxidation-Protective Coatings

Carbon-carbon materials are being developed for high temperature use in gas turbine engines and other applications. They have high specific strength and stiffness at elevated temperature, as well as thermal shock resistance. Silicon carbide based coatings are commonly used to protect the material from oxidation

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

SummaryHematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion

The C-Band All-Sky Survey (C-BASS): Constraining diffuse Galactic radio emission in the North Celestial Pole region

The C-Band All-Sky Survey C-BASS is a high-sensitivity all-sky radio survey at an angular resolution of 45 arcmin and a frequency of 4.7 GHz. We present a total intensity 4.7 GHz map of the North Celestial Pole (NCP) region of sky, above declination +80 deg, which is limited by source confusion at a level of ~0.6 mK rms. We apply the template-fitting (cross-correlation) technique to WMAP and Planck data, using the C-BASS map as the synchrotron template, to investigate the contribution of diffuse foreground emission at frequencies ~20-40 GHz. We quantify the anomalous microwave emission (AME) that is correlated with far-infrared dust emission. The AME amplitude does not change significantly (<10%) when using the higher frequency C-BASS 4.7 GHz template instead of the traditional Haslam 408 MHz map as a tracer of synchrotron radiation. We measure template coefficients of $9.93\pm0.35$ and $9.52\pm0.34$ K per unit $\tau_{353}$ when using the Haslam and C-BASS synchrotron templates, respectively. The AME contributes $55\pm2\,\mu$K rms at 22.8 GHz and accounts for ~60% of the total foreground emission. Our results suggest that a harder (flatter spectrum) component of synchrotron emission is not dominant at frequencies >5 GHz; the best-fitting synchrotron temperature spectral index is $\beta=-2.91\pm0.04$ from 4.7 to 22.8 GHz and $\beta=-2.85\pm0.14$ from 22.8 to 44.1 GHz. Free-free emission is weak, contributing ~$7\,\mu$K rms (~7%) at 22.8 GHz. The best explanation for the AME is still electric dipole emission from small spinning dust grains.Comment: 18 pages, 6 figures, version matches version accepted by MNRA

C-Band All-Sky Survey: A First Look at the Galaxy

We present an analysis of the diffuse emission at 5 GHz in the first quadrant of the Galactic plane using two months of preliminary intensity data taken with the C-Band All Sky Survey (C-BASS) northern instrument at the Owens Valley Radio Observatory, California. Combining C-BASS maps with ancillary data to make temperature-temperature plots we find synchrotron spectral indices of $\beta = -2.65 \pm 0.05$ between 0.408 GHz and 5 GHz and $\beta = -2.72 \pm 0.09$ between 1.420 GHz and 5 GHz for $-10^{\circ} < |b| < -4^{\circ}$, $20^{\circ} < l < 40^{\circ}$. Through the subtraction of a radio recombination line (RRL) free-free template we determine the synchrotron spectral index in the Galactic plane ($|b| < 4^{\circ}$) to be $\beta = -2.56 \pm 0.07$ between 0.408 GHz and 5 GHz, with a contribution of $53 \pm 8$ per cent from free-free emission at 5\,GHz. These results are consistent with previous low frequency measurements in the Galactic plane. By including C-BASS data in spectral fits we demonstrate the presence of anomalous microwave emission (AME) associated with the HII complexes W43, W44 and W47 near 30 GHz, at 4.4 sigma, 3.1 sigma and 2.5 sigma respectively. The CORNISH VLA 5 GHz source catalogue rules out the possibility that the excess emission detected around 30\;GHz may be due to ultra-compact HII regions. Diffuse AME was also identified at a 4 sigma level within $30^{\circ} < l < 40^{\circ}$, $-2^{\circ} < b < 2^{\circ}$ between 5 GHz and 22.8 GHz.Comment: 16 pages, 9 figures, submitted to MNRAS, referee's corrections made, awaiting for final approval for publicatio

Astronomical Receiver Modelling Using Scattering Matrices

Proper modelling of astronomical receivers is vital: it describes the systematic errors in the raw data, guides the receiver design process, and assists data calibration. In this paper we describe a method of analytically modelling the full signal and noise behaviour of arbitrarily complex radio receivers. We use electrical scattering matrices to describe the signal behaviour of individual components in the receiver, and noise correlation matrices to describe their noise behaviour. These are combined to produce the full receiver model. We apply this approach to a specified receiver architecture: a hybrid of a continous comparison radiometer and correlation polarimeter designed for the C-Band All-Sky Survey. We produce analytic descriptions of the receiver Mueller matrix and noise temperature, and discuss how imperfections in crucial components affect the raw data. Many of the conclusions drawn are generally applicable to correlation polarimeters and continuous comparison radiometers.Comment: 18 pages, 8 figures, accepted for publication in MNRA

Qualitative, rather than quantitative, differences between HLA-DQ alleles affect HLA-DQ immunogenicity in organ transplantation

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections.</p

Qualitative, rather than quantitative, differences between HLA‐DQ alleles affect HLA‐DQ immunogenicity in organ transplantation

Prolonging the lifespan of transplanted organs is critical to combat the shortage of this life-saving resource. Chronic rejection, with irreversible demise of the allograft, is often caused by the development of donor-specific HLA antibodies. Currently, enumerating molecular (amino acid) mismatches between recipient and donor is promoted to identify patients at higher risk of developing HLA antibodies, for use in organ allocation, and immunosuppression-minimization strategies. We have counseled against the incorporation of such approaches into clinical use and hypothesized that not all molecular mismatches equally contribute to generation of donor-specific immune responses. Herein, we document statistical shortcomings in previous study design: for example, use of individuals who lack the ability to generate donor-specific-antibodies (HLA identical) as part of the negative cohort. We provide experimental evidence, using CRISPR-Cas9-edited cells, to rebut the claim that the HLAMatchmaker eplets represent “functional epitopes.” We further used unique sub-cohorts of patients, those receiving an allograft with two HLA-DQ mismatches yet developing antibodies only to one mismatch (2MM1DSA), to interrogate differential immunogenicity. Our results demonstrate that mismatches of DQα05-heterodimers exhibit the highest immunogenicity. Additionally, we demonstrate that the DQα chain critically contributes to the overall qualities of DQ molecules. Lastly, our data proposes that an augmented risk to develop donor-specific HLA-DQ antibodies is dependent on qualitative (evolutionary and functional) divergence between recipient and donor, rather than the mere number of molecular mismatches. Overall, we propose an immunological mechanistic rationale to explain differential HLA-DQ immunogenicity, with potential ramifications for other pathological processes such as autoimmunity and infections

The C-Band All-Sky Survey (C-BASS): New Constraints on the Integrated Radio Spectrum of M 31

The Andromeda galaxy (M31) is our closest neighbouring spiral galaxy, making it an ideal target for studying the physics of the interstellar medium in a galaxy very similar to our own. Using new observations of M31 at 4.76GHz by the C-Band All-Sky Survey (C-BASS), and all available radio data at $1^\circ$ resolution, we produce the integrated spectrum and put new constraints on the synchrotron spectral index and anomalous microwave emission (AME) from M31. We use aperture photometry and spectral modelling to fit for the integrated spectrum of M31, and subtract a comprehensive model of nearby background radio sources. The AME in M31 is detected at $3\sigma$ significance with a peak near 30GHz and flux density $0.27\pm0.09$Jy. The synchrotron spectral index of M31 is flatter than our own Galaxy at $\alpha = -0.66 \pm 0.03$ with no strong evidence of spectral curvature. The emissivity of AME, averaged over the total emission from M31 is lower than typical AME sources in our Galaxy, implying that AME is not uniformly distributed throughout M31 and instead is likely confined to sub-regions -- this will need to be confirmed using future higher resolution observations around 20--30GHz.Comment: 16 pages, 6 figures, submitted to MNRA