Grxcr1 promotes hair bundle development by destabilizing the physical interaction between Harmonin and Sans usher syndrome proteins

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Cell Reports 25 (2018): 1281–1291, doi:10.1016/j.celrep.2018.10.005.Morphogenesis and mechanoelectrical transduction of the hair cell mechanoreceptor depend on the correct assembly of Usher syndrome (USH) proteins into highly organized macromolecular complexes. Defects in these proteins lead to deafness and vestibular areflexia in USH patients. Mutations in a non-USH protein, glutaredoxin domain-containing cysteine-rich 1 (GRXCR1), cause non-syndromic sensorineural deafness. To understand the deglutathionylating enzyme function of GRXCR1 in deafness, we generated two grxcr1 zebrafish mutant alleles. We found that hair bundles are thinner in homozygous grxcr1 mutants, similar to the USH1 mutants ush1c (Harmonin) and ush1ga (Sans). In vitro assays showed that glutathionylation promotes the interaction between Ush1c and Ush1ga and that Grxcr1 regulates mechanoreceptor development by preventing physical interaction between these proteins without affecting the assembly of another USH1 protein complex, the Ush1c- Cadherin23-Myosin7aa tripartite complex. By elucidating the molecular mechanism through which Grxcr1 functions, we also identify a mechanism that dynamically regulates the formation of Usher protein complexes.This work was supported by grants from the NIH (DC004186, OD011195, and HD22486)

Non-invasive Spatial Mapping of Frequencies in Atrial Fibrillation: Correlation With Contact Mapping

Introduction: Regional differences in activation rates may contribute to the electrical substrates that maintain atrial fibrillation (AF), and estimating them non-invasively may help guide ablation or select anti-arrhythmic medications. We tested whether non-invasive assessment of regional AF rate accurately represents intracardiac recordings. Methods: In 47 patients with AF (27 persistent, age 63 ± 13 years) we performed 57-lead non-invasive Electrocardiographic Imaging (ECGI) in AF, simultaneously with 64-pole intracardiac signals of both atria. ECGI was reconstructed by Tikhonov regularization. We constructed personalized 3D AF rate distribution maps by Dominant Frequency (DF) analysis from intracardiac and non-invasive recordings. Results: Raw intracardiac and non-invasive DF differed substantially, by 0.54 Hz [0.13 - 1.37] across bi-atrial regions (R2 = 0.11). Filtering by high spectral organization reduced this difference to 0.10 Hz (cycle length difference of 1 - 11 ms) [0.03 - 0.42] for patient-level comparisons (R2 = 0.62), and 0.19 Hz [0.03 - 0.59] and 0.20 Hz [0.04 - 0.61] for median and highest DF, respectively. Non-invasive and highest DF predicted acute ablation success (p = 0.04). Conclusion: Non-invasive estimation of atrial activation rates is feasible and, when filtered by high spectral organization, provide a moderate estimate of intracardiac recording rates in AF. Non-invasive technology could be an effective tool to identify patients who may respond to AF ablation for personalized therapy

Spatiotemporal coordination of cell division and growth during organ morphogenesis

A developing plant organ exhibits complex spatiotemporal patterns of growth, cell division, cell size, cell shape, and organ shape. Explaining these patterns presents a challenge because of their dynamics and cross-correlations, which can make it difficult to disentangle causes from effects. To address these problems, we used live imaging to determine the spatiotemporal patterns of leaf growth and division in different genetic and tissue contexts. In the simplifying background of the speechless (spch) mutant, which lacks stomatal lineages, the epidermal cell layer exhibits defined patterns of division, cell size, cell shape, and growth along the proximodistal and mediolateral axes. The patterns and correlations are distinctive from those observed in the connected subepidermal layer and also different from the epidermal layer of wild type. Through computational modelling we show that the results can be accounted for by a dual control model in which spatiotemporal control operates on both growth and cell division, with cross-connections between them. The interactions between resulting growth and division patterns lead to a dynamic distributions of cell sizes and shapes within a deforming leaf. By modulating parameters of the model, we illustrate how phenotypes with correlated changes in cell size, cell number, and organ size may be generated. The model thus provides an integrated view of growth and division that can act as a framework for further experimental study

The SAMI Galaxy Survey: spatially resolved metallicity and ionization mapping

We present gas-phase metallicity and ionization parameter maps of 25 star-forming face-on spiral galaxies from the SAMI Galaxy Survey Data Release 1. Self-consistent metallicity and ionization parameter maps are calculated simultaneously through an iterative process to account for the interdependence of the strong emission line diagnostics involving ([O II]+[O III])/Hβ (R23) and [O III]/[O II](O32). The maps are created on a spaxel-by-spaxel basis because H II regions are not resolved at the SAMI spatial resolution. We combine the SAMI data with stellar mass, star formation rate (SFR), effective radius (Re), ellipticity, and position angles (PA) from the GAMA survey to analyse their relation to the metallicity and ionization parameter. We find a weak trend of steepening metallicity gradient with galaxy stellar mass, with values ranging from −0.03 to −0.20 dex/Re. Only two galaxies show radial gradients in the ionization parameter. We find that the ionization parameter has no significant correlation with either SFR, sSFR (specific SFR), or metallicity. For several individual galaxies, we find the structure in the ionization parameter maps suggestive of spiral arm features. We find a typical ionization parameter range of 7.0 < log (q) < 7.8 for our galaxy sample with no significant overall structure. An ionization parameter range of this magnitude is large enough to caution the use of metallicity diagnostics that have not considered the effects of a varying ionization parameter distribution

The SAMI Galaxy Survey : mass as the driver of the kinematic morphology - density relation in clusters

We examine the kinematic morphology of early-type galaxies (ETGs) in eight galaxy clusters in the Sydney-AAO Multi-object Integral-field spectrograph Galaxy Survey. The clusters cover a mass range of 14.2log(M200/M☉) <15.2 and we measure spatially resolved stellar kinematics for 315 member galaxies with stellar masses 10.0 < log(M*/M☉) ≤ 11.7 within 1 R 200 of the cluster centers. We calculate the spin parameter, λ R , and use this to classify the kinematic morphology of the galaxies as fast or slow rotators (SRs). The total fraction of SRs in the ETG population is F SR = 0.14 ± 0.02 and does not depend on host cluster mass. Across the eight clusters, the fraction of SRs increases with increasing local overdensity. We also find that the slow-rotator fraction increases at small clustercentric radii (R cl < 0.3 R 200), and note that there is also an increase in the slow-rotator fraction at R cl ~ 0.6 R 200. The SRs at these larger radii reside in the cluster substructure. We find that the strongest increase in the slow-rotator fraction occurs with increasing stellar mass. After accounting for the strong correlation with stellar mass, we find no significant relationship between spin parameter and local overdensity in the cluster environment. We conclude that the primary driver for the kinematic morphology–density relationship in galaxy clusters is the changing distribution of galaxy stellar mass with the local environment. The presence of SRs in the substructure suggests that the cluster kinematic morphology–density relationship is a result of mass segregation of slow-rotating galaxies forming in groups that later merge with clusters and sink to the cluster center via dynamical friction.Publisher PDFPeer reviewe

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen