Regulated Formation of an Amyloid-like Translational Repressor Governs Gametogenesis

Message-specific translational control is required for gametogenesis. In yeast, the RNA-binding protein Rim4 mediates translational repression of numerous mRNAs, including the B-type cyclin CLB3, which is essential for establishing the meiotic chromosome segregation pattern. Here, we show that Rim4 forms amyloid-like aggregates and that it is the amyloid-like form of Rim4 that is the active, translationally repressive form of the protein. Our data further show that Rim4 aggregation is a developmentally regulated process. Starvation induces the conversion of monomeric Rim4 into amyloid-like aggregates, thereby activating the protein to bring about repression of translation. At the onset of meiosis II, Rim4 aggregates are abruptly degraded allowing translation to commence. Although amyloids are best known for their role in the etiology of diseases such as Alzheimer’s, Parkinson’s, and diabetes by forming toxic protein aggregates, our findings show that cells can utilize amyloid-like protein aggregates to function as central regulators of gametogenesis.Charles A. King Trust (Postdoctoral Fellowship)American Cancer Society (Fellowship)National Institutes of Health (U.S.) (Grants GM62207, GM77537, and GM094303

Challenging Perceptions of Disability through Performance Poetry Methods: The "Seen but Seldom Heard" Project.

This paper considers performance poetry as a method to explore lived experiences of disability. We discuss how poetic inquiry used within a participatory arts-based research framework can enable young people to collectively question society’s attitudes and actions towards disability. Poetry will be considered as a means to develop a more accessible and effective arena in which young people with direct experience of disability can be empowered to develop new skills that enable them to tell their own stories. Discussion of how this can challenge audiences to critically reflect upon their own perceptions of disability will also be developed

Carnegie Hubble Program: A Mid-Infrared Calibration of the Hubble Constant

Using a mid-infrared calibration of the Cepheid distance scale based on recent observations at 3.6 um with the Spitzer Space Telescope, we have obtained a new, high-accuracy calibration of the Hubble constant. We have established the mid-IR zero point of the Leavitt Law (the Cepheid Period-Luminosity relation) using time-averaged 3.6 um data for ten high-metallicity, Milky Way Cepheids having independently-measured trigonometric parallaxes. We have adopted the slope of the PL relation using time-averaged 3.6 um data for 80 long-period Large Magellanic Cloud (LMC) Cepheids falling in the period range 0.8 < log(P) < 1.8. We find a new reddening-corrected distance to the LMC of 18.477 +/- 0.033 (systematic) mag. We re-examine the systematic uncertainties in H0, also taking into account new data over the past decade. In combination with the new Spitzer calibration, the systematic uncertainty in H0 over that obtained by the Hubble Space Telescope (HST) Key Project has decreased by over a factor of three. Applying the Spitzer calibration to the Key Project sample, we find a value of H0 = 74.3 with a systematic uncertainty of +/-2.1 (systematic) km/s/Mpc, corresponding to a 2.8% systematic uncertainty in the Hubble constant. This result, in combination with WMAP7 measurements of the cosmic microwave background anisotropies and assuming a flat universe, yields a value of the equation of state for dark energy, w0 = -1.09 +/- 0.10. Alternatively, relaxing the constraints on flatness and the numbers of relativistic species, and combining our results with those of WMAP7, Type Ia supernovae and baryon acoustic oscillations yields w0 = -1.08 +/- 0.10 and a value of N_eff = 4.13 +/- 0.67, mildly consistent with the existence of a fourth neutrino species.Comment: 27 pages, 8 figures, Accepted for publication in Ap

Characterization of a Novel Fusion Protein from IpaB and IpaD of Shigella spp. and Its Potential as a Pan-Shigella Vaccine

Shigellosis is an important disease in the developing world, where about 90 million people become infected with Shigella spp. each year. We previously demonstrated that the type three secretion apparatus (T3SA) proteins IpaB and IpaD are protective antigens in the mouse lethal pulmonary model. In order to simplify vaccine formulation and process development, we have evaluated a vaccine design that incorporates both of these previously tested Shigella antigens into a single polypeptide chain. To determine if this fusion protein (DB fusion) retains the antigenic and protective capacities of IpaB and IpaD, we immunized mice with the DB fusion and compared the immune response to that elicited by the IpaB/IpaD combination vaccine. Purification of the DB fusion required coexpression with IpgC, the IpaB chaperone, and after purification it maintained the highly α-helical characteristics of IpaB and IpaD. The DB fusion also induced comparable immune responses and retained the ability to protect mice against Shigella flexneri and S. sonnei in the lethal pulmonary challenge. It also offered limited protection against S. dysenteriae challenge. Our results show the feasibility of generating a protective Shigella vaccine comprised of the DB fusion

Carnegie Supernova Project-II: Extending the Near-Infrared Hubble Diagram for Type Ia Supernovae to z∼0.1z\sim0.1

The Carnegie Supernova Project-II (CSP-II) was an NSF-funded, four-year program to obtain optical and near-infrared observations of a "Cosmology" sample of $\sim100$ Type Ia supernovae located in the smooth Hubble flow ($0.03 \lesssim z \lesssim 0.10$). Light curves were also obtained of a "Physics" sample composed of 90 nearby Type Ia supernovae at $z \leq 0.04$ selected for near-infrared spectroscopic time-series observations. The primary emphasis of the CSP-II is to use the combination of optical and near-infrared photometry to achieve a distance precision of better than 5%. In this paper, details of the supernova sample, the observational strategy, and the characteristics of the photometric data are provided. In a companion paper, the near-infrared spectroscopy component of the project is presented.Comment: 43 pages, 10 figures, accepted for publication in PAS

Clinical Characteristics and Survival of Pulmonary Arterial Hypertension With or Without Interstitial Lung Disease in Systemic Sclerosis

Objectives To describe the clinical phenotype and prognosis of people in the Australian Scleroderma (SSc) Cohort Study with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD). Methods Participants meeting ACR/EULAR criteria for SSc were divided into four mutually exclusive groups: those meeting criteria for PAH (PAH-only), ILD (ILD-only), concurrent PAH and ILD (PAH-ILD) or neither PAH nor ILD (SSc-only). Logistic or linear regression analyses were used for associations between clinical features, health-related quality of life (HRQoL) and physical function. Survival analysis was performed using Kaplan–Meier estimates and Cox-regression modelling. Results Of 1561 participants, 7% fulfilled criteria for PAH-only, 24% ILD-only, 7% PAH-ILD and 62% SSc-only. People with PAH-ILD were more frequently male, with diffuse skin involvement, higher inflammatory markers, older age of SSc onset and higher frequency of extensive ILD than the cohort overall (p \u3c 0.001). People of Asian race more frequently developed PAH-ILD (p \u3c 0.001). People with PAH-ILD or PAH-only had worse WHO functional class and 6-min-walk-distance than ILD-only (p \u3c 0.001). HRQoL scores were worst in those with PAH-ILD (p \u3c 0.001). Survival was reduced in the PAH-only and PAH-ILD groups (p \u3c 0.01). Multivariable hazard modelling demonstrated the worst prognosis in extensive ILD and PAH (HR = 5.65 95% CI 3.50–9.12 p \u3c 0.01), followed by PAH-only (HR = 4.21 95% CI 2.89–6.13 p \u3c 0.01) and PAH with limited ILD (HR = 2.46 95% CI 1.52–3.99 p \u3c 0.01). Conclusions The prevalence of concurrent PAH-ILD in the ASCS is 7%, with poorer survival in those patients with PAH-ILD compared to ILD or SSc alone. The presence of PAH confers a poorer overall prognosis than even extensive ILD; however, further data are required to better understand the clinical outcomes of this high-risk patient group

Variation in histone configurations correlates with gene expression across nine inbred strains of mice.

The diversity outbred (DO) mice and their inbred founders are widely used models of human disease. However, although the genetic diversity of these mice has been well documented, their epigenetic diversity has not. Epigenetic modifications, such as histone modifications and DNA methylation, are important regulators of gene expression, and as such are a critical mechanistic link between genotype and phenotype. Therefore, creating a map of epigenetic modifications in the DO mice and their founders is an important step toward understanding mechanisms of gene regulation and the link to disease in this widely used resource. To this end, we performed a strain survey of epigenetic modifications in hepatocytes of the DO founders. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that the epigenetic landscape was highly variable across the DO founders and was associated with variation in gene expression across strains. We found that epigenetic state imputed into a population of DO mice recapitulated the association with gene expression seen in the founders suggesting that both histone modifications and DNA methylation are highly heritable mechanisms of gene expression regulation. We illustrate how DO gene expression can be aligned with inbred epigenetic states to identify putative cis-regulatory regions. Finally, we provide a data resource that documents strain-specific variation in chromatin state and DNA methylation in hepatocytes across nine widely used strains of laboratory mice

The Hubble Constant and the Expansion Age of the Universe

The Hubble constant, which measures the expansion rate, together with the total energy density of the Universe, sets the size of the observable Universe, its age, and its radius of curvature. Excellent progress has been made recently toward the measurement of the Hubble constant: a number of different methods for measuring distances have been developed and refined, and a primary project of the Hubble Space Telescope has been the accurate calibration of this difficult-to-measure parameter. The recent progress in these measurements is summarized, and areas where further work is needed are discussed. Currently, for a wide range of possible cosmological models, the Universe appears to have a kinematic age less than about 14 +/- 2 billion years. Combined with current estimates of stellar ages, the results favor a low-matter-density universe. They are consistent with either an open universe, or a flat universe with a non-zero value of the cosmological constant.Comment: 25 page review, 3 figures, to be published in the David Schramm Memorial Volume of Physics Reports, latex file; elsar

Determinants of the voltage dependence of G protein modulation within calcium channel β subunits

CaVβ subunits of voltage-gated calcium channels contain two conserved domains, a src-homology-3 (SH3) domain and a guanylate kinase-like (GK) domain with an intervening HOOK domain. We have shown in a previous study that, although Gβγ-mediated inhibitory modulation of CaV2.2 channels did not require the interaction of a CaVβ subunit with the CaVα1 subunit, when such interaction was prevented by a mutation in the α1 subunit, G protein modulation could not be removed by a large depolarization and showed voltage-independent properties (Leroy et al., J Neurosci 25:6984–6996, 2005). In this study, we have investigated the ability of mutant and truncated CaVβ subunits to support voltage-dependent G protein modulation in order to determine the minimal domain of the CaVβ subunit that is required for this process. We have coexpressed the CaVβ subunit constructs with CaV2.2 and α2δ-2, studied modulation by the activation of the dopamine D2 receptor, and also examined basal tonic modulation. Our main finding is that the CaVβ subunit GK domains, from either β1b or β2, are sufficient to restore voltage dependence to G protein modulation. We also found that the removal of the variable HOOK region from β2a promotes tonic voltage-dependent G protein modulation. We propose that the absence of the HOOK region enhances Gβγ binding affinity, leading to greater tonic modulation by basal levels of Gβγ. This tonic modulation requires the presence of an SH3 domain, as tonic modulation is not supported by any of the CaVβ subunit GK domains alone

The Distance to NGC 1316 (Fornax A) From Observations of Four Type Ia Supernovae

The giant elliptical galaxy NGC 1316 (Fornax A) is a well-studied member of the Fornax Cluster and a prolific producer of Type Ia supernovae, having hosted four observed events since 1980. Here we present detailed optical and near-infrared light curves of the spectroscopically normal SN 2006dd. These data are used, along with previously published photometry of the normal SN 1980N and SN 1981D, and the fast-declining, low-luminosity SN 2006mr, to compute independent estimates of the host reddening for each supernova, and the distance to NGC 1316. From the three normal supernovae, we find a distance of 17.8 +/- 0.3 (random) +/- 0.3 (systematic) Mpc for Ho = 72. Distance moduli derived from the "EBV" and Tripp methods give values that are mutually consistent to 4 -- 8%. Moreover, the weighted means of the distance moduli for these three SNe for three methods agree to within 3%. This consistency is encouraging and supports the premise that Type Ia supernovae are reliable distance indicators at the 5% precision level or better. On the other hand, the two methods used to estimate the distance of the fast-declining SN 2006mr both yield a distance to NGC 1316 which is 25-30% larger. This disparity casts doubt on the suitability of fast-declining events for estimating extragalactic distances. Modest-to-negligible host galaxy reddening values are derived for all four supernovae. Nevertheless, two of them (SN 2006dd and SN 2006mr) show strong NaID interstellar lines in the host galaxy system. The strength of this absorption is completely inconsistent with the small reddening values derived from the supernova light curves if the gas in NGC 1316 is typical of that found in the interstellar medium of the Milky Way. In addition, the equivalent width of the NaID lines in SN 2006dd appear to have weakened significantly some 100-150 days after explosion.Comment: 50 pages, 13 figures, 10 tables; constructive comments welcome. Accepted for publication in A