Pre-emptive Quality Control of a Misfolded Membrane Protein by Ribosome-Driven Effects.

Cells possess multiple mechanisms that protect against the accumulation of toxic aggregation-prone proteins. Here, we identify a pre-emptive pathway that reduces synthesis of membrane proteins that have failed to properly assemble in the endoplasmic reticulum (ER). We show that loss of the ER membrane complex (EMC) or mutation of the Sec61 translocon causes reduced synthesis of misfolded forms of the yeast ABC transporter Yor1. Synthesis defects are rescued by various ribosomal mutations, as well as by reducing cellular ribosome abundance. Genetic and biochemical evidence point to a ribosome-associated quality-control pathway triggered by ribosome collisions when membrane domain insertion and/or folding fails. In support of this model, translation initiation also contributes to synthesis defects, likely by modulating ribosome abundance on the message. Examination of translation efficiency across the yeast membrane proteome revealed that polytopic membrane proteins have relatively low ribosome abundance, providing evidence for translational tuning to balance protein synthesis and folding. We propose that by modulating translation rates of poorly folded proteins, cells can pre-emptively protect themselves from potentially toxic aberrant transmembrane proteins

Close genetic linkage between X linked retinitis pigmentosa and a restriction fragment length polymorphism identified by recombinant DNA probe L1.28

Retinitis pigmentosa (RP) is a group of retinal degeneration characterized by progressive visual field loss, night blindness and pigmentary retinopathy. Its prevalence is in the region of 1-2 in 5,000 of the general population, making it one of the commoner causes of blindness in early and middle life. Although 36-48% of RP patients are isolated cases, the remainder show autosomal dominant, autosomal recessive or X-linked modes of inheritance. The X-linked variety ( XLRP ) is found in 14-22% of RP families in the UK. In the present study, X chromosome-specific recombinant DNA probes which can detect restriction fragment length polymorphisms have been used to localize the XLRP gene(s) to a subregion of the X chromosome using linkage analysis. One of the probes, L1.28, has been shown to be closely linked to XLRP in five kindreds, with 95% confidence limits of 0-15 centimorgans (maximum LOD score of 7.89 at a distance of 3 centimorgans). This suggests that the XLRP locus lies on the proximal part of the short arm of the X chromosome. This probe is potentially useful for carrier detection and early diagnosis in about 40% of cases, provided that genetic heterogeneity can be excluded by analysis of further families

Observational Evidence from Supernovae for an Accelerating Universe and a Cosmological Constant

We present observations of 10 type Ia supernovae (SNe Ia) between 0.16 < z < 0.62. With previous data from our High-Z Supernova Search Team, this expanded set of 16 high-redshift supernovae and 34 nearby supernovae are used to place constraints on the Hubble constant (H_0), the mass density (Omega_M), the cosmological constant (Omega_Lambda), the deceleration parameter (q_0), and the dynamical age of the Universe (t_0). The distances of the high-redshift SNe Ia are, on average, 10% to 15% farther than expected in a low mass density (Omega_M=0.2) Universe without a cosmological constant. Different light curve fitting methods, SN Ia subsamples, and prior constraints unanimously favor eternally expanding models with positive cosmological constant (i.e., Omega_Lambda > 0) and a current acceleration of the expansion (i.e., q_0 < 0). With no prior constraint on mass density other than Omega_M > 0, the spectroscopically confirmed SNe Ia are consistent with q_0 <0 at the 2.8 sigma and 3.9 sigma confidence levels, and with Omega_Lambda >0 at the 3.0 sigma and 4.0 sigma confidence levels, for two fitting methods respectively. Fixing a ``minimal'' mass density, Omega_M=0.2, results in the weakest detection, Omega_Lambda>0 at the 3.0 sigma confidence level. For a flat-Universe prior (Omega_M+Omega_Lambda=1), the spectroscopically confirmed SNe Ia require Omega_Lambda >0 at 7 sigma and 9 sigma level for the two fitting methods. A Universe closed by ordinary matter (i.e., Omega_M=1) is ruled out at the 7 sigma to 8 sigma level. We estimate the size of systematic errors, including evolution, extinction, sample selection bias, local flows, gravitational lensing, and sample contamination. Presently, none of these effects reconciles the data with Omega_Lambda=0 and q_0 > 0.Comment: 36 pages, 13 figures, 3 table files Accepted to the Astronomical Journa

Supernova Limits on the Cosmic Equation of State

We use Type Ia supernovae studied by the High-Z Supernova Search Team to constrain the properties of an energy component which may have contributed to accelerating the cosmic expansion. We find that for a flat geometry the equation of state parameter for the unknown component, alpha_x=P_x/rho_x, must be less than -0.55 (95% confidence) for any value of Omega_m and is further limited to alpha_x<-0.60 (95%) if Omega_m is assumed to be greater than 0.1 . These values are inconsistent with the unknown component being topological defects such as domain walls, strings, or textures. The supernova data are consistent with a cosmological constant (alpha_x=-1) or a scalar field which has had, on average, an equation of state parameter similar to the cosmological constant value of -1 over the redshift range of z=1 to the present. Supernova and cosmic microwave background observations give complementary constraints on the densities of matter and the unknown component. If only matter and vacuum energy are considered, then the current combined data sets provide direct evidence for a spatially flat Universe with Omega_tot=Omega_m+Omega_Lambda = 0.94 +/- 0.26 (1-sigma).Comment: Accepted for publication in ApJ, 3 figure

CMBPol Mission Concept Study: Prospects for polarized foreground removal

In this report we discuss the impact of polarized foregrounds on a future CMBPol satellite mission. We review our current knowledge of Galactic polarized emission at microwave frequencies, including synchrotron and thermal dust emission. We use existing data and our understanding of the physical behavior of the sources of foreground emission to generate sky templates, and start to assess how well primordial gravitational wave signals can be separated from foreground contaminants for a CMBPol mission. At the estimated foreground minimum of ~100 GHz, the polarized foregrounds are expected to be lower than a primordial polarization signal with tensor-to-scalar ratio r=0.01, in a small patch (~1%) of the sky known to have low Galactic emission. Over 75% of the sky we expect the foreground amplitude to exceed the primordial signal by about a factor of eight at the foreground minimum and on scales of two degrees. Only on the largest scales does the polarized foreground amplitude exceed the primordial signal by a larger factor of about 20. The prospects for detecting an r=0.01 signal including degree-scale measurements appear promising, with 5 sigma_r ~0.003 forecast from multiple methods. A mission that observes a range of scales offers better prospects from the foregrounds perspective than one targeting only the lowest few multipoles. We begin to explore how optimizing the composition of frequency channels in the focal plane can maximize our ability to perform component separation, with a range of typically 40 < nu < 300 GHz preferred for ten channels. Foreground cleaning methods are already in place to tackle a CMBPol mission data set, and further investigation of the optimization and detectability of the primordial signal will be useful for mission design.Comment: 42 pages, 14 figures, Foreground Removal Working Group contribution to the CMBPol Mission Concept Study, v2, matches AIP versio

Hubble Space Telescope and Ground-Based Observations of Type Ia Supernovae at Redshift 0.5: Cosmological Implications

We present observations of the Type Ia supernovae (SNe) 1999M, 1999N, 1999Q, 1999S, and 1999U, at redshift z~0.5. They were discovered in early 1999 with the 4.0~m Blanco telescope at Cerro Tololo Inter-American Observatory by the High-z Supernova Search Team (HZT) and subsequently followed with many ground-based telescopes. SNe 1999Q and 1999U were also observed with the Hubble Space Telescope. We computed luminosity distances to the new SNe using two methods, and added them to the high-z Hubble diagram that the HZT has been constructing since 1995. The new distance moduli confirm the results of previous work. At z~0.5, luminosity distances are larger than those expected for an empty universe, implying that a ``Cosmological Constant,'' or another form of ``dark energy,'' has been increasing the expansion rate of the Universe during the last few billion years.Comment: 68 pages, 22 figures. Scheduled for the 01 February 2006 issue of Ap.J. (v637

Conceptualising social justice and sociocultural issues within physical education teacher education: international perspectives

Background: Physical education (PE) and physical education teacher education (PETE) have a substantial literature base that advocates for students to develop a critical consciousness, appreciate multiple perspectives, and engage in actions to enhance social justice (Tinning 2016). Analysing sociocultural issues, critically reflecting on beliefs, knowledge, biography and values, and developing a sense of agency to enact change, have been recognised as an integral part of the PETE knowledge base for some time (Fernández-Balboa 1997). However, there remain differences in how social justice itself is conceptualised and enacted. Social justice is aligned heavily with critical and ‘post’ theories where taking action for justice, democracy and power are central; but social justice is also found in humanist beliefs in student-centredness and equality and has been co-opted by neoliberal forces that promote individual responsibility. While a lack of consensus is not in itself a problem (Bialystok 2014), diverse definitions might contribute to confusion (Randall and Robinson 2016) and lead to uncertainty over what and how to teach for social justice. Purpose: In order to work towards greater certainty around concepts of social justice in the PETE community, this project sought to map variations in definition and conceptualisation of social justice and sociocultural issues among physical education teacher educators (PETEs) and physical education and sport pedagogy (PESP) educators, as part of a wider project on social justice and sociocultural perspectives and practices in PETE. Methods: PETE and PESP faculty (n=72) in North America, Europe, and Australasia engaged in an in-depth interview, during which they were asked how they define social justice and sociocultural issues. Additional information about participants’ social identity was collected. A constant comparative method of analysing participants’ definitions mapped a range of concepts building on the theoretical framework of neoliberal, humanist, critical and ‘post’ approaches to social justice. Findings: The data demonstrate that there are a range of understandings about sociocultural issues and social justice. Most commonly, some participants articulated a humanist approach to social justice by encouraging their pre-service teachers (PSTs) to have awareness of equality of opportunity in relation to gender, sexuality and/or racism. Less prevalent, but strongly stated by those who conceptualised social justice in these terms, was the importance to take action for democracy, empowerment or critical reflection. The terms diversity and equality, framed in neoliberal and humanist discourses, were most commonly used within the United States (US), while critical pedagogy and alignment with critical and ‘post’ theories were more prevalent in Australia and New Zealand. Conclusion: Differences exist in the ways social justice is conceptualised in PETE. While this can be attributed to the influence of local issues, it is also reflective of what intellectual tools, such as humanism or critical theory, are available for problematising social issues. The range of non-critical concepts found raises concern that PSTs are not getting the tools to enact social justice or tackle sociocultural issues.

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1