Elimination of the BKCa Channel's High-Affinity Ca2+ Sensitivity

We report here a combination of site-directed mutations that eliminate the high-affinity Ca2+ response of the large-conductance Ca2+-activated K+ channel (BKCa), leaving only a low-affinity response blocked by high concentrations of Mg2+. Mutations at two sites are required, the “Ca2+ bowl,” which has been implicated previously in Ca2+ binding, and M513, at the end of the channel's seventh hydrophobic segment. Energetic analyses of mutations at these positions, alone and in combination, argue that the BKCa channel contains three types of Ca2+ binding sites, one of low affinity that is Mg2+ sensitive (as has been suggested previously) and two of higher affinity that have similar binding characteristics and contribute approximately equally to the power of Ca2+ to influence channel opening. Estimates of the binding characteristics of the BKCa channel's high-affinity Ca2+-binding sites are provided

A controlled study of cold dust content in galaxies from z=0−2z=0-2

At $z=1-3$, the formation of new stars is dominated by dusty galaxies whose far-IR emission indicates they contain colder dust than local galaxies of a similar luminosity. We explore the reasons for the evolving IR emission of similar galaxies over cosmic time using: 1) Local galaxies from GOALS $(L_{\rm IR}=10^{11}-10^{12}\,L_\odot)$; 2) Galaxies at $z\sim0.1-0.5$ from the 5MUSES ($L_{\rm IR}=10^{10}-10^{12}\,L_\odot$); 3) IR luminous galaxies spanning $z=0.5-3$ from GOODS and Spitzer xFLS ($L_{\rm IR}>10^{11}\,L_\odot$). All samples have Spitzer mid-IR spectra, and Herschel and ground-based submillimeter imaging covering the full IR spectral energy distribution, allowing us to robustly measure $L_{\rm IR}^{\rm\scriptscriptstyle SF}$, $T_{\rm dust}$, and $M_{\rm dust}$ for every galaxy. Despite similar infrared luminosities, $z>0.5$ dusty star forming galaxies have a factor of 5 higher dust masses and 5K colder temperatures. The increase in dust mass is linked with an increase in the gas fractions with redshift, and we do not observe a similar increase in stellar mass or star formation efficiency. $L_{160}^{\rm\scriptscriptstyle SF}/L_{70}^{\rm\scriptscriptstyle SF}$, a proxy for $T_{\rm dust}$, is strongly correlated with $L_{\rm IR}^{\rm\scriptscriptstyle SF}/M_{\rm dust}$ independently of redshift. We measure merger classification and galaxy size for a subsample, and there is no obvious correlation between these parameters and $L_{\rm IR}^{\rm \scriptscriptstyle SF}/M_{\rm dust}$ or $L_{160}^{\rm\scriptscriptstyle SF}/L_{70}^{\rm\scriptscriptstyle SF}$. In dusty star forming galaxies, the change in $L_{\rm IR}^{\rm\scriptscriptstyle SF}/M_{\rm dust}$ can fully account for the observed colder dust temperatures, suggesting that any change in the spatial extent of the interstellar medium is a second order effect.Comment: Accepted for publication in ApJ. 21 pages, 11 figure

Crystal Structure of the N-Terminal Domain of Nup358/RanBP2

Key steps in mRNA export are the nuclear assembly of messenger ribonucleoprotein particles (mRNPs), the translocation of mRNPs through the nuclear pore complex (NPC), and the mRNP remodeling events at the cytoplasmic side of the NPC. Nup358/RanBP2 is a constituent of the cytoplasmic filaments of the NPC specific to higher eukaryotes and provides a multitude of binding sites for the nucleocytoplasmic transport machinery. Here, we present the crystal structure of the Nup358 N-terminal domain (NTD) at 0.95 Å resolution. The structure reveals an α-helical domain that harbors three central tetratricopeptide repeats (TPRs), flanked on each side by an additional solvating amphipathic α helix. Overall, the NTD adopts an unusual extended conformation that lacks the characteristic peptide-binding groove observed in canonical TPR domains. Strikingly, the vast majority of the NTD surface exhibits an evolutionarily conserved, positive electrostatic potential, and we demonstrate that the NTD possesses the capability to bind single-stranded RNA in solution. Together, these data suggest that the NTD contributes to mRNP remodeling events at the cytoplasmic face of the NPC

Seeing double with K2: Testing re-inflation with two remarkably similar planets around red giant branch stars

Despite more than 20 years since the discovery of the first gas giant planet with an anomalously large radius, the mechanism for planet inflation remains unknown. Here, we report the discovery of EPIC228754001.01, an inflated gas giant planet found with the NASA K2 Mission, and a revised mass for another inflated planet, K2-97b. These planets reside on ~9 day orbits around host stars which recently evolved into red giants. We constrain the irradiation history of these planets using models constrained by asteroseismology and Keck/HIRES spectroscopy and radial velocity measurements. We measure planet radii of 1.31 +\- 0.11 Rjup and and 1.30 +\- 0.07 Rjup, respectively. These radii are typical for planets receiving the current irradiation, but not the former, zero age main sequence irradiation of these planets. This suggests that the current sizes of these planets are directly correlated to their current irradiation. Our precise constraints of the masses and radii of the stars and planets in these systems allow us to constrain the planetary heating efficiency of both systems as 0.03% +0.03%/-0.02%. These results are consistent with a planet re-inflation scenario, but suggest the efficiency of planet re-inflation may be lower than previously theorized. Finally, we discuss the agreement within 10% of stellar masses and radii, and planet masses, radii, and orbital periods of both systems and speculate that this may be due to selection bias in searching for planets around evolved stars.Comment: 18 pages, 15 figures, accepted to AJ. Figures 11, 12, and 13 are the key figures of the pape

Genome wide association mapping in <i>Arabidopsis thaliana</i> identifies novel genes involved in linking allyl glucosinolate to altered biomass and defense

A key limitation in modern biology is the ability to rapidly identify genes underlying newly identified complex phenotypes. Genome wide association studies (GWAS) have become an increasingly important approach for dissecting natural variation by associating phenotypes with genotypes at a genome wide level. Recent work is showing that the Arabidopsis thaliana defense metabolite, allyl glucosinolate (GSL), may provide direct feedback regulation, linking defense metabolism outputs to the growth, and defense responses of the plant. However, there is still a need to identify genes that underlie this process. To start developing a deeper understanding of the mechanism(s) that modulate the ability of exogenous allyl GSL to alter growth and defense, we measured changes in plant biomass and defense metabolites in a collection of natural 96 A. thaliana accessions fed with 50 μM of allyl GSL. Exogenous allyl GSL was introduced exclusively to the roots and the compound transported to the leaf leading to a wide range of heritable effects upon plant biomass and endogenous GSL accumulation. Using natural variation we conducted GWAS to identify a number of new genes which potentially control allyl responses in various plant processes. This is one of the first instances in which this approach has been successfully utilized to begin dissecting a novel phenotype to the underlying molecular/polygenic basis

How was it for you? Experiences of participatory design in the UK health service

Improving co-design methods implies that we need to understand those methods, paying attention to not only the effect of method choices on design outcomes, but also how methods affect the people involved in co-design. In this article, we explore participants' experiences from a year-long participatory health service design project to develop ‘Better Outpatient Services for Older People’. The project followed a defined method called experience-based design (EBD), which represented the state of the art in participatory service design within the UK National Health Service. A sample of participants in the project took part in semi-structured interviews reflecting on their involvement in and their feelings about the project. Our findings suggest that the EBD method that we employed was successful in establishing positive working relationships among the different groups of stakeholders (staff, patients, carers, advocates and design researchers), although conflicts remained throughout the project. Participants' experiences highlighted issues of wider relevance in such participatory design: cost versus benefit, sense of project momentum, locus of control, and assumptions about how change takes place in a complex environment. We propose tactics for dealing with these issues that inform the future development of techniques in user-centred healthcare design

Coiling Instability of Multilamellar Membrane Tubes with Anchored Polymers

We study experimentally a coiling instability of cylindrical multilamellar stacks of phospholipid membranes, induced by polymers with hydrophobic anchors grafted along their hydrophilic backbone. Our system is unique in that coils form in the absence of both twist and adhesion. We interpret our experimental results in terms of a model in which local membrane curvature and polymer concentration are coupled. The model predicts the occurrence of maximally tight coils above a threshold polymer occupancy. A proper comparison between the model and experiment involved imaging of projections from simulated coiled tubes with maximal curvature and complicated torsions.Comment: 11 pages + 7 GIF figures + 10 JPEG figure

Recurrent Variational Approach to the Two-Leg Hubbard Ladder

We applied the Recurrent Variational Approach to the two-leg Hubbard ladder. At half-filling, our variational Ansatz was a generalization of the resonating valence bond state. At finite doping, hole pairs were allowed to move in the resonating valence bond background. The results obtained by the Recurrent Variational Approach were compared with results from Density Matrix Renormalization Group.Comment: 10 pages, 14 Postscript figure

Toward the End of Time

The null-brane space-time provides a simple model of a big crunch/big bang singularity. A non-perturbative definition of M-theory on this space-time was recently provided using matrix theory. We derive the fermion couplings for this matrix model and study the leading quantum effects. These effects include particle production and a time-dependent potential. Our results suggest that as the null-brane develops a big crunch singularity, the usual notion of space-time is replaced by an interacting gluon phase. This gluon phase appears to constitute the end of our conventional picture of space and time.Comment: 31 pages, reference adde

Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality