A novel N-terminal extension in mitochondrial TRAP1 serves as a thermal regulator of chaperone activity.

Hsp90 is a conserved chaperone that facilitates protein homeostasis. Our crystal structure of the mitochondrial Hsp90, TRAP1, revealed an extension of the N-terminal β-strand previously shown to cross between protomers in the closed state. In this study, we address the regulatory function of this extension or 'strap' and demonstrate its responsibility for an unusual temperature dependence in ATPase rates. This dependence is a consequence of a thermally sensitive kinetic barrier between the apo 'open' and ATP-bound 'closed' conformations. The strap stabilizes the closed state through trans-protomer interactions. Displacement of cis-protomer contacts from the apo state is rate-limiting for closure and ATP hydrolysis. Strap release is coupled to rotation of the N-terminal domain and dynamics of the nucleotide binding pocket lid. The strap is conserved in higher eukaryotes but absent from yeast and prokaryotes suggesting its role as a thermal and kinetic regulator, adapting Hsp90s to the demands of unique cellular and organismal environments

Effect of Intergalactic Medium on the Observability of Lyman Alpha Emitters during Cosmic Reionization

We perform a systematic study of how the inhomogeneities in the Inter-Galactic Medium (IGM) affect the observability of Lyman Alpha Emitters (LAEs) around the Epoch of Reionization. We focus on the IGM close to the galaxies as the detailed ionization distribution and velocity fields of this region could significantly influence the scattering of Ly-alpha photons off neutral H atoms as they traverse the IGM after escaping from the galaxy. We simulate the surface brightness (SB) maps and spectra of more than 100 LAEs at z=7.7 as seen by an observer at z=0. To achieve this, we extract the source properties of galaxies and their surrounding IGM from cosmological simulations of box sizes 5-30 Mpc/h and follow the coupled radiative transfer of ionizing and Ly-alpha radiation through the IGM using CRASH-alpha. We find that the simulated SB profiles are extended and their detailed structure is affected by inhomogeneities in the IGM, especially at high neutral fractions. The detectability of LAEs and the fraction of the flux observed depend heavily on the shape of the SB profile and the SB threshold (SB_th) of the observational campaign. Only ultradeep observations (e.g. SB_th ~ 10^-23 ergs/s/cm^2/arcsec^2) would be able to obtain the true underlying mass-luminosity relation and luminosity functions of LAEs. The details of our results depend on whether Ly-alpha photons are significantly shifted in the galaxy to longer wavelengths, the mean ionization fraction in the IGM and the clustering of ionizing sources. These effects can lead to an easier escape of Ly-alpha photons with less scattering in the IGM and a concentrated SB profile similar to the one of a point source. Finally, we show that the SB profiles are steeper at high ionization fraction for the same LAE sample which can potentially be observed from the stacked profile of a large number of LAEs.Comment: 22 pages, 23 figures, 2 tables, Accepted by MNRAS. Minor change

The role of necrosis, acute hypoxia and chronic hypoxia in 18F-MISO PET image contrast: a computational modelling study

Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) is a promising technique for imaging tumour hypoxia, and a potential target for radiotherapy dose-painting. However, the relationship between FMISO uptake and oxygen partial pressure (PO2) is yet to be quantified fully. Tissue oxygenation varies over distances much smaller than clinical PET resolution (<100 µm vs. ~4 mm), and cyclic variations in tumour perfusion have been observed on timescales shorter than typical FMISO PET studies (~20 min vs. a few hours). Furthermore, tracer uptake may be decreased in voxels containing some degree of necrosis. This work develops a computational model of FMISO uptake in millimetre-scale tumour regions. Coupled partial differential equations govern the evolution of oxygen and FMISO distributions, and a dynamic vascular source map represents temporal variations in perfusion. Local FMISO binding capacity is modulated by the necrotic fraction. Outputs include spatiotemporal maps of PO2 and tracer accumulation, enabling calculation of tissue-to-blood ratios (TBRs) and time-activity curves (TACs) as a function of mean tissue oxygenation. The model is characterised using experimental data, finding half-maximal FMISO binding at local PO2 of 1.4 mmHg (95% CI: 0.3-2.6 mmHg) and half-maximal necrosis at 1.2 mmHg (0.1-4.9 mmHg). Simulations predict a non-linear non-monotonic relationship between FMISO activity (4 hr post-injection) and mean tissue PO2: tracer uptake rises sharply from negligible levels in avascular tissue, peaking at ~5 mmHg and declining towards blood activity in well-oxygenated conditions. Greater temporal variation in perfusion increases peak TBRs (range 2.20-5.27) as a result of smaller predicted necrotic fraction, rather than fundamental differences in FMISO accumulation under acute hypoxia. Identical late FMISO uptake can occur in regions with differing PO2 and necrotic fraction, but simulated TACs indicate that additional early-phase information may allow discrimination of hypoxic and necrotic signals. We conclude that a robust approach to FMISO interpretation (and dose-painting prescription) is likely to be based on dynamic PET analysis

The Atacama Cosmology Telescope: Sunyaev-Zel'dovich Selected Galaxy Clusters at 148 GHz from Three Seasons of Data

[Abridged] We present a catalog of 68 galaxy clusters, of which 19 are new discoveries, detected via the Sunyaev-Zel'dovich effect (SZ) at 148 GHz in the Atacama Cosmology Telescope (ACT) survey of 504 square degrees on the celestial equator. A subsample of 48 clusters within the 270 square degree region overlapping SDSS Stripe 82 is estimated to be 90% complete for M_500c > 4.5e14 Msun and 0.15 < z < 0.8. While matched filters are used to detect the clusters, the sample is studied further through a "Profile Based Amplitude Analysis" using a single filter at a fixed \theta_500 = 5.9' angular scale. This new approach takes advantage of the "Universal Pressure Profile" (UPP) to fix the relationship between the cluster characteristic size (R_500) and the integrated Compton parameter (Y_500). The UPP scalings are found to be nearly identical to an adiabatic model, while a model incorporating non-thermal pressure better matches dynamical mass measurements and masses from the South Pole Telescope. A high signal to noise ratio subsample of 15 ACT clusters is used to obtain cosmological constraints. We first confirm that constraints from SZ data are limited by uncertainty in the scaling relation parameters rather than sample size or measurement uncertainty. We next add in seven clusters from the ACT Southern survey, including their dynamical mass measurements based on galaxy velocity dispersions. In combination with WMAP7 these data simultaneously constrain the scaling relation and cosmological parameters, yielding \sigma_8 = 0.829 \pm 0.024 and \Omega_m = 0.292 \pm 0.025. The results include marginalization over a 15% bias in dynamical mass relative to the true halo mass. In an extension to LCDM that incorporates non-zero neutrino mass density, we combine our data with WMAP7+BAO+Hubble constant measurements to constrain \Sigma m_\nu < 0.29 eV (95% C. L.).Comment: 32 pages, 21 figures To appear in J. Cosmology and Astroparticle Physic

The Atacama Cosmology Telescope: Dusty Star-Forming Galaxies and Active Galactic Nuclei in the Southern Survey

We present a catalog of 191 extragalactic sources detected by the Atacama Cosmology Telescope (ACT) at 148 GHz and/or 218 GHz in the 2008 Southern survey. Flux densities span 14-1700 mJy, and we use source spectral indices derived using ACT-only data to divide our sources into two sub-populations: 167 radio galaxies powered by central active galactic nuclei (AGN), and 24 dusty star-forming galaxies (DSFGs). We cross-identify 97% of our sources (166 of the AGN and 19 of the DSFGs) with those in currently available catalogs. When combined with flux densities from the Australian Telescope 20 GHz survey and follow-up observations with the Australia Telescope Compact Array, the synchrotron-dominated population is seen to exhibit a steepening of the slope of the spectral energy distribution from 20 to 148 GHz, with the trend continuing to 218 GHz. The ACT dust-dominated source population has a median spectral index of 3.7+0.62-0.86, and includes both local galaxies and sources with redshifts as great as 5.6. Dusty sources with no counterpart in existing catalogs likely belong to a recently discovered subpopulation of DSFGs lensed by foreground galaxies or galaxy groups.Comment: 13 pages, 8 figures, 4 table

The Atacama Cosmology Telescope: A Measurement of the Cosmic Microwave Background Power Spectrum at 148 and 218 GHz from the 2008 Southern Survey

We present measurements of the cosmic microwave background (CMB) power spectrum made by the Atacama Cosmology Telescope at 148 GHz and 218 GHz, as well as the cross-frequency spectrum between the two channels. Our results clearly show the second through the seventh acoustic peaks in the CMB power spectrum. The measurements of these higher-order peaks provide an additional test of the {\Lambda}CDM cosmological model. At l > 3000, we detect power in excess of the primary anisotropy spectrum of the CMB. At lower multipoles 500 < l < 3000, we find evidence for gravitational lensing of the CMB in the power spectrum at the 2.8{\sigma} level. We also detect a low level of Galactic dust in our maps, which demonstrates that we can recover known faint, diffuse signals.Comment: 19 pages, 13 figures. Submitted to ApJ. This paper is a companion to Hajian et al. (2010) and Dunkley et al. (2010

The Atacama Cosmology Telescope: Data Characterization and Map Making

We present a description of the data reduction and mapmaking pipeline used for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from 2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2 hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial equator. We discuss sources of statistical and systematic noise, calibration, telescope pointing, and data selection. Out of 1260 survey hours and 1024 detectors per array, 816 hours and 593 effective detectors remain after data selection for this frequency band, yielding a 38% survey efficiency. The total sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units. Atmospheric brightness fluctuations constitute the main contaminant in the data and dominate the detector noise covariance at low frequencies in the TOD. The maps were made by solving the least-squares problem using the Preconditioned Conjugate Gradient method, incorporating the details of the detector and noise correlations. Cross-correlation with WMAP sky maps, as well as analysis from simulations, reveal that our maps are unbiased at multipoles ell > 300. This paper accompanies the public release of the 148 GHz southern stripe maps from 2008. The techniques described here will be applied to future maps and data releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions