Revised stratigraphy of the Blanchetown Clay, Murray Basin: age constraints on the evolution of paleo Lake Bungunnia

Paleo Lake Bungunnia covered more than 40 000 km2 of southern Australia during the Plio-Pleistocene, although the age and origin of the lake remain controversial. The Blanchetown Clay is the main depositional unit and outcrop at Nampoo Station in far-western New South Wales provides the most continuous lacustrine section preserved in the basin. Here the Blanchetown Clay represents the maximum lake fill and comprises: (i) a basal well-sorted sand with interbedded clay (Chowilla Sand), representing initial flooding at the time of lake formation; (ii) a thick sequence of green-grey clay comprised dominantly of kaolinite and illite, with the apparently cyclic occurrence of illite interpreted to represent cool and dry glacial climatic intervals; and (iii) a 2.6 m-thick sequence of finely laminated silt and silty clay, here defined as the Nampoo Member of the Blanchetown Clay. New magnetostratigraphic data constrain the age of the oldest lake sediments to be younger than 2.581 Ma (Matuyama-Gauss boundary) and probably as young as 2.4 Ma. This age is significantly younger than the age of 3.2 Ma previously suggested for lake formation. The youngest Blanchetown Clay is older than 0.781 Ma (Brunhes-Matuyama boundary) and probably as old as 1.2 Ma. The Nampoo Station section provides a framework for the construction of a regional Plio-Pleistocene stratigraphy in the Murray Basin.<br /

Electronic sculpting of ligand-GPCR subtype selectivity:the case of angiotensin II

GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (<i>K</i>_i = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range

Molecular Basis of ß-­arrestin Coupling to Formoterol-­Bound ß1-­adrenoceptor

The β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G-protein-mimetic nanobody6 Nb80. βarr1 couples to β1AR in a manner distinct to that7 of Gs coupling to β2AR-the finger loop of βarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in βarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. β1AR coupled to βarr1 shows considerable differences in structure compared with β1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of β1AR, and find that formoterol has a lower affinity for the β1AR-βarr1 complex than for the β1AR-Gs complex. The structural differences between these complexes of β1AR provide a foundation for the design of small molecules that could bias signalling in the β-adrenoceptors

Students\u2019 experiences of cooperation with nurse teacher during their clinical placements: an empirical study in a Western European context.

In many European countries during the last decade, the clinical role of the nurse teacher has changed from a clinical skilled practitioner to a liaison person working between educational and health care provider organisations. This study explored pre-registration nursing students' perceptions of cooperation with nurse teachers during their clinical placements in nine Western European countries. The study also assessed the type and range of e-communication between students and nurse teachers and whom the students\u2019 perceived as their most important professional role model. The study is a descriptive survey. Quantitative data were collected from 17 higher education institutes of nursing located in the northern, middle and southern parts of Europe. The purposive sample (N=1903) comprised students who had participated in courses which included clinical placements. The data were analysed using descriptive statistics. Comparisons between the groups were made using cross-tabulation. The majority (57%) of students met their nurse teacher 1-3 times during their placement while 13% of the students did not meet their nurse teacher at all. Additionally, 66% of respondents used some form of e-communication (e-mail, mobile text messages etc.) to communicate with their nurse teacher. It is important to clarify the division of labour between nurse teachers and Mentors. There are both opportunities and challenges in how to utilise information technology to more effectively promote cooperation between students and nurse teachers

Comparative Analysis of the Heptahelical Transmembrane Bundles of G Protein-Coupled Receptors

Background: G protein-coupled receptors represent a large family of eukaryotic membrane proteins, and are involved in almost all physiological processes in humans. Recent advances in the crystallographic study of these receptors enable a detailed comparative analysis of the commonly shared heptahelical transmembrane bundle. Systematic comparison of the bundles from a variety of receptors is indispensable for understanding not only of the structural diversification optimized for the binding of respective ligands but also of the structural conservation required for the common mechanism of activation accompanying the interaction changes among the seven helices. Methodology/Principal Findings: We have examined the bundles of 94 polypeptide chains from almost all available structures of 11 receptors, which we classified into either inactivated chain or activated chain, based on the type of bound ligand. For the inactivated chains, superposition of 200 residue bundles by secondary structure matching demonstrated that the bound ligands share a laterally limited cavity in the extracellular section of the bundle. Furthermore, a distinct feature was found for helix III of bovine rhodopsin, which might have evolved to lower its activity in the presence of 11-cis-retinal, to a level that other receptors could hardly achieve with any currently available ligands. Conclusions/Significance: Systematic analysis described here would be valuable for understanding of the rearrangement o

Spectrum of neuroimaging findings post-proton beam therapy in a large pediatric cohort

PURPOSE: Proton beam therapy (PBT) is now well established for the treatment of certain pediatric brain tumors. The intrinsic properties of PBT are known to reduce long-term negative effects of photon radiotherapy (PRT). To better understand the intracranial effects of PBT, we analyzed the longitudinal imaging changes in a cohort of children with brain tumors treated by PBT with clinical and radiotherapy dose correlations. MATERIALS AND METHODS: Retrospective imaging review of 46 patients from our hospital with brain tumors treated by PBT. The imaging findings were correlated with clinical and dose parameters. RESULTS: Imaging changes were assessed by reviewing serial magnetic resonance imaging (MRI) scans following PBT over a follow-up period ranging from 1 month to 7 years. Imaging changes were observed in 23 patients undergoing PBT and categorized as pseudoprogression (10 patients, 43%), white matter changes (6 patients, 23%), parenchymal atrophy (6 patients, 23%), and cerebral large vessel arteriopathy (5 patients, 25%). Three patients had more than one type of imaging change. Clinical symptoms attributable to PBT were observed in 13 (28%) patients. CONCLUSION: In accordance with published literature, we found evidence of varied intracranial imaging changes in pediatric brain tumor patients treated with PBT. There was a higher incidence (10%) of large vessel cerebral arteriopathy in our cohort than previously described in the literature. Twenty-eight percent of patients had clinical sequelae as a result of these changes, particularly in the large vessel arteriopathy subgroup, arguing the need for angiographic and perfusion surveillance to pre-empt any morbidities and offer potential neuro-protection

The Atacama Cosmology Telescope: A Measurement of the 600< ell <8000 Cosmic Microwave Background Power Spectrum at 148 GHz

We present a measurement of the angular power spectrum of the cosmic microwave background (CMB) radiation observed at 148 GHz. The measurement uses maps with 1.4' angular resolution made with data from the Atacama Cosmology Telescope (ACT). The observations cover 228 square degrees of the southern sky, in a 4.2-degree-wide strip centered on declination 53 degrees South. The CMB at arcminute angular scales is particularly sensitive to the Silk damping scale, to the Sunyaev-Zel'dovich (SZ) effect from galaxy clusters, and to emission by radio sources and dusty galaxies. After masking the 108 brightest point sources in our maps, we estimate the power spectrum between 600 < \ell < 8000 using the adaptive multi-taper method to minimize spectral leakage and maximize use of the full data set. Our absolute calibration is based on observations of Uranus. To verify the calibration and test the fidelity of our map at large angular scales, we cross-correlate the ACT map to the WMAP map and recover the WMAP power spectrum from 250 < ell < 1150. The power beyond the Silk damping tail of the CMB is consistent with models of the emission from point sources. We quantify the contribution of SZ clusters to the power spectrum by fitting to a model normalized at sigma8 = 0.8. We constrain the model's amplitude ASZ < 1.63 (95% CL). If interpreted as a measurement of sigma8, this implies sigma8^SZ < 0.86 (95% CL) given our SZ model. A fit of ACT and WMAP five-year data jointly to a 6-parameter LCDM model plus terms for point sources and the SZ effect is consistent with these results.Comment: 15 pages, 8 figures. Accepted for publication in Ap

Mapping the Complete Reaction Path of a Complex Photochemical Reaction

We probe the dynamics of dissociating CS2 molecules across the entire reaction pathway upon excitation. Photoelectron spectroscopy measurements using laboratory-generated femtosecond extreme ultraviolet pulses monitor the competing dissociation, internal conversion, and intersystem crossing dynamics. Dissociation occurs either in the initially excited singlet manifold or, via intersystem crossing, in the triplet manifold. Both product channels are monitored and show that despite being more rapid, the singlet dissociation is the minor product and that triplet state products dominate the final yield. We explain this by consideration of accurate potential energy curves for both the singlet and triplet states. We propose that rapid internal conversion stabilises the singlet population dynamically, allowing for singlet-triplet relaxation via intersystem crossing and efficient formation of spin-forbidden dissociation products on longer timescales. The study demonstrates the importance of measuring the full reaction pathway for defining accurate reaction mechanisms

The Atacama Cosmology Telescope (ACT): Beam Profiles and First SZ Cluster Maps

The Atacama Cosmology Telescope (ACT) is currently observing the cosmic microwave background with arcminute resolution at 148 GHz, 218 GHz, and 277 GHz. In this paper, we present ACT's first results. Data have been analyzed using a maximum-likelihood map-making method which uses B-splines to model and remove the atmospheric signal. It has been used to make high-precision beam maps from which we determine the experiment's window functions. This beam information directly impacts all subsequent analyses of the data. We also used the method to map a sample of galaxy clusters via the Sunyaev-Zel'dovich (SZ) effect, and show five clusters previously detected with X-ray or SZ observations. We provide integrated Compton-y measurements for each cluster. Of particular interest is our detection of the z = 0.44 component of A3128 and our current non-detection of the low-redshift part, providing strong evidence that the further cluster is more massive as suggested by X-ray measurements. This is a compelling example of the redshift-independent mass selection of the SZ effect.Comment: 16 pages, 10 figures. Accepted for publication in ApJS. See Marriage et al. (arXiv:1010.1065) and Menanteau et al. (arXiv:1006.5126) for additional cluster result

The Atacama Cosmology Telescope: Cosmological Parameters from the 2008 Power Spectra

We present cosmological parameters derived from the angular power spectrum of the cosmic microwave background (CMB) radiation observed at 148 GHz and 218 GHz over 296 deg^2 with the Atacama Cosmology Telescope (ACT) during its 2008 season. ACT measures fluctuations at scales 500<l<10000. We fit a model for the lensed CMB, Sunyaev-Zel'dovich (SZ), and foreground contribution to the 148 GHz and 218 GHz power spectra, including thermal and kinetic SZ, Poisson power from radio and infrared point sources, and clustered power from infrared point sources. The power from thermal and kinetic SZ at 148 GHz is estimated to be B_3000 = 6.8+-2.9 uK^2, where B_l=l(l+1)C_l/2pi. We estimate primary cosmological parameters from the 148 GHz spectrum, marginalizing over SZ and source power. The LCDM cosmological model is a good fit to the data, and LCDM parameters estimated from ACT+WMAP are consistent with the 7-year WMAP limits, with scale invariant n_s = 1 excluded at 99.7% CL (3sigma). A model with no CMB lensing is disfavored at 2.8sigma. By measuring the third to seventh acoustic peaks, and probing the Silk damping regime, the ACT data improve limits on cosmological parameters that affect the small-scale CMB power. The ACT data combined with WMAP give a 6sigma detection of primordial helium, with Y_P = 0.313+-0.044, and a 4sigma detection of relativistic species, assumed to be neutrinos, with Neff = 5.3+-1.3 (4.6+-0.8 with BAO+H0 data). From the CMB alone the running of the spectral index is constrained to be dn/dlnk = -0.034 +- 0.018, the limit on the tensor-to-scalar ratio is r<0.25 (95% CL), and the possible contribution of Nambu cosmic strings to the power spectrum is constrained to string tension Gmu<1.6 \times 10^-7 (95% CL).Comment: 20 pages, 13 figures. Submitted to ApJ. This paper is a companion to Hajian et al. (2010) and Das et al. (2010