Atmospheric circulation of tidally locked exoplanets: a suite of benchmark tests for dynamical solvers

The complexity of atmospheric modelling and its inherent non-linearity, together with the limited amount of data of exoplanets available, motivate model intercomparisons and benchmark tests. In the geophysical community, the Held-Suarez test is a standard benchmark for comparing dynamical core simulations of the Earth's atmosphere with different solvers, based on statistically-averaged flow quantities. In the present study, we perform analogues of the Held-Suarez test for tidally-locked exoplanets with the GFDL-Princeton Flexible Modeling System (FMS) by subjecting both the spectral and finite difference dynamical cores to a suite of tests, including the standard benchmark for Earth, a hypothetical tidally-locked Earth, a "shallow" hot Jupiter model and a "deep" model of HD 209458b. We find qualitative and quantitative agreement between the solvers for the Earth, tidally-locked Earth and shallow hot Jupiter benchmarks, but the agreement is less than satisfactory for the deep model of HD 209458b. Further investigation reveals that closer agreement may be attained by arbitrarily adjusting the values of the horizontal dissipation parameters in the two solvers, but it remains the case that the magnitude of the horizontal dissipation is not easily specified from first principles. Irrespective of radiative transfer or chemical composition considerations, our study points to limitations in our ability to accurately model hot Jupiter atmospheres with meteorological solvers at the level of ten percent for the temperature field and several tens of percent for the velocity field. Direct wind measurements should thus be particularly constraining for the models. Our suite of benchmark tests also provides a reference point for researchers wishing to adapt their codes to study the atmospheric circulation regimes of tidally-locked Earths/Neptunes/Jupiters.Comment: Accepted by MNRAS, 23 pages, 17 figures, 2 tables. No changes from previous version, except MNRAS wants no hyphen in the title. Sample movies of simulations are available at http://www.phys.ethz.ch/~kheng/fms

Cooperativity and the origins of rapid, single-exponential kinetics in protein folding

The folding of naturally occurring, single domain proteins is usually well-described as a simple, single exponential process lacking significant trapped states. Here we further explore the hypothesis that the smooth energy landscape this implies, and the rapid kinetics it engenders, arises due to the extraordinary thermodynamic cooperativity of protein folding. Studying Miyazawa-Jernigan lattice polymers we find that, even under conditions where the folding energy landscape is relatively optimized (designed sequences folding at their temperature of maximum folding rate), the folding of protein-like heteropolymers is accelerated when their thermodynamic cooperativity enhanced by enhancing the non-additivity of their energy potentials. At lower temperatures, where kinetic traps presumably play a more significant role in defining folding rates, we observe still greater cooperativity-induced acceleration. Consistent with these observations, we find that the folding kinetics of our computational models more closely approximate single-exponential behavior as their cooperativity approaches optimal levels. These observations suggest that the rapid folding of naturally occurring proteins is, at least in part, consequences of their remarkably cooperative folding

Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials

Background Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer’s disease (AD). Methods Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale and the Disability Assessment for Dementia. Results A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. Conclusions These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. Trial registration Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143; registered 2 May 2008

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed

Mechano-energetics of the asynchronous and resynchronized heart

Abnormal electrical activation of the ventricles creates major abnormalities in cardiac mechanics. Local contraction patterns, as reflected by measurements of local strain, are not only out of phase, but often also show opposing length changes in early and late activated regions. As a consequence, the efficiency of cardiac pump function (the amount of stroke work generated by a unit of oxygen consumed) is approximately 30% lower in asynchronous than in synchronous hearts. Moreover, the amount of work performed in myocardial segments becomes considerably larger in late than in early activated regions. Cardiac Resynchronization Therapy (CRT) improves mechano-energetics of the previously asynchronous heart in various ways: it alleviates impediment of the abnormal contraction on blood flow, it increases myocardial efficiency, it recruits contraction in the previously early activated septum and it creates a more uniform distribution of myocardial blood flow. These factors act together to increase the range of cardiac work that can be delivered by the patients’ heart, an effect that can explain the increased exercise tolerance and quality of life reported in several CRT trials

Animal Models of Dyssynchrony

Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT

Building a model: developing genomic resources for common milkweed (Asclepias syriaca) with low coverage genome sequencing

<p>Abstract</p> <p>Background</p> <p>Milkweeds (<it>Asclepias </it>L.) have been extensively investigated in diverse areas of evolutionary biology and ecology; however, there are few genetic resources available to facilitate and compliment these studies. This study explored how low coverage genome sequencing of the common milkweed (<it>Asclepias syriaca </it>L.) could be useful in characterizing the genome of a plant without prior genomic information and for development of genomic resources as a step toward further developing <it>A. syriaca </it>as a model in ecology and evolution.</p> <p>Results</p> <p>A 0.5× genome of <it>A. syriaca </it>was produced using Illumina sequencing. A virtually complete chloroplast genome of 158,598 bp was assembled, revealing few repeats and loss of three genes: <it>accD, clpP</it>, and <it>ycf1</it>. A nearly complete rDNA cistron (18S-5.8S-26S; 7,541 bp) and 5S rDNA (120 bp) sequence were obtained. Assessment of polymorphism revealed that the rDNA cistron and 5S rDNA had 0.3% and 26.7% polymorphic sites, respectively. A partial mitochondrial genome sequence (130,764 bp), with identical gene content to tobacco, was also assembled. An initial characterization of repeat content indicated that Ty1/<it>copia</it>-like retroelements are the most common repeat type in the milkweed genome. At least one <it>A. syriaca </it>microread hit 88% of <it>Catharanthus roseus </it>(Apocynaceae) unigenes (median coverage of 0.29×) and 66% of single copy orthologs (COSII) in asterids (median coverage of 0.14×). From this partial characterization of the <it>A. syriaca </it>genome, markers for population genetics (microsatellites) and phylogenetics (low-copy nuclear genes) studies were developed.</p> <p>Conclusions</p> <p>The results highlight the promise of next generation sequencing for development of genomic resources for any organism. Low coverage genome sequencing allows characterization of the high copy fraction of the genome and exploration of the low copy fraction of the genome, which facilitate the development of molecular tools for further study of a target species and its relatives. This study represents a first step in the development of a community resource for further study of plant-insect co-evolution, anti-herbivore defense, floral developmental genetics, reproductive biology, chemical evolution, population genetics, and comparative genomics using milkweeds, and <it>A. syriaca </it>in particular, as ecological and evolutionary models.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe