Holographic metastability

We show how supersymmetric QCD in a slice of AdS can naturally acquire metastable vacua. The formulation closely follows that of Intriligator, Seiberg and Shih (ISS), with an "electric" sector on the UV brane and a "magnetic" sector on the IR brane. However the 't Hooft anomaly matching that constrains the Seiberg duality central to ISS is replaced by anomaly inflow and cancellation, and the source of strong coupling is the CFT to which the theory couples rather than the gauge groups. The theory contains an anomaly free R-symmetry that, when broken by UV effects, leads to an O'Raifeartaigh model on the IR brane. In contrast to ISS, the R-symmetry breaking in the UV can be maximal, and yet the R-symmetry breaking in the IR theory remains under strict control: there is no need for retrofitting of small parameters.Comment: 20 pages, 2 figure

Inconsistent strategies to spin up models in CMIP5: Implications for ocean biogeochemical model performance assessment

This is the final version of the article. Available from EGU via the DOI in this record.During the fifth phase of the Coupled Model Intercomparison Project (CMIP5) substantial efforts were made to systematically assess the skill of Earth system models. One goal was to check how realistically representative marine biogeochemical tracer distributions could be reproduced by models. In routine assessments model historical hindcasts were compared with available modern biogeochemical observations. However, these assessments considered neither how close modeled biogeochemical reservoirs were to equilibrium nor the sensitivity of model performance to initial conditions or to the spin-up protocols. Here, we explore how the large diversity in spin-up protocols used for marine biogeochemistry in CMIP5 Earth system models (ESMs) contributes to model-to-model differences in the simulated fields. We take advantage of a 500-year spin-up simulation of IPSL-CM5A-LR to quantify the influence of the spin-up protocol on model ability to reproduce relevant data fields. Amplification of biases in selected biogeochemical fields (O2, NO3, Alk-DIC) is assessed as a function of spin-up duration. We demonstrate that a relationship between spin-up duration and assessment metrics emerges from our model results and holds when confronted with a larger ensemble of CMIP5 models. This shows that drift has implications for performance assessment in addition to possibly aliasing estimates of climate change impact. Our study suggests that differences in spin-up protocols could explain a substantial part of model disparities, constituting a source of model-to-model uncertainty. This requires more attention in future model intercomparison exercises in order to provide quantitatively more correct ESM results on marine biogeochemistry and carbon cycle feedbacks.We sincerely thank I. Kriest, F. Joos, the anonymous reviewer and A. Yool for their useful comments on this paper. This work was supported by H2020 project CRESCENDO “Coordinated Research in Earth Systems and Climate: Experiments, kNowledge, Dissemination and Outreach”, which received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 641816 and by the EU FP7 project CARBOCHANGE “Changes in carbon uptake and emissions by oceans in a changing climate” which received funding from the European community’s Seventh Framework Programme under grant agreement no. 264879. Supercomputing time was provided by GENCI (Grand Equipement National de Calcul Intensif) at CCRT (Centre de Calcul Recherche et Technologie), allocation 016178. Finally, we are grateful to the ESGF project which makes data available for all the community. Roland Séférian is grateful to Aurélien Ribes for his kind advices on statistics. Jerry Tjiputra acknowledges ORGANIC project (239965/F20) funded by the Research Council of Norway. Christoph Heinze and Jerry Tjiputra are grateful for support through project EVA – Earth system modelling of climate variations in the Anthropocene (229771/E10) funded by the Research Council of Norway, as well as CPU-time and mass storage provided through NOTUR project NN2345K as well as NorStore project NS2345K. Keith Lindsay and Scott C. Doney acknowledge support from the National Science Foundation

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

Sagittal realignment osteotomy for increased posterior tibial slope after opening-wedge high tibial osteotomy: a case report

A 40 year old welder who underwent opening-wedge high tibial osteotomy for correction of alignment in a varus knee developed persistent pain with loss of knee extension. The posterior tibial slope increased from 9 degrees to 20 degrees after the osteotomy and caused the anteromedial knee pain and limited extension. The patient then underwent a revision osteotomy using a closing wedge technique to correct tibial slope. The osteotomy was performed, first from the medial cortex in the lateral direction, and second in the anteroposterior direction to remove the tibial bone in wedge shape and obtain full extension of the knee. The posterior tibial slope decreased to 8 degrees after the revision osteotomy and the patients returned to pain-free daily life. We reviewed this unique technique for correction of sagittal malalignment using a closing-wedge osteotomy for revision after opening-wedge osteotomy

No Consistent Simulated Trends in the Atlantic Meridional Overturning Circulation for the Past 6,000 Years

The Atlantic Meridional Overturning Circulation (AMOC) is a key feature of the North Atlantic with global ocean impacts. The AMOC's response to past changes in forcings during the Holocene provides important context for the coming centuries. Here, we investigate AMOC trends using an emerging set of transient simulations using multiple global climate models for the past 6,000 years. Although some models show changes, no consistent trend in overall AMOC strength during the mid-to-late Holocene emerges from the ensemble. We interpret this result to suggest no overall change in AMOC, which fits with our assessment of available proxy reconstructions. The decadal variability of the AMOC does not change in ensemble during the mid- and late-Holocene. There are interesting AMOC changes seen in the early Holocene, but their nature depends a lot on which inputs are used to drive the experiment

Spectral and morphological analysis of the remnant of supernova 1987A with alma and atca

published_or_final_versio

A Kernel for Open Source Drug Discovery in Tropical Diseases

Open source drug discovery, a promising alternative avenue to conventional patent-based drug development, has so far remained elusive with few exceptions. A major stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. This paper introduces the results from a newly assembled computational pipeline for identifying protein targets for drug discovery in ten organisms that cause tropical diseases. We have also experimentally tested two promising targets for their binding to commercially available drugs, validating one and invalidating the other. The resulting kernel provides a base of drug targets and lead candidates around which an open source community can nucleate. We invite readers to donate their judgment and in silico and in vitro experiments to develop these targets to the point where drug optimization can begin

Sensory deprivation in Staphylococcus aureus

Bacteria use two-component systems (TCSs) to sense and respond to environmental changes. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Here we show that S. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. Characterization of S. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches