Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface.

DiC14-amidine is a cationic lipid that was originally designed as a lipid nanocarrier for nucleic acid transport, and turned out to be a Toll-like receptor 4 (TLR4) agonist as well. We found that while E. coli lipopolysaccharide (LPS) is a TLR4 agonist in all species, diC14-amidine nanoliposomes are full agonists for human, mouse and cat receptors but weak horse agonists. Taking advantage of this unusual species specificity, we used chimeric constructs based on the human and horse sequences and identified two regions in the human TLR4 that modulate the agonist activity of diC14-amidine. Interestingly, these regions lie outside the known LPS-binding domain. Competition experiments also support our hypothesis that diC14-amidine interacts primarily with TLR4 hydrophobic crevices located at the edges of the TLR4/TLR4* dimerization interface. We have characterized potential binding modes using molecular docking analysis and suggest that diC14-amidine nanoliposomes activate TLR4 by facilitating its dimerization in a process that is myeloid differentiation 2 (MD-2)-dependent and cluster of differentiation 14 (CD14)-independent. Our data suggest that TLR4 may be activated through binding at different anchoring points, expanding the repertoire of TLR4 ligands to non-MD-2-binding lipids.C.L. is a IEF Marie Curie Action Research Fellow (TLR4-CAT PIEF-GA-2012-326481) and would like to thank the Wiener-Anspach Foundation for financial support. K.L.I. was supported by a HBLB Veterinary Research Training scholarship. This work was supported by program grant support from the Wellcome Trust and the MRC to N.J.G and C.E.B.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00018-015-1915-

Sediment sources and connectivity linked to hydrologic pathways and geomorphic processes: a conceptual model to specify sediment sources and pathways through space and time

Sediment connectivity is a conceptualization for the transfer and storage of sediment among different geomorphic compartments across upland landscapes and channel networks. Sediment connectivity and dysconnectivity are linked to the water cycle and hydrologic systems with the associated multiscale interactions with climate, soil, topography, ecology, and landuse/landcover under natural variability and human intervention. We review current sediment connectivity and modeling approaches evaluating and quantifying water and sediment transfer in catchment systems. Many studies highlight the interaction between sediment and water in defining landscape connectivity, but many efforts to quantify and/or simulate sediment connectivity rely on the topographic/structural controls on sediment erosion and delivery. More recent modeling efforts integrate functional and structural connectivity to capture hydrologic properties influencing sediment delivery. Though the recent modeling development is encouraging, a comprehensive sediment connectivity framework, which integrates geomorphic and hydrologic processes across spatiotemporal scales, has not yet been accomplished. Such an effort requires understanding the hydrologic and geomorphic processes that control sediment source, storage, and transport at different spatiotemporal scales and across various geophysical conditions. We propose a path for developing this new understanding through an integrated hydrologic and sediment connectivity conceptual model that broadly categorizes dominant processes and patterns relevant to understanding sediment flux dynamics. The conceptual model describes hydrologic–sediment connectivity regimes through spatial-temporal feedback between hydrologic processes and geomorphic drivers. We propose that in combining hydrologic and sediment connectivity into a single conceptual model, patterns emerge such that catchments will exist in a single characteristic behavior at a particular instance, which would shift with space and time, and with landscape disturbances. Using the conceptual model as a “thinking” tool, we extract case studies from a multidisciplinary literature review—from hydrology, geomorphology, biogeochemistry, and watershed modeling to remote-sensing technology—that correspond to each of the dominant hydrologic–sediment connectivity regimes. Sediment and water interactions in real-world examples through various observational and modeling techniques illustrate the advancements in the spatial and temporal scales of landscape connectivity observations and simulations. The conceptual model and case studies provide a foundation for advancing the understanding and predictive capability of watershed sediment processes at multiple spatiotemporal scales. Plain language summary: Soil erosion and movement across the landscape are closely linked to rain events and flow pathways. Landscape connectivity is a way to consider how soil erosion from different parts of the landscape is connected to the streams. We explore where soil erosion occurs and how eroded soil moves across the landscape through the interaction with rainfall and drainage. The comprehensive understanding of sediment connectivity and its dependence on rainfall characteristics and watershed hydrology may help to inform the effective distribution of conservation funds and management actions to address water pollution from excess sediment

Coronary flow reserve in stress-echo lab. From pathophysiologic toy to diagnostic tool

The assessment of coronary flow reserve by transthoracic echocardiography has recently been introduced into clinical practice with gratifying results for the diagnosis of left anterior descending artery disease simultaneously reported by several independent laboratories. This technological novelty is changing the practice of stress echo for 3 main reasons. First, adding coronary flow reserve to regional wall motion allows us to have – in the same sitting – high specificity (regional wall motion) and a high sensitivity (coronary flow reserve) diagnostic marker, with an obvious improvement in overall diagnostic accuracy. Second, the technicalities of coronary flow reserve shift the balance of stress choice in favour of vasodilators, which are a more robust hyperemic stress and are substantially easier to perform with dual imaging than dobutamine or exercise. Third, the coronary flow reserve adds a quantitative support to the exquisitely qualitative assessment of wall motion analysis, thereby facilitating the communication of stress echo results to the cardiological world outside the echo lab. The next challenges involve the need to expand the exploration of coronary flow reserve to the right and circumflex coronary artery and to prove the additional prognostic value – if any – of coronary flow reserve over regional wall motion analysis, which remains the cornerstone of clinically-driven diagnosis in the stress echo lab

The New Sorgentina Fusion Source-NSFS: 14 MeV neutrons for fusion and beyond

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What is missing in autonomous discovery: Open challenges for the community

Self-driving labs (SDLs) leverage combinations of artificial intelligence, automation, and advanced computing to accelerate scientific discovery. The promise of this field has given rise to a rich community of passionate scientists, engineers, and social scientists, as evidenced by the development of the Acceleration Consortium and recent Accelerate Conference. Despite its strengths, this rapidly developing field presents numerous opportunities for growth, challenges to overcome, and potential risks of which to remain aware. This community perspective builds on a discourse instantiated during the first Accelerate Conference, and looks to the future of self-driving labs with a tempered optimism. Incorporating input from academia, government, and industry, we briefly describe the current status of self-driving labs, then turn our attention to barriers, opportunities, and a vision for what is possible. Our field is delivering solutions in technology and infrastructure, artificial intelligence and knowledge generation, and education and workforce development. In the spirit of community, we intend for this work to foster discussion and drive best practices as our field grows

On the long term behavior of meandering rivers

In spite of notable advances in the description of river morphodynamics, the long-term dynamics of meandering rivers is still an open question, in particular, regarding the existence of a possible statistical steady state and its scaling properties induced by the competing action of cutoffs and reach elongation. By means of extensive numerical simulations, using three fluid dynamic models of different complexity and analysis of real data from the Amazon, North America, and Russia, we show that the reach cutoffs, besides providing stability and self-confinement to the meander belt, also act as a dynamical filter on several hydrodynamic mechanisms, selecting only those that really dominate the long-term dynamics. The results show that the long-term equilibrium conditions are essentially governed by only one spatial scale (proportional to the ratio of the river depth and the friction coefficient) and one temporal scale (proportional to the square of the spatial scale divided by the river width, the mean longitudinal velocity, and the erodibility coefficient) that contain the most important fluid dynamic quantities. The ensuing statistical long-term behavior of meandering rivers proves to be universal and largely unaffected by the details of the fluid dynamic processes that govern the short-term river behavio

Recovery of distal coronary flow reserve in LAD and LCx after Y-Graft intervention assessed by transthoracic echocardiography

<p>Abstract</p> <p>Background</p> <p>Y- graft (Y-G) is a graft formed by the Left Internal Mammary Artery (LIMA) connected to the Left Anterior Descending Artery (LAD) and by a free Right Internal Mammary Artery (RIMA) connected to LIMA and to a Marginal artery of Left Circumflex Artery (LCx). Aim of the work was to study the flow of this graft during a six months follow-up to assess whether the graft was able to meet the request of all the left coronary circulation, and to assess whether it could be done by evaluation of coronary flow reserve (CFR).</p> <p>Methods</p> <p>In 13 consecutive patients submitted to Y-G (13 men), CFR was measured in distal LAD and in distal LCx from 1 week after , every two months, up to six months after operation (a total of 8 tests for each patient) by means of transthoracic echocardiography (TTE) and Adenosine infusion (140 mcg/kg/min for 3-6 min). A Sequoia 256, Acuson-Siemens, was used. Contrast was used when necessary (Levovist 300 mg/ml solution at a rate of 0,5-1 ml/min). Max coronary flow diastolic velocity post-/pre-test ≥2 was considered normal CFR.</p> <p>Results</p> <p>Coronary arteriography revealed patency of both branches of Y-G after six months. Accuracy of TTE was 100% for LAD and 85% for LCx. Feasibility was 100% for LAD and 85% for LCx. CFR improved from baseline in LAD (2.21 ± 0.5 to 2.6 ± 0.5, p = 0.03) and in LCx (1.7 ± 1 to 2.12 ± 1, p = 0.05). CFR was under normal at baseline in 30% of patients <it>vs </it>8% after six months in LAD (p = 0.027), and in 69% of patients <it>vs </it>30% after six months in LCx (p = 0.066).</p> <p>Conclusion</p> <p>CFR in Y-G is sometimes reduced in both left territories postoperatively but it improves at six months follow-up. A follow-up can be done non-invasively by TTE and CFR evaluation.</p

Neutrinos below 100 TeV from the southern sky employing refined veto techniques to IceCube data

Many Galactic sources of gamma rays, such as supernova remnants, are expected to produce neutrinos with a typical energy cutoff well below 100 TeV. For the IceCube Neutrino Observatory located at the South Pole, the southern sky, containing the inner part of the Galactic plane and the Galactic Center, is a particularly challenging region at these energies, because of the large background of atmospheric muons. In this paper, we present recent advancements in data selection strategies for track-like muon neutrino events with energies below 100 TeV from the southern sky. The strategies utilize the outer detector regions as veto and features of the signal pattern to reduce the background of atmospheric muons to a level which, for the first time, allows IceCube searching for point-like sources of neutrinos in the southern sky at energies between 100 GeV and several TeV in the muon neutrino charged current channel. No significant clustering of neutrinos above background expectation was observed in four years of data recorded with the completed IceCube detector. Upper limits on the neutrino flux for a number of spectral hypotheses are reported for a list of astrophysical objects in the southern hemisphere.Comment: 19 pages, 17 figures, 2 table