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  • Springer Nature  (50,144)
  • American Geophysical Union
  • Hindawi
  • National Academy of Sciences
  • 2020-2020
  • 2015-2019  (74,089)
  • 2000-2004
  • 2018  (74,089)
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  • 2015-2019  (74,089)
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  • 1
    Publication Date: 2018-07-15
    Description: Understanding the enigmatic intraplate volcanism in the Tristan da Cunha region requires knowledge of the temperature of the lithosphere and asthenosphere beneath it. We measured phasevelocity curves of Rayleigh waves using cross-correlation of teleseismic seismograms from an array of ocean-bottom seismometers around Tristan, constrained a region-average, shear-velocity structure, and inferred the temperature of the lithosphere and asthenosphere beneath the hotspot. The ocean-bottom data set presented some challenges, which required data-processing and measurement approaches different from those tuned for land-based arrays of stations. Having derived a robust, phase-velocity curve for the Tristan area, we inverted it for a shear wave velocity profile using a probabilistic (Markov chain Monte Carlo) approach. The model shows a pronounced low-velocity anomaly from 70 to at least 120 km depth. VS in the low velocity zone is 4.1–4.2 km/s, not as low as reported for Hawaii (�4.0 km/s), which probably indicates a less pronounced thermal anomaly and, possibly, less partial melting. Petrological modeling shows that the seismic and bathymetry data are consistent with a moderately hot mantle (mantle potential temperature of 1,410–1,4308C, an excess of about 50–1208C compared to the global average) and a melt fraction smaller than 1%. Both purely seismic inversions and petrological modeling indicate a lithospheric thickness of 65–70 km, consistent with recent estimates from receiver functions. The presence of warmer-than-average asthenosphere beneath Tristan is consistent with a hot upwelling (plume) from the deep mantle. However, the excess temperature we determine is smaller than that reported for some other major hotspots, in particular Hawaii.
    Repository Name: EPIC Alfred Wegener Institut
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  • 2
    Publication Date: 2019-10-04
    Description: The Antarctic silverfish (Pleuragramma antarctica) is a critically important forage species with a circumpolar distribution and is unique among other notothenioid species for its wholly pelagic life cycle. Previous studies have provided mixed evidence of population structure over regional and circumpolar scales. The aim of the present study was to test the recent population hypothesis for Antarctic silverfish, which emphasizes the interplay between life history and hydrography in shaping connectivity. A total of 1067 individuals were collected over 25 years from different locations on a circumpolar scale. Samples were genotyped at fifteen microsatellites to assess population differentiation and genetic structuring using clustering methods, F-statistics, and hierarchical analysis of variance. A lack of differentiation was found between locations connected by the Antarctic Slope Front Current (ASF), indicative of high levels of gene flow. However, gene flow was significantly reduced at the South Orkney Islands and the western Antarctic Peninsula where the ASF is absent. This pattern of gene flow emphasized the relevance of large-scale circulation as a mechanism for circumpolar connectivity. Chaotic genetic patchiness characterized population structure over time, with varying patterns of differentiation observed between years, accompanied by heterogeneous standard length distributions. The present study supports a more nuanced version of the genetic panmixia hypothesis that reflects physical-biological interactions over the life history.
    Repository Name: EPIC Alfred Wegener Institut
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  • 3
    Publication Date: 2020-02-12
    Description: Four years after the Genomic Observatories Network was formally established as a collaboration between the Group on Earth Observations Biodiversity Observation Network and the Genomic Standards Consortium, we review the development of the network. Considering institutional infrastructure, we note the growing role of omic observation in active and increasingly interlinked marine networks, with examples such as EMBRC/ASSEMBLE, International Long Term Ecological Research Network, AtlantOS, National Association of Marine Labs, Smithsonian MarineGEO, and Partnership on Observation of the Global Oceans. We also note some key human elements essential to meeting the networks' goals, address how the community is evolving, and why performing seemingly simple tasks within a broadly distributed community presents significant challenges even among those who have agreed to use standards. From the perspectives above, we review lessons learned from use cases that leverage Genomic Observatories Network, such as the Autonomous Reef Monitoring Structures (ARMS), Ocean Sampling Day (OSD) and myOSD, which included experiences with citizen science. Looking forward, we survey 1) promising new technologies for in situ biological observation (e.g., cheap 3D printed omics samplers), 2) progress towards adoption of omics methods in marine policy and conservation programs, and 3) opportunities that a Genomic Observatory brings, alone or embedded in a network, to address novel scientific questions and support Essential Biodiversity Variables, Essential Ocean Variables, and indices such as the Ocean Health Index. Given the data intensive nature of omics investigation, we note emerging cyberinfrastructure solutions, such as the Genomic Observatories Metadatabase (GeOMe), an open-access repository for geographic and ecological metadata associated with biosamples, and predictive modeling efforts, such as those of the Island Digital Ecosystem Avatar (IDEA) Consortium. Finally, we explore the potential of Genomic Observatories as components of high-resolution calibration sites. Such observatories would provide super-contextualized "data trusts" for machine learning and artificial intelligence applications that draw on multi-omic observation.
    Repository Name: EPIC Alfred Wegener Institut
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  • 4
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    American Geophysical Union
    In:  EPIC32018 Ocean Sciences Meeting, Portland, Oregon, USA, 2018-02-11-2018-02-16American Geophysical Union
    Publication Date: 2020-02-12
    Description: Target audience: All ocean scientists who wish to share or discover best practice documents in their domain. Background: A working group convened under the AtlantOS project and including partners from ODIP, IODE, JCOMM, IEEE, and AWI is currently developing new technologies and approaches for handling best practices (BPs) across ocean science. The goal of the working group is to create a sustained repository for BPs, to ease their propagation and adoption. Goals: After briefly describing its work, the BP working group will engage town hall participants in a discussion on 1) how best to find and centrally archive BPs in participants' disciplines and 2) what capacities a central archive of BPs would need to help participants create, discover, share, and archive their BPs. The participant input gathered will be used to further the development of a multidisciplinary repository for BPs and better harmonise ocean observation.
    Repository Name: EPIC Alfred Wegener Institut
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  • 5
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    Springer Nature
    In:  EPIC3Nature Communications, Springer Nature, 9(3537), ISSN: 2041-1723
    Publication Date: 2018-09-17
    Description: Stable water isotope records from Antarctica are key for our understanding of Quaternary climate variations. However, the exact quantitative interpretation of these important climate proxy records in terms of surface temperature, ice sheet height and other climatic changes is still a matter of debate. Here we report results obtained with an atmospheric general circulation model equipped with water isotopes, run at a high-spatial horizontal resolution of one-by-one degree. Comparing different glacial maximum ice sheet reconstructions, a best model data match is achieved for the PMIP3 reconstruction. Reduced West Antarctic elevation changes between 400 and 800 m lead to further improved agreement with ice core data. Our modern and glacial climate simulations support the validity of the isotopic paleothermometer approach based on the use of present-day observations and reveal that a glacial ocean state as displayed in the GLAMAP reconstruction is suitable for capturing the observed glacial isotope changes in Antarctic ice cores.
    Repository Name: EPIC Alfred Wegener Institut
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  • 6
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    Springer Nature
    In:  EPIC3Nature Communications, Springer Nature, 9(1), pp. 715, ISSN: 2041-1723
    Publication Date: 2018-03-04
    Description: There is a strong spatial correlation between submarine slope failures and the occurrence of gas hydrates. This has been attributed to the dynamic nature of gas hydrate systems and the potential reduction of slope stability due to bottom water warming or sea level drop. However, 30 years of research into this process found no solid supporting evidence. Here we present new reflection seismic data from the Arctic Ocean and numerical modelling results supporting a different link between hydrates and slope stability. Hydrates reduce sediment permeability and cause build-up of overpressure at the base of the gas hydrate stability zone. Resulting hydro-fracturing forms pipe structures as pathways for overpressured fluids to migrate upward. Where these pipe structures reach shallow permeable beds, this overpressure transfers laterally and destabilises the slope. This process reconciles the spatial correlation of submarine landslides and gas hydrate, and it is independent of environmental change and water depth.
    Repository Name: EPIC Alfred Wegener Institut
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  • 7
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    Springer Nature
    In:  EPIC3Scientific Data, Springer Nature, 5, pp. 180058, ISSN: 2052-4463
    Publication Date: 2018-04-15
    Description: Arctic tundra landscapes are composed of a complex mosaic of patterned ground features, varying in soil moisture, vegetation composition, and surface hydrology over small spatial scales (10–100 m). The importance of microtopography and associated geomorphic landforms in influencing ecosystem structure and function is well founded, however, spatial data products describing local to regional scale distribution of patterned ground or polygonal tundra geomorphology are largely unavailable. Thus, our understanding of local impacts on regional scale processes (e.g., carbon dynamics) may be limited. We produced two key spatiotemporal datasets spanning the Arctic Coastal Plain of northern Alaska (~60,000 km2) to evaluate climate-geomorphological controls on arctic tundra productivity change, using (1) a novel 30m classification of polygonal tundra geomorphology and (2) decadal-trends in surface greenness using the Landsat archive (1999–2014). These datasets can be easily integrated and adapted in an array of local to regional applications such as (1) upscaling plot-level measurements (e.g., carbon/energy fluxes), (2) mapping of soils, vegetation, or permafrost, and/or (3) initializing ecosystem biogeochemistry, hydrology, and/or habitat modeling.
    Repository Name: EPIC Alfred Wegener Institut
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  • 8
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    Springer Nature
    In:  EPIC3Scientific Reports, Springer Nature, 8(6514), pp. 1-7, ISSN: 2045-2322
    Publication Date: 2018-04-30
    Description: The field of Arctic sea ice prediction on “weather time scales” is still in its infancy with little existing understanding of the limits of predictability. This is especially true for sea ice deformation along so-called Linear Kinematic Features (LKFs) including leads that are relevant for marine operations. Here the potential predictability of the sea ice pack in the wintertime Arctic up to ten days ahead is determined, exploiting the fact that sea ice-ocean models start to show skill at representing sea ice deformation at high spatial resolutions. Results are based on ensemble simulations with a high-resolution sea ice-ocean model driven by atmospheric ensemble forecasts. The predictability of LKFs as measured by different metrics drops quickly, with predictability being almost completely lost after 4–8 days. In contrast, quantities such as sea ice concentration or the location of the ice edge retain high levels of predictability throughout the full 10-day forecast period. It is argued that the rapid error growth for LKFs is mainly due to the chaotic behaviour of the atmosphere associated with the low predictability of near surface wind divergence and vorticity; initial condition uncertainty for ice thickness is found to be of minor importance as long as LKFs are initialized at the right locations.
    Repository Name: EPIC Alfred Wegener Institut
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  • 9
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    Springer Nature
    In:  EPIC3Scientific Reports, Springer Nature, 8(1), pp. 2345, ISSN: 2045-2322
    Publication Date: 2018-04-15
    Description: Arctic tundra ecosystems have experienced unprecedented change associated with climate warming over recent decades. Across the Pan-Arctic, vegetation productivity and surface greenness have trended positively over the period of satellite observation. However, since 2011 these trends have slowed considerably, showing signs of browning in many regions. It is unclear what factors are driving this change and which regions/landforms will be most sensitive to future browning. Here we provide evidence linking decadal patterns in arctic greening and browning with regional climate change and local permafrost-driven landscape heterogeneity. We analyzed the spatial variability of decadal-scale trends in surface greenness across the Arctic Coastal Plain of northern Alaska (~60,000 km²) using the Landsat archive (1999–2014), in combination with novel 30 m classifications of polygonal tundra and regional watersheds, finding landscape heterogeneity and regional climate change to be the most important factors controlling historical greenness trends. Browning was linked to increased temperature and precipitation, with the exception of young landforms (developed following lake drainage), which will likely continue to green. Spatiotemporal model forecasting suggests carbon uptake potential to be reduced in response to warmer and/or wetter climatic conditions, potentially increasing the net loss of carbon to the atmosphere, at a greater degree than previously expected.
    Repository Name: EPIC Alfred Wegener Institut
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  • 10
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    American Geophysical Union
    In:  EPIC3Journal of Geophysical Research: Oceans, American Geophysical Union, ISSN: 2169-9275
    Publication Date: 2018-09-20
    Description: Gradually decaying Arctic sea ice changes the boundary conditions at the surface, separating ocean and atmosphere. In recent years, substantial reductions in sea ice during winter have been observed in the Atlantic sector of the Arctic Ocean, which forms the gateway for warm water inflow from the midlatitudes. In this study, we used routine output from the Mercator Ocean global operational system (MOGOS) to assess the efficiency of winter thermohaline convection transporting heat from deep layers to the ocean surface along the Atlantic origin water (AW) pathway, between Svalbard and Franz Joseph Land in the Nansen Basin. Positive temperature extremes in the AW layer in midwinter promote favorable prerequisite conditions for deep‐reaching thermohaline convection, with explicit signs captured by the MOGOS. Balance equations with several assumptions for the compact region around the position (81.30°N, 31°E) of the long‐term (2004–2010) mooring demonstrated that winter heat loss at the ocean surface is mainly compensated by convective heat flux from the AW layer. Heat and salt fluxes, associated with horizontal advection, are compatible with convective fluxes, while contribution of ice formation/melt is substantially smaller. Conclusion about the dominant role of vertical convection in shaping thermohaline structure and reducing sea ice in winter is supported by correlation analysis of the MOGOS output and mooring‐based measurements. Unfavorable background conditions (thick and consolidated sea ice in combination with specific directions of ice drift) may significantly alter convection development, as demonstrated for two sequential years with substantially different external forcing.
    Repository Name: EPIC Alfred Wegener Institut
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  • 11
    Publication Date: 2019-03-26
    Description: In the Ionian Sea (Central Mediterranean) the slow convergence between Africa and Eurasia results in the formation of a narrow subduction zone. The nature of the crust of the subducting plate remains debated and could represent the last remnants of the Neo-Tethys ocean. The origin of the Ionian basin is also under discussion, especially concerning the rifting mechanisms as the Malta Escarpment could represent a remnant of this opening. This subduction retreat toward the south-east (motion occurring since the last 35 Ma) but is confined to the narrow Ionian Basin. A major lateral slab tear fault is required to accommodate the slab roll-back. This fault is thought to propagate along the eastern Sicily margin but its precise location remains controversial. This study focuses on the deep crustal structure of the Eastern-Sicily margin and the Malta Escarpment. We present two two-dimensional P-wave velocity models obtained from forward modeling of wide-angle seismic data acquired onboard the R/V Meteor during the DIONYSUS cruise in 2014. The results image an oceanic crust within the Ionian basin as well as the deep structure of the Malta Escarpment, which presents characteristics of a transform margin. A deep and asymmetrical sedimentary basin is imaged south of the Messina strait and seems to have opened between the Calabrian and Peloritan continental terranes. The interpretation of the velocity models suggests that the tear fault is located east of the Malta Escarpment, along the Alfeo fault system (AFS).
    Description: The DIONYSUS cruise is funded through the Deutsche Forschungsgemeinschaft DFG.
    Description: Published
    Description: 2090-2114
    Description: 1T. Struttura della Terra
    Description: JCR Journal
    Keywords: Crustal structure ; Subduction ; Crustal structure of the Ionian basin and eastern Sicily margin: results from a wide-angle seismic survey.
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 12
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    Springer Nature
    In:  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
    Publication Date: 2019-03-26
    Description: In the following we present a new non-invasive methodology aimed at the diagnosis of stone building materials used in historical buildings and architectural elements. This methodology consists of the integrated sequential application of in situ proximal sensing methodologies such as the 3D Terrestrial Laser Scanner for the 3D modelling of investigated objects together with laboratory and in situ non-invasive multi-techniques acoustic data, preceded by an accurate petrographical study of the investigated stone materials by optical and scanning electron microscopy. The increasing necessity to integrate different types of techniques in the safeguard of the Cultural Heritage is the result of the following two interdependent factors: 1) The diagnostic process on the building stone materials of monuments is increasingly focused on difficult targets in critical situations. In these cases, the diagnosis using only one type of non-invasive technique may not be sufficient to investigate the conservation status of the stone materials of the superficial and inner parts of the studied structures 2) Recent technological and scientific developments in the field of non-invasive diagnostic techniques for different types of materials favors and supports the acquisition, processing and interpretation of huge multidisciplinary datasets.
    Description: Regione Autonoma della Sardegna (RAS) (Sardinian Autonomous Region), Regional Law 7th August 2007, no. 7, Promotion of scientific research and technological innovation in Sardinia (Italy).
    Description: Published
    Description: 4334
    Description: 5T. Sismologia, geofisica e geologia per l'ingegneria sismica
    Description: JCR Journal
    Keywords: Non-invasive methodology ; Stone building materials ; Diagnosis ; 3D Terrestrial Laser Scanner ; Non-invasive multi-techniques acoustic data ; Microscopy ; Methodology for the non-destructive diagnosis of architectural elements ; Cultural Heritage
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 13
    Publication Date: 2018-02-16
    Description: Muon tomography measures the flux of cosmic muons crossing geological bodies to determine their density. The telescopes used to perform measurements are exposed to noise fluxes with high intensities relative to the tiny flux of interest. We give experimental evidences of a so far never described source of noise caused by a flux of upward going particles. Data acquired on La Soufrière of Guadeloupe and Mount Etna reveal that upward going particles are detected only when the rear side of the telescope is exposed to a wide volume of atmosphere located below the altitude of the telescope and with a rock obstruction less than several tens of meters. Biases produced on density muon radiographies by upward going fluxes are quantified, and correction procedures are applied to radiographies of La Soufrière.
    Description: Published
    Description: 6334–6339
    Description: 2V. Struttura e sistema di alimentazione dei vulcani
    Description: JCR Journal
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 14
    Publication Date: 2019-11-22
    Description: The dynamics of effusive events is controlled by the interplay between conduit geometry and source conditions. Dyke‐like geometries have been traditionally assumed for describing conduits during effusive eruptions, but their depth‐dependent and temporal modifications are largely unknown. We present a novel model which describes the evolution of conduit geometry during effusive eruptions by using a quasi steady state approach based on a 1‐D conduit model and appropriate criteria for describing fluid shear stress and elastic deformation. This approach provides time‐dependent trends for effusion rate, conduit geometry, exit velocity, and gas flow. Fluid shear stress leads to upward widening conduits, whereas elastic deformation becomes relevant only during final phases of effusive eruptions. Simulations can reproduce different trends of effusion rate, showing the effect of magma source conditions and country rock properties on the eruptive dynamics. This model can be potentially applied for data inversion in order to study specific case studies.
    Description: Published
    Description: 7471-7480
    Description: 5V. Processi eruttivi e post-eruttivi
    Description: JCR Journal
    Keywords: Magma ascent ; Effusive eruption ; Conduit geometry ; 04.08. Volcanology
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 15
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    American Geophysical Union
    In:  EPIC3American Geophysical Union Fall Meeting, Washington D.C., USA, 2018-12-10-2018-12-14Washington D.C., American Geophysical Union
    Publication Date: 2018-12-23
    Description: Tabular ground ice bodies are widely spread on Eurasian and North American Arctic plains. Exposed tabular ground ice in coastal bluffs favors the activation of thermal abrasion and thermal denudation, which in turn causes increasing coastal destruction rates. Thermo-denudation under conditions of ground ice exposures includes thawing of ice and frozen sediments along retreating headwalls of retrogressive thaw slumps and their constant enlargement. Thermo-cirques and thermo-terraces are two basic landform types that either feature channelized or broad open outlets, depending on the initial ice body outcrop by the denudation processes inland or in the retreating coastal bluffs. We study key-sites on Kolguev Island (Barents Sea) and on Yugorsky Peninsula (Kara Sea), continuing and extending earlier research efforts on coastal dynamics in the region. New data on thermo-denudation and thermo-abrasion rates for these key-sites have been obtained using a set of multi-temporal satellite images of high and very-high spatial resolution covering the period from 2002 to 2016. For orthorectification purposes of imagery collected prior to TanDEM-X acquisitions, we used an edited version of the 12 m TanDEM-X DEM. Along erosive coastline segments the former relief situation was reconstructed through extrapolation of coastal bluff edge elevation values and restoration of the coastal plain relief towards the sea. On the western coast of Kolguev Island, average coastal bluff retreat rates between 2002 and 2012 varied from 1.7 to 2.4 m/year, while averaged rates of thermo-cirques headwalls retreat were 2.6 m/year. Maximum rates at some sections increased up to 14.5-15.1 m/year in the recent past. High rates of thermo-denudation increase were not only observed on western Kolguev Island, but also on the Yugorsky Peninsula, were rates raised up to 13 m/year in recent years. Activation of thermo-denudation is also noted in other parts of Kara Sea coasts and were generally correlated with changing environmental factors, particularly expressed in an increase on the thaw index during recent years.
    Repository Name: EPIC Alfred Wegener Institut
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  • 16
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    American Geophysical Union
    In:  EPIC3AGU Fall Meeting 2018, Washington DC, 2018-12-10-2018-12-14Washington DC, American Geophysical Union
    Publication Date: 2019-01-06
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  • 17
    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the National Academy of Sciences.of the United States of America 115 (2018): 3398-3403, doi:10.1073/pnas.1715382115.
    Description: Plant nitrogen (N) use is a key component of the N cycle in terrestrial ecosystems. The supply of N to plants affects community species composition and ecosystem processes such as photosynthesis and carbon (C) accumulation. However, the availabilities and relative importance of different N forms to plants are not well understood. While nitrate (NO3−) is a major N form used by plants worldwide, it is discounted as a N source for Arctic tundra plants because of extremely low NO3− concentrations in Arctic tundra soils, undetectable soil nitrification, and plant-tissue NO3− that is typically below detection limits. Here we reexamine NO3− use by tundra plants using a sensitive denitrifier method to analyze plant-tissue NO3−. Soil-derived NO3− was detected in tundra plant tissues, and tundra plants took up soil NO3− at comparable rates to plants from relatively NO3−-rich ecosystems in other biomes. Nitrate assimilation determined by 15N enrichments of leaf NO3− relative to soil NO3− accounted for 4 to 52% (as estimated by a Bayesian isotope-mixing model) of species-specific total leaf N of Alaskan tundra plants. Our finding that in situ soil NO3− availability for tundra plants is high has important implications for Arctic ecosystems, not only in determining species compositions, but also in determining the loss of N from soils via leaching and denitrification. Plant N uptake and soil N losses can strongly influence C uptake and accumulation in tundra soils. Accordingly, this evidence of NO3− availability in tundra soils is crucial for predicting C storage in tundra.
    Description: his study was supported by the Kyoto University Foundation, the Sumitomo Foundation, Program for Next Generation World-Leading Researcher (Grant GS008) and Grant-in-Aid for Scientific Research (KAKENHI Grants 26252020, 26550004, 17H06297, and P09316) from the Japan Society for Promotion of Science, the National Natural Science Foundation of China (Grants 41730855, 41522301, and 41473081), the National Key Research and Development Program of China (Grants 2016YFA0600802 and 2017YFC0210101), and the 11th Recruitment Program of Global Experts (the Thousand Talents Plan) for Young Professionals granted by the central budget of China.
    Keywords: Arctic tundra plants ; Nitrogen dynamics ; Plant nitrate ; Soil nitrate ; Stable isotopes
    Repository Name: Woods Hole Open Access Server
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  • 18
    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the National Academy of Sciences.of the United States of America 115 (2018): 6756–6761, doi:10.1073/pnas.1804351115.
    Description: The existence of a chemosynthetic subseafloor biosphere was immediately recognized when deep-sea hot springs were discovered in 1977. However, quantifying how much new carbon is fixed in this environment has remained elusive. In this study, we incubated natural subseafloor communities under in situ pressure/temperature and measured their chemosynthetic growth efficiency and metabolic rates. Combining these data with fluid flux and in situ chemical measurements, we derived empirical constraints on chemosynthetic activity in the natural environment. Our study shows subseafloor microorganisms are highly productive (up to 1.4 Tg C produced yearly), fast-growing (turning over every 17–41 hours), and physiologically diverse. These estimates place deep-sea hot springs in a quantitative framework and allow us to assess their importance for global biogeochemical cycles.
    Description: This research was funded by a grant of the Dimensions of Biodiversity program of the US National Science Foundation (NSF-OCE-1136727 to S.M.S. and J.S.S.). Funding for J.M. was further provided by doctoral fellowships from the Natural Sciences and Engineering Research Council of Canada (PGSD3-430487-2013, PGSM-405117-2011) and the National Aeronautics and Space Administration Earth Systems Science Fellowship (PLANET14F-0075), an award from the Canadian Meteorological and Oceanographic Society, and the WHOI Academic Programs Office.
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  • 19
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Eos 86 (2005): 90, doi:10.1029/2005EO090004.
    Description: RayGUI 2.0 is a new version of RayGUI, a graphical user interface (GUI) to the seismic travel time modeling program of Zelt and Smith [1992]. It represents a significant improvement over the previous version of RayGUI (RayGUI 1.04; Loss et al.[1998a,1998b]).
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  • 20
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2000. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Solid Earth 105 (2000): 5835-5857, doi:10.1029/1999JB900318.
    Description: We use new seismic and gravity data collected during the 1994 Los Angeles Region Seismic Experiment (LARSE) to discuss the origin of the California Inner Continental Borderland (ICB) as an extended terrain possibly in a metamorphic core complex mode. The data provide detailed crustal structure of the Borderland and its transition to mainland southern California. Using tomographic inversion as well as traditional forward ray tracing to model the wide-angle seismic data, we find little or no sediments, low (#6.6 km/s) P wave velocity extending down to the crust-mantle boundary, and a thin crust (19 to 23 km thick). Coincident multichannel seismic reflection data show a reflective lower crust under Catalina Ridge. Contrary to other parts of coastal California, we do not find evidence for an underplated fossil oceanic layer at the base of the crust. Coincident gravity data suggest an abrupt increase in crustal thickness under the shelf edge, which represents the transition to the western Transverse Ranges. On the shelf the Palos Verdes Fault merges downward into a landward dipping surface which separates “basement” from low-velocity sediments, but interpretation of this surface as a detachment fault is inconclusive. The seismic velocity structure is interpreted to represent Catalina Schist rocks extending from top to bottom of the crust. This interpretation is compatible with a model for the origin of the ICB as an autochthonous formerly hot highly extended region that was filled with the exhumed metamorphic rocks. The basin and ridge topography and the protracted volcanism probably represent continued extension as a wide rift until ;13 m.y. ago. Subduction of the young and hot Monterey and Arguello microplates under the Continental Borderland, followed by rotation and translation of the western Transverse Ranges, may have provided the necessary thermomechanical conditions for this extension and crustal inflow.
    Description: The LARSE experiment was funded by NSF EAR-9416774, the U.S. Geological Survey’s Earthquake Hazards and Coastal and Marine Programs, and by the Southern California Earthquake Center (SCEC).
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  • 21
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 40 (2013): 4244-4248, doi:10.1002/grl.50830.
    Description: Active tectonic regions where plate boundaries transition from subduction to strike slip can take several forms, such as triple junctions, acute, and obtuse corners. Well‐documented slab tears that are associated with high rates of intermediate‐depth seismicity are considered here: Gibraltar arc, the southern and northern ends of the Lesser Antilles arc, and the northern end of Tonga trench. Seismicity at each of these locations occurs, at times, in the form of swarms or clusters, and various authors have proposed that each marks an active locus of tear propagation. The swarms and clusters start at the top of the slab below the asthenospheric wedge and extend 30–60 km vertically downward within the slab. We propose that these swarms and clusters are generated by fluid‐related embrittlement of mantle rocks. Focal mechanisms of these swarms generally fit the shear motion that is thought to be associated with the tearing process.
    Keywords: Slab tear ; Intermediate seismicity ; Subduction corner
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  • 22
    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the National Academy of Sciences.of the United States of America 115 (2018): 7729-7734, doi:10.1073/pnas.1805428115.
    Description: Identifying physical processes responsible for historical coastal sea-level changes is important for anticipating future impacts. Recent studies sought to understand the drivers of interannual to multidecadal sea-level changes on the United States Atlantic and Gulf coasts. Ocean dynamics, terrestrial water storage, vertical land motion, and melting of land ice were highlighted as important mechanisms of sea-level change along this densely populated coast on these time scales. While known to exert an important control on coastal ocean circulation, variable river discharge has been absent from recent discussions of drivers of sea-level change. We update calculations from the 1970s, comparing annual river-discharge and coastal sea-level data along the Gulf of Maine, Mid-Atlantic Bight, South Atlantic Bight, and Gulf of Mexico during 1910–2017. We show that river-discharge and sea-level changes are significantly correlated (p〈0.01), such that sea level rises between 0.01 and 0.08 cm for a 1 km3 annual river-discharge increase, depending on region. We formulate a theory that describes the relation between river-discharge and halosteric sea-level changes (i.e., changes in sea level related to salinity) as a function of river discharge, Earth’s rotation, and density stratification. This theory correctly predicts the order of observed increment sea-level change per unit river-discharge anomaly, suggesting a causal relation. Our results have implications for remote sensing, climate modeling, interpreting Common Era proxy sea-level reconstructions, and projecting coastal flood risk.
    Description: C.G.P. and R.M.P. acknowledge support from NASA Contract NNH16CT01C (which also supported C.M.L.), NASA Jet Propulsion Laboratory Subcontract 1569246, and National Science Foundation Award 1558966. C.G.P. also acknowledges support from The Investment in Science Fund at Woods Hole Oceanographic Institution. A.C.K. and S.E.E. acknowledge NSF Awards OCE-1458921 and OCE-1458903, respectively.
    Keywords: Coastal sea level ; Coastal river plumes ; Coastal flood risk ; Climate modeling ; Physical oceanography
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  • 23
    Publication Date: 2022-05-25
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Proceedings of the National Academy of Sciences of the United States of America 115 (2018): 8161-8166, doi:10.1073/pnas.1806296115.
    Description: Copper is an essential cofactor of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Inherited loss-of-function mutations in several genes encoding proteins required for copper delivery to CcO result in diminished CcO activity and severe pathologic conditions in affected infants. Copper supplementation restores CcO function in patient cells with mutations in two of these genes, COA6 and SCO2, suggesting a potential therapeutic approach. However, direct copper supplementation has not been therapeutically effective in human patients, underscoring the need to identify highly efficient copper transporting pharmacological agents. By using a candidate-based approach, we identified an investigational anticancer drug, elesclomol (ES), that rescues respiratory defects of COA6-deficient yeast cells by increasing mitochondrial copper content and restoring CcO activity. ES also rescues respiratory defects in other yeast mutants of copper metabolism, suggesting a broader applicability. Low nanomolar concentrations of ES reinstate copper-containing subunits of CcO in a zebrafish model of copper deficiency and in a series of copper-deficient mammalian cells, including those derived from a patient with SCO2 mutations. These findings reveal that ES can restore intracellular copper homeostasis by mimicking the function of missing transporters and chaperones of copper, and may have potential in treating human disorders of copper metabolism.
    Description: This work was supported by National Institutes of Health Awards R01GM111672 (to V.M.G.), R01 DK110195 (to B.-E.K.), and DK 44464 (to J.D.G.); Welch Foundation Grant A-1810 (to V.M.G.); and Canadian Institutes of Health Research Operating Grant MOP 133562 (to S.C.L.).
    Keywords: Copper ; Mitochondria ; Elesclomol ; Cytochrome c oxidase
    Repository Name: Woods Hole Open Access Server
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  • 24
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2013. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Solid Earth 105 (2013): 2915-2923, doi:10.1002/jgrb.50227.
    Description: The fore‐arc region of the northeast Caribbean plate north of Puerto Rico and the Virgin Islands has been the site of numerous seismic swarms since at least 1976. A 6 month deployment of five ocean bottom seismographs recorded two such tightly clustered swarms, along with additional events. Joint analyses of the ocean bottom seismographs and land‐based seismic data reveal that the swarms are located at depths of 50–150 km. Focal mechanism solutions, found by jointly fitting P wave first‐motion polarities and S/P amplitude ratios, indicate that the broadly distributed events outside the swarm generally have strike‐ and dip‐slip mechanisms at depths of 50–100 km, while events at depths of 100–150 km have oblique mechanisms. A stress inversion reveals two distinct stress regimes: The slab segment east of 65°W longitude is dominated by trench‐normal tensile stresses at shallower depths (50–100 km) and by trench‐parallel tensile stresses at deeper depths (100–150 km), whereas the slab segment west of 65°W longitude has tensile stresses that are consistently trench normal throughout the depth range at which events were observed (50–100 km). The simple stress pattern in the western segment implies relatively straightforward subduction of an unimpeded slab, while the stress pattern observed in the eastern segment, shallow trench‐normal tension and deeper trench‐normal compression, is consistent with flexure of the slab due to rollback. These results support the hypothesis that the subducting North American plate is tearing at or near these swarms. The 35 year record of seismic swarms at this location and the recent increase in seismicity suggest that the tear is still propagating.
    Keywords: Subduction ; Slab‐tear ; Caribbean ; Focal mechanism ; Stress inversion
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  • 25
    Publication Date: 2022-05-25
    Description: Author Posting. © American Geophysical Union, 2004. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Eos 85 (2004): 349,354, doi:10.1029/2004EO370001 .
    Description: The Puerto Rico Trench, the deepest part of the Atlantic Ocean, is located where the North American (NOAM) plate is subducting under the Caribbean plate (Figure l). The trench region may pose significant seismic and tsunami hazards to Puerto Rico and the U.S.Virgin Islands, where 4 million U.S. citizens reside. Widespread damage in Puerto Rico and Hispaniola from an earthquake in 1787 was estimated to be the result of a magnitude 8 earthquake north of the islands [McCann et al., 2004]. A tsunami killed 40 people in NW Puerto Rico following a magnitude 7.3 earthquake in 1918 [Mercado and McCann, 1998]. Large landslide escarpments have been mapped on the seafloor north of Puerto Rico [Mercado et al., 2002; Schwab et al., 1991],although their ages are unknown.
    Description: Funding was provided by the NOAA Office of Ocean Exploration and the USGS Coastal and Marine Program
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  • 26
    Publication Date: 2022-03-25
    Description: Lagoon development in ice-rich permafrost environments such as the Alaskan Beaufort Sea coastline and the Yedoma coastlines of northern Siberia represents a key mechanism of marine inundation of permafrost along the Arctic coastal plains. Here we show lithological, geochronological, and geochemical data from a core drilled in 1999 in Ivashkina Lagoon on the Bykovsky Peninsula in northeastern Siberia. This study extends previous studies of the Ivashkina Lagoon, and provides a first dated geochronological context for sedimentation and lithological characteristics. In addition, we report ground temperature measurements from different borehole sites in and around the lagoon to support our analysis of the thermokarst lagoon environment. Furthermore, a change detection study was carried out using historical aerial photography and modern satellite imagery for the 1982 to 2016 period. Several stages of landscape dynamics were reconstructed, starting with an initial Yedoma Ice Complex that covered the area during the late Pleistocene and which was locally thawed by thermokarst lake development during the Late Glacial with subsequent lacustrine sedimentation. A final stage completed the landscape dynamics during the last few hundreds of years. This stage was characterized by lake drainage and lagoon development, including strong reworking of surface sediments. By extrapolating the organic carbon data from Ivashkina Lagoon to the lagoons of the Bykovsky Peninsula, we estimate that lagoons contain 1.68 ± 0.04 Mt of organic carbon in their upper 6 m.
    Repository Name: EPIC Alfred Wegener Institut
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  • 27
    Publication Date: 2022-06-16
    Description: The Laptev and Eastern Siberian shelves are the world’s broadest shallow shelf systems. Large Siberian rivers and coastal erosion of up to meters per summer deliver large volumes of terrestrial matter into the Arctic shelf seas. In this chapter we investigate the applicability of Ocean Colour Remote Sensing during the ice-free summer season in the Siberian Laptev Sea region. We show that the early summer river peak discharge may be traced using remote sensing in years characterized by early sea-ice retreat. In the summer time after the peak discharge, the spreading of the main Lena River plume east and north-east of the Lena River Delta into the shelf system becomes hardly traceable using optical remote sensing methods. Measurements of suspended particulate matter (SPM) and coloured dissolved organic matter (cDOM) are of the same magnitude in the coastal waters of Buor Khaya Bay as in the Lena River. Match-up analyses of in situ chlorophyll-a (Chl-a) show that standard Medium Resolution Imaging Spectrometer (MERIS) and Moderate Resolution Imaging Spectroradiometer (MODIS) satellite-derived Chl-a is not a valid remote sensing product for the coastal waters and the inner shelf region of the Laptev Sea. All MERIS and MODIS-derived Chl-a products are overestimated by at least a factor of ten, probably due to absorption by the extraordinarily high amount of non-algal particles and cDOM in these coastal and inner-shelf waters. Instead, Ocean Colour remote sensing provides information on wide-spread resuspension over shallows and lateral advection visible in satellite-derived turbidity. Satellite Sea Surface Temperature (SST) data clearly show hydrodynamics and delineate the outflow of the Lena River for hundreds of kilometres out into the shelf seas.
    Repository Name: EPIC Alfred Wegener Institut
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  • 28
    Publication Date: 2024-05-08
    Description: The authors regret an error in the published article, where incorrect data was used to produce Figure 2, showing the temporal development of pH over the duration of the experiment. The corrected Fig. 2 shows that the error did not affect the interpretation of nor the conclusions drawn from the present dataset. The original article has been corrected.
    Repository Name: EPIC Alfred Wegener Institut
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  • 29
    Publication Date: 2024-04-11
    Description: Arctic river deltas are highly dynamic environments in the northern circumpolar permafrost region that are affected by fluvial, coastal, and permafrost-thaw processes. They are characterized by thick sediment deposits containing large but poorly constrained amounts of frozen organic carbon and nitrogen. This study presents new data on soil organic carbon and nitrogen storage as well as accumulation rates from the Ikpikpuk and Fish Creek river deltas, two small, permafrost-dominated Arctic river deltas on the Arctic Coastal Plain of northern Alaska. A soil organic carbon storage of 42.4 ± 1.6 and 37.9 ± 3.5 kg C m− 2 and soil nitrogen storage of 2.1 ± 0.1 and 2.0 ± 0.2 kg N m− 2 was found for the first 2 m of soil for the Ikpikpuk and Fish Creek river delta, respectively. While the upper meter of soil contains 3.57 Tg C, substantial amounts of carbon (3.09 Tg C or 46%) are also stored within the second meter of soil (100–200 cm) in the two deltas. An increasing and inhomogeneous distribution of C with depth is indicative of the dominance of deltaic depositional rather than soil forming processes for soil organic carbon storage. Largely, mid- to late Holocene radiocarbon dates in our cores suggest different carbon accumulation rates for the two deltas for the last 2000 years. Rates up to 28 g C m− 2 year− 1 for the Ikpikpuk river delta are about twice as high as for the Fish Creek river delta. With this study, we highlight the importance of including these highly dynamic permafrost environments in future permafrost carbon estimations.
    Repository Name: EPIC Alfred Wegener Institut
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  • 30
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    Springer Nature
    In:  EPIC3BIOspektrum, Springer Nature, 24(7), pp. 750-751, ISSN: 0947-0867
    Publication Date: 2024-05-03
    Repository Name: EPIC Alfred Wegener Institut
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  • 31
    Publication Date: 2018-12-21
    Description: Growth rate is one of the most important and most complex phenotypic characteristics of unicellular microorganisms, which determines the genetic mutations that dominate at the population level, and ultimately whether the population will survive. Translating changes at the genetic level to their growth-rate consequences remains a subject of intense interest, since such a mapping could rationally direct experiments to optimize antibiotic efficacy or bioreactor productivity. In this work, we directly map transcriptional profiles to growth rates by gathering published gene-expression data from Escherichia coli and Saccharomyces cerevisiae with corresponding growth-rate measurements. Using a machine-learning technique called k-nearest-neighbors regression, we build a model which predicts growth rate from gene expression. By exploiting the correlated nature of gene expression and sparsifying the model, we capture 81% of the variance in growth rate of the E. coli dataset, while reducing the number of features from 〉4,000 to 9. In S. cerevisiae, we account for 89% of the variance in growth rate, while reducing from 〉5,500 dimensions to 18. Such a model provides a basis for selecting successful strategies from among the combinatorial number of experimental possibilities when attempting to optimize complex phenotypic traits like growth rate.
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  • 32
    Publication Date: 2018-01-08
    Description: Increasing evidence suggests that early neurodevelopmental defects in Huntington’s disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.
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  • 33
    Publication Date: 2018-06-18
    Description: Phenotypic novelties are an important but poorly understood category of morphological diversity. They can provide insights into the origins of phenotypic variation, but we know relatively little about their genetic origins. Cichlid fishes display remarkable diversity in craniofacial anatomy, including several novelties. One aspect of this variation is a conspicuous, exaggerated snout that has evolved in a single Malawi cichlid lineage and is associated with foraging specialization and increased ecological success. We examined the developmental and genetic origins for this phenotype and found that the snout is composed of two hypertrophied tissues: the intermaxillary ligament (IML), which connects the right and left sides of the upper jaw, and the overlying loose connective tissue. The IML is present in all cichlids, but in its exaggerated form it interdigitates with the more superficial connective tissue and anchors to the epithelium, forming a unique ligament–epithelial complex. We examined the Transforming growth factor β (Tgfβ) → Scleraxis (Scx) candidate pathway and confirmed a role for these factors in snout development. We demonstrate further that experimental up-regulation of Tgfβ is sufficient to produce an expansion of scx expression and concomitant changes in snout morphology. Genetic and genomic mapping show that core members of canonical Tgfβ signaling segregate with quantitative trait loci (QTL) for snout variation. These data also implicate a candidate for ligament development, adam12, which we confirm using the zebrafish model. Collectively, these data provide insights into ligament morphogenesis, as well as how an ecologically relevant novelty can arise at the molecular level.
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  • 34
    Publication Date: 2018-07-02
    Description: Throughout three domains of life, alanyl-tRNA synthetases (AlaRSs) recognize a G3:U70 base pair in the acceptor stem of tRNAAla as the major identity determinant of tRNAAla. The crystal structure of the archaeon Archaeoglobus fulgidus AlaRS in complex with tRNAAla provided the basis for G3:U70 recognition with residues (Asp and Asn) that are conserved in the three domains [Naganuma M, et al. (2014) Nature 510:507–511]. The recognition mode is unprecedented, with specific accommodation of the dyad asymmetry of the G:U wobble pair and exclusion of the dyad symmetry of a Watson–Crick pair. With this conserved mode, specificity is based more on “fit” than on direct recognition of specific atomic groups. Here, we show that, in contrast to the archaeal complex, the Escherichia coli enzyme uses direct positive (energetically favorable) minor groove recognition of the unpaired 2-amino of G3 by Asp and repulsion of a competing base pair by Asn. Strikingly, mutations that disrupted positive recognition by the E. coli enzyme had little or no effect on G:U recognition by the human enzyme. Alternatively, Homo sapiens AlaRS selects G:U without positive recognition and uses Asp instead to repel a competitor. Thus, the widely conserved Asp-plus-Asn architecture of AlaRSs can select G:U in a straightforward (bacteria) or two different unconventional (eukarya/archaea) ways. The adoption of different modes for recognition of a widely conserved G:U pair in alanine tRNAs suggests an early and insistent role for G:U in the development of the genetic code.
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  • 35
    Publication Date: 2018-06-05
    Description: In the field of X-ray microcomputed tomography (μCT) there is a growing need to reduce acquisition times at high spatial resolution (approximate micrometers) to facilitate in vivo and high-throughput operations. The state of the art represented by synchrotron light sources is not practical for certain applications, and therefore the development of high-brightness laboratory-scale sources is crucial. We present here imaging of a fixed embryonic mouse sample using a compact laser–plasma-based X-ray light source and compare the results to images obtained using a commercial X-ray μCT scanner. The radiation is generated by the betatron motion of electrons inside a dilute and transient plasma, which circumvents the flux limitations imposed by the solid or liquid anodes used in conventional electron-impact X-ray tubes. This X-ray source is pulsed (duration 1010 photons per pulse), small (diameter 15 keV. Stable X-ray performance enabled tomographic imaging of equivalent quality to that of the μCT scanner, an important confirmation of the suitability of the laser-driven source for applications. The X-ray flux achievable with this approach scales with the laser repetition rate without compromising the source size, which will allow the recording of high-resolution μCT scans in minutes.
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  • 36
    Publication Date: 2018-08-01
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  • 37
    Publication Date: 2018-09-18
    Description: Materials and structures that enable long-term, intimate coupling of flexible electronic devices to biological systems are critically important to the development of advanced biomedical implants for biological research and for clinical medicine. By comparison with simple interfaces based on arrays of passive electrodes, the active electronics in such systems provide powerful and sometimes essential levels of functionality; they also demand long-lived, perfect biofluid barriers to prevent corrosive degradation of the active materials and electrical damage to the adjacent tissues. Recent reports describe strategies that enable relevant capabilities in flexible electronic systems, but only for capacitively coupled interfaces. Here, we introduce schemes that exploit patterns of highly doped silicon nanomembranes chemically bonded to thin, thermally grown layers of SiO2 as leakage-free, chronically stable, conductively coupled interfaces. The results can naturally support high-performance, flexible silicon electronic systems capable of amplified sensing and active matrix multiplexing in biopotential recording and in stimulation via Faradaic charge injection. Systematic in vitro studies highlight key considerations in the materials science and the electrical designs for high-fidelity, chronic operation. The results provide a versatile route to biointegrated forms of flexible electronics that can incorporate the most advanced silicon device technologies with broad applications in electrical interfaces to the brain and to other organ systems.
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  • 38
    Publication Date: 2018-06-25
    Description: Protein homeostasis is critically important for cell viability. Key to this process is the refolding of misfolded or aggregated proteins by molecular chaperones or, alternatively, their degradation by proteases. In most prokaryotes and in chloroplasts and mitochondria, protein degradation is performed by the caseinolytic protease ClpP, a tetradecamer barrel-like proteolytic complex. Dysregulating ClpP function has shown promise in fighting antibiotic resistance and as a potential therapy for acute myeloid leukemia. Here we use methyl–transverse relaxation-optimized spectroscopy (TROSY)–based NMR, cryo-EM, biochemical assays, and molecular dynamics simulations to characterize the structural dynamics of ClpP from Staphylococcus aureus (SaClpP) in wild-type and mutant forms in an effort to discover conformational hotspots that regulate its function. Wild-type SaClpP was found exclusively in the active extended form, with the N-terminal domains of its component protomers in predominantly β-hairpin conformations that are less well-defined than other regions of the protein. A hydrophobic site was identified that, upon mutation, leads to unfolding of the N-terminal domains, loss of SaClpP activity, and formation of a previously unobserved split-ring conformation with a pair of 20-Å-wide pores in the side of the complex. The extended form of the structure and partial activity can be restored via binding of ADEP small-molecule activators. The observed structural plasticity of the N-terminal gates is shown to be a conserved feature through studies of Escherichia coli and Neisseria meningitidis ClpP, suggesting a potential avenue for the development of molecules to allosterically modulate the function of ClpP.
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  • 39
    Publication Date: 2018-07-30
    Description: Humans can integrate social contextual information into decision-making processes to adjust their responses toward inequity. This context dependency emerges when individuals receive more (i.e., advantageous inequity) or less (i.e., disadvantageous inequity) than others. However, it is not clear whether context-dependent processing of advantageous and disadvantageous inequity involves differential neurocognitive mechanisms. Here, we used fMRI to address this question by combining an interactive game that modulates social contexts (e.g., interpersonal guilt) with computational models that enable us to characterize individual weights on inequity aversion. In each round, the participant played a dot estimation task with an anonymous coplayer. The coplayer would receive pain stimulation with 50% probability when either of them responded incorrectly. At the end of each round, the participant completed a variant of dictator game, which determined payoffs for him/herself and the coplayer. Computational modeling demonstrated the context dependency of inequity aversion: when causing pain to the coplayer (i.e., guilt context), participants cared more about the advantageous inequity and became more tolerant of the disadvantageous inequity, compared with other conditions. Consistently, neuroimaging results suggested the two types of inequity were associated with differential neurocognitive substrates. While the context-dependent processing of advantageous inequity was associated with social- and mentalizing-related processes, involving left anterior insula, right dorsolateral prefrontal cortex, and dorsomedial prefrontal cortex, the context-dependent processing of disadvantageous inequity was primarily associated with emotion- and conflict-related processes, involving left posterior insula, right amygdala, and dorsal anterior cingulate cortex. These results extend our understanding of decision-making processes related to inequity aversion.
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  • 40
    Publication Date: 2018-11-05
    Description: Electrochemistry is an old but still flourishing field of research due to the importance of the efficiency and kinetics of electrochemical reactions in industrial processes and (bio-)electrochemical devices. The heterogeneous electron transfer from an electrode to a reactant in the solution has been well studied for metal, semiconductor, metal oxide, and carbon electrodes. For those electrode materials, there is little correlation between the electronic transport within the electrode material and the electron transfer occurring at the interface between the electrode and the solution. Here, we investigate the heterogeneous electron transfer between a conducting polymer electrode and a redox couple in an electrolyte. As a benchmark system, we use poly(3,4-ethylenedioxythiophene) (PEDOT) and the Ferro/ferricyanide redox couple in an aqueous electrolyte. We discovered a strong correlation between the electronic transport within the PEDOT electrode and the rate of electron transfer to the organometallic molecules in solution. We attribute this to a percolation-based charge transport within the polymer electrode directly involved in the electron transfer. We show the impact of this finding by optimizing an electrochemical thermogalvanic cell that transforms a heat flux into electrical power. The power generated by the cell increased by four orders of magnitude on changing the morphology and conductivity of the polymer electrode. As all conducting polymers are recognized to have percolation transport, we believe that this is a general phenomenon for this family of conductors.
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  • 41
    Publication Date: 2018-07-18
    Description: We derive a principled information-theoretic account of cross-language semantic variation. Specifically, we argue that languages efficiently compress ideas into words by optimizing the information bottleneck (IB) trade-off between the complexity and accuracy of the lexicon. We test this proposal in the domain of color naming and show that (i) color-naming systems across languages achieve near-optimal compression; (ii) small changes in a single trade-off parameter account to a large extent for observed cross-language variation; (iii) efficient IB color-naming systems exhibit soft rather than hard category boundaries and often leave large regions of color space inconsistently named, both of which phenomena are found empirically; and (iv) these IB systems evolve through a sequence of structural phase transitions, in a single process that captures key ideas associated with different accounts of color category evolution. These results suggest that a drive for information-theoretic efficiency may shape color-naming systems across languages. This principle is not specific to color, and so it may also apply to cross-language variation in other semantic domains.
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  • 42
    Publication Date: 2018-11-12
    Description: The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is a master regulator of adipocyte differentiation and is the target for the insulin-sensitizing thiazolidinedione (TZD) drugs used to treat type 2 diabetes. In cell-based in vitro studies, the transcriptional activity of PPARγ is inhibited by covalent attachment of small ubiquitin-related modifier (SUMOylation) at K107 in its N terminus. However, whether this posttranslational modification is relevant in vivo remains unclear. Here, using mice homozygous for a mutation (K107R) that prevents SUMOylation at this position, we demonstrate that PPARγ is SUMOylated at K107 in white adipose tissue. We further show that in the context of diet-induced obesity PPARγ-K107R–mutant mice have enhanced insulin sensitivity without the corresponding increase in adiposity that typically accompanies PPARγ activation by TZDs. Accordingly, the PPARγ-K107R mutation was weaker than TZD treatment in stimulating adipocyte differentiation in vitro. Moreover, we found that both the basal and TZD-dependent transcriptomes of inguinal and epididymal white adipose tissue depots were markedly altered in the K107R-mutant mice. We conclude that PPARγ SUMOylation at K107 is physiologically relevant and may serve as a pharmacologic target for uncoupling PPARγ’s beneficial insulin-sensitizing effect from its adverse effect of weight gain.
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  • 43
    Publication Date: 2018-01-18
    Description: To compensate for sensory processing delays, the visual system must make predictions to ensure timely and appropriate behaviors. Recent work has found predictive information about the stimulus in neural populations early in vision processing, starting in the retina. However, to utilize this information, cells downstream must be able to read out the predictive information from the spiking activity of retinal ganglion cells. Here we investigate whether a downstream cell could learn efficient encoding of predictive information in its inputs from the correlations in the inputs themselves, in the absence of other instructive signals. We simulate learning driven by spiking activity recorded in salamander retina. We model a downstream cell as a binary neuron receiving a small group of weighted inputs and quantify the predictive information between activity in the binary neuron and future input. Input weights change according to spike timing–dependent learning rules during a training period. We characterize the readouts learned under spike timing–dependent synaptic update rules, finding that although the fixed points of learning dynamics are not associated with absolute optimal readouts they convey nearly all of the information conveyed by the optimal readout. Moreover, we find that learned perceptrons transmit position and velocity information of a moving-bar stimulus nearly as efficiently as optimal perceptrons. We conclude that predictive information is, in principle, readable from the perspective of downstream neurons in the absence of other inputs. This suggests an important role for feedforward prediction in sensory encoding.
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  • 44
    Publication Date: 2018-05-29
    Description: One-quarter of the 28 types of natural collagen exist as heterotrimers. The oligomerization state of collagen affects the structure and mechanics of the extracellular matrix, providing essential cues to modulate biological and pathological processes. A lack of high-resolution structural information limits our mechanistic understanding of collagen heterospecific self-assembly. Here, the 1.77-Å resolution structure of a synthetic heterotrimer demonstrates the balance of intermolecular electrostatics and hydrogen bonding that affects collagen stability and heterospecificity of assembly. Atomistic simulations and mutagenesis based on the solved structure are used to explore the contributions of specific interactions to energetics. A predictive model of collagen stability and specificity is developed for engineering novel collagen structures.
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  • 45
    Publication Date: 2018-10-17
    Description: Global climate models robustly predict that global mean precipitation should increase at roughly 2–3%K−1, but the origin of these values is not well understood. Here we develop a simple theory to help explain these values. This theory combines the well-known radiative constraint on precipitation, which says that condensation heating from precipitation is balanced by the net radiative cooling of the free troposphere, with an invariance of radiative cooling profiles when expressed in temperature coordinates. These two constraints yield a picture in which mean precipitation is controlled primarily by the depth of the troposphere, when measured in temperature coordinates. We develop this theory in idealized simulations of radiative–convective equilibrium and also demonstrate its applicability to global climate models.
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  • 46
    Publication Date: 2018-12-24
    Description: Food security relies on the resilience of staple food crops to climatic variability and extremes, but the climate resilience of European wheat is unknown. A diversity of responses to disturbance is considered a key determinant of resilience. The capacity of a sole crop genotype to perform well under climatic variability is limited; therefore, a set of cultivars with diverse responses to weather conditions critical to crop yield is required. Here, we show a decline in the response diversity of wheat in farmers’ fields in most European countries after 2002–2009 based on 101,000 cultivar yield observations. Similar responses to weather were identified in cultivar trials among central European countries and southern European countries. A response diversity hotspot appeared in the trials in Slovakia, while response diversity “deserts” were identified in Czechia and Germany and for durum wheat in southern Europe. Positive responses to abundant precipitation were lacking. This assessment suggests that current breeding programs and cultivar selection practices do not sufficiently prepare for climatic uncertainty and variability. Consequently, the demand for climate resilience of staple food crops such as wheat must be better articulated. Assessments and communication of response diversity enable collective learning across supply chains. Increased awareness could foster governance of resilience through research and breeding programs, incentives, and regulation.
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  • 47
    Publication Date: 2018-11-20
    Description: T cell receptor (TCR) repertoire data contain information about infections that could be used in disease diagnostics and vaccine development, but extracting that information remains a major challenge. Here we developed a statistical framework to detect TCR clone proliferation and contraction from longitudinal repertoire data. We applied this framework to data from three pairs of identical twins immunized with the yellow fever vaccine. We identified 600 to 1,700 responding TCRs in each donor and validated them using three independent assays. While the responding TCRs were mostly private, albeit with higher overlap between twins, they could be well-predicted using a classifier based on sequence similarity. Our method can also be applied to samples obtained postinfection, making it suitable for systematic discovery of new infection-specific TCRs in the clinic.
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  • 48
    Publication Date: 2018-02-05
    Description: The diamond anvil cell (DAC) is considered one of the dominant devices to generate ultrahigh static pressure. The development of the DAC technique has enabled researchers to explore rich high-pressure science in the multimegabar pressure range. Here, we investigated the behavior of the DAC up to 400 GPa, which is the accepted pressure limit of a conventional DAC. By using a submicrometer synchrotron X-ray beam, double cuppings of the beveled diamond anvils were observed experimentally. Details of pressure loading, distribution, gasket-thickness variation, and diamond anvil deformation were studied to understand the generation of ultrahigh pressures, which may improve the conventional DAC techniques.
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  • 49
    Publication Date: 2018-11-13
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  • 50
    Publication Date: 2018-06-04
    Description: The resurrection of ancestral enzymes of now-extinct organisms (paleogenetics) is a developing field that allows the study of evolutionary hypotheses otherwise impossible to be tested. In the present study, we target fungal peroxidases that play a key role in lignin degradation, an essential process in the carbon cycle and often a limiting step in biobased industries. Ligninolytic peroxidases are secreted by wood-rotting fungi, the origin of which was recently established in the Carboniferous period associated with the appearance of these enzymes. These first peroxidases were not able to degrade lignin directly and used diffusible metal cations to attack its phenolic moiety. The phylogenetic analysis of the peroxidases of Polyporales, the order in which most extant wood-rotting fungi are included, suggests that later in evolution these enzymes would have acquired the ability to degrade nonphenolic lignin using a tryptophanyl radical interacting with the bulky polymer at the surface of the enzyme. Here, we track this powerful strategy for lignin degradation as a phenotypic trait in fungi and show that it is not an isolated event in the evolution of Polyporales. Using ancestral enzyme resurrection, we study the molecular changes that led to the appearance of the same surface oxidation site in two distant peroxidase lineages. By characterization of the resurrected enzymes, we demonstrate convergent evolution at the amino acid level during the evolution of these fungi and track the different changes leading to phylogenetically distant ligninolytic peroxidases from ancestors lacking the ability to degrade nonphenolic lignin.
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  • 51
    Publication Date: 2018-08-20
    Description: The hydroxyl radical (OH) is the primary oxidant in the troposphere, and the impact of its fluctuations on the methane budget has been disputed in recent years, however measurements of OH are insufficient to characterize global interannual fluctuations relevant for methane. Here, we use a 6,000-y control simulation of preindustrial conditions with a chemistry-climate model to quantify the natural variability in OH and internal feedbacks governing that variability. We find that, even in the absence of external forcing, maximum OH changes are 3.8 ± 0.8% over a decade, which is large in the context of the recent methane growth from 2007–2017. We show that the OH variability is not a white-noise process. A wavelet analysis indicates that OH variability exhibits significant feedbacks with the same periodicity as the El Niño–Southern Oscillation (ENSO). We find intrinsically generated modulation of the OH variability, suggesting that OH may show periods of rapid or no change in future decades that are solely due to the internal climate dynamics (as opposed to external forcings). An empirical orthogonal function analysis further indicates that ENSO is the dominant mode of OH variability, with the modulation of OH occurring primarily through lightning NOx. La Niña is associated with an increase in convection in the Tropical Pacific, which increases the simulated occurrence of lightning and allows for more OH production. Understanding this link between OH and ENSO may improve the predictability of the oxidative capacity of the troposphere and assist in elucidating the causes of current and historical trends in methane.
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  • 52
    Publication Date: 2018-03-05
    Description: Induced B7-H1 expression in the tumor microenvironment initiates adaptive resistance, which impairs immune functions and leads to tumor escape from immune destruction. Antibody blockade of the B7-H1/PD-1 interaction overcomes adaptive resistance, leading to regression of advanced human cancers and survival benefits in a significant fraction of patients. In addition to cancer cells, B7-H1 is expressed on dendritic cells (DCs), but its role in DC functions is less understood. DCs can present multiple antigens (Ags) to stimulate dominant or subdominant T cell responses. Here, we show that immunization with multiple tumor Ag-loaded DCs, in the absence of B7-H1, vastly enhances cytotoxic T lymphocyte (CTL) responses to dominant Ag. In sharp contrast, CTL responses to subdominant Ag were paradoxically suppressed, facilitating outgrowth of tumor variants carrying only subdominant Ag. Suppressed CTL responses to subdominant Ag are largely due to the loss of B7-H1–mediated protection of DCs from the lysis of CTL against dominant Ag. Therefore, B7-H1 expression on DCs may help maintain the diversity of CTL responses to multiple tumor Ags. Interestingly, a split immunization approach, which presents dominant and subdominant Ags with different DCs, promoted CTL responses to all Ags and prevented tumor escape in murine tumor models. These findings have implications for the design of future combination cancer immunotherapies.
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  • 53
    Publication Date: 2018-01-08
    Description: Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.
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  • 54
    Publication Date: 2018-11-27
    Description: Hepatocellular carcinoma (HCC) is one of the most frequent forms of liver cancer, and effective treatment methods are limited due to tumor heterogeneity. There is a great need for comprehensive approaches to stratify HCC patients, gain biological insights into subtypes, and ultimately identify effective therapeutic targets. We stratified HCC patients and characterized each subtype using transcriptomics data, genome-scale metabolic networks and network topology/controllability analysis. This comprehensive systems-level analysis identified three distinct subtypes with substantial differences in metabolic and signaling pathways reflecting at genomic, transcriptomic, and proteomic levels. These subtypes showed large differences in clinical survival associated with altered kynurenine metabolism, WNT/β-catenin–associated lipid metabolism, and PI3K/AKT/mTOR signaling. Integrative analyses indicated that the three subtypes rely on alternative enzymes (e.g., ACSS1/ACSS2/ACSS3, PKM/PKLR, ALDOB/ALDOA, MTHFD1L/MTHFD2/MTHFD1) to catalyze the same reactions. Based on systems-level analysis, we identified 8 to 28 subtype-specific genes with pivotal roles in controlling the metabolic network and predicted that these genes may be targeted for development of treatment strategies for HCC subtypes by performing in silico analysis. To validate our predictions, we performed experiments using HepG2 cells under normoxic and hypoxic conditions and observed opposite expression patterns between genes expressed in high/moderate/low-survival tumor groups in response to hypoxia, reflecting activated hypoxic behavior in patients with poor survival. In conclusion, our analyses showed that the heterogeneous HCC tumors can be stratified using a metabolic network-driven approach, which may also be applied to other cancer types, and this stratification may have clinical implications to drive the development of precision medicine.
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  • 55
    Publication Date: 2018-04-23
    Description: Hepatocellular carcinoma (HCC) is a highly lethal cancer that has a high rate of recurrence, in part because of cancer stem cell (CSC)-dependent field cancerization. Acyclic retinoid (ACR) is a synthetic vitamin A-like compound capable of preventing the recurrence of HCC. Here, we performed a genome-wide transcriptome screen and showed that ACR selectively suppressed the expression of MYCN, a member of the MYC family of basic helix–loop–helix–zipper transcription factors, in HCC cell cultures, animal models, and liver biopsies obtained from HCC patients. MYCN expression in human HCC was correlated positively with both CSC and Wnt/β-catenin signaling markers but negatively with mature hepatocyte markers. Functional analysis showed repressed cell-cycle progression, proliferation, and colony formation, activated caspase-8, and induced cell death in HCC cells following silencing of MYCN expression. High-content single-cell imaging analysis and flow cytometric analysis identified a MYCN+ CSC subpopulation in the heterogeneous HCC cell cultures and showed that these cells were selectively killed by ACR. Particularly, EpCAM+ cells isolated using a cell-sorting system showed increased MYCN expression and sensitivity to ACR compared with EpCAM− cells. In a long-term (〉10 y) follow-up study of 102 patients with HCC, MYCN was expressed at higher levels in the HCC tumor region than in nontumor regions, and there was a positive correlation between MYCN expression and recurrence of de novo HCC but not metastatic HCC after curative treatment. In summary, these results suggest that MYCN serves as a prognostic biomarker and therapeutic target of ACR for liver CSCs in de novo HCC.
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  • 56
    Publication Date: 2018-07-11
    Description: What forces direct brain organization and its plasticity? When brain regions are deprived of their input, which regions reorganize based on compensation for the disability and experience, and which regions show topographically constrained plasticity? People born without hands activate their primary sensorimotor hand region while moving body parts used to compensate for this disability (e.g., their feet). This was taken to suggest a neural organization based on functions, such as performing manual-like dexterous actions, rather than on body parts, in primary sensorimotor cortex. We tested the selectivity for the compensatory body parts in the primary and association sensorimotor cortex of people born without hands (dysplasic individuals). Despite clear compensatory foot use, the primary sensorimotor hand area in the dysplasic subjects showed preference for adjacent body parts that are not compensatorily used as effectors. This suggests that function-based organization, proposed for congenital blindness and deafness, does not apply to the primary sensorimotor cortex deprivation in dysplasia. These findings stress the roles of neuroanatomical constraints like topographical proximity and connectivity in determining the functional development of primary cortex even in extreme, congenital deprivation. In contrast, increased and selective foot movement preference was found in dysplasics’ association cortex in the inferior parietal lobule. This suggests that the typical motor selectivity of this region for manual actions may correspond to high-level action representations that are effector-invariant. These findings reveal limitations to compensatory plasticity and experience in modifying brain organization of early topographical cortex compared with association cortices driven by function-based organization.
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  • 57
    Publication Date: 2018-07-05
    Description: Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1–12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4–NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4–NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4–NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable.
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  • 58
    Publication Date: 2018-03-19
    Description: Facial expressions of emotion in humans are believed to be produced by contracting one’s facial muscles, generally called action units. However, the surface of the face is also innervated with a large network of blood vessels. Blood flow variations in these vessels yield visible color changes on the face. Here, we study the hypothesis that these visible facial colors allow observers to successfully transmit and visually interpret emotion even in the absence of facial muscle activation. To study this hypothesis, we address the following two questions. Are observable facial colors consistent within and differential between emotion categories and positive vs. negative valence? And does the human visual system use these facial colors to decode emotion from faces? These questions suggest the existence of an important, unexplored mechanism of the production of facial expressions of emotion by a sender and their visual interpretation by an observer. The results of our studies provide evidence in favor of our hypothesis. We show that people successfully decode emotion using these color features, even in the absence of any facial muscle activation. We also demonstrate that this color signal is independent from that provided by facial muscle movements. These results support a revised model of the production and perception of facial expressions of emotion where facial color is an effective mechanism to visually transmit and decode emotion.
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  • 59
    Publication Date: 2018-11-05
    Description: Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis–regulating miR-183-96-182 cluster (fold change = 1.41–2.38; P = 0.029–0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention.
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  • 60
    Publication Date: 2018-07-02
    Description: Brain “inflammaging,” a low-grade and chronic inflammation, is a major hallmark for aging-related neurodegenerative diseases. Here, by profiling H3K27ac and gene expression patterns in human and mouse brains, we found that age-related up-regulated (Age-Up) and down-regulated (Age-Down) genes have distinct H3K27ac patterns. Although both groups show promoter H3K27ac, the Age-Up genes, enriched for inflammation-related functions, are additionally marked by broad H3K27ac distribution over their gene bodies, which is progressively reduced during aging. Age-related gene expression changes can be predicted by gene-body H3K27ac level. Contrary to the presumed transcription activation function of promoter H3K27ac, we found that broad gene-body hyper H3K27ac suppresses overexpression of inflammaging genes. Altogether, our findings revealed opposite regulations by H3K27ac of Age-Up and Age-Down genes and a mode of broad gene-body H3K27ac in repressing transcription.
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  • 61
    Publication Date: 2018-02-06
    Description: Although the motility of the flagellated bacteria,Escherichia coli, has been widely studied, the effect of viscosity on swimming speed remains controversial. The swimming mode of wild-typeE. coliis often idealized as a run-and-tumble sequence in which periods of swimming at a constant speed are randomly interrupted by a sudden change of direction at a very low speed. Using a tracking microscope, we follow cells for extended periods of time in Newtonian liquids of varying viscosity and find that the swimming behavior of a single cell can exhibit a variety of behaviors, including run and tumble and “slow random walk” in which the cells move at a relatively low speed. Although the characteristic swimming speed varies between individuals and in different polymer solutions, we find that the skewness of the speed distribution is solely a function of viscosity and can be used, in concert with the measured average swimming speed, to determine the effective running speed of each cell. We hypothesize that differences in the swimming behavior observed in solutions of different viscosity are due to changes in the flagellar bundling time, which increases as the viscosity rises, due to the lower rotation rate of the flagellar motor. A numerical simulation and the use of resistive force theory provide support for this hypothesis.
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  • 62
    Publication Date: 2018-03-05
    Description: Eukaryotic gene regulation is a complex process, often coordinated by the action of tens to hundreds of proteins. Although previous biochemical studies have identified many components of the basal machinery and various ancillary factors involved in gene regulation, numerous gene-specific regulators remain undiscovered. To comprehensively survey the proteome directing gene expression at a specific genomic locus of interest, we developed an in vitro nuclease-deficient Cas9 (dCas9)-targeted chromatin-based purification strategy, called “CLASP” (Cas9 locus-associated proteome), to identify and functionally test associated gene-regulatory factors. Our CLASP method, coupled to mass spectrometry and functional screens, can be efficiently adapted for isolating associated regulatory factors in an unbiased manner targeting multiple genomic loci across different cell types. Here, we applied our method to isolate the Drosophila melanogaster histone cluster in S2 cells to identify several factors including Vig and Vig2, two proteins that bind and regulate core histone H2A and H3 mRNA via interaction with their 3′ UTRs.
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  • 63
    Publication Date: 2018-07-02
    Description: The ability to control the activity of CRISPR-dCas9 with precise spatiotemporal resolution will enable tight genome regulation of user-defined endogenous genes for studying the dynamics of transcriptional regulation. Optogenetic devices with minimal phototoxicity and the capacity for deep tissue penetration are extremely useful for precise spatiotemporal control of cellular behavior and for future clinic translational research. Therefore, capitalizing on synthetic biology and optogenetic design principles, we engineered a far-red light (FRL)-activated CRISPR-dCas9 effector (FACE) device that induces transcription of exogenous or endogenous genes in the presence of FRL stimulation. This versatile system provides a robust and convenient method for precise spatiotemporal control of endogenous gene expression and also has been demonstrated to mediate targeted epigenetic modulation, which can be utilized to efficiently promote differentiation of induced pluripotent stem cells into functional neurons by up-regulating a single neural transcription factor, NEUROG2. This FACE system might facilitate genetic/epigenetic reprogramming in basic biological research and regenerative medicine for future biomedical applications.
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  • 64
    Publication Date: 2018-11-14
    Description: That fire facilitated the late Miocene C4 grassland expansion is widely suspected but poorly documented. Fire potentially tied global climate to this profound biosphere transition by serving as a regional-to-local driver of vegetation change. In modern environments, seasonal extremes in moisture amplify the occurrence of fire, disturbing forest ecosystems to create niche space for flammable grasses, which in turn provide fuel for frequent fires. On the Indian subcontinent, C4 expansion was accompanied by increased seasonal extremes in rainfall (evidenced by δ18Ocarbonate), which set the stage for fuel accumulation and fire-linked clearance during wet-to-dry seasonal transitions. Here, we test the role of fire directly by examining the abundance and distribution patterns of fire-derived polycyclic aromatic hydrocarbons (PAHs) and terrestrial vegetation signatures in n-alkane carbon isotopes from paleosol samples of the Siwalik Group (Pakistan). Two million years before the C4 grassland transition, fire-derived PAH concentrations increased as conifer vegetation declined, as indicated by a decrease in retene. This early increase in molecular fire signatures suggests a transition to more fire-prone vegetation such as a C3 grassland and/or dry deciduous woodland. Between 8.0 and 6.0 million years ago, fire, precipitation seasonality, and C4-grass dominance increased simultaneously (within resolution) as marked by sharp increases in fire-derived PAHs, δ18Ocarbonate, and 13C enrichment in n-alkanes diagnostic of C4 grasses. The strong association of evidence for fire occurrence, vegetation change, and landscape opening indicates that a dynamic fire–grassland feedback system was both a necessary precondition and a driver for grassland ecology during the first emergence of C4 grasslands.
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  • 65
    Publication Date: 2018-06-18
    Description: To quantitatively evaluate brain tissue and its corresponding function, knowledge of the 3D cellular distribution is essential. The gold standard to obtain this information is histology, a destructive and labor-intensive technique where the specimen is sliced and examined under a light microscope, providing 3D information at nonisotropic resolution. To overcome the limitations of conventional histology, we use phase-contrast X-ray tomography with optimized optics, reconstruction, and image analysis, both at a dedicated synchrotron radiation endstation, which we have equipped with X-ray waveguide optics for coherence and wavefront filtering, and at a compact laboratory source. As a proof-of-concept demonstration we probe the 3D cytoarchitecture in millimeter-sized punches of unstained human cerebellum embedded in paraffin and show that isotropic subcellular resolution can be reached at both setups throughout the specimen. To enable a quantitative analysis of the reconstructed data, we demonstrate automatic cell segmentation and localization of over 1 million neurons within the cerebellar cortex. This allows for the analysis of the spatial organization and correlation of cells in all dimensions by borrowing concepts from condensed-matter physics, indicating a strong short-range order and local clustering of the cells in the granular layer. By quantification of 3D neuronal “packing,” we can hence shed light on how the human cerebellum accommodates 80% of the total neurons in the brain in only 10% of its volume. In addition, we show that the distribution of neighboring neurons in the granular layer is anisotropic with respect to the Purkinje cell dendrites.
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  • 66
    Publication Date: 2018-09-04
    Description: The animal kingdom exhibits a great diversity of organismal form (i.e., disparity). Whether the extremes of disparity were achieved early in animal evolutionary history or clades continually explore the limits of possible morphospace is subject to continuing debate. Here we show, through analysis of the disparity of the animal kingdom, that, even though many clades exhibit maximal initial disparity, arthropods, chordates, annelids, echinoderms, and mollusks have continued to explore and expand the limits of morphospace throughout the Phanerozoic, expanding dramatically the envelope of disparity occupied in the Cambrian. The “clumpiness” of morphospace occupation by living clades is a consequence of the extinction of phylogenetic intermediates, indicating that the original distribution of morphologies was more homogeneous. The morphological distances between phyla mirror differences in complexity, body size, and species-level diversity across the animal kingdom. Causal hypotheses of morphologic expansion include time since origination, increases in genome size, protein repertoire, gene family expansion, and gene regulation. We find a strong correlation between increasing morphological disparity, genome size, and microRNA repertoire, but no correlation to protein domain diversity. Our results are compatible with the view that the evolution of gene regulation has been influential in shaping metazoan disparity whereas the invasion of terrestrial ecospace appears to represent an additional gestalt, underpinning the post-Cambrian expansion of metazoan disparity.
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  • 67
    Publication Date: 2018-06-05
    Description: In plants, plasma membrane-embedded CELLULOSE SYNTHASE (CESA) enzyme complexes deposit cellulose polymers into the developing cell wall. Cellulose synthesis requires two different sets of CESA complexes that are active during cell expansion and secondary cell wall thickening, respectively. Hence, developing xylem cells, which first undergo cell expansion and subsequently deposit thick secondary walls, need to completely reorganize their CESA complexes from primary wall- to secondary wall-specific CESAs. Using live-cell imaging, we analyzed the principles underlying this remodeling. At the onset of secondary wall synthesis, the primary wall CESAs ceased to be delivered to the plasma membrane and were gradually removed from both the plasma membrane and the Golgi. For a brief transition period, both primary wall- and secondary wall-specific CESAs coexisted in banded domains of the plasma membrane where secondary wall synthesis is concentrated. During this transition, primary and secondary wall CESAs displayed discrete dynamic behaviors and sensitivities to the inhibitor isoxaben. As secondary wall-specific CESAs were delivered and inserted into the plasma membrane, the primary wall CESAs became concentrated in prevacuolar compartments and lytic vacuoles. This adjustment in localization between the two CESAs was accompanied by concurrent decreased primary wall CESA and increased secondary wall CESA protein abundance. Our data reveal distinct and dynamic subcellular trafficking patterns that underpin the remodeling of the cellulose biosynthetic machinery, resulting in the removal and degradation of the primary wall CESA complex with concurrent production and recycling of the secondary wall CESAs.
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  • 68
    Publication Date: 2018-04-13
    Description: The discovery that endoplasmic reticulum (ER) luminal chaperones such as GRP78/BiP can escape to the cell surface upon ER stress where they regulate cell signaling, proliferation, apoptosis, and immunity represents a paradigm shift. Toward deciphering the mechanisms, we report here that, upon ER stress, IRE1α binds to and triggers tyrosine kinase SRC activation, leading to ASAP1 phosphorylation and Golgi accumulation of ASAP1 and Arf1-GTP, resulting in KDEL receptor dispersion from the Golgi and suppression of retrograde transport. At the cell surface, GRP78 binds to and acts in concert with a glycosylphosphatidylinositol-anchored protein, CD109, in blocking TGF-β signaling by promoting the routing of the TGF-β receptor to the caveolae, thereby disrupting its binding to and activation of Smad2. Collectively, we uncover a SRC-mediated signaling cascade that leads to the relocalization of ER chaperones to the cell surface and a mechanism whereby GRP78 counteracts the tumor-suppressor effect of TGF-β.
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  • 69
    Publication Date: 2018-03-05
    Description: Treatment of bacterial infections is becoming a serious clinical challenge due to the global dissemination of multidrug antibiotic resistance, necessitating the search for alternative treatments to disarm the virulence mechanisms underlying these infections. Uropathogenic Escherichia coli (UPEC) employs multiple chaperone–usher pathway pili tipped with adhesins with diverse receptor specificities to colonize various host tissues and habitats. For example, UPEC F9 pili specifically bind galactose or N-acetylgalactosamine epitopes on the kidney and inflamed bladder. Using X-ray structure-guided methods, virtual screening, and multiplex ELISA arrays, we rationally designed aryl galactosides and N-acetylgalactosaminosides that inhibit the F9 pilus adhesin FmlH. The lead compound, 29β-NAc, is a biphenyl N-acetyl-β-galactosaminoside with a Ki of ∼90 nM, representing a major advancement in potency relative to the characteristically weak nature of most carbohydrate–lectin interactions. 29β-NAc binds tightly to FmlH by engaging the residues Y46 through edge-to-face π-stacking with its A-phenyl ring, R142 in a salt-bridge interaction with its carboxylate group, and K132 through water-mediated hydrogen bonding with its N-acetyl group. Administration of 29β-NAc in a mouse urinary tract infection (UTI) model significantly reduced bladder and kidney bacterial burdens, and coadministration of 29β-NAc and mannoside 4Z269, which targets the type 1 pilus adhesin FimH, resulted in greater elimination of bacteria from the urinary tract than either compound alone. Moreover, FmlH specifically binds healthy human kidney tissue in a 29β-NAc–inhibitable manner, suggesting a key role for F9 pili in human kidney colonization. Thus, these glycoside antagonists of FmlH represent a rational antivirulence strategy for UPEC-mediated UTI treatment.
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  • 70
    Publication Date: 2018-05-14
    Description: The bright ultrafast pulses of X-ray Free-Electron Lasers allow investigation into the structure of matter under extreme conditions. We have used single pulses to ionize and probe water as it undergoes a phase transition from liquid to plasma. We report changes in the structure of liquid water on a femtosecond time scale when irradiated by single 6.86 keV X-ray pulses of more than 106 J/cm2. These observations are supported by simulations based on molecular dynamics and plasma dynamics of a water system that is rapidly ionized and driven out of equilibrium. This exotic ionic and disordered state with the density of a liquid is suggested to be structurally different from a neutral thermally disordered state.
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  • 71
    Publication Date: 2018-12-17
    Description: The E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) acts as a molecular rheostat for the immune deficiency (IMD) pathway of the tick Ixodes scapularis. How XIAP activates the IMD pathway in response to microbial infection remains ill defined. Here, we identified the XIAP enzymatic substrate p47 as a positive regulator of the I. scapularis IMD network. XIAP polyubiquitylates p47 in a lysine 63-dependent manner and interacts with the p47 ubiquitin-like (UBX) module. p47 also binds to Kenny (IKKγ/NEMO), the regulatory subunit of the inhibitor of nuclear factor (NF)- κB kinase complex. Replacement of the amino acid lysine to arginine within the p47 linker region completely abrogated molecular interactions with Kenny. Furthermore, mitigation of p47 transcription levels through RNA interference in I. scapularis limited Kenny accumulation, reduced phosphorylation of IKKβ (IRD5), and impaired cleavage of the NF-κB molecule Relish. Accordingly, disruption of p47 expression increased microbial colonization by the Lyme disease spirochete Borrelia burgdorferi and the rickettsial agent Anaplasma phagocytophilum. Collectively, we highlight the importance of ticks for the elucidation of paradigms in arthropod immunology. Manipulating immune signaling cascades within I. scapularis may lead to innovative approaches to reducing the burden of tick-borne diseases.
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  • 72
    Publication Date: 2018-04-04
    Description: Current strategies used to quantitatively describe the biological diversity of lipids by mass spectrometry are often limited in assessing the exact structural variability of individual molecular species in detail. A major challenge is represented by the extensive isobaric overlap present among lipids, hampering their accurate identification. This is especially true for cardiolipins, a mitochondria-specific class of phospholipids, which are functionally involved in many cellular functions, including energy metabolism, cristae structure, and apoptosis. Substituted with four fatty acyl side chains, cardiolipins offer a particularly high potential to achieve complex mixtures of molecular species. Here, we demonstrate how systematically generated high-performance liquid chromatography-mass spectral data can be utilized in a mathematical structural modeling approach, to comprehensively analyze and characterize the molecular diversity of mitochondrial cardiolipin compositions in cell culture and disease models, cardiolipin modulation experiments, and a broad variety of frequently studied model organisms.
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  • 73
    Publication Date: 2018-01-08
    Description: The Born–Oppenheimer approximation (BOA) provides the foundation for virtually all computational studies of chemical binding and reactivity, and it is the justification for the widely used “balls and springs” picture of molecules. The BOA assumes that nuclei effectively stand still on the timescale of electronic motion, due to their large masses relative to electrons. This implies electrons never change their energy quantum state. When molecules react, atoms must move, meaning that electrons may become excited in violation of the BOA. Such electronic excitation is clearly seen for: (i) Schottky diodes where H adsorption at Ag surfaces produces electrical “chemicurrent;” (ii) Au-based metal–insulator–metal (MIM) devices, where chemicurrents arise from H–H surface recombination; and (iii) Inelastic energy transfer, where H collisions with Au surfaces show H-atom translation excites the metal’s electrons. As part of this work, we report isotopically selective hydrogen/deuterium (H/D) translational inelasticity measurements in collisions with Ag and Au. Together, these experiments provide an opportunity to test new theories that simultaneously describe both nuclear and electronic motion, a standing challenge to the field. Here, we show results of a recently developed first-principles theory that quantitatively explains both inelastic scattering experiments that probe nuclear motion and chemicurrent experiments that probe electronic excitation. The theory explains the magnitude of chemicurrents on Ag Schottky diodes and resolves an apparent paradox––chemicurrents exhibit a much larger isotope effect than does H/D inelastic scattering. It also explains why, unlike Ag-based Schottky diodes, Au-based MIM devices are insensitive to H adsorption.
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  • 74
    Publication Date: 2018-02-27
    Description: Abasic sites are among the most abundant DNA lesions and interfere with DNA replication and transcription, but the mechanism of their action on transcription remains unknown. Here we applied a combined structural and biochemical approach for a comprehensive investigation of how RNA polymerase II (Pol II) processes an abasic site, leading to slow bypass of lesion. Encounter of Pol II with an abasic site involves two consecutive slow steps: insertion of adenine opposite a noninstructive abasic site (the A-rule), followed by extension of the 3′-rAMP with the next cognate nucleotide. Further studies provided structural insights into the A-rule: ATP is slowly incorporated into RNA in the absence of template guidance. Our structure revealed that ATP is bound to the Pol II active site, whereas the abasic site is located at an intermediate state above the Bridge Helix, a conserved structural motif that is cirtical for Pol II activity. The next extension step occurs in a template-dependent manner where a cognate substrate is incorporated, despite at a much slower rate compared with nondamaged template. During the extension step, neither the cognate substrate nor the template base is located at the canonical position, providing a structural explanation as to why this step is as slow as the insertion step. Taken together, our studies provide a comprehensive understanding of Pol II stalling and bypass of the abasic site in the DNA template.
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  • 75
    Publication Date: 2018-10-19
    Description: An immense repertoire of protein chemical modifications catalyzed by enzymes is available as proteomics data. Quantifying the impact of the conformational dynamics of the modified peptide remains challenging to understand the decisive kinetics and amino acid sequence specificity of these enzymatic reactions in vivo, because the target peptide must be disordered to accommodate the specific enzyme-binding site. Here, we were able to control the conformation of a single-molecule peptide chain by applying mechanical force to activate and monitor its specific cleavage by a model protease. We found that the conformational entropy impacts the reaction in two distinct ways. First, the flexibility and accessibility of the substrate peptide greatly increase upon mechanical unfolding. Second, the conformational sampling of the disordered peptide drives the specific recognition, revealing force-dependent reaction kinetics. These results support a mechanism of peptide recognition based on conformational selection from an ensemble that we were able to quantify with a torsional free-energy model. Our approach can be used to predict how entropy affects site-specific modifications of proteins and prompts conformational and mechanical selectivity.
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  • 76
    Publication Date: 2018-12-03
    Description: To meet their purine demand, cells activate the de novo purine biosynthetic pathway and transiently cluster the pathway enzymes into metabolons called purinosomes. Recently, we have shown that purinosomes were spatially colocalized with mitochondria and microtubules, yet it remained unclear as to what drives these associations and whether a relationship between them exist. Here, we employed superresolution imaging methods to describe purinosome transit in the context of subcellular localization. Time-resolved imaging of purinosomes showed that these assemblies exhibit directed motion as they move along a microtubule toward mitochondria, where upon colocalization, a change in purinosome motion was observed. A majority of purinosomes colocalized with mitochondria were also deemed colocalized with microtubules. Nocodazole-dependent microtubule depolymerization resulted in a loss in the purinosome–mitochondria colocalization, suggesting that the association of purinosomes with mitochondria is facilitated by microtubule-directed transport, and thereby supporting our notion of an interdependency between these subcellular components in maximizing purine production through the de novo purine biosynthetic pathway.
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  • 77
    Publication Date: 2018-10-09
    Description: Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the cellular and molecular regulation of intestinal epithelial homeostasis remains largely undefined. Here, we show that the C-type lectin receptor LSECtin (Clec4g) on macrophages is required for protection against dextran sulfate sodium-induced colitis. Mechanistically, LSECtin promotes apoptotic cell clearance by macrophages and induces the production of antiinflammatory/tissue repair factors in an engulfment-dependent manner, which in turn stimulates epithelial cell proliferation. Deletion of LSECtin results in defective engulfment by colon macrophages, leading to aberrant proresolving factor production and impaired intestinal epithelium repair. Collectively, our findings suggest that LSECtin-dependent corpse clearance by macrophages can direct intestinal regeneration and maintenance of the mucosal barrier after injury.
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  • 78
    Publication Date: 2018-03-26
    Description: Regeneration of skeletal muscle in response to injury occurs through fusion of a population of stem cells, known as satellite cells, with injured myofibers. Myomixer, a muscle-specific membrane micropeptide, cooperates with the transmembrane protein Myomaker to regulate embryonic myoblast fusion and muscle formation. To investigate the role of Myomixer in muscle regeneration, we used CRISPR/Cas9-mediated genome editing to generate conditional knockout Myomixer alleles in mice. We show that genetic deletion of Myomixer in satellite cells using a tamoxifen-regulated Cre recombinase transgene under control of the Pax7 promoter abolishes satellite cell fusion and prevents muscle regeneration, resulting in severe muscle degeneration after injury. Satellite cells devoid of Myomixer maintain expression of Myomaker, demonstrating that Myomaker alone is insufficient to drive myoblast fusion. These findings, together with prior studies demonstrating the essentiality of Myomaker for muscle regeneration, highlight the obligatory partnership of Myomixer and Myomaker for myofiber formation throughout embryogenesis and adulthood.
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  • 79
    Publication Date: 2018-04-30
    Description: The efficacy of influenza vaccines varies from one year to the next, with efficacy during the 2017–2018 season anticipated to be lower than usual. However, the impact of low-efficacy vaccines at the population level and their optimal age-specific distribution have yet to be ascertained. Applying an optimization algorithm to a mathematical model of influenza transmission and vaccination in the United States, we determined the optimal age-specific uptake of low-efficacy vaccine that would minimize incidence, hospitalization, mortality, and disability-adjusted life-years (DALYs), respectively. We found that even relatively low-efficacy influenza vaccines can be highly impactful, particularly when vaccine uptake is optimally distributed across age groups. As vaccine efficacy declines, the optimal distribution of vaccine uptake shifts toward the elderly to minimize mortality and DALYs. Health practitioner encouragement and concerted recruitment efforts are required to achieve optimal coverage among target age groups, thereby minimizing influenza morbidity and mortality for the population overall.
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  • 80
    Publication Date: 2018-12-17
    Description: We discuss the need to make economic evaluations of vaccines antimicrobial resistance (AMR)-sensitive and ways to do so. Such AMR-sensitive evaluations can play a role in value-for-money comparisons of different vaccines within a national immunization program, or in comparisons of vaccine-centric and non-vaccine-centric technologies within an anti-AMR program. In general terms, incremental cost-effectiveness ratios and rates of return and their associated decision rules are unaltered by consideration of AMR-related value. The decision metrics need to have their various health, cost, and socioeconomic terms disaggregated into resistance-related subcategories, which in turn have to be measured carefully before they are reaggregated. The fundamental scientific challenges lie primarily in quantifying the causal impact of health technologies on resistance-related health outcomes, and secondarily in ascertaining the economic value of those outcomes. We emphasize the importance of evaluating vaccines in the context of other potentially complementary and substitutable nonvaccine technologies. Complementarity implies that optimal spending on each set of interventions is positive, and substitutability implies that the ratio of spending will depend on relative value for money. We exemplify this general point through a qualitative discussion of the complementarities and (especially the) substitutability between pneumococcal conjugate vaccines and antimicrobial stewardship and between research and development (R&D) of a gonorrhea vaccine versus R&D of a gonorrhea antibiotic. We propose a roadmap for future work, which includes quantifying the causal effects of vaccination and other health technologies on short-term and long-term resistance-related outcomes, measuring the health-sector costs and broader socioeconomic consequences of resistance-related mortality and morbidity, and evaluating vaccines in the context of nonvaccine complements and substitutes.
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  • 81
    Publication Date: 2018-01-30
    Description: Microglia, the brain’s innate immune cells, have highly motile processes which constantly survey the brain to detect infection, remove dying cells, and prune synapses during brain development. ATP released by tissue damage is known to attract microglial processes, but it is controversial whether an ambient level of ATP is needed to promote constant microglial surveillance in the normal brain. Applying the ATPase apyrase, an enzyme which hydrolyzes ATP and ADP, reduces microglial process ramification and surveillance, suggesting that ambient ATP/ADP maintains microglial surveillance. However, attempting to raise the level of ATP/ADP by blocking the endogenous ecto-ATPase (termed NTPDase1/CD39), which also hydrolyzes ATP/ADP, does not affect the cells’ ramification or surveillance, nor their membrane currents, which respond to even small rises of extracellular [ATP] or [ADP] with the activation of K+ channels. This indicates a lack of detectable ambient ATP/ADP and ecto-ATPase activity, contradicting the results with apyrase. We resolve this contradiction by demonstrating that contamination of commercially available apyrase by a high K+ concentration reduces ramification and surveillance by depolarizing microglia. Exposure to the same K+ concentration (without apyrase added) reduced ramification and surveillance as with apyrase. Dialysis of apyrase to remove K+ retained its ATP-hydrolyzing activity but abolished the microglial depolarization and decrease of ramification produced by the undialyzed enzyme. Thus, applying apyrase affects microglia by an action independent of ATP, and no ambient purinergic signaling is required to maintain microglial ramification and surveillance. These results also have implications for hundreds of prior studies that employed apyrase to hydrolyze ATP/ADP.
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  • 82
    Publication Date: 2018-04-23
    Description: Neurotransmitter switching in the adult mammalian brain occurs following photoperiod-induced stress, but the mechanism of regulation is unknown. Here, we demonstrate that elevated activity of dopaminergic neurons in the paraventricular nucleus of the hypothalamus (PaVN) in the adult rat is required for the loss of dopamine expression after long-day photoperiod exposure. The transmitter switch occurs exclusively in PaVN dopaminergic neurons that coexpress vesicular glutamate transporter 2 (VGLUT2), is accompanied by a loss of dopamine type 2 receptors (D2Rs) on corticotrophin-releasing factor (CRF) neurons, and can lead to increased release of CRF. Suppressing activity of all PaVN glutamatergic neurons decreases the number of inhibitory PaVN dopaminergic neurons, indicating homeostatic regulation of transmitter expression in the PaVN.
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  • 83
    Publication Date: 2018-04-02
    Description: Memory formation is believed to result from changes in synapse strength and structure. While memories may persist for the lifetime of an organism, the proteins and lipids that make up synapses undergo constant turnover with lifetimes from minutes to days. The molecular basis for memory maintenance may rely on a subset of long-lived proteins (LLPs). While it is known that LLPs exist, whether such proteins are present at synapses is unknown. We performed an unbiased screen using metabolic pulse-chase labeling in vivo in mice and in vitro in cultured neurons combined with quantitative proteomics. We identified synaptic LLPs with half-lives of several months or longer. Proteins in synaptic fractions generally exhibited longer lifetimes than proteins in cytosolic fractions. Protein turnover was sensitive to pharmacological manipulations of activity in neuronal cultures or in mice exposed to an enriched environment. We show that synapses contain LLPs that may underlie stabile long-lasting changes in synaptic structure and function.
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  • 84
    Publication Date: 2018-12-03
    Description: Synaptic inhibition controls a neuron’s output via functionally distinct inputs at two subcellular compartments, the cell body and the dendrites. It is unclear whether the assembly of these distinct inhibitory inputs can be regulated independently by neurotransmission. In the mammalian retina, γ-aminobutyric acid (GABA) release from starburst amacrine cells (SACs) onto the dendrites of on–off direction-selective ganglion cells (ooDSGCs) is essential for directionally selective responses. We found that ooDSGCs also receive GABAergic input on their somata from other amacrine cells (ACs), including ACs containing the vasoactive intestinal peptide (VIP). When net GABAergic transmission is reduced, somatic, but not dendritic, GABAA receptor clusters on the ooDSGC increased in number and size. Correlative fluorescence imaging and serial electron microscopy revealed that these enlarged somatic receptor clusters are localized to synapses. By contrast, selectively blocking vesicular GABA release from either SACs or VIP ACs did not alter dendritic or somatic receptor distributions on the ooDSGCs, showing that neither SAC nor VIP AC GABA release alone is required for the development of inhibitory synapses in ooDSGCs. Furthermore, a reduction in net GABAergic transmission, but not a selective reduction from SACs, increased excitatory drive onto ooDSGCs. This increased excitation may drive a homeostatic increase in ooDSGC somatic GABAA receptors. Differential regulation of GABAA receptors on the ooDSGC’s soma and dendrites could facilitate homeostatic control of the ooDSGC’s output while enabling the assembly of the GABAergic connectivity underlying direction selectivity to be indifferent to altered transmission.
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  • 85
    Publication Date: 2018-04-30
    Description: Adult newborn hippocampal granule cells (abGCs) contribute to spatial learning and memory. abGCs are thought to play a specific role in pattern separation, distinct from developmentally born mature GCs (mGCs). Here we examine at which exact cell age abGCs are synaptically integrated into the adult network and which forms of synaptic plasticity are expressed in abGCs and mGCs. We used virus-mediated labeling of abGCs and mGCs to analyze changes in spine morphology as an indicator of plasticity in rats in vivo. High-frequency stimulation of the medial perforant path induced long-term potentiation in the middle molecular layer (MML) and long-term depression in the nonstimulated outer molecular layer (OML). This stimulation protocol elicited NMDA receptor-dependent homosynaptic spine enlargement in the MML and heterosynaptic spine shrinkage in the inner molecular layer and OML. Both processes were concurrently present on individual dendritic trees of abGCs and mGCs. Spine shrinkage counteracted spine enlargement and thus could play a homeostatic role, normalizing synaptic weights. Structural homosynaptic spine plasticity had a clear onset, appearing in abGCs by 28 d postinjection (dpi), followed by heterosynaptic spine plasticity at 35 dpi, and at 77 dpi was equally as present in mature abGCs as in mGCs. From 35 dpi on, about 60% of abGCs and mGCs showed significant homo- and heterosynaptic plasticity on the single-cell level. This demonstration of structural homo- and heterosynaptic plasticity in abGCs and mGCs defines the time course of the appearance of synaptic plasticity and integration for abGCs.
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  • 86
    Publication Date: 2018-11-19
    Description: Fruit growth and ripening are controlled by multiple phytohormones. How these hormones coordinate and interact with each other to control these processes at the molecular level is unclear. We found in the early stages of Fragaria vesca (woodland strawberry) fruit development, auxin increases both widths and lengths of fruits, while gibberellin [gibberellic acid (GA)] mainly promotes their longitudinal elongation. Auxin promoted GA biosynthesis and signaling by activating GA biosynthetic and signaling genes, suggesting auxin function is partially dependent on GA function. To prevent the repressive effect of abscisic acid (ABA) on fruit growth, auxin and GA suppressed ABA accumulation during early fruit development by activating the expression of FveCYP707A4a encoding cytochrome P450 monooxygenase that catalyzes ABA catabolism. At the onset of fruit ripening, both auxin and GA levels decreased, leading to a steep increase in the endogenous level of ABA that drives fruit ripening. ABA repressed the expression of FveCYP707A4a but promoted that of FveNCED, a rate-limiting step in ABA biosynthesis. Accordingly, altering FveCYP707A4a expression changed the endogenous ABA levels and affected FveNCED expression. Hence, ABA catabolism and biosynthesis are tightly linked by feedback and feedforward loops to limit ABA contents for fruit growth and to quickly increase ABA contents for the onset of fruit ripening. These results indicate that FveCYP707A4a not only regulates ABA accumulation but also provides a hub to coordinate fruit size and ripening times by relaying auxin, GA, and ABA signals.
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  • 87
    Publication Date: 2018-05-14
    Description: Periodic fluctuations in past biodiversity, speciation, and extinction have been proposed, with extremely long periods ranging from 26 to 62 million years, although forcing mechanisms remain speculative. In contrast, well-understood periodic Milankovitch climate forcing represents a viable driver for macroevolutionary fluctuations, although little evidence for such fluctuation exists except during the Late Cenozoic. The reality, magnitude, and drivers of periodic fluctuations in macroevolutionary rates are of interest given long-standing debate surrounding the relative roles of intrinsic biotic interactions vs. extrinsic environmental factors as drivers of biodiversity change. Here, we show that, over a time span of 60 million years, between 9 and 16% of the variance in biological turnover (i.e., speciation probability plus species extinction probability) in a major Early Paleozoic zooplankton group, the graptoloids, can be explained by long-period astronomical cycles (Milankovitch “grand cycles”) associated with Earth’s orbital eccentricity (2.6 million years) and obliquity (1.3 million years). These grand cycles modulate climate variability, alternating times of relative stability in the environment with times of maximum volatility. We infer that these cycles influenced graptolite speciation and extinction through climate-driven changes to oceanic circulation and structure. Our results confirm the existence of Milankovitch grand cycles in the Early Paleozoic Era and show that known processes related to the mechanics of the Solar System were shaping marine macroevolutionary rates comparatively early in the history of complex life. We present an application of hidden Markov models to macroevolutionary time series and protocols for the evaluation of statistical significance in spectral analysis.
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  • 88
    Publication Date: 2018-07-16
    Description: Subunits in multimeric ring-shaped motors must coordinate their activities to ensure correct and efficient performance of their mechanical tasks. Here, we study WT and arginine finger mutants of the pentameric bacteriophage φ29 DNA packaging motor. Our results reveal the molecular interactions necessary for the coordination of ADP–ATP exchange and ATP hydrolysis of the motor’s biphasic mechanochemical cycle. We show that two distinct regulatory mechanisms determine this coordination. In the first mechanism, the DNA up-regulates a single subunit’s catalytic activity, transforming it into a global regulator that initiates the nucleotide exchange phase and the hydrolysis phase. In the second, an arginine finger in each subunit promotes ADP–ATP exchange and ATP hydrolysis of its neighbor. Accordingly, we suggest that the subunits perform the roles described for GDP exchange factors and GTPase-activating proteins observed in small GTPases. We propose that these mechanisms are fundamental to intersubunit coordination and are likely present in other ring ATPases.
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  • 89
  • 90
    Publication Date: 2018-03-05
    Description: Membrane proteins interact with a myriad of lipid species in the biological membrane, leading to a bewildering number of possible protein−lipid assemblies. Despite this inherent complexity, the identification of specific protein−lipid interactions and the crucial role of lipids in the folding, structure, and function of membrane proteins is emerging from an increasing number of reports. Fundamental questions remain, however, regarding the ability of specific lipid binding events to membrane proteins to alter remote binding sites for lipids of a different type, a property referred to as allostery [Monod J, Wyman J, Changeux JP (1965)J Mol Biol12:88–118]. Here, we use native mass spectrometry to determine the allosteric nature of heterogeneous lipid binding events to membrane proteins. We monitored individual lipid binding events to the ammonia channel (AmtB) fromEscherichia coli, enabling determination of their equilibrium binding constants. We found that different lipid pairs display a range of allosteric modulation. In particular, the binding of phosphatidylethanolamine and cardiolipin-like molecules to AmtB exhibited the largest degree of allosteric modulation, inspiring us to determine the cocrystal structure of AmtB in this lipid environment. The 2.45-Å resolution structure reveals a cardiolipin-like molecule bound to each subunit of the trimeric complex. Mutation of a single residue in AmtB abolishes the positive allosteric modulation observed for binding phosphatidylethanolamine and cardiolipin-like molecules. Our results demonstrate that specific lipid−protein interactions can act as allosteric modulators for the binding of different lipid types to integral membrane proteins.
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  • 91
    Publication Date: 2018-08-01
    Description: Nucleation is a core scientific concept that describes the formation of new phases and materials. While classical nucleation theory is applied across wide-ranging fields, nucleation energy landscapes have never been directly measured at the atomic level, and experiments suggest that nucleation rates often greatly exceed the predictions of classical nucleation theory. Multistep nucleation via metastable states could explain unexpectedly rapid nucleation in many contexts, yet experimental energy landscapes supporting such mechanisms are scarce, particularly at nanoscale dimensions. In this work, we measured the nucleation energy landscape of diamond during chemical vapor deposition, using a series of diamondoid molecules as atomically defined protonuclei. We find that 26-carbon atom clusters, which do not contain a single bulk atom, are postcritical nuclei and measure the nucleation barrier to be more than four orders of magnitude smaller than prior bulk estimations. These data support both classical and nonclassical concepts for multistep nucleation and growth during the gas-phase synthesis of diamond and other semiconductors. More broadly, these measurements provide experimental evidence that agrees with recent conceptual proposals of multistep nucleation pathways with metastable molecular precursors in diverse processes, ranging from cloud formation to protein crystallization, and nanoparticle synthesis.
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  • 92
    Publication Date: 2018-06-18
    Description: Many mammalian genes are transcribed during short bursts of variable frequencies and sizes that substantially contribute to cell-to-cell variability. However, which molecular mechanisms determine bursting properties remains unclear. To probe putative mechanisms, we combined temporal analysis of transcription along the circadian cycle with multiple genomic reporter integrations, using both short-lived luciferase live microscopy and single-molecule RNA-FISH. Using the Bmal1 circadian promoter as our model, we observed that rhythmic transcription resulted predominantly from variations in burst frequency, while the genomic position changed the burst size. Thus, burst frequency and size independently modulated Bmal1 transcription. We then found that promoter histone-acetylation level covaried with burst frequency, being greatest at peak expression and lowest at trough expression, while remaining unaffected by the genomic location. In addition, specific deletions of ROR-responsive elements led to constitutively elevated histone acetylation and burst frequency. We then investigated the suggested link between histone acetylation and burst frequency by dCas9p300-targeted modulation of histone acetylation, revealing that acetylation levels influence burst frequency more than burst size. The correlation between acetylation levels at the promoter and burst frequency was also observed in endogenous circadian genes and in embryonic stem cell fate genes. Thus, our data suggest that histone acetylation-mediated control of transcription burst frequency is a common mechanism to control mammalian gene expression.
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  • 93
    Publication Date: 2018-07-02
    Description: Cell division requires the assembly of a protein complex called the divisome. The divisome assembles in a hierarchical manner, with FtsA functioning as a hub to connect the Z-ring with the rest of the divisome and FtsN arriving last to activate the machine to synthesize peptidoglycan. FtsEX arrives as the Z-ring forms and acts on FtsA to initiate recruitment of the other divisome components. In the absence of FtsEX, recruitment is blocked; however, a multitude of conditions allow FtsEX to be bypassed. Here, we find that all such FtsEX bypass conditions, as well as the bypass of FtsK, depend upon the interaction of FtsN with FtsA, which promotes the back-recruitment of the late components of the divisome. Furthermore, our results suggest that these bypass conditions enhance the weak interaction of FtsN with FtsA and its periplasmic partners so that the divisome proteins are brought to the Z-ring when the normal hierarchical pathway is disrupted.
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  • 94
    Publication Date: 2018-08-17
    Description: Variations in a multitude of material microenvironmental properties have been observed across tissues in vivo, and these have profound effects on cell phenotype. Phenomenological experiments have suggested that certain of these features of the physical microenvironment, such as stiffness, could sensitize cells to other features; meanwhile, mechanistic studies have detailed a number of biophysical mechanisms for this sensing. However, the broad molecular consequences of these potentially complex and nonlinear interactions bridging from biophysical sensing to phenotype have not been systematically characterized, limiting the overall understanding and rational deployment of these biophysical cues. Here, we explore these interactions by employing a 3D cell culture system that allows for the independent control of culture substrate stiffness, stress relaxation, and adhesion ligand density to systematically explore the transcriptional programs affected by distinct combinations of biophysical parameters using RNA-seq. In mouse mesenchymal stem cells and human cortical neuron progenitors, we find dramatic coupling among these substrate properties, and that the relative contribution of each property to changes in gene expression varies with cell type. Motivated by the bioinformatic analysis, the stiffness of hydrogels encapsulating mouse mesenchymal stem cells was found to regulate the secretion of a wide range of cytokines, and to accordingly influence hematopoietic stem cell differentiation in a Transwell coculture model. These results give insights into how biophysical features are integrated by cells across distinct tissues and offer strategies to synthetic biologists and bioengineers for designing responses to a cell’s biophysical environment.
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  • 95
    Publication Date: 2018-03-26
    Description: Metal acquisition is vital to pathogens for successful infection within hosts. Staphylopine (StP), a broad-spectrum metallophore biosynthesized by the major human pathogen, Staphylococcus aureus, plays a central role in transition-metal acquisition and bacterial virulence. The StP-like biosynthesis loci are present in various pathogens, and the proteins responsible for StP/metal transportation have been determined. However, the molecular mechanisms of how StP/metal complexes are recognized and transported remain unknown. We report multiple structures of the extracytoplasmic solute-binding protein CntA from the StP/metal transportation system in apo form and in complex with StP and three different metals. We elucidated a sophisticated metal-bound StP recognition mechanism and determined that StP/metal binding triggers a notable interdomain conformational change in CntA. Furthermore, CRISPR/Cas9-mediated single-base substitution mutations and biochemical analysis highlight the importance of StP/metal recognition for StP/metal acquisition. These discoveries provide critical insights into the study of novel metal-acquisition mechanisms in microbes.
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  • 96
    Publication Date: 2018-12-31
    Description: T cells proliferate vigorously following acute depletion of CD4+ Foxp3+ T regulatory cells [natural Tregs (nTregs)] and also when naive T cells are transferred to syngeneic, nTreg-deficient Rag1−/− hosts. Here, using mice raised in an antigen-free (AF) environment, we show that proliferation in these two situations is directed to self ligands rather than food or commensal antigens. In both situations, the absence of nTregs elevates B7 expression on host dendritic cells (DCs) and enables a small subset of naive CD4 T cells with high self affinity to respond overtly to host DCs: bidirectional T/DC interaction ensues, leading to progressive DC activation and reciprocal strong proliferation of T cells accompanied by peripheral Treg (pTreg) formation. Likewise, high-affinity CD4 T cells proliferate vigorously and form pTregs when cultured with autologous DCs in vitro in the absence of nTregs: this anti-self response is MHCII/peptide dependent and elicited by the raised level of B7 on cultured DCs. The data support a model in which self tolerance is imposed via modulation of CD28 signaling and explains the pathological effects of superagonistic CD28 antibodies.
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  • 97
    Publication Date: 2018-02-20
    Description: Many histological methods require staining of the cytoplasm, which provides instrumental details for diagnosis. One major limitation is the production of 2D images obtained by destructive preparation of 3D tissue samples. X-ray absorption micro- and nanocomputed tomography (microCT and nanoCT) allows for a nondestructive investigation of a 3D tissue sample, and thus aids to determine regions of interest for further histological examinations. However, application of microCT and nanoCT to biological samples (e.g., biopsies) is limited by the missing contrast within soft tissue, which is important to visualize morphological details. We describe an eosin-based preparation overcoming the challenges of contrast enhancement and selectivity for certain tissues. The eosin-based staining protocol is suitable for whole-organ staining, which then enables high-resolution microCT imaging of whole organs and nanoCT imaging of smaller tissue pieces retrieved from the original sample. Our results demonstrate suitability of the eosin-based staining method for diagnostic screening of 3D tissue samples without impeding further diagnostics through histological methods.
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  • 98
    Publication Date: 2018-12-04
    Description: Dynamic functions of biological organisms often rely on arrays of actively deformable microstructures undergoing a nearly unlimited repertoire of predetermined and self-regulated reconfigurations and motions, most of which are difficult or not yet possible to achieve in synthetic systems. Here, we introduce stimuli-responsive microstructures based on liquid-crystalline elastomers (LCEs) that display a broad range of hierarchical, even mechanically unfavored deformation behaviors. By polymerizing molded prepolymer in patterned magnetic fields, we encode any desired uniform mesogen orientation into the resulting LCE microstructures, which is then read out upon heating above the nematic–isotropic transition temperature (TN–I) as a specific prescribed deformation, such as twisting, in- and out-of-plane tilting, stretching, or contraction. By further introducing light-responsive moieties, we demonstrate unique multifunctionality of the LCEs capable of three actuation modes: self-regulated bending toward the light source at T 〈 TN–I, magnetic-field–encoded predetermined deformation at T 〉 TN–I, and direction-dependent self-regulated motion toward the light at T 〉 TN–I. We develop approaches to create patterned arrays of microstructures with encoded multiple area-specific deformation modes and show their functions in responsive release of cargo, image concealment, and light-controlled reflectivity. We foresee that this platform can be widely applied in switchable adhesion, information encryption, autonomous antennae, energy harvesting, soft robotics, and smart buildings.
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  • 99
    Publication Date: 2018-03-12
    Description: We describe and demonstrate an empirical strategy useful for discovering and replicating empirical effects in psychological science. The method involves the design of a metastudy, in which many independent experimental variables—that may be moderators of an empirical effect—are indiscriminately randomized. Radical randomization yields rich datasets that can be used to test the robustness of an empirical claim to some of the vagaries and idiosyncrasies of experimental protocols and enhances the generalizability of these claims. The strategy is made feasible by advances in hierarchical Bayesian modeling that allow for the pooling of information across unlike experiments and designs and is proposed here as a gold standard for replication research and exploratory research. The practical feasibility of the strategy is demonstrated with a replication of a study on subliminal priming.
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  • 100
    Publication Date: 2018-01-16
    Description: Bardet–Biedl syndrome (BBS) is a ciliopathy resulting from defects in the BBSome, a conserved protein complex. BBSome mutations affect ciliary membrane composition, impairing cilia-based signaling. The mechanism by which the BBSome regulates ciliary membrane content remains unknown. Chlamydomonas bbs mutants lack phototaxis and accumulate phospholipase D (PLD) in the ciliary membrane. Single particle imaging revealed that PLD comigrates with BBS4 by intraflagellar transport (IFT) while IFT of PLD is abolished in bbs mutants. BBSome deficiency did not alter the rate of PLD entry into cilia. Membrane association and the N-terminal 58 residues of PLD are sufficient and necessary for BBSome-dependent transport and ciliary export. The replacement of PLD’s ciliary export sequence (CES) caused PLD to accumulate in cilia of cells with intact BBSomes and IFT. The buildup of PLD inside cilia impaired phototaxis, revealing that PLD is a negative regulator of phototactic behavior. We conclude that the BBSome is a cargo adapter ensuring ciliary export of PLD on IFT trains to regulate phototaxis.
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