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  • Oxford University Press  (35,543)
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  • 1
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    Oxford University Press
    In:  EPIC3Geophysical Journal International, Oxford University Press, 208(1), pp. 449-467, ISSN: 1365-246X
    Publication Date: 2016-12-03
    Description: The Mozambique Ridge, a prominent basement high in the southwestern Indian Ocean, consists of four major geomorphological segments associated with numerous phases of volcanic activity in the Lower Cretaceous. The nature and origin of the Mozambique Ridge have been intensely debated with one hypothesis suggesting a Large Igneous Province origin. High-resolution seismic reflection data reveal a large number of extrusion centres with a random distribution throughout the southern Mozambique Ridge and the nearby Transkei Rise. Intra-basement reflections emerge from the extrusion centres and are interpreted to represent massive lava flow sequences. Such lava flow sequences are characteristic of eruptions leading to the formation of continental and oceanic flood basalt provinces, hence supporting a Large Igneous Province origin of the Mozambique Ridge. We observe evidence for widespread post-sedimentary magmatic activity that we correlate with a southward propagation of the East African Rift System. Based on our volumetric analysis of the southern Mozambique Ridge we infer a rapid sequential emplacement between ~131 Ma and ~125 Ma, which is similar to the short formation periods of other Large Igneous Provinces like the Agulhas Plateau.
    Repository Name: EPIC Alfred Wegener Institut
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  • 2
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    Oxford University Press
    In:  EPIC3Marine Plankton, Marine Plankton, Oxford University Press, 704 p., ISBN: 9780199233267
    Publication Date: 2017-05-11
    Repository Name: EPIC Alfred Wegener Institut
    Type: Inbook , peerRev
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  • 3
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    Oxford University Press
    In:  EPIC3Marine Plankton, Marine Plankton, Oxford University Press, 704 p., ISBN: 9780199233267
    Publication Date: 2017-04-28
    Repository Name: EPIC Alfred Wegener Institut
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  • 4
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    Oxford University Press
    In:  EPIC3Marine Plankton, Marine Plankton, Oxford University Press, 704 p., ISBN: 9780199233267
    Publication Date: 2017-05-11
    Repository Name: EPIC Alfred Wegener Institut
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  • 5
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    Oxford University Press
    Publication Date: 2017-04-04
    Description: We provide an updated present-day stress map for the Italian territory. Following the World Stress Map (WSM) Project guidelines, we list the different stress indicators, explaining the criteria used to select data. We discuss the data, which will also be included in the 2016 release of the WSM, highlighting the areas for which we have added stress information. Our map displays the minimum horizontal stress orientations inferred from crustal stress indicators down to 40 km depth using data of A–C quality, updated for earthquakes until December 2015. We have completely reviewed all data, and the data set now contains 855 entries, in contrast to the previous 715. The number of data with A–C quality of 630 corresponds to an increase of 26 per cent relative to the previous data set. In particular, the new data set contains the results of the analysis of borehole breakouts, critically reviewed data from earthquake focal mechanisms, data concerning active faults, formal inversions of focal mechanisms of seismic sequences or of restricted areas and one stress determination from overcoring. The new data set defines the stress field in areas not well covered by the previous data: the region north to the Po Plain and the central Adriatic sea, both characterized by a thrust- and strike-faulting regime, the northern Sicilian belt with a prevailing normal-faulting regime, and the Ionian sea with a strike-slip regime.
    Description: Published
    Description: 1525-1531
    Description: 2T. Tettonica attiva
    Description: JCR Journal
    Description: restricted
    Keywords: Seismicity and tectonics ; Dynamics: seismotectonics ; Crustal structure ; Europe ; 04. Solid Earth::04.07. Tectonophysics::04.07.05. Stress
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 6
    Publication Date: 2017-04-04
    Description: Although there are many methods for investigating tectonic structures, many faults remain hidden, and they can endanger the life and property of people living along them. The slopes of volcanoes are covered with such hidden faults, near which strong earthquakes and gas releases can appear. Revealing hidden faults can therefore contribute significantly to the protection of people living in volcanic areas. In the study, seven different techniques were used for making measurements of in-soil radon concentrations in order to search for hidden faults on the SE flank of the Mt. Etna volcano. These reported methods had previously been proved to be useful tools for investigating fault structures. The main aim of the experiment presented here was to evaluate the usability of these methods in the geological conditions of the Mt. Etna region, and to find the best place for continual radon monitoring using a permanent station in the near future.
    Description: Published
    Description: 70-73
    Description: 5V. Sorveglianza vulcanica ed emergenze
    Description: JCR Journal
    Description: restricted
    Keywords: Mt. Etna ; soil gas ; hidden faults ; radon ; 04. Solid Earth::04.02. Exploration geophysics::04.02.01. Geochemical exploration
    Repository Name: Istituto Nazionale di Geofisica e Vulcanologia (INGV)
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  • 7
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    Oxford University Press
    In:  EPIC3ICES Journal of Marine Science, Oxford University Press, 73, pp. 772-782, ISSN: 1054-3139
    Publication Date: 2016-11-30
    Description: Global warming and ocean acidification are among the most important stressors for aquatic ecosystems in the future. To investigate their direct and indirect effects on a near-natural plankton community, a multiple-stressor approach is needed. Hence, we set up mesocosms in a full-factorial design to study the effects of both warming and high CO2 on a Baltic Sea autumn plankton community, concentrating on the impacts on microzooplankton (MZP). MZP abundance, biomass, and species composition were analysed over the course of the experiment. We observed that warming led to a reduced time-lag between the phytoplankton bloom and an MZP biomass maximum. MZP showed a significantly higher growth rate and an earlier biomass peak in the warm treatments while the biomass maximum was not affected. Increased pCO2 did not result in any significant effects on MZP biomass, growth rate, or species composition irrespective of the temperature, nor did we observe any significant interactions between CO2 and temperature. We attribute this to the high tolerance of this estuarine plankton community to fluctuations in pCO2, often resulting in CO2 concentrations higher than the predicted end-of-century concentration for open oceans. In contrast, warming can be expected to directly affect MZP and strengthen its coupling with phytoplankton by enhancing its grazing pressure.
    Repository Name: EPIC Alfred Wegener Institut
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  • 8
    Publication Date: 2022-05-25
    Description: Author Posting. © Crown Copyright, 2015. This article is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 204 (2016): 1-20, doi:10.1093/gji/ggv416.
    Description: The Canada Basin and the southern Alpha-Mendeleev ridge complex underlie a significant proportion of the Arctic Ocean, but the geology of this undrilled and mostly ice-covered frontier is poorly known. New information is encoded in seismic wide-angle reflections and refractions recorded with expendable sonobuoys between 2007 and 2011. Velocity–depth samples within the sedimentary succession are extracted from published analyses for 142 of these records obtained at irregularly spaced stations across an area of 1.9E + 06 km2. The samples are modelled at regional, subregional and station-specific scales using an exponential function of inverse velocity versus depth with regionally representative parameters determined through numerical regression. With this approach, smooth, non-oscillatory velocity–depth profiles can be generated for any desired location in the study area, even where the measurement density is low. Practical application is demonstrated with a map of sedimentary thickness, derived from seismic reflection horizons interpreted in the time domain and depth converted using the velocity–depth profiles for each seismic trace. A thickness of 12–13 km is present beneath both the upper Mackenzie fan and the middle slope off of Alaska, but the sedimentary prism thins more gradually outboard of the latter region. Mapping of the observed-to-predicted velocities reveals coherent geospatial trends associated with five subregions: the Mackenzie fan; the continental slopes beyond the Mackenzie fan; the abyssal plain; the southwestern Canada Basin; and, the Alpha-Mendeleev magnetic domain. Comparison of the subregional velocity–depth models with published borehole data, and interpretation of the station-specific best-fitting model parameters, suggests that sandstone is not a predominant lithology in any of the five subregions. However, the bulk sand-to-shale ratio likely increases towards the Mackenzie fan, and the model for this subregion compares favourably with borehole data for Miocene turbidites in the eastern Gulf of Mexico. The station-specific results also indicate that Quaternary sediments coarsen towards the Beaufort-Mackenzie and Banks Island margins in a manner that is consistent with the variable history of Laurentide Ice Sheet advance documented for these margins. Lithological factors do not fully account for the elevated velocity–depth trends that are associated with the southwestern Canada Basin and the Alpha-Mendeleev magnetic domain. Accelerated porosity reduction due to elevated palaeo-heat flow is inferred for these regions, which may be related to the underlying crustal types or possibly volcanic intrusion of the sedimentary succession. Beyond exploring the variation of an important physical property in the Arctic Ocean basin, this study provides comparative reference for global studies of seismic velocity, burial history, sedimentary compaction, seismic inversion and overpressure prediction, particularly in mudrock-dominated successions.
    Keywords: Numerical approximations and analysis ; Spatial analysis ; Controlled source seismology ; Acoustic properties ; Sedimentary basin processes ; Large igneous provinces ; Crustal structure ; Arctic region
    Repository Name: Woods Hole Open Access Server
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  • 9
    Publication Date: 2022-05-25
    Description: © The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Genome Biology and Evolution 7 (2015): 3207-3225, doi:10.1093/gbe/evv210.
    Description: High-throughput sequencing of reduced representation libraries obtained through digestion with restriction enzymes—generically known as restriction site associated DNA sequencing (RAD-seq)—is a common strategy to generate genome-wide genotypic and sequence data from eukaryotes. A critical design element of any RAD-seq study is knowledge of the approximate number of genetic markers that can be obtained for a taxon using different restriction enzymes, as this number determines the scope of a project, and ultimately defines its success. This number can only be directly determined if a reference genome sequence is available, or it can be estimated if the genome size and restriction recognition sequence probabilities are known. However, both scenarios are uncommon for nonmodel species. Here, we performed systematic in silico surveys of recognition sequences, for diverse and commonly used type II restriction enzymes across the eukaryotic tree of life. Our observations reveal that recognition sequence frequencies for a given restriction enzyme are strikingly variable among broad eukaryotic taxonomic groups, being largely determined by phylogenetic relatedness. We demonstrate that genome sizes can be predicted from cleavage frequency data obtained with restriction enzymes targeting “neutral” elements. Models based on genomic compositions are also effective tools to accurately calculate probabilities of recognition sequences across taxa, and can be applied to species for which reduced representation data are available (including transcriptomes and neutral RAD-seq data sets). The analytical pipeline developed in this study, PredRAD (https://github.com/phrh/PredRAD), and the resulting databases constitute valuable resources that will help guide the design of any study using RAD-seq or related methods.
    Description: This research was supported by the Office of Ocean Exploration and Research of the National Oceanic and Atmospheric Administration (NA09OAR4320129 to T.S.); the Division of Ocean Sciences of the National Science Foundation (OCE-1131620 to T.S.); the Astrobiology Science and Technology for Exploring Planets program of the National Aeronautics and Space Administration (NNX09AB76G to T.S.); and the Academic Programs Office (Ocean Ventures Fund to S.H.), the Ocean Exploration Institute (Fellowship support to T.M.S.), and the Ocean Life Institute of the Woods Hole Oceanographic Institution (internal grant to T.M.S. and S.H.).
    Keywords: RAD-seq ; Reduced representation sequencing ; PredRAD ; Experimental design ; Genome size prediction ; Restriction recognition sequence probability
    Repository Name: Woods Hole Open Access Server
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  • 10
    Publication Date: 2022-05-25
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Molecular Biology and Evolution 34 (2017): 1890-1901, doi:10.1093/molbev/msx125.
    Description: The highly conserved ADAR enzymes, found in all multicellular metazoans, catalyze the editing of mRNA transcripts by the deamination of adenosines to inosines. This type of editing has two general outcomes: site specific editing, which frequently leads to recoding, and clustered editing, which is usually found in transcribed genomic repeats. Here, for the first time, we looked for both editing of isolated sites and clustered, non-specific sites in a basal metazoan, the coral Acropora millepora during spawning event, in order to reveal its editing pattern. We found that the coral editome resembles the mammalian one: it contains more than 500,000 sites, virtually all of which are clustered in non-coding regions that are enriched for predicted dsRNA structures. RNA editing levels were increased during spawning and increased further still in newly released gametes. This may suggest that editing plays a role in introducing variability in coral gametes.
    Description: This work was supported by the Australian Research Council (to PK), the European Research Council (grant 311257), the I-CORE Program of the Planning and Budgeting Committee in Israel (grants 41/11 and 1796/12), and the Israel Science Foundation (1380/14).
    Keywords: RNA editing ; ADAR ; Evolution ; Coral
    Repository Name: Woods Hole Open Access Server
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  • 11
    Publication Date: 2022-05-25
    Description: © The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nucleic Acids Research 44 (2016): e157, doi:10.1093/nar/gkw738.
    Description: Site-directed RNA editing (SDRE) is a strategy to precisely alter genetic information within mRNAs. By linking the catalytic domain of the RNA editing enzyme ADAR to an antisense guide RNA, specific adenosines can be converted to inosines, biological mimics for guanosine. Previously, we showed that a genetically encoded iteration of SDRE could target adenosines expressed in human cells, but not efficiently. Here we developed a reporter assay to quantify editing, and used it to improve our strategy. By enhancing the linkage between ADAR's catalytic domain and the guide RNA, and by introducing a mutation in the catalytic domain, the efficiency of converting a UAG premature termination codon (PTC) to tryptophan (UGG) was improved from ∼11% to ∼70%. Other PTCs were edited, but less efficiently. Numerous off-target edits were identified in the targeted mRNA, but not in randomly selected endogenous messages. Off-target edits could be eliminated by reducing the amount of guide RNA with a reduction in on-target editing. The catalytic rate of SDRE was compared with those for human ADARs on various substrates and found to be within an order of magnitude of most. These data underscore the promise of site-directed RNA editing as a therapeutic or experimental tool.
    Description: National Institutes of Health [1R0111223855, 1R01NS64259]; Cystic Fibrosis Foundation Therapeutics [Rosent14XXO]; Infrastructural support was provided by the National Institutes of Health [NIGMS 1P20GM103642, NIMHD 8G12-MD007600]; National Science Foundation [DBI 0115825, DBI 1337284]; Department of Defense [52680-RT-ISP].
    Repository Name: Woods Hole Open Access Server
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  • 12
    Publication Date: 2022-05-25
    Description: Author Posting. © The Authors, 2016. This article is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 208 (2017): 1026-1042, doi:10.1093/gji/ggw435.
    Description: In recent years, marine controlled source electromagnetics (CSEM) has found increasing use in hydrocarbon exploration due to its ability to detect thin resistive zones beneath the seafloor. It is the purpose of this paper to evaluate the physics of CSEM for an ocean whose electrical thickness is comparable to or much thinner than that of the overburden using the in-line configuration through examination of the elliptically polarized seafloor electric field, the time-averaged energy flow depicted by the real part of the complex Poynting vector, energy dissipation through Joule heating and the Fréchet derivatives of the seafloor field with respect to the subseafloor conductivity that is assumed to be isotropic. The deep water (ocean layer electrically much thicker than the overburden) seafloor EM response for a model containing a resistive reservoir layer has a greater amplitude and reduced phase as a function of offset compared to that for a half-space, or a stronger and faster response. For an ocean whose electrical thickness is comparable to or much smaller than that of the overburden, the electric field displays a greater amplitude and reduced phase at small offsets, shifting to a stronger amplitude and increased phase at intermediate offsets and a weaker amplitude and enhanced phase at long offsets, or a stronger and faster response that first changes to stronger and slower, and then transitions to weaker and slower. These transitions can be understood by visualizing the energy flow throughout the structure caused by the competing influences of the dipole source and guided energy flow in the reservoir layer, and the air interaction caused by coupling of the entire subseafloor resistivity structure with the sea surface. A stronger and faster response occurs when guided energy flow is dominant, while a weaker and slower response occurs when the air interaction is dominant. However, at intermediate offsets for some models, the air interaction can partially or fully reverse the direction of energy flux in the reservoir layer toward rather than away from the source, resulting in a stronger and slower response. The Fréchet derivatives are dominated by preferential sensitivity to the reservoir layer conductivity for all water depths except at high frequencies, but also display a shift with offset from the galvanic to the inductive mode in the underburden and overburden due to the interplay of guided energy flow and the air interaction. This means that the sensitivity to the horizontal conductivity is almost as strong as to the vertical component in the shallow parts of the subsurface, and in fact is stronger than the vertical sensitivity deeper down. However, the sensitivity to horizontal conductivity is still weak compared to the vertical component within thin resistive regions. The horizontal sensitivity is gradually decreased when the water becomes deep. These observations in part explain the success of shallow towed CSEM using only measurements of the in-line component of the electric field.
    Keywords: Electrical properties ; Marine electromagnetics
    Repository Name: Woods Hole Open Access Server
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  • 13
    Publication Date: 2022-05-25
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Bioscience 67 (2017): 760–768, doi:10.1093/biosci/bix059.
    Description: As the sampling frequency and resolution of Earth observation imagery increase, there are growing opportunities for novel applications in population monitoring. New methods are required to apply established analytical approaches to data collected from new observation platforms (e.g., satellites and unmanned aerial vehicles). Here, we present a method that estimates regional seasonal abundances for an understudied and growing population of gray seals (Halichoerus grypus) in southeastern Massachusetts, using opportunistic observations in Google Earth imagery. Abundance estimates are derived from digital aerial survey counts by adapting established correction-based analyses with telemetry behavioral observation to quantify survey biases. The result is a first regional understanding of gray seal abundance in the northeast US through opportunistic Earth observation imagery and repurposed animal telemetry data. As species observation data from Earth observation imagery become more ubiquitous, such methods provide a robust, adaptable, and cost-effective solution to monitoring animal colonies and understanding species abundances.
    Description: We would like to thank generous support from International Fund for Animal Welfare, the Bureau of Ocean Energy, and the Oak Foundation for funding support for the telemetry devices.
    Keywords: Abundance estimation ; Gray seals (Halichoerus grypus) ; Cape Cod ; Remote sensing ; Earth observation
    Repository Name: Woods Hole Open Access Server
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  • 14
    Publication Date: 2022-05-25
    Description: Author Posting. © The Authors, 2017. This article is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 211 (2017): 1046–1061, doi:10.1093/gji/ggx360.
    Description: In recent years, marine controlled source electromagnetics (CSEM) has found increasing use in hydrocarbon exploration due to its ability to detect thin resistive zones beneath the seafloor. It is the purpose of this paper to evaluate the physics of CSEM for an ocean whose electrical thickness is comparable to or much thinner than that of the overburden using the in-line configuration through examination of the elliptically-polarized seafloor electric field, the time-averaged energy flow depicted by the real part of the complex Poynting vector, energy dissipation through Joule heating and the Fréchet derivatives of the seafloor field with respect to the sub-seafloor conductivity that is assumed to be transversely anisotropic, with a vertical-to-horizontal resistivity ratio of 3:1. For an ocean whose electrical thickness is comparable to that of the overburden, the seafloor electromagnetic response for a model containing a resistive reservoir layer has a greater amplitude and reduced phase as a function of offset compared to that for a halfspace, or a stronger and faster response, and displays little to no evidence for the air interaction. For an ocean whose electrical thickness is much smaller than that of the overburden, the electric field displays a greater amplitude and reduced phase at small offsets, shifting to a stronger amplitude and increased phase at intermediate offsets, and a weaker amplitude and enhanced phase at long offsets, or a stronger and faster response that first changes to stronger and slower, and then transitions to weaker and slower. By comparison to the isotropic case with the same horizontal conductivity, transverse anisotropy stretches the Poynting vector and the electric field response from a thin resistive layer to much longer offsets. These phenomena can be understood by visualizing the energy flow throughout the structure caused by the competing influences of the dipole source and guided energy flow in the reservoir layer, and the air interaction caused by coupling of the entire sub-seafloor resistivity structure with the sea surface. The Fréchet derivatives are dominated by preferential sensitivity to the vertical conductivity in the reservoir layer and overburden at short offsets. The horizontal conductivity Fréchet derivatives are weaker than to comparable to the vertical derivatives at long offsets in the substrate. This means that the sensitivity to the horizontal conductivity is present in the shallow parts of the subsurface. In the presence of transverse anisotropy, it is necessary to go to higher frequencies to sense the horizontal conductivity in the overburden as compared to an isotropic model with the same horizontal conductivity. These observations in part explain the success of shallow towed CSEM using only measurements of the in-line component of the electric field.
    Description: This work was supported at WHOI by an Independent Research and Development award, and by the Walter A. and Hope Noyes Smith Chair for Excellence in Oceanography.
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  • 15
    Publication Date: 2022-06-20
    Description: A major uncertainty in determining the mass balance of the Antarctic ice sheet from measurements of satellite gravimetry, and to a lesser extent satellite altimetry, is the poorly known correction for the ongoing deformation of the solid Earth caused by glacial isostatic adjustment (GIA). Although much progress has been made in consistently modeling the ice-sheet evolution throughout the last glacial cycle, as well as the induced bedrock deformation caused by these load changes, forward models of GIA remain ambiguous due to the lack of observational constraints on the ice sheet's past extent and thickness and mantle rheology beneath the continent. As an alternative to forward-modeling GIA, we estimate GIA from multiple space-geodetic observations: Gravity Recovery and Climate Experiment (GRACE), Envisat/ICESat and Global Positioning System (GPS). Making use of the different sensitivities of the respective satellite observations to current and past surface-mass (ice mass) change and solid Earth processes, we estimate GIA based on viscoelastic response functions to disc load forcing. We calculate and distribute the viscoelastic response functions according to estimates of the variability of lithosphere thickness and mantle viscosity in Antarctica. We compare our GIA estimate with published GIA corrections and evaluate its impact in determining the ice-mass balance in Antarctica from GRACE and satellite altimetry. Particular focus is applied to the Amundsen Sea Sector in West Antarctica, where uplift rates of several centimetres per year have been measured by GPS. We show that most of this uplift is caused by the rapid viscoelastic response to recent ice-load changes, enabled by the presence of a low-viscosity upper mantle in West Antarctica. This paper presents the second and final contributions summarizing the work carried out within a European Space Agency funded study, REGINA (www.regina-science.eu).
    Repository Name: EPIC Alfred Wegener Institut
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  • 16
    Publication Date: 2022-05-26
    Description: Author Posting. © Oxford University Press, 2016. This article is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 205 (2016): 728-743, doi:10.1093/gji/ggw044.
    Description: While elasticity is a defining characteristic of the Earth's lithosphere, it is often ignored in numerical models of long-term tectonic processes in favour of a simpler viscoplastic description. Here we assess the consequences of this assumption on a well-studied geodynamic problem: the growth of normal faults at an extensional plate boundary. We conduct 2-D numerical simulations of extension in elastoplastic and viscoplastic layers using a finite difference, particle-in-cell numerical approach. Our models simulate a range of faulted layer thicknesses and extension rates, allowing us to quantify the role of elasticity on three key observables: fault-induced topography, fault rotation, and fault life span. In agreement with earlier studies, simulations carried out in elastoplastic layers produce rate-independent lithospheric flexure accompanied by rapid fault rotation and an inverse relationship between fault life span and faulted layer thickness. By contrast, models carried out with a viscoplastic lithosphere produce results that may qualitatively resemble the elastoplastic case, but depend strongly on the product of extension rate and layer viscosity U × ηL. When this product is high, fault growth initially generates little deformation of the footwall and hanging wall blocks, resulting in unrealistic, rigid block-offset in topography across the fault. This configuration progressively transitions into a regime where topographic decay associated with flexure is fully accommodated within the numerical domain. In addition, high U × ηL favours the sequential growth of multiple short-offset faults as opposed to a large-offset detachment. We interpret these results by comparing them to an analytical model for the fault-induced flexure of a thin viscous plate. The key to understanding the viscoplastic model results lies in the rate-dependence of the flexural wavelength of a viscous plate, and the strain rate dependence of the force increase associated with footwall and hanging wall bending. This behaviour produces unrealistic deformation patterns that can hinder the geological relevance of long-term rifting models that assume a viscoplastic rheology.
    Description: This work was supported by NSF grants OCE-11-54238 (JAO, MDB), EAR-10-10432 (MDB) and OCE-11-55098 (GI), as well as a WHOI Deep Exploration Institute grant and start-up support from the University of Idaho (EM).
    Keywords: Mid-ocean ridge processes ; Continental tectonics: extensional ; Lithospheric flexure ; Mechanics, theory, and modelling
    Repository Name: Woods Hole Open Access Server
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  • 17
    Publication Date: 2022-05-26
    Description: © The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Conservation Physiology 4 (2016): cow014, doi:10.1093/conphys/cow014.
    Description: Reproduction of mysticete whales is difficult to monitor, and basic parameters, such as pregnancy rate and inter-calving interval, remain unknown for many populations. We hypothesized that baleen plates (keratinous strips that grow downward from the palate of mysticete whales) might record previous pregnancies, in the form of high-progesterone regions in the sections of baleen that grew while the whale was pregnant. To test this hypothesis, longitudinal baleen progesterone profiles from two adult female North Atlantic right whales (Eubalaena glacialis) that died as a result of ship strike were compared with dates of known pregnancies inferred from calf sightings and post-mortem data. We sampled a full-length baleen plate from each female at 4 cm intervals from base (newest baleen) to tip (oldest baleen), each interval representing ∼60 days of baleen growth, with high-progesterone areas then sampled at 2 or 1 cm intervals. Pulverized baleen powder was assayed for progesterone using enzyme immunoassay. The date of growth of each sampling location on the baleen plate was estimated based on the distance from the base of the plate and baleen growth rates derived from annual cycles of stable isotope ratios. Baleen progesterone profiles from both whales showed dramatic elevations (two orders of magnitude higher than baseline) in areas corresponding to known pregnancies. Baleen hormone analysis shows great potential for estimation of recent reproductive history, inter-calving interval and general reproductive biology in this species and, possibly, in other mysticete whales.
    Description: This work was supported by the Eppley Foundation for Research, the National Oceanographic and Atmospheric Administration Marine Mammal Health and Stranding Program and the Woods Hole Oceanographic Institution Ocean Life Institute.
    Keywords: Baleen ; Cetacea ; Marine mammals ; Pregnancy ; Progesterone ; Reproduction
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  • 18
    Publication Date: 2022-05-26
    Description: Author Posting. © The Author(s), 2016. This article is posted here by permission of The Royal Astronomical Society for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 205 (2016): 785-795, doi:10.1093/gji/ggw036.
    Description: An L-configured, three-component short period seismic array was deployed on the Ross Ice Shelf, Antarctica during November 2014. Polarization analysis of ambient noise data from these stations shows linearly polarized waves for frequency bands between 0.2 and 2 Hz. A spectral peak at about 1.6 Hz is interpreted as the resonance frequency of the water column and is used to estimate the water layer thickness below the ice shelf. The frequency band from 4 to 18 Hz is dominated by Rayleigh and Love waves propagating from the north that, based on daily temporal variations, we conclude were generated by field camp activity. Frequency–slowness plots were calculated using beamforming. Resulting Love and Rayleigh wave dispersion curves were inverted for the shear wave velocity profile within the firn and ice to ∼150 m depth. The derived density profile allows estimation of the pore close-off depth and the firn–air content thickness. Separate inversions of Rayleigh and Love wave dispersion curves give different shear wave velocity profiles within the firn. We attribute this difference to an effective anisotropy due to fine layering. The layered structure of firn, ice, water and the seafloor results in a characteristic dispersion curve below 7 Hz. Forward modelling the observed Rayleigh wave dispersion curves using representative firn, ice, water and sediment structures indicates that Rayleigh waves are observed when wavelengths are long enough to span the distance from the ice shelf surface to the seafloor. The forward modelling shows that analysis of seismic data from an ice shelf provides the possibility of resolving ice shelf thickness, water column thickness and the physical properties of the ice shelf and underlying seafloor using passive-source seismic data.
    Description: PDB, AD and PG were supported by NSF Grant PLR 1246151. RAS was supported by NSF Grant PLR-1246416. DAW, RA and AN were supported under NSF Grants PLR-1142518, 1141916 and 1142126, respectively. PDB also received support from the California Department of Parks and Recreation, Division of Boating and Waterways under contract 11-106-107.
    Keywords: Glaciology ; Surface waves and free oscillations ; Seismic anisotropy ; Antarctica
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  • 19
    Publication Date: 2022-05-26
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Genome Biology and Evolution 9 (2017): 659-676, doi:10.1093/gbe/evx023.
    Description: Understanding and predicting the fate of populations in changing environments require knowledge about the mechanisms that support phenotypic plasticity and the adaptive value and evolutionary fate of genetic variation within populations. Atlantic killifish (Fundulus heteroclitus) exhibit extensive phenotypic plasticity that supports large population sizes in highly fluctuating estuarine environments. Populations have also evolved diverse local adaptations. To yield insights into the genomic variation that supports their adaptability, we sequenced a reference genome and 48 additional whole genomes from a wild population. Evolution of genes associated with cell cycle regulation and apoptosis is accelerated along the killifish lineage, which is likely tied to adaptations for life in highly variable estuarine environments. Genome-wide standing genetic variation, including nucleotide diversity and copy number variation, is extremely high. The highest diversity genes are those associated with immune function and olfaction, whereas genes under greatest evolutionary constraint are those associated with neurological, developmental, and cytoskeletal functions. Reduced genetic variation is detected for tight junction proteins, which in killifish regulate paracellular permeability that supports their extreme physiological flexibility. Low-diversity genes engage in more regulatory interactions than high-diversity genes, consistent with the influence of pleiotropic constraint on molecular evolution. High genetic variation is crucial for continued persistence of species given the pace of contemporary environmental change. Killifish populations harbor among the highest levels of nucleotide diversity yet reported for a vertebrate species, and thus may serve as a useful model system for studying evolutionary potential in variable and changing environments.
    Description: This work was primarily supported by a grant from the National Science Foundation (collaborative research grants DEB-1265282, DEB-1120512, DEB-1120013, DEB-1120263, DEB-1120333, DEB-1120398 to J.K.C., D.L.C., M.E.H., S.I.K., M.F.O., J.R.S., W.W., and A.W.). Further support was provided by the National Institute of Environmental Health Sciences (1R01ES021934-01 to A.W., P42ES7373 to T.H.H., P42ES007381 to M.E.H., and R01ES019324 to J.R.S.), the National Institute of General Medical Sciences (P20GM103423 and P20GM104318 to B.L.K.), and the National Science Foundation (DBI-0640462 and XSEDE-MCB100147 to D.G.).
    Keywords: Population genomics ; Genome sequence ; Comparative genomics ; Adaptation ; Genetic diversity
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  • 20
    Publication Date: 2022-05-26
    Description: © The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Conservation Physiology 5 (2017): cox061, doi:10.1093/conphys/cox061.
    Description: Recent studies have demonstrated that some hormones are present in baleen powder from bowhead (Balaena mysticetus) and North Atlantic right (Eubalaena glacialis) whales. To test the potential generalizability of this technique for studies of stress and reproduction in large whales, we sought to determine whether all major classes of steroid and thyroid hormones are detectable in baleen, and whether these hormones are detectable in other mysticetes. Powdered baleen samples were recovered from single specimens of North Atlantic right, bowhead, blue (Balaenoptera [B.]musculus), sei (B. borealis), minke (B. acutorostrata), fin (B. physalus), humpback (Megaptera novaeangliae) and gray (Eschrichtius robustus) whales. Hormones were extracted with a methanol vortex method, after which we tested all species with commercial enzyme immunoassays (EIAs, Arbor Assays) for progesterone, testosterone, 17β-estradiol, cortisol, corticosterone, aldosterone, thyroxine and tri-iodothyronine, representing a wide array of steroid and thyroid hormones of interest for whale physiology research. In total, 64 parallelism tests (8 species × 8 hormones) were evaluated to verify good binding affinity of the assay antibodies to hormones in baleen. We also tested assay accuracy, although available sample volume limited this test to progesterone, testosterone and cortisol. All tested hormones were detectable in baleen powder of all species, and all assays passed parallelism and accuracy tests. Although only single individuals were tested, the consistent detectability of all hormones in all species indicates that baleen hormone analysis is likely applicable to a broad range of mysticetes, and that the EIA kits tested here perform well with baleen extract. Quantification of hormones in baleen may be a suitable technique with which to explore questions that have historically been difficult to address in large whales, including pregnancy and inter-calving interval, age of sexual maturation, timing and duration of seasonal reproductive cycles, adrenal physiology and metabolic rate.
    Description: This work was supported by (1) the Center for Bioengineering Innovation at Northern Arizona University and (2) the New England Aquarium.
    Keywords: Baleen ; Cetaceans ; Hormones ; Marine mammals ; Reproduction ; Stress
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  • 21
    Publication Date: 2022-05-26
    Description: © The Author(s), 2017. 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 114 (2017): 13114-13119, doi: 10.1073/pnas.1702143114.
    Description: During the Mid-Pleistocene Transition (MPT; 1,200–800 kya), Earth’s orbitally paced ice age cycles intensified, lengthened from ∼40,000 (∼40 ky) to ∼100 ky, and became distinctly asymmetrical. Testing hypotheses that implicate changing atmospheric CO2 levels as a driver of the MPT has proven difficult with available observations. Here, we use orbitally resolved, boron isotope CO2 data to show that the glacial to interglacial CO2 difference increased from ∼43 to ∼75 μatm across the MPT, mainly because of lower glacial CO2 levels. Through carbon cycle modeling, we attribute this decline primarily to the initiation of substantive dust-borne iron fertilization of the Southern Ocean during peak glacial stages. We also observe a twofold steepening of the relationship between sea level and CO2-related climate forcing that is suggestive of a change in the dynamics that govern ice sheet stability, such as that expected from the removal of subglacial regolith or interhemispheric ice sheet phase-locking. We argue that neither ice sheet dynamics nor CO2 change in isolation can explain the MPT. Instead, we infer that the MPT was initiated by a change in ice sheet dynamics and that longer and deeper post-MPT ice ages were sustained by carbon cycle feedbacks related to dust fertilization of the Southern Ocean as a consequence of larger ice sheets.
    Description: Research was supported by National Environmental Research Council (NERC) Studentship NE/I528626/1 (to T.B.C.); NERC Grant NE/P011381/1 (to T.B.C., M.P.H., G.L.F., E.J.R., and P.A.W.); NERC Fellowships NE/K00901X/1 (to M.P.H.), NE/I006346/1 (to G.L.F. and R.D.P), and NE/H006273/1 (to R.D.P.); Royal Society Wolfson Awards (to G.L.F. and P.A.W.); Australian Research Council Laureate Fellowship FL1201000050 (to E.J.R.); Swiss National Science Foundation Grant PP00P2-144811 (to S.L.J.); ETH Research Grant ETH-04 11-1 (to S.L.J.); European Research Council Consolidator Grant (ERC CoG) Grant 617462 (to H.P.); and NERC UK IODP Grant NE/F00141X/1 (to P.A.W.).
    Keywords: Boron isotopes ; MPT ; Geochemistry ; Carbon dioxide ; Paleoclimate
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  • 22
    Publication Date: 2022-05-26
    Description: © International Council for the Exploration of the Sea, 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in ICES Journal of Marine Science 73 (2016): 1839-1850, doi: 10.1093/icesjms/fsw086.
    Description: For terrestrial and marine benthic ecologists, landscape ecology provides a framework to address issues of complexity, patchiness, and scale—providing theory and context for ecosystem based management in a changing climate. Marine pelagic ecosystems are likewise changing in response to warming, changing chemistry, and resource exploitation. However, unlike spatial landscapes that migrate slowly with time, pelagic seascapes are embedded in a turbulent, advective ocean. Adaptations from landscape ecology to marine pelagic ecosystem management must consider the nature and scale of biophysical interactions associated with organisms ranging from microbes to whales, a hierarchical organization shaped by physical processes, and our limited capacity to observe and monitor these phenomena across global oceans. High frequency, multiscale, and synoptic characterization of the 4-D variability of seascapes are now available through improved classification methods, a maturing array of satellite remote sensing products, advances in autonomous sampling of multiple levels of biological complexity, and emergence of observational networks. Merging of oceanographic and ecological paradigms will be necessary to observe, manage, and conserve species embedded in a dynamic seascape mosaic, where the boundaries, extent, and location of features change with time.
    Description: This work was supported by NASA grant NNX14AP62A “National Marine Sanctuaries as Sentinel Sites for a Demonstration Marine Biodiversity Observation Network (MBON)” funded under the National Ocean Partnership Program (NOPP RFP NOAA-NOS-IOOS-2014-2003803 in partnership between NOAA, BOEM, and NASA), the NOAA Integrated Ocean Observing System (IOOS) Program Office, and the LenFest Ocean Program.
    Keywords: Biodiversity ; Conservation ; Landscape ; Ocean observations ; Pelagic ; Phytoplankton ; Seascape
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  • 23
    Publication Date: 2017-11-13
    Description: Legionella pneumophilais the causative agent of a severe pneumonia called Legionnaires’ disease. A single strain ofL. pneumophilaencodes a repertoire of over 300 different effector proteins that are delivered into host cells by the Dot/Icm type IV secretion system during infection. The large number ofL. pneumophilaeffectors has been a limiting factor in assessing the importance of individual effectors for virulence. Here, a transposon insertion sequencing technology called INSeq was used to analyze replication of a pool of effector mutants in parallel both in a mouse model of infection and in cultured host cells. Loss-of-function mutations in genes encoding effector proteins resulted in host-specific or broad virulence phenotypes. Screen results were validated for several effector mutants displaying different virulence phenotypes using genetic complementation studies and infection assays. Specifically, loss-of-function mutations in the gene encoding LegC4 resulted in enhancedL. pneumophilain the lungs of infected mice but not within cultured host cells, which indicates LegC4 augments bacterial clearance by the host immune system. The effector proteins RavY and Lpg2505 were important for efficient replication within both mammalian and protozoan hosts. Further analysis of Lpg2505 revealed that this protein functions as a metaeffector that counteracts host cytotoxicity displayed by the effector protein SidI. Thus, this study identified a large cohort of effectors that contribute toL. pneumophilavirulence positively or negatively and has demonstrated regulation of effector protein activities by cognate metaeffectors as being critical for host pathogenesis.
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  • 24
    Publication Date: 2016-05-02
    Description: Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington’s disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.
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  • 25
    Publication Date: 2016-03-16
    Description: FliI and FliJ form the FliI6FliJ ATPase complex of the bacterial flagellar export apparatus, a member of the type III secretion system. The FliI6FliJ complex is structurally similar to the α3β3γ complex of F1-ATPase. The FliH homodimer binds to FliI to connect the ATPase complex to the flagellar base, but the details are unknown. Here we report the structure of the homodimer of a C-terminal fragment of FliH (FliHC2) in complex with FliI. FliHC2shows an unusually asymmetric homodimeric structure that markedly resembles the peripheral stalk of the A/V-type ATPases. The FliHC2–FliI hexamer model reveals that the C-terminal domains of the FliI ATPase face the cell membrane in a way similar to the F/A/V-type ATPases. We discuss the mechanism of flagellar ATPase complex formation and a common origin shared by the type III secretion system and the F/A/V-type ATPases.
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  • 26
    Publication Date: 2017-05-15
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  • 27
    Publication Date: 2017-07-27
    Description: Nuclear hormone receptors (NRs) regulate physiology by sensing lipophilic ligands and adapting cellular transcription appropriately. A growing understanding of the impact of circadian clocks on mammalian transcription has sparked interest in the interregulation of transcriptional programs. Mammalian clocks are based on a transcriptional feedback loop featuring the transcriptional activators circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), and transcriptional repressors cryptochrome (CRY) and period (PER). CRY1 and CRY2 bind independently of other core clock factors to many genomic sites, which are enriched for NR recognition motifs. Here we report that CRY1/2 serve as corepressors for many NRs, indicating a new facet of circadian control of NR-mediated regulation of metabolism and physiology, and specifically contribute to diurnal modulation of drug metabolism.
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  • 28
    Publication Date: 2017-07-31
    Description: Homodimeric KIF17 and heterotrimeric KIF3AB are processive, kinesin-2 family motors that act jointly to carry out anterograde intraflagellar transport (IFT), ferrying cargo along microtubules (MTs) toward the tips of cilia. How IFT trains attain speeds that exceed the unloaded rate of the slower, KIF3AB motor remains unknown. By characterizing the motility properties of kinesin-2 motors as a function of load we find that the increase in KIF3AB velocity, elicited by forward loads from KIF17 motors, cannot alone account for the speed of IFT trains in vivo. Instead, higher IFT velocities arise from an increased likelihood that KIF3AB motors dissociate from the MT, resulting in transport by KIF17 motors alone, unencumbered by opposition from KIF3AB. The rate of transport is therefore set by an equilibrium between a faster state, where only KIF17 motors move the train, and a slower state, where at least one KIF3AB motor on the train remains active in transport. The more frequently the faster state is accessed, the higher the overall velocity of the IFT train. We conclude that IFT velocity is governed by (i) the absolute numbers of each motor type on a given train, (ii) how prone KIF3AB is to dissociation from MTs relative to KIF17, and (iii) how prone both motors are to dissociation relative to binding MTs.
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  • 29
    Publication Date: 2017-03-06
    Description: Riboswitches are RNAs that form complex, folded structures that selectively bind small molecules or ions. As with certain groups of protein enzymes and receptors, some riboswitch classes have evolved to change their ligand specificity. We developed a procedure to systematically analyze known riboswitch classes to find additional variants that have altered their ligand specificity. This approach uses multiple-sequence alignments, atomic-resolution structural information, and riboswitch gene associations. Among the discoveries are unique variants of the guanine riboswitch class that most tightly bind the nucleoside 2′-deoxyguanosine. In addition, we identified variants of the glycine riboswitch class that no longer recognize this amino acid, additional members of a rare flavin mononucleotide (FMN) variant class, and also variants of c-di-GMP-I and -II riboswitches that might recognize different bacterial signaling molecules. These findings further reveal the diverse molecular sensing capabilities of RNA, which highlights the potential for discovering a large number of additional natural riboswitch classes.
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  • 30
    Publication Date: 2017-11-21
    Description: This paper evaluates current stakeholder involvement (SI) practices in science through a web-based survey among scholars and researchers engaged in sustainability or transition research. It substantiates previous conceptual work with evidence from practice by building on four ideal types of SI in science. The results give an interesting overview of the varied landscape of SI in sustainability science, ranging from the kinds of topics scientists work on with stakeholders, over scientific trade-offs that arise in the field, to improvements scientists wish for. Furthermore, the authors describe a discrepancy between scientists’ ideals and practices when working with stakeholders. On the conceptual level, the data reflect that the democratic type of SI is the predominant one concerning questions on the understanding of science, the main goal, the stage of involvement in the research process, and the science–policy interface. The fact that respondents expressed agreement to several types shows they are guided by multiple and partly conflicting ideals when working with stakeholders. We thus conclude that more conceptual exchange between practitioners, as well as more qualitative research on the concepts behind practices, is needed to better understand the stakeholder–scientist nexus.
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  • 31
    Publication Date: 2017-06-26
    Description: Foundry-based routes to transient silicon electronic devices have the potential to serve as the manufacturing basis for “green” electronic devices, biodegradable implants, hardware secure data storage systems, and unrecoverable remote devices. This article introduces materials and processing approaches that enable state-of-the-art silicon complementary metal-oxide-semiconductor (CMOS) foundries to be leveraged for high-performance, water-soluble forms of electronics. The key elements are (i) collections of biodegradable electronic materials (e.g., silicon, tungsten, silicon nitride, silicon dioxide) and device architectures that are compatible with manufacturing procedures currently used in the integrated circuit industry, (ii) release schemes and transfer printing methods for integration of multiple ultrathin components formed in this way onto biodegradable polymer substrates, and (iii) planarization and metallization techniques to yield interconnected and fully functional systems. Various CMOS devices and circuit elements created in this fashion and detailed measurements of their electrical characteristics highlight the capabilities. Accelerated dissolution studies in aqueous environments reveal the chemical kinetics associated with the underlying transient behaviors. The results demonstrate the technical feasibility for using foundry-based routes to sophisticated forms of transient electronic devices, with functional capabilities and cost structures that could support diverse applications in the biomedical, military, industrial, and consumer industries.
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  • 32
    Publication Date: 2016-06-13
    Description: Single-nucleotide polymorphisms (SNPs) in a gene sequence are markers for a variety of human diseases. Detection of SNPs with high specificity and sensitivity is essential for effective practical implementation of personalized medicine. Current DNA sequencing, including SNP detection, primarily uses enzyme-based methods or fluorophore-labeled assays that are time-consuming, need laboratory-scale settings, and are expensive. Previously reported electrical charge-based SNP detectors have insufficient specificity and accuracy, limiting their effectiveness. Here, we demonstrate the use of a DNA strand displacement-based probe on a graphene field effect transistor (FET) for high-specificity, single-nucleotide mismatch detection. The single mismatch was detected by measuring strand displacement-induced resistance (and hence current) change and Dirac point shift in a graphene FET. SNP detection in large double-helix DNA strands (e.g., 47 nt) minimize false-positive results. Our electrical sensor-based SNP detection technology, without labeling and without apparent cross-hybridization artifacts, would allow fast, sensitive, and portable SNP detection with single-nucleotide resolution. The technology will have a wide range of applications in digital and implantable biosensors and high-throughput DNA genotyping, with transformative implications for personalized medicine.
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  • 33
    Publication Date: 2017-04-10
    Description: G protein-coupled receptor (GPCR) signaling occurs in complex spatiotemporal patterns that are difficult to probe using standard pharmacological and genetic approaches. A powerful approach for dissecting GPCRs is to use light-controlled pharmacological agents that are tethered covalently and specifically to genetically engineered receptors. However, deficits in our understanding of the mechanism of such photoswitches have limited application of this approach and its extension to other GPCRs. In this study, we have harnessed the power of bioorthogonal tethering to SNAP and CLIP protein tags to create a family of light-gated metabotropic glutamate receptors (mGluRs). We define the mechanistic determinants of photoswitch efficacy, including labeling efficiency, dependence on photoswitch structure, length dependence of the linker between the protein tag and the glutamate ligand, effective local concentration of the glutamate moiety, and affinity of the receptor for the ligand. We improve the scheme for photoswitch synthesis as well as photoswitch efficiency, and generate seven light-gated group II/III mGluRs, including variants of mGluR2, 3, 6, 7, and 8. Members of this family of light-controlled receptors can be used singly or in specifically labeled, independently light-controlled pairs for multiplexed control of receptor populations.
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  • 34
    Publication Date: 2016-12-12
    Description: The recent breakthroughs in assembling long error-prone reads were based on the overlap-layout-consensus (OLC) approach and did not utilize the strengths of the alternative de Bruijn graph approach to genome assembly. Moreover, these studies often assume that applications of the de Bruijn graph approach are limited to short and accurate reads and that the OLC approach is the only practical paradigm for assembling long error-prone reads. We show how to generalize de Bruijn graphs for assembling long error-prone reads and describe the ABruijn assembler, which combines the de Bruijn graph and the OLC approaches and results in accurate genome reconstructions.
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  • 35
    Publication Date: 2017-05-01
    Description: Root hair polar growth is endogenously controlled by auxin and sustained by oscillating levels of reactive oxygen species (ROS). These cells extend several hundred-fold their original size toward signals important for plant survival. Although their final cell size is of fundamental importance, the molecular mechanisms that control it remain largely unknown. Here we show that ROS production is controlled by the transcription factor RSL4, which in turn is transcriptionally regulated by auxin through several auxin response factors (ARFs). In this manner, auxin controls ROS-mediated polar growth by activating RSL4, which then up-regulates the expression of genes encoding NADPH oxidases (also known as RESPIRATORY BURST OXIDASE HOMOLOG proteins) and class III peroxidases, which catalyze ROS production. Chemical or genetic interference with ROS balance or peroxidase activity affects root hair final cell size. Overall, our findings establish a molecular link between auxin and ROS-mediated polar root hair growth.
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  • 36
    Publication Date: 2016-12-07
    Description: Teeth and denticles belong to a specialized class of mineralizing epithelial appendages called odontodes. Although homology of oral teeth in jawed vertebrates is well supported, the evolutionary origin of teeth and their relationship with other odontode types is less clear. We compared the cellular and molecular mechanisms directing development of teeth and skin denticles in sharks, where both odontode types are retained. We show that teeth and denticles are deeply homologous developmental modules with equivalent underlying odontode gene regulatory networks (GRNs). Notably, the expression of the epithelial progenitor and stem cell marker sex-determining region Y-related box 2 (sox2) was tooth-specific and this correlates with notable differences in odontode regenerative ability. Whereas shark teeth retain the ancestral gnathostome character of continuous successional regeneration, new denticles arise only asynchronously with growth or after wounding. Sox2+ putative stem cells associated with the shark dental lamina (DL) emerge from a field of epithelial progenitors shared with anteriormost taste buds, before establishing within slow-cycling cell niches at the (i) superficial taste/tooth junction (T/TJ), and (ii) deep successional lamina (SL) where tooth regeneration initiates. Furthermore, during regeneration, cells from the superficial T/TJ migrate into the SL and contribute to new teeth, demonstrating persistent contribution of taste-associated progenitors to tooth regeneration in vivo. This data suggests a trajectory for tooth evolution involving cooption of the odontode GRN from nonregenerating denticles bysox2+ progenitors native to the oral taste epithelium, facilitating the evolution of a novel regenerative module of odontodes in the mouth of early jawed vertebrates: the teeth.
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  • 37
    Publication Date: 2017-10-16
    Description: A number of domestication hypotheses suggest that dogs have acquired a more tolerant temperament than wolves, promoting cooperative interactions with humans and conspecifics. This selection process has been proposed to resemble the one responsible for our own greater cooperative inclinations in comparison with our closest living relatives. However, the socioecology of wolves and dogs, with the former relying more heavily on cooperative activities, predicts that at least with conspecifics, wolves should cooperate better than dogs. Here we tested similarly raised wolves and dogs in a cooperative string-pulling task with conspecifics and found that wolves outperformed dogs, despite comparable levels of interest in the task. Whereas wolves coordinated their actions so as to simultaneously pull the rope ends, leading to success, dogs pulled the ropes in alternate moments, thereby never succeeding. Indeed in dog dyads it was also less likely that both members simultaneously engaged in other manipulative behaviors on the apparatus. Different conflict-management strategies are likely responsible for these results, with dogs’ avoidance of potential competition over the apparatus constraining their capacity to coordinate actions. Wolves, in contrast, did not hesitate to manipulate the ropes simultaneously, and once cooperation was initiated, rapidly learned to coordinate in more complex conditions as well. Social dynamics (rank and affiliation) played a key role in success rates. Results call those domestication hypotheses that suggest dogs evolved greater cooperative inclinations into question, and rather support the idea that dogs’ and wolves’ different social ecologies played a role in affecting their capacity for conspecific cooperation and communication.
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  • 38
    Publication Date: 2016-04-18
    Description: The oxygenation of the atmosphere ∼2.45–2.32 billion years ago (Ga) is one of the most significant geological events to have affected Earth’s redox history. Our understanding of the timing and processes surrounding this key transition is largely dependent on the development of redox-sensitive proxies, many of which remain unexplored. Here we report a shift from negative to positive copper isotopic compositions (δ65CuERM-AE633) in organic carbon-rich shales spanning the period 2.66–2.08 Ga. We suggest that, before 2.3 Ga, a muted oxidative supply of weathering-derived copper enriched in 65Cu, along with the preferential removal of 65Cu by iron oxides, left seawater and marine biomass depleted in 65Cu but enriched in 63Cu. As banded iron formation deposition waned and continentally sourced Cu became more important, biomass sampled a dissolved Cu reservoir that was progressively less fractionated relative to the continental pool. This evolution toward heavy δ65Cu values coincides with a shift to negative sedimentary δ56Fe values and increased marine sulfate after the Great Oxidation Event (GOE), and is traceable through Phanerozoic shales to modern marine settings, where marine dissolved and sedimentary δ65Cu values are universally positive. Our finding of an important shift in sedimentary Cu isotope compositions across the GOE provides new insights into the Precambrian marine cycling of this critical micronutrient, and demonstrates the proxy potential for sedimentary Cu isotope compositions in the study of biogeochemical cycles and oceanic redox balance in the past.
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  • 39
    Publication Date: 2016-03-28
    Description: Atmospheric nitrogen (N) deposition has been shown to decrease plant species richness along regional deposition gradients in Europe and in experimental manipulations. However, the general response of species richness to N deposition across different vegetation types, soil conditions, and climates remains largely unknown even though responses may be contingent on these environmental factors. We assessed the effect of N deposition on herbaceous richness for 15,136 forest, woodland, shrubland, and grassland sites across the continental United States, to address how edaphic and climatic conditions altered vulnerability to this stressor. In our dataset, with N deposition ranging from 1 to 19 kg N⋅ha−1⋅y−1, we found a unimodal relationship; richness increased at low deposition levels and decreased above 8.7 and 13.4 kg N⋅ha−1⋅y−1 in open and closed-canopy vegetation, respectively. N deposition exceeded critical loads for loss of plant species richness in 24% of 15,136 sites examined nationwide. There were negative relationships between species richness and N deposition in 36% of 44 community gradients. Vulnerability to N deposition was consistently higher in more acidic soils whereas the moderating roles of temperature and precipitation varied across scales. We demonstrate here that negative relationships between N deposition and species richness are common, albeit not universal, and that fine-scale processes can moderate vegetation responses to N deposition. Our results highlight the importance of contingent factors when estimating ecosystem vulnerability to N deposition and suggest that N deposition is affecting species richness in forested and nonforested systems across much of the continental United States.
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  • 40
    Publication Date: 2016-02-29
    Description: Heat-shock protein of 90 kDa (Hsp90) is an essential molecular chaperone that adopts different 3D structures associated with distinct nucleotide states: a wide-open, V-shaped dimer in the apo state and a twisted, N-terminally closed dimer with ATP. Although the N domain is known to mediate ATP binding, how Hsp90 senses the bound nucleotide and facilitates dimer closure remains unclear. Here we present atomic structures of human mitochondrial Hsp90N (TRAP1N) and a composite model of intact TRAP1 revealing a previously unobserved coiled-coil dimer conformation that may precede dimer closure and is conserved in intact TRAP1 in solution. Our structure suggests that TRAP1 normally exists in an autoinhibited state with the ATP lid bound to the nucleotide-binding pocket. ATP binding displaces the ATP lid that signals the cis-bound ATP status to the neighboring subunit in a highly cooperative manner compatible with the coiled-coil intermediate state. We propose that TRAP1 is a ligand-activated molecular chaperone, which couples ATP binding to dramatic changes in local structure required for protein folding.
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  • 41
    Publication Date: 2016-01-08
    Description: Cell adhesion and migration are highly dynamic biological processes that play important roles in organ development and cancer metastasis. Their tight regulation by small GTPases and protein phosphorylation make interrogation of these key processes of great importance. We now show that the conserved dual-specificity phosphatase human cell-division cycle 14A (hCDC14A) associates with the actin cytoskeleton of human cells. To understand hCDC14A function at this location, we manipulated native loci to ablate hCDC14A phosphatase activity (hCDC14APD) in untransformed hTERT-RPE1 and colorectal cancer (HCT116) cell lines and expressed the phosphatase in HeLa FRT T-Rex cells. Ectopic expression of hCDC14A induced stress fiber formation, whereas stress fibers were diminished in hCDC14APD cells. hCDC14APD cells displayed faster cell migration and less adhesion than wild-type controls. hCDC14A colocalized with the hCDC14A substrate kidney- and brain-expressed protein (KIBRA) at the cell leading edge and overexpression of KIBRA was able to reverse the phenotypes of hCDC14APD cells. Finally, we show that ablation of hCDC14A activity increased the aggressive nature of cells in an in vitro tumor formation assay. Consistently, hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer, to suggest that hCDC14A may directly contribute to the metastatic potential of tumors. Thus, we have uncovered an unanticipated role for hCDC14A in cell migration and adhesion that is clearly distinct from the mitotic and cytokinesis functions of Cdc14/Flp1 in budding and fission yeast.
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  • 42
    Publication Date: 2016-02-08
    Description: The bromodomain and extraterminal domain (BET) protein family are promising therapeutic targets for a range of diseases linked to transcriptional activation, cancer, viral latency, and viral integration. Tandem bromodomains selectively tether BET proteins to chromatin by engaging cognate acetylated histone marks, and the extraterminal (ET) domain is the focal point for recruiting a range of cellular and viral proteins. BET proteins guide γ-retroviral integration to transcription start sites and enhancers through bimodal interaction with chromatin and the γ-retroviral integrase (IN). We report the NMR-derived solution structure of the Brd4 ET domain bound to a conserved peptide sequence from the C terminus of murine leukemia virus (MLV) IN. The complex reveals a protein–protein interaction governed by the binding-coupled folding of disordered regions in both interacting partners to form a well-structured intermolecular three-stranded β sheet. In addition, we show that a peptide comprising the ET binding motif (EBM) of MLV IN can disrupt the cognate interaction of Brd4 with NSD3, and that substitutions of Brd4 ET residues essential for binding MLV IN also impair interaction of Brd4 with a number of cellular partners involved in transcriptional regulation and chromatin remodeling. This suggests that γ-retroviruses have evolved the EBM to mimic a cognate interaction motif to achieve effective integration in host chromatin. Collectively, our findings identify key structural features of the ET domain of Brd4 that allow for interactions with both cellular and viral proteins.
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  • 43
    Publication Date: 2016-05-03
    Description: Understanding the ultralow velocity zones (ULVZs) places constraints on the chemical composition and thermal structure of deep Earth and provides critical information on the dynamics of large-scale mantle convection, but their origin has remained enigmatic for decades. Recent studies suggest that metallic iron and carbon are produced in subducted slabs when they sink beyond a depth of 250 km. Here we show that the eutectic melting curve of the iron−carbon system crosses the current geotherm near Earth’s core−mantle boundary, suggesting that dense metallic melt may form in the lowermost mantle. If concentrated into isolated patches, such melt could produce the seismically observed density and velocity features of ULVZs. Depending on the wetting behavior of the metallic melt, the resultant ULVZs may be short-lived domains that are replenished or regenerated through subduction, or long-lasting regions containing both metallic and silicate melts. Slab-derived metallic melt may produce another type of ULVZ that escapes core sequestration by reacting with the mantle to form iron-rich postbridgmanite or ferropericlase. The hypotheses connect peculiar features near Earth's core−mantle boundary to subduction of the oceanic lithosphere through the deep carbon cycle.
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  • 44
    Publication Date: 2017-04-03
    Description: Possible transition between two phases of supercooled liquid water, namely the low- and high-density liquid water, has been only predicted to occur below 230 K from molecular dynamics (MD) simulation. However, such a phase transition cannot be detected in the laboratory because of the so-called “no-man’s land” under deeply supercooled condition, where only crystalline ices have been observed. Here, we show MD simulation evidence that, inside an isolated carbon nanotube (CNT) with a diameter of 1.25 nm, both low- and high-density liquid water states can be detected near ambient temperature and above ambient pressure. In the temperature–pressure phase diagram, the low- and high-density liquid water phases are separated by the hexagonal ice nanotube (hINT) phase, and the melting line terminates at the isochore end point near 292 K because of the retracting melting line from 292 to 278 K. Beyond the isochore end point (292 K), low- and high-density liquid becomes indistinguishable. When the pressure is increased from 10 to 600 MPa along the 280-K isotherm, we observe that water inside the 1.25-nm-diameter CNT can undergo low-density liquid to hINT to high-density liquid reentrant first-order transitions.
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  • 45
    Publication Date: 2017-01-30
    Description: Rotaviruses (RVs) are highly important pathogens that cause severe diarrhea among infants and young children worldwide. The understanding of the molecular mechanisms underlying RV replication and pathogenesis has been hampered by the lack of an entirely plasmid-based reverse genetics system. In this study, we describe the recovery of recombinant RVs entirely from cloned cDNAs. The strategy requires coexpression of a small transmembrane protein that accelerates cell-to-cell fusion and vaccinia virus capping enzyme. We used this system to obtain insights into the process by which RV nonstructural protein NSP1 subverts host innate immune responses. By insertion into the NSP1 gene segment, we recovered recombinant viruses that encode split-green fluorescent protein–tagged NSP1 and NanoLuc luciferase. This technology will provide opportunities for studying RV biology and foster development of RV vaccines and therapeutics.
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  • 46
    Publication Date: 2016-02-08
    Description: The short-lived 26Al radionuclide is thought to have been admixed into the initially 26Al-poor protosolar molecular cloud before or contemporaneously with its collapse. Bulk inner Solar System reservoirs record positively correlated variability in mass-independent 54Cr and 26Mg*, the decay product of 26Al. This correlation is interpreted as reflecting progressive thermal processing of in-falling 26Al-rich molecular cloud material in the inner Solar System. The thermally unprocessed molecular cloud matter reflecting the nucleosynthetic makeup of the molecular cloud before the last addition of stellar-derived 26Al has not been identified yet but may be preserved in planetesimals that accreted in the outer Solar System. We show that metal-rich carbonaceous chondrites and their components have a unique isotopic signature extending from an inner Solar System composition toward a 26Mg*-depleted and 54Cr-enriched component. This composition is consistent with that expected for thermally unprocessed primordial molecular cloud material before its pollution by stellar-derived 26Al. The 26Mg* and 54Cr compositions of bulk metal-rich chondrites require significant amounts (25–50%) of primordial molecular cloud matter in their precursor material. Given that such high fractions of primordial molecular cloud material are expected to survive only in the outer Solar System, we infer that, similarly to cometary bodies, metal-rich carbonaceous chondrites are samples of planetesimals that accreted beyond the orbits of the gas giants. The lack of evidence for this material in other chondrite groups requires isolation from the outer Solar System, possibly by the opening of disk gaps from the early formation of gas giants.
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  • 47
    Publication Date: 2017-01-31
    Description: Mammalian intrinsic apoptosis requires activation of the initiator caspase-9, which then cleaves and activates the effector caspases to execute cell killing. The heptameric Apaf-1 apoptosome is indispensable for caspase-9 activation by together forming a holoenzyme. The molecular mechanism of caspase-9 activation remains largely enigmatic. Here, we report the cryoelectron microscopy (cryo-EM) structure of an apoptotic holoenzyme and structure-guided biochemical analyses. The caspase recruitment domains (CARDs) of Apaf-1 and caspase-9 assemble in two different ways: a 4:4 complex docks onto the central hub of the apoptosome, and a 2:1 complex binds the periphery of the central hub. The interface between the CARD complex and the central hub is required for caspase-9 activation within the holoenzyme. Unexpectedly, the CARD of free caspase-9 strongly inhibits its proteolytic activity. These structural and biochemical findings demonstrate that the apoptosome activates caspase-9 at least in part through sequestration of the inhibitory CARD domain.
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  • 48
    Publication Date: 2016-04-25
    Description: Growing suspension rates predict major negative life outcomes, including adult incarceration and unemployment. Experiment 1 tested whether teachers (n = 39) could be encouraged to adopt an empathic rather than punitive mindset about discipline—to value students’ perspectives and sustain positive relationships while encouraging better behavior. Experiment 2 tested whether an empathic response to misbehavior would sustain students’ (n = 302) respect for teachers and motivation to behave well in class. These hypotheses were confirmed. Finally, a randomized field experiment tested a brief, online intervention to encourage teachers to adopt an empathic mindset about discipline. Evaluated at five middle schools in three districts (Nteachers = 31; Nstudents = 1,682), this intervention halved year-long student suspension rates from 9.6% to 4.8%. It also bolstered respect the most at-risk students, previously suspended students, perceived from teachers. Teachers’ mindsets about discipline directly affect the quality of teacher–student relationships and student suspensions and, moreover, can be changed through scalable intervention.
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  • 49
    Publication Date: 2017-02-08
    Description: TheTrypanosoma cruziascorbate peroxidase is, by sequence analysis, a hybrid type A member of class I heme peroxidases [TcAPx-cytochromecperoxidase (CcP)], suggesting both ascorbate (Asc) and cytochromec(Cc) peroxidase activity. Here, we show that the enzyme reacts fast with H2O2(k= 2.9 × 107M−1⋅s−1) and catalytically decomposes H2O2using Cc as the reducing substrate with higher efficiency than Asc (kcat/Km= 2.1 × 105versus 3.5 × 104M−1⋅s−1, respectively). Visible-absorption spectra of purified recombinantTcAPx-CcP after H2O2reaction denote the formation of a compound I-like product, characteristic of the generation of a tryptophanyl radical-cation (Trp233•+). Mutation of Trp233to phenylalanine (W233F) completely abolishes the Cc-dependent peroxidase activity. In addition to Trp233•+, a Cys222-derived radical was identified by electron paramagnetic resonance spin trapping, immunospin trapping, and MS analysis after equimolar H2O2addition, supporting an alternative electron transfer (ET) pathway from the heme. Molecular dynamics studies revealed that ET between Trp233and Cys222is possible and likely to participate in the catalytic cycle. Recognizing the ability ofTcAPx-CcP to use alternative reducing substrates, we searched for its subcellular localization in the infective parasite stages (intracellular amastigotes and extracellular trypomastigotes).TcAPx-CcP was found closely associated with mitochondrial membranes and, most interestingly, with the outer leaflet of the plasma membrane, suggesting a role at the host–parasite interface.TcAPx-CcP overexpressers were significantly more infective to macrophages and cardiomyocytes, as well as in the mouse model of Chagas disease, supporting the involvement ofTcAPx-CcP in pathogen virulence as part of the parasite antioxidant armamentarium.
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  • 50
    Publication Date: 2016-03-15
    Description: Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as an S-adenosylmethionine–dependent α-N-methyltransferase that converts phomopsin A to anN,N-dimethylated congener (phomopsin E), and show that the methyltransferases involved in dikaritin biosynthesis have evolved differently and likely have broad substrate specificities. Genome mining studies identified eight previously unknown dikaritins in different strains, highlighting the untapped capacity of RiPP biosynthesis in fungi and setting the stage for investigating the biological activities and unknown biosynthetic transformations of this family of fungal natural products.
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  • 51
    Publication Date: 2016-06-13
    Description: Throughout history, psychologists and philosophers have proposed that good sleep benefits memory, yet current studies focusing on the relationship between traditionally reported sleep features (e.g., minutes in sleep stages) and changes in memory performance show contradictory findings. This discrepancy suggests that there are events occurring during sleep that have not yet been considered. The autonomic nervous system (ANS) shows strong variation across sleep stages. Also, increases in ANS activity during waking, as measured by heart rate variability (HRV), have been correlated with memory improvement. However, the role of ANS in sleep-dependent memory consolidation has never been examined. Here, we examined whether changes in cardiac ANS activity (HRV) during a daytime nap were related to performance on two memory conditions (Primed and Repeated) and a nonmemory control condition on the Remote Associates Test. In line with prior studies, we found sleep-dependent improvement in the Primed condition compared with the Quiet Wake control condition. Using regression analyses, we compared the proportion of variance in performance associated with traditionally reported sleep features (model 1) vs. sleep features and HRV during sleep (model 2). For both the Primed and Repeated conditions, model 2 (sleep + HRV) predicted performance significantly better (73% and 58% of variance explained, respectively) compared with model 1 (sleep only, 46% and 26% of variance explained, respectively). These findings present the first evidence, to our knowledge, that ANS activity may be one potential mechanism driving sleep-dependent plasticity.
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  • 52
    Publication Date: 2016-11-14
    Description: Adolescents’ participation in intergroup conflicts comprises an imminent global risk, and understanding its neural underpinnings may open new perspectives. We assessed Jewish-Israeli and Arab-Palestinian adolescents for brain response to the pain of ingroup/outgroup protagonists using magnetoencephalography (MEG), one-on-one positive and conflictual interactions with an outgroup member, attitudes toward the regional conflict, and oxytocin levels. A neural marker of ingroup bias emerged, expressed via alpha modulations in the somatosensory cortex (S1) that characterized an automatic response to the pain of all protagonists followed by rebound/enhancement to ingroup pain only. Adolescents’ hostile social interactions with outgroup members and uncompromising attitudes toward the conflict influenced this neural marker. Furthermore, higher oxytocin levels in the Jewish-Israeli majority and tighter brain-to-brain synchrony among group members in the Arab-Palestinian minority enhanced the neural ingroup bias. Findings suggest that in cases of intractable intergroup conflict, top-down control mechanisms may block the brain’s evolutionary-ancient resonance to outgroup pain, pinpointing adolescents’ interpersonal and sociocognitive processes as potential targets for intervention.
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  • 53
    Publication Date: 2016-04-11
    Description: The origins of human abilities for mathematics are debated: Some theories suggest that they are founded upon evolutionarily ancient brain circuits for number and space and others that they are grounded in language competence. To evaluate what brain systems underlie higher mathematics, we scanned professional mathematicians and mathematically naive subjects of equal academic standing as they evaluated the truth of advanced mathematical and nonmathematical statements. In professional mathematicians only, mathematical statements, whether in algebra, analysis, topology or geometry, activated a reproducible set of bilateral frontal, Intraparietal, and ventrolateral temporal regions. Crucially, these activations spared areas related to language and to general-knowledge semantics. Rather, mathematical judgments were related to an amplification of brain activity at sites that are activated by numbers and formulas in nonmathematicians, with a corresponding reduction in nearby face responses. The evidence suggests that high-level mathematical expertise and basic number sense share common roots in a nonlinguistic brain circuit.
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  • 54
    Publication Date: 2017-04-11
    Description: There is a growing effort in creating chiral transport of sound waves. However, most approaches so far have been confined to the macroscopic scale. Here, we propose an approach suitable to the nanoscale that is based on pseudomagnetic fields. These pseudomagnetic fields for sound waves are the analogue of what electrons experience in strained graphene. In our proposal, they are created by simple geometrical modifications of an existing and experimentally proven phononic crystal design, the snowflake crystal. This platform is robust, scalable, and well-suited for a variety of excitation and readout mechanisms, among them optomechanical approaches.
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  • 55
    Publication Date: 2016-07-18
    Description: Neurodevelopmental origins of functional variation in older age are increasingly being acknowledged, but identification of how early factors impact human brain and cognition throughout life has remained challenging. Much focus has been on age-specific mechanisms affecting neural foundations of cognition and their change. In contrast to this approach, we tested whether cerebral correlates of general cognitive ability (GCA) in development could be extended to the rest of the lifespan, and whether early factors traceable to prenatal stages, such as birth weight and parental education, may exert continuous influences. We measured the area of the cerebral cortex in a longitudinal sample of 974 individuals aged 4–88 y (1,633 observations). An extensive cortical region was identified wherein area related positively to GCA in development. By tracking area of the cortical region identified in the child sample throughout the lifespan, we showed that the cortical change trajectories of higher and lower GCA groups were parallel through life, suggesting continued influences of early life factors. Birth weight and parental education obtained from the Norwegian Mother–Child Cohort study were identified as such early factors of possible life-long influence. Support for a genetic component was obtained in a separate twin sample (Vietnam Era Twin Study of Aging), but birth weight in the child sample had an effect on cortical area also when controlling for possible genetic differences in terms of parental height. Our results provide novel evidence for stability in brain–cognition relationships throughout life, and indicate that early life factors impact brain and cognition for the entire life course.
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  • 56
    Publication Date: 2016-02-29
    Description: As a new type of topological materials, ZrTe5 shows many exotic properties under extreme conditions. Using resistance and ac magnetic susceptibility measurements under high pressure, while the resistance anomaly near 128 K is completely suppressed at 6.2 GPa, a fully superconducting transition emerges. The superconducting transition temperature Tc increases with applied pressure, and reaches a maximum of 4.0 K at 14.6 GPa, followed by a slight drop but remaining almost constant value up to 68.5 GPa. At pressures above 21.2 GPa, a second superconducting phase with the maximum Tc of about 6.0 K appears and coexists with the original one to the maximum pressure studied in this work. In situ high-pressure synchrotron X-ray diffraction and Raman spectroscopy combined with theoretical calculations indicate the observed two-stage superconducting behavior is correlated to the structural phase transition from ambient Cmcm phase to high-pressure C2/m phase around 6 GPa, and to a mixture of two high-pressure phases of C2/m and P-1 above 20 GPa. The combination of structure, transport measurement, and theoretical calculations enable a complete understanding of the emerging exotic properties in 3D topological materials under extreme environments.
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  • 57
    Publication Date: 2016-04-11
    Description: Madagascar’s lemurs display a diverse array of feeding strategies with complex relationships to seed dispersal mechanisms in Malagasy plants. Although these relationships have been explored previously on a case-by-case basis, we present here the first comprehensive analysis of lemuriform feeding, to our knowledge, and its hypothesized effects on seed dispersal and the long-term survival of Malagasy plant lineages. We used a molecular phylogenetic framework to examine the mode and tempo of diet evolution, and to quantify the associated morphological space occupied by Madagascar’s lemurs, both extinct and extant. Using statistical models and morphometric analyses, we demonstrate that the extinction of large-bodied lemurs resulted in a significant reduction in functional morphological space associated with seed dispersal ability. These reductions carry potentially far-reaching consequences for Malagasy ecosystems, and we highlight large-seeded Malagasy plants that appear to be without extant animal dispersers. We also identify living lemurs that are endangered yet occupy unique and essential dispersal niches defined by our morphometric analyses.
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  • 58
    Publication Date: 2017-04-24
    Description: Kin selection theory predicts that, where kin discrimination is possible, animals should typically act more favorably toward closer genetic relatives and direct aggression toward less closely related individuals. Contrary to this prediction, we present data from an 18-y study of wild banded mongooses, Mungos mungo, showing that females that are more closely related to dominant individuals are specifically targeted for forcible eviction from the group, often suffering severe injury, and sometimes death, as a result. This pattern cannot be explained by inbreeding avoidance or as a response to more intense local competition among kin. Instead, we use game theory to show that such negative kin discrimination can be explained by selection for unrelated targets to invest more effort in resisting eviction. Consistent with our model, negative kin discrimination is restricted to eviction attempts of older females capable of resistance; dominants exhibit no kin discrimination when attempting to evict younger females, nor do they discriminate between more closely or less closely related young when carrying out infanticidal attacks on vulnerable infants who cannot defend themselves. We suggest that in contexts where recipients of selfish acts are capable of resistance, the usual prediction of positive kin discrimination can be reversed. Kin selection theory, as an explanation for social behavior, can benefit from much greater exploration of sequential social interactions.
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  • 59
    Publication Date: 2017-07-03
    Description: In biology, last names have been used as proxy for genetic relatedness in pioneering studies of neutral theory and human migrations. More recently, analyzing the last name distribution of Italian academics has raised the suspicion of nepotism, with faculty hiring their relatives for academic posts. Here, we analyze three large datasets containing the last names of all academics in Italy, researchers from France, and those working at top public institutions in the United States. Through simple randomizations, we show that the US academic system is geographically well-mixed, whereas Italian academics tend to work in their native region. By contrasting maiden and married names, we can detect academic couples in France. Finally, we detect the signature of nepotism in the Italian system, with a declining trend. The claim that our tests detect nepotism as opposed to other effects is supported by the fact that we obtain different results for the researchers hired after 2010, when an antinepotism law was in effect.
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  • 60
    Publication Date: 2016-07-25
    Description: Family background—kinship—can propagate careers. The evidence for academic nepotism is littered with complex associations and disputed causal inferences. Surname clustering, albeit with very careful consideration of surnames’ flows across regions and time periods, can be used to reflect family ties. We examined surname patterns in the health science literature, by country, across five decades. Over 21 million papers indexed in the MEDLINE/PubMed database were analyzed. We identified relevant country-specific kinship trends over time and found that authors who are part of a kin tend to occupy central positions in their collaborative networks. Just as kin build potent academic networks with their own resources, societies may do well to provide equivalent support for talented individuals with fewer resources, on the periphery of networks.
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  • 61
    Publication Date: 2017-10-23
    Description: Skin tissues, in particular the epidermis, are severely affected by zinc deficiency. However, the zinc-mediated mechanisms that maintain the cells that form the epidermis have not been established. Here, we report that the zinc transporter ZIP10 is highly expressed in the outer root sheath of hair follicles and plays critical roles in epidermal development. We found that ZIP10 marked epidermal progenitor cell subsets and that ablating Zip10 caused significant epidermal hypoplasia accompanied by down-regulation of the transactivation of p63, a master regulator of epidermal progenitor cell proliferation and differentiation. Both ZIP10 and p63 are significantly increased during epidermal development, in which ZIP10-mediated zinc influx promotes p63 transactivation. Collectively, these results indicate that ZIP10 plays important roles in epidermal development via, at least in part, the ZIP10–zinc–p63 signaling axis, thereby highlighting the physiological significance of zinc regulation in the maintenance of skin epidermis.
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  • 62
    Publication Date: 2017-02-06
    Description: Intrinsically disordered regions (IDRs) are characterized by their lack of stable secondary or tertiary structure and comprise a large part of the eukaryotic proteome. Although these regions play a variety of signaling and regulatory roles, they appear to be rapidly evolving at the primary sequence level. To understand the functional implications of this rapid evolution, we focused on a highly diverged IDR inSaccharomyces cerevisiaethat is involved in regulating multiple conserved MAPK pathways. We hypothesized that under stabilizing selection, the functional output of orthologous IDRs could be maintained, such that diverse genotypes could lead to similar function and fitness. Consistent with the stabilizing selection hypothesis, we find that diverged, orthologous IDRs can mostly recapitulate wild-type function and fitness inS. cerevisiae. We also find that the electrostatic charge of the IDR is correlated with signaling output and, using phylogenetic comparative methods, find evidence for selection maintaining this quantitative molecular trait despite underlying genotypic divergence.
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  • 63
    Publication Date: 2016-07-20
    Description: The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish type I kinase PIP5Kα, we identified a structural motif unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas residues flanking the phosphate binding Arg244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how PIPKs achieve their exquisite substrate specificity.
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  • 64
    Publication Date: 2016-10-17
    Description: Cleavage of the group-specific antigen (Gag) polyprotein by HIV-1 protease represents the critical first step in the conversion of immature noninfectious viral particles to mature infectious virions. Selective pressure exerted by HIV-1 protease inhibitors, a mainstay of current anti–HIV-1 therapies, results in the accumulation of drug resistance mutations in both protease and Gag. Surprisingly, a large number of these mutations (known as secondary or compensatory mutations) occur outside the active site of protease or the cleavage sites of Gag (located within intrinsically disordered linkers connecting the globular domains of Gag to one another), suggesting that transient encounter complexes involving the globular domains of Gag may play a role in guiding and facilitating access of the protease to the Gag cleavage sites. Here, using large fragments of Gag, as well as catalytically inactive and active variants of protease, we probe the nature of such rare encounter complexes using intermolecular paramagnetic relaxation enhancement, a highly sensitive technique for detecting sparsely populated states. We show that Gag-protease encounter complexes are primarily mediated by interactions between protease and the globular domains of Gag and that the sites of transient interactions are correlated with surface exposed regions that exhibit a high propensity to mutate in the presence of HIV-1 protease inhibitors.
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  • 65
    Publication Date: 2016-06-17
    Description: Fibroblasts are common cell types in cancer stroma and lay down collagen required for survival and growth of cancer cells. Although some cancer therapy strategies target tumor fibroblasts, their origin remains controversial. Multiple publications suggest circulating mesenchymal precursors as a source of tumor-associated fibroblasts. However, we show by three independent approaches that tumor fibroblasts derive primarily from local, sessile precursors. First, transplantable tumors developing in a mouse expressing green fluorescent reporter protein (EGFP) under control of the type I collagen (Col-I) promoter (COL-EGFP) had green stroma, whereas we could not find COL-EGFP+ cells in tumors developing in the parabiotic partner lacking the fluorescent reporter. Lack of incorporation of COL-EGFP+ cells from the circulation into tumors was confirmed in parabiotic pairs of COL-EGFP mice and transgenic mice developing autochthonous intestinal adenomas. Second, transplantable tumors developing in chimeric mice reconstituted with bone marrow cells from COL-EGFP mice very rarely showed stromal fibroblasts expressing EGFP. Finally, cancer cells injected under full-thickness COL-EGFP skin grafts transplanted in nonreporter mice developed into tumors containing green stromal cells. Using multicolor in vivo confocal microscopy, we found that Col-I–expressing fibroblasts constituted approximately one-third of the stromal mass and formed a continuous sheet wrapping the tumor vessels. In summary, tumors form their fibroblastic stroma predominantly from precursors present in the local tumor microenvironment, whereas the contribution of bone marrow-derived circulating precursors is rare.
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  • 66
    Publication Date: 2016-02-29
    Description: In flowering plants, pollen tubes are guided into ovules by multiple attractants from female gametophytes to release paired sperm cells for double fertilization. It has been well-established that Ca2+ gradients in the pollen tube tips are essential for pollen tube guidance and that plasma membrane Ca2+ channels in pollen tube tips are core components that regulate Ca2+ gradients by mediating and regulating external Ca2+ influx. Therefore, Ca2+ channels are the core components for pollen tube guidance. However, there is still no genetic evidence for the identification of the putative Ca2+ channels essential for pollen tube guidance. Here, we report that the point mutations R491Q or R578K in cyclic nucleotide-gated channel 18 (CNGC18) resulted in abnormal Ca2+ gradients and strong pollen tube guidance defects by impairing the activation of CNGC18 in Arabidopsis. The pollen tube guidance defects of cngc18-17 (R491Q) and of the transfer DNA (T-DNA) insertion mutant cngc18-1 (+/−) were completely rescued by CNGC18. Furthermore, domain-swapping experiments showed that CNGC18’s transmembrane domains are indispensable for pollen tube guidance. Additionally, we found that, among eight Ca2+ channels (including six CNGCs and two glutamate receptor-like channels), CNGC18 was the only one essential for pollen tube guidance. Thus, CNGC18 is the long-sought essential Ca2+ channel for pollen tube guidance in Arabidopsis.
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  • 67
    Publication Date: 2016-12-08
    Description: Mapping posttranslational modifications (PTMs), which diversely modulate biological functions, represents a significant analytical challenge. The centerpiece technology for PTM site identification, mass spectrometry (MS), requires proteolytic cleavage in the vicinity of a PTM to yield peptides for sequencing. This requirement catalyzed our efforts to evolve MS-grade mutant PTM-directed proteases. Citrulline, a PTM implicated in epigenetic and immunological function, made an ideal first target, because citrullination eliminates arginyl tryptic sites. Bead-displayed trypsin mutant genes were translated in droplets, the mutant proteases were challenged to cleave bead-bound fluorogenic probes of citrulline-dependent proteolysis, and the resultant beads (1.3 million) were screened. The most promising mutant efficiently catalyzed citrulline-dependent peptide bond cleavage (kcat/KM= 6.9 × 105M−1⋅s−1). The resulting C-terminally citrullinated peptides generated characteristic isotopic patterns in MALDI-TOF MS, and both a fragmentation producty1ion corresponding to citrulline (176.1030m/z) and diagnostic peak pairs in the extracted ion chromatograms of LC-MS/MS analysis. Using these signatures, we identified citrullination sites in protein arginine deiminase 4 (12 sites) and in fibrinogen (25 sites, two previously unknown). The unique mass spectral features of PTM-dependent proteolytic digest products promise a generalized PTM site-mapping strategy based on a toolbox of such mutant proteases, which are now accessible by laboratory evolution.
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  • 68
    Publication Date: 2016-04-26
    Description: The primary cilium is a cellular organelle that coordinates signaling pathways critical for cell proliferation, differentiation, survival, and homeostasis. Intraflagellar transport (IFT) plays a pivotal role in assembling primary cilia. Disruption and/or dysfunction of IFT components can cause multiple diseases, including skeletal dysplasia. However, the mechanism by which IFT regulates skeletogenesis remains elusive. Here, we show that a neural crest-specific deletion of intraflagellar transport 20 (Ift20) in mice compromises ciliogenesis and intracellular transport of collagen, which leads to osteopenia in the facial region. Whereas platelet-derived growth factor receptor alpha (PDGFRα) was present on the surface of primary cilia in wild-type osteoblasts, disruption ofIft20down-regulated PDGFRα production, which caused suppression of PDGF-Akt signaling, resulting in decreased osteogenic proliferation and increased cell death. Although osteogenic differentiation in cranial neural crest (CNC)-derived cells occurred normally inIft20-mutant cells, the process of mineralization was severely attenuated due to delayed secretion of type I collagen. In control osteoblasts, procollagen was easily transported from the endoplasmic reticulum (ER) to the Golgi apparatus. By contrast, despite having similar levels of collagen type 1 alpha 1 (Col1a1) expression,Ift20mutants did not secrete procollagen because of dysfunctional ER-to-Golgi trafficking. These data suggest that in the multipotent stem cells of CNCs, IFT20 is indispensable for regulating not only ciliogenesis but also collagen intracellular trafficking. Our study introduces a unique perspective on the canonical and noncanonical functions of IFT20 in craniofacial skeletal development.
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  • 69
    Publication Date: 2017-07-03
    Description: The plant hormone cytokinin affects a diverse array of growth and development processes and responses to the environment. How a signaling molecule mediates such a diverse array of outputs and how these response pathways are integrated with other inputs remain fundamental questions in plant biology. To this end, we characterized the transcriptional network initiated by the type-B ARABIDOPSIS RESPONSE REGULATORs (ARRs) that mediate the cytokinin primary response, making use of chromatin immunoprecipitation sequencing (ChIP-seq), protein-binding microarrays, and transcriptomic approaches. By ectopic overexpression of ARR10, Arabidopsis lines hypersensitive to cytokinin were generated and used to clarify the role of cytokinin in regulation of various physiological responses. ChIP-seq was used to identify the cytokinin-dependent targets for ARR10, thereby defining a crucial link between the cytokinin primary-response pathway and the transcriptional changes that mediate physiological responses to this phytohormone. Binding of ARR10 was induced by cytokinin with binding sites enriched toward the transcriptional start sites for both induced and repressed genes. Three type-B ARR DNA-binding motifs, determined by use of protein-binding microarrays, were enriched at ARR10 binding sites, confirming their physiological relevance. WUSCHEL was identified as a direct target of ARR10, with its cytokinin-enhanced expression resulting in enhanced shooting in tissue culture. Results from our analyses shed light on the physiological role of the type-B ARRs in regulating the cytokinin response, mechanism of type-B ARR activation, and basis by which cytokinin regulates diverse aspects of growth and development as well as responses to biotic and abiotic factors.
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  • 70
    Publication Date: 2017-11-20
    Description: Equations describing the rolling of a spherical ball on a horizontal surface are obtained, the motion being activated by an internal rotor driven by a battery mechanism. The rotor is modeled as a point mass mounted inside a spherical shell and caused to move in a prescribed circular orbit relative to the shell. The system is described in terms of four independent dimensionless parameters. The equations governing the angular momentum of the ball relative to the point of contact with the plane constitute a six-dimensional, nonholonomic, nonautonomous dynamical system with cubic nonlinearity. This system is decoupled from a subsidiary system that describes the trajectories of the center of the ball. Numerical integration of these equations for prescribed values of the parameters and initial conditions reveals a tendency toward chaotic behavior as the radius of the circular orbit of the point mass increases (other parameters being held constant). It is further shown that there is a range of values of the initial angular velocity of the shell for which chaotic trajectories are realized while contact between the shell and the plane is maintained. The predicted behavior has been observed in our experiments.
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  • 71
    Publication Date: 2016-02-01
    Description: Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, platelet-derived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development. However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.
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  • 72
    Publication Date: 2016-07-19
    Description: Disturbances in amino acid metabolism, which have been observed in Huntington’s disease (HD), may account for the profound inanition of HD patients. HD is triggered by an expansion of polyglutamine repeats in the protein huntingtin (Htt), impacting diverse cellular processes, ranging from transcriptional regulation to cognitive and motor functions. We show here that the master regulator of amino acid homeostasis, activating transcription factor 4 (ATF4), is dysfunctional in HD because of oxidative stress contributed by aberrant cysteine biosynthesis and transport. Consistent with these observations, antioxidant supplementation reverses the disordered ATF4 response to nutrient stress. Our findings establish a molecular link between amino acid disposition and oxidative stress leading to cytotoxicity. This signaling cascade may be relevant to other diseases involving redox imbalance and deficits in amino acid metabolism.
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  • 73
    Publication Date: 2016-11-09
    Description: Oncogenic activation of protein kinaseBRAFdrives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations inBRAFoccur in ∼2–7% of lung adenocarcinoma (LA),BRAF-mutant LA is the most frequent cause ofBRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly theBRAFV600E-mutant allele, the spectrum ofBRAFmutations in LA includesBRAFV600E(∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such asBRAFG469AandBRAFG466V. The presence ofBRAFV600Ein LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib inBRAFV600E-mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600EBRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation inBRAF-mutant LA models. We show that PLX8394 treatment is effective in bothBRAFV600Eand certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naiveBRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncatedBRAFV600Ethat promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.
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  • 74
    Publication Date: 2016-10-24
    Description: Brown planthopper (BPH), Nilaparvata lugens Stål, is one of the most devastating insect pests of rice (Oryza sativa L.). Currently, 30 BPH-resistance genes have been genetically defined, most of which are clustered on specific chromosome regions. Here, we describe molecular cloning and characterization of a BPH-resistance gene, BPH9, mapped on the long arm of rice chromosome 12 (12L). BPH9 encodes a rare type of nucleotide-binding and leucine-rich repeat (NLR)-containing protein that localizes to the endomembrane system and causes a cell death phenotype. BPH9 activates salicylic acid- and jasmonic acid-signaling pathways in rice plants and confers both antixenosis and antibiosis to BPH. We further demonstrated that the eight BPH-resistance genes that are clustered on chromosome 12L, including the widely used BPH1, are allelic with each other. To honor the priority in the literature, we thus designated this locus as BPH1/9. These eight genes can be classified into four allelotypes, BPH1/9-1, -2, -7, and -9. These allelotypes confer varying levels of resistance to different biotypes of BPH. The coding region of BPH1/9 shows a high level of diversity in rice germplasm. Homologous fragments of the nucleotide-binding (NB) and leucine-rich repeat (LRR) domains exist, which might have served as a repository for generating allele diversity. Our findings reveal a rice plant strategy for modifying the genetic information to gain the upper hand in the struggle against insect herbivores. Further exploration of natural allelic variation and artificial shuffling within this gene may allow breeding to be tailored to control emerging biotypes of BPH.
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  • 75
    Publication Date: 2017-09-11
    Description: Protein phosphorylation by cyclic AMP-dependent protein kinase (PKA) underlies key cellular processes, including sympathetic stimulation of heart cells, and potentiation of synaptic strength in neurons. Unrestrained PKA activity is pathological, and an enduring challenge is to understand how the activity of PKA catalytic subunits is directed in cells. We developed a light-activated cross-linking approach to monitor PKA subunit interactions with temporal precision in living cells. This enabled us to refute the recently proposed theory that PKA catalytic subunits remain tethered to regulatory subunits during cAMP elevation. Instead, we have identified other features of PKA signaling for reducing catalytic subunit diffusion and increasing recapture rate. Comprehensive quantitative immunoblotting of protein extracts from human embryonic kidney cells and rat organs reveals that regulatory subunits are always in large molar excess of catalytic subunits (average ∼17-fold). In the majority of organs tested, type II regulatory (RII) subunits were found to be the predominant PKA subunit. We also examined the architecture of PKA complexes containing RII subunits using cross-linking coupled to mass spectrometry. Quantitative comparison of cross-linking within a complex of RIIβ and Cβ, with or without the prototypical anchoring protein AKAP18α, revealed that the dimerization and docking domain of RIIβ is between its second cAMP binding domains. This architecture is compatible with anchored RII subunits directing the myristylated N terminus of catalytic subunits toward the membrane for release and recapture within the plane of the membrane.
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  • 76
  • 77
    Publication Date: 2016-12-23
    Description: Although the enzymatic activity of isocitrate dehydrogenase 1 (IDH1) was defined decades ago, its functions in vivo are not yet fully understood. Cytosolic IDH1 converts isocitrate to α-ketoglutarate (α-KG), a key metabolite regulating nitrogen homeostasis in catabolic pathways. It was thought that IDH1 might enhance lipid biosynthesis in liver or adipose tissue by generating NADPH, but we show here that lipid contents are relatively unchanged in both IDH1-null mouse liver and IDH1-deficient HepG2 cells generated using the CRISPR-Cas9 system. Instead, we found that IDH1 is critical for liver amino acid (AA) utilization. Body weights of IDH1-null mice fed a high-protein diet (HPD) were abnormally low. After prolonged fasting, IDH1-null mice exhibited decreased blood glucose but elevated blood alanine and glycine compared with wild-type (WT) controls. Similarly, in IDH1-deficient HepG2 cells, glucose consumption was increased, but alanine utilization and levels of intracellular α-KG and glutamate were reduced. In IDH1-deficient primary hepatocytes, gluconeogenesis as well as production of ammonia and urea were decreased. In IDH1-deficient whole livers, expression levels of genes involved in AA metabolism were reduced, whereas those involved in gluconeogenesis were up-regulated. Thus, IDH1 is critical for AA utilization in vivo and its deficiency attenuates gluconeogenesis primarily by impairing α-KG–dependent transamination of glucogenic AAs such as alanine.
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  • 78
    Publication Date: 2016-02-08
    Description: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.
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  • 79
    Publication Date: 2016-09-12
    Description: The Late Heavy Bombardment (LHB), a hypothesized impact spike at ∼3.9 Ga, is one of the major scientific concepts to emerge from Apollo-era lunar exploration. A significant portion of the evidence for the existence of the LHB comes from histograms of 40Ar/39Ar “plateau” ages (i.e., regions selected on the basis of apparent isochroneity). However, due to lunar magmatism and overprinting from subsequent impact events, virtually all Apollo-era samples show evidence for 40Ar/39Ar age spectrum disturbances, leaving open the possibility that partial 40Ar* resetting could bias interpretation of bombardment histories due to plateaus yielding misleadingly young ages. We examine this possibility through a physical model of 40Ar* diffusion in Apollo samples and test the uniqueness of the impact histories obtained by inverting plateau age histograms. Our results show that plateau histograms tend to yield age peaks, even in those cases where the input impact curve did not contain such a spike, in part due to the episodic nature of lunar crust or parent body formation. Restated, monotonically declining impact histories yield apparent age peaks that could be misinterpreted as LHB-type events. We further conclude that the assignment of apparent 40Ar/39Ar plateau ages bears an undesirably high degree of subjectivity. When compounded by inappropriate interpretations of histograms constructed from plateau ages, interpretation of apparent, but illusory, impact spikes is likely.
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  • 80
    Publication Date: 2017-02-16
    Description: Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuringN-methyl-d-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.
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  • 81
    Publication Date: 2016-02-01
    Description: Cell-type–specific G protein-coupled receptor (GPCR) signaling regulates distinct neuronal responses to various stimuli and is essential for axon guidance and targeting during development. However, its function in axonal regeneration in the mature CNS remains elusive. We found that subtypes of intrinsically photosensitive retinal ganglion cells (ipRGCs) in mice maintained high mammalian target of rapamycin (mTOR) levels after axotomy and that the light-sensitive GPCR melanopsin mediated this sustained expression. Melanopsin overexpression in the RGCs stimulated axonal regeneration after optic nerve crush by up-regulating mTOR complex 1 (mTORC1). The extent of the regeneration was comparable to that observed after phosphatase and tensin homolog (Pten) knockdown. Both the axon regeneration and mTOR activity that were enhanced by melanopsin required light stimulation and Gq/11 signaling. Specifically, activating Gq in RGCs elevated mTOR activation and promoted axonal regeneration. Melanopsin overexpression in RGCs enhanced the amplitude and duration of their light response, and silencing them with Kir2.1 significantly suppressed the increased mTOR signaling and axon regeneration that were induced by melanopsin. Thus, our results provide a strategy to promote axon regeneration after CNS injury by modulating neuronal activity through GPCR signaling.
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  • 82
    Publication Date: 2016-06-06
    Description: Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of KrasLA1/+;P53R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial–mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelial–mesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.
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  • 83
    Publication Date: 2017-01-17
    Description: Aberrant activation of β-catenin through its activity as a transcription factor has been observed in a large proportion of human malignancies. Despite the improved understanding of the β-catenin signaling pathway over the past three decades, attempts to develop therapies targeting β-catenin remain challenging, and none of these targeted therapies have advanced to the clinic. In this study, we show that part of the challenge in antagonizing β-catenin is caused by its dual functionality as a cell adhesion molecule and a signaling molecule. In a mouse model of basal ErbB2 receptor tyrosine kinase 2 (ErbB2)-positive breast cancer (ErbB2KI), which exhibits aberrant β-catenin nuclear signaling, β-catenin haploinsufficiency induced aggressive tumor formation and metastasis by promoting the disruption of adherens junctions, dedifferentiation, and an epithelial to mesenchymal transition (EMT) transcriptional program. In contrast to the accelerated tumor onset observed in the haploid-insufficient ErbB2 tumors, deletion of both β-catenin alleles in the ErbB2KImodel had only a minor impact on tumor onset that further correlated with the retention of normal adherens junctions. We further showed that retention of adherens junctional integrity was caused by the up-regulation of the closely related family member plakoglobin (γ-catenin) that maintained both adherens junctions and the activation of Wnt target genes. In contrast to the ErbB2KIbasal tumor model, modulation of β-catenin levels had no appreciable impact on tumor onset in an ErbB2-driven model of luminal breast cancer [murine mammary tumor virus promoter (MMTV-NIC)]. These observations argue that the balance of junctional and nuclear β-catenin activity has a profound impact on tumor progression in this basal model of ErbB2-positive breast cancer.
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  • 84
    Publication Date: 2017-03-13
    Description: Life history events, such as traumatic stress, illness, or starvation, can influence us through molecular changes that are recorded in a pattern of characteristic chromatin modifications. These modifications are often associated with adaptive adjustments in gene expression that can persist throughout the lifetime of the organism, or even span multiple generations. Although these adaptations may confer some selective advantage, if they are not appropriately regulated they can also be maladaptive in a context-dependent manner. We show here that during periods of acute starvation in Caenorhabditis elegans larvae, the master metabolic regulator AMP-activated protein kinase (AMPK) plays a critical role in blocking modifications to the chromatin landscape. This ensures that gene expression remains inactive in the germ-line precursors during adverse conditions. In its absence, critical chromatin modifications occur in the primordial germ cells (PGCs) of emergent starved L1 larvae that correlate with compromised reproductive fitness of the generation that experienced the stress, but also in the subsequent generations that never experienced the initial event. Our findings suggest that AMPK regulates the activity of the chromatin modifying COMPASS complex (complex proteins associated with Set1) to ensure that chromatin marks are not established until nutrient/energy contingencies are satisfied. Our study provides molecular insight that links metabolic adaptation to transgenerational epigenetic modification in response to acute periods of starvation.
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  • 85
    Publication Date: 2016-07-18
    Description: The six-iron cofactor of [FeFe]-hydrogenases (H-cluster) is the most efficient H2-forming catalyst in nature. It comprises a diiron active site with three carbon monoxide (CO) and two cyanide (CN−) ligands in the active oxidized state (Hox) and one additional CO ligand in the inhibited state (Hox-CO). The diatomic ligands are sensitive reporter groups for structural changes of the cofactor. Their vibrational dynamics were monitored by real-time attenuated total reflection Fourier-transform infrared spectroscopy. Combination of 13CO gas exposure, blue or red light irradiation, and controlled hydration of three different [FeFe]-hydrogenase proteins produced 8 Hox and 16 Hox-CO species with all possible isotopic exchange patterns. Extensive density functional theory calculations revealed the vibrational mode couplings of the carbonyl ligands and uniquely assigned each infrared spectrum to a specific labeling pattern. For Hox-CO, agreement between experimental and calculated infrared frequencies improved by up to one order of magnitude for an apical CN− at the distal iron ion of the cofactor as opposed to an apical CO. For Hox, two equally probable isomers with partially rotated ligands were suggested. Interconversion between these structures implies dynamic ligand reorientation at the H-cluster. Our experimental protocol for site-selective 13CO isotope editing combined with computational species assignment opens new perspectives for characterization of functional intermediates in the catalytic cycle.
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  • 86
    Publication Date: 2017-12-18
    Description: The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R-mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the Drd2 gene, raises the question of whether both isoforms may equally control presynaptic and postsynaptic events. Here, we addressed this question by comparing behavioral and cellular responses of mice with the selective ablation of either D2L or D2S isoform. We establish that the presence of either D2L or D2S can support postsynaptic functions related to the control of motor activity in basal conditions. On the contrary, absence of D2S but not D2L prevents the inhibition of tyrosine hydroxylase phosphorylation and, thereby, of dopamine synthesis, supporting a major presynaptic role for D2S. Interestingly, boosting dopamine signaling in the striatum by acute cocaine administration reveals that absence of D2L, but not of D2S, strongly impairs the motor and cellular response to the drug, in a manner similar to the ablation of both isoforms. These results suggest that when the dopamine system is challenged, D2L signaling is required for the control of striatal circuits regulating motor activity. Thus, our findings show that D2L and D2S share similar functions in basal conditions but not in response to stimulation of the dopamine system.
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  • 87
    Publication Date: 2016-05-09
    Description: After entry into the nucleus, herpes simplex virus (HSV) DNA is coated with repressive proteins and becomes the site of assembly of nuclear domain 10 (ND10) bodies. These small (0.1–1 μM) nuclear structures contain both constant [e.g., promyelocytic leukemia protein (PML), Sp100, death-domain associated protein (Daxx), and so forth] and variable proteins, depending on the function of the cells or the stress to which they are exposed. The amounts of PML and the number of ND10 structures increase in cells exposed to IFN-β. On initiation of HSV-1 gene expression, ICP0, a viral E3 ligase, degrades both PML and Sp100. The earlier report that IFN-β is significantly more effective in blocking viral replication in murinePML+/+cells than in siblingPML−/−cells, reproduced here with human cells, suggests that PML acts as an effector of antiviral effects of IFN-β. To define more precisely the function of PML in HSV-1 replication, we constructed aPML−/−human cell line. We report that inPML−/−cells, Sp100 degradation is delayed, possibly because colocalization and merger of ICP0 with nuclear bodies containing Sp100 and Daxx is ineffective, and that HSV-1 replicates equally well in parental HEp-2 andPML−/−cells infected at 5 pfu wild-type virus per cell, but poorly inPML−/−cells exposed to 0.1 pfu per cell. Finally, ICP0 accumulation is reduced inPML−/−infected at low, but not high, multiplicities of infection. In essence, the very mechanism that serves to degrade an antiviral IFN-β effector is exploited by HSV-1 to establish an efficient replication domain in the nucleus.
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  • 88
    Publication Date: 2017-07-17
    Description: CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.
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  • 89
    Publication Date: 2017-07-05
    Description: Devoid of all known canonical actin-binding proteins, the prevalent parasiteGiardia lambliauses an alternative mechanism for cytokinesis. Unique aspects of this mechanism can potentially be leveraged for therapeutic development. Here, live-cell imaging methods were developed forGiardiato establish division kinetics and the core division machinery. Surprisingly,Giardiacytokinesis occurred with a median time that is ∼60 times faster than mammalian cells. In contrast to cells that use a contractile ring, actin was not concentrated in the furrow and was not directly required for furrow progression. Live-cell imaging and morpholino depletion of axonemal Paralyzed Flagella 16 indicated that flagella-based forces initiated daughter cell separation and provided a source for membrane tension. Inhibition of membrane partitioning blocked furrow progression, indicating a requirement for membrane trafficking to support furrow advancement. Rab11 was found to load onto the intracytoplasmic axonemes late in mitosis and to accumulate near the ends of nascent axonemes. These developing axonemes were positioned to coordinate trafficking into the furrow and mark the center of the cell in lieu of a midbody/phragmoplast. We show that flagella motility, Rab11, and actin coordination are necessary for proper abscission. Organisms representing three of the five eukaryotic supergroups lack myosin II of the actomyosin contractile ring. These results support an emerging view that flagella play a central role in cell division among protists that lack myosin II and additionally implicate the broad use of membrane tension as a mechanism to drive abscission.
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  • 90
    Publication Date: 2017-05-01
    Description: Photonic crystals (PCs) have emerged as one of the most widely used platforms for controlling light–matter interaction in solid-state systems. They rely on Bragg scattering from wavelength-sized periodic modulation in the dielectric environment for manipulating the electromagnetic field. A complementary approach to manipulate light–matter interaction is offered by artificial media known as metamaterials that rely on the average response of deep-subwavelength unit cells. Here we demonstrate a class of artificial photonic media termed “photonic hypercrystals” (PHCs) that combine the large broadband photonic density of states provided by hyperbolic metamaterials with the light-scattering efficiency of PCs. Enhanced radiative rate (20×) and light outcoupling (100×) from PHCs embedded with quantum dots is observed. Such designer photonic media with complete control over the optical properties provide a platform for broadband control of light–matter interaction.
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  • 91
    Publication Date: 2016-09-29
    Description: Oceans dominate emissions of dimethyl sulfide (DMS), the major natural sulfur source. DMS is important for the formation of non-sea salt sulfate (nss-SO42−) aerosols and secondary particulate matter over oceans and thus, significantly influence global climate. The mechanism of DMS oxidation has accordingly been investigated in several different model studies in the past. However, these studies had restricted oxidation mechanisms that mostly underrepresented important aqueous-phase chemical processes. These neglected but highly effective processes strongly impact direct product yields of DMS oxidation, thereby affecting the climatic influence of aerosols. To address these shortfalls, an extensive multiphase DMS chemistry mechanism, the Chemical Aqueous Phase Radical Mechanism DMS Module 1.0, was developed and used in detailed model investigations of multiphase DMS chemistry in the marine boundary layer. The performed model studies confirmed the importance of aqueous-phase chemistry for the fate of DMS and its oxidation products. Aqueous-phase processes significantly reduce the yield of sulfur dioxide and increase that of methyl sulfonic acid (MSA), which is needed to close the gap between modeled and measured MSA concentrations. Finally, the simulations imply that multiphase DMS oxidation produces equal amounts of MSA and sulfate, a result that has significant implications for nss-SO42− aerosol formation, cloud condensation nuclei concentration, and cloud albedo over oceans. Our findings show the deficiencies of parameterizations currently used in higher-scale models, which only treat gas-phase chemistry. Overall, this study shows that treatment of DMS chemistry in both gas and aqueous phases is essential to improve the accuracy of model predictions.
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  • 92
    Publication Date: 2017-05-09
    Description: Applied pressure drives the heavy-fermion antiferromagnet CeRhIn5 toward a quantum critical point that becomes hidden by a dome of unconventional superconductivity. Magnetic fields suppress this superconducting dome, unveiling the quantum phase transition of local character. Here, we show that 5% magnetic substitution at the Ce site in CeRhIn5, either by Nd or Gd, induces a zero-field magnetic instability inside the superconducting state. This magnetic state not only should have a different ordering vector than the high-field local-moment magnetic state, but it also competes with the latter, suggesting that a spin-density-wave phase is stabilized in zero field by Nd and Gd impurities, similarly to the case of Ce0.95Nd0.05CoIn5. Supported by model calculations, we attribute this spin-density wave instability to a magnetic-impurity-driven condensation of the spin excitons that form inside the unconventional superconducting state.
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  • 93
    Publication Date: 2017-05-08
    Description: Microalgae have potential to help meet energy and food demands without exacerbating environmental problems. There is interest in the unicellular green alga Chromochloris zofingiensis, because it produces lipids for biofuels and a highly valuable carotenoid nutraceutical, astaxanthin. To advance understanding of its biology and facilitate commercial development, we present a C. zofingiensis chromosome-level nuclear genome, organelle genomes, and transcriptome from diverse growth conditions. The assembly, derived from a combination of short- and long-read sequencing in conjunction with optical mapping, revealed a compact genome of ∼58 Mbp distributed over 19 chromosomes containing 15,274 predicted protein-coding genes. The genome has uniform gene density over chromosomes, low repetitive sequence content (∼6%), and a high fraction of protein-coding sequence (∼39%) with relatively long coding exons and few coding introns. Functional annotation of gene models identified orthologous families for the majority (∼73%) of genes. Synteny analysis uncovered localized but scrambled blocks of genes in putative orthologous relationships with other green algae. Two genes encoding beta-ketolase (BKT), the key enzyme synthesizing astaxanthin, were found in the genome, and both were up-regulated by high light. Isolation and molecular analysis of astaxanthin-deficient mutants showed that BKT1 is required for the production of astaxanthin. Moreover, the transcriptome under high light exposure revealed candidate genes that could be involved in critical yet missing steps of astaxanthin biosynthesis, including ABC transporters, cytochrome P450 enzymes, and an acyltransferase. The high-quality genome and transcriptome provide insight into the green algal lineage and carotenoid production.
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  • 94
    Publication Date: 2016-06-27
    Description: Red blood cells (RBCs) can be cleared from circulation when alterations in their size, shape, and deformability are detected. This function is modulated by the spleen-specific structure of the interendothelial slit (IES). Here, we present a unique physiological framework for development of prognostic markers in RBC diseases by quantifying biophysical limits for RBCs to pass through the IES, using computational simulations based on dissipative particle dynamics. The results show that the spleen selects RBCs for continued circulation based on their geometry, consistent with prior in vivo observations. A companion analysis provides critical bounds relating surface area and volume for healthy RBCs beyond which the RBCs fail the “physical fitness test” to pass through the IES, supporting independent experiments. Our results suggest that the spleen plays an important role in determining distributions of size and shape of healthy RBCs. Because mechanical retention of infected RBC impacts malaria pathogenesis, we studied key biophysical parameters for RBCs infected with Plasmodium falciparum as they cross the IES. In agreement with experimental results, surface area loss of an infected RBC is found to be a more important determinant of splenic retention than its membrane stiffness. The simulations provide insights into the effects of pressure gradient across the IES on RBC retention. By providing quantitative biophysical limits for RBCs to pass through the IES, the narrowest circulatory bottleneck in the spleen, our results offer a broad approach for developing quantitative markers for diseases such as hereditary spherocytosis, thalassemia, and malaria.
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  • 95
    Publication Date: 2016-04-11
    Description: The sexual blood stage of the human malaria parasitePlasmodium falciparumundergoes remarkable biophysical changes as it prepares for transmission to mosquitoes. During maturation, midstage gametocytes show low deformability and sequester in the bone marrow and spleen cords, thus avoiding clearance during passage through splenic sinuses. Mature gametocytes exhibit increased deformability and reappear in the peripheral circulation, allowing uptake by mosquitoes. Here we define the reversible changes in erythrocyte membrane organization that underpin this biomechanical transformation. Atomic force microscopy reveals that the length of the spectrin cross-members and the size of the skeletal meshwork increase in developing gametocytes, then decrease in mature-stage gametocytes. These changes are accompanied by relocation of actin from the erythrocyte membrane to the Maurer’s clefts. Fluorescence recovery after photobleaching reveals reversible changes in the level of coupling between the membrane skeleton and the plasma membrane. Treatment of midstage gametocytes with cytochalasin D decreases the vertical coupling and increases their filterability. A computationally efficient coarse-grained model of the erythrocyte membrane reveals that restructuring and constraining the spectrin meshwork can fully account for the observed changes in deformability.
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  • 96
    Publication Date: 2017-05-08
    Description: Tumors of distinct tissues of origin and genetic makeup display common hallmark cellular phenotypes, including sustained proliferation, suppression of cell death, and altered metabolism. These phenotypic commonalities have been proposed to stem from disruption of conserved regulatory mechanisms evolved during the transition to multicellularity to control fundamental cellular processes such as growth and replication. Dating the evolutionary emergence of human genes through phylostratigraphy uncovered close association between gene age and expression level in RNA sequencing data from The Cancer Genome Atlas for seven solid cancers. Genes conserved with unicellular organisms were strongly up-regulated, whereas genes of metazoan origin were primarily inactivated. These patterns were most consistent for processes known to be important in cancer, implicating both selection and active regulation during malignant transformation. The coordinated expression of strongly interacting multicellularity and unicellularity processes was lost in tumors. This separation of unicellular and multicellular functions appeared to be mediated by 12 highly connected genes, marking them as important general drivers of tumorigenesis. Our findings suggest common principles closely tied to the evolutionary history of genes underlie convergent changes at the cellular process level across a range of solid cancers. We propose altered activity of genes at the interfaces between multicellular and unicellular regions of human gene regulatory networks activate primitive transcriptional programs, driving common hallmark features of cancer. Manipulation of cross-talk between biological processes of different evolutionary origins may thus present powerful and broadly applicable treatment strategies for cancer.
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  • 97
    Publication Date: 2016-04-11
    Description: Depressive and manic phases in bipolar disorder show opposite constellations of affective, cognitive, and psychomotor symptoms. At a neural level, these may be related to topographical disbalance between large-scale networks, such as the default mode network (DMN) and sensorimotor network (SMN). We investigated topographical patterns of variability in the resting-state signal—measured by fractional SD (fSD) of the BOLD signal—of the DMN and SMN (and other networks) in two frequency bands (Slow5 and Slow4) with their ratio and clinical correlations in depressed (n = 20), manic (n = 20), euthymic (n = 20) patients, and healthy controls (n = 40). After controlling for global signal changes, the topographical balance between the DMN and SMN, specifically in the lowest frequency band, as calculated by the Slow5 fSD DMN/SMN ratio, was significantly increased in depression, whereas the same ratio was significantly decreased in mania. Additionally, Slow5 variability was increased in the DMN and decreased in the SMN in depressed patients, whereas the opposite topographical pattern was observed in mania. Finally, the Slow5 fSD DMN/SMN ratio correlated positively with clinical scores of depressive symptoms and negatively with those of mania. Results were replicated in a smaller independent bipolar disorder sample. We demonstrated topographical abnormalities in frequency-specific resting-state variability in the balance between DMN and SMN with opposing patterns in depression and mania. The Slow5 DMN/SMN ratio was tilted toward the DMN in depression but was shifted toward the SMN in mania. The Slow5 fSD DMN/SMN pattern could constitute a state-biomarker in diagnosis and therapy.
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  • 98
    Publication Date: 2017-06-26
    Description: Since at least the 1920s, it has been reported that common chimpanzees (Pan troglodytes) differ from humans in being capable of exceptional feats of “super strength,” both in the wild and in captive environments. A mix of anecdotal and more controlled studies provides some support for this view; however, a critical review of available data suggests that chimpanzee mass-specific muscular performance is a more modest 1.5 times greater than humans on average. Hypotheses for the muscular basis of this performance differential have included greater isometric force-generating capabilities, faster maximum shortening velocities, and/or a difference in myosin heavy chain (MHC) isoform content in chimpanzee relative to human skeletal muscle. Here, we show that chimpanzee muscle is similar to human muscle in its single-fiber contractile properties, but exhibits a much higher fraction of MHC II isoforms. Unlike humans, chimpanzee muscle is composed of ∼67% fast-twitch fibers (MHC IIa+IId). Computer simulations of species-specific whole-muscle models indicate that maximum dynamic force and power output is 1.35 times higher in a chimpanzee muscle than a human muscle of similar size. Thus, the superior mass-specific muscular performance of chimpanzees does not stem from differences in isometric force-generating capabilities or maximum shortening velocities—as has long been suggested—but rather is due in part to differences in MHC isoform content and fiber length. We propose that the hominin lineage experienced a decline in maximum dynamic force and power output during the past 7–8 million years in response to selection for repetitive, low-cost contractile behavior.
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  • 99
    Publication Date: 2017-05-30
    Description: We used whole-genome resequencing data from a population of Drosophila melanogaster to investigate the causes of the negative correlation between the within-population synonymous nucleotide site diversity (πS) of a gene and its degree of divergence from related species at nonsynonymous nucleotide sites (KA). By using the estimated distributions of mutational effects on fitness at nonsynonymous and UTR sites, we predicted the effects of background selection at sites within a gene on πS and found that these could account for only part of the observed correlation between πS and KA. We developed a model of the effects of selective sweeps that included gene conversion as well as crossing over. We used this model to estimate the average strength of selection on positively selected mutations in coding sequences and in UTRs, as well as the proportions of new mutations that are selectively advantageous. Genes with high levels of selective constraint on nonsynonymous sites were found to have lower strengths of positive selection and lower proportions of advantageous mutations than genes with low levels of constraint. Overall, background selection and selective sweeps within a typical gene reduce its synonymous diversity to ∼75% of its value in the absence of selection, with larger reductions for genes with high KA. Gene conversion has a major effect on the estimates of the parameters of positive selection, such that the estimated strength of selection on favorable mutations is greatly reduced if it is ignored.
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  • 100
    Publication Date: 2017-01-23
    Description: Long-standing racial differences in US life expectancy suggest that black Americans would be exposed to significantly more family member deaths than white Americans from childhood through adulthood, which, given the health risks posed by grief and bereavement, would add to the disadvantages that they face. We analyze nationally representative US data from the National Longitudinal Study of Youth (n= 7,617) and the Health and Retirement Study (n= 34,757) to estimate racial differences in exposure to the death of family members at different ages, beginning in childhood. Results indicate that blacks are significantly more likely than whites to have experienced the death of a mother, a father, and a sibling from childhood through midlife. From young adulthood through later life, blacks are also more likely than whites to have experienced the death of a child and of a spouse. These results reveal an underappreciated layer of racial inequality in the United States, one that could contribute to the intergenerational transmission of health disadvantage. By calling attention to this heightened vulnerability of black Americans, our findings underscore the need to address the potential impact of more frequent and earlier exposure to family member deaths in the process of cumulative disadvantage.
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