bluuebunny/crossref_metadata_2025 huggingface dataset:
ADHD Medication in the Longer Term
Authors: Taylor Eric
Published: April 2019

Abstract. This review starts from the finding that there is strong persistence of ADHD problems into adult life, despite the availability of effective treatment with stimulants and other drugs. Short-term trials in adults reveal that those drugs can still be efficacious in adults. Pharmacoepidemiology studies, on the other hand, clearly show that most young people discontinue medication during adolescence. Neuropharmacology research suggests a waning of stimulant effects after a few years. Longitudinal studies are scarce but provide some evidence that prognosis is often determined by factors other than the core symptoms of inattentiveness and impulsive overactivity. The implications for clinical practice are discussed. Continuing care, especially during the follow-up after initial therapy, needs further development.
Catalyzing Transformations to Sustainability in the World's Mountains
Authors: Klein J. A. , Tucker C. M. , Nolin A. W. , Hopping K. A. , Reid R. S. , Steger C. , Grêt‐Regamey A. , Lavorel S. , Müller B. , Yeh E. T. , Boone R. B. , Bourgeron P. , Butsic V. , Castellanos E. , Chen X. , Dong S. K. , Greenwood G. , Keiler M. , Marchant R. , Seidl R. , Spies T. , Thorn J. , Yager K. ,   the Mountain Sentinels Network
Published: April 2019

Mountain social‐ecological systems (MtSES) are vital to humanity, providing ecosystem services to over half the planet's human population. Despite their importance, there has been no global assessment of threats to MtSES, even as they face unprecedented challenges to their sustainability. With survey data from 57 MtSES sites worldwide, we test a conceptual model of the types and scales of stressors and ecosystem services in MtSES and explore their distinct configurations according to their primary economic orientation and land use. We find that MtSES worldwide are experiencing both gradual and abrupt climatic, economic, and governance changes, with policies made by outsiders as the most ubiquitous challenge. Mountains that support primarily subsistence‐oriented livelihoods, especially agropastoral systems, deliver abundant services but are also most at risk. Moreover, transitions from subsistence‐ to market‐oriented economies are often accompanied by increased physical connectedness, reduced diversity of cross‐scale ecosystem services, lowered importance of local knowledge, and shifting vulnerabilities to threats. Addressing the complex challenges facing MtSES and catalyzing transformations to MtSES sustainability will require cross‐scale partnerships among researchers, stakeholders, and decision makers to jointly identify desired futures and adaptation pathways, assess trade‐offs in prioritizing ecosystem services, and share best practices for sustainability. These transdisciplinary approaches will allow local stakeholders, researchers, and practitioners to jointly address MtSES knowledge gaps while simultaneously focusing on critical issues of poverty and food security.
Evidence for Low‐Temperature Diffuse Venting at North Pond, Western Flank of the Mid‐Atlantic Ridge
Authors: Villinger H. W. , Müller P. , Bach W. , Becker K. , Orcutt B. N. , Kaul N. , Wheat C. G.
Published: April 2019

During expedition MSM37 on the German RV Maria S. Merian, bottom water temperature and sediment temperature profiles were measured in the vicinity of North Pond (western flank of Mid‐Atlantic Ridge) during exploratory dives with Remotely Operated Vehicle Jason II. In addition, push cores were taken at locations with high sediment temperature gradients. We could identify two locations where sediment temperature gradients exceed 1 K/m and bottom water temperatures showed an anomaly of up to 0.04 °C above background. We interpret these observations as clear indication of low‐temperature diffuse venting of fluids that have traveled through the uppermost crust. We can safely assume that the observed phenomena are widespread at ridge flank settings where sediment cover is thin or absent, and hence, we can explain the efficient heat mining on ridge flanks. Due to the difficulties of locating diffuse low‐temperature discharge sites and due to the fact that discharge can occur through thin sediment cover as well as through sediment‐free basement outcrops, it will be very difficult to quantify fluxes of energy and mass from low‐temperature diffuse venting in ridge flank settings; however, thermal anomalies may be used to locate sites of discharge for geochemical, microbial, and hydrologic characterization.
Multispectral and Multi‐instrument Observation of TIDs Following the Total Solar Eclipse of 21 August 2017
Authors: Aryal Saurav , Geddes George , Finn Susanna C. , Mrak Sebastijan , Galkin Ivan , Cnossen Ingrid , Cook Timothy , Chakrabarti Supriya
Published: April 2019

Wave‐like structures in the upper atmospheric nightglow brightness were observed on the night of 22 August 2017, approximately 8 hr following a total solar eclipse. These wave‐like perturbations are signatures of atmospheric gravity waves and associated traveling ionospheric disturbances (TIDs). Observations were made in the red line (OI 630.0 nm) and the green line (OI 557.7 nm) from Carbondale, IL, at 2–10 UTC on 22 August 2017. Based on wavelet analyses, the dominant time period in both the red and green lines was around 1.5 hr. Differential total electron content data obtained from Global Positioning System total electron content measurements at Carbondale, IL, and ionospheric parameters from digisonde measurements at Idaho National Laboratory and Millstone Hill showed a similar dominant time period. Based on these observations and their correlation with geomagnetic indices, the TIDs appear to be associated with geomagnetic disturbances. In addition, by modeling the ionosphere‐thermosphere system's response to the eclipse, it was seen that while the eclipse enhanced the O/N2 ratio and electron density (Ne) at 250 km during our observation period, it did not affect the TIDs. Vertical (7 m/s) and meridional (616 m/s) phase velocities of the TIDs were estimated using cross‐correlation analysis between red and green line brightness profiles and spectral analysis of the differential total electron content keogram, respectively. This provides a method to characterize the three‐dimensional wave properties of TIDs.
Seismic Structure of the Changbai Intraplate Volcano in NE China From Joint Inversion of Ambient Noise and Receiver Functions
Authors: Zhu Hongxiang , Tian You , Zhao Dapeng , Li Honghao , Liu Cai
Published: April 2019

We study the detailed 3‐D crustal and upper mantle structure beneath the active Changbai intraplate volcano in Northeast China by conducting a trans‐dimensional Bayesian inversion of teleseismic receiver functions and Rayleigh‐wave group velocity dispersions from ambient noise. More than 12,000 teleseismic receiver functions recorded at 78 seismic stations and 1,573 group velocity dispersions are used in this study. Receiver‐function H‐κ stacking measurements reveal a thick crust (~40 km) with a high Vp/Vs ratio (~1.8) beneath the Changbai volcano. Our joint inversion results show a heterogeneous crustal structure in the study region. A low‐velocity body at depths of 8–15 km is revealed directly beneath the Changbai volcano, which has a lateral extent of ~100 km in the north–south direction and may reflect a large magma chamber in the midcrust. Our results also reveal a 5–10 km depressed Moho and a low‐velocity anomaly in the uppermost mantle beneath the Changbai volcano. These features may indicate an upwelling channel of the asthenospheric material with a high mafic composition, and the mafic intrusion attaches to the bottom of the crust and thus deepens the Moho beneath the volcano. Our results support the notion that the Changbai volcanism is caused by hot and wet mantle upwelling associated with subduction‐driven corner flow in the big mantle wedge above the stagnant Pacific slab in the mantle transition zone.
Crustal Imaging With Bayesian Inversion of Teleseismic P Wave Coda Autocorrelation
Authors: Tork Qashqai Mehdi , Saygin Erdinc , Kennett B. L. N.
Published: April 2019

The autocorrelation of the seismic transmission response of a layered medium (autocorrelogram), in the presence of a free surface, corresponds to the reflection response. Despite many studies on the imaging of local structures through retrieval and forward modeling of stacked autocorrelograms, there is limited work on the inversion of these data. In this study, we demonstrate that the probabilistic inversion of autocorrelograms is efficient and can be used as an alternative imaging tool when other approaches are not applicable. Here, we calculate autocorrelograms of teleseismic P wave coda recorded on more than 1,200 permanent and temporary seismic stations across Australia and utilize a Bayesian framework to invert these data for crustal imaging. The results show patterns of structures consistent with those seen in previous crustal models constructed from receiver function, seismic reflection, and refraction methods. The new approach can therefore image large‐scale crustal structures comparable to those from other seismological methods.
Estuarine Dissolved Organic Carbon Flux From Space: With Application to Chesapeake and Delaware Bays
Authors: Signorini Sergio R. , Mannino Antonio , Friedrichs Marjorie A. M. , St‐Laurent Pierre , Wilkin John , Tabatabai Aboozar , Najjar Raymond G. , Hofmann Eileen E. , Da Fei , Tian Hanqin , Yao Yuanzhi
Published: April 2019

This study uses a neural network model trained with in situ data, combined with satellite data and hydrodynamic model products, to compute the daily estuarine export of dissolved organic carbon (DOC) at the mouths of Chesapeake Bay (CB) and Delaware Bay (DB) from 2007 to 2011. Both bays show large flux variability with highest fluxes in spring and lowest in fall as well as interannual flux variability (0.18 and 0.27 Tg C/year in 2008 and 2010 for CB; 0.04 and 0.09 Tg C/year in 2008 and 2011 for DB). Based on previous estimates of total organic carbon (TOCexp) exported by all Mid‐Atlantic Bight estuaries (1.2 Tg C/year), the DOC export (CB + DB) of 0.3 Tg C/year estimated here corresponds to 25% of the TOCexp. Spatial and temporal covariations of velocity and DOC concentration provide contributions to the flux, with larger spatial influence. Differences in the discharge of fresh water into the bays (74 billion m3/year for CB and 21 billion m3/year for DB) and their geomorphologies are major drivers of the differences in DOC fluxes for these two systems. Terrestrial DOC inputs are similar to the export of DOC at the bay mouths at annual and longer time scales but diverge significantly at shorter time scales (days to months). Future efforts will expand to the Mid‐Atlantic Bight and Gulf of Maine, and its major rivers and estuaries, in combination with coupled terrestrial‐estuarine‐ocean biogeochemical models that include effects of climate change, such as warming and CO2 increase.
An Estimate of Thorium 234 Partition Coefficients Through Global Inverse Modeling
Authors: Le Gland Guillaume , Aumont Olivier , Mémery Laurent
Published: April 2019

Thorium‐234 (234Th), an insoluble radioisotope scavenged by marine particles, can be used as a proxy of the biological carbon pump. Thorium‐234 observations can constrain biogeochemical models, but a necessary first step is to estimate the poorly known partition coefficients between particulate and dissolved phases. In this study, the 234Th partition coefficients for five particle types, differing in size and chemical composition, are estimated by fitting a global 3‐D 234Th model based on the coupled ocean general circulation‐biogeochemistry model NEMO‐PISCES (at a resolution of 2°) to a global 234Th data set (including GEOTRACES data). Surface partition coefficients are estimated between 0.79 and 16.7×106. Biogenic silica has the smallest partition coefficients. Small particulate organic carbon and lithogenic dust have the largest. Thorium‐234 observations at depth cannot be recovered without allowing partition coefficients to increase by one order of magnitude from surface to 1,000 m deep. In our time‐dependent global 3‐D model, the biases introduced by three common assumptions made in biological carbon pump studies can be quantified. First, using the C:234Th ratio of large particles alone leads to an overestimation of carbon export at the base of the euphotic layer, by up to a factor 2. Furthermore, assuming steady state and neglecting transport by advection and diffusion can bias fluxes by as much as 50%, especially at high latitudes and in upwellings, with a sign and intensity depending on the season.
The Fate of Surface Freshwater Entering the Indonesian Seas
Authors: Kida Shinichiro , Richards Kelvin J. , Sasaki Hideharu
Published: April 2019

The Indonesian Seas receive one of the largest amounts of rainfall around the globe. Part of this freshwater disperses to the Indian Ocean through the Indonesian Throughflow (ITF), the Pacific and Indian interocean exchange flow, making the Indonesian Seas a major source of freshwater, and plays an important part of the global hydrological cycle. By using a Lagrangian particle tracking model, we examine the pathways behind the dispersion of freshwater that the Indonesian Seas receive through precipitation. The model suggests that the dispersion from the near‐surface water of the Indonesian Seas occurs in about 6 months, primarily through advection to the surrounding seas, followed by evaporation, entrainment, and vertical mixing. The Lombok Strait and the Timor Strait are the major outflowing straits, and the freshwater exiting through these straits are found to originate from limited areas and seasons. The sources for the Lombok Strait outflow are the Java Sea precipitated freshwater during boreal fall and winter, while the sources for the Timor Strait outflow are the Flores‐Banda Seas and Arafura Sea precipitated freshwater during winter and spring. Mixing with the thermocline water is found to occur when the monsoonal winds induce upwelling events in winter and summer, along the shelf breaks and steep coastlines surrounding the Flores‐Banda Seas. Vertical mixing provides a pathway for the surface freshwater to enter the ITF thermocline, and our model suggests that it is the Java Sea precipitated freshwater during winter that is entering the ITF thermocline along its main pathway.
Modeling Ice Shelf Cavities and Tabular Icebergs Using Lagrangian Elements
Authors: Stern A. A. , Adcroft A. , Sergienko O.
Published: April 2019

Most ocean climate models do not represent ice shelf calving in a physically realistic way, even though the calving of icebergs is a major component of the mass balance for Antarctic ice shelves. The infrequency of large calving events together with the difficulty of placing observational instruments around icebergs means that little is known about how calving icebergs affect the ocean. In this study we present a novel model of an ice shelf coupled to an ocean circulation model, where the ice shelf is constructed of Lagrangian elements that allow simulation of iceberg calving. The Lagrangian ice shelf model is used to simulate the flow beneath a static idealized ice shelf, to verify that it can reproduce the results of an existing Eulerian model simulation with an identical configuration. The Lagrangian model is then used to simulate the ocean's response to a calved iceberg drifting away from the ice shelf. The results show how a calving event and subsequent iceberg drift affect the ocean. At the ice front, the calving event leads to a warming of the ocean surface and cooling of the water column at depth, allowing cooler waters to enter the ice shelf cavity, leading to reduced melt rates within the cavity. A Taylor column is observed below the iceberg, which moves with the iceberg as it drifts into the open ocean. As the iceberg drifts further from the ice shelf, the circulation within the ice shelf cavity tends toward a new steady state, consistent with the new ice shelf geometry.
Retrieval of Aerosol Size Distributions From In Situ Particle Counter Measurements: Instrument Counting Efficiency and Comparisons With Satellite Measurements
Authors: Deshler Terry , Luo Beiping , Kovilakam Mahesh , Peter Thomas , Kalnajs Lars E.
Published: April 2019

The method to derive aerosol size distributions from in situ stratospheric measurements from the University of Wyoming is modified to include an explicit counting efficiency function (CEF) to describe the channel‐dependent instrument counting efficiency. This is motivated by Kovilakam and Deshler's (2015, https://doi.org/10.1002/2015JD023303) discovery of an error in the calibration method applied to the optical particle counter (OPC40) developed in the late 1980s and used from 1991 to 2012. The method can be applied to other optical aerosol instruments for which counting efficiencies have been measured. The CEF employed is the integral of the Gaussian distribution representing the instrument response at any one aerosol channel, the aerosol counting efficiency. Results using the CEF are compared to previous derivations of aerosol size distributions (Deshler et al., 2003, https://doi.org/10.1029/2002JD002514) applied to the measurements before and after Kovilakam and Deshler's correction of number concentration for the OPC40 calibration error. The CEF method is found, without any tuning parameter, to reproduce or improve upon the Kovilakam and Deshler's results, thus accounting for the calibration error without any external comparisons other than the laboratory determined counting efficiency at each aerosol channel. Moments of the new aerosol size distributions compare well with aerosol extinctions measured by Stratospheric Aerosol and Gas Experiment II and Halogen Occultation Experiment in the volcanic period 1991–1996, generally within ±40%, the precision of OPC40 moments, and in the nonvolcanic period after 1996, generally within ±20%. Stratospheric Aerosol and Gas Experiment II and Halogen Occultation Experiment estimates of aerosol surface area are generally in agreement with those derived using the new CEF method.
Late Cretaceous Extreme Warmth at High Southern Latitudes
Authors: Cook Terri
Published: April 2019

New proxy data indicate sea surface temperatures at high southern latitudes reached over 35�C during a period of extreme greenhouse climate that began about 100 million years ago.
The Influence of Post‐accretion Sedimentation on Marine Magnetic Anomalies
Authors: Granot R. , Dyment J.
Published: April 2019

Marine magnetic anomalies are a critical observation used to investigate seafloor spreading and the transition between oceanic and continental crust at passive margins. However, pronounced post‐accretion sedimentation disturbs the thermal state of the crust and therefore alters its remanent magnetization. To study the link between sedimentation and magnetization of the oceanic crust, we built a series of thermomagnetic forward models coupled with different sedimentation histories. We test our approach against observations from the early Cretaceous southern South Atlantic Ocean. Our simulations suggest that, depending on the thickness of post‐accretion sediments, the remanent magnetization of the extrusive basalts is partly or completely removed. Therefore, the typical long‐wavelength sea surface marine magnetic anomalies observed above oceanic crust covered by a thick sedimentary pile is almost entirely generated by the magnetization of the deeper crustal layers.
Assessing the Ability of Zonal δ18O Contrast in Benthic Foraminifera to Reconstruct Deglacial Evolution of Atlantic Meridional Overturning Circulation
Authors: Gu Sifan , Liu Zhengyu , Lynch‐Stieglitz Jean , Jahn Alexandra , Zhang Jiaxu , Lindsay Keith , Wu Lixin
Published: April 2019

δ18O in foraminifera (δ18Oc) is a useful proxy for density, and the strength of the Atlantic Meridional Overturning Circulation (AMOC) can be reconstructed by the zonal density contrast in the Atlantic. However, whether the deglacial zonal δ18Oc contrast can represent the AMOC change is still unclear. δ18Oc contrast across the Florida Straits has been hypothesized as a proxy for the AMOC evolution during the last deglaciation, but the strength of Florida Current could also be influenced by wind forcing. Here we examine the ability of the zonal δ18Oc contrast to reconstruct AMOC in a deglacial model simulation. The model simulation suggests that the deglacial variation of the Florida Current strength is dominated by AMOC, with the wind effect on the variation of the Florida Current being negligible. Furthermore, the δ18Oc contrast across the western boundary along the entire Atlantic and the basin‐wide δ18Oc contrast in the North Atlantic in the upper ocean can also be used to reconstruct AMOC. However, using basin‐wide δ18Oc contrast to reconstruct AMOC in the South Atlantic is not possible at all water depths. In the subtropical South Atlantic, the basin‐wide δ18Oc contrast is decoupled from the density contrast between 400 to 600 m through the deglaciation because of the deglacial change of the Antarctic Intermediate Water. Therefore, δ18Oc is a useful proxy to reconstruct past density and in turn past AMOC, but caution has to be used when using the basin‐wide δ18Oc contrast to reconstruct the basin‐wide density contrast in the South Atlantic.
Organopolymer with dual chromophores and fast charge-transfer properties for sustainable photocatalysis
Authors: Smith Justin D. , Jamhawi Abdelqader M. , Jasinski Jacek B. , Gallou Fabrice , Ge Jin , Advincula Rigoberto , Liu Jinjun , Handa Sachin
Published: April 2019

Photocatalytic polymers offer an alternative to prevailing organometallics and nanomaterials, and they may benefit from polymer-mediated catalytic and material enhancements. MPC-1, a polymer photoredox catalyst reported herein, exhibits enhanced catalytic activity arising from charge transfer states (CTSs) between its two chromophores. Oligomeric and polymeric MPC-1 preparations both promote efficient hydrodehalogenation of α-halocarbonyl compounds while exhibiting different solubility properties. The polymer is readily recovered by filtration. MPC-1-coated vessels enable batch and flow photocatalysis, even with opaque reaction mixtures, via “backside irradiation.” Ultrafast transient absorption spectroscopy indicates a fast charge-transfer process within 20 ps of photoexcitation. Time-resolved photoluminescence measurements reveal an approximate 10 ns lifetime for bright valence states. Ultrafast measurements suggest a long CTS lifetime. Empirical catalytic activities of small-molecule models of MPC-1 subunits support the CTS hypothesis. Density functional theory (DFT) and time-dependent DFT calculations are in good agreement with experimental spectra, spectral peak assignment, and proposed underlying energetics.
Multiple myeloma immunoglobulin lambda translocations portend poor prognosis
Authors: Barwick Benjamin G. , Neri Paola , Bahlis Nizar J. , Nooka Ajay K. , Dhodapkar Madhav V. , Jaye David L. , Hofmeister Craig C. , Kaufman Jonathan L. , Gupta Vikas A. , Auclair Daniel , Keats Jonathan J. , Lonial Sagar , Vertino Paula M. , Boise Lawrence H.
Published: April 2019

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.
Nuclear membrane protein Lem2 regulates nuclear size through membrane flow
Authors: Kume Kazunori , Cantwell Helena , Burrell Alana , Nurse Paul
Published: April 2019

The size of the membrane-bound nucleus scales with cell size in a wide range of cell types but the mechanisms determining overall nuclear size remain largely unknown. Here we investigate the role of fission yeast inner nuclear membrane proteins in determining nuclear size, and propose that the Lap2-Emerin-Man1 domain protein Lem2 acts as a barrier to membrane flow between the nucleus and other parts of the cellular membrane system. Lem2 deletion increases membrane flow into and out of the nuclear envelope in response to changes in membrane synthesis and nucleocytoplasmic transport, altering nuclear size. The endoplasmic reticulum protein Lnp1 acts as a secondary barrier to membrane flow, functionally compensating for lack of Lem2. We propose that this is part of the mechanism that maintains nuclear size proportional to cellular membrane content and thus to cell size. Similar regulatory principles may apply to other organelles in the eukaryotic subcellular membrane network.
Sr[Li2Al2O2N2]:Eu2+—A high performance red phosphor to brighten the future
Authors: Hoerder Gregor J. , Seibald Markus , Baumann Dominik , Schröder Thorsten , Peschke Simon , Schmid Philipp C. , Tyborski Tobias , Pust Philipp , Stoll Ion , Bergler Michael , Patzig Christian , Reißaus Stephan , Krause Michael , Berthold Lutz , Höche Thomas , Johrendt Dirk , Huppertz Hubert
Published: April 2019

Innovative materials for phosphor converted white light-emitting diodes are in high demand owing to the huge potential of the light-emitting diode technology to reduce energy consumption worldwide. As the primary blue diode is already highly optimized, the conversion phosphors are of crucial importance for any further improvements. We report on the discovery of the high performance red phosphor Sr[Li2Al2O2N2]:Eu2+meeting all requirements for a phosphor’s optical properties. It combines the optimal spectral position for a red phosphor, as defined in the 2016 Research & Development-plan of the United States government, with an exceptionally small spectral full width at half maximum and excellent thermal stability. A white mid-power phosphor-converted light-emitting diode prototype utilising Sr[Li2Al2O2N2]:Eu2+shows an increase of 16% in luminous efficacy compared to currently available commercial high colour-rendering phosphor-converted light-emitting diodes, while retaining excellent high colour rendition. This phosphor enables a big leap in energy efficiency of white emitting phosphor-converted light-emitting-diodes.
TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila
Authors: Lee Byoungchun , Barretto Elizabeth C. , Grewal Savraj S.
Published: April 2019

Animals often develop in environments where conditions such as food, oxygen and temperature fluctuate. The ability to adapt their metabolism to these fluctuations is important for normal development and viability. In most animals, low oxygen (hypoxia) is deleterious. However some animals can alter their physiology to tolerate hypoxia. Here we show that TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila. We find that hypoxia rapidly suppresses TORC1 signaling in Drosophila larvae via TSC-mediated inhibition of Rheb. We show that this hypoxia-mediated inhibition of TORC1 specifically in the larval fat body is essential for viability. Moreover, we find that these effects of TORC1 inhibition on hypoxia tolerance are mediated through remodeling of fat body lipid storage. These studies identify the larval adipose tissue as a key hypoxia-sensing tissue that coordinates whole-body development and survival to changes in environmental oxygen by modulating TORC1 and lipid metabolism.
A chemical toolbox for the study of bromodomains and epigenetic signaling
Authors: Wu Qin , Heidenreich David , Zhou Stanley , Ackloo Suzanne , Krämer Andreas , Nakka Kiran , Lima-Fernandes Evelyne , Deblois Genevieve , Duan Shili , Vellanki Ravi N. , Li Fengling , Vedadi Masoud , Dilworth Jeffrey , Lupien Mathieu , Brennan Paul E. , Arrowsmith Cheryl H. , Müller Susanne , Fedorov Oleg , Filippakopoulos Panagis , Knapp Stefan
Published: April 2019

Bromodomains (BRDs) are conserved protein interaction modules which recognize (read) acetyl-lysine modifications, however their role(s) in regulating cellular states and their potential as targets for the development of targeted treatment strategies is poorly understood. Here we present a set of 25 chemical probes, selective small molecule inhibitors, covering 29 human bromodomain targets. We comprehensively evaluate the selectivity of this probe-set using BROMOscanand demonstrate the utility of the set identifying roles of BRDs in cellular processes and potential translational applications. For instance, we discovered crosstalk between histone acetylation and the glycolytic pathway resulting in a vulnerability of breast cancer cell lines under conditions of glucose deprivation or GLUT1 inhibition to inhibition of BRPF2/3 BRDs. This chemical probe-set will serve as a resource for future applications in the discovery of new physiological roles of bromodomain proteins in normal and disease states, and as a toolset for bromodomain target validation.
Humanising the mouse genome piece by piece
Authors: Zhu Fei , Nair Remya R. , Fisher Elizabeth M. C. , Cunningham Thomas J.
Published: April 2019

To better understand human health and disease, researchers create a wide variety of mouse models that carry human DNA. With recent advances in genome engineering, the targeted replacement of mouse genomic regions with orthologous human sequences has become increasingly viable, ranging from finely tuned humanisation of individual nucleotides and amino acids to the incorporation of many megabases of human DNA. Here, we examine emerging technologies for targeted genomic humanisation, we review the spectrum of existing genomically humanised mouse models and the insights such models have provided, and consider the lessons learned for designing such models in the future.
Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease
Authors: Kikuchi Koichi , Saigusa Daisuke , Kanemitsu Yoshitomi , Matsumoto Yotaro , Thanai Paxton , Suzuki Naoto , Mise Koki , Yamaguchi Hiroaki , Nakamura Tomohiro , Asaji Kei , Mukawa Chikahisa , Tsukamoto Hiroki , Sato Toshihiro , Oikawa Yoshitsugu , Iwasaki Tomoyuki , Oe Yuji , Tsukimi Tomoya , Fukuda Noriko N. , HO Hsin-Jung , Nanto-Hara Fumika , Ogura Jiro , Saito Ritsumi , Nagao Shizuko , Ohsaki Yusuke , Shimada Satoshi , Suzuki Takehiro , Toyohara Takafumi , Mishima Eikan , Shima Hisato , Akiyama Yasutoshi , Akiyama Yukako , Ichijo Mariko , Matsuhashi Tetsuro , Matsuo Akihiro , Ogata Yoshiaki , Yang Ching-Chin , Suzuki Chitose , Breeggemann Matthew C. , Heymann Jurgen , Shimizu Miho , Ogawa Susumu , Takahashi Nobuyuki , Suzuki Takashi , Owada Yuji , Kure Shigeo , Mano Nariyasu , Soga Tomoyoshi , Wada Takashi , Kopp Jeffrey B. , Fukuda Shinji , Hozawa Atsushi , Yamamoto Masayuki , Ito Sadayoshi , Wada Jun , Tomioka Yoshihisa , Abe Takaaki
Published: April 2019

Diabetic kidney disease is a major cause of renal failure that urgently necessitates a breakthrough in disease management. Here we show using untargeted metabolomics that levels of phenyl sulfate, a gut microbiota-derived metabolite, increase with the progression of diabetes in rats overexpressing human uremic toxin transporter SLCO4C1 in the kidney, and are decreased in rats with limited proteinuria. In experimental models of diabetes, phenyl sulfate administration induces albuminuria and podocyte damage. In a diabetic patient cohort, phenyl sulfate levels significantly correlate with basal and predicted 2-year progression of albuminuria in patients with microalbuminuria. Inhibition of tyrosine phenol-lyase, a bacterial enzyme responsible for the synthesis of phenol from dietary tyrosine before it is metabolized into phenyl sulfate in the liver, reduces albuminuria in diabetic mice. Together, our results suggest that phenyl sulfate contributes to albuminuria and could be used as a disease marker and future therapeutic target in diabetic kidney disease.
The dynamic and structural properties of axonemal tubulins support the high length stability of cilia
Authors: Orbach Ron , Howard Jonathon
Published: April 2019

Cilia and flagella play essential roles in cell motility, sensing and development. These organelles have tightly controlled lengths, and the axoneme, which forms the core structure, has exceptionally high stability. This is despite being composed of microtubules that are often characterized as highly dynamic. To understand how ciliary tubulin contribute to stability, we develop a procedure to differentially extract tubulins from different components of axonemes purified from Chlamydomonas reinhardtii, and characterize their properties. We find that the microtubules support length stability by two distinct mechanisms: low dynamicity, and unusual stability of the protofilaments. The high stability of the protofilaments manifests itself in the formation of curved tip structures, up to a few microns long. These structures likely reflect intrinsic curvature of GTP or GDP·Pi tubulin and provide structural insights into the GTP-cap. Together, our study provides insights into growth, stability and the role of post-translational modifications of axonemal microtubules.
Low yield and abiotic origin of N2O formed by the complete nitrifier Nitrospira inopinata
Authors: Kits K. Dimitri , Jung Man-Young , Vierheilig Julia , Pjevac Petra , Sedlacek Christopher J. , Liu Shurong , Herbold Craig , Stein Lisa Y. , Richter Andreas , Wissel Holger , Brüggemann Nicolas , Wagner Michael , Daims Holger
Published: April 2019

Nitrous oxide (N2O) and nitric oxide (NO) are atmospheric trace gases that contribute to climate change and affect stratospheric and ground-level ozone concentrations. Ammonia oxidizing bacteria (AOB) and archaea (AOA) are key players in the nitrogen cycle and major producers of N2O and NO globally. However, nothing is known about N2O and NO production by the recently discovered and widely distributed complete ammonia oxidizers (comammox). Here, we show that the comammox bacterium Nitrospira inopinata is sensitive to inhibition by an NO scavenger, cannot denitrify to N2O, and emits N2O at levels that are comparable to AOA but much lower than AOB. Furthermore, we demonstrate that N2O formed by N. inopinata formed under varying oxygen regimes originates from abiotic conversion of hydroxylamine. Our findings indicate that comammox microbes may produce less N2O during nitrification than AOB.
Vps11 and Vps18 of Vps-C membrane traffic complexes are E3 ubiquitin ligases and fine-tune signalling
Authors: Segala Gregory , Bennesch Marcela A. , Ghahhari Nastaran Mohammadi , Pandey Deo Prakash , Echeverria Pablo C. , Karch François , Maeda Robert K. , Picard Didier
Published: April 2019

In response to extracellular signals, many signalling proteins associated with the plasma membrane are sorted into endosomes. This involves endosomal fusion, which depends on the complexes HOPS and CORVET. Whether and how their subunits themselves modulate signal transduction is unknown. We show that Vps11 and Vps18 (Vps11/18), two common subunits of the HOPS/CORVET complexes, are E3 ubiquitin ligases. Upon overexpression of Vps11/Vps18, we find perturbations of ubiquitination in signal transduction pathways. We specifically demonstrate that Vps11/18 regulate several signalling factors and pathways, including Wnt, estrogen receptor α (ERα), and NFκB. For ERα, we demonstrate that the Vps11/18-mediated ubiquitination of the scaffold protein PELP1 impairs the activation of ERα by c-Src. Thus, proteins involved in membrane traffic, in addition to performing their well-described role in endosomal fusion, fine-tune signalling in several different ways, including through ubiquitination.
RNA G-quadruplex is resolved by repetitive and ATP-dependent mechanism of DHX36
Authors: Tippana Ramreddy , Chen Michael C. , Demeshkina Natalia A. , Ferré-D’Amaré Adrian R. , Myong Sua
Published: April 2019

DHX36 is a DEAH-box helicase that resolves parallel G-quadruplex structures formed in DNA and RNA. The recent co-crystal structure of DHX36 bound G4-DNA revealed an intimate contact, but did not address the role of ATP hydrolysis in G4 resolving activity. Here, we demonstrate that unlike on G4-DNA, DHX36 displays ATP-independent unfolding of G4-RNA followed by ATP-dependent refolding, generating a highly asymmetric pattern of activity. Interestingly, DHX36 refolds G4-RNA in several steps, reflecting the discrete steps in forming the G4 structure. We show that the ATP-dependent activity of DHX36 arises from the RNA tail rather than the G4. Mutations that perturb G4 contact result in quick dissociation of the protein from RNA upon ATP hydrolysis, while mutations that interfere with binding the RNA tail induce dysregulated activity. We propose that the ATP-dependent activity of DHX36 may be useful for dynamically resolving various G4-RNA structures in cells.
Liquid marble-derived solid-liquid hybrid superparticles for CO2 capture
Authors: Rong Xia , Ettelaie Rammile , Lishchuk Sergey V. , Cheng Huaigang , Zhao Ning , Xiao Fukui , Cheng Fangqin , Yang Hengquan
Published: April 2019

The design of effective CO2 capture materials is an ongoing challenge. Here we report a concept to overcome current limitations associated with both liquid and solid CO2 capture materials by exploiting a solid-liquid hybrid superparticle (SLHSP). The fabrication of SLHSP involves assembly of hydrophobic silica nanoparticles on the liquid marble surface, and co-assembly of hydrophilic silica nanoparticles and tetraethylenepentamine within the interior of the liquid marble. The strong interfacial adsorption force and the strong interactions between amine and silica are identified to be key elements for high robustness. The developed SLHSPs exhibit excellent CO2 sorption capacity, high sorption rate, long-term stability and reduced amine loss in industrially preferred fixed bed setups. The outstanding performances are attributed to the unique structure which hierarchically organizes the liquid and solid at microscales.
Unraveling the dislocation core structure at a van der Waals gap in bismuth telluride
Authors: Medlin D. L. , Yang N. , Spataru C. D. , Hale L. M. , Mishin Y.
Published: April 2019

Tetradymite-structured chalcogenides such as bismuth telluride (Bi2Te3) are of significant interest for thermoelectric energy conversion and as topological insulators. Dislocations play a critical role during synthesis and processing of such materials and can strongly affect their functional properties. The dislocations between quintuple layers present special interest since their core structure is controlled by the van der Waals interactions between the layers. In this work, using atomic-resolution electron microscopy, we resolve the basal dislocation core structure in Bi2Te3, quantifying the disregistry of the atomic planes across the core. We show that, despite the existence of a stable stacking fault in the basal plane gamma surface, the dislocation core spreading is mainly due to the weak bonding between the layers, which leads to a small energy penalty for layer sliding parallel to the van der Waals gap. Calculations within a semidiscrete variational Peierls-Nabarro model informed by first-principles calculations support our experimental findings.
A small molecule promotes cartilage extracellular matrix generation and inhibits osteoarthritis development
Authors: Shi Yuanyuan , Hu Xiaoqing , Cheng Jin , Zhang Xin , Zhao Fengyuan , Shi Weili , Ren Bo , Yu Huilei , Yang Peng , Li Zong , Liu Qiang , Liu Zhenlong , Duan Xiaoning , Fu Xin , Zhang Jiying , Wang Jianquan , Ao Yingfang
Published: April 2019

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.
Mettl3-mediated mRNA m6A methylation promotes dendritic cell activation
Authors: Wang Huamin , Hu Xiang , Huang Mingyan , Liu Juan , Gu Yan , Ma Lijia , Zhou Qi , Cao Xuetao
Published: April 2019

N6-methyladenosine (m6A) modification plays important roles in various cellular responses by regulating mRNA biology. However, how m6A modification is involved in innate immunity via affecting the translation of immune transcripts remains to be further investigated. Here we report that RNA methyltransferase Mettl3-mediated mRNA m6A methylation promotes dendritic cell (DC) activation and function. Specific depletion of Mettl3 in DC resulted in impaired phenotypic and functional maturation of DC, with decreased expression of co-stimulatory molecules CD40, CD80 and cytokine IL-12, and reduced ability to stimulate T cell responses both in vitro and in vivo. Mechanistically, Mettl3-mediated m6A of CD40, CD80 and TLR4 signaling adaptor Tirap transcripts enhanced their translation in DC for stimulating T cell activation, and strengthening TLR4/NF-κB signaling-induced cytokine production. Our findings identify a new role for Mettl3-mediated m6A modification in increasing translation of certain immune transcripts for physiological promotion of DC activation and DC-based T cell response.
High-fidelity bosonic quantum state transfer using imperfect transducers and interference
Authors: Lau Hoi-Kwan , Clerk Aashish A.
Published: April 2019

We consider imperfect two-mode bosonic quantum transducers that cannot completely transfer an initial source-system quantum state due to insufficient coupling strength or other Hamiltonian non-idealities. We show that such transducers can generically be made perfect by using interference and phase-sensitive amplification. Our approach is based on the realization that a particular kind of imperfect transducer (one which implements a swapped quantum non-demolition (QND) gate) can be made into a perfect one-way transducer using feed-forward and/or injected squeezing. We show that a generic imperfect transducer can be reduced to this case by repeating the imperfect transduction operation twice, interspersed with amplification. Crucially, our scheme only requires the ability to implement squeezing operations and/or homodyne measurement on one of the two modes involved. It is thus ideally suited to schemes where there is an asymmetry in the ability to control the two coupled systems (e.g., microwave-to-optics quantum state transfer). We also discuss a correction protocol that requires no injected squeezing and/or feed-forward operation.
The multiplex network of human diseases
Authors: Halu Arda , De Domenico Manlio , Arenas Alex , Sharma Amitabh
Published: April 2019

Untangling the complex interplay between phenotype and genotype is crucial to the effective characterization and subtyping of diseases. Here we build and analyze the multiplex network of 779 human diseases, which consists of a genotype-based layer and a phenotype-based layer. We show that diseases with common genetic constituents tend to share symptoms, and uncover how phenotype information helps boost genotype information. Moreover, we offer a flexible classification of diseases that considers their molecular underpinnings alongside their clinical manifestations. We detect cohesive groups of diseases that have high intra-group similarity at both the molecular and the phenotypic level. Inspecting these disease communities, we demonstrate the underlying pathways that connect diseases mechanistically. We observe monogenic disorders grouped together with complex diseases for which they increase the risk factor. We propose potentially new disease associations that arise as a unique feature of the information flow within and across the two layers.
Topographic controls of soil organic carbon on soil-mantled landscapes
Authors: Patton Nicholas R. , Lohse Kathleen A. , Seyfried Mark S. , Godsey Sarah E. , Parsons Susan B.
Published: April 2019

Large uncertainties in global carbon (C) budgets stem from soil carbon estimates and associated challenges in distributing soil organic carbon (SOC) at local to landscape scales owing to lack of information on soil thickness and controls on SOC storage. Here we show that 94% of the fine-scale variation in total profile SOC within a 1.8 km2semi-arid catchment in Idaho, U.S.A. can be explained as a function of aspect and hillslope curvature when the entire vertical dimension of SOC is measured and fine-resolution (3 m) digital elevation models are utilized. Catchment SOC stocks below 0.3 m depth based on our SOC-curvature model account for >50% of the total SOC indicating substantial underestimation of stocks if sampled at shallower depths. A rapid assessment method introduced here also allows for accurate catchment-wide total SOC inventory estimation with a minimum of one soil pit and topographic data if spatial distribution of total profile SOC is not required. Comparison of multiple datasets shows generality in linear SOC-curvature and -soil thickness relationships at multiple scales. We conclude that mechanisms driving variations in carbon storage in hillslope catchment soils vary spatially at relatively small scales and can be described in a deterministic fashion given adequate topographic data.
Temperature and moisture are minor drivers of regional-scale soil organic carbon dynamics
Authors: González-Domínguez B. , Niklaus P. A. , Studer M. S. , Hagedorn F. , Wacker L. , Haghipour N. , Zimmermann S. , Walthert L. , McIntyre C. , Abiven S.
Published: April 2019

Storing large amounts of organic carbon, soils are a key but uncertain component of the global carbon cycle, and accordingly, of Earth System Models (ESMs). Soil organic carbon (SOC) dynamics are regulated by a complex interplay of drivers. Climate, generally represented by temperature and moisture, is regarded as one of the fundamental controls. Here, we use 54 forest sites in Switzerland, systematically selected to span near-independent gradients in temperature and moisture, to disentangle the effects of climate, soil properties, and landform on SOC dynamics. We estimated two SOC turnover times, based on bulk soil 14C measurements (τ14C) and on a 6-month laboratory soil incubation (τi). In addition, upon incubation, we measured the 14C signature of the CO2 evolved and quantified the cumulated production of dissolved organic carbon (DOC). Our results demonstrate that τi and τ14C capture the dynamics of contrasting fractions of the SOC continuum. The 14C-based τ14C primarily reflects the dynamics of an older, stabilised pool, whereas the incubation-based τi mainly captures fresh readily available SOC. Mean site temperature did not raise as a critical driver of SOC dynamics, and site moisture was only significant for τi. However, soil pH emerged as a key control of both turnover times. The production of DOC was independent of τi and not driven by climate, but primarily by the content of clay and, secondarily by the slope of the site. At the regional scale, soil physicochemical properties and landform appear to override the effect of climate on SOC dynamics.