bluuebunny/crossref_metadata_2025 huggingface dataset:
Ocean Heat Transport Into the Barents Sea: Distinct Controls on the Upward Trend and Interannual Variability
Authors: Wang Qiang , Wang Xuezhu , Wekerle Claudia , Danilov Sergey , Jung Thomas , Koldunov Nikolay , Lind Sigrid , Sein Dmitry , Shu Qi , Sidorenko Dmitry
Published: September 2019

Ocean heat transport through the Barents Sea Opening (BSO) has strong impacts on the Barents Sea ice extent and the climate. In this paper we quantified the contributions from different atmospheric forcing components to the trend and interannual variability of the BSO heat transport. Ocean‐ice model simulations were conducted in which the interannual variation of atmospheric forcing was maintained only in or outside the Arctic in two different simulations. The sum of their BSO heat transport anomalies reasonably replicated the trend and variability from a hindcast simulation. The upward trend of the BSO heat transport mainly stems from the increasing ocean temperature in the subpolar North Atlantic. For the interannual variability, the local wind and upstream forcing are similarly important. The location of the Atlantic Water boundary current in the Nordic Seas, influenced by the cyclonic atmospheric circulation, is crucial in determining part of the BSO inflow variability.
Probing the Sources of Uncertainty in Transient Warming on Different Timescales
Authors: Lutsko Nicholas J. , Popp Max
Published: September 2019

The rate of transient warming is determined by a number of factors, notably the radiative forcing from increasing CO2 concentrations and the net radiative feedback. Uncertainty in transient warming comes from both the uncertainty in each factor and from the warming's sensitivity to uncertainty in each factor. An energy balance model is used to untangle these two components of uncertainty in transient warming, which is shown to be most sensitive to uncertainty in the forcing and not to uncertainty in radiative feedbacks. Additionally, uncertainty in the efficacy of ocean heat uptake is more important than uncertainty in the rate of ocean heat uptake. Three further implications are as follows: (1) transient warming is highly sensitive to uncertainty in emissions, (2) caution is warranted when extrapolating future warming trends from short‐lived climate perturbations, and (3) climate models tuned using the historical record are highly sensitive to assumptions made about the historical forcing.
Indian Ocean Warming Trend Reduces Pacific Warming Response to Anthropogenic Greenhouse Gases: An Interbasin Thermostat Mechanism
Authors: Zhang Lei , Han Weiqing , Karnauskas Kristopher B. , Meehl Gerald A. , Hu Aixue , Rosenbloom Nan , Shinoda Toshiaki
Published: September 2019

A greater warming trend of sea surface temperature in the tropical Indian Ocean than in the tropical Pacific is a robust feature found in various observational data sets. Yet this interbasin warming contrast is not present in climate models. Here we investigate the impact of tropical Indian Ocean warming on the tropical Pacific response to anthropogenic greenhouse gas warming by analyzing results from coupled model pacemaker experiments. We find that warming in the Indian Ocean induces local negative sea level pressure anomalies, which extend to the western tropical Pacific, strengthening the zonal sea level pressure gradient and easterly trades in the tropical Pacific. The enhanced trade winds reduce sea surface temperature in the eastern tropical Pacific by increasing equatorial upwelling and evaporative cooling, which offset the greenhouse gas warming. This result suggests an interbasin thermostat mechanism, through which the Indian Ocean exerts its influence on the Pacific response to anthropogenic greenhouse gas warming.
Acceleration of Interstellar Pickup He+ at Earth's Perpendicular Bow Shock
Authors: Starkey M. J. , Fuselier S. A. , Desai M. I. , Burch J. L. , Gomez R. G. , Mukherjee J. , Russell C. T. , Lai H. , Schwartz S. J.
Published: September 2019

On 05 December 2015 the Magnetospheric MultiScale constellation observed interstellar pickup ion distributions during an inbound crossing of Earth's perpendicular bow shock near the subsolar point, which provides new insights into shock acceleration of pickup ions throughout the heliosphere. In this study we analyze the upstream and downstream velocity distributions of H+ and He+ using data from the Hot Plasma Composition Analyzer on Magnetospheric MultiScale. We derive average two‐dimensional pitch angle distributions in the upstream and downstream field‐aligned bulk plasma frame, as well as integrated one‐dimensional velocity distributions. By comparing the upstream and downstream distributions, we find evidence of accelerated H+ and He+ downstream of the shock. By comparing measured and theoretical reflection ratios for He+, we attribute a significant part of this acceleration to a single reflection at the shock.
Combined Scattering of Radiation Belt Electrons Caused by Landau and Bounce Resonant Interactions With Magnetosonic Waves
Authors: Fu Song , Ni Binbin , Zhou Ruoxian , Cao Xing , Gu Xudong
Published: September 2019

We develop a full relativistic test particle code to model the combined electron scattering effect of Landau and bounce resonances with magnetosonic waves. Test particle simulations of magnetosonic wave‐electron interactions indicate that the two resonances coexist to affect radiation belt electrons at different energies and pitch angles, and the resultant combined pitch angle scattering and energy diffusion can reach the rates of ~10−4 and ~10‐5 s, respectively, for electrons ~40–500 keV at pitch angles ~   70 ° –   80° for the given wave model (~200 pT) inside the plasmapause at L = 4.5. Comparisons with the quasi‐linear theory results show that the test particle combined scattering rates are generally an order of magnitude weaker, possibly because the electrons are moved out of the Landau resonance by the advective effect of the bounce resonance. Our investigation demonstrates that the Landau and bounce resonances with magnetosonic waves cannot be treated independently or additively in terms of quasi‐linear theory to simulate the associated radiation belt electron dynamics.
A Model of Shallow Viscoelastic Relaxation for Seismically Induced Tension Cracks in the Chile‐Peru Forearc
Authors: Luo H. , Wang K. , Sone H. , He J.
Published: September 2019

Tension cracks were generated by past megathrust earthquakes along the coastal forearc of Chile‐Peru. To explain why elastic rebound in an offshore earthquake can cause widespread permanent deformation onshore, we propose a model in which the near‐surface material exhibits viscoelastic behavior, analogous to laboratory‐observed behavior of petroleum reservoir rocks. Because of near‐surface relaxation, interseismic deformation builds up stress only in the deeper crust. Elastic rebound of the deeper crust during an earthquake induces near‐surface tension to generate cracks. We numerically demonstrate the proposed mechanism using hypothetical and real megathrust earthquakes. The location of the zone of peak tension, assumed to be responsible for the crack generation, is controlled by downdip rupture termination. A rupture farther downdip or terminating more gradually causes the zone of peak tension to be farther landward and broader. The tension cracks thus may contain important information on megathrust rupture dynamics.
Central Asian Drying at 3.3 Ma Linked to Tropical Forcing?
Authors: Su Qingda , Nie Junsheng , Meng Qingquan , Heermance Richard , Gong Lisha , Luo Zeng , Wang Zhao , Zhang Rui , Garzione Carmala
Published: September 2019

The processes controlling middle‐latitude environmental changes are poorly understood. Both high‐latitude ice sheets and tropical oceans can affect climate and environments in middle latitudes, but separating their relative contribution is challenging. Coincidence of intensive Northern Hemisphere glaciations and increased dust accumulation rates at ~2.7 Ma on the Chinese Loess Plateau and North Pacific Ocean is often used to indicate high latitudes' dominant role on middle‐latitude climate change. Here we present new and compile available evidence from the Qaidam Basin and the Tarim Basin of central Asia demonstrating a phase of drying at ~3.3 Ma. The drying is synchronous with proposed timing of closure of the Indonesian Seaway, which has been suggested to cause significant oceanic surface heat adjustments and corresponding decreased heat and moisture transport to middle/high latitudes. These new results suggest a tropical forcing of aridification for the late Pliocene central Asian environmental evolution.
Significant Impact of Rossby Waves on Air Pollution Detected by Network Analysis
Authors: Zhang Yongwen , Fan Jingfang , Chen Xiaosong , Ashkenazy Yosef , Havlin Shlomo
Published: September 2019

Air pollution fluctuations have been found to strongly depend on the weather dynamics. Here we identify the significant atmospheric processes that affect the local daily variability of air pollution. We develop a multilayered network analysis to detect the interlinks between the 500‐hPa geopotential height and surface air pollution in both China and the United States. We find that Rossby waves significantly affect air pollution fluctuations through the development of cyclone and anticyclone systems and further affect the local stability of the air and the winds. Some of these systems are remote (∼3,000 km) and lead to air pollution 1–2 days later. Thus, the impact of Rossby waves on human life is greater than previously believed. The rapid warming of the Arctic could slow down Rossby waves, thus increasing human health risks. Our method can help to determine the risk assessment of such extreme events and can improve potential predictability.
Ion Composition Boundary Layer Instabilities at Mars
Authors: Halekas J. S. , Ruhunusiri S. , McFadden J. P. , Espley J. R. , DiBraccio G. A.
Published: September 2019

The ion composition boundary layer that separates solar wind from ionospheric plasma at Mars typically contains a smooth compositional transition. However, ~10% of boundary crossings display large nonmonotonic variations in density, indicating an instability. We find that most of these instabilities occur on the flanks or downstream of the planet, and many fall into two distinct classes, which occur in different locations, under different preferred conditions. Plume events, which occur where the solar wind electric field points outward, likely represent the motion of the escaping ion plume across the spacecraft. Snowplow events, which occur where the electric field points inward, likely represent the escape of discrete parcels of plasma, which could account for ~10% of the total ion loss from Mars. Snowplow events occur under conditions that favor the development of ionospheric irregularities, which could form a seed for the snowplow mechanism that detaches and accelerates ionospheric plasma downstream.
Plug Formation Imaged Beneath the Active Craters of Sakurajima Volcano With Muography
Authors: Oláh László , Tanaka Hiroyuki K.M. , Ohminato Takao , Hamar Gergő , Varga Dezső
Published: September 2019

Sakurajima Muography Observatory captured the formation of a volcanic plug beneath the Showa crater with a spatial resolution of ∼60 m in accordance with the end of the eruption episode of Showa crater and the reactivation of Minamidake crater. The increase of average density was observed with above 3 σ standard deviation for both above the floor of Minamidake crater and beneath the floor of Showa crater, respectively, being interpreted as volcanic ejecta deposition and the formation of a volcanic plug laterally extended within a few hundreds of meters.
Sahelian Precipitation Change Induced by SST Increase: The Contrasting Roles of Regional and Larger‐Scale Drivers
Authors: Dixon Ross D. , Peyrillé Philippe , Guichard Françoise
Published: September 2019

Representing the West African Monsoon is a major challenge in climate modeling because of complex mechanisms of interaction across scales. We study the monsoon precipitation response to a 4K increase in sea surface temperatures using an idealized meridional‐vertical (2D) model, which allows separating regional‐ and larger‐scale influences. The 2D simulations reproduce key features of Atmospheric Model Intercomparison Project simulations and indicate that, in response to sea surface temperature increase, large‐scale changes induce a decrease of Sahel precipitation, while regional‐scale mechanisms generate a southward shift of the rainband. Large‐scale changes moisten and warm the free troposphere, while regional circulation changes increase low‐level moisture. Precipitation in the control simulations accounts for much of the variance in precipitation change for both Atmospheric Model Intercomparison Project and 2D simulations. This response is strongly connected to the large‐scale drivers of temperature and moisture, with an additional spread associated with the formulation of the convective parameterization.
A New Perspective for Dipolarization Front Dynamics: Electromagnetic Effects of Velocity Inhomogeneity
Authors: Lin Dong , Scales Wayne A. , Ganguli Gurudas , Fu Xiangrong , Crabtree Chris , Tejero Erik , Chen Yuxi , Fletcher Alex C.
Published: September 2019

The stability of a quasi‐static near‐Earth dipolarization front (DF) is investigated with a two‐dimensional electromagnetic particle‐in‐cell model. Strongly localized ambipolar electric fields self‐consistently generate a highly sheared dawnward
electron drift on the kinetic scale in the DF. Electromagnetic particle‐in‐cell simulations based on the observed DF thickness and gradients of plasma/magnetic field parameters reveal that the DF is susceptible to the kinetic electron‐ion hybrid (EIH) instability driven by the strong velocity inhomogeneity. The excited waves show a broadband spectrum in the lower hybrid (LH) frequency range, which has been often observed at DFs. The wavelength is comparable to the shear scale length, and the growth rate is also in the LH frequency range, which are consistent with the EIH theory. As a result of the LH wave emissions, the velocity shear is relaxed, and the DF is broadened. When the plasma beta increases, the wave mode shifts to longer wavelengths with reduced growth rates and enhanced magnetic fluctuations although the wave power is mostly in the electrostatic regime. This study highlights the role of velocity inhomogeneity in the dynamics of DF which has been long neglected. The EIH instability is suggested to be an important mechanism for the wave emissions and steady‐state structure at the DF.
Large‐Amplitude Mountain Waves in the Mesosphere Observed on 21 June 2014 During DEEPWAVE: 1. Wave Development, Scales, Momentum Fluxes, and Environmental Sensitivity
Authors: Taylor Michael J. , Pautet Pierre‐Dominique , Fritts David C. , Kaifler Bernd , Smith Steven M. , Zhao Yucheng , Criddle Neal R. , McLaughlin Pattilyn , Pendleton William R. , McCarthy Michael P. , Hernandez Gonzalo , Eckermann Stephen D. , Doyle James , Rapp Markus , Liley Ben , Russell James M.
Published: September 2019

A remarkable, large‐amplitude, mountain wave (MW) breaking event was observed on the night of 21 June 2014 by ground‐based optical instruments operated on the New Zealand South Island during the Deep Propagating Gravity Wave Experiment (DEEPWAVE). Concurrent measurements of the MW structures, amplitudes, and background environment were made using an Advanced Mesospheric Temperature Mapper, a Rayleigh Lidar, an All‐Sky Imager, and a Fabry‐Perot Interferometer. The MW event was observed primarily in the OH airglow emission layer at an altitude of ~82 km, over an ~2‐hr interval (~10:30–12:30 UT), during strong eastward winds at the OH altitude and above, which weakened with time. The MWs displayed dominant horizontal wavelengths ranging from ~40 to 70 km and temperature perturbation amplitudes as large as ~35 K. The waves were characterized by an unusual, “saw‐tooth” pattern in the larger‐scale temperature field exhibiting narrow cold phases separating much broader warm phases with increasing temperatures toward the east, indicative of strong overturning and instability development. Estimates of the momentum fluxes during this event revealed a distinct periodicity (~25 min) with three well‐defined peaks ranging from ~600 to 800 m2/s2, among the largest ever inferred at these altitudes. These results suggest that MW forcing at small horizontal scales (<100 km) can play large roles in the momentum budget of the mesopause region when forcing and propagation conditions allow them to reach mesospheric altitudes with large amplitudes. A detailed analysis of the instability dynamics accompanying this breaking MW event is presented in a companion paper, Fritts et al. (2019, https://doi.org/10.1029/2019jd030899).
Promyelocytic Leukemia (PML) gene regulation: implication towards curbing oncogenesis
Authors: Datta Neerajana , Islam Saimul , Chatterjee Uttara , Chatterjee Sandip , Panda Chinmay K. , Ghosh Mrinal K.
Published: September 2019

Dysregulation of PML, a significant tumor suppressor is linked with cancers of different histological origins, with a decreased expression observed with a higher tumor grade. This necessitates studying the mechanisms to maintain a stable expression of PML. However much less is known about the transcriptional regulation of PML, more so in the context of breast carcinoma. ERβ has emerged as a critical factor in understanding breast cancer, especially since a huge proportion of breast cancers are ERα− and thus insensitive to tamoxifen therapy. This study aims to uncover an unidentified mechanism of PML gene regulation and its stabilization in breast cancer via ERβ signalling and the impact on cellular apoptosis. We found that clinical expression of PML positively correlates with that of ERβ both in normal and breast carcinoma samples and inversely correlates with markers of cellular proliferation, hinting towards a possible mechanistic interdependence. Both mRNA and protein expression of PML were increased in response to ERβ overexpression on multiple human breast cancer cell lines. Mechanistically, luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that ERβ can interact with the PML promoter via ERE and AP1 sites to enhance its transcription. ERβ induced stable PML expression causes a decline of its target protein Survivin and simultaneously provides a stable docking platform leading to stabilisation of its target Foxo3a, further causing transcriptional upregulation of pro-apoptotic factors p21 and p27. Immunohistochemical analyses of cancer and normal breast tissues and functional assays conducted corroborated the findings. Collectively, our study identifies ERβ signalling as a novel mechanism for PML gene regulation in ERα− breast cancer. It also reveals bi-directional downstream effect in which ‘ERβ-PML-(Foxo3a/Survivin)’ network acts as a therapeutic axis by suppressing cellular survival and promoting cellular apoptosis in breast carcinoma.
Equivalency calculation of unknown enzyme inhibitors in situ the adsorbent of effect-directed autograms
Authors: Azadniya Ebrahim , Morlock Gertrud E.
Published: September 2019

The equivalency calculation of unidentified cholinesterase inhibitors of P. harmala in reference to physostigmine indicated that the developed bands led to more reliable and sensitive results, whereas using applied bands was faster and simpler.
Engineering channels of metal–organic frameworks to enhance catalytic selectivity
Authors: Liu Ye , Shen Yu , Zhang Weina , Weng Jiena , Zhao Meiting , Zhu Tingshun , Chi Yonggui Robin , Yang Yanhui , Zhang Hua , Huo Fengwei
Published: September 2019

Engineering channels of Pt/MOFs catalysts by post modification strategy can enhance size-selective catalytic performance in the hydrogenation of olefins.
Achieving long carrier lifetime and high optical gain in all-inorganic CsPbBr3 perovskite films via top and bottom surface modification
Authors: Jiang Li , Fang Zhishan , Lou Haoran , Lin Chen , Chen Zhanhang , Li Jing , He Haiping , Ye Zhizhen
Published: September 2019

Modifying both the top and bottom surfaces of CsPbBr3 perovskite films enhances carrier lifetime and optical gain remarkably.
Interactions of ions across carbon nanotubes
Authors: Juarez Fernanda , Dominguez-Flores Fabiola , Quaino Paola , Santos Elizabeth , Schmickler Wolfgang
Published: September 2019

The interactions between a pair of ions across CNTs have been investigated by DFT. The electrostatic field of the ion is almost completely screened outside of the tube but an effective attraction between the ions has arisen.
One-step synthesis of few-layer niobium carbide MXene as a promising anode material for high-rate lithium ion batteries
Authors: Zhao Jiabao , Wen Jing , Bai Lina , Xiao Junpeng , Zheng Rudong , Shan Xinyuan , Li Lu , Gao Hong , Zhang Xitian
Published: September 2019

The successful one-step synthesis of few-layer Nb2CTx can facilitate its research and development in the fields of lithium ion batteries and related energy storage devices.
Cycloaddition of CO2 with epoxides and esterification reactions using the porous redox catalyst Co-POM@MIL-101(Cr)
Authors: Marandi Afsaneh , Bahadori Mehrnaz , Tangestaninejad Shahram , Moghadam Majid , Mirkhani Valiollah , Mohammadpoor-Baltork Iraj , Frohnhoven Robert , Mathur Sanjay , Sandleben Aaron , Klein Axel
Published: September 2019

The catalytic activity of the Co-POM@MIL-101(Cr) composite in solvent-free cycloaddition of CO2 to epoxides and esterification of acetic acid with alcohols is due to an outer-sphere electron transfer mechanism using the Co(iii)/Co(ii) redox pair.
SERS-based particle tracking and molecular imaging in live cells: toward the monitoring of intracellular dynamics
Authors: Kim Jongwoo , Nam Sang Hwan , Lim Dong-Kwon , Suh Yung Doug
Published: September 2019

We report that the Raman signal from intracellular cargoes in live cells is sporadically observed and localized to a vesicular level.
Antimicrobial hexagonal boron nitride nanoplatelet composites for the thermal management of medical electronic devices
Authors: Xiong Si-Wei , Zhang Pan , Xia Yu , Fu Pei-Gen , Gai Jing-Gang
Published: September 2019

We developed a thermally conductive and antimicrobial QACs@h-BN/LLDPE composites for thermal management of medically electronic devices, it was approximately 100% against both E. coli and S. aureus and its thermal conductivity can reach 1.115 W m−1 K−1.
Exploring cysteine regulation in cancer cell survival with a highly specific “Lock and Key” fluorescent probe for cysteine
Authors: Liu Jing , Liu Mengxing , Zhang Hongxing , Wei Xuehong , Wang Juanjuan , Xian Ming , Guo Wei
Published: September 2019

Using a highly specific “lock and key” fluorescent Cys probe, we confirmed that targeting Cys metabolism to deplete intracellular Cys is a more potent strategy to sensitize cancer cells to chemotherapies.
Shape-controlled Pd nanocrystal–polyaniline heteronanostructures with modulated polyaniline thickness for efficient electrochemical ethanol oxidation
Authors: Kim Heon Chul , Kim Yena , Bando Yoshio , Yamauchi Yusuke , Hong Jong Wook
Published: September 2019

A facile synthesis method for shape-controlled Pd NC–PANI core–shell heteronanostructures with controllable PANI thickness for efficient electrochemical ethanol oxidation.
Simulations of starspot anomalies within TESS exoplanetary transit light curves
Authors: Tregloan-Reed J. , Unda-Sanzana E.
Published: September 2019

Context. The primary targets of the NASA Transiting Exoplanet Survey Satellite (TESS) are K and M dwarf stars within our solar neighbourhood. Young K and M dwarf stars are known to exhibit a high starspot coverage (≈50%), however, older stars are known to show fewer starspots. This implies that TESS transit light curves at 2 min cadence may contain starspot anomalies, and if so, will require transit-starspot models to determine accurately the properties of the system.

Aims. The goals are to determine if starspot anomalies can manifest in TESS transit light curves, to determine the detection limits of the starspot anomalies, and to examine the relationship between the change in flux caused by the starspot anomaly and the planetary transit.

Methods. We conducted 20 573 simulations of planetary transits around spotted stars using the transit-starspot model, PRISM. In total 3888 different scenarios were considered using three different host star spectral types, M4V, M1V, and K5V. The mean amplitude of the starspot anomaly was measured and compared to the photometric precision of the light curve to determine if the characteristic “blip” of the starspot anomaly was noticeable in the light curve.

Results. The simulations show that starspot anomalies are observable in TESS 2 min cadence data. The smallest starspot detectable in TESS transit light curves has a radius of ≈ 1900 km. The starspot detection limits for the three host stars are 4900 ± 1700 km (M4V), 13 800 ± 6000 km (M1V), and 15 900 ± 6800 km (K5V). The smallest change in flux of the starspot (ΔFspot = 0.00015 ± 0.00001) can be detected when the ratio of planetary to stellar radii k = 0.082 ± 0.004.

Conclusions. The results confirm known dependencies between the amplitude of the starspot anomaly and the photometric parameters of the light curve. The results facilitated the characterisation of the relationship between the change in flux of the starspot anomaly and the change in flux of the planetary transit for TESS transit light curves.
Surgeon Burnout: Defining, Identifying, and Addressing the New Reality
Authors: Senturk James C. , Melnitchouk Nelya
Published: September 2019

Surgeon wellness is a multidimensional commitment that encompasses occupational, mental, physical, emotional, and social domains. Loss of professional control, autonomy, and flexibility; inefficient processes; disjointed workplace relationships and goals; excessive administrative burdens; poor work–life balance; and frustrations with medical record and order entry systems have all been associated with burnout. Described as a syndrome of emotional exhaustion, depersonalization, and loss of a sense of personal accomplishment, burnout can have myriad untoward consequences. The strong link between surgeons' personal and professional identities can lead to a perfect storm of burnout, depression, compromised patient safety and quality of care, physician job loss and career dissatisfaction, substance abuse, damage to personal relationships, and suicide. The alarming scope of this problem cannot be confined to a single specialty or practice setting and is expected to increase without much needed changes to surgeon work practices and work environments. A heightened focus on wellness in the workplace with attention to improving workflow, scheduling, collaboration, and resource allocation is a welcome step taken by several institutions and championed by professional societies. Much more research is needed to reliably gauge the overall effectiveness of these approaches, further address the nuances of burnout as it applies specifically to surgeons, and ensure that members of the surgical workforce remain at their peak throughout the duration of their careers.
ABT-737 Triggers Caspase-Dependent Inhibition of Platelet Procoagulant Extracellular Vesicle Release during Apoptosis and Secondary Necrosis In Vitro
Authors: Wei Hao , Harper Matthew T.
Published: September 2019

Platelet lifespan is limited by activation of intrinsic apoptosis. Apoptotic platelets are rapidly cleared from the circulation in vivo. ABT-737 triggers platelet apoptosis and is a useful tool for studying this process. However, in vitro experiments lack clearance mechanisms for apoptotic platelets. To determine whether apoptotic platelets progress to secondary necrosis, apoptosis was triggered in human platelets with ABT-737, a BH3 mimetic. Platelet annexin V (AnV) binding, release of AnV+ extracellular vesicles (EVs), and loss of plasma membrane integrity were monitored by flow cytometry. ABT-737 triggered AnV binding, indicating phosphatidylserine exposure, release of AnV+ EVs, and a slow loss of plasma membrane integrity. The latter suggests that apoptotic platelets progress to secondary necrosis in vitro. These responses were dependent on caspase activation and Ca2+ entry. Surprisingly, although intracellular Ca2+ concentration increased, AnV+ EV release was not dependent on the Ca2+-dependent protease, calpain. On the contrary, ABT-737 downregulated the ability of the Ca2+ ionophore, A23187, to trigger calpain-dependent release of AnV+ EVs. This was dependent on caspase activity as, when caspases were inhibited, ABT-737 increased the ability of A23187 to trigger AnV+ EV release. These data suggest that apoptotic platelets progress to secondary necrosis unless they are cleared. This may affect the interpretation of ABT-737-triggered signaling in platelets in vitro. Ca2+-dependent AnV+ EV release is downregulated during apoptosis in a caspase-dependent manner, which may limit the potential consequences of secondary necrotic platelets.
Tie2 Activation Promotes Protection and Reconstitution of the Endothelial Glycocalyx in Human Sepsis
Authors: Drost Carolin Christina , Rovas Alexandros , Kusche-Vihrog Kristina , Van Slyke Paul , Kim Harold , Hoang Van C , Maynes Jason T. , Wennmann Dirk Oliver , Pavenstädt Hermann , Linke Wolfgang , Lukasz Alexander , Hesse Bettina , Kümpers Philipp
Published: September 2019

The endothelial glycocalyx (eGC), a carbohydrate-rich layer lining the luminal surface of the endothelium, provides a first vasoprotective barrier against vascular leakage in sepsis. We hypothesized that angiopoietin-2 (Angpt-2), antagonist of the endothelium-stabilizing receptor Tie2, induces a rapid loss of the eGC in human sepsis. Using intravital microscopy, we measured the perfused boundary region (PBR), an inverse parameter of eGC dimensions in sublingual microvessels, in patients with sepsis and age-matched nonseptic subjects. Median PBR values were significantly higher in patients compared with controls and correlated with serum Angpt-2 levels. To transfer and further explore these findings in a cell culture system, we exposed endothelial cells (ECs) to serum (5%) from a subgroup of septic patients and nonseptic controls. Confocal and atomic force microscopy revealed that sepsis serum, but not control serum, induced thinning of the eGC on human ECs in vitro, which correlated with paired PBR values obtained in vivo (r = 0.96, p < 0.01). Inhibition of Angpt-2 or Tie2 activation completely abolished eGC damage. Mechanistically, sepsis-induced eGC breakdown required the loss of its main constituent heparan sulfate; a result of heparan sulfate-specific enzyme heparanase, which was suppressed by Tie2 activation. Finally, Tie2 activation, but not Angpt-2 inhibition, initiated after septic or enzymatic damage provoked rapid refurbishment of the eGC. Our data indicate that eGC breakdown in human sepsis is mediated via Tie2 deactivation by Angpt-2. Activation of Tie2 seems to accelerate recovery of the eGC and might hold promise as a therapeutic target in human sepsis.
Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery
Authors: Salomon Ophira , Budnik Ivan , Avishai Einat , Tamarin Ilia , Bashari Dalia , Dardik Rima , Livnat Tami
Published: September 2019

Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products.

Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity.

Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration.

Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic.

Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.
Apolipoprotein B100/Low-Density Lipoprotein Regulates Proteolysis and Functions of von Willebrand Factor under Arterial Shear
Authors: Cao Wenjing , Abdelgawwad Mohammad S. , Li Jingzhi , Zheng X. Long
Published: September 2019

Background Proteolytic cleavage of von Willebrand factor (VWF) by a plasma a disintegrin and metalloproteinase with a thrombospondin type 1 motifs, member 13 (ADAMTS13) is regulated by shear stress and binding of coagulation factor VIII, platelets or platelet glycoprotein 1b, and ristocetin to VWF.

Objective Current study aims to identify novel VWF binding partners that may modulate VWF functions under physiological conditions.

Methods A deoxyribonucleic acid aptamer-based affinity purification of VWF, followed by tandem mass spectrometry, functional, and binding assays was employed.

Results Apolipoprotein B100/low-density lipoprotein (apoB100/LDL) was identified as a novel VWF-binding partner. Purified apoB100/LDL was able to accelerate the proteolytic cleavage of VWF by ADAMTS13 under shear in a concentration-dependent manner. This rate-enhancing activity was dramatically reduced when apoB100/LDL was oxidized. More interestingly, the oxidized apoB100/LDL appeared to compete with native apoB100/LDL for its enhancing activity on VWF proteolysis under shear. As a control, a purified apoA1/high-density lipoprotein (apoA1/HDL) or apoB48 exhibited a minimal or no activity enhancing VWF proteolysis by ADAMTS13 under the same conditions. Both VWF and ADAMTS13 were able to bind native or oxidized apoB100/LDL with high affinities. No binding interaction was detected between VWF (or ADAMTS13) and apoA1/HDL (or apoB48). Moreover, apoB100/LDL but not its oxidized products inhibited the adhesion of platelets to ultra large VWF released from endothelial cells under flow. Finally, significantly reduced ratios of high to low molecular weight of VWF multimers with increased levels of plasma VWF antigen were detected in LDLR−/−
mice fed with high cholesterol diet.

Conclusion These results indicate that apoB100/LDL may be a novel physiological regulator for ADAMTS13-VWF functions.
RNA editing alterations define manifestation of prion diseases
Authors: Kanata Eirini , Llorens Franc , Dafou Dimitra , Dimitriadis Athanasios , Thüne Katrin , Xanthopoulos Konstantinos , Bekas Nikolaos , Espinosa Juan Carlos , Schmitz Matthias , Marín-Moreno Alba , Capece Vincenzo , Shormoni Orr , Andréoletti Olivier , Bonn Stefan , Torres Juan María , Ferrer Isidre , Zerr Inga , Sklaviadis Theodoros
Published: September 2019

Prion diseases are fatal neurodegenerative disorders caused by misfolding of the normal prion protein into an infectious cellular pathogen. Clinically characterized by rapidly progressive dementia and accounting for 85% of human prion disease cases, sporadic Creutzfeldt–Jakob disease (sCJD) is the prevalent human prion disease. Although sCJD neuropathological hallmarks are well-known, associated molecular alterations are elusive due to rapid progression and absence of preclinical stages. To investigate transcriptome alterations during disease progression, we utilized tg340-PRNP129MM mice infected with postmortem material from sCJD patients of the most susceptible genotype (MM1 subtype), a sCJD model that faithfully recapitulates the molecular and pathological alterations of the human disease. Here we report that transcriptomic analyses from brain cortex in the context of disease progression, reveal epitranscriptomic alterations (specifically altered RNA edited pathway profiles, eg., ER stress, lysosome) that are characteristic and possibly protective mainly for preclinical and clinical disease stages. Our results implicate regulatory epitranscriptomic mechanisms in prion disease neuropathogenesis, whereby RNA-editing targets in a humanized sCJD mouse model were confirmed in pathological human autopsy material.
Regulation of GSK3 cellular location by FRAT modulates mTORC1-dependent cell growth and sensitivity to rapamycin
Authors: He Long , Fei Dennis Liang , Nagiec Michal J. , Mutvei Anders P. , Lamprakis Andreas , Kim Bo Yeon , Blenis John
Published: September 2019

Significance

The clinical effectiveness of FDA-approved anticancer rapalogs is limited because resistance is observed in multiple-tumor settings. In order to improve the efficacy of rapalogs, there is a need to improve our ability to predict and overcome rapamycin resistance. Here we report that high FRAT1/2 expression confers rapamycin resistance by excluding GSK3 from the nucleus in multiple-cancer cell lines. FRAT1 expression is frequently high in multiple cancers, and our observations provide evidence for using FRAT1/2 expression as a biomarker for rapamycin sensitivity. Moreover, our findings reveal a major mechanism for how mTORC1 regulates nuclear protein phosphorylation and signaling, and uncover a potential therapeutic approach for targeting mTORC1-driven cancers.
An ensemble of cryo-EM structures of TRiC reveal its conformational landscape and subunit specificity
Authors: Jin Mingliang , Han Wenyu , Liu Caixuan , Zang Yunxiang , Li Jiawei , Wang Fangfang , Wang Yanxing , Cong Yao
Published: September 2019

TRiC/CCT assists the folding of ∼10% of cytosolic proteins through an ATP-driven conformational cycle and is essential in maintaining protein homeostasis. Here, we determined an ensemble of cryo-electron microscopy (cryo-EM) structures of yeast TRiC at various nucleotide concentrations, with 4 open-state maps resolved at near-atomic resolutions, and a closed-state map at atomic resolution, revealing an extra layer of an unforeseen N-terminal allosteric network. We found that, during TRiC ring closure, the CCT7 subunit moves first, responding to nucleotide binding; CCT4 is the last to bind ATP, serving as an ATP sensor; and CCT8 remains ADP-bound and is hardly involved in the ATPase-cycle in our experimental conditions; overall, yeast TRiC consumes nucleotide in a 2-ring positively coordinated manner. Our results depict a thorough picture of the TRiC conformational landscape and its allosteric transitions from the open to closed states in more structural detail and offer insights into TRiC subunit specificity in ATP consumption and ring closure, and potentially in substrate processing.
Preserved capacity for learning statistical regularities and directing selective attention after hippocampal lesions
Authors: Rungratsameetaweemana Nuttida , Squire Larry R. , Serences John T.
Published: September 2019

Significance

The hippocampus is important for many kinds of learning and memory. We explored the role of the hippocampus in the learning of statistical regularities. We administered a motion discrimination task where expectation about stimulus regularities, the degree of attention afforded to the relevant stimulus, and the amount of available sensory information were manipulated. Although modestly slower overall, patients with bilateral damage to the hippocampus performed similar to controls, exhibiting a normal tendency to respond faster and more accurately when the motion direction was more probable, when the stimulus was better attended, and when more sensory evidence was present. These findings show that the ability to acquire expectations based on regularities of a sensory environment can be independent of the hippocampus.
Perseverative Behavior on Verbal Fluency Task in Patients with Huntington’s Disease: a Retrospective Study on a Large Patient Sample
Authors: De Lucia Natascia , Peluso Silvio , Roca Alessandro , De Michele Giuseppe , Trojano Luigi , Salvatore Elena
Published: September 2019

Objective

Patients with Huntington’s disease (HD) may show impairments of frontal cortical–subcortical circuits with difficulties on cognitive flexibility tasks. One marker of poor flexibility is “perseveration” behavior, which refers to inappropriate and involuntary production of iterative responses not adequate to the current task demands. This study explored frequency, type, and possible cognitive mechanisms of verbal perseverations in a large sample of HD patients.

Method

A sample of 128 patients with HD underwent phonological and category verbal fluency tests to assess perseverative errors, within a wide neuropsychological, psychopathological, motor, and functional assessment.

Results

Perseverative errors in verbal fluency task occurred in 89 (69.5%) patients. Patients showing perseverations scored significantly lower than patients without perseverations on tasks tapping executive and motor functions and on functional independence scales. Logistic regression analysis revealed a significant independent association of verbal perseverations with scores on Trail Making Test only.

Conclusions: Verbal perseverations are frequent in HD patients and are likely related with impairments of attentional switching and working memory, hampering tracking of verbal responses already produced. Perseverative behavior may serve as a useful clinical marker of cognitive and functional impairment in patients with HD.
Comparative Analysis of Cytokines of Tumor Cell Lines, Malignant and Benign Effusions Around Breast Implants
Authors: Kadin Marshall E , Morgan John , Kouttab Nick , Xu Haiying , Adams William P , Glicksman Caroline , McGuire Patricia , Sieber David , Epstein Alan L , Miranda Roberto N , Clemens Mark W
Published: September 2019

Background

More than 700 women have developed an anaplastic large T cell lymphoma (ALCL) surrounding textured surface breast implants, termed breast implant–associated ALCL (BIA-ALCL). Most patients with BIA-ALCL present with an accumulation of fluid (delayed seroma) around the implant. However, benign seromas without malignant cells complicating scar contracture, implant rupture, trauma, infection, and other causes are more common. For proper patient management and to avoid unnecessary surgery, a simple diagnostic test to identify malignant seromas is desirable.

Objectives

The aim of this study was to develop an ancillary test for the diagnosis of malignant seromas and to gain insight into the nature of the malignant cells and their microenvironment.

Methods

We employed an immunologic assay on only 50 µL of aspirated seroma fluid. The assay measures 13 cytokines simultaneously by flow cytometry. To establish a baseline for clinical studies we measured cytokines secreted by BIA-ALCL and cutaneous ALCL lines.

Results

Our study of cell line culture supernatants, and 8 malignant compared with 9 benign seromas indicates that interleukin 9 (IL-9), IL-10, IL-13, IL-22, and/or interferon γ concentrations >1000 pg/mL distinguish malignant seromas from benign seromas. IL-6, known to be a driver of malignant cells, is also elevated in benign seromas and does not distinguish them from malignant seromas.

Conclusions

The cytokine assay introduced in this study can be used together with levels of soluble CD30 to identify malignant seromas. Validation of these findings in a larger prospective patient cohort is warranted. The unique pattern of cytokine expression in malignant effusions surrounding breast implants gives further insight into the pathogenesis and cells of origin of BIA-ALCL.

Level of Evidence: 5
Hybridization and polyploidy in the weeping lizard Liolaemus chiliensis (Squamata: Liolaemidae)
Authors: Araya-Donoso Raúl , Torres-Pérez Fernando , Véliz David , Lamborot Madeleine
Published: September 2019

In reptiles, polyploidy is an unusual phenomenon that can originate from interspecific hybridization. In Chile, the lizard Liolaemus chiliensis provides a unique model with which to study the origin of polyploidy because it occurs in populations of diploid individuals and a few populations that also contain triploid and diploid–triploid mosaic lizards. To test whether L. chiliensis polyploids were hybrids between lineages within the species, we analysed the karyotype, the mitochondrial gene Cytb, seven microsatellite loci, and the linear and geometric morphometry of individuals throughout the species distribution. We found polyploidy at different localities throughout the distribution. Hybrids were detected with the microsatellite loci and morphological data. A clear relationship between hybridization and polyploidy could not be established because triploid and mosaic lizards were hybrids and purebreds. However, our results support the occurrence of both phenomena, and further research is needed to clarify how hybridization could be involved in the origin of polyploidy.
Geographical isolation and restricted gene flow drive speciation of Aegla singularis (Decapoda: Anomura: Aeglidae) in southern South America
Authors: Loretán Gisela , Rueda Eva Carolina , Cabrera Juan Manuel , Pérez-Losada Marcos , Collins Pablo Agustín , Giri Federico
Published: September 2019

Geographical isolation is a key element in allopatric speciation. If gene flow is interrupted for long enough by geographical barriers, populations can evolve independently and eventually form distinct species. Aegla singularis provides an ideal model to study this process due to the characteristics of the geographical area that it occupies and its limited dispersal ability. Aegla singularis inhabits streams of the Uruguay and Paraná River basins in the Neotropical region of South America. The basins are separated by the Sierra Central Mountains. Here we studied the speciation of A. singularis resulting from geographical isolation by using molecular and morphometric data. Individuals of A. singularis were analysed using geometric morphometrics and genetic data (COII and EFα1). We found significant differences in shape and genetics between A. singularis populations from the two basins. These differences suggest ongoing divergence due to restricted gene flow caused by the geographical barrier of the Sierra Central Mountains, indicating that the populations of the Parana and Uruguay River slopes are undergoing divergence.
Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis
Authors: Herich Sebastian , Schneider-Hohendorf Tilman , Rohlmann Astrid , Khaleghi Ghadiri Maryam , Schulte-Mecklenbeck Andreas , Zondler Lisa , Janoschka Claudia , Ostkamp Patrick , Richter Jannis , Breuer Johanna , Dimitrov Stoyan , Rammensee Hans-Georg , Grauer Oliver M , Klotz Luisa , Gross Catharina C , Stummer Walter , Missler Markus , Zarbock Alexander , Vestweber Dietmar , Wiendl Heinz , Schwab Nicholas
Published: September 2019

Specific immune-cell populations patrol the CNS in search of pathogens and tumours. Herich et al. identify CD4+ CCR5high GzmK+ effector-memory cells as a brain-surveilling subpopulation capable of crossing the uninflamed blood-brain barrier, and reveal alterations in this population in HIV+ patients with neurological symptoms and in patients with multiple sclerosis.