bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parametric Sensitivity and Uncertainty Quantification in the Version 1 of E3SM Atmosphere Model Based on Short Perturbed Parameter Ensemble Simulations
Authors: Qian Yun , Wan Hui , Yang Ben , Golaz Jean‐Christophe , Harrop Bryce , Hou Zhangshuan , Larson Vincent E. , Leung L. Ruby , Lin Guangxing , Lin Wuyin , Ma Po‐Lun , Ma Hsi‐Yen , Rasch Phil , Singh Balwinder , Wang Hailong , Xie Shaocheng , Zhang Kai 
Published: October 2018

AbstractThe atmospheric component of Energy Exascale Earth System Model version 1 has included many new features in the physics parameterizations compared to its predecessors. Potential complex nonlinear interactions among the new features create a significant challenge for understanding the model behaviors and parameter tuning. Using the one‐at‐a‐time method, the benefit of tuning one parameter may offset the benefit of tuning another parameter, or improvement in one target variable may lead to degradation in another target variable. To better understand the Energy Exascale Earth System Model version 1 model behaviors and physics, we conducted a large number of short simulations (three days) in which 18 parameters carefully selected from parameterizations of deep convection, shallow convection, and cloud macrophysics and microphysics were perturbed simultaneously using the Latin hypercube sampling method. From the perturbed parameter ensemble simulations and use of different skill score functions, we identified the most sensitive parameters, quantified how the model responds to changes of the parameters for both global mean and spatial distribution, and estimated the maximum likelihood of model parameter space for a number of important fidelity metrics. Comparison of the parametric sensitivity using simulations of two different lengths suggests that perturbed parameter ensemble using short simulations has some bearing on understanding parametric sensitivity of longer simulations. Results from this analysis provide a more comprehensive picture of the Energy Exascale Earth System Model version 1 behavior. The difficulty in reducing biases in multiple variables simultaneously highlights the need of characterizing model structural uncertainty (so‐called embedded errors) to inform future development efforts.
Snow Depth Variability at the Forest Edge in Multiple Climates in the Western United States
Authors: Currier William Ryan , Lundquist Jessica D. 
Published: October 2018

AbstractSnow depth variability between different sides of the forest edge was analyzed using airborne lidar in the Olympic Mountains, WA; Tuolumne River Watershed, CA; Jemez Caldera, NM; and the Boulder Creek Watershed, CO. At Boulder Creek there were statistically significant snow depth differences between leeward and windward forest edges (mean: 38%), which were likely the result of cold winter temperatures (−5 to −10°C), substantial wind speeds (>10–12 m/s), and the forest architecture. In the Olympic Mountains, wind speeds were similar to Boulder Creek, but snow depth differences between forest edges were not significantly different, likely due to winter temperatures near 0°C and a more continuous forest distribution. At Jemez, forest shading likely caused significant snow depth differences between north and south facing forest edges (mean: 32%). Tuolumne had similar incoming solar radiation to Jemez, but only two of the four sites contained significant snow depth differences between north and south facing forest edges (14% and 31%). The Tuolumne sites without significant edge differences received less direct solar radiation due to shading by surrounding topography. At Jemez, Boulder Creek, and Tuolumne, snow depth differences between forest edges were greater than or equal to differences between exposed and under canopy areas. Furthermore, at Jemez and Tuolumne, forest‐edge snow depth differences were similar to snow depth differences between different aspects in exposed areas. Therefore, snow depth differences between forest‐edge classifications are of similar magnitude to classifications currently used to represent subelement heterogeneity within hydrologic models. Therefore, representation of forest‐edge variability within models should be explored.
T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics
Authors: Herbert Katharine J. , Ashton Thomas M. , Prevo Remko , Pirovano Giacomo , Higgins Geoff S. 
Published: October 2018

Abstract‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
Direct cysteine sulfenylation drives activation of the Src kinase
Authors: Heppner David E. , Dustin Christopher M. , Liao Chenyi , Hristova Milena , Veith Carmen , Little Andrew C. , Ahlers Bethany A. , White Sheryl L. , Deng Bin , Lam Ying-Wai , Li Jianing , van der Vliet Albert 
Published: October 2018

AbstractThe Src kinase controls aspects of cell biology and its activity is regulated by intramolecular structural changes induced by protein interactions and tyrosine phosphorylation. Recent studies indicate that Src is additionally regulated by redox-dependent mechanisms, involving oxidative modification(s) of cysteines within the Src protein, although the nature and molecular-level impact of Src cysteine oxidation are unknown. Using a combination of biochemical and cell-based studies, we establish the critical importance of two Src cysteine residues, Cys-185 and Cys-277, as targets for H2O2-mediated sulfenylation (Cys-SOH) in redox-dependent kinase activation in response to NADPH oxidase-dependent signaling. Molecular dynamics and metadynamics simulations reveal the structural impact of sulfenylation of these cysteines, indicating that Cys-277-SOH enables solvent exposure of Tyr-416 to promote its (auto)phosphorylation, and that Cys-185-SOH destabilizes pTyr-527 binding to the SH2 domain. These redox-dependent Src activation mechanisms offer opportunities for development of Src-selective inhibitors in treatment of diseases where Src is aberrantly activated.
Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2
Authors: Pádua Ricardo A. P. , Sun Yizhi , Marko Ingrid , Pitsawong Warintra , Stiller John B. , Otten Renee , Kern Dorothee 
Published: October 2018

AbstractProtein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K’s much higher activity, demands significantly greater SHP099 concentrations to restore wild-type activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.
Manganese-catalyzed hydroboration of carbon dioxide and other challenging carbonyl groups
Authors: Erken Christina , Kaithal Akash , Sen Suman , Weyhermüller Thomas , Hölscher Markus , Werlé Christophe , Leitner Walter 
Published: October 2018

AbstractReductive functionalization of the C=O unit in carboxylic acids, carbonic acid derivatives, and ultimately in carbon dioxide itself is a challenging task of key importance for the synthesis of value-added chemicals. In particular, it can open novel pathways for the valorization of non-fossil feedstocks. Catalysts based on earth-abundant, cheap, and benign metals would greatly contribute to the development of sustainable synthetic processes derived from this concept. Herein, a manganese pincer complex [Mn(Ph2PCH2SiMe2)2NH(CO)2Br] (1) is reported to enable the reduction of a broad range of carboxylic acids, carbonates, and even CO2 using pinacolborane as reducing agent. The complex is shown to operate under mild reaction conditions (80–120 °C), low catalyst loadings (0.1–0.2 mol%) and runs under solvent-less conditions. Mechanistic studies including crystallographic characterisation of a borane adduct of the pincer complex (1) imply that metal-ligand cooperation facilitates substrate activation.
A high-energy sulfur cathode in carbonate electrolyte by eliminating polysulfides via solid-phase lithium-sulfur transformation
Authors: Li Xia , Banis Mohammad , Lushington Andrew , Yang Xiaofei , Sun Qian , Zhao Yang , Liu Changqi , Li Qizheng , Wang Biqiong , Xiao Wei , Wang Changhong , Li Minsi , Liang Jianwen , Li Ruying , Hu Yongfeng , Goncharova Lyudmila , Zhang Huamin , Sham Tsun-Kong , Sun Xueliang 
Published: October 2018

AbstractCarbonate-based electrolytes demonstrate safe and stable electrochemical performance in lithium-sulfur batteries. However, only a few types of sulfur cathodes with low loadings can be employed and the underlying electrochemical mechanism of lithium-sulfur batteries with carbonate-based electrolytes is not well understood. Here, we employ in operando X-ray absorption near edge spectroscopy to shed light on a solid-phase lithium-sulfur reaction mechanism in carbonate electrolyte systems in which sulfur directly transfers to Li2S without the formation of linear polysulfides. Based on this, we demonstrate the cyclability of conventional cyclo-S8 based sulfur cathodes in carbonate-based electrolyte across a wide temperature range, from −20 °C to 55 °C. Remarkably, the developed sulfur cathode architecture has high sulfur content (>65 wt%) with an areal loading of 4.0 mg cm−2. This research demonstrates promising performance of lithium-sulfur pouch cells in a carbonate-based electrolyte, indicating potential application in the future.
Dynamics of individual molecular shuttles under mechanical force
Authors: Naranjo Teresa , Lemishko Kateryna M. , de Lorenzo Sara , Somoza Álvaro , Ritort Felix , Pérez Emilio M. , Ibarra Borja 
Published: October 2018

AbstractMolecular shuttles are the basis of some of the most advanced synthetic molecular machines. In these devices a macrocycle threaded onto a linear component shuttles between different portions of the thread in response to external stimuli. Here, we use optical tweezers to measure the mechanics and dynamics of individual molecular shuttles in aqueous conditions. Using DNA as a handle and as a single molecule reporter, we measure thousands of individual shuttling events and determine the force-dependent kinetic rates of the macrocycle motion and the main parameters governing the energy landscape of the system. Our findings could open avenues for the real-time characterization of synthetic devices at the single molecule level, and provide crucial information for designing molecular machinery able to operate under physiological conditions.
Sources, propagation and consequences of stochasticity in cellular growth
Authors: Thomas Philipp , Terradot Guillaume , Danos Vincent , Weiße Andrea Y. 
Published: October 2018

AbstractGrowth impacts a range of phenotypic responses. Identifying the sources of growth variation and their propagation across the cellular machinery can thus unravel mechanisms that underpin cell decisions. We present a stochastic cell model linking gene expression, metabolism and replication to predict growth dynamics in single bacterial cells. Alongside we provide a theory to analyse stochastic chemical reactions coupled with cell divisions, enabling efficient parameter estimation, sensitivity analysis and hypothesis testing. The cell model recovers population-averaged data on growth-dependence of bacterial physiology and how growth variations in single cells change across conditions. We identify processes responsible for this variation and reconstruct the propagation of initial fluctuations to growth and other processes. Finally, we study drug-nutrient interactions and find that antibiotics can both enhance and suppress growth heterogeneity. Our results provide a predictive framework to integrate heterogeneous data and draw testable predictions with implications for antibiotic tolerance, evolutionary and synthetic biology.
Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection
Authors: Rolot Marion , Dougall Annette M. , Chetty Alisha , Javaux Justine , Chen Ting , Xiao Xue , Machiels Bénédicte , Selkirk Murray E. , Maizels Rick M. , Hokke Cornelis , Denis Olivier , Brombacher Frank , Vanderplasschen Alain , Gillet Laurent , Horsnell William G. C. , Dewals Benjamin G. 
Published: October 2018

AbstractInfection with parasitic helminths can imprint the immune system to modulate bystander inflammatory processes. Bystander or virtual memory CD8+ T cells (TVM) are non-conventional T cells displaying memory properties that can be generated through responsiveness to interleukin (IL)-4. However, it is not clear if helminth-induced type 2 immunity functionally affects the TVM compartment. Here, we show that helminths expand CD44hiCD62LhiCXCR3hiCD49dlo TVM cells through direct IL-4 signaling in CD8+ T cells. Importantly, helminth-mediated conditioning of TVM cells provided enhanced control of acute respiratory infection with the murid gammaherpesvirus 4 (MuHV-4). This enhanced control of MuHV-4 infection could further be explained by an increase in antigen-specific CD8+ T cell effector responses in the lung and was directly dependent on IL-4 signaling. These results demonstrate that IL-4 during helminth infection can non-specifically condition CD8+ T cells, leading to a subsequently raised antigen-specific CD8+ T cell activation that enhances control of viral infection.
Adrenal hormones mediate disease tolerance in malaria
Authors: Vandermosten Leen , Pham Thao-Thy , Knoops Sofie , De Geest Charlotte , Lays Natacha , Van der Molen Kristof , Kenyon Christopher J. , Verma Manu , Chapman Karen E. , Schuit Frans , De Bosscher Karolien , Opdenakker Ghislain , Van den Steen Philippe E. 
Published: October 2018

AbstractMalaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance.
Charge and phonon transport in PbTe-based thermoelectric materials
Authors: Xiao Yu , Zhao Li-Dong 
Published: October 2018

AbstractPbTe is a typical intermediate-temperature thermoelectric material, which has undergone extensive developments and achieved excellent high thermoelectric performance. In this perspective we summarized several strategies that were successfully applied in PbTe-based thermoelectric materials through manipulating charge and phonon transports, such as optimizing carrier density to tune Fermi level, tailoring band structure to enhance effective mass, and designing all-scale hierarchical architectures to suppress phonon propagation. Meanwhile, due to the different features of conduction and valence bands, we separately introduced the approaches to enhance performance of p-type and n-type PbTe. In p-type PbTe, the strategies of band convergence, band alignment and density of state (DOS) distortion are more effective to achieve high electrical transport properties. By contrast, flattening conduction bands and introducing deep impurity level are more suitable for n-type PbTe. Lastly, several potential strategies were proposed to further improve the thermoelectric performance of PbTe-based materials, which might be extended to other thermoelectric systems.
Quantum spin fluctuations and evolution of electronic structure in cuprates
Authors: Stepanov Evgeny A. , Peters Lars , Krivenko Igor S. , Lichtenstein Alexander I. , Katsnelson Mikhail I. , Rubtsov Alexey N. 
Published: October 2018

AbstractCorrelation effects in CuO2 layers give rise to a complicated landscape of collective excitations in high-Tc cuprates. Their description requires an accurate account for electronic fluctuations at a very broad energy range and remains a challenge for the theory. Particularly, there is no conventional explanation of the experimentally observed “resonant” antiferromagnetic mode, which is often considered to be a mediator of superconductivity. Here we model spin excitations of the hole-doped cuprates in the paramagnetic regime and show that this antiferromagnetic mode is associated with electronic transitions between anti-nodal X and Y points of the quasiparticle band that is pinned to the Fermi level. We observe that upon doping of 7–12%, the electronic spectral weight redistribution leads to the formation of a very stable quasiparticle dispersion due to strong correlation effects. The reconstruction of the Fermi surface results in a flattening of the quasiparticle band at the vicinity of the nodal MΓ/2 point, accompanied by a high density of charge carriers. Collective excitations of electrons between the nodal MΓ/2 and XM/2 points form the additional magnetic holes state in magnetic spectrum, which protects the antiferromagnetic fluctuation. Further investigation of the evolution of spin fluctuations with the temperature and doping allowed us to observe the incipience of the antiferromagnetic ordering already in the paramagnetic regime above the transition temperature. Additionally, apart from the most intensive low-energy magnetic excitations, the magnetic spectrum reveals less intensive collective spin fluctuations that correspond to electronic processes between peaks of the single-particle spectral function.
Development of a rapid and economic in vivo electrocardiogram platform for cardiovascular drug assay and electrophysiology research in adult zebrafish
Authors: Lin Min-Hsuan , Chou Huang-Cheng , Chen Yu-Fu , Liu Wangta , Lee Chi-Chun , Liu Lawrence Yu-Min , Chuang Yung-Jen 
Published: October 2018

AbstractZebrafish is a popular and favorable model organism for cardiovascular research, with an increasing number of studies implementing functional assays in the adult stage. For example, the application of electrocardiography (ECG) in adult zebrafish has emerged as an important tool for cardiac pathophysiology, toxicity, and chemical screen studies. However, few laboratories are able to perform such functional analyses due to the high cost and limited availability of a convenient in vivo ECG recording system. In this study, an inexpensive ECG recording platform and operation protocol that has been optimized for adult zebrafish ECG research was developed. The core hardware includes integration of a ready-to-use portable ECG kit with a set of custom-made needle electrode probes. A combined anesthetic formula of MS-222 and isoflurane was first tested to determine the optimal assay conditions to minimize the interference to zebrafish cardiac physiology under sedation. For demonstration, we treated wild-type zebrafish with different pharmacological agents known to affect cardiac rhythms in humans. Conserved electrophysiological responses to these drugs were induced in adult zebrafish and recorded in real time. This economic ECG platform has the potential to facilitate teaching and training in cardiac electrophysiology with adult zebrafish and to promote future translational applications in cardiovascular medicine.
Static magnetic fields reduce epileptiform activity in anesthetized rat and monkey
Authors: Rivadulla Casto , Aguilar Juan , Coletti Marcos , Aguila Jordi , Prieto Sandra , Cudeiro Javier 
Published: October 2018

AbstractIncreasing evidence indicates that static magnetic fields (SMF) reduce cortical activity in both human and animal models. The aim of this work was to investigate the effect of SMF on epileptiform cortical activity, a condition related to an abnormal increase in neuronal excitability. The first experimental block included a Pilocarpine rat model of epilepsy, in which a magnetic neodymium nickel-plated cylinder, a magnetic field of 0.5 T, or “sham” were placed over the skull. In the second experimental block, we recorded epileptic-like activity in the visual cortex of a monkey (Macaca mulatta) under control conditions and in the presence of the magnet. Between 15 and 30 minutes after the second dose of Pilocarpine, EEG changes compatible with seizure like events induced by Pilocarpine were clearly observed in the control animals (sham stimulation). Similar effects were visible in the animals exposed to the real magnet after 1–2 hours. In the monkey, SMF over the cortical focus clearly reduced abnormal activity: the intensity threshold for visual induction increased and the severity and duration decreased. These results reinforce the view that static magnets modulate cortical activity and open the door to the future therapeutic use of SMF in epilepsy as a complement to current pharmacological treatments.