bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-Class Phosphorylated-p68 Inhibitor RX-5902 Inhibits β-Catenin Signaling and Demonstrates Antitumor Activity in Triple-Negative Breast Cancer
Authors: Capasso Anna , Bagby Stacey M. , Dailey Kyrie L. , Currimjee Naomi , Yacob Betelehem W. , Ionkina Anastasia , Frank Julie G. , Kim Deog Joong , George Christina , Lee Young B. , Benaim Ely , Gittleman Brian , Hartman Sarah J. , Tan Aik Choon , Kim Jihye , Pitts Todd M. , Eckhardt S. Gail , Tentler John J. , Diamond Jennifer R. 
Published: September 2019

Abstract
RX-5902 is a first-in-class anticancer agent targeting phosphorylated-p68 and attenuating nuclear shuttling of β-catenin. The purpose of this study was to evaluate the efficacy of RX-5902 in preclinical models of triple-negative breast cancer (TNBC) and to explore effects on β-catenin expression. A panel of 18 TNBC cell lines was exposed to RX-5902, and changes in proliferation, apoptosis, cellular ploidy, and effector protein expression were assessed. Gene expression profiling was used in sensitive and resistant cell lines with pathway analysis to explore pathways associated with sensitivity to RX-5902. The activity of RX-5902 was confirmed in vivo in cell line and patient-derived tumor xenograft (PDX) models. RX-5902 demonstrated potent antiproliferative activity in vitro against TNBC cell lines with an average IC50 of 56 nmol/L in sensitive cell lines. RX-5902 treatment resulted in the induction of apoptosis, G2–M cell-cycle arrest, and aneuploidy in a subset of cell lines. RX-5902 was active in vivo against TNBC PDX models, and treatment resulted in a decrease in nuclear β-catenin. RX-5902 exhibited dose-proportional pharmacokinetics and plasma and tumor tissue in nude mice. Pathway analysis demonstrated an increase in the epithelial-to-mesenchymal transformation (EMT), TGFβ, and Wnt/β-catenin pathways associated with sensitivity to RX-5902. RX-5902 is active against in vitro and in vivo preclinical models of TNBC. Target engagement was confirmed with decreases in nuclear β-catenin and MCL-1 observed, confirming the proposed mechanism of action. This study supports the continued investigation of RX-5902 in TNBC and combinations with immunotherapy.
Sepsis Induces Prolonged Epigenetic Modifications in Bone Marrow and Peripheral Macrophages Impairing Inflammation and Wound Healing
Authors: Davis Frank M. , Schaller Matthew A. , Dendekker Aaron , Joshi Amrita D. , Kimball Andrew S. , Evanoff Holly , Wilke Carol , Obi Andrea T. , Melvin William J. , Cavassani Karen , Scola Melissa , Carson Beau , Moser Stephanie , Blanc Victoria , Engoren Milo , Moore Bethany B. , Kunkel Steven L. , Gallagher Katherine A. 
Published: September 2019

Objective:
Sepsis represents an acute life-threatening disorder resulting from a dysregulated host response. For patients who survive sepsis, there remains long-term consequences, including impaired inflammation, as a result of profound immunosuppression. The mechanisms involved in this long-lasting deficient immune response are poorly defined.

Approach and Results:

Sepsis was induced using the murine model of cecal ligation and puncture. Following a full recovery period from sepsis physiology, mice were subjected to our wound healing model and wound macrophages (CD11b+, CD3−, CD19−, Ly6G−) were sorted. Post-sepsis mice demonstrated impaired wound healing and decreased reepithelization in comparison to controls. Further, post-sepsis bone marrow–derived macrophages and wound macrophages exhibited decreased expression of inflammatory cytokines vital for wound repair (IL [interleukin]-1β, IL-12, and IL-23). To evaluate if decreased inflammatory gene expression was secondary to epigenetic modification, we conducted chromatin immunoprecipitation on post-sepsis bone marrow–derived macrophages and wound macrophages. This demonstrated decreased expression of
Mll1
, an epigenetic enzyme, and impaired histone 3 lysine 4 trimethylation (activation mark) at NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells)-binding sites on inflammatory gene promoters in bone marrow–derived macrophages and wound macrophages from postcecal ligation and puncture mice. Bone marrow transplantation studies demonstrated epigenetic modifications initiate in bone marrow progenitor/stem cells following sepsis resulting in lasting impairment in peripheral macrophage function. Importantly, human peripheral blood leukocytes from post-septic patients demonstrate a significant reduction in
MLL1
compared with nonseptic controls.

Conclusions:
These data demonstrate that severe sepsis induces stable mixed-lineage leukemia 1–mediated epigenetic modifications in the bone marrow, which are passed to peripheral macrophages resulting in impaired macrophage function and deficient wound healing persisting long after sepsis recovery.
Ser-Phosphorylation of PCSK9 (Proprotein Convertase Subtilisin-Kexin 9) by Fam20C (Family With Sequence Similarity 20, Member C) Kinase Enhances Its Ability to Degrade the LDLR (Low-Density Lipoprotein Receptor)
Authors: Ben Djoudi Ouadda Ali , Gauthier Marie-Soleil , Susan-Resiga Delia , Girard Emmanuelle , Essalmani Rachid , Black Miles , Marcinkiewicz Jadwiga , Forget Diane , Hamelin Josée , Evagelidis Alexandra , Ly Kevin , Day Robert , Galarneau Luc , Corbin Francois , Coulombe Benoit , Çaku Artuela , Tagliabracci Vincent S. , Seidah Nabil G. 
Published: September 2019

Objective:
PCSK9 (proprotein convertase subtilisin-kexin 9) enhances the degradation of the LDLR (low-density lipoprotein receptor) in endosomes/lysosomes. This study aimed to determine the sites of PCSK9 phosphorylation at Ser-residues and the consequences of such posttranslational modification on the secretion and activity of PCSK9 on the LDLR.

Approach and Results:
Fam20C (family with sequence similarity 20, member C) phosphorylates serines in secretory proteins containing the motif S-X-E/phospho-Ser, including the cholesterol-regulating PCSK9. In situ hybridization of Fam20C mRNA during development and in adult mice revealed a wide tissue distribution, including liver, but not small intestine. Here, we show that Fam20C phosphorylates PCSK9 at Serines 47, 666, 668, and 688. In hepatocytes, phosphorylation enhances PCSK9 secretion and maximizes its induced degradation of the LDLR via the extracellular and intracellular pathways. Replacing any of the 4 Ser by the phosphomimetic Glu or Asp enhanced PCSK9 activity only when the other sites are phosphorylated, whereas Ala substitutions reduced it, as evidenced by Western blotting, Elisa, and LDLR-immunolabeling. This newly uncovered PCSK9/LDLR regulation mechanism refines our understanding of the implication of global PCSK9 phosphorylation in the modulation of LDL-cholesterol and rationalizes the consequence of natural mutations, for example, S668R and E670G. Finally, the relationship of Ser-phosphorylation to the implication of PCSK9 in regulating LDL-cholesterol in the neurological Fragile X-syndrome disorder was investigated.

Conclusions:
Ser-phosphorylation of PCSK9 maximizes both its secretion and activity on the LDLR. Mass spectrometric approaches to measure such modifications were developed and applied to quantify the levels of bioactive PCSK9 in human plasma under normal and pathological conditions.
Building an Accessible, Integrated Earth Observing and Information System: The International Satellite Cloud Climatology Project as a Pathfinder
Authors: Rossow William B. , Bates John J. 
Published: September 2019

AbstractThe current heterogeneity of the existing global collection of measuring assets, satellite and surface based, is a major obstacle to creating a truly integrated, globally uniform information system. Many surveys of Earth science needs over the last 40+ years mention research-to-operations (R2O) actions that are needed to develop such a system but focus mainly on making and collecting measurements with little discussion of the processing system and the integrated team of talented scientists needed to turn raw observations into usable information or the archival system needed to make reliable information readily and widely accessible. We discuss an example of addressing the problems in producing globally uniform information from such observations: the creation in 1982–83 of the data collection, processing, and archival system for the International Satellite Cloud Climatology Project (ISCCP). ISCCP was originally built in a research environment for climate studies, but has now transitioned to a fully operational environment to extend the length of the data record for climate research. Transforming multiple satellite observations into a uniform, global set of physical information about clouds that is readily accessible was and is challenging for several reasons. In this short commentary, we reflect on the experiences and lessons learned in building the ISCCP observation–processing–archival system to address these challenges and discuss the ISCCP R2O process to serve as a pathfinder for building a global observing and information system.
Linear and Weakly Nonlinear Energetics of Global Nonhydrostatic Normal Modes
Authors: Raupp Carlos F. M. , Teruya André S. W. , Silva Dias Pedro L. 
Published: September 2019

Abstract
Here the theory of global nonhydrostatic normal modes has been further developed with the analysis of both linear and weakly nonlinear energetics of inertia–acoustic (IA) and inertia–gravity (IG) modes. These energetics are analyzed in the context of a shallow global nonhydrostatic model governing finite-amplitude perturbations around a resting, hydrostatic, and isothermal background state. For the linear case, the energy as a function of the zonal wavenumber of the IA and IG modes is analyzed, and the nonhydrostatic effect of vertical acceleration on the IG waves is highlighted. For the nonlinear energetics analysis, the reduced equations of a single resonant wave triad interaction are obtained by using a pseudoenergy orthogonality relation. Integration of the triad equations for a resonance involving a short harmonic of an IG wave, a planetary-scale IA mode, and a short IA wave mode shows that an IG mode can allow two IA modes to exchange energy in specific resonant triads. These wave interactions can yield significant modulations in the dynamical fields associated with the physical-space solution with periods varying from a daily time scale to almost a month long.
A Modeling- and Process-Oriented Study to Investigate the Projected Change of ENSO-Forced Wintertime Teleconnectivity in a Warmer World
Authors: Drouard Marie , Cassou Christophe 
Published: September 2019

Abstract
Considerable uncertainties remain about the expected changes of ENSO and associated teleconnectivity as the climate is warming. Two ensembles of pacemaker experiments using the CNRM-CM5 coupled model are designed in a perfect model framework to contrast ENSO-forced teleconnectivity between the preindustrial period versus a warmer background state (obtained from a long stabilized simulation under late-twenty-first-century RCP8.5 constant forcing). The most notable sensitivity to the mean background state is found over the North Atlantic, where the ENSO–NAO teleconnection is considerably reinforced in a warmer world. We attribute this change to (i) a stronger and eastward-extended mean upper-level jet over the North Pacific, (ii) an eastward-shifted ENSO teleconnection over the North Pacific, and (iii) an equatorward-shifted and reinforced mean jet over the North Atlantic. These altogether act as a more efficient waveguide, leading to a better penetration of synoptic storms coming from the Pacific into the Atlantic. This downstream penetration into the North Atlantic basin forces more systematically the NAO through wave breaking. The reinforcement in the teleconnection is asymmetrical with respect to the ENSO phase and is mainly sensitive to La Niña events. Even though the Pacific jet tends to retract westward and move northward during cold events, mean changes are such that both Pacific and Atlantic jets remain connected in a warmer climate by contrast to the preindustrial period, thus ensuring preferred anticyclonic wave breaking downstream over the North Atlantic leading ultimately to NAO+ events.
Non-Gaussian Cold-Side Temperature Distribution Tails and Associated Synoptic Meteorology
Authors: Loikith Paul C. , Neelin J. David 
Published: September 2019

Abstract
Non-Gaussian cold side temperature distribution tails occur in spatially coherent patterns in winter and summer across the globe. Under such conditions, future changes in extreme cold temperature exceedances may be manifested in more complex ways than if the underlying distribution were Gaussian. For example, under a uniform warm shift, locations with shorter- or longer-than-Gaussian cold side tails would experience a more or less rapid decrease in the number of extreme cold threshold exceedances, respectively, compared to if the tail were Gaussian. In many places in the mid- to high latitudes, shorter-than-Gaussian cold tails occur where there is a climatological limit on the magnitude of cold air to be transported by synoptic flow. For example, some high-latitude regions are already among the coldest in the hemisphere, thus limiting the availability of extremely cold air, in an anomalous sense, that can be transported to the region. In other short tail regions, anomalously cold air originates from or travels over large water bodies, which limits the magnitude of the cold anomaly. Long tails are often present when the cold source region is downstream of the climatological flow, requiring a highly anomalous circulation pattern to transport the cold air. The synoptic evolution of extreme cold days at several short- and long-tailed weather stations are presented to help diagnose the mechanisms behind extreme cold temperatures under conditions of non-Gaussianity. This provides a mechanistic view of how extreme cold occurs at each location, as well as an explanation for the notable deviations from Gaussianity.
Projected Changes in Daily Variability and Seasonal Cycle of Near-Surface Air Temperature over the Globe during the Twenty-First Century
Authors: Chen Jiao , Dai Aiguo , Zhang Yaocun 
Published: September 2019

AbstractIncreases in atmospheric greenhouse gases will not only raise Earth’s temperature but may also change its variability and seasonal cycle. Here CMIP5 model data are analyzed to quantify these changes in surface air temperature (Tas) and investigate the underlying processes. The models capture well the mean Tas seasonal cycle and variability and their changes in reanalysis, which shows decreasing Tas seasonal amplitudes and variability over the Arctic and Southern Ocean from 1979 to 2017. Daily Tas variability and seasonal amplitude are projected to decrease in the twenty-first century at high latitudes (except for boreal summer when Tas variability increases) but increase at low latitudes. The day of the maximum or minimum Tas shows large delays over high-latitude oceans, while it changes little at low latitudes. These Tas changes at high latitudes are linked to the polar amplification of warming and sea ice loss, which cause larger warming in winter than summer due to extra heating from the ocean during the cold season. Reduced sea ice cover also decreases its ability to cause Tas variations, contributing to the decreased Tas variability at high latitudes. Over low–midlatitude oceans, larger increases in surface evaporation in winter than summer (due to strong winter winds, strengthened winter winds in the Southern Hemisphere, and increased winter surface humidity gradients over the Northern Hemisphere low latitudes), coupled with strong ocean mixing in winter, lead to smaller surface warming in winter than summer and thus increased seasonal amplitudes there. These changes result in narrower (wider) Tas distributions over the high (low) latitudes, which may have important implications for other related fields.
Role of Residual Overturning for the Sensitivity of Southern Ocean Isopycnal Slopes to Changes in Wind Forcing
Authors: Youngs Madeleine K. , Flierl Glenn R. , Ferrari Raffaele 
Published: September 2019

AbstractThe Antarctic Circumpolar Current plays a central role in the ventilation of heat and carbon in the global ocean. In particular, the isopycnal slopes determine where each water mass outcrops and thus how the ocean interacts with the atmosphere. The region-integrated isopycnal slopes have been suggested to be eddy saturated, that is, stay relatively constant as the wind forcing changes, but whether or not the flow is saturated in realistic present day and future parameter regimes is unknown. This study analyzes an idealized two-layer quasigeostrophic channel model forced by a wind stress and a residual overturning generated by a mass flux across the interface between the two layers, with and without a blocking ridge. The sign and strength of the residual overturning set which way the isopycnal slopes change with the wind forcing, leading to an increase in slope with an increase in wind forcing for a positive overturning and a decrease in slope for a negative overturning, following the usual conventions; this behavior is caused by the dominant standing meander weakening as the wind stress weakens causing the isopycnal slopes to become more sensitive to changes in the wind stress and converge with the slopes of a flat-bottomed simulation. Eddy saturation only appears once the wind forcing passes a critical level. These results show that theories for saturation must have both topography and residual overturning in order to be complete and provide a framework for understanding how the isopycnal slopes in the Southern Ocean may change in response to future changes in wind forcing.
SwathDop: Multibeam Pulse-Coherent Doppler Sonar for Scanning 2D Velocity Sections near the Sediment–Water Interface
Authors: Razaz Mahdi , Zedel Len , Hay Alex E. 
Published: September 2019

AbstractThis paper considers the problem of accurately measuring the sediment transport over bedforms where flow evolves continuously both in time and space. For this purpose, we have developed a pulse-to-pulse coherent Doppler sonar system designed in bistatic geometry with two fan-beam transmitters symmetrically positioned on each side of a multielement receive array. The system resolves 2D velocity components within a ±20° (~0.5 m by ~0.5 m) swath. The software-defined radio data acquisition and control system limited us at present to eight independent receiver channels, and consequently the azimuthal resolution of the system is 4°. As a preliminary test of the sonar system, the system operation was simulated using a model developed to predict coherent sonar performance. The uncertainties with respect to the prescribed values and mean measurements in the model results were confined to 0.35 and 0.23 cm s−1, respectively, in the presence of strong shear (~150 s−1) and 50 cm s−1 horizontal flow. An important thing is that the model allowed us to test and develop the signal processing algorithms necessary to invert the multibeam sonar data. Using sand of 0.4-mm median diameter, the laboratory trials were carried out in active sediment transport conditions over dunes with 2-m wavelength and ~0.90 m s−1 unidirectional flow velocities. The results presented here focus mainly on 2D velocity field and indicate an average 4% deviation from the wake law and 8% from independent observations made with the wide-band multifrequency coherent Doppler profiler (MFDop) instrument under similar flow conditions.
Impact of Weak Coupling between Land and Atmosphere Data Assimilation Systems on Environment and Climate Change Canada’s Global Deterministic Prediction System
Authors: Shahabadi Maziar Bani , Bélair Stéphane , Bilodeau Bernard , Carrera Marco L. , Garand Louis 
Published: September 2019

Abstract
A new ensemble-based land surface data assimilation (DA) system is coupled with the atmospheric four-dimensional ensemble-variational data assimilation (4D-EnVar) system with the goal of improving the analyses within Environment and Climate Change Canada’s Global Deterministic Prediction System. Since 2001, the sequential assimilation of surface variables is used to generate the initial conditions to launch the Global Environmental Multiscale (GEM) coupled forecast model. The work presented here is to replace the sequential DA with an independent surface DA system, the Canadian Land Data Assimilation System (CaLDAS) assimilating screen-level observations, and to compare assimilation experiments with CaLDAS run in uncoupled and weakly coupled modes. In the uncoupled mode, CaLDAS is used to initialize the forecast without interacting with the 4D-EnVar system. In the coupled mode, the analyses generated from CaLDAS and 4D-EnVar are used to initialize the forecast model. The analyses and forecasts from uncoupled and coupled runs are evaluated against surface and radiosonde observations over different subdomains to conclude the impact of coupling CaLDAS with 4D-EnVar. Results indicate a statistically significant reduction in bias and standard deviation at the surface for screen-level temperature and dewpoint temperature on the order of 0.1 K, and in the lower troposphere between 1000 and 500 hPa on the order of 0.1 dam for geopotential height and 0.1 K for air temperature and dewpoint depression in the coupled DA runs. The positive impact persists up to 5 days over some subdomains. It is concluded that the coupled DA approach generally performs better than the uncoupled version.
US Centers for Disease Control and Prevention’s HEADS UP branding and evaluation process
Authors: Waltzman Dana , Hoffman Rosanne , Donnell Zoe , Bell Elizabeth , Sarmiento Kelly 
Published: September 2019

Background: For 15 years, the US Centers for Disease Control and Prevention’s (CDC) HEADS UP education campaign has focused on increasing awareness of concussion among children to reduce adverse outcomes from this injury. Objective: To keep pace with the rapid expansion in media coverage, research, state laws and education efforts on concussion, the CDC embarked on a comprehensive evaluation effort to assess the campaign’s brand. Method: The CDC conducted a multi-step process to evaluate HEADS UP. This included surveying partner organisations and focus groups targeting key audiences. Results: The analysis demonstrated that most (70%) partner organisations have used the materials for 4 years or longer, and more than half (51%) found the materials very useful or extremely useful. Focus groups with the campaign’s target audiences yielded insights and opportunities to refresh the CDC HEADS UP brand. The need for more compelling images, prevention facts and use of eye-catching colours was signalled by all the campaign’s target audiences. Updates focused on the use of data visualisation, more emotionally compelling images and more engaging colours. The CDC also created a new tagline to focus on concussion prevention that encourages children and young people to think about protecting their brains from concussion so that they can have a safer future. Conclusion: This paper describes the process used to update the branding of an educational health promotion campaign in order to meet the needs of key audiences. Findings can help others working to keep their educational campaigns relevant and aligned with expanding and changing public health problems.