bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth
Authors: Damaschke Nathan A. , Yang Bing , Bhusari Sachin , Avilla Mele , Zhong Weixiong , Blute Michael L. , Huang Wei , Jarrard David F. 
Published: August 2017

Abstract
Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236–47. ©2017 AACR.
JCAD Promotes Progression of Nonalcoholic Steatohepatitis to Liver Cancer by Inhibiting LATS2 Kinase Activity
Authors: Ye Juan , Li Tian-Sheng , Xu Gang , Zhao Yi-Ming , Zhang Ning-Ping , Fan Jia , Wu Jian 
Published: August 2017

Abstract
Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents are rapidly increasing. However, the mechanisms that drive development of HCC in a steatotic microenvironment remain unknown. Here we report that the obesity-associated protein JCAD is expressed at significantly higher levels in human NASH-HCC specimens compared with pericarcinoma specimens. High JCAD expression was verified in multiple hepatoma cell lines. Forced overexpression of JCAD in hepatoma cells promoted tumor growth and proliferation, whereas JCAD silencing yielded opposite effects. JCAD interacted with the kinase domain of the tumor suppressor kinase LATS2, a core component of the Hippo signaling pathway. JCAD overexpression inhibited the ability of LATS2 to phosphorylate YAP in this pathway, in turn upregulating CCND1 and GLI2 to promote hepatoma cell proliferation. JCAD was induced by fatty acid overload in hepatic cells and was highly expressed in a mouse model of NASH-precarcinoma lesions, where the ratio of phospho-YAP to YAP was decreased. In human NASH-HCC specimens, JCAD expression and YAP phosphorylation patterns paralleled with the mouse model. Our findings illuminate a new role for JCAD and its critical interplay in the Hippo signaling cascade during the transition of NASH to HCC, with potential implications for therapeutic development in this setting. Cancer Res; 77(19); 5287–300. ©2017 AACR.
Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells
Authors: Fuse Marisa A. , Plati Stephani Klingeman , Burns Sarah S. , Dinh Christine T. , Bracho Olena , Yan Denise , Mittal Rahul , Shen Rulong , Soulakova Julia N. , Copik Alicja J. , Liu Xue Zhong , Telischi Fred F. , Chang Long-Sheng , Franco Maria Clara , Fernandez-Valle Cristina 
Published: August 2017

Abstract
Neurofibromatosis type 2 (NF2) is a nervous system tumor disorder caused by inactivation of the merlin tumor suppressor encoded by the NF2 gene. Bilateral vestibular schwannomas are a diagnostic hallmark of NF2. Mainstream treatment options for NF2-associated tumors have been limited to surgery and radiotherapy; however, off-label uses of targeted molecular therapies are becoming increasingly common. Here, we investigated drugs targeting two kinases activated in NF2-associated schwannomas, c-Met and Src. We demonstrated that merlin-deficient mouse Schwann cells (MD-MSC) treated with the c-Met inhibitor, cabozantinib, or the Src kinase inhibitors, dasatinib and saracatinib, underwent a G1 cell-cycle arrest. However, when MD-MSCs were treated with a combination of cabozantinib and saracatinib, they exhibited caspase-dependent apoptosis. The combination therapy also significantly reduced growth of MD-MSCs in an orthotopic allograft mouse model by greater than 80% of vehicle. Moreover, human vestibular schwannoma cells with NF2 mutations had a 40% decrease in cell viability when treated with cabozantinib and saracatinib together compared with the vehicle control. This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR.
Clots Are Potent Triggers of Inflammatory Cell Gene Expression
Authors: Campbell Robert A. , Vieira-de-Abreu Adriana , Rowley Jesse W. , Franks Zechariah G. , Manne Bhanu Kanth , Rondina Matthew T. , Kraiss Larry W. , Majersik Jennifer J. , Zimmerman Guy A. , Weyrich Andrew S. 
Published: August 2017

Objective—
Blood vessel wall damage often results in the formation of a fibrin clot that traps inflammatory cells, including monocytes. The effect of clot formation and subsequent lysis on the expression of monocyte-derived genes involved in the development and progression of ischemic stroke and other vascular diseases, however, is unknown. Determine whether clot formation and lysis regulates the expression of human monocyte-derived genes that modulate vascular diseases.

Approach and Results—
We performed next-generation RNA sequencing on monocytes extracted from whole blood clots and using a purified plasma clot system. Numerous mRNAs were differentially expressed by monocytes embedded in clots compared with unclotted controls, and IL-8 (interleukin 8) and MCP-1 (monocyte chemoattractant protein-1) were among the upregulated transcripts in both models. Clotted plasma also increased expression of IL-8 and MCP-1, which far exceeded responses observed in lipopolysaccharide-stimulated monocytes. Upregulation of IL-8 and MCP-1 occurred in a thrombin-independent but fibrin-dependent manner. Fibrinolysis initiated shortly after plasma clot formation (ie, 1–2 hours) reduced the synthesis of IL-8 and MCP-1, whereas delayed fibrinolysis was far less effective. Consistent with these in vitro models, monocytes embedded in unresolved thrombi from patients undergoing thrombectomy stained positively for IL-8 and MCP-1.

Conclusions—
These findings demonstrate that clots are potent inducers of monocyte gene expression and that timely fibrinolysis attenuates inflammatory responses, specifically IL-8 and MCP-1. Dampening of inflammatory gene expression by timely clot lysis may contribute to the clinically proven efficacy of fibrinolytic drug treatment within hours of stroke onset.
Stasis Promotes Erythrocyte Adhesion to von Willebrand Factor
Authors: Smeets Michel W.J. , Mourik Marjon J. , Niessen Hans W.M. , Hordijk Peter L. 
Published: August 2017

Objective—
Venous thromboembolism is a major contributor to global disease burden. Leukocytes and platelets initiate thrombogenesis on blood stasis and initiate the formation of a fibrin, VWF (von Willebrand factor), and neutrophil extracellular trap scaffold for erythrocytes. However, there is little knowledge on how erythrocytes become stably incorporated into this scaffold. Recently, we described the adhesion of calcium-loaded erythrocytes to endothelial-derived VWF strings. Because VWF is part of the scaffold of venous thrombi, we questioned whether reduced flow or stasis promotes the adhesion of normal erythrocytes to VWF and whether venous thrombi show evidence of erythrocyte–VWF interactions.

Approach and Results—
In the present work, we perfused, under controlled shear conditions, washed, normal erythrocytes over surface-immobilized plasma and extracellular matrix proteins and showed that normal erythrocytes specifically bind to VWF. The interaction between erythrocytes and VWF significantly increased when the wall shear stress was reduced. Next, we investigated whether erythrocyte–VWF interactions support the structure of venous thrombi. High-resolution immunofluorescence imaging of human venous thrombi showed a striking pattern between erythrocytes, VWF, and fibrin, which suggests that VWF plays a supporting role, linking erythrocytes to fibrin in the thrombus.

Conclusions—
Our data suggest that erythrocyte retention in venous thrombi is mediated by erythrocyte–VWF or erythrocyte–VWF–fibrin interactions. Targeting erythrocyte retention could be a new strategy in the treatment or prevention of venous thrombosis.
The Nature of Task Set Representations in Working Memory
Authors: Kikumoto Atsushi , Mayr Ulrich 
Published: August 2017

Abstract
Selection and preparation of action plans (task sets) is often assumed to occur in working memory (WM). Yet, the absence of consistent evidence that WM capacity and task selection efficiency is correlated raises questions about the functional relationship between these two aspects of executive control. We used the EEG-derived contralateral delay activity (CDA) to index the WM load of task sets. In Experiment 1, we found a CDA set size effect (2 vs. 4 stimulus–response [S-R] rules) for high-WM, but not for low-WM, individuals when S-R sets were novel. In contrast, when only four task sets were presented throughout the experiment, we observed a sustained yet set size-independent use of WM for high-WM participants. Moreover, Experiment 2 showed an increase of the CDA in situations with task conflict, and this effect was larger the more that participants experienced RT conflict effects. Combined, these results indicate that even highly familiar S-R settings are maintained in WM, albeit in a compressed manner, presumably through cues to long-term memory representations. Finally, participants with low-WM capacity represented even familiar tasks in a load-dependent manner, suggesting that the establishment of effective retrieval structures itself is a capacity-limited process.
Differential Covariance: A New Class of Methods to Estimate Sparse Connectivity from Neural Recordings
Authors: Lin Tiger W. , Das Anup , Krishnan Giri P. , Bazhenov Maxim , Sejnowski Terrence J. 
Published: August 2017

With our ability to record more neurons simultaneously, making sense of these data is a challenge. Functional connectivity is one popular way to study the relationship of multiple neural signals. Correlation-based methods are a set of currently well-used techniques for functional connectivity estimation. However, due to explaining away and unobserved common inputs (Stevenson, Rebesco, Miller, & Körding, 2008 ), they produce spurious connections. The general linear model (GLM), which models spike trains as Poisson processes (Okatan, Wilson, & Brown, 2005 ; Truccolo, Eden, Fellows, Donoghue, & Brown, 2005 ; Pillow et al., 2008 ), avoids these confounds. We develop here a new class of methods by using differential signals based on simulated intracellular voltage recordings. It is equivalent to a regularized AR(2) model. We also expand the method to simulated local field potential recordings and calcium imaging. In all of our simulated data, the differential covariance-based methods achieved performance better than or similar to the GLM method and required fewer data samples. This new class of methods provides alternative ways to analyze neural signals.
Methods for Estimating 2D Cloud Size Distributions from 1D Observations
Authors: Romps David M. , Vogelmann Andrew M. 
Published: August 2017

Abstract
The two-dimensional (2D) size distribution of clouds in the horizontal plane plays a central role in the calculation of cloud cover, cloud radiative forcing, convective entrainment rates, and the likelihood of precipitation. Here, a simple method is proposed for calculating the area-weighted mean cloud size and for approximating the 2D size distribution from the 1D cloud-chord lengths measured by aircraft and vertically pointing lidar and radar. This simple method (which is exact for square clouds) compares favorably against the inverse Abel transform (which is exact for circular clouds) in the context of theoretical size distributions. Both methods also perform well when used to predict the size distribution of real clouds from a Landsat scene. When applied to a large number of Landsat scenes, the simple method is able to accurately estimate the mean cloud size. As a demonstration, the methods are applied to aircraft measurements of shallow cumuli during the Routine ARM Aerial Facility (AAF) Clouds with Low Optical Water Depths (CLOWD) Optical Radiative Observations (RACORO) campaign, which then allow for an estimate of the true area-weighted mean cloud size.
Nowcast Guidance of Afternoon Convection Initiation for Taiwan
Authors: Chang Hui-Ling , Brown Barbara G. , Chu Pao-Shin , Liou Yu-Chieng , Wang Wen-Ho 
Published: August 2017

Abstract
Focusing on afternoon thunderstorms in Taiwan during the warm season (May–October) under weak synoptic forcing, this study applied the Taiwan Auto-NowCaster (TANC) to produce 1-h likelihood nowcasts of afternoon convection initiation (ACI) using a fuzzy logic approach. The primary objective is to design more useful forecast products with uncertainty regions of predicted thunderstorms to provide nowcast guidance of ACI for forecasters. Four sensitivity tests on forecast performance were conducted to improve the usefulness of nowcasts for forecasters. The optimal likelihood threshold (Lt) for ACIs, which is the likelihood value that best corresponds to the observed ACIs, was determined to be 0.6. Because of the high uncertainty on the exact location or timing of ACIs in nowcasts, location displacement and temporal shifting of ACIs should be considered in operational applications. When a spatial window of 5 km and a temporal window of 18 min are applied, the TANC displays moderate accuracy and satisfactory discrimination with an acceptable degree of overforecasting. The nonparametric Mann–Whitney test indicated that the performance of the TANC substantially surpasses the competing Space and Time Multiscale Analysis System–Weather Research and Forecasting Model, which serves as a pertinent reference for short-range (0–6 h) forecasts at the Central Weather Bureau in Taiwan.
An Assessment of the ECMWF Extreme Forecast Index for Water Vapor Transport during Boreal Winter
Authors: Lavers David A. , Zsoter Ervin , Richardson David S. , Pappenberger Florian 
Published: August 2017

Abstract
Early awareness of extreme precipitation can provide the time necessary to make adequate event preparations. At the European Centre for Medium-Range Weather Forecasts (ECMWF), one tool that condenses the forecast information from the Integrated Forecasting System ensemble (ENS) is the extreme forecast index (EFI), an index that highlights regions that are forecast to have potentially anomalous weather conditions compared to the local climate. This paper builds on previous findings by undertaking a global verification throughout the medium-range forecast horizon (out to 15 days) on the ability of the EFI for water vapor transport [integrated vapor transport (IVT)] and precipitation to capture extreme observed precipitation. Using the ECMWF ENS for winters 2015/16 and 2016/17 and daily surface precipitation observations, the relative operating characteristic is used to show that the IVT EFI is more skillful than the precipitation EFI in forecast week 2 over Europe and western North America. It is the large-scale nature of the IVT, its higher predictability, and its relationship with extreme precipitation that result in its potential usefulness in these regions, which, in turn, could provide earlier awareness of extreme precipitation. Conversely, at shorter lead times the precipitation EFI is more useful, although the IVT EFI can provide synoptic-scale understanding. For the whole globe, the extratropical Northern Hemisphere, the tropics, and North America, the precipitation EFI is more useful throughout the medium range, suggesting that precipitation processes not captured in the IVT are important (e.g., tropical convection). Following these results, the operational implementation of the IVT EFI is currently being planned.
Dealing With Unexpected Events on the Flight Deck: A Conceptual Model of Startle and Surprise
Authors: Landman Annemarie , Groen Eric L. , van Paassen M. M. (René) , Bronkhorst Adelbert W. , Mulder Max 
Published: August 2017

Objective: A conceptual model is proposed in order to explain pilot performance in surprising and startling situations. Background: Today’s debate around loss of control following in-flight events and the implementation of upset prevention and recovery training has highlighted the importance of pilots’ ability to deal with unexpected events. Unexpected events, such as technical malfunctions or automation surprises, potentially induce a “startle factor” that may significantly impair performance. Method: Literature on surprise, startle, resilience, and decision making is reviewed, and findings are combined into a conceptual model. A number of recent flight incident and accident cases are then used to illustrate elements of the model. Results: Pilot perception and actions are conceptualized as being guided by “frames,” or mental knowledge structures that were previously learned. Performance issues in unexpected situations can often be traced back to insufficient adaptation of one’s frame to the situation. It is argued that such sensemaking or reframing processes are especially vulnerable to issues caused by startle or acute stress. Conclusion: Interventions should focus on (a) increasing the supply and quality of pilot frames (e.g., though practicing a variety of situations), (b) increasing pilot reframing skills (e.g., through the use of unpredictability in training scenarios), and (c) improving pilot metacognitive skills, so that inappropriate automatic responses to startle and surprise can be avoided. Application: The model can be used to explain pilot behavior in accident cases, to design experiments and training simulations, to teach pilots metacognitive skills, and to identify intervention methods.
Amino-functionalized mesoporous silica nanoparticles as efficient carriers for anticancer drug delivery
Authors: He Yongju , Luo Liangyu , Liang Shuquan , Long Mengqiu , Xu Hui 
Published: August 2017

Amino-functionalized mesoporous silica nanoparticles (MSN-NH2) were synthesized by a post-grafting method and further studied as carriers for doxorubicin hydrochloride (DOX) delivery. The morphology, structure, and property of MSN-NH2 and DOX-loaded MSN-NH2 (DOX@MSN-NH2) were studied using various techniques, such as transmission electron microscopy, Fourier transformed infrared spectroscopy, N2 adsorption–desorption isotherms, and zeta potentials. The drug loading and release profile as well as the in vitro cell cytotoxicity were detaily investigated. The results indicated that the loading content of DOX increased with the decrease of MSN-NH2/DOX mass ratio and/or the increase of amino density. DOX@MSN-NH2 exhibited a pH-dependent drug release, drug release increased as the pH value decreased. Compared with MSN-NH2, which were neglectable cytotoxicity against non-small-cell lung cancer (A549) cells, DOX@MSN-NH2 displayed remarkable cytotoxicity toward A549 cells in dose- and time-dependent manners. It was concluded that the as-synthesized MSN-NH2 could be used as promising drug carriers for cancer therapy.
Trade openness, labour market rigidity and economic growth: A dynamic panel data analysis
Authors: Polat Burçak , Andrés Antonio Rodríguez 
Published: August 2017

AbstractThe rapid liberalisation of trade policies since the 1990s has brought additional attention to the role of trade as an engine of economic growth. Although an abundant literature addresses the relationship between openness and economic growth, the real effect of trade liberalisation is still ambiguous and undetermined. Most previous studies have ignored the selection effects of strict labour regulations on international trade. The main objective of this study is to measure the role of labour regulations in moderating the contribution of trade to economic growth among 30 Organisation for Economic Co-operation and Development countries for the period 2006–2013. In doing so, we employ a one-step Generalised Method of Moments system estimation method. Our results reveal that openness to trade does not have a robust and significant effect on growth. However, the interaction of openness with strict labour regulations enhances the contributions of trade to growth.
The role of the endoplasmic reticulum stress response following cerebral ischemia
Authors: Hadley Gina , Neuhaus Ain A , Couch Yvonne , Beard Daniel J , Adriaanse Bryan A , Vekrellis Kostas , DeLuca Gabriele C , Papadakis Michalis , Sutherland Brad A , Buchan Alastair M 
Published: August 2017

Background Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability . Methods In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4′-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). Results In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Conclusion Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.
The actin-binding protein profilin 2 is a novel regulator of iron homeostasis
Authors: Luscieti Sara , Galy Bruno , Gutierrez Lucia , Reinke Michael , Couso Jorge , Shvartsman Maya , Di Pascale Antonio , Witke Walter , Hentze Matthias W. , Pilo Boyl Pietro , Sanchez Mayka 
Published: August 2017

Key PointsPfn2 mRNA has a functional and conserved IRE in the 3′ untranslated region. Pfn2 knockout mice display an iron phenotype with iron accumulation in specific areas of the brain and depletion of liver iron stores.