bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantitative Modeling of Virus Evolutionary Dynamics and Adaptation in Serial Passages Using Empirically Inferred Fitness Landscapes
Authors: Woo Hyung Jun , Reifman Jaques 
Published: November 2013

ABSTRACTWe describe a stochastic virus evolution model representing genomic diversification and within-host selection during experimental serial passages under cell culture or live-host conditions. The model incorporates realistic descriptions of the virus genotypes in nucleotide and amino acid sequence spaces, as well as their diversification from error-prone replications. It quantitatively considers factors such as target cell number, bottleneck size, passage period, infection and cell death rates, and the replication rate of different genotypes, allowing for systematic examinations of how their changes affect the evolutionary dynamics of viruses during passages. The relative probability for a viral population to achieve adaptation under a new host environment, quantified by the rate with which a target sequence frequency rises above 50%, was found to be most sensitive to factors related to sequence structure (distance from the wild type to the target) and selection strength (host cell number and bottleneck size). For parameter values representative of RNA viruses, the likelihood of observing adaptations during passages became negligible as the required number of mutations rose above two amino acid sites. We modeled the specific adaptation process of influenza A H5N1 viruses in mammalian hosts by simulating the evolutionary dynamics of H5 strains under the fitness landscape inferred from multiple sequence alignments of H3 proteins. In light of comparisons with experimental findings, we observed that the evolutionary dynamics of adaptation is strongly affected not only by the tendency toward increasing fitness values but also by the accessibility of pathways between genotypes constrained by the genetic code.
Earth's punctuated tectonic evolution: cause and effect
Authors: O’Neill C. , Lenardic A. , Condie K. C. 
Published: November 2013

Abstract
Peaks in the Precambrian preserved crustal record are associated with major volcanic, tectonic and climatic events. These include addition of juvenile continental crust, voluminous high-temperature volcanism, massive mantle depletion, widespread orogeny and mineralization, large apparent polar wander velocity spikes, and subsequent palaeomagnetic intensity increases. These events impinge on the glaciation record, atmospheric and ocean chemistry, and on the rise of oxygen. Here we summarize and assess a number of geodynamic models that have been proposed to explain the observed episodicity in the Precambrian record. We find that episodic behaviour from nonlinear slab-driven models best explains the observed record. Examples of such slab-driven systems include mantle avalanches or episodic subduction. In these cases, rapid descent of slabs into the mantle drives fast plate motions and convergence at the surface. This is accompanied by large-scale upwellings of deep hot mantle, which contribute to voluminous volcanism. Further modelling will determine the relative importance of each mechanism, and reinforce the fundamental contribution of the mantle to the evolution of Earth's surface systems.
Activation of the FGFR–STAT3 Pathway in Breast Cancer Cells Induces a Hyaluronan-Rich Microenvironment That Licenses Tumor Formation
Authors: Bohrer Laura R. , Chuntova Pavlina , Bade Lindsey K. , Beadnell Thomas C. , Leon Ronald P. , Brady Nicholas J. , Ryu Yungil , Goldberg Jodi E. , Schmechel Stephen C. , Koopmeiners Joseph S. , McCarthy James B. , Schwertfeger Kathryn L. 
Published: November 2013

Abstract
Aberrant activation of fibroblast growth factor receptors (FGFR) contributes to breast cancer growth, progression, and therapeutic resistance. Because of the complex nature of the FGF/FGFR axis, and the numerous effects of FGFR activation on tumor cells and the surrounding microenvironment, the specific mechanisms through which aberrant FGFR activity contributes to breast cancer are not completely understood. We show here that FGFR activation induces accumulation of hyaluronan within the extracellular matrix and that blocking hyaluronan synthesis decreases proliferation, migration, and therapeutic resistance. Furthermore, FGFR-mediated hyaluronan accumulation requires activation of the STAT3 pathway, which regulates expression of hyaluronan synthase 2 (HAS2) and subsequent hyaluronan synthesis. Using a novel in vivo model of FGFR-dependent tumor growth, we demonstrate that STAT3 inhibition decreases both FGFR-driven tumor growth and hyaluronan levels within the tumor. Finally, our results suggest that combinatorial therapies inhibiting both FGFR activity and hyaluronan synthesis is more effective than targeting either pathway alone and may be a relevant therapeutic approach for breast cancers associated with high levels of FGFR activity. In conclusion, these studies indicate a novel targetable mechanism through which FGFR activation in breast cancer cells induces a protumorigenic microenvironment. Cancer Res; 74(1); 374–86. ©2013 AACR.
Tumor Suppressive Effects of Bromodomain-Containing Protein 7 (BRD7) in Epithelial Ovarian Carcinoma
Authors: Park Young-Ae , Lee Jeong-Won , Kim Hye-Sun , Lee Yoo-Young , Kim Tae-Joong , Choi Chel Hun , Choi Jung-Joo , Jeon Hye-Kyung , Cho Young Jae , Ryu Ji Yoon , Kim Byoung-Gie , Bae Duk-Soo 
Published: November 2013

Abstract
Purpose: Bromodomain-containing protein 7 (BRD7), which is a subunit of SWI/SNF complex, has been recently suggested as a novel tumor suppressor in several cancers. In this study, we investigated the tumor suppressive effect of BRD7 in epithelial ovarian cancer.
Experimental Design: We analyzed the expression of BRD7 in human ovarian tissues with real-time PCR. To investigate the functional role of BRD7, we transfected ovarian cancer cells (A2780 and SKOV3) with BRD7 plasmid and checked the cell viability, apoptosis, and invasion. The activities of BRD7 in the signaling pathways associated with carcinogenesis were also tested. In addition, we used the orthotopic mouse model for ovarian cancer to evaluate tumor growth-inhibiting effect by administration of BRD7 plasmid.
Results: The BRD7 expression was downregulated in the ovarian cancer tissues compared with normal (P &lt; 0.05), high-grade serous cancer exhibited significantly decreased expression of BRD7 compared with low-grade (P &lt; 0.01) serous cancer. Transfection of BRD7 plasmid to A2780 (p53-wild) or SKOV3 (p53-null) ovarian cancer cells showed the tumor suppressive effects assessed by cell viability, apoptosis, and invasion assay and especially significantly decreased tumor weight in orthotopic mouse model (A2780). Moreover, we found that tumor suppressive effects of BRD7 are independent to the presence of p53 activity in ovarian cancer cells. BRD7 negatively regulated β-catenin pathway, resulting in decreased its accumulation in the nucleus.
Conclusions: These results suggested that BRD7 acts as a tumor suppressor in epithelial ovarian cancers independently of p53 activity, via negative regulation of β-catenin pathway. Clin Cancer Res; 20(3); 565–75. ©2013 AACR.
Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy
Authors: Kermer Vanessa , Hornig Nora , Harder Markus , Bondarieva Anastasiia , Kontermann Roland E. , Müller Dafne 
Published: November 2013

Abstract
Influencing the cytokine receptor network that modulates the immune response holds great potential for cancer immunotherapy. Although encouraging results have been obtained by focusing on individual members of the common γ-chain (γc) receptor family and TNF receptor superfamily so far, combination strategies might be required to further improve the effectiveness of the antitumor response. Here, we propose the combination of interleukin (IL)-15 and 4-1BBL in a single, tumor-directed molecule. Therefore, a trifunctional antibody fusion protein was generated, composed of a tumor-specific recombinant antibody, IL-15 linked to a fragment of the IL-15Rα chain (RD) and the extracellular domain of 4-1BBL. In soluble and targeted forms, the trifunctional antibody fusion protein RD_IL-15_scFv_4-1BBL was shown to stimulate activated T-cell proliferation and induce T-cell cytotoxicity to a similar degree as the bifunctional scFv_RD_IL-15 fusion protein. On the other hand, in targeted form, the trifunctional fusion protein was much more effective in inducing T-cell proliferation and IFN-γ release of unstimulated peripheral blood mononuclear cells (PBMC). Here, the additional signal enhancement could be attributed to the costimulatory activity of 4-1BBL, indicating a clear benefit for the simultaneous presentation of IL-15 and 4-1BBL in one molecule. Furthermore, the trifunctional antibody fusion protein was more effective than the corresponding bifunctional fusion proteins in reducing metastases in a tumor mouse model in vivo. Hence, the targeted combination of IL-15 and 4-BBL in the form of a trifunctional antibody-fusion protein is a promising new approach for cancer immunotherapy. Mol Cancer Ther; 13(1); 112–21. ©2013 AACR.
The SmgGDS Splice Variant SmgGDS-558 Is a Key Promoter of Tumor Growth and RhoA Signaling in Breast Cancer
Authors: Hauser Andrew D. , Bergom Carmen , Schuld Nathan J. , Chen Xiuxu , Lorimer Ellen L. , Huang Jian , Mackinnon Alexander C. , Williams Carol L. 
Published: November 2013

Abstract
Breast cancer malignancy is promoted by the small GTPases RhoA and RhoC. SmgGDS is a guanine nucleotide exchange factor that activates RhoA and RhoC in vitro. We previously reported that two splice variants of SmgGDS, SmgGDS-607, and SmgGDS-558, have different characteristics in binding and transport of small GTPases. To define the role of SmgGDS in breast cancer, we tested the expression of SmgGDS in breast tumors, and the role of each splice variant in proliferation, tumor growth, Rho activation, and NF-κB transcriptional activity in breast cancer cells. We show upregulated SmgGDS protein expression in breast cancer samples compared with normal breast tissue. In addition, Kaplan–Meier survival curves indicated that patients with high SmgGDS expression in their tumors had worse clinical outcomes. Knockdown of SmgGDS-558, but not SmgGDS-607, in breast cancer cells decreased proliferation, in vivo tumor growth, and RhoA activity. Furthermore, we found that SmgGDS promoted a Rho-dependent activation of the transcription factor NF-κB, which provides a potential mechanism to define how SmgGDS-mediated activation of RhoA promotes breast cancer. This study demonstrates that elevated SmgGDS expression in breast tumors correlates with poor survival, and that SmgGDS-558 plays a functional role in breast cancer malignancy. Taken together, these findings define SmgGDS-558 as a unique promoter of RhoA and NF-κB activity and a novel therapeutic target in breast cancer.
Implications: This study defines a new mechanism to regulate the activities of RhoA and NF-κB in breast cancer cells, and identifies SmgGDS-558 as a novel promoter of breast cancer malignancy. Mol Cancer Res; 12(1); 130–42. ©2013 AACR.
Mitotic Arrest by Tumor Suppressor RASSF1A Is Regulated via CHK1 Phosphorylation
Authors: Jiang Lingyan , Rong Rong , Sheikh M. Saeed , Huang Ying 
Published: November 2013

Abstract
The tumor suppressor RAS-association domain family 1 isoform A (RASSF1A) is known to play an important role in cell-cycle regulation. However, the molecular details about RASSF1A protein regulation are unclear. In this report, checkpoint kinase 1 (CHK1) is identified as a novel RASSF1A kinase that phosphorylates RASSF1A in vitro and under cellular conditions. Using tandem mass spectrometry and biochemical analysis, it was determined that CHK1 phosphorylates RASSF1A on Serine 184, which has been shown to be mutated in a subset of human primary nasopharyngeal carcinomas. Furthermore, Serine 184 phosphorylation of RASSF1A was significantly diminished by a CHK1-specific kinase inhibitor. Similarly, a kinase-dead CHK1 mutant was unable to phosphorylate Serine 184 whereas constitutively active-CHK1 enhanced phosphorylation. Molecular substitution of Serine 184 with aspartic acid, mimicking phosphorylation, abolished the ability of RASSF1A to interact with microtubules and induce M-phase arrest. Combined, these data indicate that phosphorylation of RASSF1A by CHK1 is important for mitotic regulation and provide valuable new insight into the regulatory mechanisms of RASSF1A function.
Implications: This study reveals that CHK1-mediated phosphorylation of RASSF1A, at Serine 184, plays an important role in cell-cycle regulation and highlights that mutation of this CHK1 phosphorylation site in nasopharyngeal carcinoma has disease relevance. Mol Cancer Res; 12(1); 119–29. ©2013 AACR.
Androgen Receptor Signaling Fuels DNA Repair and Radioresistance in Prostate Cancer
Authors: Bartek Jiri , Mistrik Martin , Bartkova Jirina 
Published: November 2013

Abstract
Summary: Successful treatment by genotoxic modalities including radiotherapy is commonly hampered by treatment resistance in advanced cancers. Two new studies now reveal that androgen receptor signaling transcriptionally upregulates a large subset of DNA repair genes, thereby enhancing the repair capacity and promoting radioresistance of prostate cancer. These results provide a mechanistic rationale for a combined treatment by ionizing radiation and androgen deprivation therapy. Cancer Discov; 3(11); 1222–4. ©2013 AACR.
See related article by Polkinghorn et al., p. 1245
See related article by Goodwin et al., p. 1254
Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice
Authors: da Silva Rafaela F. , Fraga-Silva Rodrigo A. , Steffens Sabine , Fabre Mathias , Bauer Inga , Caffa Irene , Magnone Mirko , Sociali Giovanna , Quercioli Alessandra , Pelli Graziano , Lenglet Sébastien , Galan Katia , Burger Fabienne , Calvo Sara Vázquez , Bertolotto Maria , Bruzzone Santina , Ballestrero Alberto , Patrone Franco , Dallegri Franco , Santos Robson A. S. , Stergiopulos Nikolaos , Mach François , Vuilleumier Nicolas , Montecucco Fabrizio , Nencioni Alessio 
Published: November 2013

SummaryPharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.
Observations of Temperature, Wind, Cirrus, and Trace Gases in the Tropical Tropopause Transition Layer during the MJO*
Authors: Virts Katrina S. , Wallace John M. 
Published: November 2013

Abstract
Satellite observations of temperature, optically thin cirrus clouds, and trace gases derived from the Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC), Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO), and the Microwave Limb Sounder (MLS) are analyzed in combination with Interim European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-Interim) wind and humidity fields in the tropical tropopause transition layer (TTL), using the Madden–Julian oscillation (MJO) as a carrier signal. MJO-related deep convection induces planetary-scale Kelvin and Rossby waves in the stably stratified TTL. Regions of ascent in these waves are associated with anomalously low temperatures, high radiative heating rates, enhanced cirrus occurrence, and high carbon monoxide and low ozone concentrations. Low water vapor mixing ratio anomalies lag the low temperature anomalies by about 1–2 weeks. The anomalies in all fields propagate eastward, circumnavigating the tropical belt over a roughly 40-day interval. Equatorial cross sections reveal that the anomalies tilt eastward with height in the TTL and propagate downward from the lower stratosphere into the upper troposphere.
As MJO-related convection moves into the western Pacific and dissipates, a fast-moving Kelvin wave flanked by Rossby waves propagates eastward across South America and Africa into the western Indian Ocean. The region of equatorial westerly wind anomalies behind the Kelvin wave front lengthens until it encompasses most of the tropics at the 150-hPa level, giving rise to equatorially symmetric, anomalously low zonal-mean temperature and water vapor mixing ratio and enhanced cirrus above about 100 hPa.
Boundary Layer Convergence Induced by Strong Winds across a Midlatitude SST Front*
Authors: Kilpatrick Thomas , Schneider Niklas , Qiu Bo 
Published: November 2013

Abstract
Recent studies indicate that the influence of midlatitude SST fronts extends through the marine atmospheric boundary layer (MABL) into the free atmosphere, with implications for climate variability. To better understand the mechanisms of this ocean-to-atmosphere influence, SST-induced MABL convergence is explored here with the Weather Research and Forecasting mesoscale model in an idealized, dry, two-dimensional configuration, for winds crossing from cold to warm SST and from warm to cold SST.
For strong cross-front winds, O(10 m s−1), changes in the turbulent mixing and MABL depth across the SST front lead to MABL depth-integrated convergence in the cold-to-warm case and depth-integrated divergence in the warm-to-cold case. The turbulent stress divergence term changes over a shorter length scale than the pressure gradient and Coriolis terms, such that the MABL response directly above the SST front is governed by nonrotating, internal boundary layer–like physics, which are consistent with the vertical mixing mechanism. An important consequence is that the increment in the cross-front surface stress diagnoses the vertical motion at the top of the MABL. These physics are at variance with some previously proposed SST frontal MABL models in which pressure adjustments determine the MABL convergence.
The SST-induced MABL convergence results in vertical motion that excites a stationary internal gravity wave in the free atmosphere, analogous to a mountain wave. For a 15 m s−1 cross-front wind, the gravity wave forced by an SST increase of 3°C over 200 km is comparable to that forced by an 80-m change in topography.
Projecting North American Climate over the Next 50 Years: Uncertainty due to Internal Variability*
Authors: Deser Clara , Phillips Adam S. , Alexander Michael A. , Smoliak Brian V. 
Published: November 2013

Abstract
This study highlights the relative importance of internally generated versus externally forced climate trends over the next 50 yr (2010–60) at local and regional scales over North America in two global coupled model ensembles. Both ensembles contain large numbers of integrations (17 and 40): each of which is subject to identical anthropogenic radiative forcing (e.g., greenhouse gas increase) but begins from a slightly different initial atmospheric state. Thus, the diversity of projected climate trends within each model ensemble is due solely to intrinsic, unpredictable variability of the climate system. Both model ensembles show that natural climate variability superimposed upon forced climate change will result in a range of possible future trends for surface air temperature and precipitation over the next 50 yr. Precipitation trends are particularly subject to uncertainty as a result of internal variability, with signal-to-noise ratios less than 2. Intrinsic atmospheric circulation variability is mainly responsible for the spread in future climate trends, imparting regional coherence to the internally driven air temperature and precipitation trends. The results underscore the importance of conducting a large number of climate change projections with a given model, as each realization will contain a different superposition of unforced and forced trends. Such initial-condition ensembles are also needed to determine the anthropogenic climate response at local and regional scales and provide a new perspective on how to usefully compare climate change projections across models.
Anisotropic Lagrangian Dispersion in Rotating Flows with a β Effect
Authors: Espa Stefania , Lacorata Guglielmo , Di Nitto Gabriella 
Published: November 2013

Abstract
A detailed analysis of Lagrangian tracer dispersion is performed on datasets obtained from laboratory experiments that simulate rotating turbulence in the presence of a β effect. Compatible with the limitations of the experimental apparatus, a relatively wide range of the zonostrophy index Rβ, a parameter used to characterize flow regimes in β-plane turbulence, is explored. The considered range spans from values ~O(10−1), for which the flow is nearly isotropic, to values ~O(1), corresponding to the so-called transitional range in which the flow gradually leaves the friction-dominated regime to enter the full zonostrophic regime. The degree of anistropy and the characteristic scales of the flow have been estimated by means of a Lagrangian approach based on the reconstruction of tracer trajectories and on the measure of the finite-scale Lyapunov exponents (FSLE). The FSLE analysis allows one to identify the regimes of two-particle dispersion and to relate them to the physical parameters of the system. Moreover, a Lagrangian anisotropy index (LAI) is introduced and defined in terms of the FSLE zonal and radial components, in order to describe the onset of anisotropy and to check if it is consistent with the theoretical predictions. It is remarkable that the finite-scale dispersion rates are very sensitive to the degree of anistropy of turbulence, more so than other indicators defined in terms of Eulerian quantities. Furthermore, they offer an effective diagnostic tool of the degree of anisotropy that can be used even prior to attaining a fully developed regime of zonostrophic turbulence.