Septin 9 isoforms promote tumorigenesis in mammary epithelial cells by increasing migration and ECM degradation through metalloproteinase secretion at focal adhesions

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. The cytoskeletal interacting protein Septin 9 (SEPT9), a member of the septin gene family, has been proposed to have oncogenic functions. It is a known hot spot of retroviral tagging insertion and a fusion partner of both de novo and therapy-induced mixed lineage leukemia (MLL). Of all septins, SEPT9 holds the strongest link to cancer, especially breast cancer. Murine models of breast cancer frequently exhibit SEPT9 amplification in the form of double minute chromosomes, and about 20% of human breast cancer display genomic amplification and protein over expression at the SEPT9 locus. Yet, a clear mechanism by which SEPT9 elicits tumor-promoting functions is lacking. To obtain unbiased insights on molecular signatures of SEPT9 upregulation in breast tumors, we overexpressed several of its isoforms in breast cancer cell lines. Global transcriptomic profiling supports a role of SEPT9 in invasion. Functional studies reveal that SEPT9 upregulation is sufficient to increase degradation of the extracellular matrix, while SEPT9 downregulation inhibits this process. The degradation pattern is peripheral and associated with focal adhesions (FAs), where it is coupled with increased expression of matrix metalloproteinases (MMPs). SEPT9 overexpression induces MMP upregulation in human tumors and in culture models and promotes MMP3 secretion to the media at FAs. Downregulation of SEPT9 or chemical inhibition of septin filament assembly impairs recruitment of MMP3 to FAs. Our results indicate that SEPT9 promotes upregulation and both trafficking and secretion of MMPs near FAs, thus enhancing migration and invasion of breast cancer cells

Can spatial form support urban ecosystem services: Representing patches and connectivity zones for bees using space syntax methodology

UrbanismArchitecture and The Built Environmen

Simultaneous Characterization of Two Ultrashort Optical Pulses at Different Frequencies Using a WS₂Monolayer

The precise characterization of ultrashort laser pulses has been of interest to the scientific community for many years. Frequency-resolved optical gating (FROG) has been extensively used to retrieve the temporal and spectral field distributions of ultrashort laser pulses. In this work, we exploit the high, broad-band nonlinear optical response of a WS2monolayer to simultaneously characterize two ultrashort laser pulses with different frequencies. The relaxed phase-matching conditions in a WS2monolayer enable the simultaneous acquisition of the spectra resulting from both four-wave mixing (FWM) and sum-frequency generation (SFG) nonlinear processes while varying the time delay between the two ultrashort pulses. Next, we introduce an adjusted double-blind FROG algorithm, based on iterative fast Fourier transforms between two FROG traces, to extract the intensity distribution and phase of two ultrashort pulses from the combination of their FWM and SFG FROG traces. Using this algorithm, we find an agreement between the computed and observed FROG traces for both the FWM and SFG processes. Exploiting the broad-band nonlinear response of a WS2monolayer, we additionally characterize one of the pulses using a second-harmonic generation (SHG) FROG trace to validate the pulse shapes extracted from the combination of the FWM and SFG FROG traces. The retrieved pulse shape from the SHG FROG agrees well with the pulse shape retrieved from our nondegenerate cross-correlation FROG measurement. In addition to the nonlinear parametric processes, we also observe a nonlinearly generated photoluminescence (PL) signal emitted from the WS2monolayer. Because of its nonlinear origin, the PL signal can also be used to obtain complementary autocorrelation and cross-correlation traces.QN/Kuipers LabQN/Quantum Nanoscienc

Surface mass balance and climate of the Last Glacial Maximum Northern Hemisphere ice sheets: simulations with CESM2.1

The Last Glacial Maximum (LGM, from ∼26 to 20 ka BP) was the most recent period with large ice sheets in Eurasia and North America. At that time, global temperatures were 5–7 ∘C lower than today, and sea level ∼125 m lower. LGM simulations are useful to understand earth system dynamics, including climate–ice sheet interactions, and to evaluate and improve the models representing those dynamics. Here, we present two simulations of the Northern Hemisphere ice sheet climate and surface mass balance (SMB) with the Community Earth System Model v2.1 (CESM2.1) using the Community Atmosphere Model v5 (CAM5) with prescribed ice sheets for two time periods that bracket the LGM period: 26 and 21 ka BP. CESM2.1 includes an explicit simulation of snow/firn compaction, albedo, refreezing, and direct coupling of the ice sheet surface energy fluxes with the atmosphere. The simulated mean snow accumulation is lowest for the Greenland and Barents–Kara Sea ice sheets (GrIS, BKIS) and highest for British and Irish (BIIS) and Icelandic (IcIS) ice sheets. Melt rates are negligible for the dry BKIS and GrIS, and relatively large for the BIIS, North American ice sheet complex (NAISC; i.e. Laurentide, Cordilleran, and Innuitian), Scandinavian ice sheet (SIS), and IcIS, and are reduced by almost a third in the colder (lower temperature) 26 ka BP climate compared with 21 ka BP. The SMB is positive for the GrIS, BKIS, SIS, and IcIS during the LGM (26 and 21 ka BP) and negative for the NAISC and BIIS. Relatively wide ablation areas are simulated along the southern (terrestrial), Pacific and Atlantic margins of the NAISC, across the majority of the BIIS, and along the terrestrial southern margin of the SIS. The integrated SMB substantially increases for the NAISC and BIIS in the 26 ka BP climate, but it does not reverse the negative sign. Summer incoming surface solar radiation is largest over the high interior of the NAISC and GrIS, and minimum over the BIIS and southern margin of NAISC. Summer net radiation is maximum over the ablation areas and minimum where the albedo is highest, namely in the interior of the GrIS, northern NAISC, and all of the BKIS. Summer sensible and latent heat fluxes are highest over the ablation areas, positively contributing to melt energy. Refreezing is largest along the equilibrium line altitude for all ice sheets and prevents 40 %–50 % of meltwater entering the ocean. The large simulated melt for the NAISC suggests potential biases in the climate simulation, ice sheet reconstruction, and/or highly non-equilibrated climate and ice sheet at the LGM time.Physical and Space Geodes

An Efficient Ice Sheet/Earth System Model Spin-up Procedure for CESM2-CISM2: Description, Evaluation, and Broader Applicability

Spinning up a highly complex, coupled Earth system model (ESM) is a time consuming and computationally demanding exercise. For models with interactive ice sheet components, this becomes a major challenge, as ice sheets are sensitive to bidirectional feedback processes and equilibrate over glacial timescales of up to many millennia. This work describes and demonstrates a computationally tractable, iterative procedure for spinning up a contemporary, highly complex ESM that includes an interactive ice sheet component. The procedure alternates between a computationally expensive coupled configuration and a computationally cheaper configuration where the atmospheric component is replaced by a data model. By periodically regenerating atmospheric forcing consistent with the coupled system, the data atmosphere remains adequately constrained to ensure that the broader model state evolves realistically. The applicability of the method is demonstrated by spinning up the preindustrial climate in the Community Earth System Model Version 2 (CESM2), coupled to the Community Ice Sheet Model Version 2 (CISM2) over Greenland. The equilibrium climate state is similar to the control climate from a coupled simulation with a prescribed Greenland ice sheet, indicating that the iterative procedure is consistent with a traditional spin-up approach without interactive ice sheets. These results suggest that the iterative method presented here provides a faster and computationally cheaper method for spinning up a highly complex ESM, with or without interactive ice sheet components. The method described here has been used to develop the climate/ice sheet initial conditions for transient, ice sheet-enabled simulations with CESM2-CISM2 in the Coupled Model Intercomparison Project Phase 6 (CMIP6).Physical and Space Geodes

Quantitative comparison of cities: Distribution of street and building types based on density and centrality measures

It has been argued that different urban configurations-planned vs. organic, treelike vs. grid like-perform differently when it comes to the intensity and distribution of pedestrian flows, built density and land uses. However, definitions of urban configurations are often rather abstract, ill-defined and at worse end in fixed stereotypes hiding underlying spatial complexity. Recent publications define morphological typologies based on quantitative variables (e.g. Barthelemy, 2015; Serra, 2013a; Gil et al., 2012; Berghauser Pont and Haupt, 2010) and solve some of these shortcomings. These approaches contribute to the discussion of types in two ways: firstly, they allow for the definition of types based on multiple variables in a precise and repeattable manner, enabling the study of large samples and the comparison between both cities and regions; secondly, they frame design choices in terms of types without being fixed and so open up for design explorations where the relation between the variables can be challenged to propose new types. This paper explores the typologies defined by Serra (2013a) and Berghauser Pont and Haupt (2010) further, as these target two of the most important morphological entities of urban form, namely the street network and the building structure. The purpose is to gain a better understanding of how types are composed and distributed within and across different cities. The method is based on GIS and statistical modeling of four cities to allow for a comparative analysis of four cities: Amsterdam, London, Stockholm and Gothenburg. For the street network, we process the Road-Centre-line maps to obtain a clean network model, then run segment angular analysis to calculate the space syntax measures of betweenness at different metric radii, defining the "centrality palimpsest" (Serra, 2013a). For the building structure, we process elevation data to obtain building height, then run accessible density analysis for all building density metrics (FSI, GSI, OSR, L) using the Place Syntax Tool (Berghauser Pont and Marcus, 2014). The street and building types are defined using cluster analysis (unsupervised classification), following a similar approach to Serra (2013a). The result is a typology of street ('paths') and building types ('places'), with different profiles of centrality and density across scales. The spatial distribution and frequency of these types across the four cities gives an objective summary of their spatial structure, identifying common as well as unique traits.OLD Urban Composition

Suppressed Charge Dispersion via Resonant Tunneling in a Single-Channel Transmon

We demonstrate strong suppression of charge dispersion in a semiconductor-based transmon qubit across Josephson resonances associated with a quantum dot in the junction. On resonance, dispersion is drastically reduced compared to conventional transmons with corresponding Josephson and charging energies. We develop a model of qubit dispersion for a single-channel resonance, which is in quantitative agreement with experimental data. QRD/Kouwenhoven La

Description and Demonstration of the Coupled Community Earth System Model v2 – Community Ice Sheet Model v2 (CESM2-CISM2)

Earth system/ice-sheet coupling is an area of recent, major Earth System Model (ESM) development. This work occurs at the intersection of glaciology and climate science and is motivated by a need for robust projections of sea-level rise. The Community Ice Sheet Model version 2 (CISM2) is the newest component model of the Community Earth System Model version 2 (CESM2). This study describes the coupling and novel capabilities of the model, including: (1) an advanced energy-balance-based surface mass balance calculation in the land component with downscaling via elevation classes; (2) a closed freshwater budget from ice sheet to the ocean from surface runoff, basal melting, and ice discharge; (3) dynamic land surface types; and (4) dynamic atmospheric topography. The Earth system/ice-sheet coupling is demonstrated in a simulation with an evolving Greenland Ice Sheet (GrIS) under an idealized high CO2 scenario. The model simulates a large expansion of ablation areas (where surface ablation exceeds snow accumulation) and a large increase in surface runoff. This results in an elevated freshwater flux to the ocean, as well as thinning of the ice sheet and area retreat. These GrIS changes result in reduced Greenland surface albedo, changes in the sign and magnitude of sensible and latent heat fluxes, and modified surface roughness and overall ice sheet topography. Representation of these couplings between climate and ice sheets is key for the simulation of ice and climate interactions.Physical and Space Geodes

Nanowire arrays as cell force sensors to investigate adhesin-enhanced holdfast of single cell bacteria and biofilm stability

Surface attachment of a planktonic bacteria, mediated by adhesins and extracellular polymeric substances (EPS), is a crucial step for biofilm formation. Some pathogens can modulate cell adhesiveness, impacting host colonization and virulence. A framework able to quantify cell-surface interaction forces and their dependence on chemical surface composition may unveil adhesiveness control mechanisms as new targets for intervention and disease control. Here we employed InP nanowire arrays to dissect factors involved in the early stage biofilm formation of the phytopathogen Xylella fastidiosa. Ex vivo experiments demonstrate single-cell adhesion forces up to 45 nN, depending on the cell orientation with respect to the surface. Larger adhesion forces occur at the cell poles; secreted EPS layers and filaments provide additional mechanical support. Significant adhesion force enhancements were observed for single cells anchoring a biofilm and particularly on XadA1 adhesin-coated surfaces, evidencing molecular mechanisms developed by bacterial pathogens to create a stronger holdfast to specific host tissues.Accepted Author ManuscriptBN/Nynke Dekker La

Accelerated Greenland Ice Sheet Mass Loss Under High Greenhouse Gas Forcing as Simulated by the Coupled CESM2.1-CISM2.1

The Greenland ice sheet (GrIS) is now losing mass at a rate of 0.7 mm of sea level rise (SLR) per year. Here we explore future GrIS evolution and interactions with global and regional climate under high greenhouse gas forcing with the Community Earth System Model version 2.1 (CESM2.1), which includes an interactive ice sheet component (the Community Ice Sheet Model v2.1 [CISM2.1]) and an advanced energy balance-based calculation of surface melt. We run an idealized 350-year scenario in which atmospheric CO2 concentration increases by 1% annually until reaching four times pre-industrial values at year 140, after which it is held fixed. The global mean temperature increases by 5.2 and 8.5 K by years 131–150 and 331–350, respectively. The projected GrIS contribution to global mean SLR is 107 mm by year 150 and 1,140 mm by year 350. The rate of SLR increases from 2 mm yr−1 at year 150 to almost 7 mm yr−1 by year 350. The accelerated mass loss is caused by rapidly increasing surface melt as the ablation area expands, with associated albedo feedback and increased sensible and latent heat fluxes. This acceleration occurs for a global warming of approximately 4.2 K with respect to pre-industrial and is in part explained by the quasi-parabolic shape of the ice sheet, which favors rapid expansion of the ablation area as it approaches the interior “plateau.”.Physical and Space GeodesyEnvironmental Fluid Mechanic