The alternatively-included 11a sequence modifies the effects of Mena on actin cytoskeletal organization and cell behavior

During tumor progression, alternative splicing gives rise to different Mena protein isoforms. We analyzed how Mena11a, an isoform enriched in epithelia and epithelial-like cells, affects Mena-dependent regulation of actin dynamics and cell behavior. While other Mena isoforms promote actin polymerization and drive membrane protrusion, we find that Mena11a decreases actin polymerization and growth factor-stimulated membrane protrusion at lamellipodia. Ectopic Mena11a expression slows mesenchymal-like cell motility, while isoform-specific depletion of endogenous Mena11a in epithelial-like tumor cells perturbs cell:cell junctions and increases membrane protrusion and overall cell motility. Mena11a can dampen membrane protrusion and reduce actin polymerization in the absence of other Mena isoforms, indicating that it is not simply an inactive Mena isoform. We identify a phosphorylation site within 11a that is required for some Mena11a-specific functions. RNA-seq data analysis from patient cohorts demonstrates that the difference between mRNAs encoding constitutive Mena sequences and those containing the 11a exon correlates with metastasis in colorectal cancer, suggesting that 11a exon exclusion contributes to invasive phenotypes and leads to poor clinical outcomes.Virginia and D.K. Ludwig Fund for Cancer Research (Graduate Student Fellowship)National Institutes of Health (U.S.) (GM58801)Massachusetts Institute of Technology. Ludwig Center for Molecular OncologyDavid H. Koch Institute for Integrative Cancer Research at MIT (NCI Core Grant P30-CA14051

Brag2 differentially regulates β1- and β3-integrin-dependent adhesion in endothelial cells and is involved in developmental and pathological angiogenesis

β1-Integrins are essential for angiogenesis. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated Brag2-silencing reduced EC angiogenic sprouting and migration. Brag2-siRNA transfection differentially affected α5β1- and αVβ3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and adhesion on β1-integrin ligands (fibronectin and collagen), while reducing the adhesion on the αVβ3-integrin ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of α5β1-integrin, while reducing surface expression of αVβ3-integrin. Mechanistically, Brag2-mediated αVβ3-integrin-recycling and β1-integrin endocytosis and specifically of the active/matrix-bound α5β1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via β1-integrin endocytosis. Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, β1-integrin endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Furthermore, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating β1-integrin internalization and link for the first time the process of β1-integrin endocytosis with angiogenesis.Deutsche Forschungsgemeinschaft. Transregional Collaborative Research Centre. (SFB/TR23)Deutsche Forschungsgemeinschaft. Transregional Collaborative Research Centre. (Project A2)Deutsche Forschungsgemeinschaft. Transregional Collaborative Research Centre.(Project Z5)Else Kroner-Fresenius-Stiftung (2013_A2

Convergence to SPDEs in Stratonovich form

We consider the perturbation of parabolic operators of the form $\partial_t+P(x,D)$ by large-amplitude highly oscillatory spatially dependent potentials modeled as Gaussian random fields. The amplitude of the potential is chosen so that the solution to the random equation is affected by the randomness at the leading order. We show that, when the dimension is smaller than the order of the elliptic pseudo-differential operator $P(x,D)$, the perturbed parabolic equation admits a solution given by a Duhamel expansion. Moreover, as the correlation length of the potential vanishes, we show that the latter solution converges in distribution to the solution of a stochastic parabolic equation with a multiplicative term that should be interpreted in the Stratonovich sense. The theory of mild solutions for such stochastic partial differential equations is developed. The behavior described above should be contrasted to the case of dimensions that are larger than or equal to the order of the elliptic pseudo-differential operator $P(x,D)$. In the latter case, the solution to the random equation converges strongly to the solution of a homogenized (deterministic) parabolic equation as is shown in the companion paper [2]. The stochastic model is therefore valid only for sufficiently small space dimensions in this class of parabolic problems.Comment: 21 page

WAVOS: a MATLAB toolkit for wavelet analysis and visualization of oscillatory systems

<p>Abstract</p> <p>Background</p> <p>Wavelets have proven to be a powerful technique for the analysis of periodic data, such as those that arise in the analysis of circadian oscillators. While many implementations of both continuous and discrete wavelet transforms are available, we are aware of no software that has been designed with the nontechnical end-user in mind. By developing a toolkit that makes these analyses accessible to end users without significant programming experience, we hope to promote the more widespread use of wavelet analysis.</p> <p>Findings</p> <p>We have developed the WAVOS toolkit for wavelet analysis and visualization of oscillatory systems. WAVOS features both the continuous (Morlet) and discrete (Daubechies) wavelet transforms, with a simple, user-friendly graphical user interface within MATLAB. The interface allows for data to be imported from a number of standard file formats, visualized, processed and analyzed, and exported without use of the command line. Our work has been motivated by the challenges of circadian data, thus default settings appropriate to the analysis of such data have been pre-selected in order to minimize the need for fine-tuning. The toolkit is flexible enough to deal with a wide range of oscillatory signals, however, and may be used in more general contexts.</p> <p>Conclusions</p> <p>We have presented WAVOS: a comprehensive wavelet-based MATLAB toolkit that allows for easy visualization, exploration, and analysis of oscillatory data. WAVOS includes both the Morlet continuous wavelet transform and the Daubechies discrete wavelet transform. We have illustrated the use of WAVOS, and demonstrated its utility for the analysis of circadian data on both bioluminesence and wheel-running data. WAVOS is freely available at <url>http://sourceforge.net/projects/wavos/files/</url></p

CO or no CO? Narrowing the CO abundance constraint and recovering the H2O detection in the atmosphere of WASP-127 b using SPIRou

Precise measurements of chemical abundances in planetary atmospheres are necessary to constrain the formation histories of exoplanets. A recent study of WASP-127b, a close-in puffy sub-Saturn orbiting its solar-type host star in 4.2 d, using HST and Spitzer revealed a feature-rich transmission spectrum with strong excess absorption at 4.5 um. However, the limited spectral resolution and coverage of these instruments could not distinguish between CO and/or CO2 absorption causing this signal, with both low and high C/O ratio scenarios being possible. Here we present near-infrared (0.9--2.5 um) transit observations of WASP-127 b using the high-resolution SPIRou spectrograph, with the goal to disentangle CO from CO2 through the 2.3 um CO band. With SPIRou, we detect H2O at a t-test significance of 5.3 sigma and observe a tentative (3 sigma) signal consistent with OH absorption. From a joint SPIRou + HST + Spitzer retrieval analysis, we rule out a CO-rich scenario by placing an upper limit on the CO abundance of log10[CO]<-4.0, and estimate a log10[CO2] of -3.7^(+0.8)_(-0.6), which is the level needed to match the excess absorption seen at 4.5um. We also set abundance constraints on other major C-, O-, and N-bearing molecules, with our results favoring low C/O (0.10^(+0.10)_(-0.06)), disequilibrium chemistry scenarios. We further discuss the implications of our results in the context of planet formation. Additional observations at high and low-resolution will be needed to confirm these results and better our understanding of this unusual world.Comment: 23 pages, 13 figures, Submitted for publication in the Monthly Notice of the Royal Astronomical Societ

Iron Storage within Dopamine Neurovesicles Revealed by Chemical Nano-Imaging

Altered homeostasis of metal ions is suspected to play a critical role in neurodegeneration. However, the lack of analytical technique with sufficient spatial resolution prevents the investigation of metals distribution in neurons. An original experimental setup was developed to perform chemical element imaging with a 90 nm spatial resolution using synchrotron-based X-ray fluorescence. This unique spatial resolution, combined to a high brightness, enables chemical element imaging in subcellular compartments. We investigated the distribution of iron in dopamine producing neurons because iron-dopamine compounds are suspected to be formed but have yet never been observed in cells. The study shows that iron accumulates into dopamine neurovesicles. In addition, the inhibition of dopamine synthesis results in a decreased vesicular storage of iron. These results indicate a new physiological role for dopamine in iron buffering within normal dopamine producing cells. This system could be at fault in Parkinson's disease which is characterized by an increased level of iron in the substancia nigra pars compacta and an impaired storage of dopamine due to the disruption of vesicular trafficking. The re-distribution of highly reactive dopamine-iron complexes outside neurovesicles would result in an enhanced death of dopaminergic neurons

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.publishedVersio