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Cell spreading relies on the coordinated and dynamic regulation of integrin-mediated adhesions and actin structures. Böttcher et al. show that in the periphery of adhering cells kindlin-2 binds paxillin to activate Rac1 and the Arp2/3 complex to allow for Rac1-mediated membrane protrusions., Cell spreading requires the coupling of actin-driven membrane protrusion and integrin-mediated adhesion to the extracellular matrix. The integrin-activating adaptor protein kindlin-2 plays a central role for cell adhesion and membrane protrusion by directly binding and recruiting paxillin to nascent adhesions. Here, we report that kindlin-2 has a dual role during initial cell spreading: it binds paxillin via the pleckstrin homology and F0 domains to activate Rac1, and it directly associates with the Arp2/3 complex to induce Rac1-mediated membrane protrusions. Consistently, abrogation of kindlin-2 binding to Arp2/3 impairs lamellipodia formation and cell spreading. Our findings identify kindlin-2 as a key protein that couples cell adhesion by activating integrins and the induction of membrane protrusions by activating Rac1 and supplying Rac1 with the Arp2/3 complex.

Corticothalamic axons express Contactin-2 (CNTN2/TAG-1), a neuronal recognition molecule of the immunoglobulin superfamily involved in neurogenesis, neurite outgrowth, and fasciculation. TAG-1, which is expressed transiently by cortical pyramidal neurons during embryonic development, has been shown to be fundamental for axonal recognition, cellular migration, and neuronal proliferation in the developing cortex. Although Tag-1−/− mice do not exhibit any obvious defects in the corticofugal system, the role of TAG-1+ neurons during the development of the cortex remains elusive. We have generated a mouse model expressing EGFP under the Tag-1 promoter and encompassing the coding sequence of Diptheria Toxin subunit A (DTA) under quiescence with no effect on the expression of endogenous Tag-1. We show that while the line recapitulates the expression pattern of the molecule, it highlights an extended expression in the forebrain, including multiple axonal tracts and neuronal populations, both spatially and temporally. Crossing these mice to the Emx1-Cre strain, we ablated the vast majority of TAG-1+ cortical neurons. Among the observed defects were a significantly smaller cortex, a reduction of corticothalamic axons as well as callosal and commissural defects. Such defects are common in neurodevelopmental disorders, thus this mouse could serve as a useful model to study physiological and pathophysiological cortical development., SCOPUS: ar.j, info:eu-repo/semantics/published

This paper is a re-examination of the benefits and limitations of decomposition and combination techniques in the area of forecasting, and also a contribution to the field, offering a new forecasting method. The new method is based on the disaggregation of time series components through the STL decomposition procedure, the extrapolation of linear combinations of the disaggregated sub-series, and the reaggregation of the extrapolations to obtain estimates for the global series. Applying the forecasting method to data from the NN3 and M1 Competition series, the results suggest that it can perform well relative to four other standard statistical techniques from the literature, namely the ARIMA, Theta, Holt-Winters’ and Holt’s Damped Trend methods. The relative advantages of the new method are then investigated further relative to a simple combination of the four statistical methods and a Classical Decomposition forecasting method. The strength of the method lies in its ability to predict long lead times with relatively high levels of accuracy, and to perform consistently well for a wide range of time series, irrespective of the characteristics, underlying structure and level of noise of the data.

Integrins require an activation step prior to ligand binding and signaling. How talin and kindlin contribute to these events in non-hematopoietic cells is poorly understood. Here we report that fibroblasts lacking either talin or kindlin failed to activate β1 integrins, adhere to fibronectin (FN) or maintain their integrins in a high affinity conformation induced by Mn2+. Despite compromised integrin activation and adhesion, Mn2+ enabled talin- but not kindlin-deficient cells to initiate spreading on FN. This isotropic spreading was induced by the ability of kindlin to directly bind paxillin, which in turn bound focal adhesion kinase (FAK) resulting in FAK activation and the formation of lamellipodia. Our findings show that talin and kindlin cooperatively activate integrins leading to FN binding and adhesion, and that kindlin subsequently assembles an essential signaling node at newly formed adhesion sites in a talin-independent manner. DOI: http://dx.doi.org/10.7554/eLife.10130.001, eLife digest A meshwork of proteins called the extracellular matrix surrounds the cells that make up our tissues. Integrins are adhesion proteins that sit on the membrane surrounding each cell and bind to the matrix proteins. These adhesive interactions control many aspects of cell behavior such as their ability to divide, move and survive. Before integrins can bind to the extracellular matrix they must be activated. Previous research has shown that in certain types of blood cells, proteins called talins and kindlins perform this activation. These proteins bind to the part of the integrin that extends into the cell, causing shape changes to the integrin that allow binding to the extracellular matrix. However, it is not clear whether talin and kindlin also activate integrins in other cell types. Fibroblasts are cells that help to make extracellular matrix proteins, and are an important part of connective tissue. Theodosiou et al. engineered mouse fibroblast cells to lack either talin or kindlin, and found that both of these mutant cell types were unable to activate their integrins and as a result failed to bind to an extracellular matrix protein called fibronectin. Even when cells were artificially induced to activate integrins by treating them with manganese ions, cells lacking talin or kindlin failed to fully activate integrins and hence did not adhere well to fibronectin. This suggests that talin and kindlin work together to activate integrins and to maintain them in this activated state. When treated with manganese ions, cells that lacked talin were able to flatten and spread out, whereas cells that lacked kindlin were unable to undergo this shape change. Theodosiou et al. found that this cell shape is dependent on kindlin and its ability to bind to and recruit a protein called paxillin to “adhesion sites”, where integrins connect the cell surface with the extracellular matrix. Kindlin and paxillin then work together to activate other signaling molecules to induce the cell spreading. The next challenge is to understand how talin and kindlin are activated in non-blood cells and how they maintain integrins in an active state. DOI: http://dx.doi.org/10.7554/eLife.10130.002

In the current paper, we investigate the bias introduced through the calendar time sampling of the price process of financial assets. We analyze results from a Monte Carlo simulation which point to the conclusion that the multitude of jumps reported in the literature might be, to a large extent, an artifact of the bias introduced through the previous tick sampling scheme, used for the time homogenization the price series. We advocate the use of Akima cubic splines as an alternative to the popular previous tick method. Monte Carlo simulation results confirm the suitability of Akima cubic splines in high frequency applications and the advantages of these over other calendar time sampling schemes, such as the linear interpolation and the previous tick method. Empirical results from the FX market complement the analysis.

Combination techniques and decomposition procedures have been applied to time series forecasting to enhance prediction accuracy and to facilitate the analysis of data respectively. However, the restrictive complexity of some combination techniques and the difficulties associated with the application of the decomposition results to the extrapolation of data, mainly due to the large variability involved in economic and financial time series, have limited their application and compromised their development. This paper is a re-examination of the benefits and limitations of decomposition and combination techniques in the area of forecasting, and a contribution to the field with a new forecasting methodology. The new methodology is based on the disaggregation of time series components through the STL decomposition procedure, the extrapolation of linear combinations of the disaggregated sub-series, and the reaggregation of the extrapolations to obtain estimation for the global series. With the application of the methodology to the data from the NN3 and M1 Competition series, the results suggest that it can outperform other competing statistical techniques. The power of the method lies in its ability to perform consistently well, irrespective of the characteristics, underlying structure and level of noise of the data.