Competition between SOCS36E and Drk modulates Sevenless receptor tyrosine kinase activity

Modulation of signalling pathways can trigger different cellular responses, including differences in cell fate. This modulation can be achieved by controlling the pathway activity with great precision to ensure robustness and reproducibility of the specification of cell fate. The development of the photoreceptor R7 in the Drosophila melanogasterretina has become a model in which to investigate the control of cell signalling. During R7 specification, a burst of Ras small GTPase (Ras) and mitogen-activated protein kinase (MAPK) controlled by Sevenless receptor tyrosine kinase (Sev) is required. Several cells in each ommatidium express sev. However, the spatiotemporal expression of the boss ligand and the action of negative regulators of the Sev pathway will restrict the R7 fate to a single cell. The Drosophila suppressor of cytokine signalling 36E (SOCS36E) protein contains an SH2 domain and acts as a Sev signalling attenuator. By contrast, downstream of receptor kinase (Drk), the fly homolog of the mammalian Grb2 adaptor protein, which also contains an SH2 domain, acts as a positive activator of the pathway. Here, we apply the Förster resonance energy transfer (FRET) assay to transfected Drosophila S2 cells and demonstrate that Sev binds directly to either the suppressor protein SOCS36E or the adaptor protein Drk. We propose a mechanistic model in which the competition between these two proteins for binding to the same docking site results in either attenuation of the Sev transduction in cells that should not develop R7 photoreceptors or amplification of the Ras-MAPK signal only in the R7 precursor.

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η6-p-cym)RuCl(PPh3)2]+, allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N′-di-Boc-N″-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 ≈ 80 μM), whereas the neamine conjugate (4) was inactive (IC50 ≈ 200 μM). However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 μM in DU-145 and IC50 = 11.33 μM in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 μM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 μM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

On the relationship between C and N fixation in nodulated alfalfa (Medicago sativa)

Legumes such as alfalfa (Medicago sativa L.) are vital N2-fixing crops accounting for a global N2 fixation of ~35 MtNyear-1. Although enzymatic and molecular mechanisms of nodule N2 fixation are now well documented, some uncertainty remains as to whether N2 fixation is strictly coupled with photosynthetic carbon fixation. That is, the metabolic origin and redistribution of carbon skeletons used to incorporate nitrogen are still relatively undefined. Here, we conducted isotopic labelling with both 15N2 and 13C-depleted CO2 on alfalfa plants grown under controlled conditions and took advantage of isotope ratio mass spectrometry to investigate the relationship between carbon and nitrogen turn-over in respired CO2, total organic matter and amino acids. Our results indicate that CO2 evolved by respiration had an isotopic composition similar to that in organic matter regardless of the organ considered, suggesting that the turn-over of respiratory pools strictly followed photosynthetic input. However, carbon turn-over was nearly three times greater than N turn-over in total organic matter, suggesting that new organic material synthesised was less N-rich than pre-existing organic material (due to progressive nitrogen elemental dilution) or that N remobilisation occurred to sustain growth. This pattern was not consistent with the total commitment into free amino acids where the input of new C and N appeared to be stoichiometric. The labelling pattern in Asn was complex, with contrasted C and N commitments in different organs, suggesting that neosynthesis and redistribution of new Asn molecules required metabolic remobilisation. We conclude that the production of new organic material during alfalfa growth depends on both C and N remobilisation in different organs. At the plant level, this remobilisation is complicated by allocation and metabolism in the different organs. Additional keywords: carbon exchange, carbon isotopes, nitrogen fixation, nitrogen 15 isotope

Why do university graduates regret their study program? A comparison between Spain and the Netherlands

[cat] En aquest article investiguem els factors que porten a universitaris espanyols i holandesos a lamentar els estudis cursats. Espanya i Holanda tenen un sistema educatiu molt diferent en termes de la rigidesa de l’educació secundària i el vincle entre l’educació i el mercat laboral. Comparant Espanya i Holanda ens permet aprendre sobre les conseqüències de dos sistemes educatius molt diferenciats a la probabilitat de lamentar els estudis cursats. Basant-nos en la literatura psicològica sobre l’arrepentiment/lamentació, derivem unes hipòtesis de partida que contrastem empíricament. Els resultats mostren que tant la rigidesa de l’educació secundària com el desajustament entre educació i ocupació són factors importants per explicar la lamentació dels estudis universitaris cursats. L’article conclou amb recomenacions sobre el sistema educatiu universitari.

Why do university graduates regret their study program? A comparison between Spain and the Netherlands

[cat] En aquest article investiguem els factors que porten a universitaris espanyols i holandesos a lamentar els estudis cursats. Espanya i Holanda tenen un sistema educatiu molt diferent en termes de la rigidesa de l’educació secundària i el vincle entre l’educació i el mercat laboral. Comparant Espanya i Holanda ens permet aprendre sobre les conseqüències de dos sistemes educatius molt diferenciats a la probabilitat de lamentar els estudis cursats. Basant-nos en la literatura psicològica sobre l’arrepentiment/lamentació, derivem unes hipòtesis de partida que contrastem empíricament. Els resultats mostren que tant la rigidesa de l’educació secundària com el desajustament entre educació i ocupació són factors importants per explicar la lamentació dels estudis universitaris cursats. L’article conclou amb recomenacions sobre el sistema educatiu universitari.

Synergies between optical and physical variables in intercepting parabolic targets.

Interception requires precise estimation of time-to-contact (TTC) information. A long-standing view posits that all relevant information for extracting TTC is available in the angular variables, which result from the projection of distal objecs on to the retina. The diferent timing models rooted in this tradition have consequently relied on combining visual angle and its rate of expansion in diferent ways with tau being the most well-known solution for TTC...

Entrepreneurial skills and over-education five years later. A comparison between Spain and the Netherlands

[cat] El fenòmen de la sobre-educació és freqüent i persistent a molts països. En aquest article estudiem el paper de les habilitats emprenedores en evitar la sobre-educació a la primera feina, i en sortir d’una situació de sobre-educació cinc anys després. Comparem els resultats d’Espanya i Holanda, dos països que difereixen en el seu sistema educatiu i mercat de treball. Els resultats mostren que les habilitats emprenedores ajuden a evitar i/o sortir de la sobre-educació només a Espanya, on el sistema educatiu és més flexible i menys vinculat amb el mercat de treball. En general, els nostres resultats recolzen les polítiques que promocionen el desenvolupament d’habilitats emprenedores al sistema educatiu espanyol.

The inequality trap. A comparative analysis of social spending between 1880 and 1933

[spa] Utilizando dos indicadores alternativos de redistribución –las transferencias sociales y el gasto social- durante el periodo de tiempo comprendido entre 1880 y 1933, y utilizando dos indicadores alternativos de desigualdad –el porcentaje de explotaciones agrarias no familiares y los top income shares-, este papel muestra que, al contrario de lo que muchos estudios sobre los origines del Estado del Bienestar suelen sugerir, la desigualdad no favoreció el desarrollo de la política social ni siquiera en sus etapas iniciales. Ello significa que la política social se desarrolló más rápidamente en los países que previamente ya eran más igualitarios, lo que sugiere que los países con más desigualdad se encontraban en una especie de trampa de la desigualdad, donde la desigualdad en si misma fue uno de los obstáculos a la redistribución.

The inequality trap. A comparative analysis of social spending between 1880 and 1933

[spa] Utilizando dos indicadores alternativos de redistribución –las transferencias sociales y el gasto social- durante el periodo de tiempo comprendido entre 1880 y 1933, y utilizando dos indicadores alternativos de desigualdad –el porcentaje de explotaciones agrarias no familiares y los top income shares-, este papel muestra que, al contrario de lo que muchos estudios sobre los origines del Estado del Bienestar suelen sugerir, la desigualdad no favoreció el desarrollo de la política social ni siquiera en sus etapas iniciales. Ello significa que la política social se desarrolló más rápidamente en los países que previamente ya eran más igualitarios, lo que sugiere que los países con más desigualdad se encontraban en una especie de trampa de la desigualdad, donde la desigualdad en si misma fue uno de los obstáculos a la redistribución.

Entrepreneurial skills and over-education five years later. A comparison between Spain and the Netherlands

[cat] El fenòmen de la sobre-educació és freqüent i persistent a molts països. En aquest article estudiem el paper de les habilitats emprenedores en evitar la sobre-educació a la primera feina, i en sortir d’una situació de sobre-educació cinc anys després. Comparem els resultats d’Espanya i Holanda, dos països que difereixen en el seu sistema educatiu i mercat de treball. Els resultats mostren que les habilitats emprenedores ajuden a evitar i/o sortir de la sobre-educació només a Espanya, on el sistema educatiu és més flexible i menys vinculat amb el mercat de treball. En general, els nostres resultats recolzen les polítiques que promocionen el desenvolupament d’habilitats emprenedores al sistema educatiu espanyol.

Wage differentials between native and immigrant women in Spain: accounting for differences in support

Purpose: The objective of the study is to quantify the wage gap between native and immigrant women in Spain, taking into account differences in their characteristics and the need to control for common support. If immigrant women are segregated in occupations with few native women, it is important to take this into account to analyse wage differentials between both collectives. Methodology: We use microdata from the Continuous Sample of Working Histories (Muestra Continua de Vidas Laborales) on wages and other personal characteristics such as gender, country of origin, and age to apply the matching procedure and the decomposition of the wage gap along the lines of Ñopo (2008) for the analysis of wage differentials between native and immigrant women. The advantage of this procedure is that we can simultaneously estimate the common support and the mean counterfactual wage for the women on the common support (i.e., comparing native and immigrant women with similar observable characteristics). In addition, we can describe differences not only at the mean but also along the entire wage distribution. Findings: The results obtained indicate that, on average, immigrant women earn less than native women in the Spanish labour market. This wage gap is bigger when we consider immigrant women from developing countries, but our main finding is that an important part of this wage gap is related to differences in common support (i.e., immigrant women are segregated in certain jobs with low wages different from those occupied by native women). If the need to control for common support is neglected, estimates of the wage gap will be biased. Originality: Studying the case of Spain is particularly interesting because it is a country with abundant and recent immigration. Immigrant women account for more than half of the total immigrants in Spain, and unlike other host countries, they come from a highly varied range of countries, with origins as diverse as Latin America, the Maghreb and Eastern Europe. To our knowledge, no other study has explicitly focused on the analysis of the wage differential of immigrant women in the Spanish labour market by taking into account the need to control for common support. Moreover, published papers illustrating the potentiality of Ñopo"s (2008) methodology are also very scarce.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Beaming into the rat world: enabling real-time intereaction between rat and human each at their own scale

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human"s movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Dynamic arrest in polymer melts: competition between packing and intramolecular barriers

We present molecular dynamics simulations of a simple model for polymer melts with intramolecular barriers. We investigate structural relaxation as a function of the barrier strength. Dynamic correlators can be consistently analyzed within the framework of the mode coupling theory of the glass transition. Control parameters are tuned in order to induce a competition between general packing effects and polymer-specific intramolecular barriers as mechanisms for dynamic arrest. This competition yields unusually large values of the so-called mode coupling theory exponent parameter and rationalizes qualitatively different observations for simple bead-spring and realistic polymers. The systematic study of the effect of intramolecular barriers presented here also establishes a fundamental difference between the nature of the glass transition in polymers and in simple glass formers.