Chasing the Foxo3: Insights into its new mitochondrial lair in colorectal cancer landscape

Colorectal cancer (CRC) poses a formidable challenge in terms of molecular heterogeneity, as it involves a variety of cancer-related pathways and molecular changes unique to an individual’s tumor. On the other hand, recent advances in DNA sequencing technologies provide an unprecedented capacity to comprehensively identify the genetic alterations resulting in tumorigenesis, raising the hope that new therapeutic approaches based on molecularly targeted drugs may prevent the occurrence of chemoresistance. Regulation of the transcription factor FOXO3a in response to extracellular cues plays a fundamental role in cellular homeostasis, being part of the molecular machinery that drives cells towards survival or death. Indeed, FOXO3a is controlled by a range of external stimuli, which not only influence its transcriptional activity, but also affect its subcellular localization. These regulation mechanisms are mediated by cancer-related signaling pathways that eventually drive changes in FOXO3a post-translational modifications (e.g., phosphorylation). Recent results showed that FOXO3a is imported into the mitochondria in tumor cells and tissues subjected to metabolic stress and cancer therapeutics, where it induces expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. The current review discusses the potential clinical relevance of multidrug therapies that drive cancer cell fate by regulating critical pathways converging on FOXO3a

Mapping powdery mildew (Blumeria graminis f. sp. tritici) resistance inwild and cultivated tetraploid wheats

Wheat is the most widely grown crop and represents the staple food for one third of the world’s population. Wheat is attacked by a large variety of pathogens and the use of resistant cultivars is an effective and environmentally safe strategy for controlling diseases and eliminating the use of fungicides. In this study, a collection of wild and cultivated tetraploid wheats (Triticum turgidum) were evaluated for seedling resistance (SR) and adult plant resistance (APR) to powdery mildew (Blumeria graminis) and genotyped with a 90K single nucleotide polymorphism (SNP) array to identify new sources of resistance genes. The genome-wide association mapping detected 18 quantitative trait loci (QTL) for APR and 8 QTL for SR, four of which were identical or at least closely linked to four QTL for APR. Thirteen candidate genes, containing nucleotide binding sites and leucine-rich repeats, were localized in the confidence intervals of the QTL-tagging SNPs. The marker IWB6155, associated to QPm.mgb-1AS, was located within the gene TRITD1Av1G004560 coding for a disease resistance protein. While most of the identified QTL were described previously, five QTL for APR (QPm.mgb-1AS, QPm.mgb-2BS, QPm.mgb-3BL.1, QPm.mgb-4BL, QPm.mgb-7BS.1) and three QTL for SR (QPm.mgb-3BL.3, QPm.mgb-5AL.2, QPm.mgb-7BS.2) were mapped on chromosome regions where no resistance gene was reported before. The novel QTL/genes can contribute to enriching the resistance sources available to breeders

Silica-magnesium-titanium Ziegler-Natta catalysts. Part 1: Structure of the pre-catalyst at a molecular level

In this paper, which is the first part of a more extended work, we elucidate the molecular level structure of a highly active SiO2-supported Ziegler-Natta precatalyst obtained by reacting a dehydroxylated silica and a solution of an organomagnesium compound with TiCl4. The synergetic combination of Ti K-edge and Ti L3-edge X-ray Absorption spectroscopy (XAS) and diffuse reflectance UV–Vis spectroscopies, complemented by Density Functional Theory (DFT) simulations, indicate that small TiCl3 clusters similar to β-TiCl3 coexist with isolated monomeric Ti(IV) species. Ti K-edge Extended X-ray Absorption Fine Structure (EXAFS) Spectroscopy allows the quantification of these two phases and demonstrates that the Ti(IV) sites are 6-fold coordinated (either by six chlorine ligands or by five chlorine and one oxygen ligands), but highly distorted, similar to what is modelled for TiCl4-capped MgCl2 nanoplatelets. Finally, IR spectroscopy suggests that the MgCl2 phase has a molecular character (Far-IR) and that the only accessible Mg2+ sites are uncoordinated cations acting as Lewis acid sites (IR of CO adsorbed at 100 K). Based on these experimental findings, we propose the co-existence in the precatalyst of small TiCl3 clusters and of mixed oxo-chloride magnesium-titanium structures deposited at the silica surface. The evolution of the precatalyst in the presence of the activator and of the monomer is discussed in the second part of this work

Electronic Properties of Ti Sites in Ziegler-Natta Catalysts

Although Ziegler-Natta (ZN) catalysts play a major role in the polyolefin market, a true understanding of their properties at the molecular level is still missing. In particular, there is a lack of knowledge on the electronic properties of Ti sites. Theoretical calculations predict that the electron density of the Ti sites in the precatalysts correlates with the activation energy for olefin insertion in the Ti-alkyl bond generated at these sites after activation by Al-alkyls. It is also well known that the effective charge on the Ti sites in the activated catalysts affects the olefin π-complexation. In this contribution, we exploit two electronic spectroscopies, UV-vis and Ti L2,3-edge near-edge X-ray absorption fine structure (NEXAFS), complemented with theoretical simulation to investigate three ZN precatalysts of increasing complexity (up to an industrial system) and the corresponding catalysts activated by triethylaluminum (TEAl). We provide compelling evidence for the presence of monomeric 6-fold-coordinated Ti4+ species in all of the precatalysts, which however differ in the effective charge on the Ti sites. We also unambiguously demonstrate that these sites are reduced by TEAl to two types of monomeric 5-coordinated Ti3+, either alkylated or not, and that the former are involved in ethylene polymerization. In addition, small TiCl3 clusters are formed in the industrial catalyst, likely due to the occurrence of severe reducing conditions within the catalyst pores. These data prove the potential of these two techniques, coupled with simulation, in providing an accurate description of the electronic properties of heterogeneous ZN catalysts

May the four be with you: novel IR-subtraction methods to tackle NNLO calculations

In this manuscript, we summarise all discussions originated as a result of the WorkStop/ThinkStart 3.0: paving the way to alternative NNLO strategies that took place on 4.-6. November 2019 at the Galileo Galilei Institute for Theoretical Physics (GGI). We gratefully acknowledge the support of GGI and the COST Action CA16201 PARTICLEFACE. We wish to thank toW.M. Marroquin and M. Morandini for their help in organising the workshop. P. Banerjee acknowledges support by the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701647. A.L. Cherchiglia, B. Hiller and M.Sampaio acknowledge support from Fundacao para a Ciencia e Tecnologia (FCT) through the projects UID/FIS/04564/2020 and CERN/FIS-COM/0035/2019. The work of L. Cieri has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 754496. The work of F. Driencourt-Mangin, G. Rodrigo, G. Sborlini and W.J. Torres Bobadilla is supported by the Spanish Government (Agencia Estatal de Investigacion), ERDF funds from European Commission (Grant No. FPA2017-84445-P), Generalitat Valenciana (Grant No. PROMETEO/2017/053) and from the SpanishGovernment (FJCI-2017-32128). T. Engel acknowledges support by the Swiss National Science Foundation (SNF) under contract 200021_178967. C. Gnendiger, R. Pittau, A. Signer and D. Stockinger wish to thank B. Page for his help in establishing (2.60). The work of R. J. Hernandez-Pinto is supported by CONACyT through the Project No. A1-S-33202 (Ciencia Basica) and Sistema Nacional de Investigadores. G. Pelliccioli was supported by the Bundesministerium fur Bildung und Forschung (BMBF, German Federal Ministry for Education and Research) under contract no. 05H18WWCA1. J. Pires was supported by Fundacao para a Ciencia e Tecnologia (FCT, Portugal) through the contract UIDP/50007/2020 and project CERN/FIS-PAR/0024/2019. The work of R. Pittau has been supported by the SpanishGovernment grant PID2019-106087GB-C21 and by the Junta de Andalucia project P18-FR-4314 (fondos FEDER). M. Sampaio acknowledges a research grant from CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico 303482/2017-6). C. Signorile-Signorile was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Grant no. 396021762 - TRR 257.In this manuscript, we report the outcome of the topical workshop: paving the way to alternative NNLO strategies (https://indico.ific.uv.es/e/WorkStop-ThinkStart_3.0), by presenting a discussion about different frameworks to perform precise higher-order computations for high-energy physics. These approaches implement novel strategies to deal with infrared and ultraviolet singularities in quantum field theories. A special emphasis is devoted to the local cancellation of these singularities, which can enhance the efficiency of computations and lead to discover novel mathematical properties in quantum field theories.European Commission 701647Portuguese Foundation for Science and Technology European Commission UID/FIS/04564/2020 CERN/FIS-COM/0035/2019European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant 754496Spanish Government (Agencia Estatal de Investigacion)ERDF funds from European Commission FPA2017-84445-PGeneralitat Valenciana European Commission PROMETEO/2017/053Spanish Government European Commission FJCI-2017-32128 PID2019-106087GB-C21Swiss National Science Foundation (SNSF) 200021_178967Consejo Nacional de Ciencia y Tecnologia (CONACyT) A1-S-33202Sistema Nacional de InvestigadoresFederal Ministry of Education & Research (BMBF) 05H18WWCA1Portuguese Foundation for Science and Technology UIDP/50007/2020 CERN/FIS-PAR/0024/2019Junta de Andalucia P18-FR-4314Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) 303482/2017-6German Research Foundation (DFG) 396021762 - TRR 257GGIEuropean Cooperation in Science and Technology (COST) CA16201 PARTICLEFAC

Clubbing masculinities: Gender shifts in gay men's dance floor choreographies

This is an Author's Accepted Manuscript of an article published in Journal of Homosexuality, 58(5), 608-625, 2011 [copyright Taylor & Francis], available online at: http://www.tandfonline.com/10.1080/00918369.2011.563660This article adopts an interdisciplinary approach to understanding the intersections of gender, sexuality, and dance. It examines the expressions of sexuality among gay males through culturally popular forms of club dancing. Drawing on political and musical history, I outline an account of how gay men's gendered choreographies changed throughout the 1970s, 80s, and 90s. Through a notion of “technologies of the body,” I situate these developments in relation to cultural levels of homophobia, exploring how masculine expressions are entangled with and regulated by musical structures. My driving hypothesis is that as perceptions of cultural homophobia decrease, popular choreographies of gay men's dance have become more feminine in expression. Exploring this idea in the context of the first decade of the new millennium, I present a case study of TigerHeat, one of the largest weekly gay dance club events in the United States

Respiratory chain complex I, a main regulatory target of the cAMP/PKA pathway is defective in different human diseases

In mammals, complex I (NADH-ubiquinone oxidoreductase) of the mitochondrial respiratory chain has 31 supernumerary subunits in addition to the 14 conserved from prokaryotes to humans. Multiplicity of structural protein components, as well as of biogenesis factors, makes complex I a sensible pace-maker of mitochondrial respiration. The work reviewed here shows that the cAMP/PKA pathway regulates the biogenesis, assembly and catalytic activity of complex I and mitochondrial oxygen superoxide production. The structural, functional and regulatory complexity of complex I, renders it particularly vulnerable to genetic and sporadic pathological factors. Complex I dysfunction has, indeed, been found, to be associated with several human diseases. Knowledge of the pathogenetic mechanisms of these diseases can help to develop new therapeutic strategies. (C) 2011 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved

Functional evidence of mTORβ splice variant involvement in the pathogenesis of congenital heart defects

mTOR dysregulation has been described in pathological conditions, such as cardiovascular and overgrowth disorders. Here we report on the first case of a patient with a complex congenital heart disease and an interstitial duplication in the short arm of chromosome 1, encompassing part of the mTOR gene. Our results suggest that an intragenic mTOR microduplication might play a role in the pathogenesis of non-syndromic congenital heart defects (CHDs) due to an upregulation of mTOR/Rictor and consequently an increased phosphorylation of PI3K/AKT and MEK/ERK signaling pathways in patient-derived amniocytes. This is the first report which shows a causative role of intragenic mTOR microduplication in the etiology of an isolated complex CHD

po 006 the mapk c myc axis in crc new pathogenic mechanisms and therapeutic approaches

Introduction c-Myc plays a central role in cellular proliferation, differentiation, and apoptosis. Therefore its deregulation represents a powerful trigger of tumorigenesis, particularly in colorectal cancer (CRC). It has been shown that the MEK/ERK pathway phosphorylates c-Myc on serine 62, which stabilises c-Myc by preventing ubiquitin/proteasomal degradation. We recently reported that MEK/ERK inhibition is counteracted by over-activation of p38α MAPK. Here, we identified cellular mechanisms that lead to c-Myc deregulation, which is a crucial issue for improving CRC treatment and survival. Material and methods The cross-talk between p38α and ERK was assessed in CRC cell lines and in APC Min/+ mice, a murine model of familial adenomatous polyposis. To this aim, animals were treated with the p38α inhibitor 4-(4-Fluorophenyl)−2-(4-hydroxyphenyl)−5-(4-pyridyl)−1H-imidazole (SB202190) alone or in combination with the MEK1 inhibitor N-[(2R)−2,3-Dihydroxypropoxy]−3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (PD0325901). In order to evaluate the role of p38α and ERK in c-Myc regulation, we used pharmacological inhibitors of these two kinases alone or in combination with inhibitors of the transcriptional mechanism, translational process and proteasome in CRC cell lines. Moreover, the function of p38α and ERK in Myc stabilisation was assessed by genetic ablation. Results and discussions Here we show that concomitant inhibition of the p38α and MEK/ERK pathways significantly increases the survival of APC Min/+ mice in which tumorigenesis is driven by c-Myc deregulation. Genetic ablation of p38α and ERK revealed that these two MAPKs do not regulate c-Myc expression, nor do they affect c-Myc protein translational process. We found that p38α and ERK collaborate in c-Myc stabilisation by inhibiting its proteasomal degradation in CRC cell lines. These results were also confirmed by using the p38α and ERK pharmacological inhibitors LY2228820 (Ralimetinib) and GSK1120212 (Mekinist), respectively, which are currently in clinical trials for inflammatory diseases and cancer. Conclusion Since c-MYC supports the processes required for normal growth and homeostasis, its ablation is less attractive than modulation of its expression or function. Our results confirmed the essential role of the MAPK/c-Myc axis in intestinal tumorigenesis regulation, suggesting MAPK manipulation as a potential therapeutic approach to counteract c-Myc dependent carcinogenesis