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Dendrogenin A, cholesterol metabolite, has tumor suppressive properties but the mechanisms are unknown. Here the authors show that Dendrogenin A can induce autophagy-mediated cell death in both melanoma and acute myeloid leukaemia.

Abstract Background: The development of single-cell technologies yields large datasets of information as diverse and multimodal as transcriptomes, immunophenotypes, and spatial position from tissue sections in the so-called ’spatial transcriptomics’. Currently however, user-friendly, powerful, and free algorithmic tools for straightforward analysis of spatial transcriptomic datasets are scarce. Results: Here, we introduce Single-Cell Spatial Explorer, an open-source software for multimodal exploration of spatial transcriptomics, examplified with 9 human and murine tissues datasets from 4 different technologies. Conclusions: Single-Cell Spatial Explorer is a very powerful, versatile, and interoperable tool for spatial transcriptomics analysis.

γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor’s blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.

Objective: To demonstrate that glycemia and insulin resistance are controlled by a mechanism involving the adaptive immune system and gut microbiota crosstalk. Methods: We triggered the immune system with microbial extracts specifically from the intestinal ileum contents of HFD-diabetic mice by the process of immunization. 35 days later, immunized mice were fed a HFD for up to two months in order to challenge the development of metabolic features. The immune responses were quantified. Eventually, adoptive transfer of immune cells from the microbiota-immunized mice to naïve mice was performed to demonstrate the causality of the microbiota-stimulated adaptive immune system on the development of metabolic disease. The gut microbiota of the immunized HFD-fed mice was characterized in order to demonstrate whether the manipulation of the microbiota to immune system interaction reverses the causal deleterious effect of gut microbiota dysbiosis on metabolic disease. Results: Subcutaneous injection (immunization procedure) of ileum microbial extracts prevented hyperglycemia and insulin resistance in a dose-dependent manner in response to a HFD. The immunization enhanced the proliferation of CD4 and CD8 T cells in lymphoid organs, also increased cytokine production and antibody secretion. As a mechanism explaining the metabolic improvement, the immunization procedure reversed gut microbiota dysbiosis. Finally, adoptive transfer of immune cells from immunized mice improved metabolic features in response to HFD. Conclusions: Glycemia and insulin sensitivity can be regulated by triggering the adaptive immunity to microbiota interaction. This reduces the gut microbiota dysbiosis induced by a fat-enriched diet. Keywords: Gut microbiota and metabolic diseases, Immunity, Insulin resistance

The 4G family of eukaryotic mRNA translation initiation factors is composed of three members (eIF4GI, eIF4GII, and DAP5). Their specific roles in translation initiation are under intense investigations, but how their respective intracellular amounts are controlled remains poorly understood. Here we show that eIF4GI and eIF4GII exhibit much shorter half-lives than that of DAP5. Both eIF4GI and eIF4GII proteins, but not DAP5, contain computer-predicted PEST motifs in their N-termini conserved across the animal kingdom. They are both sensitive to degradation by the proteasome. Under normal conditions, eIF4GI and eIF4GII are protected from proteasomal destruction through binding to the detoxifying enzyme NQO1 [NAD(P)H:quinone oxidoreductase]. However, when cells are exposed to oxidative stress both eIF4GI and eIF4GII, but not DAP5, are degraded by the proteasome in an N-terminal-dependent manner, and cell viability is more compromised upon silencing of DAP5. These findings indicate that the three eIF4G proteins are differentially regulated by the proteasome and that persistent DAP5 plays a role in cell survival upon oxidative stress.

El trabajo autónomo tiene una notable implantación en España y cumple una relativamente amplia funcionalidad en nuestro sistema económico y social. En el conjunto del tejido empresarial, es absolutamente hegemónica la figura del autónomo que no dispone de asalariados a su servicio, junto con el que emplea hasta dos trabajadores por cuenta ajena. Antes de la aprobación parlamentaria de la Ley 20/2007, su regulación resultaba muy fragmentaria, deficiente y obsoleta, sin atender a las profundas transformaciones que se han sucedido tras la llegada del posfordismo a este sector. Con la entrada en vigor de dicha norma, España dispone de una ley-marco, pionera en la Unión Europea y seguramente en el mundo, que establece un régimen jurídico mínimo, común e inderogable para todos los autónomos que producen en nuestro país. Este estudio, fundamentalmente jurídico, no se centra en el análisis de la citada disposición – bautizada como Estatuto del Trabajo Autónomo -, sino en su posterior desarrollo desde su aprobación el 11 julio del 2007 hasta finales del año 2008; sin embargo, a la vista de que ese proceso ha venido a coincidir con una profunda crisis económica, la indagación se complementa con un apunte crítico sobre las principales medidas de choque adoptadas por los poderes públicos para afrontar el impacto de la recesión sobre los trabajadores autónomos, para cerrarse con una reflexión sobre las implicaciones estructurales y desafíos que supone la vigencia dicho Estatuto tanto en España como en el seno de la Unión Europea./The autonomous work has a notable implantation in Spain and fulfills a relatively wide functionality in our economic and social system. In the set of the managerial, there is absolutely hegemonic the figure of the autonomous one who has not wage earners to his service, together with that it uses up to two workpeople for foreign account. Before the parliamentary approval of the Law 20/2007, his regulation was turning out to be very fragmentary, deficient and obsolete, without attending on the deep transformations that have happened after the arrival of the posfordism to this sector. With the coming into effect of the above mentioned norm, Spain has a law - frame, pioneer in the European Union and surely in the world, which establishes a juridical minimal pattern, common and unrepealable for all the autonomous ones that produce in our country. This study, fundamentally juridical, does not center on the analysis of the said disposition – baptized as Statute of the Autonomous Work-, but on his later development from his approval on July 12, 2007 until ends of the year 2008; but, in view of that this process has come to coincide with a deep economic crisis, the investigation complements itself with a critical note on the principal measurements of shock adopted by public power to confront the impact of the recession on the autonomous workpeople, to close with a reflection on the structural implications and challenges that supposes the above mentioned Statute, both in Spain and in the bosom of the European Union.

Fibroblast growth factor 1 (FGF1) is induced during myoblast differentiation at both transcriptional and translational levels. Here, we identify hnRNPM and p54nrb/NONO present in protein complexes bound to the FGF1 promoter and to the mRNA internal ribosome entry site (IRES). Knockdown or overexpression of these proteins indicate that they cooperate in activating IRES-dependent translation during myoblast differentiation, in a promoter-dependent manner. Importantly, mRNA transfection and promoter deletion experiments clearly demonstrate the impact of the FGF1 promoter on the activation of IRES-dependent translation via p54nrb and hnRNPM. Accordingly, knockdown of either p54 or hnRNPM also blocks endogenous FGF1 induction and myotube formation, demonstrating the physiological relevance of this mechanism and the role of these two proteins in myogenesis. Our study demonstrates the cooperative function of hnRNPM and p54nrb as regulators of IRES-dependent translation and indicates the involvement of a promoter-dependent mechanism.

MicroRNAs are small non-coding RNAs that physiologically modulate proteins expression, and regulate numerous cellular mechanisms. Alteration of microRNA expression has been described in cancer and is associated to tumor initiation and progression. The microRNA 148a (miR-148a) is frequently down-regulated in cancer. We previously demonstrated that its down-regulation by DNA hypermethylation is an early event in pancreatic ductal adenocarcinoma (PDAC) carcinogenesis, suggesting a tumor suppressive function. Here, we investigate the potential role of miR-148a over-expression in PDAC as a therapeutic tool. We first report the consequences of miR-148a over-expression in PDAC cell lines. We demonstrate that miR-148a over-expression has no dramatic effect on cell proliferation and cell chemo-sensitivity in four well described PDAC cell lines. We also investigate the modulation of protein expression by a global proteomic approach (2D-DIGE). We show that despite its massive over-expression, miR-148a weakly modulates protein expression, thus preventing the identification of protein targets in PDAC cell lines. More importantly, in vivo data demonstrate that modulating miR-148a expression either in the epithelia tumor cells and/or in the tumor microenvironment does not impede tumor growth. Taken together, we demonstrate herein that miR-148a does not impact PDAC proliferation both in vitro and in vivo thus suggesting a weak potential as a therapeutic tool.

BackgroundMitochondrial ATP synthase is expressed as a plasma membrane receptor for apolipoprotein A-I (apoA-I), the major protein component in High Density Lipoproteins (HDL). On hepatocytes, apoA-I binds to cell surface ATP synthase (namely ecto-F(1)-ATPase) and stimulates its ATPase activity, generating extracellular ADP. This production of extracellular ADP activates a P2Y(13)-mediated HDL endocytosis pathway. Conversely, exogenous IF1, classically known as a natural mitochondrial specific inhibitor of F(1)-ATPase activity, inhibits ecto-F(1)-ATPase activity and decreases HDL endocytosis by both human hepatocytes and perfused rat liver.Methodology/principal findingsSince recent reports also described the presence of IF1 at the plasma membrane of different cell types, we investigated whether IF1 is present in the systemic circulation in humans. We first unambiguously detected IF1 in human serum by immunoprecipitation and mass spectrometry. We then set up a competitive ELISA assay in order to quantify its level in human serum. Analyses of IF1 levels in 100 normolipemic male subjects evidenced a normal distribution, with a median value of 0.49 µg/mL and a 95% confidence interval of 0.22-0.82 µg/mL. Correlations between IF1 levels and serum lipid levels demonstrated that serum IF1 levels are positively correlated with HDL-cholesterol and negatively with triglycerides (TG).Conclusions/significanceAltogether, these data support the view that, in humans, circulating IF1 might affect HDL levels by inhibiting hepatic HDL uptake and also impact TG metabolism.

El trabajo autónomo tiene una notable implantación en España y cumple una relativamente amplia funcionalidad en nuestro sistema económico y social. En el conjunto del tejido empresarial, es absolutamente hegemónica la figura del autónomo que no dispone de asalariados a su servicio, junto con el que emplea hasta dos trabajadores por cuenta ajena. Antes de la aprobación parlamentaria de la Ley 20/2007, su regulación resultaba muy fragmentaria, deficiente y obsoleta, sin atender a las profundas transformaciones que se han sucedido tras la llegada del posfordismo a este sector. Con la entrada en vigor de dicha norma, España dispone de una ley-marco, pionera en la Unión Europea y seguramente en el mundo, que establece un régimen jurídico mínimo, común e inderogable para todos los autónomos que producen en nuestro país. Este estudio, fundamentalmente jurídico, no se centra en el análisis de la citada disposición – bautizada como Estatuto del Trabajo Autónomo -, sino en su posterior desarrollo desde su aprobación el 11 julio del 2007 hasta finales del año 2008; sin embargo, a la vista de que ese proceso ha venido a coincidir con una profunda crisis económica, la indagación se complementa con un apunte crítico sobre las principales medidas de choque adoptadas por los poderes públicos para afrontar el impacto de la recesión sobre los trabajadores autónomos, para cerrarse con una reflexión sobre las implicaciones estructurales y desafíos que supone la vigencia dicho Estatuto tanto en España como en el seno de la Unión Europea.