Caveolin-1 is required for TGF-β-induced transactivation of the EGF receptor pathway in hepatocytes through the activation of the metalloprotease TACE/ADAM17

Transforming growth factor-beta (TGF-β) plays a dual role in hepatocytes, inducing both pro- and anti-apoptotic responses, whose balance decides cell fate. Survival signals are mediated by the epidermal growth factor receptor (EGFR) pathway, which is activated by TGF-β in these cells. Caveolin-1 (Cav1) is a structural protein of caveolae linked to TGF-β receptors trafficking and signaling. Previous results have indicated that in hepatocytes, Cav1 is required for TGF-β-induced anti-apoptotic signals, but the molecular mechanism is not fully understood yet. In this work, we show that immortalized Cav1−/− hepatocytes were more sensitive to the pro-apoptotic effects induced by TGF-β, showing a higher activation of caspase-3, higher decrease in cell viability and prolonged increase through time of intracellular reactive oxygen species (ROS). These results were coincident with attenuation of TGF-β-induced survival signals in Cav1−/− hepatocytes, such as AKT and ERK1/2 phosphorylation and NFκ-B activation. Transactivation of the EGFR pathway by TGF-β was impaired in Cav1−/− hepatocytes, which correlated with lack of activation of TACE/ADAM17, the metalloprotease responsible for the shedding of EGFR ligands. Reconstitution of Cav1 in Cav1−/− hepatocytes rescued wild-type phenotype features, both in terms of EGFR transactivation and TACE/ADAM17 activation. TACE/ADAM17 was localized in detergent-resistant membrane (DRM) fractions in Cav1+/+ cells, which was not the case in Cav1−/− cells. Disorganization of lipid rafts after treatment with cholesterol-binding agents caused loss of TACE/ADAM17 activation after TGF-β treatment. In conclusion, in hepatocytes, Cav1 is required for TGF-β-mediated activation of the metalloprotease TACE/ADAM17 that is responsible for shedding of EGFR ligands and activation of the EGFR pathway, which counteracts the TGF-β pro-apoptotic effects. Therefore, Cav1 contributes to the pro-tumorigenic effects of TGF-β in liver cancer cells

DNA-interacting proteins in the spermiogenesis of the mollusc Murex brandaris

Sperm chromatin of Murex brandaris (a neogastropod mollusc) undergoes a series of structural transitions during spermiogenesis. The DNA-interacting proteins responsible for these changes as well as the mature protamines present in the ripe sperm nucleus have been characterized. The results reveal that spermiogenic nuclear proteins are protamine precursors that are subjected to a substantial number of small N-terminal deletions that gradually modify their overall charge. The composition of mature protamines is remarkably simple in turn, promoting an efficient and extremely tight packaging of DNA. The pattern of spermiogenic chromatin condensation in M. brandaris clearly departs from that corresponding to vertebrate chromatin

NF-κB and TET2 promote macrophage reprogramming in hypoxia that overrides the immunosuppressive effects of the tumor microenvironment

Macrophages orchestrate tissue homeostasis and immunity. In the tumor microenvironment (TME), macrophage presence is largely associated with poor prognosis because of their reprogramming into immunosuppressive cells. We investigated the effects of hypoxia, a TME-associated feature, on the functional, epigenetic, and transcriptional reprogramming of macrophages and found that hypoxia boosts their immunogenicity. Hypoxic inflammatory macrophages are characterized by a cluster of proinflammatory genes undergoing ten-eleven translocation-mediated DNA demethylation and overexpression. These genes are regulated by NF-κB, while HIF1α dominates the transcriptional reprogramming, demonstrated through ChIP-seq and pharmacological inhibition. In bladder and ovarian carcinomas, hypoxic inflammatory macrophages are enriched in immune-infiltrated tumors, correlating with better patient prognoses. Coculture assays and cell-cell communication analyses support that hypoxic-activated macrophages enhance T cell-mediated responses. The NF-κB-associated hypomethylation signature is displayed by a subset of hypoxic inflammatory macrophages, isolated from ovarian tumors. Our results challenge paradigms regarding the effects of hypoxia on macrophages and highlight actionable target cells to modulate anticancer immune responses

From 2D to 3D: novel nanostructured scaffolds to investigate signalling in reconstructed neuronal networks

To recreate in vitro 3D neuronal circuits will ultimately increase the relevance of results from cultured to whole-brain networks and will promote enabling technologies for neuro-engineering applications. Here we fabricate novel elastomeric scaffolds able to instruct 3D growth of living primary neurons. Such systems allow investigating the emerging activity, in terms of calcium signals, of small clusters of neurons as a function of the interplay between the 2D or 3D architectures and network dynamics. We report the ability of 3D geometry to improve functional organization and synchronization in small neuronal assemblies. We propose a mathematical modelling of network dynamics that supports such a result. Entrapping carbon nanotubes in the scaffolds remarkably boosted synaptic activity, thus allowing for the first time to exploit nanomaterial/cell interfacing in 3D growth support. Our 3D system represents a simple and reliable construct, able to improve the complexity of current tissue culture models

Well-developed deformation in 42Si

Excited states in 38,40,42Si nuclei have been studied via in-beam gamma-ray spectroscopy with multi-nucleon removal reactions. Intense radioactive beams of 40S and 44S provided at the new facility of the RIKEN Radioactive Isotope Beam Factory enabled gamma-gamma coincidence measurements. A prominent gamma line observed with an energy of 742(8) keV in 42Si confirms the 2+ state reported in an earlier study. Among the gamma lines observed in coincidence with the 2+ -> 0+ transition, the most probable candidate for the transition from the yrast 4+ state was identified, leading to a 4+_1 energy of 2173(14) keV. The energy ratio of 2.93(5) between the 2+_1 and 4+_1 states indicates well-developed deformation in 42Si at N=28 and Z=14. Also for 38,40Si energy ratios with values of 2.09(5) and 2.56(5) were obtained. Together with the ratio for 42Si, the results show a rapid deformation development of Si isotopes from N=24 to N=28

Infection Control in El Salvador: The Hospital Rosales Experience

AbstractWe describe circumstances at the Hospital Rosales, located in San Salvador, El Salvador, and some salient observations from an infection control program begun in 1978. Findings include overuse of antibiotics, especially of penicillin and chloramphenicol; a predominance of gram-negative rod infections, especially Pseudomonas aeruginosa; a relative infrequency of Staphylococcus aureus infections; an apparent doubling of the mean duration of hospitalization for patients with nosocomial infections compared with other patients (22.1 days versus 11.0 days); documentation and partial correction of deficiencies in aseptic and antiseptic practices; an outbreak of Pseudomonas aeruginosa endophthalmitis traced to the hospital's factory for the manufacturing of intravenous fluids; and attitudinal problems such as the care of patients with rabies on open wards. Prevalence surveys conducted during 1981 and 1986 suggest a dramatic increase in the recent incidence of surgical wound infection (44% v 28%, P &lt; 0.001). This latter observation suggests a direct relationship between infection rates and the hardships imposed by poverty and civil war.</jats:p

Cumulative effects of fire and drought in Mediterranean ecosystems

Altres ajuts: Enric Batllori thanks the support of a Marie Curie International Incoming Fellowship (PIFF-GA-2013-625547) and Miquel De Caceres the support of a Spanish Ramon y Cajal Fellowship. Lluís Brotons and Francisco Lloret thank the support of the projects FORESTCAST, NEWFORESTS,INFORMED, SECADIN, and BIOCLIM.The occurrence of multiple disturbances can jointly affect the recovery capacity of ecosystems, potentially leading to changes in vegetation dynamics or loss of resilience. The effects of interacting disturbances on ecosystems are, however, not well understood. We use a model system based on Mediterranean-type ecosystems (MTEs) to examine how the interplay between vegetation regeneration traits and compound, stochastic disturbances modulate ecosystem dynamics. We developed a state-and-transition simulation model including two tree species with contrasting regeneration strategies (seeder vs. resprouter) and a shrubland formation. We aim to assess potential compositional switches under contrasted scenarios of compound fire-drought regimes, and to characterize the cumulative effects of fire-drought (synergism vs. antagonism) relative to the effects of individual disturbance regimes. Our simulation results indicate that interaction between moderate fire and sporadic drought recurrence-as opposed to chronic dryness-can act as a strong mechanism generating highly heterogeneous landscapes in which different regeneration types coexist, as observed in MTEs. Resprouters dominated under individual, moderate disturbance regimes of fire or drought, whereas the interaction of the two disturbances promoted the long-term coexistence of both tree regeneration strategies. However, shrubland expansion and persistence at the expanse of forests was favored by increases in drought recurrence and associated fire-drought interactions, highlighting the potential for important vegetation changes in MTEs under climate change. Overall, the cumulative effects of fire and drought can lead to distinct landscape configurations under moderate disturbance regimes that are otherwise only attained under high frequency of individual disturbances. At the ecosystem level, however, we suggest that disturbance-induced vegetation dynamics can modify vegetation sensitivity and resilience to further disturbances precluding the prevalence of synergistic effects of the two disturbances