Changes in membrane lipids drive increased endocytosis following Fas ligation

Once activated, some surface receptors promote membrane movements that open new portals of endocytosis, in part to facilitate the internalization of their activated complexes. The prototypic death receptor Fas (CD95/Apo1) promotes a wave of enhanced endocytosis that induces a transient intermixing of endosomes with mitochondria in cells that require mitochondria to amplify death signaling. This initiates a global alteration in membrane traffic that originates from changes in key membrane lipids occurring in the endoplasmic reticulum (ER). We have focused the current study on specific lipid changes occurring early after Fas ligation. We analyzed the interaction between endosomes and mitochondria in Jurkat T cells by nanospray-Time-of-flight (ToF) Mass Spectrometry. Immediately after Fas ligation, we found a transient wave of lipid changes that drives a subpopulation of early endosomes to merge with mitochondria. The earliest event appears to be a decrease of phosphatidylcholine (PC), linked to a metabolic switch enhancing phosphatidylinositol (PI) and phosphoinositides, which are crucial for the formation of vacuolar membranes and endocytosis. Lipid changes occur independently of caspase activation and appear to be exacerbated by caspase inhibition. Conversely, inhibition or compensation of PC deficiency attenuates endocytosis, endosome-mitochondria mixing and the induction of cell death. Deficiency of receptor interacting protein, RIP, also limits the specific changes in membrane lipids that are induced by Fas activation, with parallel reduction of endocytosis. Thus, Fas activation rapidly changes the interconversion of PC and PI, which then drives enhanced endocytosis, thus likely propagating death signaling from the cell surface to mitochondria and other organelles

Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER-mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington's chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS

Capitale sociale e prosumerismo nella societ\ue0 digitale

L'elaborato, partendo dall'evoluzione del termine prosumer ne delinea quella che \ue8 la teoria e la letteratura di riferimento. Si pone particolare enfasi sull'evoluzione del processo che ne \ue8 derivata, con particolare riferimento a quelle che sono le conseguenze derivate dal cosi detto web 2.0 e dalla pervasivit\ue0 di una societ\ue0 digitale. Nel contesto digitale appunto si osservano quelle che sono le forme in cui si manifesta il capitale sociale in contesti sia off line che on line

Food sharing practices and sharing economy: How the economic crisis is reshaping Italians\u2019 food consumption habits.

Since 2008, the European and global economic crisis and the digital revolution are the two main agents of change transforming consumer behaviors. The process of digitalization is impacting markets and society at every level, and can be tied to the economic crisis in many sectors \u2013 especially concerning the relationship between mass distribution and small retailers. Within this framework, market segmentation reproduces old and new forms of social stratification and inequalities based on income, access to food, and access to information. The aim of this paper is to discuss the final results of a national survey of several universities. The survey analyzes how Italians\u2019 relationship with the food they purchase has changed as a result of both the economic crisis and increased buying opportunities. In this context, the notion of the prosumer and a sharing economy arose as the main interpretative variables of a reality in transition in which Italians adapt their alimentary needs. In doing so, they rediscover forms of the neighborhood partially forgotten and partially digitally assisted. These new consumer behaviors are also representative of a peculiar political choice that has led to a global and local solidarity movement in which people are supporting local producers and local communities instead of mass distribution. Even if the trend in this direction is evident and more ethically driven than economically, the survey emphasized how consumers enlisted in sharing economy circuits are always under the price dictatorship typical of a capitalistic system. The survey methodology used is one of a mixed method approach \u2013 both quantitative and qualitative \u2013 and also took advantage of some experimental techniques such as visual sociology and SNA

Comparative Study on Bioactive Filler/Biopolymer Scaffolds for Potential Application in Supporting Bone Tissue Regeneration

The combination of biopolymers and bioactive inorganic particles for bone tissue regeneration has been investigated in the last decades. However, several studies report discordant results on the specific synergistic effect of the compounds. A comparative study on porous scaffolds obtained by the combination of the most promising biopolymers and bioactive inorganic particles is herein reported. Specifically, porous scaffolds have been fabricated by the Thermally Induced Phase Separation method using poly(3-hydroxybutyrate-co-3-hydroxyval- erate) (PHBV), poly(lactic acid) (PLA), and poly(caprolactone) (PCL) compounded with hydroxyapatite (HAp), calcium silicate (CS), or a Mg- and Sr-rich bioglass (BG) with a nominal composition of 2.3% Na2O, 2.3% K2O, 25.6% CaO, 10.0% MgO, 10.0% SrO, 2.6% P2O5, and 47.2% SiO2. Morphological analyses revealed the formation of highly interconnected and aligned open pores. Both thermal investigations and compressive tests highlight the close similarity between PLA- and PHBV-based scaffolds in terms of the amorphous structure and stiffness when the fillers are added. On the other hand, the addition of amorphous BG in semicrystalline PCL shows a decrease of the crystallinity degree of the polymer and a consequent decrease of the compressive modulus. Preliminary in vitro investigations (direct and indirect contact tests) carried out on the composite systems revealed that all the prepared materials provide an appropriate environment for NIH 3T3 cell adhesion and proliferation, showing a total lack of cytotoxicity. The addition of all the inorganic fillers has an overall positive effect on cell proliferation, viability (Neutral Red uptake), and metabolic activity (MTT test). Interestingly, this effect is particularly evident whenever BG is added. The combination of both amorphous BGs with amorphous polymers, such as PLA and PHBV, seems to be responsible for creating the best microenvironmental cue for NIH 3T3 cell attachment and proliferation

Altered Traffic of Cardiolipin during Apoptosis: Exposure on the Cell Surface as a Trigger for "Antiphospholipid Antibodies"

Apoptosis has been reported to induce changes in the remodelling of membrane lipids; after death receptor engagement, specific changes of lipid composition occur not only at the plasma membrane, but also in intracellular membranes. This paper focuses on one important aspect of apoptotic changes in cellular lipids, namely, the redistribution of the mitochondria-specific phospholipid, cardiolipin (CL). CL predominantly resides in the inner mitochondrial membrane, even if the rapid remodelling of its acyl chains and the subsequent degradation occur in other membrane organelles. After death receptor stimulation, CL appears to concentrate into mitochondrial "raft-like" microdomains at contact sites between inner and outer mitochondrial membranes, leading to local oligomerization of proapoptotic proteins, including Bid. Clustering of Bid in CL-enriched contacts sites is interconnected with pathways of CL remodelling that intersect membrane traffic routes dependent upon actin. In addition, CL association with cytoskeleton protein vimentin was observed. Such novel association also indicated that CL molecules may be expressed at the cell surface following apoptotic stimuli. This observation adds a novel implication of biomedical relevance. The association of CL with vimentin at the cell surface may represent a "new" target antigen in the context of the apoptotic origin of anti-vimentin/CL autoantibodies in Antiphospholipid Syndrome

Webinar del CSIC: Los desafíos de la inteligencia artificial y la digitalización

Datos técnicos: 70 minutos, color, español. Ficha técnica: Gabinete de Presidencia CSIC y Departamento de ComunicaciónN