Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to ...provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.
Reversible imine bonds have been used as a strategy to develop pH-dependent antifungal systems based on grafting benzaldehyde and citral onto the surface of chitosan films. Formation of imine bonds ...was confirmed by ATR-FTIR and XPS. Aldehyde unit incorporation respect to glucosamine units of chitosan polymer was estimated by elemental analysis. The rate and extent of imine bond hydrolysis depended on the pH of the media and the chemical structure of the aldehyde. The release of the aldehydes was monitored by gas chromatography observing acidic media favours the release. Imine bond obtained from benzaldehyde was more prone to be hydrolysed than citral. Chitosan films grafted with benzaldehyde and triggered at acidic pH controlled in vitro growth of common fruit and vegetable spoilage and pathogenic fungi. The films developed could be applied in the design of food packages intended to prevent postharvest fungal spoilage.
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•An in situ process was developed to covalently graft aldehydes to the surface of chitosan films.•Synthetized imine bonds act as reversible covalent linkers of citral and benzaldehyde.•Triggering aldehyde release from the films was achieved by pH-dependent hydrolysis of CN bonds.•Aldehyde chemical structure plays a major role on imine bond reversibility.
Genetic diseases of blood cells are prime candidates for treatment through ex vivo gene editing of CD34
hematopoietic stem/progenitor cells (HSPCs), and a variety of technologies have been proposed ...to treat these disorders. Sickle cell disease (SCD) is a recessive genetic disorder caused by a single-nucleotide polymorphism in the β-globin gene (HBB). Sickle hemoglobin damages erythrocytes, causing vasoocclusion, severe pain, progressive organ damage, and premature death. We optimize design and delivery parameters of a ribonucleoprotein (RNP) complex comprising Cas9 protein and unmodified single guide RNA, together with a single-stranded DNA oligonucleotide donor (ssODN), to enable efficient replacement of the SCD mutation in human HSPCs. Corrected HSPCs from SCD patients produced less sickle hemoglobin RNA and protein and correspondingly increased wild-type hemoglobin when differentiated into erythroblasts. When engrafted into immunocompromised mice, ex vivo treated human HSPCs maintain SCD gene edits throughout 16 weeks at a level likely to have clinical benefit. These results demonstrate that an accessible approach combining Cas9 RNP with an ssODN can mediate efficient HSPC genome editing, enables investigator-led exploration of gene editing reagents in primary hematopoietic stem cells, and suggests a path toward the development of new gene editing treatments for SCD and other hematopoietic diseases.
In this work, a comparative analysis of energy and environmental performances, on four types of urban passenger buses powertrains was carried out within the well-to-wheel scope in Argentina, Chile ...and Brazil. The powertrains studied were: internal combustion engine fed with diesel, fuel cell hybrid electric vehicle fed with hydrogen, battery electric vehicle fed with electricity and hybrid electric vehicle fed with diesel. The aim of the study is to understand what the influence of the energy pathway, the electricity mix, the driving conditions and different ranges is, in the current and future deployment of urban passenger vehicles. We found that the electric vehicles are markedly superior in the tank to wheel step, nevertheless actions to improve their energy and environmental performance should focus on how to generate clean energy within the electricity mix and with what technologies. For the fuel cell powered buses to be competitive, the production share of hydrogen from wind or other zero emission technologies should be more than 50%. In Argentina and Chile, the buses with internal combustion engines are still an important alternative in the current scenario only for long ranges, instead Brazil turns out to be ideal the application of full electric buses.
•We compare different buses powertrains using energy and environmental analysis.•The study is framed to Argentina, Brazil and Chile and performed for 4 different buses.•The study was made for present (2017) and future (2030) scenarios.•We use 2 different standard driving cycles and 4 ranges.•An index to compare the energy and environmental sustainability is used.
An evaluation of a multiplex PCR assay (Bruce-ladder) was performed in seven laboratories using 625 Brucella strains from different animal and geographical origins. This robust test can differentiate ...in a single step all of the classical Brucella species, including those found in marine mammals and the S19, RB51, and Rev.1 vaccine strains.
Glyphosate is a large-spectrum herbicide that was introduced on the market in 1974. Due to its important impact on the crop industry, it has been significantly diversified and expanded being ...considered the most successful herbicide in history. Currently, its massive use has led to a wide environmental diffusion and its human consumption through food products has made possible to detect it in urine, serum, and breast milk samples. Nevertheless, recent studies have questioned its safety and international agencies have conflicting opinions about its effects on human health, mainly as an endocrine-disrupting chemical (EDC) and its carcinogenic capacity. Here, we conduct a comprehensive review where we describe the most important findings of the glyphosate effects in the endocrine system and asses the mechanistic evidence to classify it as an EDC. We use as guideline the ten key characteristics (KCs) of EDC proposed in the expert consensus statement published in 2020 (La Merrill et al., 2020) and discuss the scopes of some epidemiological studies for the evaluation of glyphosate as possible EDC. We conclude that glyphosate satisfies at least 8 KCs of an EDC, however, prospective cohort studies are still needed to elucidate the real effects in the human endocrine system.
•Glyphosate is the active component of the most commonly used herbicide in the world.•There is conflicting evidence regarding the effects of glyphosate in the endocrine system.•This is the first review that consolidates the mechanistic evidence on glyphosate as endocrine-disrupting chemical (EDC).•Glyphosate satisfies at least 8 key characteristics of an EDC.•Prospective cohort studies are needed in order to elucidate whether glyphosate is an EDC.
Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we ...studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.
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•In macrophages, LPS-induced ROS production requires mitochondrial mitofusin 2•Mfn2 is required for the production of cytokines, phagocytosis, and antigen processing•Survival from bacterial infection or septic shock is compromised in Mfn2−/− mice
Tur et al. show that LPS-induced stress in macrophages requires mitofusin 2, which affects mitochondrial respiration and ROS production. The lack of Mfn2 in macrophages blocks the triggering of pro-inflammatory responses, phagocytosis, and antigen presentation.
Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments. The pathways ...regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signalling, usually associated with senescence, not after transient DNA damage responses (DDRs). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell-cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Furthermore, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell-cycle checkpoints and DNA repair, a new and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
We present a photometric study of the dwarf galaxy population in the core region ( rvir/4) of the Fornax galaxy cluster based on deep u′g′i′ photometry from the Next Generation Fornax Cluster Survey. ...All imaging data were obtained with the Dark Energy Camera mounted on the 4 m Blanco telescope at the Cerro Tololo Interamerican Observatory. We identify 258 dwarf galaxy candidates with luminosities −17 Mg′ −8 mag, corresponding to typical stellar masses of , reaching ∼3 mag deeper in point-source luminosity and ∼4 mag deeper in surface brightness sensitivity compared to the classic Fornax Cluster Catalog. Morphological analysis shows that the dwarf galaxy surface-brightness profiles are well represented by single-component Sérsic models with average Sérsic indices of and average effective radii of . Color-magnitude relations indicate a flattening of the galaxy red sequence at faint galaxy luminosities, similar to the one recently discovered in the Virgo cluster. A comparison with population synthesis models and the galaxy mass-metallicity relation reveals that the average faint dwarf galaxy is likely older than ∼5 Gyr. We study galaxy scaling relations between stellar mass, effective radius, and stellar mass surface density over a stellar mass range covering six orders of magnitude. We find that over the sampled stellar mass range several distinct mechanisms of galaxy mass assembly can be identified: (1) dwarf galaxies assemble mass inside the half-mass radius up to , (2) isometric mass assembly occurs in the range , and (3) massive galaxies assemble stellar mass predominantly in their halos at and above.
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