Sex-related differences in death control of somatic cells

In 2001, The United States Institute of Medicine (IOM) Committee on Understanding the Biology of Sex and Gender Differences concluded that ‘Sex…should be considered when designing and analysing studies in all areas and at all levels of biomedical and health-related research…’ and stated an apparent paradox i.e.: ‘every cell has a sex’ 1. Sex is defined as ‘the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement’ whereas gender is defined as ‘a person's self representation as male or female, or how that person is responded to by social institutions based on the individual's gender presentation. Gender is rooted in biology and shaped by environment and experience’ 1. It is unchallenged that there are health differences between males and females and that social and cultural factors could contribute to the observed differences. Anyway, the sex-dependent differences also have a biological base which sometimes has not been deeply investigated. Scientists studying health differences between male and female aim to both considering social/cultural environment and investigating biological/molecular mechanisms different between sexes. Some experimental studies have elucidated important differences in cell death control 2. A sex disparity, in fact, has been shown both in the propensity to apoptosis and in the activation of the autophagic pathway. In the context of cell fate control, hormones represent important regulators of both apoptosis and autophagy. In the cardiovascular system, for example, oestrogens inhibit cardiomyocyte apoptosis by decreasing reactive oxygen species production and increasing intracellular antioxidants 3. Oestrogens may also indirectly control autophagy as they up-regulate urocortin 4, a neuropeptide hormone able to inhibiting autophagy in cardiomyocytes. Conversely, increasing evidence suggests possible adverse effects of androgens on the vasculature showing that androgens, as opposed to oestrogens, may worsen vascular dysfunction in men, thus contributing to sex-based differences in cardiovascular diseases 5. However, it is currently emerging that some cell death programs are differentially controlled by sex-related hormone-independent cellular genetics. Differences in cell death sensitivity in male and female may then occur in the absence of an hormonal context. This is not an immediately obvious finding; Penaloza C et al., 6 have shown that the apoptosis amount differs between the sexes in isolated embryonic cells exposed to similar conditions and this happens at embryonal stages where there are no hormonal influences. Previous studies had reported a sexual dimorphism in embryonic neuronal signal transduction pathways and consequently differences in cell survival 7. Death pathways in XX and XY cells have been poorly investigated as most studies have been performed on established cells lines often irrespective of their male or female origin. Recently, using freshly isolated cells from male and female individuals gave important information on sex disparity in cell fate control. Such sex specificity has been in part clarified thanks to cell culture models where sex steroids can be removed from the media. Even sex-related differences in caspase activation have been found to be independent on hormone exposure. More in detail, cell death occurring in cortical neurons after ischaemia proceeds predominantly via an apoptosis-inducing factor-dependent pathway (a caspase-independent pathway) in male neurons while proceeds via a cytochrome C-dependent pathway (a process mediated by caspase activation) in female neurons 8. In this context, a sex-specific microRNA expression after ischaemia has been described in in vivo studies. In particular, it has been demonstrated that microRNA-23a, by binding the mRNA of the caspase inhibitor named XIAP, induces its translational repression in females, leading to enhanced caspase signalling in the ischaemic female brain. This effect has been shown to be independent of circulating oestrogen levels 9. Sex differences in ischaemic brain injury and cerebrovascular regulation have been observed in clinical and experimental studies and an important determinant of such differences is also represented by the integrity of endothelial cells. In fact, endothelial function is improved in women compared with men, contributing to female cellular higher resistance after ischaemic brain injury. Gupta NC et al. 10 showed that female cerebrovascular endothelial cells express lower level of soluble epoxide hydrolase and consequently have higher levels of vasoprotective epoxyeicosatrienoic acids as compared with male endothelial cells. This study therefore presents a novel additional mechanism underlying differences between male and female cells in apoptotic response after oxygen-glucose deprivation, contributing to explain higher resistance observed in females as compared with males. This study remarks again that differences between male and female cells do not necessarily depend on the hormonal context but may be inherent the cells. We believe that this apparently paradoxical concept has not been sufficiently highlighted in the scientific literature. The present ‘Letter to the Editor’ therefore aims at underlining such an important issue which deserves more attention and discussion in the researchers' community. A practical consequence of sex-dependent discrepancies in cell death control is that cellular response to any stimulus or treatment, in any physiological or pathological context, may well depend on the sex of the cell line used; journals guidelines should therefore require authors to state in any case the sex of the cell lines used in any in vitro study. In addition, at least to some extent, sex-matched or sex-unmatched cell controls may be necessary in many experimental settings. In conclusion, sex-related differences in cell death mechanism may have strong implications for experimental studies and sexual dimorphism dependent on chromosomal rather than hormonal differences have important implications for planning preclinical studies and clinical interventions

Gli impatti del Ponte: sottosviluppo insostenibile

Il governo ha ribadito la volontà di proseguire con il progetto del ponte sullo Stretto di Messina, all'interno del quadro di investimenti tesi ad accele­rare la ripresa economica; ha tuttavia azzerato le risorse disponibili per l’operazione, tradendo forse la vera natura dell’enunciazione suddetta: quella della reiterazione-sempre piùstanca e senza convinzione- di una declaratoria ormai rituale quanto improbabile. L’Unione Europea, dal canto suo, ha definitivamente cancellato l’opera dalla lista delle infrastrutture considerate prioritarie e quindi finanziabili con risorse comunitarie. Nonostante le posizioni governative ufficiali, vista anche la crescente opposizione e le critiche di diversi ambiti politici, sociali e scientifici, secondo cui l'attraversamento dello Stretto dovrebbe essere cancellato, l’operazione appare tuttora quanto mai incerta. L'articolo ricostruisce le vicende relative al progetto del ponte, dall'origi­nario dibattito post-unitario sulla necessità di un collegamento stabile tra la Sicilia ed il Continente, alla redazione delle prime ipotesi di piano nel secon­do dopoguerra, all'idea di "area metropolitana dello Stretto e conurbazione del ponte" contenuta nel progetto '80, alle posizioni critiche che, rispetto a tali concetti, sono maturate negli studi relativi alle più recenti versioni del progetto. Nella seconda parte si descrivono gli elementi principali del "progetto di attraversamento aereo dello Stretto di Messina" presentato dalla società dello Stretto al governo il 31/12/02 (progetto preliminare, che ha registrato il parere positivo con prescrizioni del CIPE nel 2005), di cui è stata di recente presentata la versione “definitiva”; e ancora note tratte dalle "Osservazioni sullo studio di impatto ambientale", avanzate per conto di Legambiente, WWF, Italia Nostra e di altre associazioni ambientaliste, da un gruppo di studio coordinato dall'autore delle note presenti, riassumendo anche recenti lavori di aggiornamento (Bettini, Guerzoni, Ziparo, 2002; Pieroni, 2000; Pieroni, Ziparo, 2010; Marino, 2011)

Transfected poly(I:C) activates different dsRNA receptors leading to apoptosis or immunoadjuvant response in androgen-independent prostate cancer cells

Background: Castration-resistant prostate cancer (CRPC) is refractory to chemo-radiotherapy. Results: Transfection of the synthetic analog of dsRNA poly(I:C) simultaneously stimulates apoptosis and IFN- expression through different pathways in androgen-independent prostate cancer (PCa) cells. Conclusion: Dual parallel pathways triggered by distinct receptors activate direct and immunologically mediated antitumor effects in advanced PCa. Significance: The proapoptotic/immunoadjuvant poly(I:C)-Lipofectamine complex may offer new therapeutic insights into CRPC

Reversal or no reversal: the evolution of the star formation rate–density relation up to z ∼ 1.6

We investigate the evolution of the star formation rate (SFR)–density relation in the Extended Chandra Deep Field South and the Great Observatories Origin Deep Survey fields up to z ∼ 1.6. In addition to the ‘traditional method’, in which the environment is defined according to a statistical measurement of the local galaxy density, we use a ‘dynamical’ approach, where galaxies are classified according to three different environment regimes: group, ‘filament-like’ and field. Both methods show no evidence of an SFR–density reversal. Moreover, group galaxies show a mean SFR lower than other environments up to z ∼ 1, while at earlier epochs group and field galaxies exhibit consistent levels of star formation (SF) activity. We find that processes related to a massive dark matter halo must be dominant in the suppression of the SF below z ∼ 1, with respect to purely density-related processes. We confirm this finding by studying the distribution of galaxies in different environments with respect to the so-called main sequence (MS) of star-forming galaxies. Galaxies in both group and ‘filament-like’ environments preferentially lie below the MS up to z ∼ 1, with group galaxies exhibiting lower levels of star-forming activity at a given mass. At z > 1, the star-forming galaxies in groups reside on the MS. Groups exhibit the highest fraction of quiescent galaxies up to z ∼ 1, after which group, ‘filament-like’ and field environments have a similar mix of galaxy types. We conclude that groups are the most efficient locus for SF quenching. Thus, a fundamental difference exists between bound and unbound objects, or between dark matter haloes of different masses

Cancer microenvironment and endoplasmic reticulum stress response

Different stressful conditions such as hypoxia, nutrient deprivation, pH changes, or reduced vascularization, potentially able to act as growth-limiting factors for tumor cells, activate the unfolded protein response (UPR). UPR is therefore involved in tumor growth and adaptation to severe environments and is generally cytoprotective in cancer. The present review describes the molecular mechanisms underlying UPR and able to promote survival and proliferation in cancer. The critical role of UPR activation in tumor growth promotion is discussed in detail for a few paradigmatic tumors such as prostate cancer and melanoma

Lipid storage and autophagy in melanoma cancer cells

Cancer stem cells (CSC) represent a key cellular subpopulation controlling biological features such as cancer progression in all cancer types. By using melanospheres established from human melanoma patients, we compared less differentiated melanosphere-derived CSC to differentiating melanosphere-derived cells. Increased lipid uptake was found in melanosphere-derived CSC vs. differentiating melanosphere-derived cells, paralleled by strong expression of lipogenic factors Sterol Regulatory Element-Binding Protein-1 (SREBP-1) and Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ). An inverse relation between lipid-storing phenotype and autophagy was also found, since microtubule-associated protein 1A/1B-Light Chain 3 (LC3) lipidation is reduced in melanosphere-derived CSC. To investigate upstream autophagy regulators, Phospho-AMP activated Protein Kinase (P-AMPK) and Phospho-mammalian Target of Rapamycin (P-mTOR) were analyzed; lower P-AMPK and higher P-mTOR expression in melanosphere-derived CSC were found, thus explaining, at least in part, their lower autophagic activity. In addition, co-localization of LC3-stained autophagosome spots and perilipin-stained lipid droplets was demonstrated mainly in differentiating melanosphere-derived cells, further supporting the role of autophagy in lipid droplets clearance. The present manuscript demonstrates an inverse relationship between lipid-storing phenotype and melanoma stem cells differentiation, providing novel indications involving autophagy in melanoma stem cells biology

LoCuSS: Exploring the selection of faint blue background galaxies for cluster weak-lensing

Cosmological constraints from galaxy clusters rely on accurate measurements of the mass and internal structure of clusters. An important source of systematic uncertainty in cluster mass and structure measurements is the secure selection of background galaxies that are gravitationally lensed by clusters. This issue has been shown to be particular severe for faint blue galaxies. We therefore explore the selection of faint blue background galaxies, by reference to photometric redshift catalogs derived from the COSMOS survey and our own observations of massive galaxy clusters at z~0.2. We show that methods relying on photometric redshifts of galaxies in/behind clusters based on observations through five filters, and on deep 30-band COSMOS photometric redshifts are both inadequate to identify safely faint blue background galaxies. This is due to the small number of filters used by the former, and absence of massive galaxy clusters at redshifts of interest in the latter. We therefore develop a pragmatic method to combine both sets of photometric redshifts to select a population of blue galaxies based purely on photometric analysis. This sample yields stacked weak-lensing results consistent with our previously published results based on red galaxies. We also show that the stacked clustercentric number density profile of these faint blue galaxies is consistent with expectations from consideration of the lens magnification signal of the clusters. Indeed, the observed number density of blue background galaxies changes by ~10-30 per cent across the radial range over which other surveys assume it to be flat.Comment: submitted to MNRA

The adherent/invasive escherichia coli (AIEC) strain LF82 invades and persists in human prostate cell lineRWPE-1 activating a strong inflammatory response

Adherent/invasive Escherichia coli (AIEC) strains have recently been receiving increased attention because they are more prevalent and persistent in the intestine of Crohn's disease (CD) patients than in healthy subjects. Since AIEC strains show a high percentage of similarity to extraintestinal pathogenic E. coli (ExPEC), neonatal meningitis-associated E. coli (NMEC), and uropathogenic E. coli (UPEC) strains, here we compared AIEC strain LF82 with a UPEC isolate (strain EC73) to assess whether LF82 would be able to infect prostate cells as an extraintestinal target. The virulence phenotypes of both strains were determined by using the RWPE-1 prostate cell line. The results obtained indicated that LF82 and EC73 are able to adhere to, invade, and survive within prostate epithelial cells. Invasion was confirmed by immunofluorescence and electron microscopy. Moreover, cytochalasin D and colchicine strongly inhibited bacterial uptake of both strains, indicating the involvement of actin microfilaments and microtubules in host cell invasion. Moreover, both strains belong to phylogenetic group B2 and are strong biofilm producers. In silico analysis reveals that LF82 shares with UPEC strains several virulence factors: namely, type 1 pili, the group II capsule, the vacuolating autotransporter toxin, four iron uptake systems, and the pathogenic island (PAI). Furthermore, compared to EC73, LF82 induces in RWPE-1 cells a marked increase of phosphorylation of mitogen-activated protein kinases (MAPKs) and of NF-κB already by 5 min postinfection, thus inducing a strong inflammatory response. Our in vitro data support the hypothesis that AIEC strains might play a role in prostatitis, and, by exploiting host-cell signaling pathways controlling the innate immune response, likely facilitate bacterial multiplication and dissemination within the male genitourinary trac

The role of autophagy in liver epithelial cells and its Impact on systemic homeostasis

Autophagy plays a role in several physiological and pathological processes as it controls the turnover rate of cellular components and influences cellular homeostasis. The liver plays a central role in controlling organisms’ metabolism, regulating glucose storage, plasma proteins and bile synthesis and the removal of toxic substances. Liver functions are particularly sensitive to autophagy modulation. In this review we summarize studies investigating how autophagy influences the hepatic metabolism, focusing on fat accumulation and lipids turnover. We also describe how autophagy affects bile production and the scavenger function within the complex homeostasis of the liver. We underline the role of hepatic autophagy in counteracting the metabolic syndrome and the associated cardiovascular risk. Finally, we highlight recent reports demonstrating how the autophagy occurring within the liver may affect skeletal muscle homeostasis as well as different extrahepatic solid tumors, such as melanoma

Robots for Exploration, Digital Preservation and Visualization of Archeological Sites

Monitoring and conservation of archaeological sites are important activities necessary to prevent damage or to perform restoration on cultural heritage. Standard techniques, like mapping and digitizing, are typically used to document the status of such sites. While these task are normally accomplished manually by humans, this is not possible when dealing with hard-to-access areas. For example, due to the possibility of structural collapses, underground tunnels like catacombs are considered highly unstable environments. Moreover, they are full of radioactive gas radon that limits the presence of people only for few minutes. The progress recently made in the artificial intelligence and robotics field opened new possibilities for mobile robots to be used in locations where humans are not allowed to enter. The ROVINA project aims at developing autonomous mobile robots to make faster, cheaper and safer the monitoring of archaeological sites. ROVINA will be evaluated on the catacombs of Priscilla (in Rome) and S. Gennaro (in Naples)