Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER+ breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context

Occurrence of proteinaceous moieties in S-and O-rich Late Tithonian kerogen (Kashpir oil Shales, Russia)

Abstract The polar fraction, isolated from the o-line pyrolysate at 400 C of a Late Tithonian, sulphur-and oxygen-rich, kerogen was examined via Raney Nickel desulphurization and TMAH thermochemolysis. Important information on this kerogen, not accessible via conventional pyrolysis, was thus obtained: (i) its structure is not simply based on alkyl skeletons cross-linked by ether and (poly)sulphide bridges, (ii) TMAH thermochemolysis aorded direct evidence of the survival of proteinaceous moieties in this 140 million years old kerogen and (iii) encapsulation within an aliphatic organic matrix was probably the main pathway reponsible for such a conspicuous preservation, also possibly favoured by the presence of numerous sulphur links.

Delivery of Complex Organic Compounds from Evolved Stars to the Solar System

Stars in the late stages of evolution are able to synthesize complex organic compounds with aromatic and aliphatic structures over very short time scales. These compounds are ejected into the interstellar medium and distributed throughout the Galaxy. The structures of these compounds are similar to the insoluble organic matter found in meteorites. In this paper, we discuss to what extent stellar organics has enriched the primordial Solar System and possibly the early Earth

Aquatic Organic Matter in the Seine Basin: Sources, Spatio-Temporal Variability, Impact of Urban Discharges and Influence on Micro-pollutant Speciation

International audienc

New insights into the structure and chemistry of Titan's tholins via C-13 and N-15 solid state nuclear magnetic resonance spectroscopy

Tholins are complex C,N-containing organic compounds produced in the laboratory. They are considered to provide materials that are analogous to those responsible for the haze observed in Titan’s atmosphere. These compounds present an astrobiological interest due to their ability to release amino acids upon hydrolysis. Their chemical structure has been investigated using a large number of techniques. However, to date no detailed nuclear magnetic resonance (NMR) study has been performed on these materials despite the high potential of this technique for investigating the environment of given nuclei. Here 13C and 15N solid state NMR spectroscopy was applied to obtain new insights into the chemical structure of tholins produced through plasma discharge in gaseous N2single bondCH4 mixtures designed to simulate the atmosphere of Titan. Due to the low natural abundance of these isotopes, a 13C and 15N-enriched tholin sample was synthesized using isotopically enriched gas precursors. Various pulse sequences including 13C and 15N single pulse, 1Hsingle bond13C and 1Hsingle bond15N cross-polarisation and 1Hsingle bond15Nsingle bond13C double cross-polarisation were used. These techniques allowed complete characterisation of the chemical and structural environments of the carbon and nitrogen atoms. The NMR assignments were supplemented and confirmed by ab initio electronic structure calculations for model structures and molecular fragments

Development of global temperature and pH calibrations based on bacterial 3-hydroxy fatty acids in soils

Gram-negative bacteria produce specific membrane lipids, i.e. 3-hydroxy fatty acids with 10 to 18 C atoms. They have been recently proposed as temperature and pH proxies in terrestrial settings. Nevertheless, the existing correlations between pH or temperature and indices derived from 3-OH FA distribution are based on a small soil dataset (ca. 70 samples) and only applicable regionally. The aim of this study was to investigate the applicability of 3-OH FAs as mean annual air temperature (MAAT) and pH proxies at the global level. This was achieved using an extended soil dataset of 168 topsoils distributed worldwide, covering a wide range of temperatures (5 to 30 ∘C) and pH (3 to 8). The response of 3-OH FAs to temperature and pH was compared to that of established branched glycerol dialkyl glycerol tetraether (GDGT)-based proxies (MBT'5Me/CBT). Strong linear relationships between 3-OH-FA-derived indices (RAN15, RAN17 and RIAN) and MAAT or pH could only be obtained locally for some of the individual transects. This suggests that these indices cannot be used as palaeoproxies at the global scale using simple linear regression models, in contrast with the MBT'5Me and CBT. However, strong global correlations between 3-OH FA relative abundances and MAAT or pH were shown by using other algorithms (multiple linear regression, k-NN and random forest models). The applicability of the three aforementioned models for palaeotemperature reconstruction was tested and compared with the MAAT record from a Chinese speleothem. The calibration based on the random forest model appeared to be the most robust. It generally showed similar trends with previously available records and highlighted known climatic events poorly visible when using local 3-OH FA calibrations. Altogether, these results demonstrate the potential of 3-OH FAs as palaeoproxies in terrestrial settings

Orthorexic tendencies are linked with difficulties with emotion identification and regulation.

Background: Orthorexia nervosa (ON) is characterised by an unhealthy obsession with healthy eating and while it is not recognised as an eating disorder (or any disorder), current research is exploring similarities and differences with such disorders. The literature has shown that individuals with eating disorders have difficulties identifying and describing emotions (known as alexithymia) as well as regulating them. However no research to date has looked at whether people with orthorexic tendencies also suffer from difficulties with emotions. In this paper, we refer to people with orthorexic tendencies but do not assume that their healthy eating is at a pathological level needing clinical attention. Methods: The current study examined this by asking 196 healthy adults with an interest in healthy eating to complete four questionnaires to measure ON (ORTO-15 - reduced to ORTO-7CS), eating psychopathology (EAT-26), alexithymia (TAS-20) and emotion dysregulation (DERS-16). Results: We found that difficulties identifying and regulating emotions was associated with symptoms of ON, similar to what is found in other eating disorders. We suggest that ON behaviours may be used as a coping strategy in order to feel in control in these participants who have poor emotion regulation abilities. Conclusions: Our results show that individuals with ON tendencies may share similar difficulties with emotions compared to other eating disorders. While important, our results are limited by the way we measured ON behaviours and we recommend that further research replicate our findings once a better and more specific tool is developed and validated to screen for ON characteristics more accurately

Invasive pulmonary aspergillosis in patients with decompensated cirrhosis: case series

BACKGROUND: Opportunistic invasive fungal infections are increasingly frequent in intensive care patients. Their clinical spectrum goes beyond the patients with malignancies, and for example invasive pulmonary aspergillosis has recently been described in critically ill patients without such condition. Liver failure has been suspected to be a risk factor for aspergillosis. CASE PRESENTATION: We describe three cases of adult respiratory distress syndrome with sepsis, shock and multiple organ failure in patients with severe liver failure among whom two had positive Aspergillus antigenemia and one had a positive Aspergillus serology. In all cases bronchoalveolar lavage fluid was positive for Aspergillus fumigatus. Outcome was fatal in all cases despite treatment with voriconazole and agressive symptomatic treatment. CONCLUSION: Invasive aspergillosis should be among rapidly raised hypothesis in cirrhotic patients developing acute respiratory symptoms and alveolar opacities