Hydrogen and carbon derived from disolved H2O and CO2 in minerals and melts

A detailed evaluation of the dissolution, mechanism of water and carbon dioxide in nominally anhydrous and carbonate-free minerals leads to a number of consequences which appear important for the petrology of mantle-derived rocks and their melting behavior in the presence of fluids. (1) The dissolution of water leads to the formation of OH- which may react to form molecular H2, O- and eventually peroxy anions, O22-. (2) The molecular hydrogen (see pt. 1) may escape, resulting in a system stoichiometrically enriched in oxygen, which may exsolve at certain well-defined temperatures as molecular O2. (3) Dissolved carbon dioxide may form carbonate ions, CO32-, but — more important — it dissociates to form very mobile "atomic" C and O-. The C atoms are bonded to either two or one O- as CO22- or CO-. (4) Strains induced by the dipolar species CO2 and CO- (see pl. 3) may lead to defect ordering which causes otherwise non-ferroelectric minerals to become ferroelectric. (5) Applied non-uniform stress will cause a diffusion flux of the dissolved carbon (see pt. 3), which may be fast, carrying carbon over geologically significant distances. (6) The experimentally observable CO2 evolution from heated silicate minerals is not a proof of an initial presence of CO22-, because C02 also evolves from CO3-2, the atomically dissolved carbon. (7) The dissolution of CO2 in solid silicates proceeds via chemisorption even at P = 1 bar and room temperature. Hence, the solid rock reservoir of the Earth may contribute to buffering the CO2 partial pressure of the atmosphere. (8) Reaction of dissolved "atomic" C with cations, hydrogen and lattice oxygen may lead to metallo-organic compounds. (9) Hydrocarbons, considerably mor complex than methane, are formed at fractured crystal surfaces as a result of the reactions of dissolved "atomic" C with H2 (see pl. 1). (10) Nitrogen may also be dissolved in silicate minerals. Upon heating it exsolves as N2 or react with "atomic" C, H2 and O- to give amino compounds. A quantitative assessment of the local strains associated with dissolved carbon species, with molecular hydrogen and the peroxy anions will allow us to calculate the solubility difference for CO2 and H2O in solids and melts.Un examen détaillé des mécanismes de dissolution de l'eau et du CO2 dans des minéraux nominalement anhydres et exempts de carbonates conduit à diverses conséquences qui paraissent importantes pour la pétrologie des roches originaires du manteau et leur fusion en présence de fluides. (1) La dissolution d'eau conduit à la formation de OH- qui peuvent réagir pour former de l'H2 moléculaire, O- et en fin de compte des cuivres peroxydes O22-. (2) L'hydrogène moléculaire (voir le point 1) peut s'échapper, laissant un système stoéchiométriquement enrichi en oxygène, qui peut se dégager à certaines températures bien définies sous forme de O2 moléculaire. (3) Le CO2 dissous peut former des ions carbonates, CO22-, mais, et de manière plus importante, il se dissocie pour former O- et du carbone "atomique" C très mobile. Les atomes de C sont liés à un ou deux O- sous forme de CO22- ou CO-. (4) Les déformations induites par les espèces dipolaires CO22- et CO- (voir le point 3) peuvent conduire à des défauts semblables à ceux qui provoquent la transition ferro-électrique - non-ferroélectrique des minéraux. (5) L'application de contraintes non uniformes cause un flux de diffusion du carbone dissous (voir le point 3), qui peut être rapide, transportant le carbone sur des distances importantes. (6) Le dégagement observé de CO2 d'un minéral silicaté chauffé n'est pas la preuve de la présence initiale de CO32-, parce que du CO2 se dégage aussi à partir de CO32-, le carbone atomique dissous. (7) La dissolution de CO2 dans des silicates solides se produit par chimisorption même à P = 1 bar et à température ambiante. Ainsi, les roches terrestres contribuent à tamponner la pression partielle de CO2 de l'atmosphère. (8) La réaction du carbone "atomique" dissous C avec des cations, de l'hydrogène ou de l'oxygène du réseau peut conduire à des composés métallo-organiques. (9) Des hydrocarbures, considérablement plus complexes que le méthane, sont formés sur les surfaces de fracture des minéraux, à la suite des réactions du carbone atomique dissous avec H2 (voir le point 1). (10) L'azote peut également être dissous dans les minéraux silicatés. Lors d'un chauffage, il se dégage sous forme de N2 ou réagit avec le C "atomique", H2 et O- pour donner des composés aminés. Une évaluation quantitative des déformations locales associées aux espèces de carbone dissoutes, à l'hydrogène moléculaire et aux anions peroxydes nous permettront de calculer les différences de solubilité du CO2 et de H2O dans les minéraux et les liquides.Freund Friedemann, Wengeler Heinz, Kathrein Hendrik, Knobel Rolf, Oberheuser Gert, Maiti Gobinda C., Reil Dieter, Knipping Uwe, Kötz Jürgen. Hydrogen and carbon derived from disolved H2O and CO2 in minerals and melts. In: Bulletin de Minéralogie, volume 106, 1-2, 1983. Silicates liquides

Whole genome RNAi screens reveal a critical role of REV3 in coping with replication stress

REV3, the catalytic subunit of translesion polymerase zeta (polζ), is commonly associated with DNA damage bypass and repair. Despite sharing accessory subunits with replicative polymerase δ, very little is known about the role of polζ in DNA replication. We previously demonstrated that inhibition of REV3 expression induces persistent DNA damage and growth arrest in cancer cells. To reveal determinants of this sensitivity and obtain insights into the cellular function of REV3, we performed whole human genome RNAi library screens aimed at identification of synthetic lethal interactions with REV3 in A549 lung cancer cells. The top confirmed hit was RRM1, the large subunit of ribonucleotide reductase (RNR), a critical enzyme of de novo nucleotide synthesis. Treatment with the RNR-inhibitor hydroxyurea (HU) synergistically increased the fraction of REV3-deficient cells containing single stranded DNA (ssDNA) as indicated by an increase in replication protein A (RPA). However, this increase was not accompanied by accumulation of the DNA damage marker γH2AX suggesting a role of REV3 in counteracting HU-induced replication stress (RS). Consistent with a role of REV3 in DNA replication, increased RPA staining was confined to HU-treated S-phase cells. Additionally, we found genes related to RS to be significantly enriched among the top hits of the synthetic sickness/lethality (SSL) screen further corroborating the importance of REV3 for DNA replication under conditions of RS

Inhibition of REV3 Expression Induces Persistent DNA Damage and Growth Arrest in Cancer Cells12

REV3 is the catalytic subunit of DNA translesion synthesis polymerase ζ. Inhibition of REV3 expression increases the sensitivity of human cells to a variety of DNA-damaging agents and reduces the formation of resistant cells. Surprisingly, we found that short hairpin RNA-mediated depletion of REV3 per se suppresses colony formation of lung (A549, Calu-3), breast (MCF-7, MDA-MB-231), mesothelioma (IL45 and ZL55), and colon (HCT116 +/-p53) tumor cell lines, whereas control cell lines (AD293, LP9-hTERT) and the normal mesothelial primary culture (SDM104) are less affected. Inhibition of REV3 expression in cancer cells leads to an accumulation of persistent DNA damage as indicated by an increase in phospho-ATM, 53BP1, and phospho-H2AX foci formation, subsequently leading to the activation of the ATM-dependent DNA damage response cascade. REV3 depletion in p53-proficient cancer cell lines results in a G1 arrest and induction of senescence as indicated by the accumulation of p21 and an increase in senescence-associated β-galactosidase activity. In contrast, inhibition of REV3 expression in p53-deficient cells results in growth inhibition and a G2/M arrest. A small fraction of the p53-deficient cancer cells can overcome the G2/M arrest, which results in mitotic slippage and aneuploidy. Our findings reveal that REV3 depletion per se suppresses growth of cancer cell lines from different origin, whereas control cell lines and a mesothelial primary culture were less affected. Thus, our findings indicate that depletion of REV3 not only can amend cisplatin-based cancer therapy but also can be applied for susceptible cancers as a potential monotherapy

Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

BACKGROUND: Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP) is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. METHODS: The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. RESULTS: We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the animals with lung carcinoma xenografts. CONCLUSION: In normal cells, serum starvation in vitro induces a cell cycle arrest and protects from CDDP induced toxicity. In contrast, proliferation of cancer cells is only moderately reduced by serum starvation whereas CDDP toxicity is enhanced. The combination of CDDP treatment with short term food starvation improved outcome in vivo. Therefore, starvation has the potential to enhance the therapeutic index of cisplatin-based therapy

Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring

BACKGROUND Serum biomarkers can improve diagnosis and treatment of malignant pleural mesothelioma (MPM). However, the evaluation of potential new serum biomarker candidates is hampered by a lack of assay technologies for their clinical evaluation. Here we followed a hypothesis-driven targeted proteomics strategy for the identification and clinical evaluation of MPM candidate biomarkers in serum of patient cohorts. RESULTS Based on the hypothesis that cell surface exposed glycoproteins are prone to be released from tumor-cells to the circulatory system, we screened the surfaceome of model cell lines for potential MPM candidate biomarkers. Selected Reaction Monitoring (SRM) assay technology allowed for the direct evaluation of the newly identified candidates in serum. Our evaluation of 51 candidate biomarkers in the context of a training and an independent validation set revealed a reproducible glycopeptide signature of MPM in serum which complemented the MPM biomarker mesothelin. CONCLUSIONS Our study shows that SRM assay technology enables the direct clinical evaluation of protein-derived candidate biomarker panels for which clinically reliable ELISA's currently do not exist