The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

Tumour drug-resistant ABCB1 gene expression is regulated at the chromatin level through epigenetic mechanisms. We examined the effects of the histone deacetylase inhibitor trichostatin A (TSA) on ABCB1 gene expression in small cell lung carcinoma (SCLC) drug-sensitive (H69WT) or etoposide-resistant (H69VP) cells. We found that TSA induced an increase in ABCB1 expression in drug-sensitive cells, but strongly decreased it in drug-resistant cells. These up- and downregulations occurred at the transcriptional level. Protein synthesis inhibition reduced these modulations, but did not completely suppress them. Differential temporal patterns of histone acetylation were observed at the ABCB1 promoter: increase in H4 acetylation in both cell lines, but different H3 acetylation with a progressive increase in H69WT cells but a transient one in H69VP cells. ABCB1 regulations were not related with the methylation status of the promoter −50GC, −110GC, and Inr sites, and did not result in further changes to these methylation profiles. Trichostatin A treatment did not modify MBD1 binding to the ABCB1 promoter and similarly increased PCAF binding in both H69 cell lines. Our results suggest that in H69 drug-resistant SCLC cell line TSA induces downregulation of ABCB1 expression through a transcriptional mechanism, independently of promoter methylation, and MBD1 or PCAF recruitment

Relative thermodynamic stability of the [C,N,O] linkages as an indication of the most abundant structures in the ISM

Context. Most of the compounds detected in the interstellar medium (ISM) that possess isomers correspond to the thermodynamically most stable isomer of a given chemical formula. Using the minimun energy principle (MEP) as a pragmatic tool is particularly efficient for less than six atoms, but for larger systems combinatorial analysis gives an intractable numbers of isomers. Aims. To make the MEP more applicable, we look for a chemical sieve to filter the thermodynamic data needed to determine which isomers of complex organic molecules (COMs) have higher chances of being present in the ISM. To do so, we investigate whether the nature of the [C,N,O] elementary fragment can be determinant for the stabilization of COMs, taking C2H3NO as a case study. Methods. We employed standard quantum chemistry methods to determine the ordering of fragments and derivatives on the energy scale. Density functional theory treatments were systematically performed, together with high-level coupled cluster calculations to refine relative energies. Results. For C2H3NO we find methylisocyanate CH3NCO, which is a compound that was very recently detected in the ISM, to be the most stable isomer in a corpus of 40 isomers of lowest energy. In neutral form we find the stability ordering of NCO > ONC; the same is true for the negative ion. Attachments of R=H, CH3, C2H5, HC2, H2CCH, and C6H5 and metals Al and Mg to the nitrogen atom of the NCO fragment provide the most stable isomers. The energy differences between the successive isomers on the energy scale R-NCO, R-OCN, R-CNO, and R-ONC are of the same order of magnitude for all carbonaceous R. Conclusions. Combining the criterion of most stable linkage with the MEP concept should greatly reduce the window of potential targets to be searched for in the ISM. Compounds containing the NCO linkage should be preferential targets of future research

About the detection of urea in the interstellar medium: the energetic aspect

Context. The results of an observational search for gas phase urea, (NH2)2CO toward the Sgr B2-LMH region, have been reported recently. In spite of strong presumptions, whether it is urea or another species (for example an isomer) seems to remain a pending question. Aims. In this note, we consider the energetic aspect of this would-be detection by addressing the relative stabilities of the 22 isomers that can possibly be formed with the CH4N2O set of atoms. By extension, we also consider the 22 sulphur analogues of CH4N2S chemical formula. Methods. The question was first addressed by means of quantum density functional theory (DFT) simulations. The hybrid B3LYP functional was used throughout. The geometries of the 44 molecules part of this survey were fully optimized and verified to be real minima by vibrational analysis. The lowest isomers found this way were then reconsidered in higher level post Hartree-Fock MP2 and coupled cluster CCSD and CCSD(T) calculations to derive more accurate energy differences and dipole moments, whose knowledge is crucial for interpreting micro- and millimetre-wave spectra. Results. We found that urea and thio-urea are the most stable compounds in their respective families. The closest isomers on the energy scale are the iminol tautomeric forms, HN=COH-NH2 and HN=CSH-NH2, whose rotational constants and dipole moments have also been determined. Conclusions. That urea is the lowest energy isomer possibly formed is a strong argument making the detection of this species more than probable. After formamide and acetamide, this result confirms the greatest stability of the -[NH-C=O]- linkage, underlining the interest of the minimum energy criterion as a tool for the primary search of target molecules. Additionally, thio-urea should the analogue to search for

Helium isotope in the accreted ice of subglacial lake Vostok (Antarctica)

Goldschmidt 2010: Earth, Energy, and the Environment Knoxville Tennessee, USAInternational audienc

Métrologie du tritium dans différentes matrices: cas du tritium organiquement lié (TOL)

International audienceThe measurement of tritium in its various forms (mainly gas (HT), water (HTO) or solid (hydrides)), is an important key step for evaluating health and environmental risks and finally, dosimetry assessment. In vegetable or animal samples, tritium is often associated with the free water fraction, but may be included in the organic form as organically bound tritium (OBT). In this case, 2 forms exist: (i) a fraction called exchangeable or labile (E-OBT), bound to oxygen and nitrogen atoms, and (ii) a so-called non-exchangeable fraction (NE-OBT) bound to carbon atoms. The main technique for tritium analysis is liquid scintillation, which enables one to measure concentrations in the range of several Bq.L-1. The standards (AFNOR, ISO) published to date relate only to tritium analysis in water. Only one CETAMA method addresses OBT analysis in biological environments. This method has been tested since 2001 through intercomparison circuits on grass samples collected from the environment. Regarding tritium analysis in water, the strengths are reliability of this analysis at low concentrations (order of Bq.L-1), robustness and simplicity, and weaknesses are linked to problems of background, conservation and contamination of samples. Concerning OBT analysis, the analysis is reliable for values around 50 Bq.kg-1 of fresh sample. The weaknesses are problems of contamination, reproducibility, analysis time (2 to 6 days) and lack of reference materials. The difficulty to date is the separation between E-OBT and NE-OBT, that will need experimental validation. © 2010 EDP Sciences.La mesure du tritium sous ses différentes formes (gaz (HT), eau (HTO), ou solide (hydrures)), est une étape importante pour l’évaluation des risques sanitaires et environnementaux associés et in fine son estimation dosimétrique. Dans les échantillons du règne végétal ou animal, le tritium est associé à la fraction eau libre et est inclus dans les composés organiques sous forme de tritium organiquement lié (TOL). Dans ce cas, 2 formes existent : (i) la fraction dite échangeable ou labile (TOL-E) liée à des atomes d’oxygène et d’azote ; (ii) la fraction dite non échangeable (TOL-NE) liée aux atomes de carbones. La technique de référence pour l’analyse du tritium est la scintillation liquide permettant de mesurer des concentrations de l’ordre de quelques Bq.L-1. Les normes (AFNOR, ISO) publiées à ce jour ne concernent que l’analyse du tritium dans l’eau. Seule une méthode CETAMA aborde la mesure du TOL dans des milieux biologiques. Cette méthode a été testée depuis 2001 via des circuits d’intercomparaisons sur des échantillons d’herbe prélevés dans l’environnement. Concernant l’analyse du tritium dans les eaux, les principaux points forts sont la fiabilité de cette analyse pour des concentrations de l’ordre de 1 Bq.L-1, la robustesse et la simplicité de mise en œuvre. Les points faibles sont essentiellement liés à des problèmes de bruit de fond, de conservation et de contamination des échantillons. Concernant l’analyse du TOL, l’analyse est fiable pour des valeurs de l’ordre de 50 Bq.kg-1 d’échantillon frais. Les points faibles sont des problèmes de contamination, de reproductibilité, de temps d’analyse (2 à 6 jours) et l’absence de matériaux de référence. La difficulté à ce jour est la séparation entre TOL-E et TOL-NE qui doit être validée expérimentalement

Distribuição do tempo de residência em um grande aquífero livre–semiconfinado nos Pampas Argentinos usando traçadores 3H/3He e CFC

International audienc