Thermodynamic energetics underlying genomic instability and whole-genome doubling in cancer.

Genomic instability contributes to tumorigenesis through the amplification and deletion of cancer driver genes. DNA copy number (CN) profiling of ensembles of tumors allows a thermodynamic analysis of the profile for each tumor. The free energy of the distribution of CNs is found to be a monotonically increasing function of the average chromosomal ploidy. The dependence is universal across several cancer types. Surprisal analysis distinguishes two main known subgroups: tumors with cells that have or have not undergone whole-genome duplication (WGD). The analysis uncovers that CN states having a narrower distribution are energetically more favorable toward the WGD transition. Surprisal analysis also determines the deviations from a fully stable-state distribution. These deviations reflect constraints imposed by tumor fitness selection pressures. The results point to CN changes that are more common in high-ploidy tumors and thus support altered selection pressures upon WGD.

Intracellular redox potential is correlated with miRNA expression in MCF7 cells under hypoxic conditions.

Hypoxia is a ubiquitous feature of cancers, encouraging glycolytic metabolism, proliferation, and resistance to therapy. Nonetheless, hypoxia is a poorly defined term with confounding features described in the literature. Redox biology provides an important link between the external cellular microenvironment and the cell's response to changing oxygen pressures. In this paper, we demonstrate a correlation between intracellular redox potential (measured using optical nanosensors) and the concentrations of microRNAs (miRNAs) involved in the cell's response to changes in oxygen pressure. The correlations were established using surprisal analysis (an approach derived from thermodynamics and information theory). We found that measured redox potential changes reflect changes in the free energy computed by surprisal analysis of miRNAs. Furthermore, surprisal analysis identified groups of miRNAs, functionally related to changes in proliferation and metastatic potential that played the most significant role in the cell's response to changing oxygen pressure.

Gas-Phase Photoluminescence and Photodissociation of Silver-Capped Hexagold Clusters.

We report on the radiative and nonradiative deactivation pathways of selected charge states of the stoichiometric hexagold phosphine-stabilized ionic clusters, [(C)(AuDppy)6Ag2·(BF4) x](4- x)+ with x = 2 and 3 (Dppy = diphenylphosphino-2-pyridine), combining gas-phase photoluminescence and photodissociation with quantum chemical computations. These clusters possess an identical isostructural core made of a hyper-coordinated carbon at their center octahedrally surrounded by six gold ions, and two silver ions at their apexes. Their luminescence and fragmentation behavior upon photoexcitation was investigated under mass and charge control in an ion trap. The experimental and computational results shed light on the electronic states involved in the optical transitions as well as on their core, ligand, or charge transfer character. Gas-phase results are discussed in relation with condensed phase measurements, as well as previous observations in solution and on metal-organic frameworks. The monocationic species ( x = 3) is found to be less stable than the dicationic one ( x = 2). In the luminescence spectrum of the monocationic species, a shoulder at short wavelength can be observed and is assigned to fragment emission. This fragment formation appears to be favored for the monocation by the existence of a low lying singlet state energetically overlapping with the triplet state manifold, which is populated quickly after photoexcitation.

[Prediction of the molecular response to pertubations from single cell measurements]. / Prédiction de la réponse moléculaire à des perturbations mesurée sur des cellules uniques.

The response of protein signalization networks to perturbations is analysed from single cell measurements. This experimental approach allows characterizing the fluctuations in protein expression levels from cell to cell. The analysis is based on an information theoretic approach grounded in thermodynamics leading to a quantitative version of Le Chatelier principle which allows to predict the molecular response. Two systems are investigated: human macrophages subjected to lipopolysaccharide challenge, analogous to the immune response against Gram-negative bacteria and the response of the proteins involved in the mTOR signalizing network of GBM cancer cells to changes in partial oxygen pressure.

Surprisal analysis of Glioblastoma Multiform (GBM) microRNA dynamics unveils tumor specific phenotype.

Gliomablastoma multiform (GBM) is the most fatal form of all brain cancers in humans. Currently there are limited diagnostic tools for GBM detection. Here, we applied surprisal analysis, a theory grounded in thermodynamics, to unveil how biomolecule energetics, specifically a redistribution of free energy amongst microRNAs (miRNAs), results in a system deviating from a non-cancer state to the GBM cancer -specific phenotypic state. Utilizing global miRNA microarray expression data of normal and GBM patients tumors, surprisal analysis characterizes a miRNA system response capable of distinguishing GBM samples from normal tissue biopsy samples. We indicate that the miRNAs contributing to this system behavior is a disease phenotypic state specific to GBM and is therefore a unique GBM-specific thermodynamic signature. MiRNAs implicated in the regulation of stochastic signaling processes crucial in the hallmarks of human cancer, dominate this GBM-cancer phenotypic state. With this theory, we were able to distinguish with high fidelity GBM patients solely by monitoring the dynamics of miRNAs present in patients' biopsy samples. We anticipate that the GBM-specific thermodynamic signature will provide a critical translational tool in better characterizing cancer types and in the development of future therapeutics for GBM.

Glioblastoma cellular architectures are predicted through the characterization of two-cell interactions.

To understand how pairwise cellular interactions influence cellular architectures, we measured the levels of functional proteins associated with EGF receptor (EGFR) signaling in pairs of U87EGFR variant III oncogene receptor cells (U87EGFRvIII) at varying cell separations. Using a thermodynamics-derived approach we analyzed the cell-separation dependence of the signaling stability, and identified that the stable steady state of EGFR signaling exists when two U87EGFRvIII cells are separated by 80-100 µm. This distance range was verified as the characteristic intercellular separation within bulk cell cultures. EGFR protein network signaling coordination for the U87EGFRvIII system was lowest at the stable state and most similar to isolated cell signaling. Measurements of cultures of less tumorigenic U87PTEN cells were then used to correctly predict that stable EGFR signaling occurs for those cells at smaller cell-cell separations. The intimate relationship between functional protein levels and cellular architectures explains the scattered nature of U87EGFRvIII cells relative to U87PTEN cells in glioblastoma multiforme tumors.

Hypoxia induces a phase transition within a kinase signaling network in cancer cells.

Hypoxia is a near-universal feature of cancer, promoting glycolysis, cellular proliferation, and angiogenesis. The molecular mechanisms of hypoxic signaling have been intensively studied, but the impact of changes in oxygen partial pressure (pO2) on the state of signaling networks is less clear. In a glioblastoma multiforme (GBM) cancer cell model, we examined the response of signaling networks to targeted pathway inhibition between 21% and 1% pO2. We used a microchip technology that facilitates quantification of a panel of functional proteins from statistical numbers of single cells. We find that near 1.5% pO2, the signaling network associated with mammalian target of rapamycin (mTOR) complex 1 (mTORC1)--a critical component of hypoxic signaling and a compelling cancer drug target--is deregulated in a manner such that it will be unresponsive to mTOR kinase inhibitors near 1.5% pO2, but will respond at higher or lower pO2 values. These predictions were validated through experiments on bulk GBM cell line cultures and on neurosphere cultures of a human-origin GBM xenograft tumor. We attempt to understand this behavior through the use of a quantitative version of Le Chatelier's principle, as well as through a steady-state kinetic model of protein interactions, both of which indicate that hypoxia can influence mTORC1 signaling as a switch. The Le Chatelier approach also indicates that this switch may be thought of as a type of phase transition. Our analysis indicates that certain biologically complex cell behaviors may be understood using fundamental, thermodynamics-motivated principles.

Gas phase fullerene anions hydrogenation by methanol followed by IRMPA dehydrogenation.

The characterization in the gas phase of the mechanisms responsible for hydride formation can contribute to the development of new materials for hydrogen storage. The present work provides evidence of a hydrogenation-dehydrogenation catalytic cycle for C(60)(*-) anions in the gas phase using methanol vapor at room temperature as hydrogen donor. The involvement of methanol in the reaction is confirmed by experiments using CD(3)OD and CD(3)OH. C(60) hydride anions with up to 11 hydrogen atoms are identified via elemental composition analysis using FT-ICR mass spectrometry. For the longer reaction times, partial conversion of the C(60) hydride ions into oxygen containing ion products occurs. Dehydrogenation using infrared multiphoton activation with a CO(2) laser restores the C(60)(*-) anions.

Combined Mössbauer spectral and density functional theory determination of the magnetic easy-axis in two high-spin iron(II) 2-pyrazinecarboxylate complexes.

A combination of density functional theory (DFT) calculations and Mössbauer spectroscopy has been used to determine that the magnetic easy-axis is coincident with its crystallographic c-axis in [Fe(pca)(2)(py)(2)] x py, where pac is the 2-pyrazinecarboxylate ligand. This easy-axis bisects the approximately axial O-Fe-O coordination axes of molecules adjacent to each other along the b-axis. In {[Fe(pca)(2)(H(2)O)] x H(2)O}(n) the easy magnetic axis is not coincident with any of its crystallographic axes nor with the Fe-O(water) coordination axis, but is coincident with one of the Fe...Fe axes in the crystal structure. The DFT calculations, which use the B3LYP functional and the 6-311++G(d,p) basis set, yield s-electron probability densities and electric field gradient tensors for the iron(II) ion that are in excellent agreement with the observed iron-57 Mössbauer spectral isomer shifts and quadrupole interactions. The gas phase results are very similar for calculations based either on the X-ray structures of the two complexes or on their optimized structures; the optimized structures indicate that the iron to ligand bond distances increase in the absence of any solid-state lattice interactions. The results of a normal coordinate vibrational mode analysis of the two optimized structures are compared with the observed infrared spectra.

A density functional theory calculation of the electronic properties of several high-spin and low-spin iron(II) pyrazolylborate complexes.

Density functional theory has been used to study the electronic spin-state properties of low-spin Fe[HB(pz)3]2, high-spin Fe[HB(3-Mepz)3]2, high-spin Fe[HB(3,5-Me 2pz)3]2, and high-spin Fe[HB(3,4,5-Me 3pz)3]2 complexes that exhibit very different iron(II) electronic spin-sate crossover behaviors with changing temperature and pressure. Excellent agreement is obtained between the experimentally observed Mössbauer-effect quadrupole splittings and isomer shifts of these complexes and those calculated with the B3LYP functional and various different basis sets for both the high-spin and low-spin states of iron(II). The calculations for Fe[HB(pz)3]2 that use the LANL2DZ, 6-31++G(d,p), and 6-311++G(d,p) basis sets for iron all lead to very similar electric field gradients and thus quadrupole splittings. The initial calculations, which were based upon the known X-ray structures, were followed by structural optimization, an optimization that led to small increases in the Fe-N bond distances. Optimization led to at most trivial changes in the intraligand bond distances and angles. The importance of the 3-methyl-H...H-3-methyl nonbonded intramolecular interligand interactions in controlling the minimum Fe-N bond distances and determining the iron(II) spin state both in Fe[HB(3-Mepz)3]2 and in the related methyl-substituted complexes has been identified.