Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma

Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer overall prognosis. Among patients that recurred, we found the correlation of greater modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients' survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.Comment: 32 pages, 6 figure

Fe(I)-Mediated Reductive Cleavage and Coupling of CO_2: An Fe^(II)(μ-O,μ-CO)Fe^(II) Core

THF solutions of a new iron(I) source, [PhBP^(CH2_Cy_3)]Fe ([PhBP^(CH_2Cy_3)] = [PhBP(CH_2P(CH_2Cy)_2)_3]-), effect the reductive cleavage of CO_2 via O-atom transfer at ambient temperature. The dominant reaction pathway is bimetallic and leads to the formation of a structurally unprecedented diiron Fe^(II)(μ-O)(μ-CO)Fe^(II) core. X-ray data are also available to suggest that bimetallic reductive CO_2 coupling to generate oxalate occurs as a minor reaction pathway. These initial observations forecast a diverse reaction landscape between CO_2 and iron(I) synthons

CO_2 reduction by Fe(I): solvent control of C-O cleavage versus C-C coupling

This manuscript explores the product distribution of the reaction of carbon dioxide with reactive iron(I) complexes supported by tris(phosphino)borate ligands, [PhBP^R_3]- ([PhBP^R_3]- =[PhB(CH_2PR_2)_3]-; R = CH_2Cy,Ph, ^iPr, mter; mter = 3,5-meta-terphenyl). Our studies reveal an interesting and unexpected role for the solvent medium with respect to the course of the CO_2 activation reaction. For instance, exposure of methylcyclohexane (MeCy) solutions of [PhBP^(CH_2Cy)_3 ]Fe(PR’_3) to CO_2 yields the partial decarbonylation product {[PhBP^(CH_2Cy)_3 ]Fe}_2(µ-O)(µ-CO). When the reaction is instead carried out in benzene or THF, reductive coupling of CO_2 occurs to give the bridging oxalate species {[PhBP^(CH_2Cy_3 ]Fe}_2(µ- κOO’: κOO’-oxalato). Reaction studies aimed at understanding this solvent effect are presented, and suggest that the product profile is ultimately determined by the ability of the solvent to coordinate the iron center. When more sterically encumbering auxiliary ligands are employed to support the iron(I) center (i.e., [PhBP^(Ph)_3]- and [PhBP^(iPr)_3 ]-), complete decarbonylation is observed to afford structurally unusual diiron(II) products of the type {[PhBP^R_3]Fe}_2(µ-O). A mechanistic hypothesis that is consistent with the collection of results described is offered, and suggests that reductive coupling of CO_2 likely occurs from an electronically saturated “Fe^(II)–CO_2-” species

Interaction and thermodynamics of spinons in the XX chain

The mapping between the fermion and spinon compositions of eigenstates in the one-dimensional spin-1/2 XX model on a lattice with N sites is used to describe the spinon interaction from two different perspectives: (i) For finite N the energy of all eigenstates is expressed as a function of spinon momenta and spinon spins, which, in turn, are solutions of a set of Bethe ansatz equations. The latter are the basis of an exact thermodynamic analysis in the spinon representation of the XX model. (ii) For N -> infinity the energy per site of spinon configurations involving any number of spinon orbitals is expressed as a function of reduced variables representing momentum, filling, and magnetization of each orbital. The spins of spinons in a single orbital are found to be coupled in a manner well described by an Ising-like equivalent-neighbor interaction, switching from ferromagnetic to antiferromagnetic as the filling exceeds a critical level. Comparisons are made with results for the Haldane-Shastry model.Comment: 16 pages, 3 figure

Sub-wavelength imaging with a left-handed material flat lens

We study numerically, by means of the pseudospectral time-domain method, the unique features of imaging by a flat lens made of a left-handed metamaterial that possesses the property of negative refraction. We confirm the earlier finding that a left-handed flat lens can provide near-perfect imaging of a point source and a pair of point sources with clear evidence of the sub-wavelength resolution. We illustrate the limitation of the resolution in the time-integrated image due to the presence of surface waves.Comment: 4 pages, RevTeX, 6 figures; added references and some discussio

Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages

Although Fas (CD95) is recognized as a death receptor that induces apoptosis, recent studies indicate that the Fas/FasL system can induce pro-inflammatory cytokine production by macrophages independent of conventional caspase-mediated apoptotic signaling. The precise mechanism(s) by which Fas activates macrophage inflammation is unknown. We hypothesized that Fas stimulates rapid release of high mobility group box 1 (HMGB1) that acts in an autocrine and/or paracrine manner to stimulate pro-inflammatory cytokine production via a Toll-like receptor-4 (TLR4)/Interleukin-1 receptor associated kinase-4 (IRAK4)-dependent mechanism. Following Fas activation, HMGB1 was released within 1 hr from viable RAW267.4 cells and primary murine peritoneal macrophages. HMGB1 release was more rapid following Fas activation compared to LPS stimulation. Neutralization of HMGB1 with an inhibitory anti-HMGB1 monoclonal antibody strongly inhibited Fas-induced production of tumor necrosis factor (TNF) and macrophage inflammatory protein-2 (MIP-2). Both Fas-induced HMGB1 release and associated pro-inflammatory cytokine production were significantly decreased from Tlr4-/- and Irak4-/- macrophages, but not Tlr2-/- macrophages. These findings reveal a novel mechanism underlying Fas-mediated pro-inflammatory physiological responses in macrophages. We conclude that Fas activation induces rapid, TLR4/IRAK4-dependent release of HMGB1 that contributes to Fas-mediated pro-inflammatory cytokine production by viable macrophages