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Cancer specific inhibitors reflective of unique metabolic needs, are rare. We describe a novel small molecule, Gboxin, that specifically inhibits primary mouse and human glioblastoma (GBM) cell growth but not mouse embryo fibroblasts or neonatal astrocytes. Gboxin rapidly and irreversibly compromises GBM oxygen consumption. Reliant on its positive charge, Gboxin associates with mitochondrial oxidative phosphorylation complexes in a proton gradient dependent manner and inhibits F0F1 ATP synthase activity. Gboxin resistant cells require a functional mitochondrial permeability transition pore that regulates pH impeding matrix accumulation. Administration of a pharmacologically stable Gboxin analog inhibits GBM allografts and patient derived xenografts. Gboxin toxicity extends to established human cancer cell lines of diverse organ origin and exposes the elevated proton gradient pH in cancer cell mitochondria as a new mode of action for antitumor reagent development.

We report measurements of the vacuum ultraviolet (VUV) emission spectra of a microwave-discharge hydrogenflow lamp (MDHL), a common tool in astrochemistry laboratories working on ice VUV photoprocessing. The MDHL provides hydrogen Ly-α (121.6 nm) and H 2 molecular emission in the 110-180 nm range. We show that the spectral characteristics of the VUV light emitted in this range, in particular the relative proportion of Ly-α to molecular emission bands, strongly depend on the pressure of H 2 inside the lamp, the lamp geometry (F type versus T type), the gas used (pure H 2 versus H 2 seeded in He), and the optical properties of the window used (MgF 2 versus CaF 2). These different configurations are used to study the VUV irradiation of CO ice at 14 K. In contrast to the majority of studies dedicated to the VUV irradiation of astrophysical ice analogs, which have not taken into consideration the emission spectrum of the MDHL, our results show that the processes induced by photons in CO ice from a broad energy range are different and more complex than the sum of individual processes induced by monochromatic sources spanning the same energy range, as a result of the existence of multistate electronic transitions and discrepancy in absorption cross sections between parent molecules and products in the Ly-α and H 2 molecular emission ranges.

Context. Methanol is a common component of interstellar and circumstellar ice mantles and is often used as an evolution indicator in star-forming regions. The observations of gas-phase methanol in the interiors of dense molecular clouds at temperatures as low as 10 K suggest that non-thermal ice desorption must be active. Ice photodesorption has been proposed to explain the abundances of gas-phase molecules toward the coldest regions. Aims. Laboratory experiments were performed to investigate the potential photodesorption of methanol toward the coldest regions. Methods. Solid methanol was deposited at 8 K and UV-irradiated at various temperatures starting from 8 K. The irradiation of the ice was monitored by means of infrared spectroscopy and the molecules in the gas phase were detected using quadrupole mass spectroscopy. Fully deuterated methanol was used for confirmation of the results. Results. The photodesorption of methanol to the gas phase was not observed in the mass spectra at different irradiation temperatures. We estimate an upper limit of 3 × 10 −5 molecules per incident photon. On the other hand, photon-induced desorption of the main photoproducts was clearly observed. Conclusions. The negligible photodesorption of methanol could be explained by the ability of UV-photons in the 114−180 nm (10.87−6.88 eV) range to dissociate this molecule efficiently. Therefore, the presence of gas-phase methanol in the absence of thermal desorption remains unexplained. On the other hand, we find CH 4 to desorb from irradiated methanol ice, which was not found to desorb in the pure CH 4 ice irradiation experiments.

Context. The vacuum-UV (VUV) absorption cross sections of most molecular solids present in interstellar ice mantles with the exception of H 2 O, NH 3 , and CO 2 have not been reported yet. Models of ice photoprocessing depend on the VUV absorption cross section of the ice to estimate the penetration depth and radiation dose, and in the past, gas phase cross section values were used as an approximation. Aims. We aim to estimate the VUV absorption cross section of molecular ice components. Methods. Pure ices composed of CO, H 2 O, CH 3 OH, NH 3 , or H 2 S were deposited at 8 K. The column density of the ice samples was measured in situ by infrared spectroscopy in transmittance. VUV spectra of the ice samples were collected in the 120−160 nm (10.33−7.74 eV) range using a commercial microwave-discharged hydrogen flow lamp. Results. We provide VUV absorption cross sections of the reported molecular ices. Our results agree with those previously reported for H 2 O and NH 3 ices. Vacuum-UV absorption cross section of CH 3 OH, CO, and H 2 S in solid phase are reported for the first time. H 2 S presents the highest absorption in the 120−160 nm range. Conclusions. Our method allows fast and readily available VUV spectroscopy of ices without the need to use a synchrotron beamline. We found that the ice absorption cross sections can be very different from the gas-phase values, and therefore, our data will significantly improve models that simulate the VUV photoprocessing and photodesorption of ice mantles. Photodesorption rates of pure ices, expressed in molecules per absorbed photon, can be derived from our data.

Context. Ice mantles that formed on top of dust grains are photoprocessed by the secondary ultraviolet (UV) field in cold and dense molecular clouds. UV photons induce photochemistry and desorption of ice molecules. Experimental simulations dedicated to ice analogs under astrophysically relevant conditions are needed to understand these processes. Aims. We present UV-irradiation experiments of a pure CO 2 ice analog. Calibration of the quadrupole mass spectrometer allowed us to quantify the photodesorption of molecules to the gas phase. This information was added to the data provided by the Fourier transform infrared spectrometer on the solid phase to obtain a complete quantitative study of the UV photoprocessing of an ice analog. Methods. Experimental simulations were performed in an ultra-high vacuum chamber. Ice samples were deposited onto an infrared transparent window at 8K and were subsequently irradiated with a microwave-discharged hydrogen flow lamp. After irradiation, ice samples were warmed up until complete sublimation was attained. Results. Photolysis of CO 2 molecules initiates a network of photon-induced chemical reactions leading to the formation of CO, CO 3 , O 2 , and O 3 . During irradiation, photon-induced desorption of CO and, to a lesser extent, O 2 and CO 2 took place through a process called indirect desorption induced by electronic transitions, with maximum photodesorption yields (Y pd ) of ∼1.2 × 10 −2 molecules incident photon −1 , ∼9.3 × 10 −4 molecules incident photon −1 , and ∼1.1 × 10 −4 molecules incident photon −1 , respectively. Conclusions. Calibration of mass spectrometers allows a direct quantification of photodesorption yields instead of the indirect values that were obtained from infrared spectra in most previous works. Supplementary information provided by infrared spectroscopy leads to a complete quantification, and therefore a better understanding, of the processes taking place in UV-irradiated ice mantles.

Objective To determine the role of toll-like receptor 2 in cardiac dysfunction during polymicrobial sepsis. Design Controlled animal study. Setting University hospital research laboratory. Subjects Male C57BL/6, wild-type, toll-like receptor 2−/−. Intervention Polymicrobial peritonitis, a clinically relevant model of sepsis, was generated by cecum ligation and puncture. Wild-type and toll-like receptor 2−/− mice were divided into sham and cecum ligation and puncture groups. The sham animals underwent laparotomy but without cecum ligation and puncture. Twenty-four hours after surgeries, the cardiac function was assessed by serial echocardiography in vivo, a pressure transducer catheter was inserted into the left ventricles of isolated hearts (Langendorff model), and in vitro measurement of Ca2+ transients and sarcomere shortening in adult cardiomyocytes were isolated from the sham and septic animals. In addition, myocardial and serum cytokines, blood white blood cell counts, peritoneal neutrophil recruitment, chemokine receptor expression, and survival rates were examined. Measurements and Results Compared to septic wild-type mice, toll-like receptor 2−/− mice had markedly improved cardiac function during sepsis, as demonstrated by in vivo tissue Doppler imaging, better-preserved left ventricle function in isolated heart, and improved sarcomere shortening measured in single cardiomyocytes. There was also a significant survival benefit in toll-like receptor 2−/− mice compared to wild-type mice. These favorable outcomes in toll-like receptor 2−/− mice were associated with attenuated cardiodepressant cytokine levels in the myocardium and serum and enhanced neutrophil migratory function. Conclusions These studies suggest that toll-like receptor 2 signaling plays a critical role in mediating cardiomyopathy, deleterious myocardial and systemic inflammation, and high mortality during polymicrobial sepsis.

Pure methanol ices have been irradiated with monochromatic soft X-rays of 300 and 550 eV close to the 1s resonance edges of C and O, respectively, and with a broadband spectrum (250-1200 eV). The infrared (IR) spectra of the irradiated ices show several new products of astrophysical interest such as CH 2 OH, H 2 CO, CH 4 , HCOOH, HCOCH 2 OH, CH 3 COOH, CH 3 OCH 3 , HCOOCH 3 , and (CH 2 OH) 2 , as well as HCO, CO, and CO 2 . The effect of X-rays is the result of the combined interactions of photons and electrons with the ice. A significant contribution to the formation and growth of new species in the CH 3 OH ice irradiated with X-rays is given by secondary electrons, whose energy distribution depends on the energy of X-ray photons. Within a single experiment, the abundances of the new products increase with the absorbed energy. Monochromatic experiments show that product abundances also increase with the photon energy. However, the abundances per unit energy of newly formed species show a marked decrease in the broadband experiment as compared to irradiations with monochromatic photons, suggesting a possible regulatory role of the energy deposition rate. The number of new molecules produced per absorbed eV in the X-ray experiments has been compared to those obtained with electron and ultraviolet (UV) irradiation experiments.