Massive abiotic methane production in eclogite during cold subduction.

Methane (CH4) is a critical but overlooked component in the study of the deep carbon cycle. Abiotic CH4 produced by serpentinization of ultramafic rocks has received extensive attention, but its formation and flux in mafic rocks during subduction remain poorly understood. Here, we report massive CH4-rich fluid inclusions in well-zoned garnet from eclogites in Western Tianshan, China. Petrological characteristics and carbon-hydrogen isotopic compositions confirm the abiotic origin of this CH4. Reconstructed P-T-fO2-fluid trajectories and Deep Earth Water modeling imply that massive abiotic CH4 was generated during cold subduction at depths of 50-120 km, whereas CO2 was produced during exhumation. The massive production of abiotic CH4 in eclogites may result from multiple mechanisms during prograde high pressure-ultrahigh pressure metamorphism. Our flux calculation proposes that abiotic CH4 that has been formed in HP-UHP eclogites in cold subduction zones may represent one of the largest, yet overlooked, sources of abiotic CH4 on Earth.

Impact of cigarette smoke on physical-chemical and molecular proprieties of human skin in an ex vivo model.

BACKGROUND: This is a study about the skin ageing exposome, focusing on the effect of cigarette smoke. Human living skin explants (HSE) were exposed to cigarette smoke (CS) of two cigarettes for 2 hours using a custom-made exposure chamber, the Pollubox® . Effects on the surface physico-chemistry and molecular properties of the skin were analyzed and reported for the first time. BASIC PROCEDURES: To this end, transcriptomic study followed by immunohistochemistry, MDA (Malondialdehyde Dosage), and surface physio-chemistry data: surface free energy determination, TEWL (Trans Epidermal Water Loss), skin pH and FT-IR (Fourier Transform-Infrared) spectroscopy of the explant were collected from untreated and treated HSE. MAIN FINDINGS: Results showed a decrease of the total surface free energy of the treated HSE. This decrease reflected higher interactions with polar compounds from the environment and consequently a decrease of the surface hydrophobicity. Additionally, an increase of TEWL and skin pH was observed after treatment. The transcriptomic analysis showed downregulation of mitochondrial genes (PON2-NDUFA4L2-ATP1A1-ALDH2-PRODH) combined with an increase of MDA in CS-treated HSE. CONCLUSIONS: CS-induced oxidation of lipids at HSE surface alters the skin barrier: interactions with polar products are enhanced and the lipid chain packing at the surface is modified. Consequently, skin permeability could increase which correlated with repression of CA9 and AQP1 genes. Beside activation of AHR-NRF2 pathway in CS-exposed HSE, our results suggested that mitochondrial functions were strongly impacted and oxidized lipids failed to be eliminated promoting skin barrier alteration. A mitophagy activity was suggested through the confirmation of PINK1 accumulation in the epidermis by immunostaining.

Heat pain modulation with virtual water during a virtual hand illusion.

Immersive virtual reality is a powerful method to modify the environment and thereby influence experience. The present study used a virtual hand illusion and context manipulation in immersive virtual reality to examine top-down modulation of pain. Participants received painful heat stimuli on their forearm and placed an embodied virtual hand (co-located with their real one) under a virtual water tap, which dispensed virtual water under different experimental conditions. We aimed to induce a temperature illusion by a red, blue or white light suggesting warm, cold or no virtual water. In addition, the sense of agency was manipulated by allowing participants to have high or low control over the virtual hand's movements. Most participants experienced a thermal sensation in response to the virtual water and associated the blue and red light with cool/cold or warm/hot temperatures, respectively. Importantly, the blue light condition reduced and the red light condition increased pain intensity and unpleasantness, both compared to the control condition. The control manipulation influenced the sense of agency, but did not influence pain ratings. The large effects revealed in our study suggest that context effects within an embodied setting in an immersive virtual environment should be considered within VR based pain therapy.

FDG PET/MRI Imaging of an Angiosarcoma in a Popliteal Aneurysm and Tibial Head After Popliteal Graft.

Angiosarcomas are rare aggressive neoplasms with a wide variety of anatomic locations, one third of them presenting multifocal. Molecular imaging with PET/CT and PET/MR plays an emerging role in staging sarcomas. This case demonstrates the value of PET/MR imaging of an angiosarcoma with involvement of the tibial head and a popliteal aneurysm with histopathologic correlation.

Microstructure-stiffness relationships of ten European and tropical hardwood species.

Hardwood species exhibit a huge anatomical variability. This makes them perfect study objects for exploring relations between structural features at different length scales and corresponding stiffness properties of wood. We carry out microscopic analysis, nanoindentation tests, as well as macroscale ultrasonic and quasi-static tension tests and build a complete set of microstructural and corresponding micromechanical data of ten different (European and tropical) hardwood species. In addition, we apply micromechanical modeling to further elucidate the individual influences of particular structural features, which might appear only in a superimposed manner in experiments. The test results confirm the dominant influences of the microfibril angle on the stiffness at cell wall level and of density at the macroscopic scale. Vessels and ray cells affect the macroscopic stiffness of the wood tissue not only through their content, but also through their arrangement and shape: A ring-porous structure results in comparably higher longitudinal but lower radial stiffness than a diffuse-porous one. As for ray cells, large and particularly compactly shaped bundles might reduce the stiffness in tangential direction because of the fiber deviations they cause. Moreover, vessel and ray content might affect the relation between nanoindentation modulus and density-corrected macroscopic longitudinal stiffness.

Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.

BACKGROUND: Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRalpha/beta, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRalpha/beta, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine. METHODOLOGY/FINDINGS: Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 microM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC(50)); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/beta-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination. CONCLUSIONS: These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination.

Pharmacokinetics of masitinib in cats.

Masitinib is the first veterinary drug recently approved in Europe to treat mast cell tumours in dogs (Hahn et al. JVIM, Masivet). This inhibitor is selective and highly efficient in blocking c-Kit, PDGFR, and Lyn tyrosine kinase activities. It showed good efficacy and acceptable toxicity in several animal studies such as mice, rats, rabbits and dogs (Dubreuil P, et al. submitted, and Hahn et al. (J Vet Intern Med 22(6):8, 2008)). C-kit is a tyrosine kinase receptor that plays a critical role in the biology of mast cells including differentiation, survival, migration and cytokine/mediator release. Mast cells are involved in a number of allergy-and immune-related diseases in cats such as asthma (Reinero Carol et al. Vet Immunol Immunopathol 121(3-4):9, 2008), inflammatory bowel disease, (Janeczko et al. Vet Mic 128(1-2):15, 2008), and feline mast cell tumours (Rassnick et al. J Am Vet Med Assoc 232(8):1200-1205, 2008). Therefore, there might be a strong rationale to use masitinib in these indications. Here, we report the results of a preliminary pharmacokinetic study of masitinib in cats which showed a good bioavailability of ~60% in both sexes. We propose that an oral dose of 10-15 mg/kg masitinib is appropriate to achieve adequate plasma concentrations.

HuR interacts with human immunodeficiency virus type 1 reverse transcriptase, and modulates reverse transcription in infected cells.

Reverse transcription of the genetic material of human immunodeficiency virus type 1 (HIV-1) is a critical step in the replication cycle of this virus. This process, catalyzed by reverse transcriptase (RT), is well characterized at the biochemical level. However, in infected cells, reverse transcription occurs in a multiprotein complex - the reverse transcription complex (RTC) - consisting of viral genomic RNA associated with viral proteins (including RT) and, presumably, as yet uncharacterized cellular proteins. Very little is known about the cellular proteins interacting with the RTC, and with reverse transcriptase in particular. We report here that HIV-1 reverse transcription is affected by the levels of a nucleocytoplasmic shuttling protein - the RNA-binding protein HuR. A direct protein-protein interaction between RT and HuR was observed in a yeast two-hybrid screen and confirmed in vitro by homogenous time-resolved fluorescence (HTRF). We mapped the domain interacting with HuR to the RNAse H domain of RT, and the binding domain for RT to the C-terminus of HuR, partially overlapping the third RRM RNA-binding domain of HuR. HuR silencing with specific siRNAs greatly impaired early and late steps of reverse transcription, significantly inhibiting HIV-1 infection. Moreover, by mutagenesis and immunoprecipitation studies, we could not detect the binding of HuR to the viral RNA. These results suggest that HuR may be involved in and may modulate the reverse transcription reaction of HIV-1, by an as yet unknown mechanism involving a protein-protein interaction with HIV-1 RT.

Crystal structure of the retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture.

The retinoblastoma susceptibility protein, Rb, has a key role in regulating cell-cycle progression via interactions involving the central "pocket" and C-terminal regions. While the N-terminal domain of Rb is dispensable for this function, it is nonetheless strongly conserved and harbors missense mutations found in hereditary retinoblastoma, indicating that disruption of its function is oncogenic. The crystal structure of the Rb N-terminal domain (RbN), reveals a globular entity formed by two rigidly connected cyclin-like folds. The similarity of RbN to the A and B boxes of the Rb pocket domain suggests that Rb evolved through domain duplication. Structural and functional analysis provides insight into oncogenicity of mutations in RbN and identifies a unique phosphorylation-regulated site of protein interaction. Additionally, this analysis suggests a coherent conformation for the Rb holoprotein in which RbN and pocket domains directly interact, and which can be modulated through ligand binding and possibly Rb phosphorylation.

Inhibition of early steps of HIV-1 replication by SNF5/Ini1.

To replicate, human immunodeficiency virus, type 1 (HIV-1) needs to integrate a cDNA copy of its RNA genome into a chromosome of the host cell, a step controlled by the viral integrase (IN) protein. Viral integration involves the participation of several cellular proteins. SNF5/Ini1, a subunit of the SWI/SNF chromatin remodeling complex, was the first cofactor identified to interact with IN. We report here that SNF5/Ini1 interferes with early steps of HIV-1 replication. Inhibition of SNF5/Ini1 expression by RNA interference increases HIV-1 replication. Using quantitative PCR, we show that both the 2-long terminal repeat circle and integrated DNA forms accumulate upon SNF5/Ini1 knock down. By yeast two-hybrid assay, we screened a library of HIV-1 IN random mutants obtained by PCR random mutagenesis using SNF5/Ini1 as prey. Two different mutants of interaction, IN E69G and IN K71R, were impaired for SNF5/Ini1 interaction. The E69G substitution completely abolished integrase catalytic activity, leading to a replication-defective virus. On the contrary, IN K71R retained in vitro integrase activity. K71R substitution stimulates viral replication and results in higher infectious titers. Taken together, these results suggest that, by interacting with IN, SNF5/Ini1 interferes with early steps of HIV-1 infection.

Hormone pattern after misoprostol administration for a nonviable first-trimester gestation.

OBJECTIVE: To evaluate serial hormone concentrations in subjects treated with vaginally administered misoprostol for early pregnancy failure. DESIGN: As part of a randomized clinical trial, serum was collected on treatment days 1, 3, 8, and 15. SETTING: Multicenter clinical trial. PATIENT(S): Women with a nonviable first-trimester pregnancy. INTERVENTION(S): Serum concentrations of human chorionic gonadotropin (hCG), progesterone, and sex hormone binding globulin (SHBG) were evaluated. MAIN OUTCOME MEASURE(S): A logistic regression model was constructed to assess the associations of percent and complete expulsion of the gestational sac and/or successful management. RESULT(S): The percent change from the day of treatment until the first follow-up visit was predictive for complete expulsion for progesterone (P) (P<.005) and hCG (P<.005), but not for SHBG. The actual value was not significantly associated with complete expulsion or successful management. A decrease (day 1-3) of 79% for both hCG and P was associated with a 90% probability of complete passage of the gestational sac. A 90% probability of successful management was noted if P decreased by 78% on day 3 or 59% on day 7, or hCG decreased by 74% on day 3 or 78% on day 7 compared with pretreatment values. CONCLUSION(S): Percent change, but not absolute change, in serial hormone values are strongly associated with both the complete expulsion of the gestational sac with one dose of misoprostol and ultimate success.