Abstract
Methyl isocyanate (CH3NCO) belongs to a select group of interstellar molecules considered to be relevant precursors in the formation of larger organic compounds, including those with peptide ...bonds. The molecule has only been detected in a couple of high-mass protostars and potentially on comets. A formation route on icy grains has been postulated for this molecule but experimental evidence is lacking. Here we extend the range of environments where methyl isocyanate is found and unambiguously identify CH3NCO through the detection of 43 unblended transitions in the ALMA Protostellar Interferometric Line Survey (PILS) of the low-mass solar-type protostellar binary IRAS 16293−2422. The molecule is detected towards both components of the binary with a ratio HNCO/CH3NCO ∼ 4–12. The isomers CH3CNO and CH3OCN are not identified, resulting in upper abundance ratios of CH3NCO/CH3CNO > 100 and CH3NCO/CH3OCN > 10. The resulting abundance ratios compare well with those found for related N-containing species towards high-mass protostars. To constrain its formation, a set of cryogenic UHV experiments is performed. VUV irradiation of CH4:HNCO mixtures at 20 K strongly indicate that methyl isocyanate can be formed in the solid state through CH3 and (H)NCO recombinations. Combined with gas-grain models that include this reaction, the solid-state route is found to be a plausible scenario to explain the methyl isocyanate abundances found in IRAS 16293−2422.
In an attempt to understand the findings presented in the Comment by Greaves et al. (2023, https://doi.org/10.1029/2023GL103539), we followed their data analysis methodology, omitting the hot and ...cold‐load calibrations that are an important part of the standard SOFIA GREAT instrument calibration procedure. This process requires scaling of the Venus off‐source spectra by an arbitrary factor, which in turn introduces residuals of the intrinsic receiver bandpass shape as spurious components in the resulting line/continuum spectra. Although these additional artifacts can be reduced via Fourier‐domain spectral filtering, their removal depends on an ill‐constrained interpolation of the Venus continuum across the PH3 spectral line positions, resulting in an unreliable final spectrum. We therefore conclude that the PH3 lines claimed to be detected in the Comment by Greaves et al. (2023, https://doi.org/10.1029/2023GL103539) originate from data/analysis artifacts, and confirm our original result that there is no evidence for phosphine in the SOFIA Venus data.
Plain Language Summary
We performed observations using a unique, flying telescope—the Stratospheric Observatory for Infrared Astronomy (SOFIA)—to search for a gas called phosphine in the atmosphere of Venus, which has been suggested to be an indicator for life. The observations, published by Cordiner et al. (2022, https://doi.org/10.1029/2022gl101055), were analyzed carefully but showed no evidence of phosphine. Our findings were called into question in the Comment by Greaves et al. (2023, https://doi.org/10.1029/2023GL103539), who claimed to find phosphine lines in the SOFIA observations after following an unconventional data analysis method. We have investigated their method, and conclude that it is likely to introduce spurious signals into the data, so the claimed phosphine detection is therefore not significant.
Key Points
The revised calibration procedure adopted by Greaves et al. (2023, https://doi.org/10.1029/2023GL103539) introduces additional receiver artifacts into the SOFIA 4G2 Venus spectra
The claimed PH3 detection is likely a result of this, combined with interpolation artifacts that occur during subsequent Fourier filtering
We confirm our original conclusion that there is no evidence for phosphine in the SOFIA GREAT Venus data
Label retention assays remain the state‐of‐the‐art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo. They are commonly used in organs with rapid cell ...turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish “washout” of label from transit amplifying cell populations. Conclusion: Four possible hepatic stem cell niches are identified by this approach: the canal of Hering (proximal biliary tree), intralobular bile ducts, periductal “null” mononuclear cells, and peribiliary hepatocytes. These results confirm several different and often contradictory lines of investigation regarding the intrahepatic location of stem/progenitor cells and suggest that the liver has a multi‐tiered, flexible system of regeneration rather than a single stem/progenitor cell location. (HEPATOLOGY 2008.)
The presence of phosphine (PH3) in the atmosphere of Venus was reported by Greaves et al. based on observations of the J = 1–0 transition at 267 GHz using ground-based, millimeter-wave spectroscopy. ...This unexpected discovery presents a challenge for our understanding of Venus's atmosphere, and has led to a reappraisal of the possible sources and sinks of atmospheric phosphorous-bearing gases. Here we present results from a search for PH3 on Venus using the German REceiver for Astronomy at Terahertz Frequencies instrument aboard the Stratospheric Observatory for Infrared Astronomy aircraft, over three flights conducted in November 2021. Multiple PH3 transitions were targeted at frequencies centered on 533 and 1,067 GHz, but no evidence for atmospheric PH3 was detected. Through radiative transfer modeling, we derived a disk-averaged upper limit on the PH3 abundance of 0.8 ppb in the altitude range 75–110 km, which is more stringent than previous ground-based studies.
We have employed γ-irradiation at cryogenic temperatures (77 K and also ∼6 K) of the ternary complexes of camphor, dioxygen, and ferro-cytochrome P450cam to inject the “second” electron of the ...catalytic process. We have used EPR and ENDOR spectroscopies to characterize the primary product of reduction as well as subsequent states created by annealing reduced oxyP450, both the WT enzyme and the D251N and T252A mutants, at progressively higher temperatures. (i) The primary product upon reduction of oxyP450 4 is the end-on, “H-bonded peroxo” intermediate 5A. (ii) This converts even at cryogenic temperatures to the hydroperoxo-ferriheme species, 5B, in a step that is sensitive to these mutations.Yields of 5B are as high as 40%. (iii) In WT and D251N P450s, brief annealing in a narrow temperature range around 200 K causes 5B to convert to a product state, 7A, in which the product 5-exo-hydroxycamphor is coordinated to the ferriheme in a nonequilibrium configuration. Chemical and EPR quantitations indicate the reaction pathway involving 5B yields 5-exo-hydroxycamphor quantitatively. Analogous (but less extensive) results are seen for the alternate substrate, adamantane. (iv) Although the T252A mutation does not interfere with the formation of 5B, the cryoreduced oxyT252A does not yield product, which suggests that 5B is a key intermediate at or near the branch-point that leads either to product formation or to nonproductive “uncoupling” and H2O2 production. The D251N mutation appears to perturb multiple stages in the catalytic cycle. (v) There is no spectroscopic evidence for the buildup of a high-valence oxyferryl/porphyrin π-cation radical intermediate, 6. However, ENDOR spectroscopy of 7A in H2O and D2O buffers shows that 7A contains hydroxycamphor, rather than water, bound to Fe3+, and that the proton removed from the C(5) carbon of substrate during hydroxylation is trapped as the hydroxyl proton. This demonstrates that hydroxylation of substrates by P450cam in fact occurs by the formation and reaction of 6. (vi) Annealing at ≥220 K converts the initial product state 7A to the equilibrium product state 7, with the transition occurring via a second nonequilibrium product state, 7B, in the D251N mutant; in states 7B and 7 the hydroxycamphor hydroxyl proton no longer is trapped. (vii) The present results are discussed in the context of other efforts to detect intermediates in the P450 catalytic cycle.
The mechanisms for in vivo production of bone marrow-derived hepatocytes (BMDHs) remain largely unclear. We investigated whether granulocyte colony-stimulating factor (G-CSF)-mediated mobilization of ...hematopoietic cells increases the phenomenon. Recurrent liver injury in mice expressing green fluorescent protein (EGFP) in all hematopoietic-derived cells was produced by 3 months of carbon tetrachloride (CCL4) injections. Histologically, there were necrotic foci with histiocyte-rich infiltrates, but little oval cell proliferation. Subsequently, some animals were mobilized with G-CSF for 1, 2, or 3 weeks. Animals were sacrificed 1 month after growth factor treatment. BMDH percentages were lower than previously reported, though G-CSF mobilization significantly augmented BMDH production in injured livers. BMDHs originating from in vivo fusion were evaluated by transplanting female EGFP+ cells into male mice. Binucleated, EGFP+ hepatocytes with one Y chromosome, indicating fusion, were identified. In conclusion, (1) mobilization of hematopoietic cells increases BMDH production and (2) as with the FAH-null model, the first model demonstrating hematopoietic/hepatocyte fusion, recurring CCl4-induced injury has macrophage-rich infiltrates, a blunted oval cell response, and a predominantly in vivo fusion process for circulating cell engraftment into the liver. These findings open the possibility of using hematopoietic growth factors to treat nonhematopoietic degenerative diseases.
Efficient and error-free DNA repair is critical for safeguarding genome integrity, yet it is also linked to radio- and chemoresistance of malignant tumors. miR-34a, a potent tumor suppressor, ...influences a large set of p53-regulated genes and contributes to p53-mediated apoptosis. However, the effects of miR-34a on the processes of DNA damage and repair are not entirely understood. We explored tet-inducible miR-34a-expressing human p53 wild-type and R273H p53 mutant GBM cell lines, and found that miR-34a influences the broad spectrum of 53BP1-mediated DNA damage response. It escalates both post-irradiation and endogenous DNA damage, abrogates radiation-induced G
2
/M arrest and drastically increases the number of irradiated cells undergoing mitotic catastrophe. Furthermore, miR-34a downregulates 53BP1 and inhibits its recruitment to the sites of DNA double-strand breaks. We conclude that whereas miR-34a counteracts DNA repair, it also contributes to the p53-independent elimination of distressed cells, thus preventing the rise of genomic instability in tumor cell populations. These properties of miR-34a can potentially be exploited for DNA damage-effecting therapies of malignancies.
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