Oxalyl diisothiocyanate, ((CO)NCS)2, has been studied in solid argon matrices at 4.2 K with the aid of infrared (IR) spectroscopy. The spectra show mainly signals attributed to the most stable ...anti‐anti conformer, which is corroborated by comparison to computed anharmonic fundamental IR transitions. Upon irradiation with 254 nm UV light, oxalyl diisothiocyanate eliminates carbon monoxide under formation of carbonyl diisothiocyanate, CO(NCS)2. This reaction is only slightly exothermic by 0.4 kcal mol−1 at the DLPNO‐CCSD(T)/def2‐QZVPP//B3LYP‐D3/def2‐TZVPP level of theory. Remarkably, photolysis produces mostly the less stable syn‐anti conformer of carbonyl diisothiocyanate. Subsequent annealing at 30 K for two minutes results in a structural relaxation to the 0.7 kcal mol−1 more stable syn‐syn conformer confirming a low torsional barrier height between the isomers.
When deposited in a solid argon matrix and subsequently irradiated with UV light, oxalyl diisothiocyanate shows photodecarbonylation under formation of carbonyl diisothiocyanate in an exited conformational state. During consecutive annealing, the molecule relaxes into its ground state. This has been shown by IR spectroscopy and corroborated by high‐level quantum mechanical calculations.
Thermolysis of thiirane oxide leads to production of highly reactive sulfur monoxide. The liberated SO can in turn be trapped with a diene scavenger forming dihydrothiophene oxide. Since the ...intermediate diatomic possesses a triplet ground state, the SO transfer can proceed on two spin‐state surfaces. Here, we study the competition between singlet concerted and stepwise triplet diradical mechanisms utilizing the M06‐2X density functional as well as CCSD(T) and MRCI+Q wavefunction theories. We find that the decomposition of thiirane oxide prefers to pass through a triplet diradical intermediate that becomes accessible from a nearby minimum energy crossing point (MECP). Hence, the thermolysis of thiirane oxide is expected to predominantly release triplet ground state sulfur monoxide in agreement with previous experimental reports. The addition of 3SO to 1,3‐butadiene initially generates an allylic diradical, that ring‐closes to a thiirane oxide through another MECP, and a subsequent rearrangement gives access to the final product.
Quantum chemical computations reveal that thiirane oxide decomposes through a stepwise diradical mechanism producing triplet ground state sulfur monoxide. This pathway is preferred over the alternative singlet concerted mechanism despite the need for a spin state change.
When regulated firms are offered compensation to prevent them from relocating, efficiency requires that payments be distributed across firms so as to equalize marginal relocation probabilities, ...weighted by the damage caused by relocation. We formalize this fundamental economic logic and apply it to analyzing compensation rules proposed under the EU Emissions Trading Scheme, where emission permits are allocated free of charge to carbon-intensive and trade-exposed industries. We show that this practice results in substantial overcompensation for given carbon leakage risk. Efficient permit allocation reduces the aggregate risk of job loss by more than half without increasing aggregate compensation.
TC3A: The Cancer 3′ UTR Atlas Feng, Xin; Li, Lei; Wagner, Eric J ...
Nucleic acids research,
01/2018, Volume:
46, Issue:
D1
Journal Article
Peer reviewed
Open access
Abstract
Widespread alternative polyadenylation (APA) occurs during enhanced cellular proliferation and transformation. Recently, we demonstrated that CFIm25-mediated 3′ UTR shortening through APA ...promotes glioblastoma tumor growth in vitro and in vivo, further underscoring its significance to tumorigenesis. Here, we report The Cancer 3′ UTR Atlas (TC3A), a comprehensive resource of APA usage for 10,537 tumors across 32 cancer types. These APA events represent potentially novel prognostic biomarkers and may uncover novel mechanisms for the regulation of cancer driver genes. TC3A is built on top of the now de facto standard cBioPortal. Therefore, the large community of existing cBioPortal users and clinical researchers will find TC3A familiar and immediately usable. TC3A is currently fully functional and freely available at http://tc3a.org.
We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P‐glycoprotein (P‐gp) substrate). ...Rifampin increased midazolam metabolism, greatly reducing the area under the concentration–time curve (AUC0–∞). The midazolam AUC0–∞ returned to baseline with a half‐life of ~8 days. Rifampin's effect on the AUC0–3 h of digoxin was biphasic: the AUC0–3 h increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion–transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P‐gp‐mediated transport of digoxin with a half‐maximal inhibitory concentration (IC50) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P‐gp. These results suggest modifications to drug–drug interaction (DDI) trial designs.
Clinical Pharmacology & Therapeutics (2011) 89 2, 234–242. doi:10.1038/clpt.2010.271
Indirect evidence strongly suggests that oxidation reactions of cytosine and its minor derivative 5-methylcytosine play a major role in mutagenesis and cancer. Therefore, there is an emerging ...necessity to identify the final oxidation products of these reactions, to search for their formation in cellular DNA, and to assess their mutagenic features. In this Account, we report and discuss the main •OH and one-electron-mediated oxidation reactions, two of the most potent sources of DNA damage, of cytosine and 5-methylcytosine nucleosides that have been recently characterized. The addition of •OH to the 5,6-unsaturated double bond of cytosine and 5-methylcytosine generates final degradation products that resemble those observed for uracil and thymine. The main product from the oxidation of cytosine, cytosine glycol, has been shown to undergo dehydration at a much faster rate as a free nucleoside than when inserted into double-stranded DNA. On the other hand, the predominant •OH addition at C5 of cytosine or 5-methylcytosine leads to the formation of 5-hydroxy-5,6-dihydro radicals that give rise to novel products with an imidazolidine structure. The mechanism of the formation of imidazolidine products is accounted for by rearrangement reactions that in the presence of molecular oxygen likely involve an intermediate pyrimidine endoperoxide. The reactions of the radical cations of cytosine and 5-methylcytosine are governed by competitive hydration, mainly at C6 of the pyrimidine ring, and deprotonation from the exocyclic amino and methyl group, leading in most cases to products similar to those generated by •OH. 5-Hydroxypyrimidines, the dehydration products of cytosine and uracil glycols, have a low oxidation potential, and their one-electron oxidation results in a cascade of decomposition reactions involving the formation of isodialuric acid, dialuric acid, 5-hydroxyhydantoin, and its hydroxyketone isomer. In biology, GC → AT transitions are the most common mutations in the genome of aerobic organisms, including the lacI gene in bacteria, lacI transgenes in rodents, and the HPRT gene in rodents and humans, so a more complete understanding of cytosine oxidation is an essential research goal. The data and insights presented here shed new light on oxidation reactions of cytosine and 5-methylcytosine and should facilitate their validation in cellular DNA.
Adoptive transfer of thymus‐derived natural regulatory T cells (nTregs) effectively suppresses disease in murine models of autoimmunity and graft‐versus‐host disease (GVHD). TGFß induces Foxp3 ...expression and suppressive function in stimulated murine CD4+25‐ T cells, and these induced Treg (iTregs), like nTreg, suppress auto‐ and allo‐reactivity in vivo. However, while TGFß induces Foxp3 expression in stimulated human T cells, the expanded cells lack suppressor cell function. Here we show that Rapamycin (Rapa) enhances TGFß‐dependent Foxp3 expression and induces a potent suppressor function in naive (CD4+ 25–45RA+) T cells. Rapa/TGFß iTregs are anergic, express CD25 at levels higher than expanded nTregs and few cells secrete IL‐2, IFNγ or IL‐17 even after PMA and Ionomycin stimulation in vitro. Unlike other published methods of inducing Treg function, Rapa/TGFß induces suppressive function even in the presence of memory CD4+ T cells. A single apheresis unit of blood yields an average ∼240 × 109 (range ∼70–560 × 109) iTregs from CD4+25‐ T cells in ≤2 weeks of culture. Most importantly, Rapa/TGFß iTregs suppress disease in a xenogeneic model of GVHD. This study opens the door for iTreg cellular therapy for human diseases.
This study demonstrates that potent suppressive function is induced when human CD4+25− T cells are expanded in the presence of rapamycin and TGFβ, and that adoptive transfer of these induced regulatory T cells ameliorates disease in a xenogeneic model of graft versus host disease.
A unique feature of generalised parton distributions is their relation to the QCD energy–momentum tensor. In particular, they provide access to the mechanical properties of the proton i.e. the ...distributions of pressure and shear stress induced by its quark and gluon structure. In principle the pressure distribution can be experimentally determined in a model-independent way from a dispersive analysis of deeply virtual Compton scattering data through the measurement of the subtraction constant. In practice the kinematic coverage and accuracy of existing experimental data make this endeavour a challenge. Elaborating on recent global fits of deeply virtual Compton scattering measurements using artificial neural networks, our analysis presents the current knowledge on this subtraction constant and assesses the impact of the most frequent systematic assumptions made in this field of research. This study will pave the way for future works when more precise data will become available, e.g. obtained in the foreseen electron-ion colliders EIC and EIcC.
We study the exclusive electroproduction of a photon pair in the kinematical regime where the diphoton invariant mass is large and where the nucleon flies almost in its original direction. We discuss ...the relative importance of the QCD process where the two photons originate from a quark line compared to the single (double) Bethe-Heitler processes where one (two) photons originate from the lepton line. This process turns out to be a promising tool to study generalized parton distributions in the nucleon, both at the medium energy of JLab and at a high energy electron ion collider.
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