RÉSUMÉ
Postconsumer plastics are generally perceived as valueless with only a small portion of plastic waste being closed-loop recycled into similar products while most of them are discarded in landfills. Depositing plastic waste in landfills not only harms the environment but also signifies a substantial economic loss. Alternatively, constructing value-added chemical feedstocks via mining the waste-derived intermediate species as a carbon (C) source under mild electrochemical conditions is a sustainable strategy to realize the circular economy. This proof-of-concept work provides an attractive "turning trash to treasure" strategy by integrating electrocatalytic polyethylene terephthalate (PET) plastic upcycling with a chemical C-S coupling reaction to synthesize organosulfur compounds, hydroxymethanesulfonate (HMS). HMS can be produced efficiently (Faradaic efficiency, FE of â¼70%) via deliberately capturing electrophilic intermediates generated in the PET monomer (ethylene glycol, EG) upcycling process, followed by coupling them with nucleophilic sulfur (S) species (i.e., SO32- and HSO3-). Unlike many previous studies conducted under alkaline conditions, PET upcycling was performed over an amorphous MnO2 catalyst under near-neutral conditions, allowing for the stabilization of electrophilic intermediates. The compatibility of this strategy was further investigated by employing biomass-derived compounds as substrates. Moreover, comparable HMS yields can be achieved with real-world PET plastics, showing its enormous potential in practical application. Lastly, Density function theory (DFT) calculation reveals that the C-C cleavage step of EG is the rate-determining step (RDS), and amorphous MnO2 significantly decreases the energy barriers for both RDS and C-S coupling when compared to the crystalline counterpart.
RÉSUMÉ
Upcycling plastic wastes into value-added chemicals is a promising approach to put end-of-life plastic wastes back into their ecocycle. As one of the polyesters that is used daily, polyethylene terephthalate (PET) plastic waste is employed here as the model substrate. Herein, a nickel (Ni)-based catalyst was prepared via electrochemically depositing copper (Cu) species on Ni foam (NiCu/NF). The NiCu/NF formed Cu/CuO and Ni/NiO/Ni(OH)2 core-shell structures before electrolysis and reconstructed into NiOOH and CuOOH/Cu(OH)2 active species during the ethylene glycol (EG) oxidation. After oxidation, the Cu and Ni species evolved into more reduced species. An indirect mechanism was identified as the main EG oxidation (EGOR) mechanism. In EGOR, NiCu60s/NF catalyst exhibited an optimal Faradaic efficiency (FE, 95.8%) and yield rate (0.70 mmol cm-2 h-1) for formate production. Also, over 80% FE of formate was achieved when a commercial PET plastic powder hydrolysate was applied. Furthermore, commercial PET plastic water bottle waste was employed as a substrate for electrocatalytic upcycling, and pure terephthalic acid (TPA) was recovered only after 1 h electrolysis. Lastly, density functional theory (DFT) calculation revealed that the key role of Cu was significantly reducing the Gibbs free-energy barrier (ΔG) of EGOR's rate-determining step (RDS), promoting catalysts' dynamic evolution, and facilitating the C-C bond cleavage.
RÉSUMÉ
Eukaryotic life benefits from-and ofttimes critically relies upon-the de novo biosynthesis and supply of vitamins and micronutrients from bacteria. The micronutrient queuosine (Q), derived from diet and/or the gut microbiome, is used as a source of the nucleobase queuine, which once incorporated into the anticodon of tRNA contributes to translational efficiency and accuracy. Here, we report high-resolution, substrate-bound crystal structures of the Sphaerobacter thermophilus queuine salvage protein Qng1 (formerly DUF2419) and of its human ortholog QNG1 (C9orf64), which together with biochemical and genetic evidence demonstrate its function as the hydrolase releasing queuine from queuosine-5'-monophosphate as the biological substrate. We also show that QNG1 is highly expressed in the liver, with implications for Q salvage and recycling. The essential role of this family of hydrolases in supplying queuine in eukaryotes places it at the nexus of numerous (patho)physiological processes associated with queuine deficiency, including altered metabolism, proliferation, differentiation and cancer progression.
Sujet(s)
Chloroflexi , Glycosidases , Nucléoside Q , Humains , Guanine/métabolisme , Micronutriments , Nucléoside Q/métabolisme , Protéines , ARN de transfert/métabolisme , Glycosidases/composition chimique , Chloroflexi/enzymologieRÉSUMÉ
BACKGROUND: Multiparametric risk assessment tools determine mortality risk in patients with pulmonary arterial hypertension (PAH) by combining invasive and noninvasive variables so management strategies can be tailored to individuals. RESEARCH QUESTION: Can a risk score based on common echocardiographic parameters risk-stratify patients with PAH? STUDY DESIGN AND METHODS: A Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) echocardiographic risk score (REVEAL-ECHO) was derived using retrospective echocardiographic data from 2,400 adult patients with PAH enrolled in the REVEAL registry database. A stepwise Cox regression model identified echocardiographic parameters significantly predictive of survival. Values were assigned to each selected parameter based on survival at 12 months' follow-up (Kaplan-Meier estimates). The REVEAL-ECHO risk score was the sum of individual values. Patients were categorized as having low, intermediate, or high risk based on Kaplan-Meier-predicted 12-month survival. RESULTS: The risk score included four echocardiographic parameters-right ventricular (RV) chamber enlargement, reduced RV systolic function, tricuspid regurgitation severity, and pericardial effusion-and accounted for PAH etiology. Higher REVEAL-ECHO risk scores signaled lower probability of 12-month survival. Statistically significant separation of mortality risk was observed among the risk strata: intermediate vs low (hazard ratio [HR], 1.43; 95% CI, 1.17-1.75; P = .0004) and high vs low (HR, 2.60; 95% CI, 2.19-3.10; P < .0001). Augmentation of the REVEAL Lite 2 risk calculator with REVEAL-ECHO risk scores achieved separation of REVEAL Lite 2 into four risk groups and identified a subgroup of patients with a low REVEAL Lite 2 risk score who were at higher risk (intermediate-low risk) and a subgroup of patients with an intermediate REVEAL Lite 2 risk score who also were at higher risk (intermediate-high risk). INTERPRETATION: A REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required.
Sujet(s)
Hypertension pulmonaire , Hypertension artérielle pulmonaire , Adulte , Humains , Hypertension artérielle pulmonaire/imagerie diagnostique , Études rétrospectives , Taux de survie , Échocardiographie , Hypertension artérielle pulmonaire primitive familiale , Appréciation des risques , Facteurs de risqueRÉSUMÉ
BACKGROUND: Although older patients are at increased risk for venous thromboembolism (VTE), thromboprophylaxis is underused because of bleeding concerns. The MARINER trial evaluated whether rivaroxaban reduced symptomatic postdischarge VTE in acutely ill medical patients. OBJECTIVES: We hypothesized that rivaroxaban would have a favorable benefit/risk profile in patients ≥75 years of age. METHODS: Patients were randomized in a double-blind manner at hospital discharge to rivaroxaban (10 mg/day for creatinine clearance ≥50 ml/min; 7.5 mg/day for ≥30-<50 ml/min) or placebo for 45 days. Using a Cox proportional hazard model including treatment as a covariate, we compared the risk of the primary efficacy outcome (symptomatic VTE plus VTE-related death in the intention-to-treat population) and safety outcome (International Society on Thrombosis and Haemostasis major bleeding in the safety population) in the prespecified subgroups of patients ≥ and <75 years of age. RESULTS: The primary event rate in patients ≥75 years of age was 2-fold higher than that in those <75 years. The incidence of the primary efficacy outcomes in both age groups was numerically lower with rivaroxaban than with placebo (≥75: 1.2% and 1.6%, HR 0.73, 95% CI 0.43-1.22; <75 0.6% and 0.8%, HR 0.78, 95% CI 0.46-1.32; interaction p-value for age group = .85). The incidence of major bleeding was low and similar in the two age and treatment groups (interaction p value for age group = .35). CONCLUSION: Symptomatic VTE and VTE-related death occur frequently in older patients with acute medical illness. The benefit/risk profile of rivaroxaban in patients ≥75 years of age appears consistent with that observed in the general population.
Sujet(s)
Rivaroxaban , Thromboembolisme veineux , Post-cure , Sujet âgé , Anticoagulants/effets indésirables , Humains , Sortie du patient , Facteurs de risque , Rivaroxaban/effets indésirables , Résultat thérapeutique , Thromboembolisme veineux/diagnostic , Thromboembolisme veineux/traitement médicamenteux , Thromboembolisme veineux/prévention et contrôleRÉSUMÉ
The storage of solar energy in chemical bonds will depend on pH-universal catalysts that are not only impervious to acid, but actually thrive in it. Whereas other homogeneous water oxidation catalysts are less active in acid, we report a catalyst that maintained high electrocatalytic turnover frequency at pH values as low as 1.1 and 0.43 (kcat =1501±608â s-1 and 831±254â s-1 , respectively). Moreover, current densities, related to catalytic reaction rates, ranged from 15 to 50â mA cm-2 mM-1 comparable to those reported for state-of-the-art heterogeneous catalysts and 30 to 100 times greater than those measured for two prominent literature homogeneous catalysts at pHâ 1.1 and 0.43. The catalyst also exhibited excellent durability when a chemical oxidant was used (CeIV , 7400 turnovers, TOF 0.88â s-1 ). Preliminary computational studies suggest that the unusual active-site sulfonate group acts a proton relay even in strong acid, as intended.
RÉSUMÉ
Many cancers lack the expression of methylthioadenosine phosphorylase (MTAP). These cancers require adenylosuccinate synthetase (AdSS) for nucleic acid synthesis. By inhibiting adenylosuccinate synthetase, we potentially have a new therapeutic agent. Bisubstrate inhibitors were synthesized and evaluated against purified AdSS. The best activity was obtained with adenosine bearing a four-carbon linker that connects the N-formyl-N-hydroxy moiety to the 6-position of the purine nucleoside.
Sujet(s)
Conception de médicament , Antienzymes/pharmacologie , Nucléoside purique/pharmacologie , Antienzymes/synthèse chimique , Antienzymes/composition chimique , Humains , Structure moléculaire , Nucléoside purique/synthèse chimique , Nucléoside purique/composition chimique , Purine nucleoside phosphorylaseRÉSUMÉ
Optical signals of gas temperature, species concentration, and electric field are monitored in simple mixtures at room temperature and in the fuel-rich region of a hydrogen diffusion flame. A two-beam pure-rotational coherent anti-Stokes Raman scattering (CARS) approach was utilized for the temperature and species detection, where the combined pump/Stokes pulse doubled as the electric field induced second harmonic generation (EFISHG) pump for the electric field detection. Time-averaged EFISHG signals in environments with argon, nitrogen, oxygen, hydrogen, and air were found to match the relative hyperpolarizabilities of the molecules tabulated in literature. Measurements in a dynamic H2-air environment represented the ability to monitor the signal dependence of species on a single-shot basis. Time-averaged EFISHG signals in different thermal environments showed the expected â1T2 EFISHG signal dependence when also correcting for relative H2/N2 concentrations. Finally, measurements in a flame showed the ability to monitor the EFISHG signal dependence on the gas temperature on a single-shot basis in a plasma discharge environment.
RÉSUMÉ
Current and past clinical trials in pulmonary hypertension, while valuable, are limited by the absence of mechanistic aims, by dissatisfaction with endpoints and the inability to share data. Clinical studies in pulmonary hypertension might be enhanced by a consortium approach that utilizes the expertise of academic medicine, the treatment initiatives of the pharmaceutical industry and study design from funding agencies interested in biological mechanisms. A meeting of interested parties, the Pulmonary Hypertension Academic Research Consortium (PHARC), was held from 30 April to 1 May 2012 in Bethesda, Maryland. Members at the conference were from the USA Federal Drug Administration (FDA); pharmaceutical industry (Pfizer, Novartis, Bayer and Gilead); USA National Institutes of Health (NHLBI); the Pulmonary Vascular Research Institute (PVRI), a non-governmental organization (NGO); and research and clinical members of pulmonary hypertension programs of international scope. A recommendation to develop a clinical trials consortium was the product of the working group on academic standards in clinical trials. The working group concluded that clinical trials hold immense promise to move the field of pulmonary hypertension forward if the trials are designed by a consortium with input from multiple groups. This would result in study design, conduct and analysis determined by consortium members with a high degree of independent function. The components of a well-balanced consortium that give it scientific effectiveness are: (1) the consortium can work with multiple companies simultaneously; (2) sponsors with special interests, such as testing biological mechanisms, can add investigations to a study at lower cost than with present granting strategies; (3) data handling including archiving, analysis and future sharing would be improved; (4) ancillary studies supported by the collection and dissemination of tissues and fluids would generate a broader approach to discovery than is now possible; and (5) development of improved endpoints in consultation with regulatory agencies, industry and academia would be possible.
RÉSUMÉ
Fe(II)- and α-ketoglutarate (α-KG)-dependent dioxygenases are a large and diverse superfamily of mononuclear, non-heme enzymes that perform a variety of oxidative transformations typically coupling oxidative decarboxylation of α-KG with hydroxylation of a prime substrate. The biosynthetic gene clusters for several nucleoside antibiotics that contain a modified uridine component, including the lipopeptidyl nucleoside A-90289 from Streptomyces sp. SANK 60405, have recently been reported, revealing a shared open reading frame with sequence similarity to proteins annotated as α-KG:taurine dioxygenases (TauD), a well characterized member of this dioxygenase superfamily. We now provide in vitro data to support the functional assignment of LipL, the putative TauD enzyme from the A-90289 gene cluster, as a non-heme, Fe(II)-dependent α-KG:UMP dioxygenase that produces uridine-5'-aldehyde to initiate the biosynthesis of the modified uridine component of A-90289. The activity of LipL is shown to be dependent on Fe(II), α-KG, and O(2), stimulated by ascorbic acid, and inhibited by several divalent metals. In the absence of the prime substrate UMP, LipL is able to catalyze oxidative decarboxylation of α-KG, although at a significantly reduced rate. The steady-state kinetic parameters using optimized conditions were determined to be K(m)(α-KG) = 7.5 µM, K(m)(UMP) = 14 µM, and k(cat) ≈ 80 min(-1). The discovery of this new activity not only sets the stage to explore the mechanism of LipL and related dioxygenases further but also has critical implications for delineating the biosynthetic pathway of several related nucleoside antibiotics.
Sujet(s)
Azépines/métabolisme , Protéines bactériennes/métabolisme , Mixed function oxygenases/métabolisme , Streptomyces/enzymologie , Uracile/biosynthèse , Azépines/composition chimique , Protéines bactériennes/composition chimique , Protéines bactériennes/génétique , Catalyse , Escherichia coli/enzymologie , Escherichia coli/génétique , Fer/composition chimique , Fer/métabolisme , Acides cétoglutariques/composition chimique , Acides cétoglutariques/métabolisme , Mixed function oxygenases/composition chimique , Mixed function oxygenases/génétique , Famille multigénique/physiologie , Oxygène/composition chimique , Oxygène/métabolisme , Uracile/analogues et dérivés , Uracile/composition chimiqueRÉSUMÉ
Several derivatives of hadacidin have been developed and evaluated for activity against adenylosuccinate synthetase.
Sujet(s)
Glycine/analogues et dérivés , Adenylosuccinate synthase/antagonistes et inhibiteurs , Adenylosuccinate synthase/métabolisme , Glycine/synthèse chimique , Glycine/composition chimique , Glycine/pharmacologie , Penicillium/métabolismeRÉSUMÉ
Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in many retinal diseases is reactive Müller cell gliosis, an untreatable condition that leads to tissue scarring and even blindness. Here, we demonstrate that the vimentin-targeting small molecule withaferin A (WFA) is a novel chemical probe of GFAP. Using molecular modeling studies that build on the x-ray crystal structure of tetrameric vimentin rod 2B domain we reveal that the WFA binding site is conserved in the corresponding domain of tetrameric GFAP. Consequently, we demonstrate that WFA covalently binds soluble recombinant tetrameric human GFAP at cysteine 294. In cultured primary astrocytes, WFA binds to and down-regulates soluble vimentin and GFAP expression to cause cell cycle G(0)/G(1) arrest. Exploiting a chemical injury model that overexpresses vimentin and GFAP in retinal Müller glia, we demonstrate that systemic delivery of WFA down-regulates soluble vimentin and GFAP expression in mouse retinas. This pharmacological knockdown of soluble IFs results in the impairment of GFAP filament assembly and inhibition of cell proliferative response in Müller glia. We further show that a more severe GFAP filament assembly deficit manifests in vimentin-deficient mice, which is partly rescued by WFA. These findings illustrate WFA as a chemical probe of type III IFs and illuminate this class of withanolide as a potential treatment for diverse gliosis-dependent central nervous system traumatic injury conditions and diseases, and for orphan IF-dependent pathologies.
Sujet(s)
Ergostérol/analogues et dérivés , Protéine gliofibrillaire acide/métabolisme , Gliose , Rétine , Dégénérescence de la rétine , Vimentine/métabolisme , Animaux , Astrocytes/cytologie , Astrocytes/effets des médicaments et des substances chimiques , Astrocytes/métabolisme , Cycle cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Cycline D3/métabolisme , Inhibiteur p27 de kinase cycline-dépendante/métabolisme , Ergostérol/composition chimique , Ergostérol/métabolisme , Ergostérol/pharmacologie , Protéine gliofibrillaire acide/génétique , Gliose/métabolisme , Gliose/anatomopathologie , Humains , Souris , Souris knockout , Modèles moléculaires , Structure secondaire des protéines , Protéines recombinantes/génétique , Protéines recombinantes/métabolisme , Rétine/effets des médicaments et des substances chimiques , Rétine/métabolisme , Rétine/anatomopathologie , Dégénérescence de la rétine/métabolisme , Dégénérescence de la rétine/anatomopathologie , Vimentine/composition chimique , Vimentine/génétique , WithanolidesRÉSUMÉ
There are two independent molecules in the asymmetric unit of the title cyclo-hexa-none derivative, C(14)H(24)OS, in which both cyclo-hexane rings exhibit chair conformations. They are also equatorial to each other, which permits the ethanethiol substituent to be in a syn conformation with the α-H atom of the parent attached cyclo-hexa-none.
RÉSUMÉ
PURPOSE: The copper transporter 1 (CTR1) is a major influx transporter for platinum drugs. However, the accumulation of cisplatin in human ovarian carcinoma cells is limited by the fact that cisplatin triggers the down-regulation and proteasomal degradation of CTR1, thereby limiting its own uptake. We sought to determine whether proteasome inhibition using bortezomib would prevent human CTR1 (hCTR1) degradation and increase platinum accumulation in ovarian cancer cells. EXPERIMENTAL DESIGN: The effects of bortezomib on human hCTR1 expression and cisplatin accumulation were measured by Western blot, flow cytometric, and confocal digital imaging analyses. Platinum accumulation was measured by inductively coupled plasma mass spectrometry and bortezomib concentrations by liquid chromatography/mass spectrometry. RESULTS: Bortezomib blocked the cisplatin-induced down-regulation of hCTR1 in a concentration-dependent manner and increased cisplatin uptake 1.6- to 2.4-fold. Median effect analysis showed a combination index of 0.37 at 50% cell kill, indicating a high level of synergy. The effect of bortezomib was muted in cells lacking both alleles of CTR1, showing that bortezomib was working primarily through its effect on blocking hCTR1 degradation. I.p. administration of bortezomib produced a peritoneal/plasma area under the curve ratio of 252 in a murine model. I.p. administration of bortezomib before i.p. cisplatin increased platinum accumulation in peritoneal tumors by 33% (P = 0.006). CONCLUSIONS: Proteasomal inhibition prevented cisplatin-induced down-regulation of hCTR1 in ovarian cancer cells and enhanced drug uptake and cell killing in a synergistic manner. Bortezomib shows a large pharmacologic advantage when administered i.p. There is a strong rationale for the combined i.p. administration of bortezomib and cisplatin.
Sujet(s)
Antinéoplasiques/pharmacologie , Acides boroniques/pharmacologie , Transporteurs de cations/métabolisme , Cisplatine/pharmacologie , Systèmes de délivrance de médicaments , Régulation de l'expression des gènes tumoraux , Tumeurs de l'ovaire/traitement médicamenteux , Tumeurs du péritoine/traitement médicamenteux , Pyrazines/pharmacologie , Animaux , Bortézomib , Lignée cellulaire tumorale , Transporteur-1 du cuivre , Femelle , Humains , Souris , Souris nude , Proteasome endopeptidase complex/métabolismeRÉSUMÉ
3-Hydroxyanthranilic acid (HAA), a compound generated during tryptophan metabolism initiated by indoleamine 2,3-dioxygenase, is known to induce T cell death, but its molecular target is not known. Here we report that HAA inhibits NF-kappaB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-kappaB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-kappaB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-kappaB activation or induce cell death upon Toll-like receptor 4 stimulation in dendritic cells. Thus, HAA is a natural inhibitor that restrains T cell expansion and activation.
Sujet(s)
Acide 3-hydroxy-anthranilique/pharmacologie , Asthme/immunologie , Asthme/prévention et contrôle , Protein-Serine-Threonine Kinases/antagonistes et inhibiteurs , Protein-Serine-Threonine Kinases/métabolisme , Lymphocytes T/effets des médicaments et des substances chimiques , Lymphocytes T/enzymologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Asthme/induit chimiquement , Lignée cellulaire , Modèles animaux de maladie humaine , Activation enzymatique/effets des médicaments et des substances chimiques , Humains , Activation des lymphocytes/effets des médicaments et des substances chimiques , Souris , Modèles moléculaires , Facteur de transcription NF-kappa B/métabolisme , Phosphorylation/effets des médicaments et des substances chimiques , Protein-Serine-Threonine Kinases/composition chimique , Structure tertiaire des protéines , Pyruvate dehydrogenase acetyl-transferring kinase , Récepteurs aux antigènes des cellules T/immunologie , Récepteurs aux antigènes des cellules T/métabolisme , Lymphocytes T/cytologie , Lymphocytes T/immunologieRÉSUMÉ
Full details of a systematic exploration of the intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles are disclosed in which the scope and utility of the reaction are defined.
Sujet(s)
Oxadiazoles/composition chimique , Cyclisation , Structure moléculaire , StéréoisomérieRÉSUMÉ
A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).