Unified prebiotically plausible synthesis of pyrimidine and purine RNA ribonucleotides.

Theories about the origin of life require chemical pathways that allow formation of life's key building blocks under prebiotically plausible conditions. Complex molecules like RNA must have originated from small molecules whose reactivity was guided by physico-chemical processes. RNA is constructed from purine and pyrimidine nucleosides, both of which are required for accurate information transfer, and thus Darwinian evolution. Separate pathways to purines and pyrimidines have been reported, but their concurrent syntheses remain a challenge. We report the synthesis of the pyrimidine nucleosides from small molecules and ribose, driven solely by wet-dry cycles. In the presence of phosphate-containing minerals, 5'-mono- and diphosphates also form selectively in one-pot reactions. The pathway is compatible with purine synthesis, allowing the concurrent formation of all Watson-Crick bases.

Characteristics of stakeholder involvement in systematic and rapid reviews: a methodological review in the area of health services research.

OBJECTIVE: Engaging stakeholders in reviews is considered to generate more relevant evidence and to facilitate dissemination and use. As little is known about stakeholder involvement, we assessed the characteristics of their engagement in systematic and rapid reviews and the methodological quality of included studies. Stakeholders were people with a particular interest in the research topic. DESIGN: Methodological review. SEARCH STRATEGY: Four databases (Medline, Embase, Cochrane database of systematic reviews, databases of the University of York, Center for Reviews and Dissemination (CRD)) were searched based on an a priori protocol. Four types of reviews (Cochrane and non-Cochrane systematic reviews, rapid and CRD rapid reviews) were retrieved between January 2011 and October 2015, pooled by potential review type and duplicates excluded. Articles were randomly ordered and screened for inclusion and exclusion criteria until 30 reviews per group were reached. Their methodological quality was assessed using AMSTAR and stakeholder characteristics were collected. RESULTS: In total, 57 822 deduplicated citations were detected with potential non-Cochrane systematic reviews being the biggest group (56 986 records). We found stakeholder involvement in 13% (4/30) of Cochrane, 20% (6/30) of non-Cochrane, 43% (13/30) of rapid and 93% (28/30) of CRD reviews. Overall, 33% (17/51) of the responding contact authors mentioned positive effects of stakeholder involvement. A conflict of interest statement remained unmentioned in 40% (12/30) of non-Cochrane and in 27% (8/30) of rapid reviews, but not in Cochrane or CRD reviews. At most, half of non-Cochrane and rapid reviews mentioned an a priori study protocol in contrast to all Cochrane reviews. CONCLUSION: Stakeholder engagement was not general practice, except for CRD reviews, although it was more common in rapid reviews. Reporting factors, such as including an a priori study protocol and a conflict of interest statement should be considered in conjunction with involving stakeholders.

A one-pot, water compatible synthesis of pyrimidine nucleobases under plausible prebiotic conditions.

Herein, we report a new prebiotically plausible pathway towards a pyrimidine nucleobase in continuous manner. The route involves simultaneous methylation and carbamoylation of cyanoacetylene-derived α,ß-unsaturated thioamide with N-methyl-N-nitrosourea (MNU) in aqueous media. This provides S-methylpyrimidinone in one-pot, which can be converted into a variety of 4-substituted pyrimidine nucleobases including cytosine and uracil.

Emissive Synthetic Cofactors: A Highly Responsive NAD+ Analogue Reveals Biomolecular Recognition Features.

Apart from its vital function as a redox cofactor, nicotinamide adenine dinucleotide (NAD+ ) has emerged as a crucial substrate for NAD+ -consuming enzymes, including poly(ADP-ribosyl)transferase 1 (PARP1) and CD38/CD157. Their association with severe diseases, such as cancer, Alzheimer's disease, and depressions, necessitates the development of new analytical tools based on traceable NAD+ surrogates. Here, the synthesis, photophysics and biochemical utilization of an emissive, thieno[3,4-d]pyrimidine-based NAD+ surrogate, termed Nth AD+ , are described. Its preparation was accomplished by enzymatic conversion of synthetic th ATP by nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1). The new NAD+ analogue possesses useful photophysical features including redshifted absorption and emission maxima as well as a relatively high quantum yield. Serving as a versatile substrate, Nth AD+ was reduced by alcohol dehydrogenase (ADH) to Nth ADH and afforded th ADP-ribose (th ADPr) upon hydrolysis by NAD+ -nucleosidase (NADase). Furthermore, Nth AD+ was engaged in cholera toxin A (CTA)-catalyzed mono(th ADP-ribosyl)ation, but was found incapable in promoting PARP1-mediated poly(th ADP-ribosyl)ation. Due to its high photophysical responsiveness, Nth AD+ is suited for spectroscopic real-time monitoring. Intriguingly, and as an N7-lacking NAD+ surrogate, the thieno-based cofactor showed reduced compatibility (i.e., functional similarity compared to native NAD+ ) relative to its isothiazolo-based analogue. The distinct tolerance, displayed by diverse NAD+ producing and consuming enzymes, suggests unique biological recognition features and dependency on the purine N7 moiety, which is found to be of importance, if not essential, for PARP1-mediated reactions.