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The nature of the first genetic polymer is the subject of major debate 1 . Although the ‘RNA world’ theory suggests that RNA was the first replicable information carrier of the prebiotic era—that is, prior to the dawn of life 2 , 3 —other evidence implies that life may have started with a heterogeneous nucleic acid genetic system that included both RNA and DNA 4 . Such a theory streamlines the eventual ‘genetic takeover’ of homogeneous DNA from RNA as the principal information-storage molecule, but requires a selective abiotic synthesis of both RNA and DNA building blocks in the same local primordial geochemical scenario. Here we demonstrate a high-yielding, completely stereo-, regio- and furanosyl-selective prebiotic synthesis of the purine deoxyribonucleosides: deoxyadenosine and deoxyinosine. Our synthesis uses key intermediates in the prebiotic synthesis of the canonical pyrimidine ribonucleosides (cytidine and uridine), and we show that, once generated, the pyrimidines persist throughout the synthesis of the purine deoxyribonucleosides, leading to a mixture of deoxyadenosine, deoxyinosine, cytidine and uridine. These results support the notion that purine deoxyribonucleosides and pyrimidine ribonucleosides may have coexisted before the emergence of life 5 . A prebiotic synthesis of the purine DNA nucleosides (deoxyadenosine and deoxyinosine) in which the pyrimidine RNA nucleosides (cytidine and uridine) persist has implications for the coexistence of DNA and RNA at the dawn of life.

We classify the weakly interacting fixed points of general gauge theories coupled to matter and explain how the competition between gauge and matter fluctuations gives rise to a rich spectrum of high- and low-energy fixed points. The pivotal role played by Yukawa couplings is emphasised. Necessary and sufficient conditions for asymptotic safety of gauge theories are also derived, in conjunction with strict no go theorems. Implications for phase diagrams of gauge theories and physics beyond the Standard Model are indicated.

A bstract Building on recent advances in the understanding of gauge-Yukawa theories we explore possibilities to UV-complete the Standard Model in an asymptotically safe manner. Minimal extensions are based on a large flavor sector of additional fermions coupled to a scalar singlet matrix field. We find that asymptotic safety requires fermions in higher representations of SU(3) C × SU(2) L . Possible signatures at colliders are worked out and include R -hadron searches, diboson signatures and the evolution of the strong and weak coupling constants.

Sesterterpenoids are a rare terpene class harboring untapped chemodiversity and bioactivities. Their structural diversity originates primarily from the scaffold-generating sesterterpene synthases (STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (−)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (−)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT–TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering.

The last common ancestor of all living arthropods had biramous postantennal appendages, with an endopodite and exopodite branching off the limb base. Morphological evidence for homology of these rami between crustaceans and chelicerates has, however, been challenged by data from clonal composition and from knockout of leg patterning genes. Cambrian arthropod fossils have been cited as providing support for competing hypotheses about biramy but have shed little light on additional lateral outgrowths, known as exites. Here we draw on microtomographic imaging of the Cambrian great-appendage arthropod Leanchoilia to reveal a previously undetected exite at the base of most appendages, composed of overlapping lamellae. A morphologically similar, and we infer homologous, exite is documented in the same position in members of the trilobite-allied Artiopoda. This early Cambrian exite morphology supplements an emerging picture from gene expression that exites may have a deeper origin in arthropod phylogeny than has been appreciated. The common ancestor of all living arthropods had biramous postantennal appendages, with an endopodite and exopodite branching off the limb base. This study uses microtomographic imaging of the Cambrian arthropod Leanchoilia to reveal a previously undetected exite at the base of most appendages, suggesting a deeper origin for exites in arthropod phylogeny.

Unconstrained amides that undergo fast hydrolysis under mild conditions are valuable sources of information about how amide bonds may be activated in enzymatic transformations. We report a compound possessing an unconstrained amide bond surrounded by an amino and a carboxyl group, each mounted in close proximity on a bicyclic scaffold. Fast amide hydrolysis of this model compound was found to depend on the presence of both the amino and carboxyl functions, and to involve a proton transfer in the rate-limiting step. Possible mechanisms for the hydrolytic cleavage and their relevance to peptide bond cleavage catalyzed by natural enzymes are discussed. Experimental observations suggest that the most probable mechanisms of the model compound hydrolysis might include a twisted amide intermediate and a rate-determining proton transfer.

ABSTRACT Purpose To understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context. Methods Multi-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformation pathways as a function of temperature and humidity. XRPD and thermogravimetric analysis (TGA) to characterise bulk samples. Monitoring of in-situ dehydration using solid-state 13 C CP/MAS spectroscopy. Results At 25°C, anhydrous sodium naproxen (AH) transforms directly to one dihydrate polymorph (DH-II). At 50°C, AH transforms stepwise to a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both dihydrate polymorphs transform to the same MH. Conclusions The properties of the polymorphic dihydrate control the transformation pathways of sodium naproxen.

Background In recent years, the development of the [ 18 F]difluoromethyl radical ([ 18 F]2-((difluoromethyl)sulfonyl)benzo[ d ]thiazole, [ 18 F] 4 ), and [ 18 F]difluorocarbene ([ 18 F]1-chloro-4-((difluoromethyl)sulfonyl)benzene, [ 18 F] 10 ) prosthetic groups, has paved the way towards direct 18 F-difluoromethylation in routine PET tracer synthesis with high molar activity. However, limitations in their syntheses may be hindering their widespread adoption by the radiochemistry community. Firstly, the synthesis of the precursors 2-((bromofluoromethyl)thio)benzo[ d ]thiazole ( 3 ) and (bromofluoromethyl)(4-chlorophfenyl)sulfane ( 8 ) requires the use of the ozone-depleting dibromofluoromethane, a reagent that is not-commercially available. Secondly, the reported syntheses of [ 18 F] 4 and [ 18 F] 10 are lengthy and require semi-preparative HPLC purification prior to the 18 F-difluoromethylation step. Finally, in the case of [ 18 F] 10 , very large amounts of precursor material (200 μmol) are required for difluorocarbene insertion. The aim of this work was to develop a halofluorocarbon-free radiosynthesis of [ 18 F] 4 and [ 18 F] 10 on the GE TRACERlab FX FN module. Additionally, another aim was to develop a chromatography-free, fully-automated synthesis of [ 18 F] 10 on the GE FX FN module. Results Precursors 3 and 8 were synthesised in 21% and 54% yield via decarboxylative bromination, which circumvented the need for ozone-depleting dibromofluoromethane. Difluoromethyl reagents [ 18 F] 4 and [ 18 F] 10 were synthesised on a GE FX FN module with semi-prep HPLC purification in 4% and 3% RCY (decay-corrected), respectively. The synthesis of [ 18 F] 10 was further simplified through elimination of the semi-prep HPLC purification in favour of a cartridge-based solid-phase extraction (SPE) trapping and elution approach (on an alumina SPE cartridge loaded in series with a C18 Sep-Pak plus SPE cartridge) to give [ 18 F] 10 in 10.1% ± 1.9% ( n  = 6, decay-corrected) RCY (97% ± 3% RCP, 1.5–11 GBq/μmol). Finally, a fully automated 18 F-difluoromethylation radiosynthesis with [ 18 F] 10 was developed on two GE FX FN modules linked together to yield the model 18 F-difluoromethylated compound in adequate amounts for biological studies, in under two hours (99.0 MBq, 0.8% RCY {decay-corrected}, 1.5 GBq/μmol, 103 min total synthesis time). Therefore, we have established a path forward for routine automated synthesis of radiotracers via [ 18 F]difluorocarbene insertion with [ 18 F] 10 . Conclusions A halofluorocarbon, chromatography-free synthesis on the GE FX FN module afforded difluorocarbene reagent [ 18 F] 10 in 10.1% ± 1.9% RCY (decay-corrected). Additionally, a fully-automated three-step [ 18 F]difluorocarbene insertion radiosynthesis using two tandem FX FN s is described for the first time, providing a path forward to the full automation of [ 18 F]difluorocarbene insertion on two-reactor systems. Graphical abstract

Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated with an increased antibiotic activity against bacterial strains possessing high level vancomycin resistance mediated by the reprogramming of peptidoglycan biosynthesis to use precursors terminating in D-Ala-D-Lac in place of D-Ala-D-Ala. Polymerization occurs via interaction of Zn(II) with the N-terminal methylleucine group of vancomycin, and we show that the activity of other glycopeptide antibiotics with this feature can also be similarly augmented by Zn(II). Construction and analysis of a model strain predominantly using D-Ala-D-Lac precursors for peptidoglycan biosynthesis during normal growth supports the hypothesis that Zn(II) mediated vancomycin polymerization enhances the binding affinity towards these precursors.