This paper concerns conditions for the approximation of functions in certain general spaces using radial-basis-function networks. It has been shown in recent papers that certain classes of radial-basis-function networks are broad enough for universal approximation. In this paper these results are considerably extended and sharpened.

While tetracyclines are an important class of antibiotics in agriculture and the clinic, their efficacy is threatened by increasing resistance. Resistance to tetracyclines can occur through efflux, ribosomal protection, or enzymatic inactivation. Surprisingly, tetracycline enzymatic inactivation has remained largely unexplored despite providing the distinct advantage of antibiotic clearance. The tetracycline destructases are a recently-discovered family of tetracycline-inactivating flavoenzymes from pathogens and soil metagenomes with a high potential for broad dissemination. Here, we show tetracycline destructases accommodate tetracycline-class antibiotics in diverse and novel orientations for catalysis, and antibiotic binding drives unprecedented structural dynamics facilitating tetracycline inactivation. We identify a key inhibitor binding mode that locks the flavin adenine dinucleotide cofactor in an inactive state, functionally rescuing tetracycline activity. Our results reveal the potential of a novel tetracycline/tetracycline destructase inhibitor combination therapy strategy to overcome resistance by enzymatic inactivation and restore the use of an important class of antibiotics.

Industrial symbiosis (IS), one of the founding notions within the field of industrial ecology, has diffused throughout significant parts of the world as a practice that can reduce the ecological impact of the industrial processes of groups of firms. In this article, we propose a fresh look at this research topic, building on the considerable advances that have been made in the last 15 years in understanding how IS comes about. We propose a conceptual and theoretical framework for taking on the challenge of comparative analysis at a global level. This requires developing an approach to address a solution to the problem of equivalence: the difficulty of comparing instances of IS across different institutional contexts. The proposed framework emphasizes IS as a process and attempts to address the obstacles to comparative study by (1) identifying terminology to examine IS variants, (2) providing a typology of IS dynamics, and (3) formulating key research questions to illuminate a way forward. In developing our argument, we build on the collective experiences of collaborative research efforts in North America, Europe, and Asia as evidenced in recent overviews of the literature. Note:The PLUS sign indicates the name of the core organization and that others from the same region or category also participated on the named team, as appropriate. Names of team leaders appear in bold.

Isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway generates commercially important products and is a target for antimicrobial drug development. MEP pathway regulation is poorly understood in microorganisms. We employ a forward genetics approach to understand MEP pathway regulation in the malaria parasite, Plasmodium falciparum. The antimalarial fosmidomycin inhibits the MEP pathway enzyme deoxyxylulose 5-phosphate reductoisomerase (DXR). Fosmidomycin-resistant P. falciparum are enriched for changes in the PF3D7_1033400 locus (hereafter referred to as PfHAD1), encoding a homologue of haloacid dehalogenase (HAD)-like sugar phosphatases. We describe the structural basis for loss-of-function PfHAD1 alleles and find that PfHAD1 dephosphorylates a variety of sugar phosphates, including glycolytic intermediates. Loss of PfHAD1 is required for fosmidomycin resistance. Parasites lacking PfHAD1 have increased MEP pathway metabolites, particularly the DXR substrate, deoxyxylulose 5-phosphate. PfHAD1 therefore controls substrate availability to the MEP pathway. Because PfHAD1 has homologs in plants and bacteria, other HAD proteins may be MEP pathway regulators.

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