The impact of 8-aryl-and 8-heteroaryl-2'-deoxyguanosine derivatives on G-quadruplex formation

Guanine and G-rich oligonucleotides are known to self-assemble in the presence of a variety of cations to form higher ordered structures known as Gquadruplexes. We have synthesized a library of 8-aryl/heteroaryl-2'-deoxyguanosine derivatives (8ArGs) that are also able to self-assemble into quadruplex structures. We demonstrate that the properties of such quadruplexes can be modulated by the nature of the groups attached to the guanine base. These supramolecules are potentially useful in the development of self-assembled nanodevices

Synthesis of 8-heteroaryl-2'-deoxyguanosine derivatives

We describe the synthesis of 8-heteroaromatic-2'-deoxyguanosine analogues using Suzuki-Miyaura or Stille conditions. Unprotected and protected 8-bromo-2â?²-deoxyguanosine was coupled with commercially available heteroarylboronic acids or the trialkyltin derivatives of 2-pyridylbromides either with or without microwave irradiation in good yields

A Klebsiella pneumoniae antibiotic resistance mechanism that subdues host defences and promotes virulence

Klebsiella pneumoniae is an important cause of multidrug-resistant infections worldwide. Recent studies highlight the emergence of multidrug-resistant K.\ua0pneumoniae strains which show resistance to colistin, a last-line antibiotic, arising from mutational inactivation of the mgrB regulatory gene. However, the precise molecular resistance mechanisms of mgrB-associated colistin resistance and its impact on virulence remain unclear. Here, we constructed an mgrB gene K.\ua0pneumoniae mutant and performed characterisation of its lipid A structure, polymyxin and antimicrobial peptide resistance, virulence and inflammatory responses upon infection. Our data reveal that mgrB mutation induces PhoPQ-governed lipid A remodelling which confers not only resistance to polymyxins, but also enhances K. pneumoniae virulence by decreasing antimicrobial peptide susceptibility and attenuating early host defence response activation. Overall, our findings have important implications for patient management and antimicrobial stewardship, while also stressing antibiotic resistance development is not inexorably linked with subdued bacterial fitness and virulence

Enabling collaborative numerical modeling in earth sciences using knowledge infrastructure

Knowledge Infrastructure is an intellectual framework for creating, sharing, and distributing knowledge. In this paper, we use Knowledge Infrastructure to address common barriers to entry to numerical modeling in Earth sciences: computational modeling education, replicating published model results, and reusing published models to extend research. We outline six critical functional requirements: 1) workflows designed for new users; 2) a community-supported collaborative web platform; 3) distributed data storage; 4) a software environment; 5) a personalized cloud-based high-performance computing platform; and 6) a standardized open source modeling framework. Our methods meet these functional requirements by providing three interactive computational narratives for hands-on, problem-based research demonstrating how to use Landlab on HydroShare. Landlab is an open-source toolkit for building, coupling, and exploring two-dimensional numerical models. HydroShare is an online collaborative environment for the sharing of data and models. We describe the methods we are using to accelerate knowledge development by providing a suite of modular and interoperable process components that allows students, domain experts, collaborators, researchers, and sponsors to learn by exploring shared data and modeling resources. The system is designed to support uses on the continuum from fully-developed modeling applications to prototyping research software tools

Education for innovation and entrepreneurship in the food system: the Erasmus+ BoostEdu approach and results

Innovation and entrepreneurship are key factors to provide added value for food systems. Based on the findings of the Erasmus+ Strategic Partnership BoostEdu, the objective of this paper is to provide answers to three knowledge gaps: 1) identify the needs for innovation and entrepreneurship (I&E) in the food sector; 2) understand the best way to organize learning; 3) provide flexibility in turbulent times. BoostEdu aimed to provide a platform for continuing education within I&E for food professionals and was carried out through co-creation workshops and the development of an e-learning course. The results of the project in particular during the Covid-19 pandemics, highlighted the need for flexible access to modules that are complementary to other sources and based on a mix of theoretical concepts and practical experiences. The main lessons learned concern the need of co-creation and co-learning processes to identify suitable practices for the use of innovative digital technologies

Testing fluvial erosion models using the transient response of bedrock rivers to tectonic forcing in the Apennines, Italy

The transient response of bedrock rivers to a drop in base level can be used to discriminate between competing fluvial erosion models. However, some recent studies of bedrock erosion conclude that transient river long profiles can be approximately characterized by a transport‐limited erosion model, while other authors suggest that a detachment‐limited model best explains their field data. The difference is thought to be due to the relative volume of sediment being fluxed through the fluvial system. Using a pragmatic approach, we address this debate by testing the ability of end‐member fluvial erosion models to reproduce the well‐documented evolution of three catchments in the central Apennines (Italy) which have been perturbed to various extents by an independently constrained increase in relative uplift rate. The transport‐limited model is unable to account for the catchments’response to the increase in uplift rate, consistent with the observed low rates of sediment supply to the channels. Instead, a detachment‐limited model with a threshold corresponding to the field‐derived median grain size of the sediment plus a slope‐dependent channel width satisfactorily reproduces the overall convex long profiles along the studied rivers. Importantly, we find that the prefactor in the hydraulic scaling relationship is uplift dependent, leading to landscapes responding faster the higher the uplift rate, consistent with field observations. We conclude that a slope‐ dependent channel width and an entrainment/erosion threshold are necessary ingredients when modeling landscape evolution or mapping the distribution of fluvial erosion rates in areas where the rate of sediment supply to channels is low

Jarlmanns saga og Hermanns: A Translation

Agnete Lothʼs edition of the longer version of Jarlmanns saga og Hermanns included an accompanying English paraphrase (by Gillian Fellows Jensen), but there has never been a full translation into English, much less of the shorter version as edited by Hugo Rydberg. We rectify that omission here, providing a normalized text of Rydbergʼs edition with an English translation alongside in the hopes of making this entertaining saga more accessible to a wider audience

Walking a Supramolecular Tightrope: A Self-Assembled Dodecamer from an 8-Aryl-2′-deoxyguanosine Derivative

Guanosine quadruplexes (GQs) have emerged in recent years as key players in the development of promising functional nanostruc-tures.1 GQs are formed by the self-assembly of guanosine subunits into planar tetramers (G-tetrads) that stack on each other, assisted by the complexation of a metal cation such as K+ or Na+. Alternatively, GQs can also form via the folding of G-rich oligonucleotides (e.g., DNA, RNA) leading to monomeric, dimeric, and tetrameric structures via the association of one, two, or four oligonucleotides, respectively.1d,2 In the latter, the number of G-tetrads is primarily controlled by the sequence (intrinsic param-eter) of the oligonucleotide, whereas, in the former, such control can be primarily achieved by adjusting extrinsic parameters (e.g., concentration, temperature, solvent,3 the cation template,4 and/or its counteranion5). Controlling the molecularity via intrinsic parameters (i.e., structural information in the supramolecula

A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus