CRISPR-Cas antimicrobials: Challenges and future prospects

This is the final version. Available from PLoS via the DOI in this record.Antimicrobial resistance (AMR) poses a serious threat to modern medicine and may render common infections untreatable. The discovery of new antibiotics has come to a relative standstill during the last decade [1], and developing novel approaches to tackle the spread of AMR genes will require significant efforts in the coming years [2]. In 2014, several groups independently demonstrated how CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR–associated), a bacterial immune system now widely used for genome editing, can selectively remove AMR genes from bacterial populations. Here, we discuss the current state of the field of CRISPR-Cas antimicrobials, the challenges ahead, and how they may be overcome.Biotechnology & Biological Sciences Research Council (BBSRC)Medical Research CouncilNatural Environment Research CouncilWellcome TrustEuropean Research CouncilPeople Programme (Marie Curie Actions) of the European Union’s Horizon 202

11 x 11 Domineering is Solved: The first player wins

We have developed a program called MUDoS (Maastricht University Domineering Solver) that solves Domineering positions in a very efficient way. This enables the solution of known positions so far (up to the 10 x 10 board) much quicker (measured in number of investigated nodes). More importantly, it enables the solution of the 11 x 11 Domineering board, a board up till now far out of reach of previous Domineering solvers. The solution needed the investigation of 259,689,994,008 nodes, using almost half a year of computation time on a single simple desktop computer. The results show that under optimal play the first player wins the 11 x 11 Domineering game, irrespective if Vertical or Horizontal starts the game. In addition, several other boards hitherto unsolved were solved. Using the convention that Vertical starts, the 8 x 15, 11 x 9, 12 x 8, 12 x 15, 14 x 8, and 17 x 6 boards are all won by Vertical, whereas the 6 x 17, 8 x 12, 9 x 11, and 11 x 10 boards are all won by Horizontal

Forman's Ricci curvature - From networks to hypernetworks

Networks and their higher order generalizations, such as hypernetworks or multiplex networks are ever more popular models in the applied sciences. However, methods developed for the study of their structural properties go little beyond the common name and the heavy reliance of combinatorial tools. We show that, in fact, a geometric unifying approach is possible, by viewing them as polyhedral complexes endowed with a simple, yet, the powerful notion of curvature - the Forman Ricci curvature. We systematically explore some aspects related to the modeling of weighted and directed hypernetworks and present expressive and natural choices involved in their definitions. A benefit of this approach is a simple method of structure-preserving embedding of hypernetworks in Euclidean N-space. Furthermore, we introduce a simple and efficient manner of computing the well established Ollivier-Ricci curvature of a hypernetwork.Comment: to appear: Complex Networks '18 (oral presentation

Discovering duplicate tasks in transition systems for the simplification of process models

This work presents a set of methods to improve the understandability of process models. Traditionally, simplification methods trade off quality metrics, such as fitness or precision. Conversely, the methods proposed in this paper produce simplified models while preserving or even increasing fidelity metrics. The first problem addressed in the paper is the discovery of duplicate tasks. A new method is proposed that avoids overfitting by working on the transition system generated by the log. The method is able to discover duplicate tasks even in the presence of concurrency and choice. The second problem is the structural simplification of the model by identifying optional and repetitive tasks. The tasks are substituted by annotated events that allow the removal of silent tasks and reduce the complexity of the model. An important feature of the methods proposed in this paper is that they are independent from the actual miner used for process discovery.Peer ReviewedPostprint (author's final draft

Domestic ventilation rates, indoor humidity and dust mite allergens : are our homes causing the asthma pandemic?

This paper is concerned with historical changes in domestic ventilation rates, relative humidity and the associated risk of house dust mite colonization. A controlled trial evaluated allergen and water vapour control measures on the level of house dust mite (HDM) Der p1 allergen and indoor humidity, concurrently with changes in lung function in 54 subjects who completed the protocol. Mechanical heat recovery ventilation units significantly reduced moisture content in the active group, while HDM allergen reservoirs in carpets and beds were reduced by circa 96%. Self reported health status confirmed a significant clinical improvement in the active group. The study can form the basis for assessing minimum winter ventilation rates that can suppress RH below the critical ambient equilibrium humidity of 60% and thus inhibit dust mite colonization and activity in temperate and maritime in' uenced climatic regions

First principles modelling of magnesium titanium hydrides

Mixing Mg with Ti leads to a hydride Mg(x)Ti(1-x)H2 with markedly improved (de)hydrogenation properties for x < 0.8, as compared to MgH2. Optically, thin films of Mg(x)Ti(1-x)H2 have a black appearance, which is remarkable for a hydride material. In this paper we study the structure and stability of Mg(x)Ti(1-x)H2, x= 0-1 by first-principles calculations at the level of density functional theory. We give evidence for a fluorite to rutile phase transition at a critical composition x(c)= 0.8-0.9, which correlates with the experimentally observed sharp decrease in (de)hydrogenation rates at this composition. The densities of states of Mg(x)Ti(1-x)H2 have a peak at the Fermi level, composed of Ti d states. Disorder in the positions of the Ti atoms easily destroys the metallic plasma, however, which suppresses the optical reflection. Interband transitions result in a featureless optical absorption over a large energy range, causing the black appearance of Mg(x)Ti(1-x)H2.Comment: 22 pages, 9 figures, 4 table

Constraints on the shapes of galaxy dark matter haloes from weak gravitational lensing

We study the shapes of galaxy dark matter haloes by measuring the anisotropy of the weak gravitational lensing signal around galaxies in the second Red-sequence Cluster Survey (RCS2). We determine the average shear anisotropy within the virial radius for three lens samples: all galaxies with 19<m_r'<21.5, and the `red' and `blue' samples, whose lensing signals are dominated by massive low-redshift early-type and late-type galaxies, respectively. To study the environmental dependence of the lensing signal, we separate each lens sample into an isolated and clustered part and analyse them separately. We also measure the azimuthal dependence of the distribution of physically associated galaxies around the lens samples. We find that these satellites preferentially reside near the major axis of the lenses, and constrain the angle between the major axis of the lens and the average location of the satellites to =43.7 deg +/- 0.3 deg for the `all' lenses, =41.7 deg +/- 0.5 deg for the `red' lenses and =42.0 deg +/- 1.4 deg for the `blue' lenses. For the `all' sample, we find that the anisotropy of the galaxy-mass cross-correlation function =0.23 +/- 0.12, providing weak support for the view that the average galaxy is embedded in, and preferentially aligned with, a triaxial dark matter halo. Assuming an elliptical Navarro-Frenk-White (NFW) profile, we find that the ratio of the dark matter halo ellipticity and the galaxy ellipticity f_h=e_h/e_g=1.50+1.03-1.01, which for a mean lens ellipticity of 0.25 corresponds to a projected halo ellipticity of e_h=0.38+0.26-0.25 if the halo and the lens are perfectly aligned. For isolated galaxies of the `all' sample, the average shear anisotropy increases to =0.51+0.26-0.25 and f_h=4.73+2.17-2.05, whilst for clustered galaxies the signal is consistent with zero. (abridged)Comment: 28 pages, 23 figues, accepted for publication in A&

CRISPR-Cas immunity leads to a coevolutionary arms race between Streptococcus thermophilus and lytic phage

This is the final version. Available on open access from the Royal Society via the DOI in this recordData accessibility: The datasets supporting this article have been uploaded as part of the electronic supplementary material, tables.CRISPR-Cas is an adaptive prokaryotic immune system that prevents phage infection. By incorporating phage-derived 'spacer' sequences into CRISPR loci on the host genome, future infections from the same phage genotype can be recognized and the phage genome cleaved. However, the phage can escape CRISPR degradation by mutating the sequence targeted by the spacer, allowing them to re-infect previously CRISPR-immune hosts, and theoretically leading to coevolution. Previous studies have shown that phage can persist over long periods in populations of Streptococcus thermophilus that can acquire CRISPR-Cas immunity, but it has remained less clear whether this coexistence was owing to coevolution, and if so, what type of coevolutionary dynamics were involved. In this study, we performed highly replicated serial transfer experiments over 30 days with S. thermophilus and a lytic phage. Using a combination of phenotypic and genotypic data, we show that CRISPR-mediated resistance and phage infectivity coevolved over time following an arms race dynamic, and that asymmetry between phage infectivity and host resistance within this system eventually causes phage extinction. This work provides further insight into the way CRISPR-Cas systems shape the population and coevolutionary dynamics of bacteria-phage interactions. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'.European Union Horizon 202

Minard revisited: exploring augmented reality in information design

This study intends to test and confirm the interest and viability of incorporating augmented reality (AR) technologies in cultural mediation driven by information design, focusing on narrative representation. It is specifically intended to explore semantic relations between reality and virtuality in augmented narratives, ie. expanded narratives through the multimodality enhanced by the use of interactive processes based in augmented reality systems. Departing from Charles Minard’s Figurative Map (1869), three experiments were conducted, in order to reinterpret the program embodied in that artefact, testing several hypotheses in which, through augmented reality, the combination of different modes and media configures different semantic relations between real and virtual. The action-reflection approach undertaken with Figurative Map experiments enabled us to observe and openly systematize different augmented reality functions regarding the physical instance, which can potentially expand traditional forms of information design. Although they are not entirely extrapolatable, the proposal of virtual functions regarding reality were repurposed and adapted from the illustration field, specifically from the semantic relation between text and image. It is acknowledged that this is an open model to be reconsidered and reformulated through several action-reflection iterations and fostered through the narrative study.publishe