Bacterial biodiversity drives the evolution of CRISPR-based phage resistance

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record About half of all bacteria carry genes for CRISPR–Cas adaptive immune systems, which provide immunological memory by inserting short DNA sequences from phage and other parasitic DNA elements into CRISPR loci on the host genome. Whereas CRISPR loci evolve rapidly in natural environments, bacterial species typically evolve phage resistance by the mutation or loss of phage receptors under laboratory conditions. Here we report how this discrepancy may in part be explained by differences in the biotic complexity of in vitro and natural environments. Specifically, by using the opportunistic pathogen Pseudomonas aeruginosa and its phage DMS3vir, we show that coexistence with other human pathogens amplifies the fitness trade-offs associated with the mutation of phage receptors, and therefore tips the balance in favour of the evolution of CRISPR-based resistance. We also demonstrate that this has important knock-on effects for the virulence of P. aeruginosa, which became attenuated only if the bacteria evolved surface-based resistance. Our data reveal that the biotic complexity of microbial communities in natural environments is an important driver of the evolution of CRISPR–Cas adaptive immunity, with key implications for bacterial fitness and virulence.European CommissionNatural Environment Research Council (NERC

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

Transient eco-evolutionary dynamics early in a phage epidemic have strong and lasting impact on the long-term evolution of bacterial defences

This is the final version. Available on open access from Public Library of Science (PLoS) via the DOI in this recordData Availability: Data and code are available online https://doi.org/10.5281/zenodo.8193506Organisms have evolved a range of constitutive (always active) and inducible (elicited by parasites) defence mechanisms, but we have limited understanding of what drives the evolution of these orthogonal defence strategies. Bacteria and their phages offer a tractable system to study this: Bacteria can acquire constitutive resistance by mutation of the phage receptor (surface mutation, sm) or induced resistance through their CRISPR-Cas adaptive immune system. Using a combination of theory and experiments, we demonstrate that the mechanism that establishes first has a strong advantage because it weakens selection for the alternative resistance mechanism. As a consequence, ecological factors that alter the relative frequencies at which the different resistances are acquired have a strong and lasting impact: High growth conditions promote the evolution of sm resistance by increasing the influx of receptor mutation events during the early stages of the epidemic, whereas a high infection risk during this stage of the epidemic promotes the evolution of CRISPR immunity, since it fuels the (infection-dependent) acquisition of CRISPR immunity. This work highlights the strong and lasting impact of the transient evolutionary dynamics during the early stages of an epidemic on the long-term evolution of constitutive and induced defences, which may be leveraged to manipulate phage resistance evolution in clinical and applied settings.Natural Environment Research Council (NERC)European Research Council (ERC)Biotechnology and Biological Sciences Research Council (BBSRC

Supersymmetric Fokker-Planck strict isospectrality

I report a study of the nonstationary one-dimensional Fokker-Planck solutions by means of the strictly isospectral method of supesymmetric quantum mechanics. The main conclusion is that this technique can lead to a space-dependent (modulational) damping of the spatial part of the nonstationary Fokker-Planck solutions, which I call strictly isospectral damping. At the same time, using an additive decomposition of the nonstationary solutions suggested by the strictly isospectral procedure and by an argument of Englefield [J. Stat. Phys. 52, 369 (1988)], they can be normalized and thus turned into physical solutions, i.e., Fokker-Planck probability densities. There might be applications to many physical processes during their transient periodComment: revised version, scheduled for PRE 56 (1 August 1997) as a B

So you call that research? : mending methodological biases in strategy and organization departments of top business schools

We believe that all strategy and organization (SO) scholars should be able to decide for themselves whether to specialize in certain parts of the knowledge cycle or adopt a broader, multi-method view on the scientific process. In a situation of ―methodological pluralism‖, individuals might choose to contribute to the construction of new administrative theories by means of qualitative works like case studies, ethnographies, biographies, or grounded theory studies (e.g., see Denzin and Lincoln, 2000). Others could then specialize in testing these theories by means of experiments, surveys, or longitudinal econometric studies (e.g., see Lewis-Beck, 1987-2004). Again others could combine both approaches in Herculean attempts to conduct high-impact, integrative research with the potential to change the way we understand the field as a whole

Removal of AMR plasmids using a mobile, broad host-range CRISPR-Cas9 delivery tool

This is the final version. Available on open access from the Microbiology Society via the DOI in this recordAntimicrobial resistance (AMR) genes are widely disseminated on plasmids. Therefore, interventions aimed at blocking plasmid uptake and transfer may curb the spread of AMR. Previous studies have used CRISPR-Cas-based technology to remove plasmids encoding AMR genes from target bacteria, using either phage- or plasmid-based delivery vehicles that typically have narrow host ranges. To make this technology feasible for removal of AMR plasmids from multiple members of complex microbial communities, an efficient, broad host-range delivery vehicle is needed. We engineered the broad host-range IncP1-plasmid pKJK5 to encode cas9 programmed to target an AMR gene. We demonstrate that the resulting plasmid pKJK5::csg has the ability to block the uptake of AMR plasmids and to remove resident plasmids from Escherichia coli. Furthermore, due to its broad host range, pKJK5::csg successfully blocked AMR plasmid uptake in a range of environmental, pig- and human-associated coliform isolates, as well as in isolates of two species of Pseudomonas. This study firmly establishes pKJK5::csg as a promising broad host-range CRISPR-Cas9 delivery tool for AMR plasmid removal, which has the potential to be applied in complex microbial communities to remove AMR genes from a broad range of bacterial species.Medical Research Council (MRC)Biotechnology and Biological Sciences Research Council (BBSRC)Lister Institute for Preventative MedicineJPI-AMR HARISSA programme (MISTAR)Bundesministerium für Bildung und ForschungEuropean Research Council (ERC)College of Life and Environmental Sciences, University of Exete

Bound states in the continuum in open Aharonov-Bohm rings

Using formalism of effective Hamiltonian we consider bound states in continuum (BIC). They are those eigen states of non-hermitian effective Hamiltonian which have real eigen values. It is shown that BICs are orthogonal to open channels of the leads, i.e. disconnected from the continuum. As a result BICs can be superposed to transport solution with arbitrary coefficient and exist in propagation band. The one-dimensional Aharonov-Bohm rings that are opened by attaching single-channel leads to them allow exact consideration of BICs. BICs occur at discrete values of energy and magnetic flux however it's realization strongly depend on a way to the BIC's point.Comment: 5 pgaes, 4 figure

Promoting the achievement in schools of children and young people in care

As of March 2017, there were 72,670 children and young people in care in England. The number of looked after children has continued to increase steadily over the last eight years. Sixty per cent of these children are in care because of abuse or neglect and three-quarters are placed in foster care arrangements. Children and young people who are in or have experienced care remain one of the lowest performing groups in terms of educational outcomes. The average Attainment 8 score for children in care is 19.3 compared to 44.5 for non-looked after children and 19.3 for children in need. In 2017 there was an increase in the percentage of children in care achieving a pass in English and Mathematics from 17.4% to 17.5% and also in entering EBacc. Care leavers can experience poorer employment and health outcomes after leaving school compared to their peers. They are over-represented amongst the offender population and those who experience homelessness. However, research is emerging to show that children and young people in care can have very positive experiences of school if they are supported effectively to reach their full potential academically and socially. The purpose of this report is to share practice in local authorities (LA) from across England and Wales that is contributing to improved outcomes and school experiences for children and young people in care. The case studies were all undertaken as part of the Promoting the Achievement of Looked after Children (PALAC) programme between 2014 and 2017. This report presents an account of the programme, including the activities undertaken by the participants and the outcomes of the programme to date for pupils in care and staff in the participating virtual schools (VS) and local authorities

Is food addiction a predictor of treatment outcome among patients with eating disorder?

ObjectivesThe study aimed to examine whether food addiction (FA) was associated with greater severity in both binge eating disorders (BED) and bulimia nervosa and, therefore, to determine if FA was predictive of treatment outcome.MethodSeventy-one adult patients with bulimia nervosa and BED (42 and 29, respectively) participated in the study. FA was assessed by means of the Yale Food Addiction Scale.ResultsThe results confirmed a high prevalence of FA in patients with binge disorders (around 87%) and also its association with a greater severity of the disorder (i.e., related to an increased eating psychopathology and greater frequency of binge eating episodes). Although FA did not appear as a predictor of treatment outcome in general terms, when the diagnostic subtypes were considered separately, FA was associated with poor prognosis in the BED group. In this vein, FA appeared as a mediator in the relationship between ED severity and treatment outcome.DiscussionsOur findings suggest that FA may act as an indicator of ED severity, and it would be a predictor of treatment outcome in BED but not in BN.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152018/1/erv2705.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152018/2/erv2705_am.pd