Use of Nanopore Sequencing to Characterise the Genomic Architecture of Mobile Genetic Elements Encoding bla CTX-M-15 in Escherichia coli Causing Travellers' Diarrhoea

Increasing levels of antimicrobial resistance (AMR) have been documented in Escherichia coli causing travellers’ diarrhoea, particularly to the third-generation cephalosporins. Diarrhoeagenic E. coli (DEC) can act as a reservoir for the exchange of AMR genes between bacteria residing in the human gut, enabling them to survive and flourish through the selective pressures of antibiotic treatments. Using Oxford Nanopore Technology (ONT), we sequenced eight isolates of DEC from four patients’ specimens who had all recently returned to the United Kingdome from Pakistan. Sequencing yielded two DEC harbouring bla(CTX-M-15) per patient, all with different sequence types (ST) and belonging to five different pathotypes. The study aimed to determine whether bla(CTX-M-15) was located on the chromosome or plasmid and to characterise the drug-resistant regions to better understand the mechanisms of onward transmission of AMR determinants. Patients A and C both had one isolate where bla(CTX-M-15) was located on the plasmid (899037 & 623213, respectively) and one chromosomally encoded (899091 & 623214, respectively). In patient B, bla(CTX-M-15) was plasmid-encoded in both DEC isolates (786605 & 7883090), whereas in patient D, bla(CTX-M-15) was located on the chromosome in both DEC isolates (542093 & 542099). The two bla(CTX-M-15)-encoding plasmids associated with patient B were different although the bla(CTX-M-15)-encoding plasmid isolated from 788309 (IncFIB) exhibited high nucleotide similarity to the bla(CTX-M-15)-encoding plasmid isolated from 899037 (patient A). In the four isolates where bla(CTX-M-15) was chromosomally encoded, two isolates (899091 & 542099) shared the same insertion site. The bla(CTX-M-15) insertion site in isolate 623214 was described previously, whereas that of isolate 542093 was unique to this study. Analysis of Nanopore sequencing data enables us to characterise the genomic architecture of mobile genetic elements encoding AMR determinants. These data may contribute to a better understanding of persistence and onward transmission of AMR determinants in multidrug-resistant (MDR) E. coli causing gastrointestinal and extra-intestinal infections

Fast-evolving noncoding sequences in the human genome

BACKGROUND: Gene regulation is considered one of the driving forces of evolution. Although protein-coding DNA sequences and RNA genes have been subject to recent evolutionary events in the human lineage, it has been hypothesized that the large phenotypic divergence between humans and chimpanzees has been driven mainly by changes in gene regulation rather than altered protein-coding gene sequences. Comparative analysis of vertebrate genomes has revealed an abundance of evolutionarily conserved but noncoding sequences. These conserved noncoding (CNC) sequences may well harbor critical regulatory variants that have driven recent human evolution. RESULTS: Here we identify 1,356 CNC sequences that appear to have undergone dramatic human-specific changes in selective pressures, at least 15% of which have substitution rates significantly above that expected under neutrality. The 1,356 'accelerated CNC' (ANC) sequences are enriched in recent segmental duplications, suggesting a recent change in selective constraint following duplication. In addition, single nucleotide polymorphisms within ANC sequences have a significant excess of high frequency derived alleles and high F(ST)values relative to controls, indicating that acceleration and positive selection are recent in human populations. Finally, a significant number of single nucleotide polymorphisms within ANC sequences are associated with changes in gene expression. The probability of variation in an ANC sequence being associated with a gene expression phenotype is fivefold higher than variation in a control CNC sequence. CONCLUSION: Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation

Phytosaurs

p. 57-96, [9] p. of plates (1 folded) : ill. ; 27 cm.Includes bibliographical references (p. 95-96)

Universals, Laws, and Governance

Proponents of the dispositional theory of properties typically claim that their view is not one that offers a realist, governing conception of laws. My first aim is to show that, contrary to this claim, if one commits to dispositionalism then one does not automatically give up on a robust, realist theory of laws. This is because dispositionalism can readily be developed within a Platonic framework of universals. Second, I argue that there are good reasons for realist dispositionalists to favour a Platonic view. This is because the alternative Aristotelian version of dispositionalism, on which universals are immanent entities, is unstable for various reasons. My final aim is to address a common criticism facing Platonic theories of laws, which is the problem of how external entities can play an explanatory role where the world’s law-like patterns of behaviour are concerned. I argue that the Platonists’ response to the one over many problem can help to shed light on this matter, and a possible solution is sketched, one which makes use of the notions of essence, constitution and ontological dependence

Clinical implementation of a knowledge based planning tool for prostate VMAT

Abstract Background A knowledge based planning tool has been developed and implemented for prostate VMAT radiotherapy plans providing a target average rectum dose value based on previously achievable values for similar rectum/PTV overlap. The purpose of this planning tool is to highlight sub-optimal clinical plans and to improve plan quality and consistency. Methods A historical cohort of 97 VMAT prostate plans was interrogated using a RayStation script and used to develop a local model for predicting optimum average rectum dose based on individual anatomy. A preliminary validation study was performed whereby historical plans identified as “optimal” and “sub-optimal” by the local model were replanned in a blinded study by four experienced planners and compared to the original clinical plan to assess whether any improvement in rectum dose was observed. The predictive model was then incorporated into a RayStation script and used as part of the clinical planning process. Planners were asked to use the script during planning to provide a patient specific prediction for optimum average rectum dose and to optimise the plan accordingly. Results Plans identified as “sub-optimal” in the validation study observed a statistically significant improvement in average rectum dose compared to the clinical plan when replanned whereas plans that were identified as “optimal” observed no improvement when replanned. This provided confidence that the local model can identify plans that were suboptimal in terms of rectal sparing. Clinical implementation of the knowledge based planning tool reduced the population-averaged mean rectum dose by 5.6Gy. There was a small but statistically significant increase in total MU and femoral head dose and a reduction in conformity index. These did not affect the clinical acceptability of the plans and no significant changes to other plan quality metrics were observed. Conclusions The knowledge-based planning tool has enabled substantial reductions in population-averaged mean rectum dose for prostate VMAT patients. This suggests plans are improved when planners receive quantitative feedback on plan quality against historical data

International Coercion, Emulation and Policy Diffusion: Market-Oriented Infrastructure Reforms, 1977-1999

Why do some countries adopt market-oriented reforms such as deregulation, privatization and liberalization of competition in their infrastructure industries while others do not? Why did the pace of adoption accelerate in the 1990s? Building on neo-institutional theory in sociology, we argue that the domestic adoption of market-oriented reforms is strongly influenced by international pressures of coercion and emulation. We find robust support for these arguments with an event-history analysis of the determinants of reform in the telecommunications and electricity sectors of as many as 205 countries and territories between 1977 and 1999. Our results also suggest that the coercive effect of multilateral lending from the IMF, the World Bank or Regional Development Banks is increasing over time, a finding that is consistent with anecdotal evidence that multilateral organizations have broadened the scope of the “conditionality” terms specifying market-oriented reforms imposed on borrowing countries. We discuss the possibility that, by pressuring countries into policy reform, cross-national coercion and emulation may not produce ideal outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/40099/3/wp713.pd

US Cosmic Visions: New Ideas in Dark Matter 2017: Community Report

This white paper summarizes the workshop "U.S. Cosmic Visions: New Ideas in Dark Matter" held at University of Maryland on March 23-25, 2017.Comment: 102 pages + reference

Low Fidelity Imitation of Atypical Biological Kinematics in Autism Spectrum Disorders Is Modulated by Self-Generated Selective Attention.

We examined whether adults with autism had difficulty imitating atypical biological kinematics. To reduce the impact that higher-order processes have on imitation we used a non-human agent model to control social attention, and removed end-state target goals in half of the trials to minimise goal-directed attention. Findings showed that only neurotypical adults imitated atypical biological kinematics. Adults with autism did, however, become significantly more accurate at imitating movement time. This confirmed they engaged in the task, and that sensorimotor adaptation was self-regulated. The attentional bias to movement time suggests the attenuation in imitating kinematics might be a compensatory strategy due to deficits in lower-level visuomotor processes associated with self-other mapping, or selective attention modulated the processes that represent biological kinematics