Foraging environment determines the genetic architecture and evolutionary potential of trophic morphology in cichlid fishes

Phenotypic plasticity allows organisms to change their phenotype in response to shifts in the environment. While a central topic in current discussions of evolutionary potential, a comprehensive understanding of the genetic underpinnings of plasticity is lacking in systems undergoing adaptive diversification. Here, we investigate the genetic basis of phenotypic plasticity in a textbook adaptive radiation, Lake Malawi cichlid fishes. Specifically, we crossed two divergent species to generate an F3 hybrid mapping population. At early juvenile stages, hybrid families were split and reared in alternate foraging environments that mimicked benthic/scraping or limnetic/sucking modes of feeding. These alternate treatments produced a variation in morphology that was broadly similar to the major axis of divergence among Malawi cichlids, providing support for the flexible stem theory of adaptive radiation. Next, we found that the genetic architecture of several morphological traits was highly sensitive to the environment. In particular, of 22 significant quantitative trait loci (QTL), only one was shared between the environments. In addition, we identified QTL acting across environments with alternate alleles being differentially sensitive to the environment. Thus, our data suggest that while plasticity is largely determined by loci specific to a given environment, it may also be influenced by loci operating across environments. Finally, our mapping data provide evidence for the evolution of plasticity via genetic assimilation at an important regulatory locus, ptch1. In all, our data address long-standing discussions about the genetic basis and evolution of plasticity. They also underscore the importance of the environment in affecting developmental outcomes, genetic architectures, morphological diversity and evolutionary potential

Maximal supergravity in D=10: forms, Borcherds algebras and superspace cohomology

We give a very simple derivation of the forms of $N=2,D=10$ supergravity from supersymmetry and SL(2,\bbR) (for IIB). Using superspace cohomology we show that, if the Bianchi identities for the physical fields are satisfied, the (consistent) Bianchi identities for all of the higher-rank forms must be identically satisfied, and that there are no possible gauge-trivial Bianchi identities ($dF=0$) except for exact eleven-forms. We also show that the degrees of the forms can be extended beyond the spacetime limit, and that the representations they fall into agree with those predicted from Borcherds algebras. In IIA there are even-rank RR forms, including a non-zero twelve-form, while in IIB there are non-trivial Bianchi identities for thirteen-forms even though these forms are identically zero in supergravity. It is speculated that these higher-rank forms could be non-zero when higher-order string corrections are included.Comment: 15 pages. Published version. Some clarification of the tex

IIA/IIB Supergravity and Ten-forms

We perform a careful investigation of which p-form fields can be introduced consistently with the supersymmetry algebra of IIA and/or IIB ten-dimensional supergravity. In particular the ten-forms, also known as "top-forms", require a careful analysis since in this case, as we will show, closure of the supersymmetry algebra at the linear level does not imply closure at the non-linear level. Consequently, some of the (IIA and IIB) ten-form potentials introduced in earlier work of some of us are discarded. At the same time we show that new ten-form potentials, consistent with the full non-linear supersymmetry algebra can be introduced. We give a superspace explanation of our work. All of our results are precisely in line with the predictions of the E(11) algebra.Comment: 17 page

Supersymmetric geometries of IIA supergravity I

IIA supergravity backgrounds preserving one supersymmetry locally admit four types of Killing spinors distinguished by the orbits of $Spin(9,1)$ on the space of spinors. We solve the Killing spinor equations of IIA supergravity with and without cosmological constant for Killing spinors representing two of these orbits, with isotropy groups $Spin(7)$ and $Spin(7)\ltimes\mathbb{R}^8$. In both cases, we identify the geometry of spacetime and express the fluxes in terms of the geometry. We find that the geometric constraints of backgrounds with a $Spin(7)\ltimes\mathbb{R}^8$ invariant Killing spinor are identical to those found for heterotic backgrounds preserving one supersymmetry.Comment: 21 page

Carvedilol targets beta-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a β-arrestin-biased β-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to β-adrenergic blockade but is dependent on β-arrestins and is reversed by β-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via β-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment

The Distribution of Fitness Effects of Beneficial Mutations in Pseudomonas aeruginosa

Understanding how beneficial mutations affect fitness is crucial to our understanding of adaptation by natural selection. Here, using adaptation to the antibiotic rifampicin in the opportunistic pathogen Pseudomonas aeruginosa as a model system, we investigate the underlying distribution of fitness effects of beneficial mutations on which natural selection acts. Consistent with theory, the effects of beneficial mutations are exponentially distributed where the fitness of the wild type is moderate to high. However, when the fitness of the wild type is low, the data no longer follow an exponential distribution, because many beneficial mutations have large effects on fitness. There is no existing population genetic theory to explain this bias towards mutations of large effects, but it can be readily explained by the underlying biochemistry of rifampicin–RNA polymerase interactions. These results demonstrate the limitations of current population genetic theory for predicting adaptation to severe sources of stress, such as antibiotics, and they highlight the utility of integrating statistical and biophysical approaches to adaptation

Development and formative evaluation of the e-Health implementation toolkit

<b>Background</b> The use of Information and Communication Technology (ICT) or e-Health is seen as essential for a modern, cost-effective health service. However, there are well documented problems with implementation of e-Health initiatives, despite the existence of a great deal of research into how best to implement e-Health (an example of the gap between research and practice). This paper reports on the development and formative evaluation of an e-Health Implementation Toolkit (e-HIT) which aims to summarise and synthesise new and existing research on implementation of e-Health initiatives, and present it to senior managers in a user-friendly format.<p></p> <b>Results</b> The content of the e-HIT was derived by combining data from a systematic review of reviews of barriers and facilitators to implementation of e-Health initiatives with qualitative data derived from interviews of "implementers", that is people who had been charged with implementing an e-Health initiative. These data were summarised, synthesised and combined with the constructs from the Normalisation Process Model. The software for the toolkit was developed by a commercial company (RocketScience). Formative evaluation was undertaken by obtaining user feedback. There are three components to the toolkit - a section on background and instructions for use aimed at novice users; the toolkit itself; and the report generated by completing the toolkit. It is available to download from http://www.ucl.ac.uk/pcph/research/ehealth/documents/e-HIT.xls<p></p> <b>Conclusions</b> The e-HIT shows potential as a tool for enhancing future e-Health implementations. Further work is needed to make it fully web-enabled, and to determine its predictive potential for future implementations

On Unbounded Composition Operators in L2L^2-Spaces

Fundamental properties of unbounded composition operators in $L^2$-spaces are studied. Characterizations of normal and quasinormal composition operators are provided. Formally normal composition operators are shown to be normal. Composition operators generating Stieltjes moment sequences are completely characterized. The unbounded counterparts of the celebrated Lambert's characterizations of subnormality of bounded composition operators are shown to be false. Various illustrative examples are supplied