Alternative infill strategies for expensive multi-objective optimisation

This is the author accepted manuscript. The final version is available from ACM via the DOI in this record.Many multi-objective optimisation problems incorporate computationally or financially expensive objective functions. State-of-the-art algorithms therefore construct surrogate model(s) of the parameter space to objective functions mapping to guide the choice of the next solution to expensively evaluate. Starting from an initial set of solutions, an infill criterion — a surrogate-based indicator of quality — is extremised to determine which solution to evaluate next, until the budget of expensive evaluations is exhausted. Many successful infill criteria are dependent on multi-dimensional integration, which may result in infill criteria that are themselves impractically expensive. We propose a computationally cheap infill criterion based on the minimum probability of improvement over the estimated Pareto set. We also present a range of set-based scalarisation methods modelling hypervolume contribution, dominance ratio and distance measures. These permit the use of straightforward expected improvement as a cheap infill criterion. We investigated the performance of these novel strategies on standard multi-objective test problems, and compared them with the popular SMS-EGO and ParEGO methods. Unsurprisingly, our experiments show that the best strategy is problem dependent, but in many cases a cheaper strategy is at least as good as more expensive alternatives.This research was supported by the Engineering and Physical Sciences Research Council [grant number EP/M017915/1]

Esociformes: Esocidae, Pikes, and Umbridae (Mudminnows)

The order Esociformes (Pikes and Mudminnows) comprises two families, Esocidae (Pikes) and Umbridae (Mudminnows). The Pikes are a small Holarctic (Northern Hemisphere) family, that includes large, elongate predators with duckbill-like snouts full of sharp teeth. Popular with sport fishers, the largest Pikes fight fiercely on hook and line. As piscivorous, voracious, ambush predators, the Pikes play an important functional role in the trophic ecology and fish assemblage structure of many aquatic systems, especially in northern lakes. Other esocids, such as the Olympic Mudminnow, Novumbra hubbsi, and Blackfishes, genus Dallia, are interesting because of their tolerance of low dissolved oxygen and pH. The Alaska Blackfish, Dallia pectoralis, and the Northern Pike, Esox lucius, can also withstand the extremely cold conditions of the Arctic and subarctic waters of Canada, Alaska, and Siberia. The name Esocidae is derived from Linnaeus’s (1758) generic name for Pike, Esox, from the Latin word esox meaning Pike, which came originally from the Greek isox or possibly the Gaelic eog, ehawe (salmon) (Boschung & Mayden 2004)

Slingshot: a PiggyBac based transposon system for tamoxifen-inducible ‘self-inactivating’ insertional mutagenesis

We have developed a self-inactivating PiggyBac transposon system for tamoxifen inducible insertional mutagenesis from a stably integrated chromosomal donor. This system, which we have named ‘Slingshot’, utilizes a transposon carrying elements for both gain- and loss-of-function screens in vitro. We show that the Slingshot transposon can be efficiently mobilized from a range of chromosomal loci with high inducibility and low background generating insertions that are randomly dispersed throughout the genome. Furthermore, we show that once the Slingshot transposon has been mobilized it is not remobilized producing stable clonal integrants in all daughter cells. To illustrate the efficacy of Slingshot as a screening tool we set out to identify mediators of resistance to puromycin and the chemotherapeutic drug vincristine by performing genetrap screens in mouse embryonic stem cells. From these genome-wide screens we identified multiple independent insertions in the multidrug resistance transporter genes Abcb1a/b and Abcg2 conferring resistance to drug treatment. Importantly, we also show that the Slingshot transposon system is functional in other mammalian cell lines such as human HEK293, OVCAR-3 and PE01 cells suggesting that it may be used in a range of cell culture systems. Slingshot represents a flexible and potent system for genome-wide transposon-mediated mutagenesis with many potential applications

Imidazol-1-ylethylindazole Voltage-Gated Sodium Channel Ligands Are Neuroprotective during Optic Neuritis in a Mouse Model of Multiple Sclerosis

[Image: see text] A series of imidazol-1-ylethylindazole sodium channel ligands were developed and optimized for sodium channel inhibition and in vitro neuroprotective activity. The molecules exhibited displacement of a radiolabeled sodium channel ligand and selectivity for blockade of the inactivated state of cloned neuronal Na(v) channels. Metabolically stable analogue 6 was able to protect retinal ganglion cells during optic neuritis in a mouse model of multiple sclerosis

Downregulation of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) in human hepatocellular carcinoma and their prognostic significance

<p>Abstract</p> <p>Background</p> <p>Organic cation transporters (OCT) are responsible for the uptake and intracellular inactivation of a broad spectrum of endogenous substrates and detoxification of xenobiotics and chemotherapeutics. The transporters became pharmaceutically interesting, because OCTs are determinants of the cytotoxicity of platin derivates and the transport activity has been shown to correlate with the sensitivity of tumors towards tyrosine kinase inhibitors. No data exist about the relevance of OCTs in hepatocellular carcinoma (HCC).</p> <p>Methods</p> <p>OCT1 (<it>SLC22A1</it>) and OCT3 (<it>SLC22A3</it>) mRNA expression was measured in primary human HCC and corresponding non neoplastic tumor surrounding tissue (TST) by real time PCR (n = 53). Protein expression was determined by western blot analysis and immunofluorescence. Data were correlated with the clinicopathological parameters of HCCs.</p> <p>Results</p> <p>Real time PCR showed a downregulation of <it>SLC22A1 </it>and <it>SLC22A3 </it>in HCC compared to TST (p ≤ 0.001). A low <it>SLC22A1 </it>expression was associated with a worse patient survival (p < 0.05). Downregulation was significantly associated with advanced HCC stages, indicated by a higher number of T3 tumors (p = 0.025) with a larger tumor diameter (p = 0.035), a worse differentiation (p = 0.001) and higher AFP-levels (p = 0.019). In accordance, <it>SLC22A1 </it>was less frequently downregulated in tumors with lower stages who underwent transarterial chemoembolization (p < 0.001) and liver transplantation (p = 0.001). Tumors with a low <it>SLC22A1 </it>expression (< median) showed a higher <it>SLC22A3 </it>expression compared to HCC with high <it>SLC22A1 </it>expression (p < 0.001). However, there was no significant difference in tumor characteristics according to the level of the <it>SLC22A3 </it>expression.</p> <p>In the western blot analysis we found a different protein expression pattern in tumor samples with a more diffuse staining in the immunofluorescence suggesting that especially OCT1 is not functional in advanced HCC.</p> <p>Conclusion</p> <p>The downregulation of OCT1 is associated with tumor progression and a worse patient survival.</p

Towards an interoperable ecosystem of AI and LT platforms : a roadmap for the implementation of different levels of interoperability

With regard to the wider area of AI/LT platform interoperability, we concentrate on two core aspects: (1) cross-platform search and discovery of resources and services; (2) composition of cross-platform service workflows. We devise five different levels (of increasing complexity) of platform interoperability that we suggest to implement in a wider federation of AI/LT platforms. We illustrate the approach using the five emerging AI/LT platforms AI4EU, ELG, Lynx, QURATOR and SPEAKER

5-HT2C Receptors Localize to Dopamine and GABA Neurons in the Rat Mesoaccumbens Pathway

The serotonin 5-HT2C receptor (5-HT2CR) is localized to the limbic-corticostriatal circuit, which plays an integral role in mediating attention, motivation, cognition, and reward processes. The 5-HT2CR is linked to modulation of mesoaccumbens dopamine neurotransmission via an activation of γ-aminobutyric acid (GABA) neurons in the ventral tegmental area (VTA). However, we recently demonstrated the expression of the 5-HT2CR within dopamine VTA neurons suggesting the possibility of a direct influence of the 5-HT2CR upon mesoaccumbens dopamine output. Here, we employed double-label fluorescence immunochemistry with the synthetic enzymes for dopamine (tyrosine hydroxylase; TH) and GABA (glutamic acid decarboxylase isoform 67; GAD-67) and retrograde tract tracing with FluoroGold (FG) to uncover whether dopamine and GABA VTA neurons that possess 5-HT2CR innervate the nucleus accumbens (NAc). The highest numbers of FG-labeled cells were detected in the middle versus rostral and caudal levels of the VTA, and included a subset of TH- and GAD-67 immunoreactive cells, of which >50% also contained 5-HT2CR immunoreactivity. Thus, we demonstrate for the first time that the 5-HT2CR colocalizes in DA and GABA VTA neurons which project to the NAc, describe in detail the distribution of NAc-projecting GABA VTA neurons, and identify the colocalization of TH and GAD-67 in the same NAc-projecting VTA neurons. These data suggest that the 5-HT2CR may exert direct influence upon both dopamine and GABA VTA output to the NAc. Further, the indication that a proportion of NAc-projecting VTA neurons synthesize and potentially release both dopamine and GABA adds intriguing complexity to the framework of the VTA and its postulated neuroanatomical roles