Comparison‐specific preferences:The attentional dilution effect for delay and risk

In cross-modal decisions, the options differ on many attributes, and in uni-modal decisions, they differ on few. We supply new theory and data to understand how discounting for both delay and risk differs between cross-modal and uni-modal decisions. We propose the attentional dilution effect in decision making in which (a) allocation of limited attention to an attribute determines that attribute's decision weight and (b) the attention an attribute receives is increasing in the difference between options on that attribute and decreasing in the number of other attributes that differ between options. We introduce the random order delayed compensation method and conduct two experiments focusing on delayed and risky receipt of consumer goods. Consistent with the attentional dilution effect, we find that in this domain, patience and risk tolerance are generally higher in cross-modal than uni-modal decisions. We suggest that, since many real-world choices are cross-modal, people may be more patient and risk-tolerant in their everyday life than is suggested by standard lab experiments

Time matters less when outcomes differ: uni-modal versus cross-modal comparisons in intertemporal choice

Uni-modal intertemporal decisions involve comparing options of the same type (e.g. apples now versus apples later), and cross-modal decisions involve comparing options of different types (e.g. a car now versus a vacation later). As we explain, existing models of intertemporal choice do not allow time preference to depend on whether the comparisons to be made are uni-modal or cross-modal. We test this restriction in an experiment using the delayed-compensation method, a new extension of the standard method of eliciting intertemporal preferences that allows for assessment of time preference for non-monetary and discrete outcomes, as well as for both cross-modal and uni-modal comparisons. Participants were much more averse to delay for uni-modal than cross-modal decisions. We provide two potential explanations for this effect: one drawing on multi-attribute choice, the other drawing on construal level theory

Comparison‐specific preferences: The attentional dilution effect for delay and risk

In cross‐modal decisions, the options differ on many attributes, and in uni‐modal decisions, they differ on few. We supply new theory and data to understand how discounting for both delay and risk differs between cross‐modal and uni‐modal decisions. We propose the attentional dilution effect in decision making in which (a) allocation of limited attention to an attribute determines that attribute's decision weight and (b) the attention an attribute receives is increasing in the difference between options on that attribute and decreasing in the number of other attributes that differ between options. We introduce the random order delayed compensation method and conduct two experiments focusing on delayed and risky receipt of consumer goods. Consistent with the attentional dilution effect, we find that in this domain, patience and risk tolerance are generally higher in cross‐modal than uni‐modal decisions. We suggest that, since many real‐world choices are cross‐modal, people may be more patient and risk‐tolerant in their everyday life than is suggested by standard lab experiments

Neutron reflection study of the adsorption of the phosphate surfactant NaDEHP onto alumina from water.

The adsorption of a phosphorus analogue of the surfactant AOT, sodium bis(2-ethylhexyl) phosphate (NaDEHP), at the water/alumina interface is described. The material is found to adsorb as an essentially water-free bilayer from neutron reflection measurements. This is similar to the behavior of AOT under comparable conditions, although AOT forms a thicker, more hydrated layer. The NaDEHP shows rather little variation with added salt, but a small thickening of the layer on increasing the pH, in contrast to the behavior of AOT.We thank BP plc and EPSRC for financial support for this work as well as the ISIS and ILL staff and scientists for the allocation of beam time and technical assistance with NR measurements. We also appreciate Chris Sporikou at Department of Chemistry, University of Cambridge, for help with the surfactant synthesis.This is the final version of the article. It first appeared at http://dx.doi.org/10.1021/la504837

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model

Abstract Background MicroRNAs (miRNAs) are important post-transcriptional gene regulators controlling cellular lineage specification and differentiation during embryonic development, including the gastrointestinal system. However, miRNA-mediated regulatory mechanisms involved in early embryonic development of human small intestine (SI) remains underexplored. To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage. Results We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation. Small RNA-seq profiling revealed temporal dynamics of miRNA signatures across different developmental events of the model, including definitive endoderm formation, SI lineage specification and SI regional patterning. Our multi-omic, integrative analyses showed further that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification. We demonstrated that loss of miR-182 leads to an increase in the foregut master marker SOX2. We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2. Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification. Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development. Conclusion The present study uncovers a novel facet of miRNAs in regulating prenatal SI development. We leveraged multi-omic, systems biology approaches to discover candidate miRNA regulators associated with early SI developmental events in a human organoid model. In this study, we highlighted miRNA-mediated post-transcriptional regulation relevant to the event of SI lineage specification. The candidate miRNA regulators that we identified for the other stages of SI development also warrant detailed characterization in the future

Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice.

MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insulin sensitivity. By small RNA-sequencing analysis, we identified seven hepatic miRNAs (including miR-29b) that are consistently aberrantly expressed across five different rodent models of metabolic dysfunction that share the feature of insulin resistance (IR). We also showed that hepatic miR-29b exhibits persistent dysregulation during disease progression in a rat model of diabetes, UCD-T2DM. Furthermore, we observed that hepatic levels of miR-29 family members are attenuated by interventions known to improve IR in rodent and rhesus macaque models. To examine the function of the miR-29 family in modulating insulin sensitivity, we used locked nucleic acid (LNA) technology and demonstrated that acute in vivo suppression of the miR-29 family in adult mice leads to significant reduction of fasting blood glucose (in both chow-fed lean and high-fat diet-fed obese mice) and improvement in insulin sensitivity (in chow-fed lean mice). We carried out whole transcriptome studies and uncovered candidate mechanisms, including regulation of DNA methyltransferase 3a (Dnmt3a) and the hormone-encoding gene Energy homeostasis associated (Enho). In sum, we showed that IR/T2D is linked to dysregulation of hepatic miR-29b across numerous models and that acute suppression of the miR-29 family in adult mice leads to improved glycemic control. Future studies should investigate the therapeutic utility of miR-29 suppression in different metabolic disease states.Enho; insulin resistance; liver; microRNA-29 (miR-29); UCD-T2DM

Adsorption of Aerosol-OT at the Calcite/Water Interface - Comparison of the sodium and calcium salts

AbstractThe adsorption of the surfactant Aerosol-OT (AOT) at the calcite–water interface has been investigated using batch adsorption isotherms and neutron reflection. The adsorption isotherms showed that NaAOT adsorption followed S-type adsorption behaviour with a maximum surface excess of 2.5mgm−2 but the method could not be used for the investigation of Ca(AOT)2 adsorption owing to the changes in the bulk phase behaviour of the solution. The surface excess, determined by neutron reflection at the critical micelle concentration (CMC), was 2.5mgm−2 for Ca(AOT)2 and 1.8mgm−2 for NaAOT. The time dependence of the NaAOT adsorption suggests a slow conversion from the sodium to the calcium salt of AOT at the calcite–water interface by binding calcium ions released from the slightly soluble calcite. The layer thickness in both cases was 35Å which indicates adsorption as bilayers or distorted micelles. At higher concentrations of NaAOT (∼10× CMC) adsorption of an AOT lamellar phase was evident from Bragg peaks in the specular reflection.To our knowledge, this is the first time that adsorption of a surfactant at the calcite–water interface has been investigated by neutron reflection. The technique provided significant new insight into the adsorption behaviour of AOT which would not have been accessible using traditional techniques