A simple and robust method for connecting small-molecule drugs using gene-expression signatures

Background

Interaction of a drug or chemical with a biological system can result in a gene-expression profile or signature characteristic of the event. Using a suitably robust algorithm these signatures can potentially be used to connect molecules with similar pharmacological or toxicological properties by gene expression profile. Lamb et al first proposed the Connectivity Map [Lamb et al (2006), Science 313, 1929–1935] to make successful connections among small molecules, genes, and diseases using genomic signatures.

Results

Here we have built on the principles of the Connectivity Map to present a simpler and more robust method for the construction of reference gene-expression profiles and for the connection scoring scheme, which importantly allows the valuation of statistical significance of all the connections observed. We tested the new method with two randomly generated gene signatures and three experimentally derived gene signatures (for HDAC inhibitors, estrogens, and immunosuppressive drugs, respectively). Our testing with this method indicates that it achieves a higher level of specificity and sensitivity and so advances the original method.

Conclusion

The method presented here not only offers more principled statistical procedures for testing connections, but more importantly it provides effective safeguard against false connections at the same time achieving increased sensitivity. With its robust performance, the method has potential use in the drug development pipeline for the early recognition of pharmacological and toxicological properties in chemicals and new drug candidates, and also more broadly in other 'omics sciences.

A simple colorimetric method for the quality control of 1-alkyl-3-methylimidazolium ionic liquid precursors

A simple colorimetric method to monitor the production of ionic liquid precursors is developed, which is based on the determination of 1-methylimidazole with copper(II) chloride. The synthesis of 1-ethyl-3-methylimidazolium chloride, an industrially important ionic liquid precursor, can be followed and the purity of the final product can be readily assessed in a quick and convenient manner.

Low-fat versus low-carbohydrate weight reduction diets:Effects on weight loss, insulin resistance, and cardiovascular risk: a randomized control trial

OBJECTIVE Low-fat hypocaloric diets reduce insulin resistance and prevent type 2 diabetes in those at risk. Low-carbohydrate, high-fat diets are advocated as an alternative, but reciprocal increases in dietary fat may have detrimental effects on insulin resistance and offset the benefits of weight reduction.

RESEARCH DESIGN AND METHODS We investigated a low-fat (20% fat, 60% carbohydrate) versus a low-carbohydrate (60% fat, 20% carbohydrate) weight reduction diet in 24 overweight/obese subjects ([mean ± SD] BMI 33.6 ± 3.7 kg/m2, aged 39 ± 10 years) in an 8-week randomized controlled trial. All food was weighed and distributed, and intake was calculated to produce a 500 kcal/day energy deficit. Insulin action was assessed by the euglycemic clamp and insulin secretion by meal tolerance test. Body composition, adipokine levels, and vascular compliance by pulse-wave analysis were also measured.

RESULTS Significant weight loss occurred in both groups (P < 0.01), with no difference between groups (P = 0.40). Peripheral glucose uptake increased, but there was no difference between groups (P = 0.28), and suppression of endogenous glucose production was also similar between groups. Meal tolerance–related insulin secretion decreased with weight loss with no difference between groups (P = 0.71). The change in overall systemic arterial stiffness was, however, significantly different between diets (P = 0.04); this reflected a significant decrease in augmentation index following the low-fat diet, compared with a nonsignificant increase within the low-carbohydrate group.

CONCLUSIONS This study demonstrates comparable effects on insulin resistance of low-fat and low-carbohydrate diets independent of macronutrient content. The difference in augmentation index may imply a negative effect of low-carbohydrate diets on vascular risk.

Simple heuristics: From one infinite regress to another?

Gigerenzer, Todd, and the ABC Research Group argue that optimisation under constraints leads to an infinite regress due to decisions about how much information to consider when deciding. In certain cases, however, their fast and frugal heuristics lead instead to an endless series of decisions about how best to decide.

Including disabled children at school: Is it really as simple as 'a, c, d'?

This paper presents and discusses a social justice strategy that may progress inclusion in schools. The framework for this strategy is grounded in the theoretical discussions by Nancy Fraser and Trevor Gale about distributive, redistributive, and recognitive models of social justice. None of these theoretical frameworks, however, in themselves, offer a clear way forward for marginalised and misrecognised groups, such as disabled children, who need both educational resources and recognition in inclusive classrooms. The authors propose, however, that the work of Fraser and Gale combines into a social justice strategy, which consists of three elements (agency, competency, and diversity, or ‘a, c, d’) that can lead to inclusion. When disabled children are provided with the opportunity to exercise their agency, demonstrate their competence, and transform and affirm notions of diversity, then inclusion is more likely to occur in the classroom. Data from two research projects are presented using this framework to illustrate this argument, and the proposed ‘a, c, d’ social justice strategy towards inclusion.

A bargaining set for monotonic simple games based on external and internal stability

A new bargaining set based on notions of both internal and external stability is developed in the context of endogenous coalition formation. It allows to make an explicit distinction between within-group and outside-group deviation options. This type of distinction is not present in current bargaining sets. For the class of monotonic proper simple games, the outcomes in the bargaining set are characterized. Furthermore, it is shown that the bargaining set of any homogeneous weighted majority game contains an outcome for which the underlying coalition structure consists of a minimal winning coalition and its complement.

Predator-prey interactions between brown trout Salmo trutta and native and introduced amphipods; their implications for fish diets

An attempt to improve the food base for brown trout Salmo trutta in Northern Ireland was made in 1958.59 by deliberately introducing English Gammarus pulex into several Irish rivers. In addition. another amphipod Crangonyx pseudogracilis, was later accidently introduced into II ish waters. Our study represents the first attempt to examine the trophic interactions between a native fish predator (S. trutta) and an array of these native (Gammarus duebeni celticus) and introduced (G. pulex and C. pseudogracilis) amphipods. Feeding experiments, involving young brown trout predators and ampiphod prey, revealed that the fish actively selected C. pseudogracilis relative to two alternative Gammarus prey species. Although the trout encountered the Gammarus species more than C. pseudogracilis, they were eaten less than Crangonyx. Difficulties in handling and ingestion of Gammarus by trout may be a. key component of the preference fbr the smaller, more easily handled Crangonyx. The microdistribution of the species was altered by the fish, due to predation being greater in particular microhabitats, Our study showed that the introduction of the herbivorous C. pseudogracilis into Irish freshwaters may represent a useful addition to fish diets. particularly for small and/or juvenile fish. The reprecussions of the deliberate introduction of G. pulex are less clear. It may improve feeding for fish. but only if it can coexist with indigenous macroinvertebrates and thus ultimately improve the range and quantity of possible food items in predator diets. Alternatively, being highly predatory towards other macroinvertebrates including G. d. celticus and C. pseudogracilis. G. pulex may be deleterious to the diversity of the resident benthic community and hence reduce the diversity of prey available to fish predators.