Chemical combination effects predict connectivity in biological systems

Efforts to construct therapeutically useful models of biological systems require large and diverse sets of data on functional connections between their components. Here we show that cellular responses to combinations of chemicals reveal how their biological targets are connected. Simulations of pathways with pairs of inhibitors at varying doses predict distinct response surface shapes that are reproduced in a yeast experiment, with further support from a larger screen using human tumour cells. The response morphology yields detailed connectivity constraints between nearby targets, and synergy profiles across many combinations show relatedness between targets in the whole network. Constraints from chemical combinations complement genetic studies, because they probe different cellular components and can be applied to disease models that are not amenable to mutagenesis. Chemical probes also offer increased flexibility, as they can be continuously dosed, temporally controlled, and readily combined. After extending this initial study to cover a wider range of combination effects and pathway topologies, chemical combinations may be used to refine network models or to identify novel targets. This response surface methodology may even apply to non-biological systems where responses to targeted perturbations can be measured

A Water Balance Derived Drought Index for Pinios River Basin, Greece

This study estimates hydrological drought characteristics using a water balance derived drought index in Pinios river basin, Thessaly, Greece. The concept of hydrological management at subwatershed scale has been adopted because it encompasses the areal extent of a drought event. Fourteen (14) sub-watersheds of Pinios river basin were delineated according to the major tributaries of Pinios river using GIS. For the assessment of hydrological drought, because none of the sub-watersheds have flow gauge stations at their outlets, a six-parameter monthly conceptual water balance model (UTHBAL model), has been applied regionally to simulate runoff for the period October 1960-September 2002. The synthetic runoff was normalized through Box-Cox transformation and standardized to the mean runoff to produce the water balance derived drought index for hydrological drought assessment. The standardized precipitation index (SPI) at multiple time scales and four indices of the Palmer method (i.e. PDSI, WPLM, PHDI and the Palmer moisture anomaly Z-index) were also calculated to assess hydrological droughts. The results showed that the water balance derived drought index is a good indicator of hydrological drought in all sub-watersheds, since is capable to quantify drought severity and duration. Furthermore, the drought index provides guidance on the selection of an appropriate meteorological drought index for operational hydrological drought monitoring. Hence, SPI at 3- and 6-month timescales and the WPLM could be used along with the water balance derived drought index in risk and decision analyses at the study area