Protein domain-based prediction of drug/compound–target interactions and experimental validation on LIM kinases

Predictive approaches such as virtual screening have been used in drug discovery with the objective of reducing developmental time and costs. Current machine learning and network-based approaches have issues related to generalization, usability, or model interpretability, especially due to the complexity of target proteins’ structure/function, and bias in system training datasets. Here, we propose a new method “DRUIDom” (DRUg Interacting Domain prediction) to identify bio-interactions between drug candidate compounds and targets by utilizing the domain modularity of proteins, to overcome problems associated with current approaches. DRUIDom is composed of two methodological steps. First, ligands/compounds are statistically mapped to structural domains of their target proteins, with the aim of identifying their interactions. As such, other proteins containing the same mapped domain or domain pair become new candidate targets for the corresponding compounds. Next, a million-scale dataset of small molecule compounds, including those mapped to domains in the previous step, are clustered based on their molecular similarities, and their domain associations are propagated to other compounds within the same clusters. Experimentally verified bioactivity data points, obtained from public databases, are meticulously filtered to construct datasets of active/interacting and inactive/non-interacting drug/compound–target pairs (~2.9M data points), and used as training data for calculating parameters of compound–domain mappings, which led to 27,032 high-confidence associations between 250 domains and 8,165 compounds, and a finalized output of ~5 million new compound–protein interactions. DRUIDom is experimentally validated by syntheses and bioactivity analyses of compounds predicted to target LIM-kinase proteins, which play critical roles in the regulation of cell motility, cell cycle progression, and differentiation through actin filament dynamics. We showed that LIMK-inhibitor-2 and its derivatives significantly block the cancer cell migration through inhibition of LIMK phosphorylation and the downstream protein cofilin. One of the derivative compounds (LIMKi-2d) was identified as a promising candidate due to its action on resistant Mahlavu liver cancer cells. The results demonstrated that DRUIDom can be exploited to identify drug candidate compounds for intended targets and to predict new target proteins based on the defined compound–domain relationships. Datasets, results, and the source code of DRUIDom are fully-available at: https://github.com/cansyl/DRUIDom

Sourcing Flexibility, Spot Trading, and Procurement Contract Structure

We analyze the structure and pricing of option contracts for an industrial good in the presence of spot trading. We combine the analysis of spot trading and buyers' disparate private valuations for different suppliers' products, and we jointly endogenize the determination of three major dimensions in contract design: (i) sales contracts versus options contracts, (ii) flat-price versus volume-dependent contracts, and (iii) volume discounts versus volume premia. We build a model in which a supplier of an industrial good transacts with a manufacturer who uses the supplier's product to produce an end good with an uncertain demand. We show that, consistent with industry observations, volume-dependent optimal sales contracts always demonstrate volume discounts (i.e., involve concave pricing). However, options are more complex agreements, and optimal option contracts can involve both volume discounts and volume premia. Three major contract structures commonly emerge in optimality. First, if the seller has a high discount rate relative to the buyer and the seller's production costs or the production capacity is low, the optimal contracts tend to be flat-price sales contracts. Second, when the seller has a relatively high discount rate compared to the buyer but production costs or production capacity are high, the optimal contracts are sales contracts with volume discounts. Third, if the buyer's discount rate is high relative to the seller's, then the optimal contracts tend to be volume-dependent options contracts and can involve both volume discounts and volume premia. However, when the seller's production capacity is sufficiently low, it is possible to observe flat-price option contracts. Furthermore, we provide links between production and spot market characteristics, contract design, and efficiency.National Science Foundation (U.S.) (contract CMMI-0758069)National Science Foundation (U.S.) (contract DMI-0245352

The first Doppler images of the eclipsing binary SZ Piscium

We present the first Doppler images of the active eclipsing binary system SZ Psc, based on the high-resolution spectral data sets obtained in 2004 November and 2006 September–December. The least-squares deconvolution technique was applied to derive high signal-to-noise profiles from the observed spectra of SZ Psc. Absorption features contributed by a third component of the system were detected in the LSD profiles at all observed phases. We estimated the mass and period of the third component to be about 0.9 M⊙ and 1283 ± 10 d, respectively. After removing the contribution of the third body from the least-squares deconvolved profiles, we derived the surface maps of SZ Psc. The resulting Doppler images indicate significant star-spot activities on the surface of the K subgiant component. The distributions of star-spots are more complex than that revealed by previous photometric studies. The cooler K component exhibited pronounced high-latitude spots as well as numerous low- and intermediate-latitude spot groups during the entire observing seasons, but did not show any large, stable polar cap, different from many other active RS CVn-type binaries

Local fishermen’s perceptions of the usefulness of artificial reef ecosystem services in Portugal

Proponents of artificial reef (AR) deployment are often motivated by the usefulness of such structures. The usefulness of ARs is related to their capability of providing ecosystem services/additional functions. We present two distinct Portuguese AR case studies: (1) The Nazaré reef off the central coast of Portugal and (2) the Oura reef off the Algarve coast. Semi-structured interviews were conducted with local fishermen in the fishing towns of Nazaré and Quarteira pre-and post-AR deployment. The main focus of the interviews was to understand fishermen's perception of AR usefulness (or lack thereof) in terms of nine ecosystem services/additional functions potentially provided by the ARs. We tested the null hypothesis that ARs do not provide additional ecosystem services/additional functions. When queried pre-AR deployment, fishermen indicated that ARs are most likely to provide three ecosystem services: "habitat and refuge," "biodiversity preservation" and "food production." Fishermen had similar perceptions post-deployment. For the Nazaré reef, fishermen tended to have a positive or neutral perception of ecosystem services/additional functions being provided by ARs. For the Oura reef, fishermen tended to have a mostly neutral perception of AR ecosystem services; however, there were also some positive and other negative perceptions. It was difficult for stakeholders to conceptualize some of the ecosystem services/additional functions provided by ARs prior to actively using them. As a result, some stakeholders changed their perception of the ecosystem services/additional functions after using the structures. These results indicate that stakeholders likely need to perceive ARs as useful in order for them to provide their support for AR installation. Likewise, their support is often needed to justify the use of public funds to install ARs, therefore making it imperative for resource managers to undertake similar interviews with fishermen when considering the use of ARs in other areas.MARE program, within the project "Implantacao e estudo integrado de sistemas recifais" PROMAR program "Elaboracao de estudos de caracterizacao do estado de colonizacao e impacto socioeconomico do recife artificial da Nazare" - 02-PE/2011/GJinfo:eu-repo/semantics/publishedVersio