GraphSite: Ligand Binding Site Classification with Deep Graph Learning.

The binding of small organic molecules to protein targets is fundamental to a wide array of cellular functions. It is also routinely exploited to develop new therapeutic strategies against a variety of diseases. On that account, the ability to effectively detect and classify ligand binding sites in proteins is of paramount importance to modern structure-based drug discovery. These complex and non-trivial tasks require sophisticated algorithms from the field of artificial intelligence to achieve a high prediction accuracy. In this communication, we describe GraphSite, a deep learning-based method utilizing a graph representation of local protein structures and a state-of-the-art graph neural network to classify ligand binding sites. Using neural weighted message passing layers to effectively capture the structural, physicochemical, and evolutionary characteristics of binding pockets mitigates model overfitting and improves the classification accuracy. Indeed, comprehensive cross-validation benchmarks against a large dataset of binding pockets belonging to 14 diverse functional classes demonstrate that GraphSite yields the class-weighted F1-score of 81.7%, outperforming other approaches such as molecular docking and binding site matching. Further, it also generalizes well to unseen data with the F1-score of 70.7%, which is the expected performance in real-world applications. We also discuss new directions to improve and extend GraphSite in the future.

CancerOmicsNet: a multi-omics network-based approach to anti-cancer drug profiling.

Development of novel anti-cancer treatments requires not only a comprehensive knowledge of cancer processes and drug mechanisms of action, but also the ability to accurately predict the response of various cancer cell lines to therapeutics. Numerous computational methods have been developed to address this issue, including algorithms employing supervised machine learning. Nonetheless, high prediction accuracies reported for many of these techniques may result from a significant overlap among training, validation, and testing sets, making existing predictors inapplicable to new data. To address these issues, we developed CancerOmicsNet, a graph neural network with sophisticated attention propagation mechanisms to predict the therapeutic effects of kinase inhibitors across various tumors. Emphasizing on the system-level complexity of cancer, CancerOmicsNet integrates multiple heterogeneous data, such as biological networks, genomics, inhibitor profiling, and gene-disease associations, into a unified graph structure. The performance of CancerOmicsNet, properly cross-validated at the tissue level, is 0.83 in terms of the area under the receiver operating characteristics, which is notably higher than those measured for other approaches. CancerOmicsNet generalizes well to unseen data, i.e., it can predict therapeutic effects across a variety of cancer cell lines and inhibitors. CancerOmicsNet is freely available to the academic community at https://github.com/pulimeng/CancerOmicsNet.

Strengthening spatial reasoning: elucidating the attentional and neural mechanisms associated with mental rotation skill development.

Spatial reasoning is a critical skill in many everyday tasks and in science, technology, engineering, and mathematics disciplines. The current study examined how training on mental rotation (a spatial reasoning task) impacts the completeness of an encoded representation and the ability to rotate the representation. We used a multisession, multimethod design with an active control group to determine how mental rotation ability impacts performance for a trained stimulus category and an untrained stimulus category. Participants in the experimental group (n = 18) showed greater improvement than the active control group (n = 18) on the mental rotation tasks. The number of saccades between objects decreased and saccade amplitude increased after training, suggesting that participants in the experimental group encoded more of the object and possibly had more complete mental representations after training. Functional magnetic resonance imaging data revealed distinct neural activation associated with mental rotation, notably in the right motor cortex and right lateral occipital cortex. These brain areas are often associated with rotation and encoding complete representations, respectively. Furthermore, logistic regression revealed that activation in these brain regions during the post-training scan significantly predicted training group assignment. Overall, the current study suggests that effective mental rotation training protocols should aim to improve the encoding and manipulation of mental representations.

Identifying Sentiment of Hookah-Related Posts on Twitter.

BACKGROUND: The increasing popularity of hookah (or waterpipe) use in the United States and elsewhere has consequences for public health because it has similar health risks to that of combustible cigarettes. While hookah use rapidly increases in popularity, social media data (Twitter, Instagram) can be used to capture and describe the social and environmental contexts in which individuals use, perceive, discuss, and are marketed this tobacco product. These data may allow people to organically report on their sentiment toward tobacco products like hookah unprimed by a researcher, without instrument bias, and at low costs. OBJECTIVE: This study describes the sentiment of hookah-related posts on Twitter and describes the importance of debiasing Twitter data when attempting to understand attitudes. METHODS: Hookah-related posts on Twitter (N=986,320) were collected from March 24, 2015, to December 2, 2016. Machine learning models were used to describe sentiment on 20 different emotions and to debias the data so that Twitter posts reflected sentiment of legitimate human users and not of social bots or marketing-oriented accounts that would possibly provide overly positive or overly negative sentiment of hookah. RESULTS: From the analytical sample, 352,116 tweets (59.50%) were classified as positive while 177,537 (30.00%) were classified as negative, and 62,139 (10.50%) neutral. Among all positive tweets, 218,312 (62.00%) were classified as highly positive emotions (eg, active, alert, excited, elated, happy, and pleasant), while 133,804 (38.00%) positive tweets were classified as passive positive emotions (eg, contented, serene, calm, relaxed, and subdued). Among all negative tweets, 95,870 (54.00%) were classified as subdued negative emotions (eg, sad, unhappy, depressed, and bored) while the remaining 81,667 (46.00%) negative tweets were classified as highly negative emotions (eg, tense, nervous, stressed, upset, and unpleasant). Sentiment changed drastically when comparing a corpus of tweets with social bots to one without. For example, the probability of any one tweet reflecting joy was 61.30% from the debiased (or bot free) corpus of tweets. In contrast, the probability of any one tweet reflecting joy was 16.40% from the biased corpus. CONCLUSIONS: Social media data provide researchers the ability to understand public sentiment and attitudes by listening to what people are saying in their own words. Tobacco control programmers in charge of risk communication may consider targeting individuals posting positive messages about hookah on Twitter or designing messages that amplify the negative sentiments. Posts on Twitter communicating positive sentiment toward hookah could add to the normalization of hookah use and is an area of future research. Findings from this study demonstrated the importance of debiasing data when attempting to understand attitudes from Twitter data.

GeauxDock: A novel approach for mixed-resolution ligand docking using a descriptor-based force field.

Molecular docking is an important component of computer-aided drug discovery. In this communication, we describe GeauxDock, a new docking approach that builds on the ideas of ligand homology modeling. GeauxDock features a descriptor-based scoring function integrating evolutionary constraints with physics-based energy terms, a mixed-resolution molecular representation of protein-ligand complexes, and an efficient Monte Carlo sampling protocol. To drive docking simulations toward experimental conformations, the scoring function was carefully optimized to produce a correlation between the total pseudoenergy and the native-likeness of binding poses. Indeed, benchmarking calculations demonstrate that GeauxDock has a strong capacity to identify near-native conformations across docking trajectories with the area under receiver operating characteristics of 0.85. By excluding closely related templates, we show that GeauxDock maintains its accuracy at lower levels of homology through the increased contribution from physics-based energy terms compensating for weak evolutionary constraints. GeauxDock is available at http://www.institute.loni.org/lasigma/package/dock/.