A multi-layered network model identifies Akt1 as a common modulator of neurodegeneration.

The accumulation of misfolded and aggregated proteins is a hallmark of neurodegenerative proteinopathies. Although multiple genetic loci have been associated with specific neurodegenerative diseases (NDs), molecular mechanisms that may have a broader relevance for most or all proteinopathies remain poorly resolved. In this study, we developed a multi-layered network expansion (MLnet) model to predict protein modifiers that are common to a group of diseases and, therefore, may have broader pathophysiological relevance for that group. When applied to the four NDs Alzheimer's disease (AD), Huntington's disease, and spinocerebellar ataxia types 1 and 3, we predicted multiple members of the insulin pathway, including PDK1, Akt1, InR, and sgg (GSK-3ß), as common modifiers. We validated these modifiers with the help of four Drosophila ND models. Further evaluation of Akt1 in human cell-based ND models revealed that activation of Akt1 signaling by the small molecule SC79 increased cell viability in all models. Moreover, treatment of AD model mice with SC79 enhanced their long-term memory and ameliorated dysregulated anxiety levels, which are commonly affected in AD patients. These findings validate MLnet as a valuable tool to uncover molecular pathways and proteins involved in the pathophysiology of entire disease groups and identify potential therapeutic targets that have relevance across disease boundaries. MLnet can be used for any group of diseases and is available as a web tool at http://ssbio.cau.ac.kr/software/mlnet.

A computational clinical decision-supporting system to suggest effective anti-epileptic drugs for pediatric epilepsy patients based on deep learning models using patient's medical history.

BACKGROUND: Epilepsy, a chronic brain disorder characterized by abnormal brain activity that causes seizures and other symptoms, is typically treated using anti-epileptic drugs (AEDs) as the first-line therapy. However, due to the variations in their modes of action, identification of effective AEDs often relies on ad hoc trials, which is particularly challenging for pediatric patients. Thus, there is significant value in computational methods capable of assisting in the selection of AEDs, aiming to minimize unnecessary medication and improve treatment efficacy. RESULTS: In this study, we collected 7,507 medical records from 1,000 pediatric epilepsy patients and developed a computational clinical decision-supporting system for AED selection. This system leverages three multi-channel convolutional neural network (CNN) models tailored to three specific AEDs (vigabatrin, prednisolone, and clobazam). Each CNN model predicts whether a respective AED is effective on a given patient or not. The CNN models showed AUROCs of 0.90, 0.80, and 0.92 in 10-fold cross-validation, respectively. Evaluation on a hold-out test dataset further revealed positive predictive values (PPVs) of 0.92, 0.97, and 0.91 for the three respective CNN models, representing that suggested AEDs by our models would be effective in controlling epilepsy with a high accuracy and thereby reducing unnecessary medications for pediatric patients. CONCLUSION: Our CNN models in the system demonstrated high PPVs for the three AEDs, which signifies the potential of our approach to support the clinical decision-making by assisting doctors in recommending effective AEDs within the three AEDs for patients based on their medical history. This would result in a reduction in the number of unnecessary ad hoc attempts to find an effective AED for pediatric epilepsy patients.

Autoinhibited Protein Database: a curated database of autoinhibitory domains and their autoinhibition mechanisms.

Autoinhibition, a crucial allosteric self-regulation mechanism in cell signaling, ensures signal propagation exclusively in the presence of specific molecular inputs. The heightened focus on autoinhibited proteins stems from their implication in human diseases, positioning them as potential causal factors or therapeutic targets. However, the absence of a comprehensive knowledgebase impedes a thorough understanding of their roles and applications in drug discovery. Addressing this gap, we introduce Autoinhibited Protein Database (AiPD), a curated database standardizing information on autoinhibited proteins. AiPD encompasses details on autoinhibitory domains (AIDs), their targets, regulatory mechanisms, experimental validation methods, and implications in diseases, including associated mutations and post-translational modifications. AiPD comprises 698 AIDs from 532 experimentally characterized autoinhibited proteins and 2695 AIDs from their 2096 homologs, which were retrieved from 864 published articles. AiPD also includes 42 520 AIDs of computationally predicted autoinhibited proteins. In addition, AiPD facilitates users in investigating potential AIDs within a query sequence through comparisons with documented autoinhibited proteins. As the inaugural autoinhibited protein repository, AiPD significantly aids researchers studying autoinhibition mechanisms and their alterations in human diseases. It is equally valuable for developing computational models, analyzing allosteric protein regulation, predicting new drug targets, and understanding intervention mechanisms AiPD serves as a valuable resource for diverse researchers, contributing to the understanding and manipulation of autoinhibition in cellular processes. Database URL: http://ssbio.cau.ac.kr/databases/AiPD.