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The Kinase Chemogenomic Set (KCGS): An open science resource for kinase vulnerability identification
(2019)
We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS) is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Human behaviour is inextricably linked to the interaction of emotion and cognition. For decades, emotion and cognition were perceived as separable processes, yet with mutual interactions. Recently, this differen-tiation has been challenged by more integrative approaches, but without addressing the exact neurophysiological basis of their interaction. Here, we aimed to uncover neurophysiological mechanisms of emotion-cognition interaction. We used an emotional Flanker task paired with EEG/FEM beamforming in a large cohort (N=121) of healthy human participants, obtaining high temporal and fMRI-equivalent spatial resolution. Spatially, emotion and cognition processing overlapped in the right inferior frontal gyrus (rIFG), specifically in pars triangularis. Temporally, emotion and cognition processing overlapped during the transition from emotional to cognitive processing, with a stronger interaction in β-band power leading to worse behavioral performance. Despite functionally segregated subdivisions in rIFG, frequency-specific information flowed extensively within IFG and top-down to visual areas (V2, Precuneus) – explaining the behavioral interference effect. Thus, for the first time we here show the neural mechanisms of emotion-cognition interaction in space, time, frequency and information transfer with high temporal and spatial resolution, revealing a central role for β-band activity in rIFG. Our results support the idea that rIFG plays a broad role in both inhibitory control and emotional interference inhibition as it is a site of convergence in both processes. Furthermore, our results have potential clinical implications for understanding dysfunctional emotion-cognition interaction and emotional interference inhibition in psychiatric disor-ders, e.g. major depression and substance use disorder, in which patients have difficulties in regulating emotions and executing inhibitory control.