Deep Learning Applications for Predicting Pharmacological Properties of Drugs and Drug Repurposing Using Transcriptomic Data

Molecular Pharmaceutics, Год журнала: 2016, Номер 13(7), С. 2524 - 2530

Опубликована: Май 22, 2016

Deep learning is rapidly advancing many areas of science and technology with multiple success stories in image, text, voice video recognition, robotics, autonomous driving. In this paper we demonstrate how deep neural networks (DNN) trained on large transcriptional response data sets can classify various drugs to therapeutic categories solely based their profiles. We used the perturbation samples 678 across A549, MCF-7, PC-3 cell lines from LINCS Project linked those 12 use derived MeSH. To train DNN, utilized both gene level transcriptomic processed using a pathway activation scoring algorithm, for pooled set perturbed different concentrations drug 6 24 hours. classification, DNN achieved high classification accuracy convincingly outperformed support vector machine (SVM) model every multiclass problem, however, models performed significantly better. For first time net recognize pharmacological properties biological systems conditions. also propose confusion matrices repositioning. This work proof principle applying discovery development.

Язык: Английский

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The Mechanisms and Functions of Synaptic Facilitation

Neuron, Год журнала: 2017, Номер 94(3), С. 447 - 464

Опубликована: Май 1, 2017

Язык: Английский

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Deep Sequencing of Somatosensory Neurons Reveals Molecular Determinants of Intrinsic Physiological Properties

Neuron, Год журнала: 2019, Номер 103(4), С. 598 - 616.e7

Опубликована: Июнь 24, 2019

Язык: Английский

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Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

Pharmacological Reviews, Год журнала: 2017, Номер 70(1), С. 142 - 173

Опубликована: Дек. 20, 2017

Epilepsy is a common and serious neurologic disease with strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact these discoveries wide reaching—from precise diagnosis classification syndromes to the discovery validation new drug targets development disease-targeted therapeutic strategies. About 25% genes in epilepsy encode ion channels. Much our understanding mechanisms comes from work focused on this class protein. In study, we review genetic, molecular, physiologic evidence supporting pathogenic role number different voltage- ligand-activated channels epilepsy. We also proposed for each channel highlight targeted

Язык: Английский

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Kv2 Ion Channels Determine the Expression and Localization of the Associated AMIGO-1 Cell Adhesion Molecule in Adult Brain Neurons

Frontiers in Molecular Neuroscience, Год журнала: 2018, Номер 11

Опубликована: Янв. 19, 2018

Voltage-gated K+ (Kv) channels play important roles in regulating neuronal excitability. Kv comprise four principal α subunits, and transmembrane and/or cytoplasmic auxiliary subunits that modify diverse aspects of channel function. AMIGO-1, which mediates homophilic cell adhesion underlying neurite outgrowth fasciculation during development, has recently been shown to be an subunit adult brain Kv2.1-containing channels. We show AMIGO-1 is extensively colocalized with both Kv2.1 its paralog Kv2.2 neurons across mammals, brain, there no apparent population outside these Kv2 subunits. coclustered at specific plasma membrane (PM) sites associated hypolemmal subsurface cisternae ER:PM junctions. This distinct PM clustering not observed mice lacking expression. Moreover, heterologous cells, coexpression either or sufficient drive the otherwise uniformly expressed AMIGO-1. also increases biosynthetic intracellular trafficking expression analyses knockout selective loss localization respective subunit. Together, data suggest mammalian neurons, exclusively are obligatory determining correct pattern expression, clustering.

Язык: Английский

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Molecular Determinants of BK Channel Functional Diversity and Functioning

Physiological Reviews, Год журнала: 2016, Номер 97(1), С. 39 - 87

Опубликована: Ноя. 3, 2016

Large-conductance Ca 2+ - and voltage-activated K + (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing neurosecretion. BK are tetramers in which pore-forming α subunit is coded by a single gene ( Slowpoke, KCNMA1). In this review, we first highlight importance ubiquitous channel, emphasizing role that different channelopathies. We next discuss modular nature channel-forming protein, modules (the voltage sensor binding sites) communicate with pore gates allosterically. regard, review detail allosteric models proposed explain channel activation how related structure. Considering their extremely large conductance unique selectivity , also offer an account these two apparently paradoxical characteristics can be understood consistently unison, what have learned about conduction system using ions, blockers, toxins. Attention paid here molecular sites located gating ring known crystal structure constituted four COOH termini. Despite fact gene, diversity obtained means alternative splicing modulatory β γ subunits. finish describing association or subunits change phenotype pharmacology.

Язык: Английский

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Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Physiological Reviews, Год журнала: 2022, Номер 103(1), С. 433 - 513

Опубликована: Авг. 11, 2022

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of disorders characterized by early-onset, often severe seizures EEG abnormalities on background developmental impairment that tends to worsen as consequence epilepsy. DEEs may result from both nongenetic genetic etiologies. Genetic have been associated with mutations in many genes involved different functions including cell migration, proliferation, organization, neuronal excitability, synapse transmission plasticity. Functional studies performed animal models clinical trials patients contributed elucidate pathophysiological mechanisms underlying explored the efficacy treatments. Here, we provide an extensive review phenotypic spectrum included determinants these conditions. We also brief overview most effective treatment now available emerging therapeutic approaches.

Язык: Английский

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Ctenophores and parahoxozoans independently evolved functionally diverse voltage-gated K+ channels

The Journal of General Physiology, Год журнала: 2025, Номер 157(3)

Опубликована: Фев. 27, 2025

The ctenophore species Mnemiopsis leidyi is known to have a large set of voltage-gated K+ channels, but little about the functional diversity these channels or their evolutionary history in other species. Here, we searched genomes two additional species, Beroe ovata and Hormiphora californensis, for functionally expressed subset M. channels. We found that last common ancestor three disparate lineages probably had at least 33 Two genes belong EAG family, remaining 31 Shaker family form single clade within animal/choanoflagellate phylogeny. additionally evidence 10 transcriptome early branching lineage Euplokamis dunlapae, suggesting diversification was already underway evolution. 16 Shakers they encode diverse array conductances with orthologs many classic subtypes cnidarians bilaterians. Analysis data show are wide variety cell types, including neurons, muscle, comb cells, colloblasts. Ctenophores therefore appear independently evolved much channel shared between

Язык: Английский

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Cellular resolution circuit mapping with temporal-focused excitation of soma-targeted channelrhodopsin

eLife, Год журнала: 2016, Номер 5

Опубликована: Авг. 15, 2016

We describe refinements in optogenetic methods for circuit mapping that enable measurements of functional synaptic connectivity with single-neuron resolution. By expanding a two-photon beam the imaging plane using temporal focusing method and restricting channelrhodopsin to soma proximal dendrites, we are able reliably evoke action potentials individual neurons, verify spike generation GCaMP6s, determine presence or absence connections patch-clamp electrophysiological recording.

Язык: Английский

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Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox

The Neuroscientist, Год журнала: 2018, Номер 24(4), С. 368 - 380

Опубликована: Март 15, 2018

Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy neurodevelopmental disorders, for which new genes or variants of preexisting candidate are being continuously identified at increasing rates every year. A surprising finding these efforts is the recognition that gain function potassium channel actually associated with certain types epilepsy, such as malignant migrating partial seizures infancy early-onset epileptic encephalopathy. development difficult to understand traditionally loss-of-function, not gain-of-function, hyperexcitability disorders. In this article, we describe current state field regarding gain-of-function (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCNT1) speculate on possible cellular mechanisms behind patients. Understanding how leads will provide insights into inner working neural circuits aid developing therapies.

Язык: Английский

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