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MOTIVATION: Many software libraries for using Hidden Markov Models in bioinformatics focus on inference tasks, such as likelihood calculation, parameter-fitting and alignment. However, construction of the state machines can be a laborious task, automation of which would be time-saving and less error-prone. RESULTS: We present Machine Boss, a software tool implementing not just inference and parameter-fitting algorithms, but also a set of operations for manipulating and combining automata. The aim is to make prototyping of bioinformatics HMMs as quick and easy as the construction of regular expressions, with one-line 'recipes' for many common applications. We report data from several illustrative examples involving protein-to-DNA alignment, DNA data storage and nanopore sequence analysis. AVAILABILITY AND IMPLEMENTATION: Machine Boss is released under the BSD-3 open source license and is available from http://machineboss.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Biología Computacional , Programas Informáticos , Algoritmos , Almacenamiento y Recuperación de la Información , Análisis de SecuenciaRESUMEN
MOTIVATION: The CRAM format addresses rising DNA storage costs for short-read sequencing by aligning reads to a reference genome and encoding the resulting alignment with Huffman, subexponential, Elias gamma, rANS, gzip and other codes. The CRAM codec is complex, and until now, there has been no JavaScript implementation. RESULTS: We have developed a JavaScript library, Cram-JS, that natively reads and decompresses the CRAM format on-the-fly. The library is used in the JBrowse and IGV-JS genome browsers and can readily be used by other JavaScript applications, in the web browser or in Node. AVAILABILITY AND IMPLEMENTATION: Cram-JS is written to the ES-6 standard and is available from the GitHub repository at https://github.com/GMOD/cram-js.
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Genoma , Programas Informáticos , ADN , Navegador WebRESUMEN
We present JBrowse 2, a general-purpose genome annotation browser offering enhanced visualization of complex structural variation and evolutionary relationships. It retains core features of JBrowse while adding new views for synteny, dotplots, breakpoints, gene fusions, and whole-genome overviews. It allows users to share sessions, open multiple genomes, and navigate between views. It can be embedded in a web page, used as a standalone application, or run from Jupyter notebooks or R sessions. These improvements are enabled by a ground-up redesign using modern web technology. We describe application functionality, use cases, performance benchmarks, and implementation notes for web administrators and developers.
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Genómica , Programas Informáticos , Sintenía , Genoma , Evolución Biológica , Navegador Web , InternetRESUMEN
Fatty acid amide hydrolase (FAAH) is a promising therapeutic target for the treatment of pain and CNS disorders. However, the development of potent and safe FAAH inhibitors is hindered by their off-target mediated side effect that leads to brain cell death. Its physiological off-targets and their associations with phenotypes may not be characterized using existing experimental and computational techniques as these methods fail to have sufficient proteome coverage and/or ignore native biological assemblies (BAs; i.e., protein quaternary structures). To understand the mechanisms of the side effects from FAAH inhibitors and other drugs, we develop a novel structural phenomics approach to identifying the physiological off-targets binding profile in the cellular context and on a structural proteome scale, and investigate the roles of these off-targets in impacting human physiology and pathology using text mining-based phenomics analysis. Using this integrative approach, we discover that FAAH inhibitors may bind to the dimerization interface of NMDA receptor (NMDAR) and several other BAs, and thus disrupt their cellular functions. Specifically, the malfunction of the NMDAR is associated with a wide spectrum of brain disorders that are directly related to the observed side effects of FAAH inhibitors. This finding is consistent with the existing literature, and provides testable hypotheses for investigating the molecular origin of the side effects of FAAH inhibitors. Thus, the in silico method proposed here, which can for the first time predict proteome-wide drug interactions with cellular BAs and link BA-ligand interaction with clinical outcomes, can be valuable in off-target screening. The development and application of such methods will accelerate the development of more safe and effective therapeutics.
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Metformin, a drug prescribed to treat type-2 diabetes, exhibits anti-cancer effects in a portion of patients, but the direct molecular and genetic interactions leading to this pleiotropic effect have not yet been fully explored. To repurpose metformin as a precision anti-cancer therapy, we have developed a novel structural systems pharmacology approach to elucidate metformin's molecular basis and genetic biomarkers of action. We integrated structural proteome-scale drug target identification with network biology analysis by combining structural genomic, functional genomic, and interactomic data. Through searching the human structural proteome, we identified twenty putative metformin binding targets and their interaction models. We experimentally verified the interactions between metformin and our top-ranked kinase targets. Notably, kinases, particularly SGK1 and EGFR were identified as key molecular targets of metformin. Subsequently, we linked these putative binding targets to genes that do not directly bind to metformin but whose expressions are altered by metformin through protein-protein interactions, and identified network biomarkers of phenotypic response of metformin. The molecular targets and the key nodes in genetic networks are largely consistent with the existing experimental evidence. Their interactions can be affected by the observed cancer mutations. This study will shed new light into repurposing metformin for safe, effective, personalized therapies.