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Coats, E.

Publications and source records attributed to Coats, E..

2 recordsLinked to original sources

LIVN: A testbed for learning to interact with in vitro neural networks

AO_SCPLOWBSTRACTC_SCPLOWThe investigation of cultured biological neural networks is a critical frontier in neuroscience with profound implications for the advancement of brain-machine interfaces, treatments of neurological diseases, and fundamental insights into neural computation and cognition. Advances in induced pluripotent stem cell (iPSC) technology and machine learning are converging to enable novel approaches to interrogating neural circuits in vitro. However, progress in this emerging field is hampered by the technical challenges and resource-intensive nature of acquiring datasets suitable for machine learning. Experimental recordings typically do not allow for interactive learning and generally lack ground-truth information that would enable rigorous algorithm development and validation. To overcome the limitations of experimental setups, simulated biophysical models of neurons and neuronal networks can serve as crucial accelerators. They allow for more controlled and systematic exploration than currently possible with living cultures and serve as interpretable intermediaries between abstract computational theory and complex biological reality. Using this approach, we introduce livn: an open source interactive simulation environment for learning to control in vitro neural networks. livn generates synthetic neural data with ground truth at scale, enabling the development and testing of ML models in interactive settings that mimic experimental platforms. We describe benchmark tasks that challenge ML models to exploit simulated neural dynamics and release generated synthetic datasets that mimic in vitro systems. By providing an open, extensible platform for developing and benchmarking machine learning models, livn aims to accelerate progress in both ML-driven understanding and engineering of in vitro neural systems and fundamental understanding of computation in biological neural networks.

neuroscience↗

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern - these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of [≥]1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.

cancer biology↗