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Biology subjects

Spurgeon, M. E.

Publications and source records attributed to Spurgeon, M. E..

2 recordsLinked to original sources

Quantifying Evidence for Competing Biomedical Hypotheses using Large Language Models and Bayesian Analysis

Science fundamentally depends on the generation and testing of hypotheses, many of them controversial. An explosion in scientific literature has made evaluating hypotheses even within a domain a problem of scale, and risks slowing an already extensive consensus-building process. While this challenge has prompted interest in automated hypothesis evaluation tools, existing methods have not yet proven effective for comparing hypotheses. Here, we introduce KM-GPT-DCH, an algorithm that combines co-occurrence methods with large language models (LLMs) to develop a transparent and reproducible literature-based algorithm to compare controversial hypotheses using a structured scoring approach with Bayesian methods to estimate confidence. When testing the algorithm on historical controversial hypotheses previously decided, KM-GPT-DCH chooses the correct hypothesis with high confidence several years before the scientific community or public do so. We further apply the algorithm to compare twenty unresolved controversial hypothesis pairs providing guidance for future research. The method can help researchers and the public to evaluate biomedical hypotheses such as "Is it more likely that monoamine deficiency or inflammation causes depression?" It can also be used to assess and visualize historical trends in the scientific literature. A web-based implementation of the algorithm is freely available at https://skim.morgridge.org.

bioinformatics↗

E2 displacement of CIP2A from TOPBP1 activates the DNA damage response during papillomavirus life cycles

The papillomavirus life cycle is intricately linked to epithelial differentiation, and the virus manipulates the differentiation process to facilitate viral production. One such manipulation is activation of the DNA damage response (DDR) which promotes viral replication via homologous recombination. This report demonstrates that the papillomavirus transcription/replication/segregation factor E2 activates the DNA damage response (DDR). During differentiation, E2 displacement of CIP2A from TOPBP1 causes CIP2A to bind and inhibit PP2A resulting in DDR activation via ATM phosphorylation. The DDR promotes inhibitory interaction of DBC1 with the class III deacetylase SIRT1, which further boosts the DDR via increased acetylation and stability of viral and host proteins. E2 forms a complex with TOPBP1 and ATM, while preventing ATR activation by blocking TOPBP1-ATR interaction. This "ATM up ATR down" phenotype promotes viral replication via ATM promotion of homologous recombination, and cell proliferation via inhibition of ATR. We demonstrate this mechanism of DDR activation in multiple systems: keratinocytes expressing only E2, in foreskin keratinocytes immortalized by HPV16, in HPV16 positive keratinocytes derived from a cervical lesion, in pre-neoplastic lesions induced by mouse papillomavirus MmuPV1, in head and neck cancer cell lines that retain E2 expression, and in HPV16 positive oropharyngeal patient derived xenografts that retain E2 expression. ATM inhibition preferentially killed cells expressing E2, presenting a novel strategy for treating HPV early preneoplasia and a large subset of HPV+ oropharyngeal cancers retaining E2 expression and episomal genomes.

cancer biology↗