The Institute for Creation Research (ICR) is a Creationist apologetics institute in Dallas, Texas that specializes in media promotion of pseudoscientific creation science and interpretation of the Genesis creation narrative as a historical event. The ICR adopts the Bible as an inerrant and literal documentary of scientific and historical fact as well as religious and moral truths, and espouses a Young Earth creationist worldview. It rejects evolutionary biology, which it views as a corrupting moral and social influence and threat to religious belief. The ICR was formed by Henry M. Morris in 1972 following an organizational split with the Creation Science Research Center (CSRC).Its work in the field of creation science has been rejected by mainstream science, but has been significant in shaping creationist thought in the United States by introducing creation science through fundamentalist churches and religious schools, and by engaging in public debates against supporters of evolution. The ICR also offers unaccredited graduate level programs in Biblical Apologetics, including a minor in Creation Research. The ICR also operates the ICR Discovery Center for Science & Earth History museum in Dallas, Texas.
Interpretation of variants of uncertain significance remains a major problem in genomic analysis. Whilst statistical models can be used to predict pathogenicity, they offer no insights into the biophysical mechanism of variant action, and genomic data available for training is biased towards the subpopulations who have access. Protein misfolding has been found to act as a frequent mechanism for loss of gene or domain activity, where it is typically responsible for ∼2/3 of disease-causing variants and somatic mutations. The accuracy of energy predictions however has consistently been challenged by highly variable correlation coefficients reported from different proteins, and the unknown impact of alternative structures where available. Here we address this directly through a systematic analysis of mega-scale folding experimental results, enabled by a fully automated predictive pipeline based on FoldX. We find that whilst absolute correlation coefficients are mediocre for three highly studied proteins (PIN1, Spg, and FYN, ranging from 0.29-0.43), the correlation coefficient alone does not capture the full predictive power of the estimates. Specifically, we find a clear linear relationship between experimental and theoretical result, with a small number of outlier residues responsible for reducing the correlation. We show that the quantitative accuracy of predictions can be improved by aggregating estimates taken from different structures, and that the problematic outlier residues can be both empirically and theoretically identified, allowing us to flag low-confidence values. Our findings not only provide a framework for identifying problematic mutations in advance but also offers new insights into potential improvements of the FoldX protocol for more accurate protein stability predictions. Our insights support the use of FoldX in computational saturation screens to support variant analysis. ### Competing Interest Statement The authors have declared no competing interest. Cancer Research UK, https://ror.org/054225q67, CDEPIL-Jan24/100032
DNA language models offer a new paradigm for sequence design, yet their ability to generate functional genomic sequences remains underexplored. Plasmids act as a good testbed for evaluating DNA language model generation potential due to their simplicity and ease of construction. Here, we develop an end-to-end pipeline for generative design of Escherichia coli plasmid backbones, from large-scale data curation through fine-tuning, sampling, bioinformatic assessment, and candidate selection. A curated plasmid library was assembled from PlasmidScope and Addgene, and PlasmidGPT, a GPT-2-style DNA model, was fine-tuned on these corpora using circular-aware batching and random crops. Generations (1,000 per model) were produced under two prompting strategies: a minimal ATG seed to expose default tendencies, and a GFP cassette to enforce functional context. From 1000 generated synthetic plasmids, 16 candidates survived strict filtering and these were prioritised for wet-lab validation. Three shortlisted plasmids were synthesised and found to be functional, supporting growth, antibiotic resistance, and GFP expression in E. coli . These represent, to our knowledge, the first full AI-generated plasmids to be synthesised and validated in vivo . This work demonstrates that curated fine-tuning and prompt-aware generation enable DNA language models to progress from raw sequence sampling to experimentally testable plasmid designs. The approach offers a foundation for extending DNA design optimisation beyond E. coli , toward broader applications across engineering biology.
We describe the first-in-human trial of avutometinib (RAF/MEK clamp) and defactinib (FAK inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose/schedule is avutometinib 3.2 mg OD 2/7 days and defactinib 200 mg BID 7/7 days, both drugs administered orally for 3 weeks every 4 weeks. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate (ORR) and median progression free survival (mPFS) of 42.3% (11/26; 95% confidence interval (CI): 23.4%-63.1%) and 20.1 months (95% CI: 11.2-43.9) respectively in patients with low grade serous ovarian cancer (LGSOC). This study demonstrates importance of novel combinations of targeted therapies targeting the MAPK and FAK involving intermittent dosing schedules to improve tolerability (NCT03875820/EudraCT number 2017-001035-39).
Familial neuroblastoma is an extremely rare entity with only 1 – 2% of neuroblastoma cases thought to have a familial inheritance, mainly due to PHOX2B and ALK germline mutations. 16p11.2 microdeletion syndrome has been reported to be associated with neuroblastoma. We present the first case report of a patient presenting with metastatic neuroblastoma, developmental delay, and atypical facies, in whom we identified an inherited germline 16p11.2 microdeletion.
