Predicting protein stability changes induced by single-point mutations has been a persistent challenge over the years, attracting immense interest from numerous researchers. The ability to precisely predict protein thermostability is pivotal for various subfields and applications in biochemistry, including drug development, protein evolution analysis, and enzyme synthesis. Despite the proposition of multiple methodologies aimed at addressing this issue, few approaches have successfully achieved optimal performance coupled with high computational efficiency. Two principal hurdles contribute to the existing challenges in this domain. The first is the complexity of extracting and aggregating sufficiently representative features from proteins. The second refers to the limited availability of experimental data for protein mutation analysis, further complicating the comprehensive evaluation of model performance on unseen data samples. With the advent of Large Language Models(LLM), such as the ESM models in protein research, profound interpretation of protein features is now accessibly aided by enormous training data. Therefore, LLMs are indeed to facilitate a wide range of protein research. In our study, we introduce an ESM-assisted efficient approach that integrates protein sequence and structural features to predict the thermostability changes in protein upon single-point mutations. Furthermore, we have curated a dataset meticulously designed to preclude data leakage, corresponding to two extensively employed test datasets, to facilitate a more equitable model comparison.

Even though deep neural networks (DNNs) achieve state-of-the-art results for a number of problems involving genomic data, getting DNNs to explain their decision-making process has been a major challenge due to their black-box nature. One way to get DNNs to explain their reasoning for prediction is via attribution methods which are assumed to highlight the parts of the input that contribute to the prediction the most. Given the existence of numerous attribution methods and a lack of quantitative results on the fidelity of those methods, selection of an attribution method for sequence-based tasks has been mostly done qualitatively. In this work, we take a step towards identifying the most faithful attribution method by proposing a computational approach that utilizes point mutations. Providing quantitative results on seven popular attribution methods, we find Layerwise Relevance Propagation (LRP) to be the most appropriate one for translation initiation, with LRP identifying two important biological features for translation: the integrity of Kozak sequence as well as the detrimental effects of premature stop codons.

To interpret the genetic profile present in a patient sample, it is necessary to know which mutations have important roles in the development of the corresponding cancer type. Named entity recognition is a core step in the text mining pipeline which facilitates mining valuable cancer information from the scientific literature. However, due to the scarcity of related datasets, previous NER attempts in this domain either suffer from low performance when deep learning based models are deployed, or they apply feature based machine learning models or rule based models to tackle this problem, which requires intensive efforts from domain experts, and limit the model generalization capability. In this paper, we propose EPICURE, an ensemble pre trained model equipped with a conditional random field pattern layer and a span prediction pattern layer to extract cancer mutations from text. We also adopt a data augmentation strategy to expand our training set from multiple datasets. Experimental results on three benchmark datasets show competitive results compared to the baseline models.

In 1238, the medieval Spanish ruler Alfonso X of Castile published a tome called Libro de los Juegos, or The Book of Games. It consisted of 97 parchment pages, many with beautiful color illustrations, and contains the earliest descriptions of games such as chess, dice, and backgammon. Alfonso went on to classify games into three categories: games that are played on horseback, games played dismounted (such as fencing and wrestling), and games played seated. He divided this third category even further into games that rely on the brain, games of chance, and games that rely on both. In making these distinctions, Alfonso is the unofficial founder of a field of science known as ludology--the study of games, which has attracted much interest among mathematicians, computer scientists, sociologists, and others.

Determining the primary site of origin for metastatic tumors is one of the open problems in cancer care because the efficacy of treatment often depends on the cancer tissue of origin. Classification methods that can leverage tumor genomic data and predict the site of origin are therefore of great value. Because tumor DNA point mutation data is very sparse, only limited accuracy (64.5% for 12 tumor classes) was previously demonstrated by methods that rely on point mutations as features (1). Tumor classification accuracy can be greatly improved (to over 90% for 33 classes) by relying on gene expression data (2). However, this additional data is often not readily available in clinical setting, because point mutations are better profiled and targeted by clinical mutational profiling. Here we sought to develop an accurate deep transfer learning and fine-tuning method for tumor sub-type classification, where predicted class is indicative of the primary site of origin. Our method significantly outperforms the state-of-the-art for tumor classification using DNA point mutations, reducing the error by more than 30% at the same time discriminating over many more classes on The Cancer Genome Atlas (TCGA) dataset. Using our method, we achieve state-of-the-art tumor type classification accuracy of 78.3% for 29 tumor classes relying on DNA point mutations in the tumor only.

Following the Comment of Stewart et al., we repeated our analysis on sequencing runs from The Cancer Genome Atlas (TCGA) using their suggested parameters. We found signs of oxidative damage in all sequence contexts and irrespective of the sequencing date, reaffirming that DNA damage affects mutation-calling pipelines in their ability to accurately identify somatic variations. Previously, we devised a metric termed the global imbalance value (GIV) to evaluate how mutagenic damage affects sequencing accuracy (1). We showed that mutagenic damage is pervasive in public sequencing datasets and confounds the identification of somatic variants with low to moderate (1 to 5%) allelic frequency. Following our publication, the principle of global imbalance was incorporated by the International Cancer Genome Consortium (ICGC) as one of five measures used to construct a quality rating for each cancer genome (2).