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Publications
A long-context RNA foundation model for predicting transcriptome architecture
Linking DNA sequence to genomic function remains one of the grand challenges in genetics and genomics. Here, we combine large-scale single-m… (voir plus)olecule transcriptome sequencing of diverse cancer cell lines with cutting-edge machine learning to build LoRNASH, an RNA foundation model that learns how the nucleotide sequence of unspliced pre-mRNA dictates transcriptome architecture—the relative abundances and molecular structures of mRNA isoforms. Owing to its use of the StripedHyena architecture, LoRNASH handles extremely long sequence inputs (∼65 kilobase pairs), allowing for quantitative, zero-shot prediction of all aspects of transcriptome architecture, including isoform abundance, isoform structure, and the impact of DNA sequence variants on transcript structure and abundance. We anticipate that our public data release and proof-of-concept model will accelerate varying aspects of RNA biotechnology. More broadly, we envision the use of LoRNASH as a foundation for fine-tuning of any transcriptome-related downstream prediction task, including cell-type specific gene expression, splicing, and general RNA processing.
We propose MeshUp, a technique that deforms a 3D mesh towards multiple target concepts, and intuitively controls the region where each conce… (voir plus)pt is expressed. Conveniently, the concepts can be defined as either text queries, e.g.,"a dog"and"a turtle,"or inspirational images, and the local regions can be selected as any number of vertices on the mesh. We can effectively control the influence of the concepts and mix them together using a novel score distillation approach, referred to as the Blended Score Distillation (BSD). BSD operates on each attention layer of the denoising U-Net of a diffusion model as it extracts and injects the per-objective activations into a unified denoising pipeline from which the deformation gradients are calculated. To localize the expression of these activations, we create a probabilistic Region of Interest (ROI) map on the surface of the mesh, and turn it into 3D-consistent masks that we use to control the expression of these activations. We demonstrate the effectiveness of BSD empirically and show that it can deform various meshes towards multiple objectives. Our project page is at https://threedle.github.io/MeshUp.
Submitted genomic data for respiratory viruses reflect the emergence and spread of new variants. Although delays in submission limit the uti… (voir plus)lity of these data for prospective surveillance, they may be useful for evaluating other surveillance sources. However, few studies have investigated the use of these data for evaluating aberration detection in surveillance systems. Our study used a Bayesian online change point detection algorithm (BOCP) to detect increases in the number of submitted genome samples as a means of establishing 'gold standard' dates of outbreak onset in multiple countries. We compared models using different data transformations and parameter values. BOCP detected change points that were not sensitive to different parameter settings. We also found data transformations were essential prior to change point detection. Our study presents a framework for using global genomic submission data to develop 'gold standard' dates about the onset of outbreaks due to new viral variants.
An overwhelming majority of protein-protein interaction (PPI) studies are conducted in a select few model organisms largely due to constrain… (voir plus)ts in time and cost of the associated “wet lab” experiments. In silico PPI inference methods are ideal tools to overcome these limitations, but often struggle with cross-species predictions. We present INTREPPPID, a method which incorporates orthology data using a new “quintuplet” neural network, which is constructed with five parallel encoders with shared parameters. INTREPPPID incorporates both a PPI classification task and an orthologous locality task. The latter learns embeddings of orthologues that have small Euclidean distances between them and large distances between embeddings of all other proteins. INTREPPPID outperforms all other leading PPI inference methods tested on both the intra-species and cross-species tasks using strict evaluation datasets. We show that INTREPPPID’s orthologous locality loss increases performance because of the biological relevance of the orthologue data, and not due to some other specious aspect of the architecture. Finally, we introduce PPI.bio and PPI Origami, a web server interface for INTREPPPID and a software tool for creating strict evaluation datasets, respectively. Together, these two initiatives aim to make both the use and development of PPI inference tools more accessible to the community. GRAPHICAL ABSTRACT
