In this case-control study, autoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in a portion of individuals with idiopathic myelopathy, especially those whose disease mimicked subacute combined degeneration.
Biological generative models can predict biological functions without task-specific training data but often under-perform specialized models. Here we demonstrate how to provide task-specific information without losing the general knowledge learned during pretraining by using direct preference optimization to align a model to generate stable protein sequences.
Bridge recombinases from the IS110 family of transposons, such as IS621, associate with a bridge RNA (bRNA) to mediate programmable recombination. Here we show that bRNA is weakly expressed from IS621 loci in the E. coli genome and that the IS621 recombinase–bRNA complex mediates excision less efficiently than insertion.
Many important biological functions arise not from single genes but from complex interactions encoded by entire genomes. We report the first generative design of complete bacteriophage genomes using genome language models. We generated viable bacteriophages with target host tropism, using the phage ΦX174 as our design template.
Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. We analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and 3D chromatin architecture from human hippocampal tissues spanning the adult lifespan.
Many diseases are linked to defects in Complex I subunits, but the extent to which non-mitochondrial proteins contribute to CI function is less clear. Here, we perform CRISPR screens to identify regulators of CI abundance across its N, Q, and P modules, which mediate NADH oxidation, quinone reduction, and proton pumping, respectively.
Impaired mitochondrial proteostasis underlies a broad spectrum of diseases, yet effective therapies remain limited. Here we show that deficiency of HTRA2, a mitochondrial intermembrane space protease, can be rescued by hypoxia therapy.
Programmable composition of complex systems is a longstanding goal of biological research. Generative modeling has improved the reliability of computational design, but existing methods are highly specialized and are difficult to extend or compose. Here, we introduce Proto, a high-level programming language for generative biology.
Obtaining antibodies to specific protein targets is a widely important yet experimentally laborious process. Here we introduce Germinal, a broadly enabling generative pipeline that designs antibodies against specific epitopes with nanomolar binding affinities while requiring only low-n experimental testing.
STING agonists are promising innate immune therapies, but their effectiveness is limited by the toxicity to activated T cells. Here, we identify the cationic amino acid transporter SLC7A1 as a cGAMP transporter and suggest that modulation of SLC7A1 may influence T cell susceptibility to cGAMP and its analogs.