The nucleolus is widely regarded as a specialized compartment for RNA polymerase I (Pol I)-driven ribosomal RNA transcription and ribosome biogenesis. Yet the presence of ‘atypical nucleoli’, or nucleolus-like bodies (NLBs), which lack rRNA transcription despite containing canonical nucleolar components, has long been recognized, most notably during mammalian oogenesis and spermatogenesis. NLBs have been shown […]

Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have enabled atlas-scale cellular cartography, with consortium efforts now assembling millions of cells across diverse tissues, donors, and technologies to build comprehensive references for cell identify and disease mechanism, yet the scientific value of these atlases hinges on robust computational integration across heterogeneous data sources. Unlike pairwise […]

Drug-induced seizures remain a major safety concern in drug development, yet human seizure liability is difficult to predict using conventional preclinical models. Here, we evaluated whether spontaneous calcium network activity in human induced pluripotent stem cell-derived CNS-3D Brain Organoids could predict clinically observed seizure risk across a pharmacokinetically anchored drug set. CNS-3D organoids contained neuronal […]

Osteocytes play a central role in bone remodeling, mineral metabolism, and skeletal homeostasis, but direct molecular analysis of human osteocytes remains technically challenging because they are embedded within the mineralized bone matrix. Surgically obtained human bone specimens provide valuable material for studying human bone biology; however, surface-associated cells, marrow-derived cells, and adherent soft tissues can […]

The three-dimensional organization of the bacterial chromosome is critical for gene regulation. Chromosome conformation capture (Hi-C) has enabled genome-wide mapping of chromosomal folding, yet ensemble- averaged contact maps entangle biologically specific-folding interactions (SFIs) with nonspecific polymer compaction and mask single-cell heterogeneity. Here, we developed a polymer-based simulation framework in E. coli to address these limitations. […]

Pathogenic variants in ATAD3A cause a spectrum of multisystem disorders, with a recurrent dominant-negative variant (c.1582C>T; p.Arg528Trp) associated with neurodevelopmental disease. Given the tolerance of ATAD3A to heterozygous loss of function variants, allele-specific transcript reduction represents a promising therapeutic strategy. We designed and optimized allele-specific antisense oligonucleotides (ASOs) targeting the c.1582C>T transcript and evaluated their […]

Sinefungin is a potent nucleoside antimetabolite of S-adenosylmethionine (SAM), yet its biosynthesis has remained unclear for decades. Here we detail the identification and characterization of the complete sinefungin biosynthetic gene cluster (BGC) from Streptomyces incarnatus NRRL 8089. In vitro and in vivo analyses demonstrate that the defining carbon-carbon (C-C) bond is formed not by the […]

Finding and targeting cryptic pockets could dramatically expand the druggable proteome. However, discovering these sites remains challenging since they are only open a fraction of the time. It is also difficult to predict the functional relevance of a cryptic site as this often requires insight into allostery. Here we introduce attention enabled (AE-)PocketMiner, an artificial […]

Animal tissues have diverse architectures and cell behaviors across the epithelial-mesenchymal spectrum. Cell adhesion mediated by classical cadherins is foundational. Cadherins nucleate complexes of dozens of proteins connecting junctions to the cytoskeleton and signaling downstream. Many junctional proteins are well-studied in epithelia, but less is known about roles during mesenchymal migration. The nascent myotubes of […]

Fluorescent biosensors have proven valuable for revealing the spatio-temporal dynamics of protein conformation in live cells and animals. The great majority of biosensors are genetically encoded, but genetic encoding is difficult or impossible to apply in many cases, including cells or animals with poorly understood genomes, no DNA, or sensitive to manipulation. Using biosensors without […]

Intrinsic tryptophan fluorescence is widely used as a sensitive reporter of protein conformational dynamics, yet the molecular origin of its temperature-dependent modulation remains unclear. Here we investigate the conformational dynamics of Trp134 in bovine serum albumin (BSA) using molecular dynamics (MD) simulations, free-energy calculations based on umbrella sampling and WHAM, quantum mechanical (QM) calculations, and […]