How to build the virtual cell with artificial intelligence: Priorities and opportunities.

Cells are essential to understanding health and disease, yet traditional models fall short of modeling and simulating their function and behavior. Advances in AI and omics offer groundbreaking opportunities to create an AI virtual cell (AIVC), a multi-scale, multi-modal large-neural-network-based model that can represent and simulate the behavior of molecules, cells, and tissues across diverse states. This Perspective provides a vision on their design and how collaborative efforts to build AIVCs will transform biological research by allowing high-fidelity simulations, accelerating discoveries, and guiding experimental studies, offering new opportunities for understanding cellular functions and fostering interdisciplinary collaborations in open science.

The cellular dogma.

In this essay, I will put forth what I see as a major conceptual challenge for biology in the next decade, one that is inspired by Crick's Central Dogma: understanding information flow in the cell in the most general sense.

How to Build the Virtual Cell with Artificial Intelligence: Priorities and Opportunities.

The cell is arguably the most fundamental unit of life and is central to understanding biology. Accurate modeling of cells is important for this understanding as well as for determining the root causes of disease. Recent advances in artificial intelligence (AI), combined with the ability to generate large-scale experimental data, present novel opportunities to model cells.

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans.

Immunotherapy leads to cancer eradication despite the tumor's immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules.

The cortical amygdala consolidates a socially transmitted long-term memory.

Social communication guides decision-making, which is essential for survival. Social transmission of food preference (STFP) is an ecologically relevant memory paradigm in which an animal learns a desirable food odour from another animal in a social context, creating a long-term memory. How food-preference memory is acquired, consolidated and stored is unclear.

Coordinated wound responses in a regenerative animal-algal holobiont.

Animal regeneration involves coordinated responses across cell types throughout the animal body. In endosymbiotic animals, whether and how symbionts react to host injury and how cellular responses are integrated across species remain unexplored. Here, we study the acoel Convolutriloba longifissura, which hosts symbiotic Tetraselmis sp.

Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue.

Despite gene-expression profiling being one of the most common methods to evaluate molecular dysregulation in tissues, the utilization of cell-free messenger RNA (cf-mRNA) as a blood-based non-invasive biomarker analyte has been limited compared to other RNA classes. Recent advancements in low-input RNA-sequencing and normalization techniques, however, have enabled characterization as well as accurate quantification of cf-mRNAs allowing direct pathological insights. The molecular profile of the cell-free transcriptome in multiple diseases has subsequently been characterized including, prenatal diseases, neurological disorders, liver diseases and cancers suggesting this biological compartment may serve as a disease agnostic platform.

Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung.

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture.

Spatial transcriptomics reveal neuron-astrocyte synergy in long-term memory.

Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has a key role in long-term fear memory formation. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory.

Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity.

Rapid expansion of the pulmonary microvasculature through angiogenesis drives alveolarization, the final stage of lung development that occurs postnatally and dramatically increases lung gas-exchange surface area. Disruption of pulmonary angiogenesis induces long-term structural and physiologic lung abnormalities, including bronchopulmonary dysplasia, a disease characterized by compromised alveolarization. Although endothelial cells are primary determinants of pulmonary angiogenesis, mesenchymal cells (MC) play a critical and dual role in angiogenesis and alveolarization.

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts.

Alternative splicing of latrophilin-3 controls synapse formation.

The assembly and specification of synapses in the brain is incompletely understood. Latrophilin-3 (encoded by Adgrl3, also known as Lphn3)-a postsynaptic adhesion G-protein-coupled receptor-mediates synapse formation in the hippocampus but the mechanisms involved remain unclear. Here we show in mice that LPHN3 organizes synapses through a convergent dual-pathway mechanism: activation of Gα signalling and recruitment of phase-separated postsynaptic protein scaffolds.

Cell-Free Nucleic Acids for Early Prediction of Preeclampsia.

Purpose Of Review: This review summarizes the potential of cell-free nucleic acids for predicting preeclampsia, contrasts them with other methods, and discusses these findings' relevance to preeclampsia's pathogenesis and care.

Recent Findings: Recent studies have demonstrated the utility of cell-free nucleic acids in early preeclampsia risk prediction. Encouragingly, nucleic acid measurement exhibits similar or better sensitivity as compared to standard screening assays and furthermore sheds light on preeclampsia's underlying placental biology.

Multiomics characterization of cell type repertoires for urine liquid biopsies.

Urine is assayed alongside blood in medicine, yet current clinical diagnostic tests utilize only a small fraction of its total biomolecular repertoire, potentially foregoing high-resolution insights into human health and disease. In this work, we characterized the joint landscapes of transcriptomic and metabolomic signals in human urine. We also compared the urine transcriptome to plasma cell-free RNA, identifying a distinct cell type repertoire and enrichment for metabolic signal.

Hepatitis C virus infects and perturbs liver stem cells.

The hepatitis C virus (HCV) causes liver disease, affecting millions. Even though we have effective antivirals that cure HCV, they cannot stop terminal liver disease. We used an adult stem cell-derived liver organoid system to understand how HCV infection leads to the progression of terminal liver disease.

Global and cell type-specific immunological hallmarks of severe dengue progression identified via a systems immunology approach.

Severe dengue (SD) is a major cause of morbidity and mortality. To define dengue virus (DENV) target cells and immunological hallmarks of SD progression in children's blood, we integrated two single-cell approaches capturing cellular and viral elements: virus-inclusive single-cell RNA sequencing (viscRNA-Seq 2) and targeted proteomics with secretome analysis and functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells.

Immunocomplexed Antigen Capture and Identification by Native Top-Down Mass Spectrometry.

Antibody-antigen interactions are central to the immune response. Variation of protein antigens such as isoforms and post-translational modifications can alter their antibody binding sites. To directly connect the recognition of protein antigens with their molecular composition, we probed antibody-antigen complexes by using native tandem mass spectrometry.

An inexpensive semi-automated sample processing pipeline for cell-free RNA extraction.

Despite advances in automated liquid handling and microfluidics, preparing samples for RNA sequencing at scale generally requires expensive equipment, which is beyond the reach of many academic laboratories. Manual sample preparation remains a slow, expensive and error-prone process. Here, we describe a low-cost, semi-automated pipeline to extract cell-free RNA using one of two commercially available, inexpensive and open-source robotic systems: the Opentrons OT1.

Sequential sequencing by synthesis and the next-generation sequencing revolution.

The impact of next-generation sequencing (NGS) cannot be overestimated. The technology has transformed the field of life science, contributing to a dramatic expansion in our understanding of human health and disease and our understanding of biology and ecology. The vast majority of the major NGS systems today are based on the concept of 'sequencing by synthesis' (SBS) with sequential detection of nucleotide incorporation using an engineered DNA polymerase.

Aging Fly Cell Atlas identifies exhaustive aging features at cellular resolution.

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging . We characterized 163 distinct cell types and performed an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities.

Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis.

Background: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by multifocal bile duct strictures. To date, underlying molecular mechanisms of PSC remain unclear, and therapeutic options are limited.

Methods: We performed cell-free messenger RNA (cf-mRNA) sequencing to characterize the circulating transcriptome of PSC and noninvasively investigate potentially bioactive signals that are associated with PSC.

Noninvasive Prenatal Testing Using Circulating DNA and RNA: Advances, Challenges, and Possibilities.

Prenatal screening using sequencing of circulating cell-free DNA has transformed obstetric care over the past decade and significantly reduced the number of invasive diagnostic procedures like amniocentesis for genetic disorders. Nonetheless, emergency care remains the only option for complications like preeclampsia and preterm birth, two of the most prevalent obstetrical syndromes. Advances in noninvasive prenatal testing expand the scope of precision medicine in obstetric care.

Developmental diversity and unique sensitivity to injury of lung endothelial subtypes during postnatal growth.

At birth, the lung is still immature, heightening susceptibility to injury but enhancing regenerative capacity. Angiogenesis drives postnatal lung development. Therefore, we profiled the transcriptional ontogeny and sensitivity to injury of pulmonary endothelial cells (EC) during early postnatal life.