The Caucasus was a hub for cultural and technological innovation in prehistory, yet the population history between the Greater and Lesser Caucasus remains insufficiently understood. We present genome-wide data of 205 individuals from modern Georgia and 25 from Armenia, spanning the period from the Bronze Age (BA) to the "Migration Period" (c. 3500 BCE-700 CE). Our results reveal a persisting local gene pool that, during the Middle-Late BA, absorbed additional ancestry from Anatolia and the neighboring Eurasian Steppe. In subsequent periods, we document population growth and increasing genetic diversity, supported by a high rate of individual ancestry outliers, particularly in urban centers of eastern Georgia. Among 20 Medieval individuals with artificially deformed skulls, 15 were part of local mating networks and five derived ancestry from the Eurasian Steppe, suggesting that cranial modification arrived with nomadic groups but became a locally adopted cultural practice.

Embryo models offer opportunities for understanding development and advancing medicine but rely on intricate procedures with limitations in efficiency and developmental fidelity. Here, we employ a small-molecule-only approach to induce mouse embryonic stem cells into 8- to 16-cell-like embryo founder cells, enabling the generation of a complete embryo model. These founder cells specify all blastocyst lineages, both embryonic and extraembryonic, in vivo and in vitro. The embryo model made only from embryo founder cells faithfully recapitulates development through organogenesis. During gastrulation, it forms a primitive streak via epithelial-to-mesenchymal transition, generates the three germ layers, and develops an ectoplacental cone. The model proceeds to form 6-14 somite pairs, fore-/mid-/hindbrain, a looping heart tube, optic buds, allantois, tail bud, migrating primordial germ cells, and well-defined gut. Altogether, our system using embryo founder cells enables a direct, rapid, efficient, and accurate in vitro model of embryogenesis.

Cancer-associated cachexia (CAC) is a multifactorial and currently incurable syndrome responsible for nearly one-third of cancer-related deaths. It contributes to therapy resistance and increases mortality among affected patients. In this study, we show that cancer-induced systemic inflammation alters vagal tone in CAC mouse models. This vagal dysregulation disrupts the brain-liver vagal axis, leading to a reprogramming of hepatic protein metabolism through the depletion of HNF4α, a key transcriptional regulator of liver function. The loss of HNF4α disrupts hepatic metabolism and promotes systemic inflammation, resulting in cachectic phenotypes. Interventions targeting the right cervical vagus nerve surgically, chemically, electrically, or through a non-invasive transcutaneous device attenuate CAC progression, alleviate its clinical manifestations, and synergize with chemotherapy to improve overall health and survival in mice.

Despite the evolution of hardwired homeostatic mechanisms to balance food intake with energy needs, the obesity epidemic continues to escalate globally. However, recent breakthroughs in delineating the molecular signaling pathways by which neural circuits regulate consummatory behaviors, along with transformative advances in peptide-based pharmacotherapy, are fueling the development of a new generation of safe and effective treatments for obesity. Here, we outline our current understanding of how the central nervous system controls energy homeostasis and examine how emerging insights, including those related to neuroplasticity, offer new perspectives for restoring energy balance and achieving durable weight loss. Together, these advances provide promising avenues for treating obesity and managing cardiometabolic disease.

In this issue of Cell, Ji and colleagues describe the development of SBI-810, a β-arrestin-biased modulator of neurotensin receptor 1 (NTSR1). This compound provides potent analgesia in rodent models of acute and chronic pain without side effects. This study highlights the therapeutic potential of targeting arrestin-biased GPCR signaling for non-opioid pain management.

Chimeric antigen receptor (CAR) T cell therapy has opened new possibilities for patients with refractory autoimmune diseases such as systemic sclerosis, but personalized manufacturing and treatment-related toxicities limit its broader use. In this preview, we discuss the first clinical application of an off-the-shelf, iPSC-derived CAR-NK cell product in systemic sclerosis as reported by Wang et al. in this issue of Cell.

The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.

Discrete genomic units can recombine into composite transposons that transcribe and transpose as single units, but their regulation and function are not fully understood. We report that composite transposons harbor bivalent histone marks, with activating and repressive marks in distinct regions. Genome-wide CRISPR-Cas9 screening, using a reporter driven by the hominid-specific composite transposon SVA (SINE [short interspersed nuclear element]-VNTR [variable number of tandem repeats]-Alu) in human cells, identified diverse genes that modify bivalent histone marks to regulate SVA transcription. SVA transcripts are critical for SVA's cis-regulatory function in selectively contacting and activating long-range gene expression. Remarkably, a subset of bivalent SVAs is activated during erythropoiesis to boost multiple erythroid gene expression, and knocking down these SVAs leads to deficient erythropoiesis. The RNA-dependent cis-regulatory function of SVA activates genes for myelopoiesis and can contribute to aging-associated myeloid-biased hematopoiesis. These results reveal that the cis-regulatory functions of composite transposons are bivalently regulated to control cell fate transitions in development and aging.

The prime editing (PE) system consists of a Cas9 nickase fused to a reverse transcriptase, which introduces precise edits into the target genomic region guided by a PE guide RNA. However, PE efficiency is limited by mismatch repair. To overcome this limitation, transient expression of a dominant-negative MLH1 (MLH1dn) has been used to inhibit key components of mismatch repair. Here, we designed a de novo MLH1 small binder (MLH1-SB) that binds to the dimeric interface of MLH1 and PMS2 using RFdiffusion and AlphaFold 3. The compact size of MLH1-SB enabled its integration into existing PE architectures via 2A systems, creating a PE-SB platform. The PE7-SB2 system significantly improved PE efficiency, achieving an 18.8-fold increase over PEmax and a 2.5-fold increase over PE7 in HeLa cells, as well as a 3.4-fold increase over PE7 in mice. This study highlights the potential of generative AI in advancing genome editing technology.

Genome editing technologies face challenges in achieving precise, large-scale DNA manipulations in higher organisms, including inefficiency, limited editing scales and types, and the retention of undesired sequences such as recombination sites ("scars"). Here, we present programmable chromosome engineering (PCE) and RePCE, two programmable chromosome editing systems enabling scarless kilobase-to-megabase DNA manipulations in plants and human cells. Through high-throughput engineering, we obtained Lox sites with a 10-fold reduced reversibility and applied an AI-assisted recombinase engineering method (AiCErec) to generate Cre variants with 3.5 times the recombination efficiency of the wild type. Incorporation of a Re-pegRNA-mediated scar-free strategy further enhanced editing precision, allowing scarless insertions, deletions, replacements, inversions, and translocations at the chromosomal level. Key applications include a 315-kb inversion in rice conferring herbicide resistance, scarless chromosome fusions, and a 12-Mb inversion at human disease-related sites. These advances significantly broaden the scope of genome editing applications in molecular breeding, therapeutic development, and synthetic biology.

The transition from water to land required animals to evolve specialized paw skin to support body weight and enable locomotion. We identify an evolutionarily emerged mechanism in skin epithelial cells that adapts to this mechanical demand. We show that the Slurp1 gene, conserved across tetrapods, is specifically expressed in palmoplantar skin. In humans, mutations in SLURP1 cause palmoplantar keratoderma (PPK), a condition marked by pathologically thickened skin epidermis on the soles and palms. Remarkably, reducing mechanical pressure on Slurp1 knockout paw skin fully rescues the PPK phenotype. Mechanistically, SLURP1 localizes to the endoplasmic reticulum (ER) membrane, where it binds the calcium pump SERCA2b. By preserving SERCA2b activity under mechanical pressure, SLURP1 maintains low cytoplasmic calcium levels and inhibits pressure-induced activation of the pPERK-NRF2 signaling-a pathway that can be genetically targeted to reverse PPK. These findings reveal an ER-based mechano-resistance mechanism that enhances cellular defense against prolonged mechanical pressure.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals. We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience. This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.

The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.

Interspecific hybridization may trigger species radiation by creating allele combinations and traits. Cultivated potato and its 107 wild relatives from the Petota lineage all share the distinctive trait of underground tubers, but the underlying mechanisms for tuberization and its relationship to extensive species diversification remain unclear. Through analyses of 128 genomes, including 88 haplotype-resolved genomes, we revealed that Petota is of ancient hybrid origin, with all members exhibiting stable mixed genomic ancestry, derived from the Etuberosum and Tomato lineages ca. 8-9 million years ago. Our functional experiments further validated the crucial roles of parental genes in tuberization, indicating that interspecific hybridization is a key driver of this innovative trait. This trait, along with the sorting and recombination of hybridization-derived polymorphisms, likely triggered the explosive species diversification of Petota by enabling occupation of broader ecological niches. These findings highlight how ancient hybridization fosters key innovation and drives subsequent species radiation.

Fermentation products released by the gut microbiota provide energy and regulatory functions to the host. Yet, little is known about the magnitude of this metabolic flux and its quantitative dependence on diet and microbiome composition. Here, we establish orthogonal approaches to consistently quantify this flux, integrating data on bacterial metabolism, digestive physiology, and metagenomics. From the nutrients fueling microbiota growth, most carbon ends up in fermentation products and is absorbed by the host. This harvest varies strongly with the amount of complex dietary carbohydrates and is largely independent of bacterial mucin and protein utilization. It covers 2%-5% of human energy demand for Western diets and up to 10% for non-Western diets. Microbiota composition has little impact on the total harvest but determines the amount of specific fermentation products. This consistent quantification of metabolic fluxes by our analysis framework is crucial to elucidate the gut microbiota's mechanistic functions in health and disease.

Despite the remarkable fidelity of eukaryotic DNA replication, nucleotide misincorporation errors occur in every replication cycle, generating mutations that drive genetic diseases and genome evolution. Here, we show that transcription factor (TF) proteins, key players in gene regulation, can increase mutagenesis from replication errors by directly competing with the recognition of DNA mismatches by MutSα, the primary initiator of eukaryotic mismatch repair (MMR). We demonstrate this TF-induced mutagenesis mechanism using a yeast genetic assay that quantifies the accumulation of mutations in TF binding sites. Analyses of human cancer mutations recapitulate the trends observed in yeast, with mutations arising from MYC-bound mismatches being enriched in MMR-proficient cells. These findings implicate TF-MMR competition as a critical determinant of somatic hypermutation at TF binding sites in cancer. Furthermore, our results provide a molecular mechanism for the higher-than-expected rate of rare genetic variants at TF binding sites, with important implications for regulatory DNA evolution.

Bacteria and archaea deploy diverse antiviral defense systems, many of which remain mechanistically uncharacterized. Here, we characterize Kiwa, a widespread two-component system composed of the transmembrane sensor KwaA and the DNA-binding effector KwaB. Cryogenic electron microscopy (cryo-EM) analysis reveals that KwaA and KwaB assemble into a large, membrane-associated supercomplex. Upon phage binding, KwaA senses infection at the membrane, leading to KwaB binding of ejected phage DNA and inhibition of replication and late transcription, without inducing host cell death. Although KwaB can bind DNA independently, its antiviral activity requires association with KwaA, suggesting spatial or conformational regulation. We show that the phage-encoded DNA-mimic protein Gam directly binds and inhibits KwaB but that co-expression with the Gam-targeted RecBCD system restores protection by Kiwa. Our findings support a model in which Kiwa coordinates membrane-associated detection of phage infection with downstream DNA binding by its effector, forming a spatially coordinated antiviral mechanism.

Secreted proteins are central mediators of intercellular communications and can serve as therapeutic targets in diverse diseases. The ∼1,903 human genes encoding secreted proteins are difficult to study through common genetic approaches. To address this hurdle and, more generally, to discover cancer therapeutics, we developed the Cancer Immunology Data Engine (CIDE, https://cide.ccr.cancer.gov), which incorporates 90 omics datasets spanning 8,575 tumor profiles with immunotherapy outcomes from 17 solid tumor types. CIDE systematically identifies all genes associated with immunotherapy outcomes. Then, we focused on secreted proteins prioritized by CIDE without known cancer roles and validated regulatory effects on immune checkpoint blockade for AOAH, CR1L, COLQ, and ADAMTS7 in mouse models. The top hit, acyloxyacyl hydrolase (AOAH), potentiates immunotherapies in multiple tumor models by sensitizing T cell receptors to weak antigens and protecting dendritic cells through depleting immunosuppressive arachidonoyl phosphatidylcholines and oxidized derivatives.

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.

Cells interact as dynamically evolving ecosystems. While recent single-cell and spatial multi-omics technologies quantify individual cell characteristics, predicting their evolution requires mathematical modeling. We propose a conceptual framework-a cell behavior hypothesis grammar-that uses natural language statements (cell rules) to create mathematical models. This enables systematic integration of biological knowledge and multi-omics data to generate in silico models, enabling virtual "thought experiments" that test and expand our understanding of multicellular systems and generate new testable hypotheses. This paper motivates and describes the grammar, offers a reference implementation, and demonstrates its use in developing both de novo mechanistic models and those informed by multi-omics data. We show its potential through examples in cancer and its broader applicability in simulating brain development. This approach bridges biological, clinical, and systems biology research for mathematical modeling at scale, allowing the community to predict emergent multicellular behavior.