Conformational biasing (CB) is a rapid and streamlined computational method that uses contrastive scoring by inverse folding models to predict protein variants biased toward desired conformational states. We successfully...Conformational biasing (CB) is a rapid and streamlined computational method that uses contrastive scoring by inverse folding models to predict protein variants biased toward desired conformational states. We successfully validated CB across seven diverse datasets, identifying variants of K-Ras, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, the β2 adrenergic receptor, and Src kinase with improved conformation-specific functions such as enhanced binding or enzymatic activity. Applying CB to the enzyme lipoic acid ligase (LplA), we uncovered a previously unknown mechanism controlling its promiscuous activity. Variants biased toward an "open" conformation state became more promiscuous, whereas "closed"-biased variants were more selective, enhancing LplA's utility for site-specific protein labeling with fluorophores in living cells. The speed and simplicity of CB make it a versatile tool for engineering protein dynamics with broad applications in basic research, biotechnology, and medicine.
Several millennia of human-mediated translocation of non-native pig species (genus ) to the islands of Wallacea and Oceania have considerably altered local ecosystems. To investigate the timing and trajectory of these in...Several millennia of human-mediated translocation of non-native pig species (genus ) to the islands of Wallacea and Oceania have considerably altered local ecosystems. To investigate the timing and trajectory of these introductions, we conducted both genomic analyses of 576 pig nuclear genomes and a geometric morphometric analysis of 708 modern and ancient dental remains. Our analyses demonstrate that free-living and domestic pigs in Wallacea and Oceania have diverse ancestries resulting from the introduction of multiple sequential pig populations followed by gene flow. Despite the variability in their genomic ancestry, these pigs all have a distinct tooth morphology as well as a genetic link to the Chinese domestic pig populations that accompanied the dispersal of Austronesian language speakers ~4000 to 3000 years ago via Taiwan and the Philippines.
Biological systems are inherently complex and heterogeneous. Deciphering this complexity increasingly relies on high-throughput single-cell omics methods and tools that efficiently probe the cellular phenotype and genoty...Biological systems are inherently complex and heterogeneous. Deciphering this complexity increasingly relies on high-throughput single-cell omics methods and tools that efficiently probe the cellular phenotype and genotype. Here, we present a versatile technology based on semipermeable capsules (SPCs) tailored for a variety of high-throughput nucleic acid assays, including single-cell genome and mRNA sequencing, and fluorescence-activated cell sorting-based isolation of individual transcriptomes based on a nucleic acid marker of interest. Being biocompatible, the SPCs support single-cell cultivation and clonal expansion over long periods of time, thereby overcoming a fundamental limitation of droplet microfluidics platforms. Overall, the SPCs represent a customizable and broadly applicable tool for easy-to-use, scalable single-cell omics applications that are built on multistep biochemical reactions.
Single-cell sequencing methods uncover natural and induced variation between cells. Many functional genomic methods, however, require multiple steps that cannot yet be scaled to high throughput, including assays on livin...Single-cell sequencing methods uncover natural and induced variation between cells. Many functional genomic methods, however, require multiple steps that cannot yet be scaled to high throughput, including assays on living cells. In this study, we developed capsules with amphiphilic gel envelopes (CAGEs), which selectively retain cells and large analytes while being freely accessible to media, enzymes, and reagents. Capsules enable high-throughput multistep assays combining live-cell culture with genome-wide readouts. We established methods for barcoding CAGE DNA libraries and applied them to measure persistence of gene expression programs in cells by capturing the transcriptomes of tens of thousands of expanding clones in CAGEs. The compatibility of CAGEs with diverse enzymatic reactions will facilitate the expansion of the current repertoire of single-cell high-throughput measurements and their extension to live-cell assays.
How populations adapt to their environment is a fundamental question in biology. Yet, we know surprisingly little about this process, especially for endangered species, such as nonhuman great apes. Chimpanzees, our close...How populations adapt to their environment is a fundamental question in biology. Yet, we know surprisingly little about this process, especially for endangered species, such as nonhuman great apes. Chimpanzees, our closest living relatives, are particularly notable because they inhabit diverse habitats, from rainforest to woodland-savannah. Whether genetic adaptation facilitates such habitat diversity remains unknown, despite it having wide implications for evolutionary biology and conservation. By using newly sequenced exomes from 828 wild chimpanzees (388 postfiltering), we found evidence of fine-scale genetic adaptation to habitat, with signatures of positive selection in forest chimpanzees in the same genes underlying adaptation to malaria in humans. This work demonstrates the power of noninvasive samples to reveal genetic adaptations in endangered populations and highlights the importance of adaptive genetic diversity for chimpanzees.
Determining whether sponges or ctenophores root the animal tree has important implications for understanding early animal evolution. Here, we examined support for these competing hypotheses by constructing large and high...Determining whether sponges or ctenophores root the animal tree has important implications for understanding early animal evolution. Here, we examined support for these competing hypotheses by constructing large and highly informative data matrices containing sequences from sponges, ctenophores, cnidarians, bilaterians, and diverse animal relatives. The new data matrices and 10 published datasets were analyzed in 785 topology tests conducted using integrative phylogenomics, a method that unifies concatenation and coalescence to identify genes with a consistent phylogenetic signal. All 490 statistically significant tests supported the sponge-sister hypothesis and none supported the ctenophore-sister hypothesis; the remaining 295 tests were inconclusive. These results provide compelling evidence for the sponge-sister hypothesis and suggest that integrative phylogenomics provides a robust and powerful approach for disentangling branches in the tree of life.
Although metagenomic sequencing has revealed a rich microbial biodiversity in the mammalian gut, methods to genetically alter specific species in the microbiome are highly limited. Here, we introduce Metagenomic Editing...Although metagenomic sequencing has revealed a rich microbial biodiversity in the mammalian gut, methods to genetically alter specific species in the microbiome are highly limited. Here, we introduce Metagenomic Editing (MetaEdit) as a platform technology for microbiome engineering that uses optimized CRISPR-associated transposases delivered by a broadly conjugative vector to directly modify diverse native commensal bacteria from mice and humans with new pathways at single-nucleotide genomic resolution. Using MetaEdit, we achieved in vivo genetic capture of native murine by integrating a metabolic payload that enables tunable growth control in the mammalian gut with dietary inulin. We further show in vivo editing of segmented filamentous bacteria, an immunomodulatory small-intestinal microbial species recalcitrant to cultivation. Collectively, this work provides a paradigm to precisely manipulate individual bacteria in native communities across gigabases of their metagenomic repertoire.
Álvez MB, Bergström S, Kenrick J
… +108 more, Johansson E, Åberg M, Akyildiz M, Altay O, Sköld H, Antonopoulos K, Apostolakis E, Balcioglu YH, Bergström A, Bergström G, Björkander S, Brage SE, Brodin P, Butler L, Cajander S, Danielsson H, Dayangac M, Dinler-Doganay G, Doğanay L, Enblad G, Enblad M, Fagerberg L, Falck-Jones S, Färnert A, Forsberg M, Gonzalez L, Gummesson A, Gunnarsson K, Gunnarsson I, Gyllensten U, Hesselager G, Hober A, Höglund M, Holmqvist M, Horuluoglu B, Hultgren R, Iglesias MJ, Janols H, Johansson F, Johnsson A, Klareskog L, Kotol D, Kull I, Kvarnström M, Lautenbach MJ, Liljedahl U, Lindman H, Lindskog C, Lipcsey M, Lundberg IE, Mardinoglu A, Melén E, Meng L, Merritt AS, Mulder J, Nguyen MT, Nordlund J, Norrby-Teglund A, Notarnicola A, Nowak P, Odeberg J, Oksvold P, Olsson T, Padyukov L, Pauksens K, Piehl F, Pin E, Pontén F, Rameika N, Reepalu A, Roy J, Schwenk JM, Sen M, Siika A, Simonson OE, Sivertsson Å, Sjöblom T, Sjöstedt E, Skoglund L, Smed-Sörensen A, Sondén K, Sönnerborg A, Stålberg K, Strålin K, Sundén-Cullberg J, Sundling C, Sutantiwanichkul T, Svedman FC, Svensson M, Svenungsson E, Lakshmikanth T, Tran-Minh KH, Türkez H, Unge C, Venge P, Wahren-Herlenius M, Woessmann J, Yang H, Yeşilkaya UH, Yuan M, Zeybel M, Zhang C, Zhong W, Zwahlen M, von Feilitzen K, Nilsson P, Edfors F, Uhlén M
The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. In this study, we present a pan-disease resource to enable the study of diverse disease p...The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. In this study, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and body mass index, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8262 individuals and up to 5416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research.
The symbiotic agriculture of fungus-farming termites can collapse if they fail to prevent invading weeds. Previous studies suggest a role for symbiotic fungistatic microbes in bringing about weed control. However, how te...The symbiotic agriculture of fungus-farming termites can collapse if they fail to prevent invading weeds. Previous studies suggest a role for symbiotic fungistatic microbes in bringing about weed control. However, how termites employ these microbes to suppress fungal weeds without affecting the fungal cultivar remains unknown. We show that the fungus-farming termite uses specific behaviors to remove, isolate, and suppress the growth of the fungal weed , primarily by encasing it with soil boluses containing fungistatic microbes. These behaviors efficiently suppress the weed without affecting the crop. This integration of specific behaviors with termite-derived microbes appears to be the proximate mechanism of how microbes are topically used by termites to confine the weed while keeping the crop unaffected.
Species population sizes fluctuate over time, and these temporal dynamics play a key role in governing the maintenance of biodiversity. Although modeling approaches have been developed to characterize fluctuations in spe...Species population sizes fluctuate over time, and these temporal dynamics play a key role in governing the maintenance of biodiversity. Although modeling approaches have been developed to characterize fluctuations in species abundances, the data required to parameterize these models from scratch are substantial. Here we introduce a new approach to modeling population fluctuations on decadal timescales by relating community-level dynamics to population-level patterns encoded in plant genomes. Using genomic samples taken at a single time point to generate contemporary effective population size estimates in a temperate montane forest, we accurately predict fluctuations across three censuses. Our approach facilitates the use of genomic demography to parameterize multispecies community models in ecology and shows that population genomic data can provide accurate predictions for ecological dynamics.
Science History Institute makes public multimillion-dollar collection, including Rosalind Franklin's famous DNA image, assembled by fake scientist.Science History Institute makes public multimillion-dollar collection, including Rosalind Franklin's famous DNA image, assembled by fake scientist.
Liu C, Sarnat E, Tan JA
… +14 more, Janicki J, Deyrup J, Ogasawara M, Grau ML, Qiu L, Hita Garcia F, Fischer G, Caginitoba A, Narula N, Darwell CT, Kubota Y, Pierce NE, Mikheyev AS, Economo EP
Insect populations have declined worldwide, but the extent and drivers of these declines are debated. Most studies rely on field surveys performed in the past century, leaving gaps in our understanding of longer-term tre...Insect populations have declined worldwide, but the extent and drivers of these declines are debated. Most studies rely on field surveys performed in the past century, leaving gaps in our understanding of longer-term trends. Using a "community genomics" approach, we estimated community assembly over millions of years and more recent demographic trends of ant species in the Fijian archipelago. We found that 79% of endemic species are in decline, starting after the arrival of humans approximately 3000 years ago and accelerating in the past 300 years, whereas recent arrivals are expanding. The primary correlate of population decline among endemic species was found to be sensitivity to habitat disturbance. This study demonstrates the value of contemporary collections for estimating long-term community trends and highlights the vulnerability of endemic island species to anthropogenic change.
In the United States, the summer of 2025 will be remembered as artificial intelligence's (AI's) cruel summer-a season when the unheeded risks and dangers of AI became undeniably clear. Recent months have made visible the...In the United States, the summer of 2025 will be remembered as artificial intelligence's (AI's) cruel summer-a season when the unheeded risks and dangers of AI became undeniably clear. Recent months have made visible the stakes of the unchecked use of AI: The parents of 16-year-old Adam Raine filed the first known wrongful death lawsuit against OpenAI, claiming ChatGPT contributed to their son's suicide by advising him on methods and offering to write his suicide note. A psychiatrist's investigation revealed that AI therapy chatbots encouraged troubled teens to "get rid of" parents and made sexual suggestions while falsely claiming to be licensed therapists. Reports emerged of a man hospitalized after following ChatGPT's advice to add sodium bromide to his diet. Trevis Williams reportedly spent more than 2 days wrongfully jailed after facial recognition technology misidentified him despite obvious physical differences and geolocation data proving he was miles away from the crime scene.
Plants deploy a diverse array of pattern recognition receptors (PRRs), which perceive microbe-associated molecular patterns to activate immune responses. Leucine-rich repeat receptor-like kinase subgroup XII (LRR-RLK-XII...Plants deploy a diverse array of pattern recognition receptors (PRRs), which perceive microbe-associated molecular patterns to activate immune responses. Leucine-rich repeat receptor-like kinase subgroup XII (LRR-RLK-XII) represents one of the largest PRR families owing to lineage-specific diversification. Through bioinformatics and synthetic biology approaches, we characterized LRR-RLK-XIIs from 285 plant species and identified a receptor, "SCORE," that perceives cold shock protein (CSP) peptides. SCORE orthologs from multiple angiosperm lineages exhibit CSP recognition polymorphisms, indicating recurrent selection for pathogen recognition through substitutions at key amino acid residues. Through functional phylogenomics and protein structure predictions, we engineered SCORE variants capable of detecting multiple phytopathogen CSP peptides, thus revealing the diverse PRR recognition landscape in plants. Our strategy holds promise for engineering plant immune receptors, particularly for perennial crops.
Single-cell RNA sequencing (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of messenger RNA (mRNA) measurements...Single-cell RNA sequencing (scRNA-seq) has facilitated the characterization of cell state heterogeneity and recapitulation of differentiation trajectories. However, the exclusive use of messenger RNA (mRNA) measurements comes at the risk of missing important biological information. We leveraged recent technological advances in single-cell proteomics by mass spectrometry (scp-MS) to generate an scp-MS dataset of an in vivo differentiation hierarchy encompassing >2500 human CD34+ hematopoietic stem and progenitor cells. Through integration with scRNA-seq, we identified proteins important for stem cell function, which were not indicated by their mRNA transcripts. Further, we showed that modeling translation dynamics can infer cell progression during differentiation and explain substantially more protein variation from mRNA than linear correlation. Our work offers a framework for single-cell multiomics studies across biological systems.