The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the...The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.
Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition ar...Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type-specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain.
Emani PS, Liu JJ, Clarke D
… +79 more, Jensen M, Warrell J, Gupta C, Meng R, Lee CY, Xu S, Dursun C, Lou S, Chen Y, Chu Z, Galeev T, Hwang A, Li Y, Ni P, Zhou X, PsychENCODE Consortium‡, Bakken TE, Bendl J, Bicks L, Chatterjee T, Cheng L, Cheng Y, Dai Y, Duan Z, Flaherty M, Fullard JF, Gancz M, Garrido-Martín D, Gaynor-Gillett S, Grundman J, Hawken N, Henry E, Hoffman GE, Huang A, Jiang Y, Jin T, Jorstad NL, Kawaguchi R, Khullar S, Liu J, Liu J, Liu S, Ma S, Margolis M, Mazariegos S, Moore J, Moran JR, Nguyen E, Phalke N, Pjanic M, Pratt H, Quintero D, Rajagopalan AS, Riesenmy TR, Shedd N, Shi M, Spector M, Terwilliger R, Travaglini KJ, Wamsley B, Wang G, Xia Y, Xiao S, Yang AC, Zheng S, Gandal MJ, Lee D, Lein ES, Roussos P, Sestan N, Weng Z, White KP, Won H, Girgenti MJ, Zhang J, Wang D, Geschwind D, Gerstein M, PsychENCODE Consortium
Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly proces...Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
Changes in climate shift the geographic locations that are suitable for malaria transmission because of the thermal constraints on vector mosquitos and spp. malaria parasites and the lack of availability of surface wat...Changes in climate shift the geographic locations that are suitable for malaria transmission because of the thermal constraints on vector mosquitos and spp. malaria parasites and the lack of availability of surface water for vector breeding. Previous Africa-wide assessments have tended to solely represent surface water using precipitation, ignoring many important hydrological processes. Here, we applied a validated and weighted ensemble of global hydrological and climate models to estimate present and future areas of hydroclimatic suitability for malaria transmission. With explicit surface water representation, we predict a net decrease in areas suitable for malaria transmission from 2025 onward, greater sensitivity to future greenhouse gas emissions, and different, more complex, malaria transmission patterns. Areas of malaria transmission that are projected to change are smaller than those estimated by precipitation-based estimates but are associated with greater changes in transmission season lengths.
Madi N, Cato ET, Abu Sayeed M
… +16 more, Creasy-Marrazzo A, Cuénod A, Islam K, Khabir MIU, Bhuiyan MTR, Begum YA, Freeman E, Vustepalli A, Brinkley L, Kamat M, Bailey LS, Basso KB, Qadri F, Khan AI, Shapiro BJ, Nelson EJ
Despite an increasingly detailed picture of the molecular mechanisms of bacteriophage (phage)-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. In this...Despite an increasingly detailed picture of the molecular mechanisms of bacteriophage (phage)-bacterial interactions, we lack an understanding of how these interactions evolve and impact disease within patients. In this work, we report a year-long, nationwide study of diarrheal disease patients in Bangladesh. Among cholera patients, we quantified (prey) and its virulent phages (predators) using metagenomics and quantitative polymerase chain reaction while accounting for antibiotic exposure using quantitative mass spectrometry. Virulent phage (ICP1) and antibiotics suppressed to varying degrees and were inversely associated with severe dehydration depending on resistance mechanisms. In the absence of antiphage defenses, predation was "effective," with a high predator:prey ratio that correlated with increased genetic diversity among the prey. In the presence of antiphage defenses, predation was "ineffective," with a lower predator:prey ratio that correlated with increased genetic diversity among the predators. Phage-bacteria coevolution within patients should therefore be considered in the deployment of phage-based therapies and diagnostics.
Offensperger F, Tin G, Duran-Frigola M
… +28 more, Hahn E, Dobner S, Ende CWA, Strohbach JW, Rukavina A, Brennsteiner V, Ogilvie K, Marella N, Kladnik K, Ciuffa R, Majmudar JD, Field SD, Bensimon A, Ferrari L, Ferrada E, Ng A, Zhang Z, Degliesposti G, Boeszoermenyi A, Martens S, Stanton R, Müller AC, Hannich JT, Hepworth D, Superti-Furga G, Kubicek S, Schenone M, Winter GE
Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands....Chemical modulation of proteins enables a mechanistic understanding of biology and represents the foundation of most therapeutics. However, despite decades of research, 80% of the human proteome lacks functional ligands. Chemical proteomics has advanced fragment-based ligand discovery toward cellular systems, but throughput limitations have stymied the scalable identification of fragment-protein interactions. We report proteome-wide maps of protein-binding propensity for 407 structurally diverse small-molecule fragments. We verified that identified interactions can be advanced to active chemical probes of E3 ubiquitin ligases, transporters, and kinases. Integrating machine learning binary classifiers further enabled interpretable predictions of fragment behavior in cells. The resulting resource of fragment-protein interactions and predictive models will help to elucidate principles of molecular recognition and expedite ligand discovery efforts for hitherto undrugged proteins.
U.S. plan would harness the "RNome" for medicine and more-but funding is uncertain.U.S. plan would harness the "RNome" for medicine and more-but funding is uncertain.
Statements based on the best current scientific data and analyses that bear directly on societal issues, especially ones that are critical to societal justice, equity, and health, are practical responsibilities of profes...Statements based on the best current scientific data and analyses that bear directly on societal issues, especially ones that are critical to societal justice, equity, and health, are practical responsibilities of professional scientific organizations. And they often have impact.
Last month, Duke University in North Carolina announced that it was shuttering its herbarium. The collection consists of nearly 1 million specimens representing the most comprehensive and historic set of plants from the...Last month, Duke University in North Carolina announced that it was shuttering its herbarium. The collection consists of nearly 1 million specimens representing the most comprehensive and historic set of plants from the southeastern United States. It also includes extensive holdings from other regions of the world, especially Mexico, Central America, and the West Indies. Duke plans to disperse these samples to other institutions for use or storage over the next 2 to 3 years, but this decision reflects a lack of awareness by academia that such collections are being leveraged as never before. With modern technologies spanning multiple fields of study, the holdings in herbaria and other natural history collections are not only facilitating a deeper and broader understanding of the past and present world but are also providing tools to meet both known and unforeseen challenges facing humanity. Science and society can hardly risk the loss of such an important resource.
All of Us finds new DNA variants and refines genetic risk scores in diverse groups.All of Us finds new DNA variants and refines genetic risk scores in diverse groups.
Title PO, Singhal S, Grundler MC
… +17 more, Costa GC, Pyron RA, Colston TJ, Grundler MR, Prates I, Stepanova N, Jones MEH, Cavalcanti LBQ, Colli GR, Di-Poï N, Donnellan SC, Moritz C, Mesquita DO, Pianka ER, Smith SA, Vitt LJ, Rabosky DL
Snakes and lizards (Squamata) represent a third of terrestrial vertebrates and exhibit spectacular innovations in locomotion, feeding, and sensory processing. However, the evolutionary drivers of this radiation remain po...Snakes and lizards (Squamata) represent a third of terrestrial vertebrates and exhibit spectacular innovations in locomotion, feeding, and sensory processing. However, the evolutionary drivers of this radiation remain poorly known. We infer potential causes and ultimate consequences of squamate macroevolution by combining individual-based natural history observations (>60,000 animals) with a comprehensive time-calibrated phylogeny that we anchored with genomic data (5400 loci) from 1018 species. Due to shifts in the dynamics of speciation and phenotypic evolution, snakes have transformed the trophic structure of animal communities through the recurrent origin and diversification of specialized predatory strategies. Squamate biodiversity reflects a legacy of singular events that occurred during the early history of snakes and reveals the impact of historical contingency on vertebrate biodiversity.
Education must go beyond only countering essentialist and deterministic views of genetics.Education must go beyond only countering essentialist and deterministic views of genetics.
Several widely used high school biology texts depart from established science.Several widely used high school biology texts depart from established science.
Large mammalian herbivores (megafauna) have experienced extinctions and declines since prehistory. Introduced megafauna have partly counteracted these losses yet are thought to have unusually negative effects on plants c...Large mammalian herbivores (megafauna) have experienced extinctions and declines since prehistory. Introduced megafauna have partly counteracted these losses yet are thought to have unusually negative effects on plants compared with native megafauna. Using a meta-analysis of 3995 plot-scale plant abundance and diversity responses from 221 studies, we found no evidence that megafauna impacts were shaped by nativeness, "invasiveness," "feralness," coevolutionary history, or functional and phylogenetic novelty. Nor was there evidence that introduced megafauna facilitate introduced plants more than native megafauna. Instead, we found strong evidence that functional traits shaped megafauna impacts, with larger-bodied and bulk-feeding megafauna promoting plant diversity. Our work suggests that trait-based ecology provides better insight into interactions between megafauna and plants than do concepts of nativeness.
Efficient method for creating proteins with unusual amino acids opens the door to new medicines and catalysts.Efficient method for creating proteins with unusual amino acids opens the door to new medicines and catalysts.
Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome cor...Long Covid is a debilitating condition of unknown etiology. We performed multimodal proteomics analyses of blood serum from COVID-19 patients followed up to 12 months after confirmed severe acute respiratory syndrome coronavirus 2 infection. Analysis of >6500 proteins in 268 longitudinal samples revealed dysregulated activation of the complement system, an innate immune protection and homeostasis mechanism, in individuals experiencing Long Covid. Thus, active Long Covid was characterized by terminal complement system dysregulation and ongoing activation of the alternative and classical complement pathways, the latter associated with increased antibody titers against several herpesviruses possibly stimulating this pathway. Moreover, markers of hemolysis, tissue injury, platelet activation, and monocyte-platelet aggregates were increased in Long Covid. Machine learning confirmed complement and thromboinflammatory proteins as top biomarkers, warranting diagnostic and therapeutic interrogation of these systems.
Ng MSF, Kwok I, Tan L
… +40 more, Shi C, Cerezo-Wallis D, Tan Y, Leong K, Calvo GF, Yang K, Zhang Y, Jin J, Liong KH, Wu D, He R, Liu D, Teh YC, Bleriot C, Caronni N, Liu Z, Duan K, Narang V, Ballesteros I, Moalli F, Li M, Chen J, Liu Y, Liu L, Qi J, Liu Y, Jiang L, Shen B, Cheng H, Cheng T, Angeli V, Sharma A, Loh YH, Tey HL, Chong SZ, Iannacone M, Ostuni R, Hidalgo A, Ginhoux F, Ng LG
Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, com...Neutrophils are increasingly recognized as key players in the tumor immune response and are associated with poor clinical outcomes. Despite recent advances characterizing the diversity of neutrophil states in cancer, common trajectories and mechanisms governing the ontogeny and relationship between these neutrophil states remain undefined. Here, we demonstrate that immature and mature neutrophils that enter tumors undergo irreversible epigenetic, transcriptional, and proteomic modifications to converge into a distinct, terminally differentiated dcTRAIL-R1 state. Reprogrammed dcTRAIL-R1 neutrophils predominantly localize to a glycolytic and hypoxic niche at the tumor core and exert pro-angiogenic function that favors tumor growth. We found similar trajectories in neutrophils across multiple tumor types and in humans, suggesting that targeting this program may provide a means of enhancing certain cancer immunotherapies.
Africa bears a disproportionate burden of infectious diseases, accounting for a substantial percentage of global cases. Malaria, HIV/AIDS, tuberculosis, cholera, Ebola, Lassa fever, and other tropical diseases, such as d...Africa bears a disproportionate burden of infectious diseases, accounting for a substantial percentage of global cases. Malaria, HIV/AIDS, tuberculosis, cholera, Ebola, Lassa fever, and other tropical diseases, such as dengue and chikungunya, have had a profound impact on morbidity and mortality. Various factors contribute to the higher prevalence and incidence of infectious diseases in Africa, including socioeconomic challenges, limited access to health care, inadequate sanitation and hygiene infrastructure, climate-related factors, and endemicity of certain diseases in specific regions. A skilled workforce is crucial to addressing these challenges. Unfortunately, many countries in Africa often lack the required resources, and aspiring scientists frequently seek educational and career opportunities abroad, leading to a substantial loss of talent and expertise from the continent. This talent migration, referred to as "brain drain," exacerbates the existing training gaps and hampers the sustainability of research within Africa.
The marine-based West Antarctic Ice Sheet (WAIS) is considered vulnerable to irreversible collapse under future climate trajectories, and its tipping point may lie within the mitigated warming scenarios of 1.5° to 2°C of...The marine-based West Antarctic Ice Sheet (WAIS) is considered vulnerable to irreversible collapse under future climate trajectories, and its tipping point may lie within the mitigated warming scenarios of 1.5° to 2°C of the United Nations Paris Agreement. Knowledge of ice loss during similarly warm past climates could resolve this uncertainty, including the Last Interglacial when global sea levels were 5 to 10 meters higher than today and global average temperatures were 0.5° to 1.5°C warmer than preindustrial levels. Using a panel of genome-wide, single-nucleotide polymorphisms of a circum-Antarctic octopus, we show persistent, historic signals of gene flow only possible with complete WAIS collapse. Our results provide the first empirical evidence that the tipping point of WAIS loss could be reached even under stringent climate mitigation scenarios.