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10.1126/science.1240729 | 62,058,721 | The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the β form of calcium/calmodulin-dependent pro... | 10.1038/s41583-020-0292-4 | Through a systematic proteomic screen, this study identifies the first key molecular mechanism at the LHb, the upregulation of CaMKIIβ, underlying the synaptic hyperactivity of the LHb and depression-like behaviours |
10.1126/science.1250469 | 20,406,868 | A pathway that controls our mood A brain area called the lateral habenula is involved in negative motivation and may thus play a role in depression. Shabel et al. investigated synaptic transmission in a brain pathway to the lateral habenula that transmits disappointment signals. Surprisingly, they found the simultaneou... | 10.1038/s41583-020-0292-4 | This article reports the co-release of glutamate and GABA from the EPN to LHb synapses. It demonstrates the balance of these two co-released transmitters as an important regulator of depression |
10.1101/pdb.top069906 | 26,931,605 | The identification of carcinogens in the workplace, diet, and environment through chemical carcinogenesis studies in animals has directly contributed to a reduction of cancer burden in the human population. Reduced exposure to these carcinogens through lifestyle changes, government regulation, or change in industry pra... | 10.1038/s41568-020-0275-9 | This paper is a historical perspective and methodological overview of chemical mutagenesis in animal models |
10.1126/science.1193004 | 61,588,610 | Piggybacking on Cancer Genes Transposons are mobile segments of DNA that can insert in or near important genes to cause mutations that disrupt gene function. Rad et al. (p. 1104 , published online 14 October) adapted a mutagenic transposon called Piggybac, originally derived from a moth, into a tool for discovery of ca... | 10.1038/s41568-020-0275-9 | This is the first study to demonstrate PiggyBac transposon-based genetic screening in mice |
10.1073/pnas.1512392112 | 62,144,336 | Here, we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice. Using hepatic single guide RNA (sgRNA) delivery, we targeted large gene sets to induce hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). We observed D... | 10.1038/s41568-020-0275-9 | This paper presents the first proof-of-concept positive-selection CRISPRko screen in the soma of mice, through direct in vivo delivery of CRISPR mini-libraries |
10.1073/pnas.1600582113 | 38,205,926 | Targeted transcriptional regulation is a powerful tool to study genetic mediators of cellular behavior. Here, we show that catalytically dead Cas9 (dCas9) targeted to genomic regions upstream or downstream of the transcription start site allows for specific and sustainable gene-expression level alterations in tumor cel... | 10.1038/s41568-020-0275-9 | This paper presents the first CRISPRa screen in mice exploiting ex vivo mutagenized B cell lymphoblastic leukaemia cells to identify mediators of resistance to the chemotherapy temozolomide |
10.1038/s41579-019-0196-3 | 20,813,085 | Abstract Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Seve... | 10.1038/s41579-020-0378-z | This Consensus Statement summarizes the most important definitions regarding research in antibiotic persistence |
10.1126/science.aaj2191 | 83,513,384 | Controlled experimental evolution during antibiotic treatment can help to explain the processes leading to antibiotic resistance in bacteria. Recently, intermittent antibiotic exposures have been shown to lead rapidly to the evolution of tolerance—that is, the ability to survive under treatment without developing resis... | 10.1038/s41579-020-0378-z | This work is the first to show that tolerance or persistence has a link to the evolution of antibiotic resistance |
10.1126/science.1099390 | 104,375,088 | A fraction of a genetically homogeneous microbial population may survive exposure to stress such as antibiotic treatment. Unlike resistant mutants, cells regrown from such persistent bacteria remain sensitive to the antibiotic. We investigated the persistence of single cells of Escherichia coli with the use of microflu... | 10.1038/s41579-020-0378-z | This work shows that persisters can be phenotypically generated as a response to environmental stimuli (that is, triggered persistence), but that another category of persisters can pre-exist (that is, spontaneous persistence) |
10.1126/science.1244705 | 83,085,476 | Persistent Survival The role of persister cells—dormant cells that survive multidrug treatment—in the context of bacterial pathogenesis has not been explored in depth. Using a single-cell fluorescent dilution technique, Helaine et al. (p. 204 ) examined Salmonella Typhimurium persister-cell formation in vitro and in in... | 10.1038/s41579-020-0378-z | This study is an important description of host-induced persister formation in an invasive pathogen, supporting the idea that virulence factors that allow invasion and survival in cells can coincidentally evolve persistence |
10.1038/s41396-019-0344-9 | 39,352,601 | Abstract Persisters are transiently antibiotic-tolerant cells that complicate the treatment of bacterial infections. Both theory and experiments have suggested that persisters facilitate genetic resistance by constituting an evolutionary reservoir of viable cells. Here, we provide evidence for a strong positive correla... | 10.1038/s41579-020-0378-z | This work shows an alternative mechanism for the link between the evolution of persistence and antibiotic resistance, stating that persisters themselves have higher mutation rates leading to a higher probability of evolution of resistance (or other traits) |
10.1126/science.aan4673 | 41,714,840 | As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating ... | 10.1038/s41588-022-01125-9 | A Review article describing the association between CH, aging and different types of human disease. |
10.1038/s41586-022-04785-z | 127,839,142 | Abstract Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis 1–4 . The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it intera... | 10.1038/s41588-022-01125-9 | This paper describes the lifelong evolution of CH and its links to hematological malignancy. |
10.1126/scitranslmed.3008002 | 102,964,229 | CTLA-4 blocking antibody induces secondary hypophysitis by binding to CTLA-4 antigen and initiating a type II hypersensitivity reaction. | 10.1038/s41573-021-00259-5 | This article describes the direct on-target effect of an antibody against CTLA4 in inducing hypophysitis |
10.1038/ncomms10391 | 83,025,226 | Abstract The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota’s composition. Im... | 10.1038/s41573-021-00259-5 | This is the first article to report that the microbiome may influence immune-related colitis |
10.1073/pnas.1611421113 | 29,131,783 | Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead ... | 10.1038/s41573-021-00259-5 | This paper provides evidence that expanded clonal T cells are associated with immune-related toxicities |
10.1126/science.aax4063 | 62,256,318 | The general functions of lymphatic vessels in fluid transport and immunosurveillance are well recognized. However, accumulating evidence indicates that lymphatic vessels play active and versatile roles in a tissue- and organ-specific manner during homeostasis and in multiple disease processes. This Review discusses rec... | 10.1038/s41590-022-01162-w | his Review summarizes the heterogeneity of adult lymphatic vessels exposed to different organ-specific microenvironments |
10.1084/jem.20142290 | 20,798,614 | The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater ... | 10.1038/s41590-022-01162-w | This Article describes the complexity of the dural lympathic vasculature and shows that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid via the glymphatic system |
10.1073/pnas.2002574118 | 97,013,685 | Almost 150 papers about brain lymphatics have been published in the last 150 years. Recently, the information in these papers has been synthesized into a picture of central nervous system (CNS) “glymphatics,” but the fine structure of lymphatic elements in the human brain based on imaging specific markers of lymphatic ... | 10.1038/s41590-022-01162-w | This Review summarizes the fine structure of lymphatic elements in the human brain based on imaging specific markers of the lymphatic endothelium |
10.1038/s41467-018-08163-0 | 122,480,044 | Abstract There are no conventional lymphatic vessels within the CNS parenchyma, although it has been hypothesized that lymphatics near the cribriform plate or dura maintain fluid homeostasis and immune surveillance during steady-state conditions. However, the role of these lymphatic vessels during neuroinflammation is ... | 10.1038/s41590-022-01162-w | This Article describes how lymphatic vessels near the cribriform plate undergo lymphangiogenesis in a VEGFC–VEGFR3-dependent manner during EAE, and drain both CSF and cells that were once in the CNS parenchyma |
10.1126/science.aad9195 | 20,424,058 | Baby steps toward bNAbs Some HIV-infected individuals develop heavily mutated, broadly neutralizing antibodies (bNAbs) that target HIV. Scientists aim to design vaccines that would elicit such antibodies. Jardine et al. report an important step toward this goal: They engineered an immunogen that could engage B cells fr... | 10.1038/s41565-020-00790-3 | Seminal work demonstrating that engineered immunogen could engage B cells from HIV-uninfected individuals, generating a possibility that immunogen vaccine may elicit bnAbs in people |
10.1126/science.aat9120 | 83,013,558 | In vaccine design, antigens are often arrayed in a multivalent nanoparticle form, but in vivo mechanisms underlying the enhanced immunity elicited by such vaccines remain poorly understood. We compared the fates of two different heavily glycosylated HIV antigens, a gp120-derived mini-protein and a large, stabilized env... | 10.1038/s41565-020-00790-3 | The study shows that glycosylation is critical for enhanced localization to B-cell follicles and inducing humoral immunity |
10.1038/s41467-017-01029-x | 41,525,184 | Abstract The EZH2 histone methyltransferase is required for B cells to form germinal centers (GC). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21 Cip1 ). Deletion of Cdkn1a rescues the GC reaction in Ezh2 −/− mice. Using a 3D B cell follicular organoid s... | 10.1038/s41565-020-00790-3 | The study reported a three-dimensional B-cell follicular organoid system that mimics the germinal centre reaction, to define a positive feedback loop in which B-cell epigenetics controls cell proliferation and humoral immunity |
10.1126/science.aad3439 | 125,226,975 | Diversity reigns in antibody responses During the course of an immune response, B cells specific for an invading pathogen divide. The antibodies they produce increase in affinity via somatic mutation in specialized lymph node structures called germinal centers. Tas et al. used multiphoton microscopy and sequencing to d... | 10.1038/s41565-020-00790-3 | The study used brainbow-confetti mice and sequencing to demonstrate B-cell clonal competition with one another |
10.1126/sciadv.aav9788 | 73,994,405 | Biomaterials-based nanovaccines, such as those made of poly(lactic-co-glycolic acid) (PLGA), can induce stronger immunity than soluble antigens in healthy wild-type mouse models. However, whether metabolic syndrome can influence the immunological responses of nanovaccines remains poorly understood. Here, we first show ... | 10.1038/s41565-020-00790-3 | The study highlights immunomodulation under gut-mediated metabolic syndrome conditions using advanced nanomaterials |
10.1038/s41467-018-07709-6 | 83,355,448 | Abstract The current wealth of genomic variation data identified at nucleotide level presents the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Phy... | 10.1038/s41467-020-19942-z | IMEx dataset describing the effects of targeted mutations of the amino acid sequence of a protein on molecular interactions |
10.1126/science.1226458 | 62,208,744 | Ullman Upgrade Precious metals may dominate contemporary catalysis, but the early development of synthetic organic chemistry relied on more abundant elements—a strategy that chemists are returning to now for the sake of sustainability. Copper-mediated coupling of aryl halides with amines was reported by Ullman more tha... | 10.1038/s41570-017-0052 | A light-mediated Ullmann coupling that proceeds under exceptionally mild conditions, demonstrating the capacity for metallaphotocatalysis to enable challenging transformations. |
10.1126/science.1255525 | 41,555,140 | A bright outlook for carbon coupling In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (pur... | 10.1038/s41570-017-0052 | An early report on nickel metallaphotoredox catalysis, allowing direct cross-coupling of carboxylic acids via a radical decarboxylative activation mode. |
10.1126/science.1253647 | 62,063,348 | A bright outlook for carbon coupling In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (pur... | 10.1038/s41570-017-0052 | A nickel metallaphotoredox catalysis procedure for C( sp 2 )-C( sp 3 ) cross-coupling, providing a solution for the long-standing challenge of alkyl transmetallation from boron by invoking a radical pathway. |
10.1038/s41467-017-02075-1 | 19,559,836 | Abstract G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in eukaryotes and detect a wide array of cues in the human body. Here we describe a molecular device that couples CRISPR-dCas9 genome regulation to diverse natural and synthetic extracellular signals via GPCRs. We ... | 10.1038/s41589-021-00926-z | This study is a pioneering investigation into systematically improving a synthetic receptor design (ref. 14) to meet defined performance objectives |
10.1038/s41467-020-14397-8 | 100,332,576 | Abstract Rewiring cellular sensors to trigger non-natural responses is fundamental for therapeutic cell engineering. Current designs rely on engineered receptors that are limited to single inputs, and often suffer from high leakiness and low fold induction. Here, we present Generalized Engineered Activation Regulators ... | 10.1038/s41589-021-00926-z | This study develops a signal processing strategy to rewire native actuation into synthetic actuation pathways |
10.1126/sciadv.abe9375 | 100,279,566 | Genetically engineering cells to perform customizable functions is an emerging frontier with numerous technological and translational applications. However, it remains challenging to systematically engineer mammalian cells to execute complex functions. To address this need, we developed a method enabling accurate genet... | 10.1038/s41589-021-00926-z | This study describes model-guided predictive design of genetic programs to process and/or integrate signals from multiple synthetic receptors using sophisticated logic |
10.1038/s41467-020-16160-5 | 82,347,508 | Abstract Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable clinical efficacy against B-cell malignancies, yet marked vulnerability to antigen escape and tumor relapse exists. Here we report the rational design and optimization of bispecific CAR-T cells with robust activity against heterogeneous multip... | 10.1038/s41589-021-00926-z | This study employs and optimizes the use of tandem antibody domains on synthetic receptors, a technique that has been employed in other synthetic receptor systems (ref. 50) |
10.1126/science.abc6270 | 39,819,647 | Living cells often identify their correct partner or target cells by integrating information from multiple receptors, achieving levels of recognition that are difficult to obtain with individual molecular interactions. In this study, we engineered a diverse library of multireceptor cell-cell recognition circuits by usi... | 10.1038/s41589-021-00926-z | This study explores multiple ways to integrate synthetic receptors and introduces new sensing and actuation technologies to the synNotch receptor toolkit |
10.1126/science.aat0271 | 62,630,459 | Engineering multilayered cellular structures The ability to program the manufacture of biological structures may yield new biomaterials or synthetic tissues and organs. Toda et al. engineered mammalian “sender” and “receiver” cells with synthetic cell surface ligands and receptors that controlled gene regulatory circui... | 10.1038/s41589-021-00926-z | This study demonstrates the ability of synNotch to sense soluble ligands that are tethered via surface-bound anchors and employs this new sensing ability to program patterning |
10.1126/science.abc1855 | 59,526,701 | Overexpressed tumor-associated antigens [for example, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2)] are attractive targets for therapeutic T cells, but toxic “off-tumor” cross-reaction with normal tissues that express low levels of target antigen can occur with chimeric an... | 10.1038/s41589-021-00926-z | This study tunes an integrated synNotch-CAR receptor system to achieve an ultrasensitive input-output relationship |
10.1038/s41467-018-06367-y | 41,454,340 | Abstract It is generally assumed that cells interrogate the mechanical properties of their environment by pushing and pulling on the extracellular matrix (ECM). For instance, acto-myosin-dependent contraction forces exerted at focal adhesions (FAs) allow the cell to actively probe substrate elasticity. Here, we report ... | 10.1038/s41580-021-00375-5 | This paper describes a function for clathrin-coated plaques as contractility-independent mechanosensitive structures that assemble with increasing substrate rigidity and that serve as platforms for receptor tyrosine kinase signalling |
10.1083/jcb.201710084 | 20,701,023 | We developed a general approach for investigation of how cellular processes become adapted for specific cell types during differentiation. Previous studies reported substantial differences in the morphology and dynamics of clathrin-mediated endocytosis (CME) sites. However, associating specific CME properties with dist... | 10.1038/s41580-021-00375-5 | Using genome-edited human embryonic stem cells to derive isogenic fibroblasts and neuronal progenitors, the authors show that the levels of expression of the endocytic adaptor AP2 are cell context-regulated and that this impinges on CME dynamics |
10.1038/s41467-020-16836-y | 123,372,454 | Abstract The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and the... | 10.1038/s41580-021-00375-5 | This study shows that the endocytic protein EPN3 is an oncogene with prognostic relevance in breast cancer and that it drives breast tumorigenesis through the induction of E-cadherin endocytosis, EMT and invasive behaviour |
10.1038/s41467-018-06738-5 | 82,994,990 | Abstract Plasma membrane tension regulates many key cellular processes. It is modulated by, and can modulate, membrane trafficking. However, the cellular pathway(s) involved in this interplay is poorly understood. Here we find that, among a number of endocytic processes operating simultaneously at the cell surface, a d... | 10.1038/s41580-021-00375-5 | This study describes a role for CLIC/GEEC endocytosis as a critical regulator of membrane tension in adherent cells and dissects the downstream molecular mechanism, which involves vinculin as a mechanotransducer at focal adhesion sites |
10.1038/s41467-020-14928-3 | 62,217,185 | Abstract Macropinocytic cancer cells scavenge amino acids from extracellular proteins. Here, we show that consuming necrotic cell debris via macropinocytosis (necrocytosis) offers additional anabolic benefits. A click chemistry-based flux assay reveals that necrocytosis provides not only amino acids, but sugars, fatty ... | 10.1038/s41580-021-00375-5 | This study establishes necrocytosis as a mechanism of drug resistance, demonstrating its role in supplying amino acids, sugars, fatty acids, and nucleotides for biosynthesis and evidencing that it confers resistance to therapies targeting anabolic pathways in a cell context-dependent manner |
10.1111/tra.12417 | 82,587,384 | The formation of distinct subdomains of the cell surface is crucial for multicellular organism development. The most striking example of this is apical‐basal polarization. What is much less appreciated is that underpinning an asymmetric cell surface is an equally dramatic intracellular endosome rearrangement. Here, we ... | 10.1038/s41580-021-00375-5 | This study shows that the unusual phospholipid PI(3,4)P2, together with PI(4,5)P2, is found apically enriched during the early phases of lumen formation and controls polarity establishment |
10.1038/s41467-020-17091-x | 62,107,486 | Abstract It is unclear whether the establishment of apical–basal cell polarity during the generation of epithelial lumens requires molecules acting at the plasma membrane/actin interface. Here, we show that the I-BAR-containing IRSp53 protein controls lumen formation and the positioning of the polarity determinants aPK... | 10.1038/s41580-021-00375-5 | The I-BAR containing protein, IRSp53, is shown to be an early apical determinant that binds to RAB35 and facilitates the transport and the anchoring of podocalyxin to the apical membrane initiation site, where it also controls the integrity and the shape of the plasma membrane |
10.1038/s41467-017-00553-0 | 20,236,308 | Abstract The coordination between membrane trafficking and actomyosin networks is essential to the regulation of cell and tissue shape. Here, we examine Rab protein distributions during Drosophila epithelial tissue remodeling and show that Rab35 is dynamically planar polarized. Rab35 compartments are enriched at contra... | 10.1038/s41580-021-00375-5 | By examining RAB protein distributions during cell intercalation in D. melanogaster epithelial tissue remodelling, RAB35-mediated endocytosis of plasma membrane at junctions is found to serve as a unique ratcheting device that directs progressive interface contraction |
10.1038/s41467-018-03571-8 | 29,110,329 | Abstract How cells move chemotactically remains a major unmet challenge in cell biology. Emerging evidence indicates that for interpreting noisy, shallow gradients of soluble cues a system must behave as an excitable process. Here, through an RNAi-based, high-content screening approach, we identify RAB35 as necessary f... | 10.1038/s41580-021-00375-5 | Demonstration that RAB35 plays a critical role in regulating the formation of oscillatory, apical circular ruffles that act as steering devices during chemotaxis and promote efficient migration and invasion in breast cancer |
10.1073/pnas.1614680114 | 83,333,183 | Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent ... | 10.1038/s41576-021-00363-7 | This retrospective analysis quantifies bacterial and fungal natural products identified over the years and provides a perspective on the amount of structural novelty that is still being unearthed |
10.1126/science.aaw9285 | 20,870,478 | Microorganisms living inside plants can promote plant growth and health, but their genomic and functional diversity remain largely elusive. Here, metagenomics and network inference show that fungal infection of plant roots enriched for Chitinophagaceae and Flavobacteriaceae in the root endosphere and for chitinase gene... | 10.1038/s41576-021-00363-7 | This study illustrates how metagenome mining can be used to identify biosynthetic genes responsible for a microbiome-associated phenotype, fungal disease suppression in this case |
10.1073/pnas.2006560117 | 84,504,201 | The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expan... | 10.1038/s41576-021-00363-7 | This study describes the analysis of 135,000 actinobacterial genomes to identify new analogues of the immunosuppressant polyketide rapamycin |
10.1126/science.1154990 | 38,406,715 | Operons are clusters of unrelated genes with related functions that are a feature of prokaryotic genomes. Here, we report on an operon-like gene cluster in the plant Arabidopsis thaliana that is required for triterpene synthesis (the thalianol pathway). The clustered genes are coexpressed, as in bacterial operons. Howe... | 10.1038/s41576-021-00363-7 | This analysis provides a foundation for the study of biosynthetic gene clusters in plants, making it clear that these have evolved specifically in plants themselves |
10.1126/science.aau0382 | 41,692,099 | Oceanic harmful algal blooms of Pseudo-nitzschia diatoms produce the potent mammalian neurotoxin domoic acid (DA). Despite decades of research, the molecular basis for its biosynthesis is not known. By using growth conditions known to induce DA production in Pseudo-nitzschia multiseries , we implemented transcriptome s... | 10.1038/s41576-021-00363-7 | This article presents the first (major) genome mining effort in protists, revealing the biosynthetic pathway for domoic acid production in diatoms |
10.1038/s41467-020-16376-5 | 83,395,244 | Abstract Complex polyketides are typically associated with microbial metabolism. Here, we report that animals also make complex, microbe-like polyketides. We show there is a widespread branch of fatty acid synthase- (FAS)-like polyketide synthase (PKS) proteins, which sacoglossan animals use to synthesize complex produ... | 10.1038/s41576-021-00363-7 | This study shows that animals can produce complex polyketides, with the discovery of polypropionate compounds produced by sea slugs |
10.1093/nar/gkz310 | 41,659,560 | Abstract Secondary metabolites produced by bacteria and fungi are an important source of antimicrobials and other bioactive compounds. In recent years, genome mining has seen broad applications in identifying and characterizing new compounds as well as in metabolic engineering. Since 2011, the ‘antibiotics and secondar... | 10.1038/s41576-021-00363-7 | This article describes the antiSMASH pipeline, originally established in 2011, the first automated software tool to comprehensively identify BGCs in both bacterial and fungal genomes |
10.1126/science.1259215 | 62,331,470 | Cucurbitacins are triterpenoids that confer a bitter taste in cucurbits such as cucumber, melon, watermelon, squash, and pumpkin. These compounds discourage most pests on the plant and have also been shown to have antitumor properties. With genomics and biochemistry, we identified nine cucumber genes in the pathway for... | 10.1038/s41576-021-00363-7 | This article uses genome-wide association studies to identify the BGC for cucurbitacin in cucumber, which is responsible for a characteristic bitter taste |
10.1126/sciadv.aar5459 | 41,233,162 | We develop a novel synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and encoded metabolites. | 10.1038/s41576-021-00363-7 | This paper introduces a streamlined and largely automated workflow for genome mining and gene synthesis-based expression of fungal BGCs; the authors tested 41 different fungal BGCs and detected metabolites for 22 of them |
10.1126/scitranslmed.aaa4877 | 62,059,808 | Gut bacterial strains targeted by IgA in undernourished Malawian children produce severe enteropathy in gnotobiotic mice and correlate with health status. | 10.1038/s41577-021-00506-1 | This landmark paper shows that acute undernutrition in children is characterized by increased IgA recognition of pathogenic Proteobacteria but decreased recognition of other commensals; further, IgA + Proteobacteria exacerbates undernutrition and enteropathy in mice |
10.1126/science.aat9351 | 104,311,156 | The microbiota influences obesity, yet organisms that protect from disease remain unknown. During studies interrogating host-microbiota interactions, we observed the development of age-associated metabolic syndrome (MetS). Expansion of Desulfovibrio and loss of Clostridia were key features associated with obesity in th... | 10.1038/s41577-021-00506-1 | This paper demonstrates that genetic defects in microbiota IgA targeting exacerbate obesity in mice by altering microbiota colonization patterns |
10.1126/sciimmunol.aat7117 | 15,182,532 | The gut mounts secretory immunoglobulin A (SIgA) responses to commensal bacteria through nonredundant T cell–dependent (TD) and T cell–independent (TI) pathways that promote the establishment of mutualistic host-microbiota interactions. SIgAs from the TD pathway target penetrant bacteria, and their induction requires e... | 10.1038/s41577-021-00506-1 | This paper elegantly differentiates between T cell-dependent and T cell-independent IgA responses in mice, showing that both contribute to IgA coating of the microbiota but that T cell-independent responses do not measurably affect microbiota composition |
10.1084/jem.20200275 | 18,008,195 | The gut is home to the body’s largest population of plasma cells. In healthy individuals, IgA is the dominating isotype, whereas patients with inflammatory bowel disease also produce high concentrations of IgG. In the gut lumen, secretory IgA binds pathogens and toxins but also the microbiota. However, the antigen spec... | 10.1038/s41577-021-00506-1 | This key study (alongside Sterlin et al.) defines the cross-species reactivity of human intestinal IgA clones and shows that it is dependent on somatic hypermutation, and not polyreactivity. This work further compares the binding capability of intestinal IgA from people with and without IBD |
10.1084/jem.20181635 | 12,658,491 | In humans, several grams of IgA are secreted every day in the intestinal lumen. While only one IgA isotype exists in mice, humans secrete IgA1 and IgA2, whose respective relations with the microbiota remain elusive. We compared the binding patterns of both polyclonal IgA subclasses to commensals and glycan arrays and d... | 10.1038/s41577-021-00506-1 | This key study (alongside Kabbert et al.) defines cross-species reactivity of human intestinal IgA clones. The authors demonstrate that SIgA has specific glycan-binding profiles for surface bacterial structures; they further delineate the microbiota specificity of human IgA1 and IgA2 responses throughout development |
10.1126/scitranslmed.aau9356 | 41,714,606 | IgA is prominently secreted at mucosal surfaces and coats a fraction of the commensal microbiota, a process that is critical for intestinal homeostasis. However, the mechanisms of IgA induction and the molecular targets of these antibodies remain poorly understood, particularly in humans. Here, we demonstrate that micr... | 10.1038/s41577-021-00506-1 | This paper demonstrates that human commensal Lachnospiraceae produce IgA superantigens |
10.1126/science.aaq0926 | 83,514,673 | Benign colonization of the gut Microbial communities in the gut can be highly individual. What engenders this specificity? The gut characteristically produces gram quantities of immunoglobulin A (IgA) antibody, which is presumed to protect the gut from pathogen attack. Donaldson et al. engineered strains of Bacteroides... | 10.1038/s41577-021-00506-1 | This landmark paper demonstrates that IgA could directly promote mucosal colonization of commensal Bacteroides |
10.1084/jem.20180427 | 39,234,929 | Immunoglobulin A (IgA) promotes health by regulating the composition and function of gut microbiota, but the molecular requirements for such homeostatic IgA function remain unknown. We found that a heavily glycosylated monoclonal IgA recognizing ovalbumin coats Bacteroides thetaiotaomicron (B. theta), a prominent gut s... | 10.1038/s41577-021-00506-1 | This study demonstrates that glycosylated SIgA regulated a PUL in Bacteroides , affecting inter-bacterial metabolic cooperation |
10.1126/scitranslmed.aan1217 | 80,320,875 | IgA influences bacterial fitness in the intestinal lumen and is only partially compensated for by IgM in selective IgA-deficient patients. | 10.1038/s41577-021-00506-1 | This key paper shows that IgA deficiency in humans is characterized by both loss and gain of specific IgA-recognized intestinal bacteria |
10.1038/s41467-019-11370-y | 41,579,015 | Abstract The intestinal immune system is emerging as an important contributor to obesity-related insulin resistance, but the role of intestinal B cells in this context is unclear. Here, we show that high fat diet (HFD) feeding alters intestinal IgA + immune cells and that IgA is a critical immune regulator of glucose h... | 10.1038/s41577-021-00506-1 | This study shows that high-fat diets lead to reduced SIgA levels in mice and that IgA deficiency reciprocally exacerbates obesity on a high-fat diet |
10.1126/science.aau2909 | 20,541,349 | Transforming growth factor–β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (T regs ) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (gl... | 10.1038/s41568-021-00413-6 | This study solves the crystal structure of the GARP–L-TGFβ complex and proposes a model for the integrin-dependent mechanical activation of TGFβ1. It also studies how therapeutic antibodies that bind to the complex prevent TGFβ1 release |
10.1126/sciimmunol.aai7911 | 38,282,524 | T cell immunity against cancer in mice is enhanced with platelet-specific deletion of GARP and by platelet inhibitors. | 10.1038/s41568-021-00413-6 | This article describes a major role for platelets during cancer immune evasion through TGFβ1–GARP cell surface complexes. The authors show that GARP knockout in platelets enhances antitumour immunity |
10.1126/science.1090922 | 62,257,157 | Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor–β (TGF-β) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-β type II receptor gene in mouse fibroblasts ( Tgfbr2 fspKO ). The l... | 10.1038/s41568-021-00413-6 | The authors investigate fibroblast-specific Tgfbr2 -knockout mice and show that these mice develop tumours in the epithelium of the prostate and the forestomach. They propose that loss of TGFβ signalling causes upregulation of HGF in fibroblasts, which in turns promotes carcinogenesis in the adjacent epithelium |
10.1038/s41467-020-15404-8 | 123,196,653 | Abstract Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we i... | 10.1038/s41568-021-00413-6 | This study investigates tumour immune evasion in mice deficient in Tgfbr1 in T reg cells, macrophages, and CD8 + T cells. It shows that only deletion in CD8 + T cells enhances antitumour responses. It provides evidence that TGFβ suppresses CD8 + T cell function through two mechanisms: increasing TCR activation threshol... |
10.1038/s41467-020-19920-5 | 62,015,425 | Abstract Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stroma... | 10.1038/s41568-021-00413-6 | In this study the authors investigate CAF heterogeneity upon TGFβ inhibition in mouse tumour models using single-cell RNA sequencing. The study reveals the emergence of an interferon-licensed CAF subset characterized by upregulation of antigen presentation machinery and expression of cytokines |
10.1073/pnas.1005963107 | 83,539,810 | Gut microbial composition depends on different dietary habits just as health depends on microbial metabolism, but the association of microbiota with different diets in human populations has not yet been shown. In this work, we compared the fecal microbiota of European children (EU) and that of children from a rural Afr... | 10.1038/s41579-021-00559-y | This work reports one of the first pieces of evidence that Prevotella spp. dominate the gut microbiome in ‘non-Westernized’ populations |
10.1038/s41564-018-0338-9 | 29,087,494 | Abstract Bacteriophages (phages) dramatically shape microbial community composition, redistribute nutrients via host lysis and drive evolution through horizontal gene transfer. Despite their importance, much remains to be learned about phages in the human microbiome. We investigated the gut microbiomes of humans from B... | 10.1038/s41579-021-00559-y | This study reports the discovery of large intestine megaphages associated with Prevotella and some initial characterization of their genetic features, such as the use of an alternative genetic code |
10.1126/science.aad2545 | 103,913,204 | Stomach ache for a European mummy Five thousand years ago in the European Alps, a man was shot by an arrow, then clubbed to death. His body was subsequently mummified by ice until glacier retreat exhumed him in 1991. Subsequently, this ancient corpse has provided a trove of intriguing information about copper-age Europ... | 10.1038/s41579-021-00559-y | This is one of the first studies showing that reconstruction of genomes from ancient samples is possible, which is particularly relevant to study the evolutionary history of Prevotella spp |
10.1126/science.1232251 | 62,302,011 | Axonal Actin How actin is organized in the axons and dendrites of neurons is largely unknown. Xu et al. (p. 452 , published online 13 December) imaged actin in axons and dendrites using stochastic optical reconstruction microscopy. Surprisingly, while actin in dendrites formed long filaments, the actin in axons was org... | 10.1038/s41583-021-00441-z | This article describes one of the key breakthrough discoveries in the neuroscience field achieved by super-resolution microscopy |
10.1038/ncomms10773 | 40,765,727 | Abstract The advent of super-resolution imaging (SRI) has created a need for optimized labelling strategies. We present a new method relying on fluorophore-conjugated monomeric streptavidin (mSA) to label membrane proteins carrying a short, enzymatically biotinylated tag, compatible with SRI techniques including uPAINT... | 10.1038/s41583-021-00441-z | This article reports an engineered monomeric ligand to label specifically biotinylated proteins |
10.1126/science.1127344 | 41,664,802 | We introduce a method for optically imaging intracellular proteins at nanometer spatial resolution. Numerous sparse subsets of photoactivatable fluorescent protein molecules were activated, localized (to ∼2 to 25 nanometers), and then bleached. The aggregate position information from all subsets was then assembled into... | 10.1038/s41583-021-00441-z | This is one of the first two studies, with Hess et al. (2006), using photoactivation of fluorescent proteins for single-molecule localization-based super-resolution microscopy |
10.1073/pnas.1718406115 | 60,643,948 | Transcriptome-wide identification of RNA-binding proteins (RBPs) is a prerequisite for understanding the posttranscriptional gene regulation networks. However, proteomic profiling of RBPs has been mostly limited to polyadenylated mRNA-binding proteins, leaving RBPs on nonpoly(A) RNAs, including most noncoding RNAs (ncR... | 10.1038/s41592-019-0330-1 | Utilization of RNA metabolic labeling to comprehensively capture the RNA–protein interactome independent of RNA polyadenylation |
10.1158/2159-8290.cd-14-0471 | 18,991,683 | Abstract Glioblastoma (GBM) is a highly aggressive brain cancer characterized by local invasion and angiogenic recruitment, yet metastatic dissemination is extremely rare. Here, we adapted a microfluidic device to deplete hematopoietic cells from blood specimens of patients with GBM, uncovering evidence of circulating ... | 10.1038/s41568-019-0180-2 | This paper and that by Muller et al. (2014) challenge the dogma that glioblastoma spread is restricted to the brain by demonstrating that glioma-derived CTCs are also detectable in peripheral blood |
10.1158/1078-0432.ccr-18-0862 | 122,556,242 | Abstract Purpose: Circulating tumor cells (CTCs) have clinical relevance, but their study has been limited by their low frequency. Experimental Design: We evaluated liquid biopsies by apheresis to increase CTC yield from patients suffering from metastatic prostate cancer, allow precise gene copy-number calls, and study... | 10.1038/s41568-019-0180-2 | This report shows that DLA facilitates the capture of very large numbers of CTCs, which allows the deconvolution of intra-patient heterogeneity and clonal evolution |
10.1158/1078-0432.ccr-16-3081 | 24,555,629 | Abstract Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTC) and other cells to evaluate their potential prognostic value of prostate cancer. Experimental Design: Malignancy of CTCs undergoing epithelial-to-mesenchymal transition (EMT) was confirmed by repeated F... | 10.1038/s41568-019-0180-2 | This study demonstrates that the majority of circulating cytokeratin-negative, vimentin-positive and CD45-negative cells, which could be mesenchymal CTCs or endothelial cells, have tumour-specific genomic aberrations in prostate cancer |
10.1126/science.1131669 | 122,451,703 | Since the mid-1980s, our understanding of nutrient limitation of oceanic primary production has radically changed. Mesoscale iron addition experiments (FeAXs) have unequivocally shown that iron supply limits production in one-third of the world ocean, where surface macronutrient concentrations are perennially high. The... | 10.1038/s41565-022-01227-9 | A seminal review article that describes ocean fertilization field experiments. |
10.1126/science.aau8299 | 20,774,038 | Nanomaterials are critical components in the Earth system’s past, present, and future characteristics and behavior. They have been present since Earth’s origin in great abundance. Life, from the earliest cells to modern humans, has evolved in intimate association with naturally occurring nanomaterials. This synergy beg... | 10.1038/s41565-022-01227-9 | A review article that maps the influence and fate of engineered nanoparticles on Earth, including within the oceans. |
10.1126/science.aau5631 | 20,430,285 | Catalyst design in asymmetric reaction development has traditionally been driven by empiricism, wherein experimentalists attempt to qualitatively recognize structural patterns to improve selectivity. Machine learning algorithms and chemoinformatics can potentially accelerate this process by recognizing otherwise inscru... | 10.1038/s41570-021-00260-x | A recent example of selectivity prediction with results close to experiment |
10.1186/s12966-020-00978-9 | 41,485,298 | Abstract Background Daily step counts is an intuitive metric that has demonstrated success in motivating physical activity in adults and may hold potential for future public health physical activity recommendations. This review seeks to clarify the pattern of the associations between daily steps and subsequent all-caus... | 10.1038/s41591-022-02013-9 | This article demonstrates that most activity-monitoring studies have used a brief monitoring period. |
10.1084/jem.158.2.413 | 26,413,128 | Four monoclonal antibodies against carcinoembryonic antigen (CEA) have been selected from 32 hybrids that produce antibodies against this antigen, by the criteria of high affinity for CEA and low cross-reactivity with granulocyte glycoprotein(s). The specificity of tumor localization in vivo of the four MAb, and their ... | 10.1038/s41573-020-0073-9 | Among the earliest reports of antibody-based cancer imaging; precursor to antibody-based RPT |
10.1073/pnas.89.7.3010 | 123,000,509 | We present here a method for broadly characterizing single cells at the molecular level beyond the more common morphological and transmitter/receptor classifications. The RNA from defined single cells is amplified by microinjecting primer, nucleotides, and enzyme into acutely dissociated cells from a defined region of ... | 10.1038/s41576-020-00300-0 | This article presents an interesting look at the origins of single-cell gene expression measurements |
10.1126/science.aab1601 | 41,705,559 | Chromatin state and the single cell Identifying the chromatin state of any single cell, which may or may not have a different function or represent different stages relative to others collected within any single culture, experiment, or tissue, has been challenging. Cusanovitch et al. skirted previously identified techn... | 10.1038/s41576-020-00300-0 | This study describes a pioneering example of how split-pool barcoding can be used to profile epigenetic marks in single cells |
10.1101/571208 | 54,378,913 | ABSTRACT Modern next-generation sequencing-based methods have empowered researchers to assay the epigenetic states of individual cells. Existing techniques for profiling epigenetic marks in single cells often require the use and optimization of time-intensive procedures such as drop fluidics, chromatin fragmentation, a... | 10.1038/s41576-020-00300-0 | This article outlines the application of split-pool barcoding to profiling histone modifications |
10.1093/genetics/118.1.75 | 125,330,052 | Abstract age-1(hx546) is a recessive mutant allele in Caenorhabditis elegans that results in an increase in mean life span averaging 40% and in maximal life span averaging 60% at 20 degrees; at 25 degrees age-1(hx546) averages a 65% increase in mean life span (25.3 days vs. 15.0 days) and a 110% increase in maximum lif... | 10.1038/s41586-019-1365-2 | This study describes a C. elegans mutant strain that has an extended lifespan |
10.1126/science.289.5487.2126 | 83,381,455 | Calorie restriction extends life-span in a wide variety of organisms. Although it has been suggested that calorie restriction may work by reducing the levels of reactive oxygen species produced during respiration, the mechanism by which this regimen slows aging is uncertain. Here, we mimicked calorie restriction in yea... | 10.1038/s41586-019-1365-2 | This study shows that lifespan extension by glucose restriction in yeast requires the activity of Sir2 |
10.1126/scitranslmed.aaq1564 | 20,628,263 | Treating elderly subjects with two low-dose mTOR inhibitors that selectively block TORC1 led to a decrease in infection rates. | 10.1038/s41586-019-1365-2 | One of the first examples of a randomized control trial using ageing-targeting drugs in the elderly to treat a clinical syndrome of ageing |
10.1126/science.1227166 | 104,015,382 | Stress Protector During prolonged fasting, the oxidation of fatty acids leads to increased accumulation of d -β-hydroxybutyrate (βOHB) in the bloodstream. Such increased concentrations of βOHB inhibit class I histone deacetylases. Histone acetylation in turn influences transcriptional activity at various genes. Shimazu... | 10.1038/s41586-019-1365-2 | This study shows that β-hydroxybutyrate is an epigenetic regulator that regulates FOXO3 |
10.1158/2326-6066.cir-18-0494 | 39,895,925 | Abstract Immunotherapies targeting T lymphocytes are revolutionizing cancer therapy but only benefit a subset of patients, especially in colorectal cancer. Thus, additional insight into the tumor microenvironment (TME) is required. Eosinophils are bone marrow–derived cells that have been largely studied in the context ... | 10.1038/s41568-020-0283-9 | This study is the first to subject intratumoural eosinophils to bulk RNA sequencing, which revealed a potent IFNγ-associated signature for eosinophils that likely mediates their antitumorigenic activities in CRC |
10.1002/ijc.32829 | 38,208,202 | Immune checkpoint blockade (ICB) has shown long‐term survival benefits, but only in a small fraction of cancer patients. Recent studies suggest that improved vessel perfusion by ICB positively correlates with its therapeutic outcomes. However, the underlying mechanism of such a process remains unclear. Here, we show th... | 10.1038/s41568-020-0283-9 | This study provides the first mechanistic evidence that eosinophils are important effector cells in the antitumour response that is elicited by blockade of CTLA4 |
10.1126/science.1636093 | 20,479,115 | Murine interleukin-4 (IL-4) exhibits potent antitumor activity when present at the site of tumor cell challenge. Associated with tumor cell death is the appearance of an inflammatory infiltrate comprised predominantly of eosinophils and macrophages, but with few lymphocytes. Antibodies that specifically block the accum... | 10.1038/s41568-020-0283-9 | This study demonstrates that constitutive expression of IL-4 in athymic nude mice elicits a tumour-associated eosinophil infiltrate associated with decreased tumour growth, stimulating further investigations into the role of eosinophils in cancer |
10.1523/jneurosci.3169-13.2013 | 123,036,834 | Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) sleep and are thought to play an important role in the cellular and network plasticity that occurs during this behavioral state. These slow waves of natural sleep are currently considered to be exclusively generated by intrinsi... | 10.1038/s41583-019-0223-4 | An important study showing the contribution of thalamic T-type calcium channels to cortical slow waves |
10.1523/jneurosci.1519-14.2014 | 103,712,417 | How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some... | 10.1038/s41583-019-0223-4 | First demonstration of disruption in connectivity between midline thalamus and frontal cortex, but not between sensory thalamus and cortex, occuring at loss of consciousness |
10.1523/jneurosci.1156-13.2014 | 42,506,116 | Slow oscillation is the main brain rhythm observed during deep sleep in mammals. Although several studies have demonstrated its neocortical origin, the extent of the thalamic contribution is still a matter of discussion. Using electrophysiological recordings in vivo on cats and computational modeling, we found that the... | 10.1038/s41583-019-0223-4 | The first study to show transient reductions in cortical slow waves following thalamic lesioning |
10.1126/science.aaf0902 | 20,441,164 | Perceptual memory needs slow-wave sleep We know little about the mechanisms by which the brain consolidates nondeclarative (perceptual) memories. In a series of behavioral, optogenetic, and electrophysiological experiments, Miyamoto et al. show that coordinated neuronal information flow during sleep is required for per... | 10.1038/s41583-019-0223-4 | Discovery of a mechanism that regulates memory consolidation during NREM sleep |
10.1523/jneurosci.1318-04.2004 | 123,011,810 | During much of sleep, virtually all cortical neurons undergo a slow oscillation (<1 Hz) in membrane potential, cycling from a hyperpolarized state of silence to a depolarized state of intense firing. This slow oscillation is the fundamental cellular phenomenon that organizes other sleep rhythms such as spindles and ... | 10.1038/s41583-019-0223-4 | The first demonstration of anterior to posterior propagation of sleep slow waves in the human brain |
10.1126/science.aan6203 | 20,323,401 | Memory transfer for long-term storage Explicit memory formation involves the transfer of rapidly encoded information from the hippocampus to long-term storage sites in the association cortex. Khodagholy et al. developed a microelectrode system for large-scale simultaneous electrophysiological monitoring of multiple sit... | 10.1038/s41583-019-0223-4 | Important demonstration of sleep functions being coordinated by localized regulation between brain regions |
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