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10.1073/pnas.0806560105 | 125,266,867 | Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenat... | 10.1038/s41576-018-0074-2 | In this pioneering work, the authors demonstrate that prenatal exposure to famine can lead to CpG methylation changes that may affect the postnatal life of the offspring |
10.1038/s41592-019-0686-2 | 104,421,489 | Abstract SciPy is an open-source scientific computing library for the Python programming language. Since its initial release in 2001, SciPy has become a de facto standard for leveraging scientific algorithms in Python, with over 600 unique code contributors, thousands of dependent packages, over 100,000 dependent repos... | 10.1038/s41586-020-2649-2 | Introduces the SciPy library and includes a more detailed history of NumPy and SciPy. |
10.1002/rcm.8725 | 41,390,502 | Rationale A major hurdle in identifying chemicals in mass spectrometry experiments is the availability of tandem mass spectrometry (MS/MS) reference spectra in public databases. Currently, scientists purchase databases or use public databases such as Global Natural Products Social Molecular Networking (GNPS). The MSMS‐... | 10.1038/s41579-021-00621-9 | Global Natural Products Social Molecular Networking is a Web-based MS ecosystem created by the community for the community to share, process and annotate MS/MS data |
10.1101/2020.07.08.194159 | 106,211,815 | Summary The human metabolome has remained largely unknown, with most studies annotating ∼10% of features. In nucleic acid sequencing, annotating transcripts by source has proven essential for understanding gene function. Here we generalize this concept to stool, plasma, urine and other human metabolomes, discovering th... | 10.1038/s41579-021-00621-9 | This article introduces a reference database of food to show the potential of large-scale reference data to complement the understanding of the microbiome |
10.1073/pnas.1608041113 | 107,165,085 | The potential of untargeted metabolomics to answer important questions across the life sciences is hindered because of a paucity of computational tools that enable extraction of key biochemically relevant information. Available tools focus on using mass spectrometry fragmentation spectra to identify molecules whose beh... | 10.1038/s41579-021-00621-9 | MS2LDA recognizes and annotates motifs from MS data as chemical substructures |
10.1073/pnas.1711233114 | 20,845,007 | There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial pro... | 10.1038/s41577-022-00727-y | This study shows the relationship between dysbiosis in patients with MS and disease progression by FMT into disease model mice |
10.1126/sciadv.1700492 | 83,525,737 | The headquarter of our immune system resides in the gut and modulates autoimmune disease activation in multiple sclerosis. | 10.1038/s41577-022-00727-y | This is the demonstration of microbiota composition and immune cells in the small intestine of patients with MS |
10.1038/s41467-020-15831-7 | 59,985,782 | Abstract Gut microbial dysbiosis is associated with the development of autoimmune disease, but the mechanisms by which microbial dysbiosis affects the transition from asymptomatic autoimmunity to inflammatory disease are incompletely characterized. Here, we identify intestinal barrier integrity as an important checkpoi... | 10.1038/s41577-022-00727-y | The authors show that the microbiota composition and SCFAs are altered just before disease onset in RA model mice |
10.1111/dme.13262 | 124,655,154 | Abstract Aims To investigate whether the use of antibiotics from infancy to adolescence influences the risk of Type 1 diabetes. Methods We conducted a population‐based case–control study, including all Type 1 diabetes cases in Denmark among children born between 1997 and 2012 ( n = 1578). Odds ratios associating Type 1... | 10.1038/s41577-022-00727-y | This longitudinal cohort study highlights the alteration of gut bacterial gene content and metabolites before T1D onset |
10.1126/scitranslmed.aan2306 | 41,670,992 | Commensal bacterial orthologs of the human autoantigen Ro60 may trigger cross-reactive T and B cells that initiate and sustain chronic autoimmunity in lupus. | 10.1038/s41577-022-00727-y | The authors clearly demonstrate the cross-reactivity of autoimmune T cells in patients with SLE with gut commensals |
10.1038/s41467-019-09361-0 | 38,408,494 | Abstract The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent r... | 10.1038/s41577-022-00727-y | Together with Shimokawa et al 124 , this study provides the mechanistic insights into how gut parasites exert protective effects on ADs |
10.1126/science.1189731 | 41,755,726 | Inhibiting Leukocytosis Leukocytosis—an elevated white blood cell count—contributes by unknown mechanisms to the pathogenesis of atherosclerosis and associated coronary heart disease. Now, Yvan-Charvet et al. (p. 1689 , published online 20 May; see the Perspective by Hansson and Björkholm ) show that the adenosine trip... | 10.1038/s41590-019-0402-5 | This study showed that cholesterol accumulation in HSPCs due to deficiency in cholesterol-efflux mechanisms results in HSPC expansion and myeloid differentiation associated with elevated IL-3Rβ expression. These alterations can lead to leukocytosis and accelerate atherosclerosis |
10.1126/science.aag1381 | 83,536,833 | Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of a... | 10.1038/s41590-019-0402-5 | Consistent with the findings of ref. 133, this report showed that deficiency in TET2 is associated with HSPC expansion and a myeloid bias that enhances atherosclerosis in mice deficient in the low-density lipoprotein receptor |
10.1126/science.1069516 | 4,804,617 | To begin to understand the genetic architecture of natural variation in gene expression, we carried out genetic linkage analysis of genomewide expression patterns in a cross between a laboratory strain and a wild strain of Saccharomyces cerevisiae . Over 1500 genes were differentially expressed between the parent strai... | 10.1038/s41576-020-00304-w | This study is among the first to couple linkage analysis with genome-wide gene expression data, identifying eQTLs likely to act in cis and in trans . Expression of 570 genes is statistically linked to one or more loci, indicating complex inheritance patterns for most gene expression levels |
10.7554/elife.35471 | 103,665,320 | Heritable variation in gene expression forms a crucial bridge between genomic variation and the biology of many traits. However, most expression quantitative trait loci (eQTLs) remain unidentified. We mapped eQTLs by transcriptome sequencing in 1012 yeast segregants. The resulting eQTLs accounted for over 70% of the he... | 10.1038/s41576-020-00304-w | This high-powered study of eQTLs in S. cerevisiae explains 70% of variation in gene expression and finds that the combined effects of trans -regulatory eQTLs are greater than the effects of cis -regulatory eQTLs for most genes. More than 90% of trans -eQTLs are clustered into 102 hotspot regions, with some hot spots co... |
10.1038/nature24277 | 41,678,238 | Abstract Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across... | 10.1038/s41576-020-00304-w | This large eQTL study examines regulatory variation across 49 tissues from 838 human donors. The study identifies thousands of cis - and trans -eQTLs and further examines the tissue-specificity of regulatory effects |
10.1101/gr.188193.114 | 81,421,322 | The core promoter is the regulatory sequence to which RNA polymerase is recruited and where it acts to initiate transcription. Here, we present the first comprehensive study of yeast core promoters, providing massively parallel measurements of core promoter activity and of TSS locations and relative usage for thousands... | 10.1038/s41576-020-00304-w | This study presents one of the earliest comprehensive analyses of yeast core promoters, finding that core promoter activity is highly correlated with total promoter activity and that sequence variation can tune expression in predictable ways |
10.1534/genetics.111.137075 | 57,369,180 | Abstract Evolutionary biologists attribute much of the phenotypic diversity observed in nature to the action of natural selection. However, for many phenotypic traits, especially quantitative phenotypic traits, it has been challenging to test for the historical action of selection. An important challenge for biologists... | 10.1038/s41576-020-00304-w | This study presents a framework for using empirical data describing the effects of new mutations on quantitative traits to determine neutral models of trait evolution and, subsequently, infer whether and to what extent selection has shaped existing trait variation |
10.1126/science.abj8222 | 128,106,491 | Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology. We tested the hypothesis that MS is caused by Epstein-Barr virus (EBV) in a cohort comprising more than 10 million young adults on active duty in the US military, 955 of whom were diagnosed with MS... | 10.1038/s41577-022-00718-z | This high-powered study is the first to confirm that EBV infection is directly associated with, and precedes, the development of MS |
10.4049/jimmunol.154.9.4883 | 139,063,663 | Abstract Infiltrating gamma delta T cells are potentially involved in the central nervous system demyelination in multiple sclerosis (MS). To further study this hypothesis, we analyzed the frequency and functional properties of gamma delta T cells in peripheral blood (PB) and paired cerebrospinal fluid (CSF) of patient... | 10.1038/s41577-022-00718-z | This study provides evidence to support a role for unconventional T cells in MS pathogenesis |
10.1530/acta.0.1190307 | 119,643,515 | Abstract. To investigate the hypothesis that interleukin 1 initially stimulates and then suppresses beta-cell function and that this sequential effect is directly related to interleukin 1 dose, duration of exposure, and ambient glucose concentration, insulin release was measured from cultured newborn rat islets exposed... | 10.1038/s41577-019-0213-9 | The first study to demonstrate bimodal effect of IL-1 on β-cell secretory function |
10.1073/pnas.0807627105 | 16,804,153 | Human pancreatic islet transplantation offers diabetic patients tight glucose control but has low graft survival rates. The immunosuppressive drugs that are administered to graft recipients lack the antiinflammatory benefits of corticosteroids because of their diabetogenic effects. The serum protease inhibitor α1-antit... | 10.1038/s41577-019-0213-9 | First study showing that AAT protects against inflammation-induced β-cell destruction |
10.1126/science.1061620 | 20,533,835 | We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IκB kinase β (IKKβ) attenuated insulin signaling in cultured cells, whereas IKKβ inhibition reversed insulin resistance. Thus, IKKβ, rat... | 10.1038/s41577-019-0213-9 | A seminal article showing reversal of insulin resistance by salsalate |
10.2337/db06-1650 | 104,241,365 | Activation of the innate immune system in obesity is a risk factor for the development of type 2 diabetes. The aim of the current study was to investigate the notion that increased numbers of macrophages exist in the islets of type 2 diabetes patients and that this may be explained by a dysregulation of islet-derived i... | 10.1038/s41577-019-0213-9 | Pioneering study showing macrophage infiltration in islets of humans and animals with T2D |
10.1126/science.1197294 | 20,423,393 | Laser pulses are used to enable coherent transport between the copper oxide planes of a cuprate superconductor. | 10.1038/s41586-022-04726-w | This work demonstrates targeted optical suppression of stripe order to enhance superconductivity. |
10.1126/science.aaw4911 | 38,437,797 | Fluctuating orders in solids are generally considered high-temperature precursors of broken symmetry phases. However, in some cases, these fluctuations persist to zero temperature and prevent the emergence of long-range order. Strontium titanate (SrTiO 3 ) is a quantum paraelectric in which dipolar fluctuations grow up... | 10.1038/s41586-022-04726-w | This paper experimentally demonstrates how an electromagnetic field can induce ferroelectric order at high temperature in a quantum paraelectric material. |
10.1126/science.aaw4913 | 123,045,860 | “Hidden phases” are metastable collective states of matter that are typically not accessible on equilibrium phase diagrams. These phases can host exotic properties in otherwise conventional materials and hence may enable novel functionality and applications, but their discovery and access are still in early stages. Usi... | 10.1038/s41586-022-04726-w | This paper experimentally demonstrates how an electromagnetic field can induce ferroelectric order at high temperature in a quantum paraelectric material. |
10.1126/science.1216022 | 20,601,465 | Quantum Hall Meets Metamaterial Controlling and tuning light-matter interaction is crucial for fundamental studies of cavity quantum electrodynamics and for applications in classical and quantum devices. Scalari et al. (p. 1323 ) describe a system comprising an array of metamaterial split-ring resonators and a series o... | 10.1038/s41586-022-04726-w | Demonstration of strong light–matter coupling in a two-dimensional electron system. |
10.1038/s41467-017-00876-y | 125,164,870 | Abstract The search for quantum spin liquids in frustrated quantum magnets recently has enjoyed a surge of interest, with various candidate materials under intense scrutiny. However, an experimental confirmation of a gapped topological spin liquid remains an open question. Here, we show that circularly polarized light ... | 10.1038/s41586-022-04726-w | A theoretical proposal to exploit optically induced dynamical symmetry breaking to engineer quantum spin liquids. |
10.1073/pnas.2105618118 | 135,219,725 | Significance Controlling collective phenomena in quantum materials is a promising route toward engineering material properties on demand. Strong THz lasers have been successful at inducing ferroelectricity in S r T i O 3 . Here we demonstrate, from atomistic calculations, that cavity quantum vacuum fluctuations induce ... | 10.1038/s41586-022-04726-w | Theoretical proposal for a cavity modification of the ground state of a material |
10.1210/jc.2019-00221 | 83,033,934 | Abstract Objective The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. Conclusions Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating... | 10.1038/s41574-022-00685-4 | This article provides an excellent evidence-based summary of management of postmenopausal osteoporosis |
10.1097/gme.0000000000001174 | 29,117,080 | Abstract There is a new appreciation of the perimenopause – defined as the early and late menopause transition stages as well as the early postmenopause - as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, cha... | 10.1038/s41574-022-00685-4 | This is an important summary document of perimenopausal depression and management |
10.1126/science.1164096 | 40,758,004 | Studies have shown that the bulk of eukaryotic genomes is transcribed. Transcriptome maps are frequently updated, but low-abundant transcripts have probably gone unnoticed. To eliminate RNA degradation, we depleted the exonucleolytic RNA exosome from human cells and then subjected the RNA to tiling microarray analysis.... | 10.1038/s41576-018-0013-2 | The identification of PROMPTs as major RNA exosome targets in human cells. |
10.1126/science.1240376 | 102,164,785 | Eggs and oocytes have a remarkable ability to induce transcription of sperm after normal fertilization and in somatic nuclei after somatic cell nuclear transfer. This ability of eggs and oocytes is essential for normal development. Nuclear actin and actin-binding proteins have been shown to contribute to transcription,... | 10.1038/s41576-022-00493-6 | This work provides evidence that nuclear actin polymerization is key for transcription in the context of pluripotency reprogramming |
10.1073/pnas.85.15.5576 | 80,637,450 | Cultures of human epidermal keratinocytes provide a useful experimental model with which to study the factors that regulate cell proliferation and terminal differentiation. One situation that is known to trigger premature terminal differentiation is suspension culture, when keratinocytes are deprived of substratum and ... | 10.1038/s41576-022-00493-6 | This work pioneers micropatterning to control cell geometry and mechanics and makes a strong case for mechanical control of cell differentiation, 10 years ahead of the field |
10.1126/science.276.5317.1425 | 103,731,511 | Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension. Cell spreading also was varied while maintaining the total cell-matrix contact a... | 10.1038/s41576-022-00493-6 | This study demonstrates that spatial arrangement of the ECM, and not the amount of ECM ligand, can drive a complex cellular phenotype |
10.1091/mbc.9.9.2627 | 123,030,787 | The multipotential cytokine transforming growth factor-β (TGF-β) is secreted in a latent form. Latency results from the noncovalent association of TGF-β with its processed propeptide dimer, called the latency-associated peptide (LAP); the complex of the two proteins is termed the small latent complex. Disulfide bonding... | 10.1038/s41576-022-00493-6 | This paper describes the discovery that paved the way to the idea of force-mediated liberation of TGFβ1 ligands from the ECM |
10.1126/science.aam9305 | 62,191,088 | Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our expe... | 10.1038/s41568-018-0054-z | In this study, the authors demonstrate that nitrogenated waste can be efficiently incorporated into glutamate as a substrate for downstream reactions, to maximize nitrogen use by cancer cells. |
10.1038/cddis.2016.232 | 41,530,225 | Abstract Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact... | 10.1038/s41568-018-0054-z | Proof-of-principle human ASS1-negative sarcoma xenograft study showing potentiation of ADI-PEG20 by choloroquine as a modulator of autophagy. |
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/s41576-018-0089-8 | References 31 and 32 are the first reports of single-cell chromatin accessibility |
10.1126/science.aag0025 | 38,361,847 | A close-up view inside the nucleus The nuclei of human cells contain 2 meters of genomic DNA. How does it all fit? Compaction starts with the DNA wrapping around histone octamers to form nucleosomes, but it is unclear how these further compress into mitotic chromosomes. Ou et al. describe a DNA-labeling method that all... | 10.1038/s41576-018-0089-8 | This paper shows that higher-order chromatin organization is heterogeneous across the genome and that chromatin density is the primary distinguishing property of heterochromatin and euchromatin |
10.1126/science.1256271 | 122,987,598 | Opening and closing blood enhancers As cells develop and differentiate into different types, the shape and accessibility of their DNA can change. Lara-Astiaso et al. studied this phenomenon in blood. They developed a technique that examines a relatively small number of cells to identify the changes that affect DNA duri... | 10.1038/s41576-018-0089-8 | This paper shows that acquisition of H3K4me1 (a mark commonly observed at poised enhancers) during haematopoiesis is accompanied by an increase in chromatin accessibility |
10.1073/pnas.0510790103 | 62,601,511 | The cytoarchitecture of human islets has been examined, focusing on cellular associations that provide the anatomical framework for paracrine interactions. By using confocal microscopy and multiple immunofluorescence, we found that, contrary to descriptions of prototypical islets in textbooks and in the literature, hum... | 10.1038/s41574-018-0105-2 | This early study points to critical differences in islet architecture and β-cell Ca 2+ signalling in rodent versus porcine versus human islets |
10.2337/db11-1312 | 104,344,942 | Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calciu... | 10.1038/s41574-018-0105-2 | This landmark study links β-cell-specific loss of connexin 36 gap junction channels with defective Ca 2+ signals and loss of pulsatile insulin secretion in mice |
10.1126/science.1073806 | 85,544,691 | Insulin secretion from intact mouse pancreatic islets was investigated with two-photon excitation imaging. Insulin granule exocytosis occurred mainly toward the interstitial space, away from blood vessels. The fusion pore was unusually stable with a lifetime of 1.8 seconds. Opening of the 1.4-nanometer-diameter pore wa... | 10.1038/s41574-018-0105-2 | This article presents the first study to show the orientation of insulin granule fusion in intact islets |
10.1126/science.aao0284 | 41,134,307 | The neuronal population is the key unit The responses of pairs of neurons to repeated presentations of the same stimulus are typically correlated, and an identical neuronal population can perform many functions. This suggests that the relevant units of computation are not single neurons but subspaces of the complete po... | 10.1038/s41583-022-00582-9 | This paper demonstrated that perceptual learning and attention were reflected in V4 primarily by an overlapping neural correlate: changes in correlated trial variability, which is strongly linked to performance |
10.1073/pnas.2021660118 | 45,160,543 | Memories of the images that we have seen are thought to be reflected in the reduction of neural responses in high-level visual areas such as inferotemporal (IT) cortex, a phenomenon known as repetition suppression (RS). We challenged this hypothesis with a task that required rhesus monkeys to report whether images were... | 10.1038/s41583-022-00582-9 | In the context of a visual memory task, this study demonstrated that the population subspaces encoding novelty and a task-irrelevant variable, contrast, were partially overlapping and could be disambiguated |
10.1146/annurev-ecolsys-110411-160340 | 104,396,911 | The order and timing of species immigration during community assembly can affect species abundances at multiple spatial scales. Known as priority effects, these effects cause historical contingency in the structure and function of communities, resulting in alternative stable states, alternative transient states, or com... | 10.1038/s41579-021-00604-w | This study defines mechanisms by which early-arriving species affect late-arriving species (niche pre-emption and niche modification) and describes how and when they are expected to influence community assembly outcomes |
10.1038/s41467-020-15652-8 | 123,980,903 | Abstract How complex communities assemble through the animal’s life, and how predictable the process is remains unexplored. Here, we investigate the forces that drive the assembly of rumen microbiomes throughout a cow’s life, with emphasis on the balance between stochastic and deterministic processes. We analyse the de... | 10.1038/s41579-021-00604-w | This study showed that the effects of delivery mode on the assembly of the cow rumen microbiome extend beyond initial exposure to different microbiota and they continue to affect bacterial species that arrive throughout the first few years of life |
10.1038/ncomms9413 | 84,544,793 | Abstract Host-associated bacterial communities can function as an important line of defence against pathogens in animals and plants. Empirical evidence and theoretical predictions suggest that species-rich communities are more resistant to pathogen invasions. Yet, the underlying mechanisms are unclear. Here, we experim... | 10.1038/s41579-021-00604-w | Showed that priority effects between commensal and pathogenic bacteria in the plant rhizosphere can be predicted based on overlap in resource consumption in vitro |
10.1038/ismej.2017.180 | 19,053,509 | Abstract The order and timing of species arrival during community assembly can have long term effects on community structure due to priority effects. The importance of such processes in complex bacterial communities where dispersal involves mixing of entire communities is currently not known. Here we used a transplant ... | 10.1038/s41579-021-00604-w | Demonstrated that the strength of priority effects in an aquatic community was a product of how well each community was adapted to the habitat and the amount of time between their dispersal events |
10.1146/annurev.immunol.22.012703.104803 | 125,149,186 | After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models—together with compelling data from human patients—indicate that a functional cancer immunosurveillance process indeed exists that acts as an ... | 10.1038/s41590-019-0433-y | This review (ref. 5) describes the interactions between a tumor and the immune system that govern tumor progression or clearance. This framework is important for understanding how tumors respond to immunological pressure |
10.1126/scitranslmed.aag2942 | 83,201,822 | Local chemotherapy synergizes with immunotherapy against glioblastoma, whereas systemic chemotherapy abrogates its antitumor effect. | 10.1038/s41590-019-0433-y | This study (ref. 35) demonstrated that systemic temozolomide induced immunosuppression that prevented the effectiveness of PD-1 blockade in a preclinical model |
10.1158/1078-0432.ccr-15-1516 | 45,519,925 | Abstract Purpose: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown. Experimental Design: The B16 murine mel... | 10.1038/s41590-019-0433-y | This study (ref. 67) showed that tumor location is an independent mediator of systemic immunosuppression through multiple mechanisms, including deletion and tolerance of tumor antigen-directed T cells |
10.1126/scitranslmed.aan4220 | 80,223,465 | PVSRIPO infection of tumors elicits antitumor immunity by damaging neoplastic cells and activating type I IFN responses in antigen-presenting cells. | 10.1038/s41590-019-0433-y | This study (ref. 87) demonstrated that treatment with an oncolytic poliovirus reprograms DCs, releases damage- or pathogen-associated molecular patterns, and generates sustained cytotoxic responses. |
10.1158/1078-0432.ccr-17-1846 | 83,541,506 | Abstract Purpose: T-cell dysfunction is a hallmark of glioblastoma (GBM). Although anergy and tolerance have been well characterized, T-cell exhaustion remains relatively unexplored. Exhaustion, characterized in part by the upregulation of multiple immune checkpoints, is a known contributor to failures amid immune chec... | 10.1038/s41590-019-0433-y | This study (ref. 94) delineates mechanisms of adaptive resistance in glioblastoma and describes a severe state of exhaustion among tumor-infiltrating T cells |
10.1542/peds.2020-013201 | 29,276,460 | BACKGROUND: Perinatal stroke encompasses multiple disease-specific cerebrovascular syndromes that cause lifelong neurodevelopmental morbidity for millions worldwide. Acute presentations include neonatal arterial ischemic stroke (NAIS), neonatal cerebral sinovenous thrombosis, and neonatal hemorrhagic stroke (NHS). Dela... | 10.1038/s41582-021-00503-x | Summarizes the birth prevalence of all subtypes of perinatal stroke by using a population-based cohort |
10.1111/j.1469-7580.2010.01262.x | 19,052,758 | Abstract The developing human brain can compensate for pre‐ and perinatally acquired focal lesions more effectively than the adult brain. The mechanisms by which this effective reorganization is achieved vary considerably between different functional systems, reflecting differences in the normal maturation of these sys... | 10.1038/s41582-021-00503-x | Summarizes mechanisms of post-lesional reorganization in the developing human brain, with a special emphasis on the development of motor and somatosensory pathways in children with early brain lesions |
10.1002/mrm.1910340409 | 125,327,842 | Abstract An MRI time course of 512 echo‐planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodolo... | 10.1038/s41582-021-00503-x | One of the first demonstrations of functional connectivity in the brain at rest |
10.1002/jms.4195 | 18,392,094 | Abstract Quadrupole Orbitrap instruments (Q Orbitrap) permit high‐resolution mass spectrometry‐based full scan acquisitions and have a number of acquisition modes where the quadrupole isolates a particular mass range prior to a possible fragmentation and high‐resolution mass spectrometry‐based acquisition. Selecting th... | 10.1038/s41592-021-01116-4 | A great overview of how different parameters in data acquisition can profundly affect data quality |
10.1126/science.1137406 | 80,140,146 | The roles of endocannabinoid signaling during central nervous system development are unknown. We report that CB 1 cannabinoid receptors (CB 1 Rs) are enriched in the axonal growth cones of γ-aminobutyric acid–containing (GABAergic) interneurons in the rodent cortex during late gestation. Endocannabinoids trigger CB 1 R... | 10.1038/s41583-021-00465-5 | This study demonstrates the crucial role of the eCB signalling in axonal guidance and in the formation of accurate synaptic connections |
10.1046/j.1460-9568.2003.02599.x | 60,229,747 | Abstract Previous evidence suggests that the endogenous cannabinoid system emerges relatively early during brain development in the rat. However, the pre‐ and postnatal pattern of appearance of CB 1 cannabinoid receptors in humans has not been analysed in detail. Furthermore, there is a complete lack of information abo... | 10.1038/s41583-021-00465-5 | This is an important study showing functional G protein coupling of CBRs in the human fetal brain |
10.1073/pnas.87.5.1932 | 103,762,996 | [3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 bindi... | 10.1038/s41583-021-00465-5 | This study demonstrates the anatomical expression of CB 1 R and its being the most abundant G protein receptor in the adult brain |
10.1093/nar/gkac159 | 136,258,531 | Abstract CRISPR/Cas13 effectors have garnered increasing attention as easily customizable tools for detecting and depleting RNAs of interest. Near perfect complementarity between a target RNA and the Cas13-associated guide RNA is required for activation of Cas13 ribonuclease activity. Nonetheless, the specificity of Ca... | 10.1038/s41587-022-01423-x | This paper reports that Cas13d and Cas13b have differing extents of off-target effects and highlights the need for caution when using Cas13 effectors in eukaryotic cells. |
10.1242/dev.050195 | 62,497,800 | The first two cell lineages in the mouse, the surface trophectoderm (TE) and inner cell mass (ICM), are morphologically distinguishable by E3.5, with the outer TE forming a polarized epithelial layer enclosing the apolar ICM. We show here that in mouse embryos completely lacking both maternal and zygotic E-cadherin (ca... | 10.1038/s41580-021-00363-9 | An article showing that loss of both maternal and zygotic E-cadherin disrupts embryo morphology and generates overlapping apical and basal cell domains |
10.1038/s41467-017-00977-8 | 79,872,088 | Abstract Establishment of cell polarity in the mammalian embryo is fundamental for the first cell fate decision that sets aside progenitor cells for both the new organism and the placenta. Yet the sequence of events and molecular mechanism that trigger this process remain unknown. Here, we show that de novo polarisatio... | 10.1038/s41580-021-00363-9 | Identification of early regulators of apical polarization in the embryo, with a proposed two-step model dissecting the interactions between actin filaments and polarity proteins |
10.1136/bmj.l94 | 41,612,131 | Abstract Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main ou... | 10.1038/s41572-019-0121-0 | This review, based on the Global Burden of Disease Study, provides the global and country-specific incidence (and trends in incidence) of suicide |
10.1192/bjp.bp.107.040113 | 62,254,392 | Background Suicide is a leading cause of death worldwide; however, the prevalence and risk factors for the immediate precursors to suicide – suicidal ideation, plans and attempts – are not well-known, especially in low- and middle-income countries. Aims To report on the prevalence and risk factors for suicidal behaviou... | 10.1038/s41572-019-0121-0 | This epidemiological study is one of few to compare suicidal ideation and suicidal behaviour across low-income, middle-income and high-income countries (17 countries in total) |
10.1177/1039856217743888 | 28,015,091 | Objective: To describe the new Australian approach to suicide prevention, LifeSpan, and compare it to other multi-component intervention models. Method: The components, implementation strategies and effectiveness of three multi-component intervention models are described and compared in a narrative review. Results: The... | 10.1038/s41572-019-0121-0 | This paper introduces the systems-based approach to suicide prevention and provides some key examples of where this is being used around the world |
10.1192/bjp.bp.116.197459 | 17,262,172 | Summary A range of factors can contribute to suicide, which means that a multifactorial approach to suicide prevention is necessary. Whereas randomised controlled trials may be suitable for evaluation of some interventions, others require different approaches for assessment of their impact. Also, suicide itself will no... | 10.1038/s41572-019-0121-0 | This paper discusses the need for rigorous and innovative evaluation methods in suicide prevention |
10.1210/er.2009-0041 | 45,345,370 | Via its interaction in several pathways, normal thyroid function is important to maintain normal reproduction. In both genders, changes in SHBG and sex steroids are a consistent feature associated with hyper- and hypothyroidism and were already reported many years ago. Male reproduction is adversely affected by both th... | 10.1038/s41574-021-00604-z | This is a comprehensive review on the interactions between thyroid function and human reproduction |
10.1210/jc.2019-01343 | 4,751,650 | Abstract Context Antithyroid drug (ATD) therapy in early pregnancy is associated with birth defects, but more data are needed to substantiate the risk associated with different types of ATD. Furthermore, the role of abnormal maternal thyroid function per se remains unclarified. Objective To evaluate the risk of birth d... | 10.1038/s41574-021-00604-z | This large study assessed the effects of antithyroid drug use in early pregnancy on risk of birth defects utilizing the Danish national registry |
10.1093/ajcn/nqaa071 | 104,086,799 | ABSTRACT Background Mild-to-moderate iodine deficiency, particularly in pregnancy, is prevalent; this is of concern because observational studies have shown negative associations with child neurodevelopment. Although neither the benefits nor the safety of iodine supplementation in pregnancy in areas of mild-to-moderate... | 10.1038/s41574-021-00604-z | This systematic review and meta-analysis summarizes findings of 37 randomized controlled trials, intervention studies, and observational studies on the effects of iodine supplementation in mildly-to-moderately iodine deficiency pregnant women on maternal and infant thyroid function and child neurodevelopmental outcomes |
10.1111/j.1365-294x.2005.02617.x | 104,240,566 | Abstract Speciation can be viewed as the evolution of restrictions on the freedom of genetic recombination: new combinations of alleles can be generated within species, but alleles from different species cannot be brought together. Recently, there has been increasing realization that the role of chromosomal rearrangeme... | 10.1038/s41576-020-0240-1 | This influential perspective article discusses the variation in recombination, theoretical expectations and its importance for speciation |
10.1146/annurev-genom-082908-150031 | 123,536,900 | There has been considerable excitement over the ability to construct linkage maps based only on genome-wide genotype data for single nucleotide polymorphic sites (SNPs) in a population sample. These maps, which are derived from estimates of linkage disequilibrium (LD), rely on population genetics theory to relate the d... | 10.1038/s41576-020-0240-1 | This review compares the different recombination inference methods (linkage disequilibrium-based, pedigree-based, sperm-typing and hotspot detection) in humans where the most extensive data are available |
10.1017/s0016672300010156 | 20,401,403 | (i) A computer simulation study has been made of selection on two linked loci in small populations, where both loci were assumed to have additive effects on the character under selection with no interaction between loci. If N is the effective population size, i the intensity of selection in standard units, α and β meas... | 10.1038/s41576-020-0240-1 | This article presents the theory describing the behaviour of two linked loci under selection |
10.1017/s0016672300033140 | 81,672,771 | Summary A general representation of multilocus selection is extended to allow recombination to depend on genotype. The equations simplify if modifier alleles have small effects on recombination. The evolution of such modifiers only depends on how they alter recombination between the selected loci, and does not involve ... | 10.1038/s41576-020-0240-1 | This article describes mathematical models of how recombination evolves via selection on recombination modifiers |
10.1098/rstb.2016.0455 | 107,188,995 | Recombination, the exchange of DNA between maternal and paternal chromosomes during meiosis, is an essential feature of sexual reproduction in nearly all multicellular organisms. While the role of recombination in the evolution of sex has received theoretical and empirical attention, less is known about how recombinati... | 10.1038/s41576-020-0240-1 | This review, part of the special issue ‘Evolutionary Causes and Consequences of Recombination Rate Variation in Sexual Organisms’, includes a meta-analysis characterizing the variation in recombination rates across the tree of life and outlines outstanding questions in the field |
10.1534/genetics.115.185553 | 41,745,010 | Abstract Meiotic recombination breaks down linkage disequilibrium (LD) and forms new haplotypes, meaning that it is an important driver of diversity in eukaryotic genomes. Understanding the causes of variation in recombination rate is important in interpreting and predicting evolutionary phenomena and in understanding ... | 10.1038/s41576-020-0240-1 | This article examines recombination rate variation and isolation of candidate genetic modifier loci in a natural, pedigreed population |
10.1126/science.aad0843 | 123,151,178 | Recombination: The birds and the yeast Apes and mice have a specific gene, PRDM9 , that is associated with genomic regions with high rates of recombination, called hotspots. In species with PRDM9 , hotspots move rapidly within the genome, varying among populations and closely related species (see the Perspective by Lic... | 10.1038/s41576-020-0240-1 | This article presents a good example of the population-based approach identifying recombination hotpots, their evolutionary stability and the underlying genomic features in avian populations |
10.1093/genetics/165.2.849 | 83,441,972 | Abstract Recombination nodules (RNs) are closely correlated with crossing over, and, because they are observed by electron microscopy of synaptonemal complexes (SCs) in extended pachytene chromosomes, RNs provide the highest-resolution cytological marker currently available for defining the frequency and distribution o... | 10.1038/s41576-020-0240-1 | This article is one of the early studies to use MLH1 foci to estimate recombination frequency across the genome |
10.1093/genetics/159.4.1805 | 83,558,942 | Abstract Methods of estimating two-locus sample probabilities under a neutral model are extended in several ways. Estimation of sample probabilities is described when the ancestral or derived status of each allele is specified. In addition, probabilities for two-locus diploid samples are provided. A method for using th... | 10.1038/s41576-020-0240-1 | This article presents an influential description of how the population recombination rate can be estimated from data |
10.1073/pnas.84.8.2363 | 80,117,581 | Human genetic linkage maps are most accurately constructed by using information from many loci simultaneously. Traditional methods for such multilocus linkage analysis are computationally prohibitive in general, even with supercomputers. The problem has acquired practical importance because of the current international... | 10.1038/s41576-020-0240-1 | This article is the first description of inferring multilocus linkage maps using maximum likelihood in a three-generation human pedigree |
10.1038/s41467-019-12209-2 | 85,506,395 | Abstract Meiotic crossovers (COs) ensure proper chromosome segregation and redistribute the genetic variation that is transmitted to the next generation. Large populations and the demand for genome-wide, fine-scale resolution challenge existing methods for CO identification. Taking advantage of linked-read sequencing, ... | 10.1038/s41576-020-0240-1 | This article is one of the first studies to perform bulk-gamete sequencing using linked-read technology to infer the recombination rate across the genome |
10.1038/s41467-019-12210-9 | 123,192,126 | Abstract Meiotic recombination rates vary across the genome, often involving localized crossover hotspots and coldspots. Studying the molecular basis and mechanisms underlying this variation has been challenging due to the high cost and effort required to construct individualized genome-wide maps of recombination cross... | 10.1038/s41576-020-0240-1 | This article is one of the first studies to perform bulk-gamete sequencing using linked-read technology to infer the recombination rate across the genome |
10.1038/s41467-020-16363-w | 62,057,227 | Abstract IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of ... | 10.1038/s41577-022-00796-z | This study demonstrates that TGFβ signalling sustains T H 17 cell differentiation and IL-22 production, which promotes tumour development in a murine model of colitis-associated colon cancer |
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/s41577-022-00796-z | This study reveals that blockade of TGFβ signalling in CD8 + T cells synergizes with chemoradiotherapy to suppress tumour growth in a transplantable tumour model, which is associated with increased CXCR3 expression and CD8 + T cell tumour trafficking |
10.1038/s41467-021-26352-2 | 134,135,082 | Abstract Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models th... | 10.1038/s41577-022-00796-z | The studies by Dodagatta-Marri et al. (2021) and Laine et al. (2021) demonstrate that the T reg cell-expressed integrin αVβ8 promotes TGFβ1 activation and suppresses cancer immunosurveillance in transplantable tumour models and that αVβ8 is a potential immuno-oncology target |
10.1038/s41467-020-17811-3 | 104,264,082 | Abstract TGF-β1, β2 and β3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-β inhibition thus bears the risk of undesired tumor-prom... | 10.1038/s41577-022-00796-z | This study shows that T reg cell-expressed GARP promotes tumour immune escape, which can be targeted in synergy with anti-PD1 to inhibit tumour growth in a transplantable tumour model |
10.1084/jem.20200030 | 61,797,160 | In addition to Foxp3+ CD4+ regulatory T cells (CD4+ T reg cells), Foxp3− CD8+ regulatory T cells (CD8+ T reg cells) are critical to maintain immune tolerance. However, the molecular programs that specifically control CD8+ but not CD4+ T reg cells are largely unknown. Here, we demonstrate that simultaneous disruption of... | 10.1038/s41577-022-00796-z | This study demonstrates that TGFβ cooperates with EOMES to promote homeostasis of regulatory CD8 + T cells, deficiency of which results in lethal autoimmunity |
10.1084/jem.20181868 | 103,673,543 | B cells in germinal centers (GCs) cycle between light zone (LZ) and dark zone (DZ). The cues in the GC microenvironment that regulate the transition from LZ to DZ have not been well characterized. In Peyer’s patches (PPs), transforming growth factor-β (TGFβ) promotes IgA induction in activated B cells that can then dif... | 10.1038/s41577-022-00796-z | This study uncovers discrete types of TGFβ signalling that influence B cell biology, with signalling in the Peyer patches inducing IgA class-switching in activated B cells, and signalling in the germinal centre required for transition from the light zone to the dark zone |
10.1126/scisignal.aad1884 | 20,599,278 | Blocking TGF-β signaling in natural killer cells enhances their metabolism and ability to kill tumor cells. | 10.1038/s41577-022-00796-z | This study reveals that TGFβ suppresses activation, cytolytic activity and cancer metastasis surveillance function of NK cells in association with TGFβ control of mTOR complex1 signalling |
10.1126/sciimmunol.abi8642 | 135,420,510 | Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional... | 10.1038/s41577-022-00796-z | This study demonstrates that ILC1s can exhibit lytic granule-mediated cytotoxicity and that TGFβ signalling is required to maintain the antitumour function of CD103 + ILC1s in a transgenic model of breast cancer |
10.1038/s41467-019-11998-w | 60,996,770 | Abstract Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether t... | 10.1038/s41577-022-00796-z | This study reveals differences in macrophage responsiveness to STING activation in transplantable versus spontaneous tumour models, showing spontaneous tumours to be higher in TGFβ, which limits the interferon-induced tumour regression |
10.1126/scitranslmed.aan5488 | 104,341,057 | Blockade of PD-L1 and TGF-β pathways with M7824 activates effective innate and adaptive antitumor immune responses. | 10.1038/s41577-022-00796-z | This study reveals that the bifunctional molecule M7824, with fusion of the extracellular domain of TGFBR2 (TGFβ trap) to a PDL1 antibody, suppresses primary tumour growth and metastasis more effectively than anti-PDL1 or TGFβ trap alone in transplantable tumour models |
10.1002/cpt.1211 | 60,342,319 | Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State‐of‐the‐art techniques to mea... | 10.1038/s41578-020-00269-6 | A road map for the clinical implementation of precision dosing |
10.1373/clinchem.2010.150631 | 103,486,774 | Abstract Growth hormone (GH) and insulin-like growth factor I (IGF-I) measurements are widely used in the diagnosis of disorders of GH secretion, evaluation of children with short stature from multiple causes, management of disorders that lead to nutritional insufficiency or catabolism, and monitoring both GH and IGF-I... | 10.1038/s41572-019-0071-6 | This consensus statement discusses how to improve the measurement of GH and IGF1 levels |
10.1210/jc.2016-1257 | 59,255,881 | Abstract Context: Measurement of IGF-I is essential for diagnosis and management of patients with disorders affecting the somatotropic axis. However, even when IGF-I kit manufacturers follow recent consensus guidelines, different kits can give very different results for a given sample. Objectives: We sought to establis... | 10.1038/s41572-019-0071-6 | This study attempts to establish normative data for six IGF1 assay kits on the basis of a large, random sample of the French adult population |
10.1111/cen.13331 | 40,171,781 | Summary Objective Patients with acromegaly demonstrate impaired quality of life (QoL), but data on long‐term QoL changes in treated acromegaly are limited. This study evaluates and identifies factors that influence QoL in patients with long‐term biochemical remission. Design The study consists of a cross‐sectional arm ... | 10.1038/s41572-019-0071-6 | This study evaluates factors that influence QOL in patients with acromegaly with long-term biochemical remission |
10.1136/annrheumdis-2015-208052 | 85,620,087 | Objectives To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). Methods In this multicentre, randomised, placebo-controlled phase II study, ... | 10.1038/s41590-022-01298-9 | This multicenter, randomized, placebo-controlled phase 2 study shows that the addition of denosumab (monoclonal antibody to RANKL) to methotrexate treatment has the potential to suppress bone erosion in patients with RA. |
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