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10.26434/chemrxiv.7927061.v1 | 54,402,346 | <p>Targeted protein degradation is a powerful strategy to address the canonically undruggable proteome. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. Here, we designed and synthesized conjugates capable of binding both a cell surface lysosome targeting ... | 10.1038/s41594-020-0438-0 | This paper shows the method of using chimeric macromolecular conjugates to target proteins for degradation by the lysosomal pathway |
10.1073/pnas.1408987111 | 38,387,129 | Necroptosis is considered to be complementary to the classical caspase-dependent programmed cell death pathway, apoptosis. The pseudokinase Mixed Lineage Kinase Domain-Like (MLKL) is an essential effector protein in the necroptotic cell death pathway downstream of the protein kinase Receptor Interacting Protein Kinase-... | 10.1038/s41573-019-0018-3 | This study identifies an ATP-competitive compound that binds to the pseudoactive site of MLKL and inhibits necroptosis |
10.1126/scisignal.aau0597 | 81,605,530 | The Tribbles family of pseudokinases recruits substrates to the ubiquitin ligase COP1 to facilitate ubiquitylation. CCAAT/enhancer-binding protein (C/EBP) family transcription factors are crucial Tribbles substrates in adipocyte and myeloid cell development. We found that the TRIB1 pseudokinase was able to recruit vari... | 10.1038/s41573-019-0018-3 | This study demonstrates that substrate binding alters the conformation of the TRIB1 pseudokinase domain, providing evidence that pseudokinases can undergo conformational transitions similar to those observed for active kinases |
10.1073/pnas.1423201112 | 82,929,301 | Pseudokinases lack conserved motifs typically required for kinase activity. Nearly half of pseudokinases bind ATP, but only few retain phosphotransfer activity, leaving the functional role of nucleotide binding in most cases unknown. Janus kinases (JAKs) are nonreceptor tyrosine kinases with a tandem pseudokinase–kinas... | 10.1038/s41573-019-0018-3 | This paper demonstrates that ATP binding to the JH2 pseudokinase domain of JAK2 is essential for hyperactivation of pathogenic JAK2 mutants |
10.1126/scisignal.aat7951 | 41,356,226 | A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial ... | 10.1038/s41573-019-0018-3 | This study reveals that compounds previously identified as covalent inhibitors of EGFR and HER2 can also bind to TRIB2 and induce its degradation |
10.1002/art.40784 | 60,848,943 | Objective Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting the coronary arteries. S100A12, a granulocyte‐derived agonist of both the receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR‐4), is strongly up‐regulated in KD. This study was undertaken to invest... | 10.1038/s41584-021-00709-9 | This article provides mechanistic insight on the roles of S100A12 and IL-1β in the pathogenesis of Kawasaki disease, and supports the therapeutic use of IL-1β inhibitors |
10.1038/s41467-021-25771-5 | 134,668,331 | Abstract Kawasaki disease (KD) is the most common cause of acquired heart disease in children in developed countries. Although functional and phenotypic changes of immune cells have been reported, a global understanding of immune responses underlying acute KD is unclear. Here, using single-cell RNA sequencing, we profi... | 10.1038/s41584-021-00709-9 | This article applies single-cell RNA sequencing to report that monocytes are the major contributors of inflammatory responses, including IL-1β and TNF, in Kawasaki disease |
10.1136/bmj.m2094 | 83,394,003 | Abstract Objectives To describe the characteristics of children and adolescents affected by an outbreak of Kawasaki-like multisystem inflammatory syndrome and to evaluate a potential temporal association with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Design Prospective observational study.... | 10.1038/s41584-021-00709-9 | An early report of MIS-C from the first wave of COVID-19 in mid-2020 |
10.1073/pnas.2010722117 | 20,784,009 | Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that str... | 10.1038/s41584-021-00709-9 | Evidence that SARS-CoV-2 spike protein acts as a superantigen leading to HLA class I-associated expansion of TRBV11-2 T cells in MIS-C |
10.1126/sciimmunol.abh1516 | 17,936,591 | Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these... | 10.1038/s41584-021-00709-9 | Patients with MIS-C present a unique CD4 + and CD8 + T cell TCR repertoire with a polyclonal expansion of CX 3 CR1-expressing activated (TRBV11-2)/Vβ21.3 + clonotype |
10.1101/2020.09.25.20201863 | 40,117,452 | ABSTRACT Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune ... | 10.1038/s41584-021-00709-9 | The article identifies a unique and strong activation of vascular patrolling CX 3 CR1 + CD8 + T cells in MIS-C |
10.1038/s41467-020-19130-z | 20,740,835 | Abstract Ammonia is of emerging interest as a liquefied, renewable-energy-sourced energy carrier for global use in the future. Electrochemical reduction of N 2 (NRR) is widely recognised as an alternative to the traditional Haber–Bosch production process for ammonia. However, though the challenges of NRR experiments ha... | 10.1038/s41467-022-35489-7 | This work provides a clear discussion on NOx contamination and removal |
10.1002/advs.201802109 | 20,702,476 | Abstract The enzyme nitrogenase inspires the development of novel photocatalytic and electrocatalytic systems that can drive nitrogen reduction with water under similar low‐temperature and low‐pressure conditions. While photocatalytic and electrocatalytic N 2 fixation are emerging as hot new areas of fundamental and ap... | 10.1038/s41467-022-35489-7 | This article systematically discusses the biases in various ammonia measurements |
10.1002/cncr.30496 | 41,631,320 | BACKGROUND Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups... | 10.1038/s41572-021-00324-8 | A simplified, pragmatic molecular classifier enabling the identification of four prognostically distinct molecular subtypes to diagnostic specimens, faciliating earlier informed decision-making |
10.1073/pnas.0810772105 | 29,310,111 | Heritable diseases are caused by germ-line mutations that, despite tissuewide presence, often lead to tissue-specific pathology. Here, we make a systematic analysis of the link between tissue-specific gene expression and pathological manifestations in many human diseases and cancers. Diseases were systematically mapped... | 10.1038/s41576-019-0200-9 | A pioneering large-scale analysis of expression mechanisms in the context of tissue-selective hereditary diseases |
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/s41576-019-0200-9 | An unprecedented resource of transcriptomes and eQTLs across physiological human tissues |
10.1126/science.1113694 | 103,827,988 | Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, ne... | 10.1038/s41583-019-0240-3 | This is the first study to show that reducing tau expression in tau transgenic mice can rescue neuronal loss and behavioural deficits, even when extensive neurofibrillary tangles are already present |
10.4049/jimmunol.161.9.5016 | 139,058,232 | Abstract Type I IFNs, which include IFN-α, appear to have complex and broad-ranging actions in the central nervous system (CNS) that may result in protection or injury. To better understand these issues, we generated transgenic mice that produce IFN-α1 chronically from astrocytes. These glial fibrillary acidic protein-... | 10.1038/s41577-021-00633-9 | The first description of a mouse model demonstrating CNS upregulation of interferon signalling |
10.1126/sciimmunol.aav7501 | 104,197,001 | Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg... | 10.1038/s41577-021-00633-9 | The first description of a separation-of-function mutation in STAT2, which results in an upregulation of type I interferon signalling |
10.1126/science.aau9904 | 101,940,951 | Genomic DNA forms chromatin, in which the nucleosome is the repeating unit. The mechanism by which RNA polymerase II (RNAPII) transcribes the nucleosomal DNA remains unclear. Here we report the cryo–electron microscopy structures of RNAPII-nucleosome complexes in which RNAPII pauses at the superhelical locations SHL(−6... | 10.1038/s41580-020-00308-8 | This study reveals different conformations of Pol II as it transcribes nucleosomal DNA, and how histone–DNA interactions contribute to nucleosome-dependent transcription stalling |
10.1101/gad.330167.119 | 19,476,962 | Cellular homeostasis requires transcriptional outputs to be coordinated, and many events post-transcription initiation can dictate the levels and functions of mature transcripts. To systematically identify regulators of inducible gene expression, we performed high-throughput RNAi screening of the Drosophila Metallothio... | 10.1038/s41580-020-00308-8 | Elrod et al. (2019) and Tatomer et al. (2019) provide evidence that the Integrator RNA cleavage complex mediates premature termination of promoter-proximal Pol II pausing, thereby attenuating transcription |
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/s41576-019-0173-8 | Core (2008), Seila (2008) and Preker (2008) are the first studies to independently observe divergent transcription from mammalian gene promoters |
10.1101/gr.078519.108 | 81,737,731 | We characterized the relationship of H3K4me1 and H3K4me3 at distal and proximal regulatory elements by comparing ChIP-seq profiles for these histone modifications and for two functionally different transcription factors: STAT1 in the immortalized HeLa S3 cell line, with and without interferon-gamma (IFNG) stimulation; ... | 10.1038/s41576-019-0173-8 | Heintzman (2007) and Robertson (2008) identify a signature of high H3K4me1 and low H3K4me3 at candidate enhancers that could be used to discern enhancers from promoters and predict their locations genome-wide |
10.1101/gr.204834.116 | 20,587,252 | Promoters initiate RNA synthesis, and enhancers stimulate promoter activity. Whether promoter and enhancer activities are encoded distinctly in DNA sequences is unknown. We measured the enhancer and promoter activities of thousands of DNA fragments transduced into mouse neurons. We focused on genomic loci bound by the ... | 10.1038/s41576-019-0173-8 | This is the first study to systematically compare the promoter and enhancer potentials of a large number of candidate sequences using MPRAs |
10.1523/jneurosci.22-01-00183.2002 | 104,238,683 | Protoplasmic astrocytes are increasingly thought to interact extensively with neuronal elements in the brain and to influence their activity. Recent reports have also begun to suggest that physiologically, and perhaps functionally, diverse forms of these cells may be present in the CNS. Our current understanding of ast... | 10.1038/s41583-020-0264-8 | This landmark study reveals tiling properties of adjacent astrocytes in the rat hippocampal CA1 region using iontophoresis of two different fluorescent dyes |
10.1038/s41467-018-03940-3 | 62,080,535 | Abstract Non-pial neocortical astrocytes have historically been thought to comprise largely a nondiverse population of protoplasmic astrocytes. Here we show that astrocytes of the mouse somatosensory cortex manifest layer-specific morphological and molecular differences. Two- and three-dimensional observations revealed... | 10.1038/s41583-020-0264-8 | In this paper, the authors sparsely label astrocytes in the somatosensory cortex using the Slc1a3 -Cre/ERT2 mouse line, and detail the cortical layer-specific morphology and the molecular machinery involved therein |
10.2337/diabetes.50.10.2301 | 108,158,496 | Stimulation of lipolysis and the induction of resistance to insulin’s actions on glucose metabolism are well-recognized effects of growth hormone (GH). To evaluate whether these two features are causally linked, we studied the impact of pharmacologically induced antilipolysis in seven GH-deficient patients (mean [± SE]... | 10.1038/s41574-019-0280-9 | The lipolytic action of GH is responsible for its reduction of insulin sensitivity in human volunteers |
10.1530/joe-18-0282 | 27,972,974 | Growth hormone (GH) has long been known to stimulate lipolysis and insulin resistance; however, the molecular mechanisms underlying these effects are unknown. In the present study, we demonstrate that GH acutely induces lipolysis in cultured adipocytes. This effect is secondary to the reduced expression of a negative r... | 10.1038/s41574-019-0280-9 | In both mice and cell culture models, GH regulates lipolysis and insulin sensitivity employing ERK-dependent and STAT5-dependent mechanisms to control PPARγ-mediated transcription of FSP27 |
10.1152/ajpendo.00129.2018 | 18,757,150 | The lipolytic effects of growth hormone (GH) have been known for half a century and play an important physiological role for substrate metabolism during fasting. In addition, sustained GH-induced lipolysis is causally linked to insulin resistance. However, the underlying molecular mechanisms remain elusive. In the pres... | 10.1038/s41574-019-0280-9 | In human adipocytes, GH regulates lipolysis through ERK-dependent phosphorylation of PPARγ and transcriptional regulation of FSP27 |
10.4049/jimmunol.0902584 | 41,414,938 | Abstract High concentrations of lactic acid (LA) are found under various pathophysiological conditions and are accompanied by an acidification of the environment. To study the impact of LA on TNF secretion, human LPS-stimulated monocytes were cultured with or without LA or the corresponding pH control. TNF secretion wa... | 10.1038/s41577-020-0406-2 | Together with Haas et al. (2015) and Calcinotto et al. (2012), this study demonstrates that high lactic acid production and proton accumulation inhibit the function of immune cells and represent a mechanism of immune escape |
10.31219/osf.io/sba8j | 29,108,887 | Multiple histone post-translational modifications (PTMs) originate from small molecule metabolites (e.g. acetyl-lysine from acetyl-CoA) 1. As such, we read with interest the recent Nature paper from Zhang et al. 2 reporting discovery of lysine lactylation as a novel histone mark originating from the metabolite lactate.... | 10.1038/s41577-020-0406-2 | This study highlights how lactate, in addition to its metabolic functions, can induce epigenetic modifications resulting in increased transcription of homeostatic genes |
10.1158/0008-5472.can-10-2828 | 41,673,068 | Abstract Lactate generated from pyruvate fuels production of intracellular NAD+ as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this stu... | 10.1038/s41577-020-0406-2 | This study shows how lactate released by tumour cells can enter endothelial cells and stimulate angiogenesis and tumour growth |
10.1002/art.39270 | 79,199,979 | Objective Synovial fluid pH is decreased in patients with rheumatoid arthritis (RA); however, the underlying mechanisms are unclear. We undertook this study to examine the mechanism by which synovial fluid pH is regulated and to explore the possibility of a therapeutic strategy by manipulating this mechanism. Methods W... | 10.1038/s41577-020-0406-2 | This study suggests that the lactate transporter MCT4 is a potential therapeutic target for inflammatory arthritis |
10.1126/science.1171242 | 103,724,510 | Slowing Brain Disease with Gene Therapy X-linked adrenoleukodystrophy (ALD), the hereditary brain demyelinating disorder that was featured in the movie “ Lorenzo's Oil ,” is typically treated by transplantation of bone marrow from matched donors. This treatment slows progression of the disease by introducing cells that... | 10.1038/s41591-022-01722-5 | Clinical trial using autologous bone marrow transplantation of genetically corrected cells to treat adrenoleukodystrophy |
10.1038/s41467-018-07548-5 | 81,877,749 | Abstract Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently con... | 10.1038/s41591-022-01722-5 | Study showing bone marrow–derived cells in the human brain after transplantation |
10.1126/science.abj3259 | 83,051,981 | Championing open science, an adversarial collaboration aims to unravel the footprints of consciousness | 10.1038/s41583-022-00587-4 | This work sets out how an adversarial collaboration is planning to arbitrate between integrated information and global workspace ToCs |
10.1126/sciadv.aat7603 | 83,049,721 | Adopting the framework of brain dynamics as a cornerstone of human consciousness, we determined whether dynamic signal coordination provides specific and generalizable patterns pertaining to conscious and unconscious states after brain damage. A dynamic pattern of coordinated and anticoordinated functional magnetic res... | 10.1038/s41583-022-00587-4 | This large empirical study of functional connectivity patterns across different global states of consciousness focuses on how these patterns relate to underlying structural connectivity |
10.1126/science.1057099 | 61,783,007 | Much is known about the pathways from photoreceptors to higher visual areas in the brain. However, how we become aware of what we see or of having seen at all is a problem that has eluded neuroscience. Recordings from macaque V1 during deactivation of MT+/V5 and psychophysical studies of perceptual integration suggest ... | 10.1038/s41583-022-00587-4 | This early study uses transcranial magnetic stimulation to reveal a role for re-entrant activity in conscious visual perception in humans |
10.1126/science.1202043 | 62,166,951 | Discerning the neural correlates of (un)consciousness sheds light on the mechanisms underlying vegetative states. | 10.1038/s41583-022-00587-4 | This neuroimaging study uses dynamic causal modelling to show that loss of consciousness in the vegetative state is associated with impaired top-down connectivity from frontal to temporal cortices |
10.1073/pnas.0607716103 | 103,779,137 | By using a paradigm based on metacontrast masking, we created experimental conditions in which the subjective report of consciousness differs but the objectively measured ability to discriminate visual targets does not. This approach allowed us to study the neural correlate of consciousness while having performance lev... | 10.1038/s41583-022-00587-4 | This empirical study compares conscious and unconscious visual perception in humans, controlling for performance, and reveals differences in prefrontal activation |
10.1126/science.aar7186 | 103,666,942 | Setting conscious perception alight What are the neuronal mechanisms that enable conscious perception? Why do some images remain subliminal? Van Vugt et al. trained monkeys to detect low-contrast images and compared neuronal activity in brain areas V1, V4, and the dorsolateral prefrontal cortex. Some stimuli made it in... | 10.1038/s41583-022-00587-4 | This empirical study tracks the time course of neural signals in primate frontal cortex, showing that perceived stimuli elicit sustained activity, when compared with non-perceived stimuli |
10.1126/scitranslmed.3006294 | 62,268,771 | A theory-derived index of consciousness, which quantifies the complexity of the brain’s response to a stimulus, measures the level of consciousness in awake, sleeping, anesthetized, and brain-damaged subjects. | 10.1038/s41583-022-00587-4 | This empirical study shows that a measure of the complexity of the cortical response to transcranial magnetic stimulation distinguishes between a range of global conscious states, including disorders of consciousness |
10.1373/clinchem.2011.181438 | 103,259,771 | Abstract BACKGROUND Mitochondrial diseases are clinically and genetically heterogeneous, with variable penetrance, expressivity, and differing age of onset. Disease-causing point mutations and large deletions in the mitochondrial genome often exist in a heteroplasmic state. Current molecular analyses require multiple d... | 10.1038/s41582-021-00455-2 | The key paper that established the role of deep NGS of long-range PCR-amplified mtDNA in identifying point mutations and large deletions, including heteroplasmic variants |
10.1038/ncomms15824 | 101,656,948 | Abstract Across a variety of Mendelian disorders, ∼50–75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization ch... | 10.1038/s41582-021-00455-2 | This paper shows that RNA-seq can be used to diagnose mitochondrial diseases and is the first large study to demonstrate the clinical utility of the technique in a rare disease |
10.1101/597187 | 84,352,827 | Abstract Purpose Long-read, third generation, sequencing technologies have the potential to improve current state of the art diagnostic strategies. In order to determine if long-read sequencing technologies are suitable for the diagnosis of mitochondrial disorders due to mitochondrial DNA (mtDNA) variants, particularly... | 10.1038/s41582-021-00455-2 | The first clinical use of nanopore for mtDNA variants; although accuracy problems lead to false-positive point mutations, the technology successfully sequenced the entire genome and identified deletions missed by NGS |
10.1126/science.aay7108 | 103,751,521 | Tethered interactions between the endoplasmic reticulum (ER) and other membrane-bound organelles allow for efficient transfer of ions and/or macromolecules and provide a platform for organelle fission. Here, we describe an unconventional interface between membraneless ribonucleoprotein granules, such as processing bodi... | 10.1038/s41467-022-32940-7 | This paper describes the functional roles of the interactions of processing bodies with the ER membrane |
10.1126/sciadv.abg7653 | 132,846,337 | Sarcomeric proteins FATZ-1 and α-actinin-2 associate in a tight fuzzy complex, which forms phase-separated condensates. | 10.1038/s41467-022-32940-7 | This paper describes the molecular organisation of the scaffold formed by FATZ proteins and provides molecular insights into the changes in biophysical properties during myofibrillogenesis |
10.1126/science.aaz4427 | 125,306,652 | The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplas... | 10.1038/s41467-022-32940-7 | This paper describes a novel therapeutic strategy exploiting condensate partitioning of small molecules |
10.1126/science.abf6548 | 135,444,623 | Tailoring stress responses When faced with environmental stress, cells respond by shutting down cellular processes such as translation and nucleocytoplasmic transport. At the same time, cells preserve cytoplasmic messenger RNAs in structures known as stress granules, and many cellular proteins are modified by the coval... | 10.1038/s41467-022-32940-7 | This paper describes how the cellular context modulates the assembly and disassembly of stress granules through regulating the underlying interaction network |
10.1126/science.aad4017 | 103,696,688 | Taking control of cellular NAD + concentrations Cellular concentrations of the nicotinamide adenine dinucleotide (NAD + ) are critical for proper metabolism and are often altered in aging and disease. To enable better understanding of these processes, Titov et al. altered the concentration of NAD + in particular cellul... | 10.1038/s41589-022-01012-8 | This article reports the use of Lb NOX as a tool for manipulation of NADH/NAD + ratio. The authors use Lb NOX to demonstrate that NA + |
10.1084/jem.192.5.755 | 122,852,683 | Immune surveillance by cytotoxic lymphocytes against cancer has been postulated for decades, but direct evidence for the role of cytotoxic lymphocytes in protecting against spontaneous malignancy has been lacking. As the rejection of many experimental cancers by cytotoxic T lymphocytes and natural killer cells is depen... | 10.1038/s41577-018-0061-z | This publication demonstrates that perforin-mediated tumour cell lysis controls in vivo tumour growth |
10.1126/science.1068440 | 20,822,065 | T cells that accompany allogeneic hematopoietic grafts for treating leukemia enhance engraftment and mediate the graft-versus-leukemia effect. Unfortunately, alloreactive T cells also cause graft-versus-host disease (GVHD). T cell depletion prevents GVHD but increases the risk of graft rejection and leukemic relapse. I... | 10.1038/s41577-018-0061-z | References 37 and 38 describe the occurrence of NK cell alloreactivity against AML blasts after HLA-mismatched transplantation, which occurred without exacerbating graft-versus-host disease |
10.1182/blood-2013-11-536888 | 62,463,070 | Key Points Chemotherapy and radiotherapy deplete ILCs from the blood; ILC reconstitution after allogeneic HSCT is slow. High frequencies of activated ILCs with tissue homing potential before allogeneic HSCT are associated with reduced risk for GVHD. | 10.1038/s41577-018-0061-z | This article suggests that activated ILCs following HSCT can protect against graft-versus-host disease |
10.1038/s41467-017-00678-2 | 41,492,304 | Abstract Group 2 innate lymphoid cells (ILC2s) are involved in human diseases, such as allergy, atopic dermatitis and nasal polyposis, but their function in human cancer remains unclear. Here we show that, in acute promyelocytic leukaemia (APL), ILC2s are increased and hyper-activated through the interaction of CRTH2 a... | 10.1038/s41577-018-0061-z | This article deciphers a new tolerogenic pathway involving interactions between PGD 2 and B7-H6 on tumour cells and CRTH2 and NKp30 on ILC2s, which in turn activate MDSCs via IL-13 secretion, inducing an immunosuppressive microenvironment that facilitates tumour immunoescape |
10.1182/blood-2016-09-692954 | 41,046,047 | Abstract All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes... | 10.1038/s41591-022-02198-z | A comprehensive review focused on how precursor states evolve into clinically evident myeloma. |
10.1038/s41467-019-13603-6 | 38,451,519 | Abstract Short-chain fatty acids (SCFAs) butyrate and propionate are metabolites from dietary fiber's fermentation by gut microbiota that can affect differentiation or functions of T cells, macrophages and dendritic cells. We show here that at low doses these SCFAs directly impact B cell intrinsic functions to moderate... | 10.1038/s41576-021-00421-0 | This study shows that microbiota-produced SCFAs impair intestinal and systemic antibody responses upregulating micro RNAs that target immune genes through inhibition of histone deacetylation. |
10.1126/science.157.3790.810 | 56,818,872 | A new virus-like particle has been found in Drosophila . Thus far it has been detected only in electron micrographs of certain cells capable of division, such as those in larval imaginal disks, cell lines derived from imaginal disks, cells from a genetically controlled brain tumor, and adult gut cells. It appears to be... | 10.1038/s41568-021-00387-5 | This landmark report of fly tumours and tumour suppressor genes includes impacts on transplanted hosts |
10.1126/science.1088474 | 103,909,146 | A genetic screen was designed in Drosophila to interrogate its genome for mutations sufficient to cause noninvasive tumors of the eye disc to invade neighboring or distant tissues. We found that cooperation between oncogenic Ras V12 expression and inactivation of any one of a number of genes affecting cell polarity lea... | 10.1038/s41568-021-00387-5 | This article documents tissue invasion and dispersion by a Ras-stimulated cooperative neoplastic tumour |
10.1242/dev.078261 | 20,601,812 | Inactivating mutations within adenomatous polyposis coli (APC), a negative regulator of Wnt signaling, are responsible for most sporadic and hereditary forms of colorectal cancer (CRC). Here, we use the adult Drosophila midgut as a model system to investigate the molecular events that mediate intestinal hyperplasia fol... | 10.1038/s41568-021-00387-5 | Together with Patel et al. (2015), this paper shows how tumours can induce a damage response from a wild-type stem cell niche to stimulate their growth |
10.1038/srep09061 | 29,103,830 | Abstract Angiogenesis is the term used to describe all the alterations in blood vessel growth induced by a tumour mass following hypoxic stress. The occurrence of multiple strategies of vessel recruitment favours drug resistance, greatly complicating the treatment of certain tumours. In Drosophila , oxygen is conveyed ... | 10.1038/s41568-021-00387-5 | This paper describes the host tracheal response to fly tumours, and vascular mimicry of fly tumour cells |
10.1242/dmm.000950 | 40,094,243 | SUMMARY Studies in mice and humans have demonstrated a role for the immune system in preventing the growth of tumors. Deciphering the mechanisms involved in the immune response to tumors is essential to our understanding of immune recognition and cancer progression. Here we report an innate immune response to tumors in... | 10.1038/s41568-021-00387-5 | This paper is a pioneering study of innate immune response to fly tumours |
10.1038/s41467-019-10269-y | 104,391,451 | Abstract Metastasis underlies the majority of cancer-related deaths yet remains poorly understood due, in part, to the lack of models in vivo. Here we show that expression of the EMT master inducer Snail in primary adult Drosophila intestinal tumors leads to the dissemination of tumor cells and formation of macrometast... | 10.1038/s41568-021-00387-5 | This paper is the most clear documentation to date of metastatic-like behaviour of fly tumour cells |
10.1534/genetics.107.078360 | 103,909,411 | Abstract The Drosophila neoplastic tumor suppressor genes (TSGs) coordinately control cell polarity and proliferation in epithelial and neuronal tissues. While a small group of neoplastic TSG mutations have been isolated and their corresponding genes cloned, the regulatory pathways that normally prevent inappropriate g... | 10.1038/s41568-021-00387-5 | This paper is an early demonstration that diverse fly tumours are sufficient to non-autonomously induce systemic defects in host maturation |
10.1126/science.1216689 | 107,255,530 | Small But Perfectly Formed The imaginal discs of Drosophila represent defined larval tissues that give rise to the subsequent adult appendages. These tissues regenerate in response to damage. When the imaginal discs are injured or show tumor growth, they signal to the rest of the larval animal to slow down growth and d... | 10.1038/s41568-021-00387-5 | Together with Garelli et al. (2012), this paper identifies a signal from growing organs, damaged tissues and tumours that acts on the fly brain to prevent pupation |
10.1038/s41598-020-61878-3 | 58,878,555 | Abstract Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on the HIV reservoir. HIV+, stably treated participants in whom resting CD4 + T cell-associated HIV RNA (rc... | 10.1038/s41577-021-00649-1 | Combined treatment with vorinostat and AGS-004 resulted in decreased levels of cell-associated HIV-1 RNA but no substantial impact on the replication-competent viral reservoir and no increase in HIV-1-specific immune responses |
10.1039/c4ee01303d | 20,622,157 | A detailed perspective on the use of anion-exchange membranes in fuel cells, electrolysers, flow batteries, reverse electrodialysis, and bioelectrochemical systems. | 10.1038/s41467-018-06475-9 | An important review to summarize the development of polyelectrolyte membranes for electrochemical systems |
10.1073/pnas.1821672117 | 62,062,784 | Energy storage is an integral part of modern society. A contemporary example is the lithium (Li)-ion battery, which enabled the launch of the personal electronics revolution in 1991 and the first commercial electric vehicles in 2010. Most recently, Li-ion batteries have expanded into the electricity grid to firm variab... | 10.1038/s41560-020-00759-5 | This work draws from a historical perspective the current challenges in energy storage in a broader context |
10.1126/science.aaz7681 | 83,482,109 | Ceramics are an important class of materials with widespread applications because of their high thermal, mechanical, and chemical stability. Computational predictions based on first principles methods can be a valuable tool in accelerating materials discovery to develop improved ceramics. It is essential to experimenta... | 10.1038/s41560-020-00759-5 | This work provides insights of a novel methodology to sinter bulk ceramics at ultrahigh temperature during very short times succesfully |
10.1002/ente.201901237 | 103,585,334 | All‐solid‐state batteries (ASSB) are promising candidates for future energy storage. However, only a little is known about the manufacturing costs for industrial production. Herein, a detailed bottom‐up calculation is performed to estimate the required investment and to facilitate comparison with conventional lithium‐i... | 10.1038/s41560-020-00759-5 | This work provides in-depth cost estimations of various SSB cell designs through a detailed model of the full production chain, providing hints about the need to decrease production cost to achieve competitive SSB products |
10.1126/science.1120541 | 107,186,527 | Kaposi's sarcoma–associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) mediates viral genome attachment to mitotic chromosomes. We find that N-terminal LANA docks onto chromosomes by binding nucleosomes through the folded region of histones H2A-H2B. The same LANA residues were required for both H2A-H2... | 10.1038/s41594-018-0166-x | First crystal structure of a chromatin-binding factor in complex with the nucleosome |
10.1186/1745-6150-4-29 | 40,087,649 | Abstract Background In eukaryotes, RNA interference (RNAi) is a major mechanism of defense against viruses and transposable elements as well of regulating translation of endogenous mRNAs. The RNAi systems recognize the target RNA molecules via small guide RNAs that are completely or partially complementary to a region ... | 10.1038/s41467-018-07449-7 | The hypothesis is presented that pAgos are components of a novel prokaryotic immune system that targets foreign nucleic acids |
10.1073/pnas.1321032111 | 60,130,941 | Significance We have solved crystal structures of ternary Thermus thermophilus Argonaute (Ago) complexes with guide and target DNA in cleavage-incompatible, cleavage-compatible, and postcleavage states in the 2.2- to 2.3-Å resolution range, thereby identifying the relative positions of catalytic residues, a pair of Mg ... | 10.1038/s41467-018-07449-7 | This study describes structural transitions in the active site of TtAgo during interactions with its native substrates, guide DNA and target DNA, illuminating the closure of the active site, catalytic metal binding and target cleavage |
10.1038/ncomms11846 | 19,841,563 | Abstract Argonaute proteins are key players in the gene silencing mechanisms mediated by small nucleic acids in all domains of life from bacteria to eukaryotes. However, little is known about the Argonaute protein that recognizes guide RNA/target DNA. Here, we determine the 2 Å crystal structure of Rhodobacter sphaeroi... | 10.1038/s41467-018-07449-7 | The first structure of an inactive long pAgo (RsAgo), accompanied by functional analysis of mutations in its structural elements involved in guide and target interactions |
10.1146/annurev-nucl-102014-022120 | 103,738,416 | Four decades after its prediction, the axion remains the most compelling solution to the strong-CP problem and a well-motivated dark matter candidate, inspiring a host of elegant and ultrasensitive experiments based on axion–photon mixing. This article reviews the experimental situation on several fronts. The microwave... | 10.1038/s41586-018-0542-z | A comprehensive review of present and upcoming experimental searches for axions and axion-like particles |
10.1101/gr.165845.113 | 61,435,174 | Microbiota regulate intestinal physiology by modifying host gene expression along the length of the intestine, but the underlying regulatory mechanisms remain unresolved. Transcriptional specificity occurs through interactions between transcription factors (TFs) and cis -regulatory regions (CRRs) characterized by nucle... | 10.1038/s41575-020-00357-6 | This paper demonstrates that microbial colonization did not lead to major changes in chromatin accessibility and that transcription factor binding, including by nuclear receptors, is likely to mediate much of the transcriptional response to the microbiota |
10.1101/gad.318832.118 | 80,610,367 | After acquiring competence for selected cell fates, embryonic primordia may remain plastic for variable periods before tissue identity is irrevocably determined (commitment). We investigated the chromatin basis for these developmental milestones in mouse endoderm, a tissue with recognizable rostro–caudal patterning and... | 10.1038/s41575-020-00357-6 | This paper defines developmentally important enhancers and defines a developmental window during which Cdx2 activity is critical for establishing regional identities of the intestinal epithelium |
10.1038/s41467-018-03766-z | 20,363,040 | Abstract Inflammatory bowel disease (IBD) is a chronic intestinal disorder, with two main types: Crohn’s disease (CD) and ulcerative colitis (UC), whose molecular pathology is not well understood. The majority of IBD-associated SNPs are located in non-coding regions and are hard to characterize since regulatory regions... | 10.1038/s41575-020-00357-6 | This paper identifies non-coding promoter and enhancer regions, and the SNPs and transcription factor binding sites they contain, that are common and distinct among patients with ulcerative colitis, Crohn’s disease and controls |
10.1136/gutjnl-2016-312518 | 41,579,008 | Objective The clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes. Design We examined both gene expression and gene regu... | 10.1038/s41575-020-00357-6 | This paper finds two distinct transcriptional patterns in patients with Crohn’s disease that suggest molecular subtyping based on region-specific similarities to either normal ileal or colonic tissue |
10.1101/gad.230318.113 | 39,139,107 | The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3–5 d throughout adult life. Disrupted maintenance of the intricate balance of proliferation and dif... | 10.1038/s41575-020-00357-6 | This is the first study to show that DNA methylation machinery is required for control of differentiation and proliferative processes along the crypt–villus axis of the mouse intestine, and reveals transcription factor binding sites that are enriched in differentially methylated regions in Dnmt1 mutants |
10.1136/gutjnl-2017-314817 | 107,194,439 | Objective Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited. Design We performed genome-wide DNA methylation and transcriptomi... | 10.1038/s41575-020-00357-6 | First study exploring the segment and development-specific DNA methylation and transcriptomic differences in human terminal ileum and sigmoid colon |
10.1186/s13073-018-0534-5 | 40,515,379 | Abstract Background The interplay of epigenetic processes and the intestinal microbiota may play an important role in intestinal development and homeostasis. Previous studies have established that the microbiota regulates a large proportion of the intestinal epithelial transcriptome in the adult host, but microbial eff... | 10.1038/s41575-020-00357-6 | This study reveals information about the contribution of an antibiotic treatment (and thus changes in microbiota composition) in pigs on DNA methylation, protein expression and physiology in the small intestine |
10.1101/gr.220111.116 | 39,605,504 | Microbiota influence diverse aspects of intestinal physiology and disease in part by controlling tissue-specific transcription of host genes. However, host genomic mechanisms mediating microbial control of intestinal gene expression are poorly understood. Hepatocyte nuclear factor 4 (HNF4) is the most ancient family of... | 10.1038/s41575-020-00357-6 | This study identifies microbially responsive regulatory regions genome wide and establishes the involvement of Hnf4a in regulating microbially responsive genes in the mouse and zebrafish intestine |
10.1242/dev.179432 | 101,017,429 | As embryos mature, cells undergo remarkable transitions, accompanied by shifts in transcription factor regulatory networks. Mechanisms driving developmental transitions are incompletely understood. The embryonic intestine transitions from a rapidly proliferating tube with pseudostratified epithelium (prior to murine em... | 10.1038/s41575-020-00357-6 | This is the first study to determine the genetic redundancy between Hnf4a and Hnf4g transcription factors during mouse intestinal development |
10.1136/gutjnl-2015-310283 | 29,343,527 | Objective The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investi... | 10.1038/s41575-020-00357-6 | This study investigated the interaction between diet, the microbiota and FXR signalling, and shows that FXR is required for high-fat diet to induce weight gain and that the effects might be due to differences in the microbiota observed in Fxr −/− mice |
10.1002/adfm.201102138 | 101,639,856 | Abstract The application of 1 H spin diffusion nuclear magnetic resonance (NMR) is expanded to polymer‐fullerene blends for bulk heterojunction (BHJ) organic photovoltaics (OPV) by developing a new experimental methodology for measuring the thin films used in poly‐3‐hexylthiophene–phenyl C61‐butyric acid methyl ester (... | 10.1038/s41578-020-00232-5 | ssNMR 1 H spin-diffusion measurements and analyses show that the presence of a significant population of domains of tens of nanometres in size is a common feature of high-performance OPV BHJ photoactive layers |
10.1002/adma.201903868 | 41,693,263 | Abstract The highly efficient single‐junction bulk‐heterojunction (BHJ) PM6:Y6 system can achieve high open‐circuit voltages ( V OC ) while maintaining exceptional fill‐factor (FF) and short‐circuit current ( J SC ) values. With a low energetic offset, the blend system is found to exhibit radiative and non‐radiative re... | 10.1038/s41578-020-00232-5 | This study demonstrates how multiple techniques, including ssNMR spectroscopic characterization of donor–acceptor interfaces and device physics, are used to establish structure–property relationships of a high-performance BHJ blend |
10.1016/j.trci.2015.07.001 | 29,293,586 | Abstract Introduction This study examined whether, among subjects with mild cognitive impairment (MCI), women progressed at faster rates than men. Methods We examine longitudinal rates of change from baseline in 398 MCI subjects (141 females and 257 males) in the Alzheimer's Disease Neuroimaging Initiative‐1, followed ... | 10.1038/s41582-018-0032-9 | This article provides strong evidence from the ADNI cohort of faster cognitive decline in women with MCI than in men with MCI. |
10.1111/j.1532-5415.2006.00854.x | 124,995,554 | OBJECTIVES: To investigate behavioral components of Alzheimer's disease (AD) and to analyze behavioral components in relation to disease severity, apolipoprotein E genotype (APOE), sex, years of education, age at onset, and cognitive impairment. DESIGN: Cross‐sectional study. SETTING: Data were collected from community... | 10.1038/s41582-018-0032-9 | This paper presents the largest study available documenting sex differences in psychiatric symptoms of AD. |
10.1016/j.molonc.2014.06.001 | 104,092,489 | The NTRK1 gene encodes Tropomyosin‐related kinase A (TRKA), the high‐affinity Nerve Growth Factor Receptor. NTRK1 was originally isolated from a colorectal carcinoma (CRC) sample as component of a somatic rearrangement (TPM3‐NTRK1) resulting in expression of the oncogenic chimeric protein TPM3‐TRKA, but there has been ... | 10.1038/s41571-021-00495-z | The first report of the sensitivity of NTRK fusion-positive CRC to TRKA inhibition. |
10.1126/science.aar2955 | 80,108,356 | Biomaterials can promote endogenous healing without delivering cells or therapeutics | 10.1038/s41551-022-00983-2 | A perspective that discusses the use of acellular biomaterials for tissue repair and regeneration |
10.1126/scitranslmed.3005503 | 81,903,187 | A hydrogel derived from myocardial extracellular matrix mitigates negative left ventricular remodeling and improves heart function after myocardial infarction in pigs. | 10.1038/s41551-022-00983-2 | A study showing the efficacy of an ECM hydrogel in a porcine MI model. |
10.1038/s41385-020-00336-9 | 59,781,386 | Abstract In addition to their well characterized role in mediating IgE-dependent allergic diseases, aberrant accumulation and activation of mast cells (MCs) is associated with many non-allergic inflammatory diseases, whereby their activation is likely triggered by non-IgE stimuli (e.g., IL-33). Siglec-8 is an inhibitor... | 10.1038/s41577-021-00622-y | This study demonstrates the ability of anti-Siglec-8 antibody to diminish airway inflammation and IgE-independent mast cell activation |
10.1073/pnas.76.11.5818 | 122,221,221 | Use of the specific-locus test to measure the frequency of transmitted gene mutations induced in mouse spermatogonia has shown ethylnitrosourea to be by far the most potent mutagen yet discovered in the mouse. The dose used, 250 mg/kg, gave a mutation rate 5 times as high as had been obtained with 600 R, the most effec... | 10.1038/s41576-018-0005-2 | This is a key publication describing the use of ENU to efficiently induce point mutations in mice and facilitate broad-based forward genetic screens. |
10.1152/physiolgenomics.90207.2008 | 60,475,562 | Establishing standard operating procedures (SOPs) as tools for the analysis of behavioral phenotypes is fundamental to mouse functional genomics. It is essential that the tests designed provide reliable measures of the process under investigation but most importantly that these are reproducible across both time and lab... | 10.1038/s41576-018-0005-2 | This study highlights the importance of cross-centre standardization and validation of phenotyping platforms. |
10.1038/ncomms12444 | 38,301,062 | Abstract Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutati... | 10.1038/s41576-018-0005-2 | Ageing and recurrent broad-based screening of mutants from large-scale mutagenesis programmes reveals novel gene functions underlying age-related disease. |
10.1038/ncomms15475 | 125,260,545 | Abstract The role of sex in biomedical studies has often been overlooked, despite evidence of sexually dimorphic effects in some biological studies. Here, we used high-throughput phenotype data from 14,250 wildtype and 40,192 mutant mice (representing 2,186 knockout lines), analysed for up to 234 traits, and found a la... | 10.1038/s41576-018-0005-2 | In this large study involving over 50,000 mice, the authors demonstrate that differences exist between male and female mice in the majority of phenotypic screens employed by the IMPC. |
10.1038/sdata.2017.113 | 125,183,109 | Abstract The latest project from the FANTOM consortium, an international collaborative effort initiated by RIKEN, generated atlases of transcriptomes, in particular promoters, transcribed enhancers, and long-noncoding RNAs, across a diverse set of mammalian cell types. Here, we introduce the FANTOM5 collection, bringin... | 10.1038/s41576-018-0005-2 | This paper reviews the wide impact the fifth iteration of the RIKEN-led FANTOM consortium has had on understanding cell function by the generation of a comprehensive cellular transcription atlas. |
10.1101/gr.160325.113 | 82,907,295 | Numerous new disease-gene associations have been identified by whole-exome sequencing studies in the last few years. However, many cases remain unsolved due to the sheer number of candidate variants remaining after common filtering strategies such as removing low quality and common variants and those deemed unlikely to... | 10.1038/s41576-018-0005-2 | This is an important algorithmic approach that uses genotype-to-phenotype data from model organism studies to assess the potential impact of exome variants identified in sequencing from patients with a rare disease. |
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/s41587-023-01665-3 | This paper reports the toxic side effects of Cas13’s trans -cleavage when used for RNA knockdown in eukaryotic cells. |
10.1073/pnas.1210147109 | 58,629,825 | Microscopic polyangiitis is an autoimmune small-vessel vasculitis that often manifests as focal and necrotizing glomerulonephritis and renal failure. Antineutrophil cytoplasmic Abs (ANCAs) specific for myeloperoxidase (MPO) play a role in this disease, but the role of autoreactive MPO-specific CD4 + T cells is uncertai... | 10.1038/s41572-020-0204-y | This study uses experimental models to demonstrate the role of MPO-specific CD4 + T cells in effector responses and defines a nephritogenic MPO T cell epitope |
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