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10.1200/jco.2017.35.15_suppl.103 | 95,620,043 | 103 Background: CD19-targeted CAR T cells show CR rates of 70-95% in B-ALL. Yet a subset of patients do not respond or relapse due to poor CAR T cell expansion and persistence. We hypothesized that PD-1 checkpoint pathway inhibition may improve CAR T cell expansion, function and persistence. Methods: Four children with... | 10.1038/s41577-021-00539-6 | This is one of the first studies demonstrating increased CAR T cell persistence following anti-PD1 therapy in patients with acute lymphocytic leukaemia |
10.1186/s13100-020-00214-y | 55,397,685 | Abstract Background V(D) J recombination is essential for adaptive immunity in jawed vertebrates and is initiated by the RAG1-RAG2 endonuclease. The RAG1 and RAG2 genes are thought to have evolved from a RAGL (RAG-like) transposon containing convergently-oriented RAG1-like ( RAG1L ) and RAG2-like (RAG2L) genes. Element... | 10.1038/s41577-021-00628-6 | This paper identifies RAG1L – RAG2L gene pairs and RAGL transposons in the genomes of protostomes and a cnidarian, providing evidence that the RAGL transposon arose earlier and spread more widely in evolution than previously thought |
10.1073/pnas.0509720103 | 16,671,453 | The diversity of antigen receptors in the adaptive immune system of jawed vertebrates is generated by a unique process of somatic gene rearrangement known as V(D)J recombination. The Rag1 and Rag2 proteins are the key mediators of this process. They are encoded by a compact gene cluster that has exclusively been identi... | 10.1038/s41577-021-00628-6 | This paper is the first to report a RAG1L–RAG2L gene pair in any organism other than a jawed vertebrate (in this case, the purple sea urchin S. purpuratus ), providing evidence for an early evolutionary origin for the RAG recombinase |
10.1038/s41467-022-32018-4 | 130,040,391 | Abstract Tropical cyclones (TCs) have caused extensive power outages. The impacts of TC-caused blackouts may worsen in the future as TCs and heatwaves intensify. Here we couple TC and heatwave projections and power outage and recovery process analysis to investigate how TC-blackout-heatwave compound hazard risk may var... | 10.1038/s41558-023-01596-6 | This paper presents a framework for modelling hurricane–blackout–heatwave compound hazards. |
10.1126/science.aat7554 | 125,142,286 | The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets ex... | 10.1038/s41590-021-00994-2 | This study unraveled the complexity of the CNS myeloid landscape, and the dynamics of several myeloid populations by single-cell RNA sequencing |
10.1126/sciimmunol.abb8786 | 81,085,205 | T cells provide critical immune surveillance to the central nervous system (CNS), and the cerebrospinal fluid (CSF) is thought to be a main route for their entry. Further characterization of the state of T cells in the CSF in healthy individuals is important for understanding how T cells provide protective immune surve... | 10.1038/s41590-021-00994-2 | This study provides insight into the T cell landscape in the CNS compartments |
10.1038/s41467-019-08352-5 | 104,353,972 | Abstract Alzheimer’s disease (AD) is a heterogeneous disorder with multiple etiologies. Harnessing the immune system by blocking the programmed cell death receptor (PD)-1 pathway in an amyloid beta mouse model was shown to evoke a sequence of immune responses that lead to disease modification. Here, blocking PD-L1, a P... | 10.1038/s41590-021-00994-2 | This study demonstrates the pivotal part that MDMs , via MSR1, play in protecting the brain in a model of tauopathy |
10.1126/science.1244917 | 83,452,688 | Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecula... | 10.1038/s41586-020-2168-1 | These three papers 27–29 report the discovery of a suprising mechanism of action for one of the best-selling drugs in the world; similar to auxin, lenalidomide stabilizes an interaction between a substrate (IKZF1 and/or IKZF3) and an ubiquitin ligase (CRBN), resulting in ubiquitination and degradation of the IKZF prote... |
10.1126/science.1177319 | 125,224,198 | Thalidomide Teratogenicity Target In the late 1950s and early 1960s, thalidomide was prescribed to pregnant women as a cure for morning sickness, but it was then found to have developmental defects, most obviously, stunted limbs in thousands of babies. Although its use was banned worldwide, thalidomide has since been f... | 10.1038/s41586-020-2168-1 | This seminal paper set in motion the series of discoveries that culminated in the unravelling of the unusual mechanism of action of lenalidomide |
10.1073/pnas.141230798 | 125,178,091 | The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF c... | 10.1038/s41586-020-2168-1 | This work provided the first demonstration that it is possible to specify the degradation of a defined target by inducing its proximity to an ubiquitin ligase using a synthetic molecule |
10.1073/pnas.83.5.1453 | 21,960,339 | Previous studies have shown that heteroconjugates of monoclonal antibodies in which one of the component antibodies is directed at the T-cell receptor and the other is directed against any chosen site can focus effector T cells to function at the targeted site. We report here the production of a hybrid hybridoma cell l... | 10.1038/s41586-020-2168-1 | These two papers 54,55 launched the field of bispecific CD3 engagers for use in cancer immunotherapy |
10.1126/science.1158545 | 100,627,332 | Previous attempts have shown the potential of T cells in immunotherapy of cancer. Here, we report on the clinical activity of a bispecific antibody construct called blinatumomab, which has the potential to engage all cytotoxic T cells in patients for lysis of cancer cells. Doses as low as 0.005 milligrams per square me... | 10.1038/s41586-020-2168-1 | More than 20 years after research on bispecific CD3 engagers began, this paper provided the first compelling demonstration of the tremendous clinical potential of this class of bispecific molecules |
10.1126/scitranslmed.aax8861 | 82,963,874 | T cell–retargeting therapies have transformed the therapeutic landscape of oncology. Regardless of the modality, T cell activating therapies are commonly accompanied by systemic cytokine release, which can progress to deadly cytokine release syndrome (CRS). Because of incomplete mechanistic understanding of the relatio... | 10.1038/s41586-020-2168-1 | These authors report that it is possible to uncouple cytokine release from the anti-tumour activity of BCEs, which could lead to an enhanced therapeutic index for BCEs |
10.1152/japplphysiol.01063.2003 | 62,046,232 | The hand is one of the most fascinating and sophisticated biological motor systems. The complex biomechanical and neural architecture of the hand poses challenging questions for understanding the control strategies that underlie the coordination of finger movements and forces required for a wide variety of behavioral t... | 10.1038/s41583-021-00528-7 | This is a review of the factors that constrain manual behaviour |
10.1152/jn.2000.83.3.1469 | 109,418,123 | Human fingers have sufficiently more muscles than joints such that every fingertip force of submaximal magnitude can be produced by an infinite number of muscle coordination patterns. Nevertheless, the nervous system seems to effortlessly select muscle coordination patterns when sequentially producing fingertip forces ... | 10.1038/s41583-021-00528-7 | This study shows that the patterns of muscle activations that drive fingertip forces are consistent across force levels |
10.1146/annurev-neuro-070918-050216 | 29,088,734 | What changes in neural architecture account for the emergence and expansion of dexterity in primates? Dexterity, or skill in performing motor tasks, depends on the ability to generate highly fractionated patterns of muscle activity. It also involves the spatiotemporal coordination of activity in proximal and distal mus... | 10.1038/s41583-021-00528-7 | This is a neuroanatomically focused review of cortical motor areas |
10.1146/annurev-neuro-070918-050436 | 82,983,547 | Hand dexterity has uniquely developed in higher primates and is thought to rely on the direct corticomotoneuronal (CM) pathway. Recent studies have shown that rodents and carnivores lack the direct CM pathway but can control certain levels of dexterous hand movements through various indirect CM pathways. Some homologou... | 10.1038/s41583-021-00528-7 | This is a review of neural pathways mediating recovery after injury to the CNS |
10.1073/pnas.0808362106 | 19,178,867 | We used retrograde transneuronal transport of rabies virus from single muscles of rhesus monkeys to identify cortico-motoneuronal (CM) cells in the primary motor cortex (M1) that make monosynaptic connections with motoneurons innervating shoulder, elbow, and finger muscles. We found that M1 has 2 subdivisions. A rostra... | 10.1038/s41583-021-00528-7 | This study describes the differences between ‘old’ (rostral) and ‘new’ (caudal) M1, delineated on the basis of the absence or presence of CM cells |
10.1146/annurev-neuro-070815-013913 | 59,033,593 | Human studies in the past three decades have provided us with an emerging understanding of how cortical and spinal networks collaborate to ensure the vast repertoire of human behaviors. Humans have direct cortical connections to spinal motoneurons, which bypass spinal interneurons and exert a direct (willful) muscle co... | 10.1038/s41583-021-00528-7 | This is a review of the role of spinal and supraspinal reflexes in the control of movement |
10.1152/jn.1975.38.4.871 | 80,013,424 | Experiments were made on the posterior parietal association cortical areas 5 and in 17 hemispheres of 11 monkeys, 6 M. mulatta and 5 M. arctoides. The electrical signs of the activity of single cortical cells were recorded with microelectrodes in waking animals as they carried out certain behavioral acts in response to... | 10.1038/s41583-021-00528-7 | This is a classic study of the role of the PPC in reaching |
10.7554/elife.15278 | 20,662,066 | Grasping requires translating object geometries into appropriate hand shapes. How the brain computes these transformations is currently unclear. We investigated three key areas of the macaque cortical grasping circuit with microelectrode arrays and found cooperative but anatomically separated visual and motor processes... | 10.1038/s41583-021-00528-7 | This study shows interplay between different regions of the parietal and frontal lobes during reach and grasp |
10.1113/jphysiol.1979.sp012619 | 20,621,018 | 1. Single unit impulses were recorded with percutaneously inserted tungsten needle electrodes from the median nerve in conscious human subjects. 2. A sample of 334 low threshold mechanoreceptive units innervating the glabrous skin area of the hand were studied. In accordance with earlier investigations, the units were ... | 10.1038/s41583-021-00528-7 | This article provides a classic description of the tactile sensors in the human hand |
10.1002/cphy.c100086 | 39,230,714 | Abstract Animal movement is immensely varied, from the simplest reflexive responses to the most complex, dexterous voluntary tasks. Here, we focus on the control of movement in mammals, including humans. First, the sensory inputs most closely implicated in controlling movement are reviewed, with a focus on somatosensor... | 10.1038/s41583-021-00528-7 | This article describes the proprioceptive mechanisms that support motor control |
10.1113/jphysiol.2011.215236 | 62,651,838 | Abstract Motor units serve both as the mechanical apparatus and the final stage of neural processing through which motor behaviours are enacted. Therefore, knowledge about the contractile properties and organization of the neural inputs to motor units supplying finger muscles is essential for understanding the control ... | 10.1038/s41583-021-00528-7 | This is a review of motor unit organization in human hand muscles |
10.1002/cne.902410405 | 67,621,402 | Abstract Area 2 is a traditional architectonic subdivision of anterior parietal cortex in macaque monkeys, but its overall somatotopic organization and responsiveness to different types of somatic stimuli are poorly understood, and there are uncertainties concerning its rostral and caudal extent. The goals of the prese... | 10.1038/s41583-021-00528-7 | The article describes the body maps in the somatosensory cortex |
10.1073/pnas.1305509110 | 105,302,995 | Significance Our exquisite tactile sensitivity to surface texture allows us to distinguish silk from satin or even good silk from cheap silk. We show that the tactile perception of natural textures relies on two neural mechanisms. Coarse textural features, for example, the individual elements of Braille, are represente... | 10.1038/s41583-021-00528-7 | This study shows that texture signals are conveyed by three populations of nerve fibres using two different neural codes |
10.1126/science.abd0380 | 107,147,897 | Prosthetic arms controlled by a brain-computer interface can enable people with tetraplegia to perform functional movements. However, vision provides limited feedback because information about grasping objects is best relayed through tactile feedback. We supplemented vision with tactile percepts evoked using a bidirect... | 10.1038/s41583-021-00528-7 | This study shows that robotic arm control is improved when tactile feedback is conveyed via intracortical microstimulation |
10.1126/science.aat8407 | 83,479,843 | The pathologic accumulation and aggregation of α-synuclein (α-syn) underlies Parkinson’s disease (PD). The molecular mechanisms by which pathologic α-syn causes neurodegeneration in PD are not known. Here, we found that pathologic α-syn activates poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase-1 (PARP-1), and PA... | 10.1038/s41589-020-00708-z | This article demonstrates the important role of poly(ADP-ribose) as an endogenous cofactor of α-synuclein to regulate its aggregation and pathology in cells |
10.1073/pnas.1922741117 | 83,517,154 | Posttranslational modifications (PTMs) of α-synuclein (α-syn), e.g., phosphorylation, play an important role in modulating α-syn pathology in Parkinson’s disease (PD) and α-synucleinopathies. Accumulation of phosphorylated α-syn fibrils in Lewy bodies and Lewy neurites is the histological hallmark of these diseases. Ho... | 10.1038/s41589-020-00708-z | This study reveals the structural basis of how a disease-associated phosphorylation induces the formation of a new fibril structure of α-synuclein with enhanced stability and neurotoxicity |
10.1073/pnas.1808845116 | 20,409,713 | A compelling link is emerging between the posttranslational modification O-GlcNAc and protein aggregation. A prime example is α-synuclein, which forms toxic aggregates that are associated with neurodegeneration in Parkinson’s and related diseases. α-Synuclein has been shown to be O-GlcNAcylated at nine different positi... | 10.1038/s41589-020-00708-z | This study highlights that GlcNAcylation at different sites of α-synuclein exhibits distinctive effects on α-synuclein aggregation and toxicity |
10.1084/jem.20172020 | 62,078,902 | To understand how infection by Mycobacterium tuberculosis (Mtb) is modulated by host cell phenotype, we characterized those host phagocytes that controlled or supported bacterial growth during early infection, focusing on the ontologically distinct alveolar macrophage (AM) and interstitial macrophage (IM) lineages. Usi... | 10.1038/s41579-022-00763-4 | This study demonstrates that macrophage populations have differential abilities to restrict M. tuberculosis growth during in vivo infection |
10.1038/s41590-021-01066-1 | 128,117,076 | Abstract Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis ( Mtb ). Intravenous (i.v.) vaccination with Bacille Calmette–Guérin (BCG) provides nearly complete protection against TB in rhesus macaques, bu... | 10.1038/s41579-022-00763-4 | This article suggests that intravenous BCG mediates protection against M. tuberculosis through humoral immunity, with IgM titres correlating with reduced bacterial burden |
10.4049/jimmunol.1301236 | 38,306,752 | Abstract Effector T cells control intracellular infection by secreting cytokines and through contact-dependent cytolysis. Because cytokines can diffuse and act at a distance, we determined whether cytokine diffusion is sufficient to control Mycobacterium tuberculosis or whether direct recognition of infected cells by C... | 10.1038/s41579-022-00763-4 | This study illustrates the requirement for direct contact between infected macrophages and M. tuberculosis -specific CD4 + T cells for their effector functions |
10.1073/pnas.1711373114 | 20,388,646 | Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. t... | 10.1038/s41579-022-00763-4 | This study reports that host tryptophan metabolites generated by indoleamine 2,3-dioxygenase contribute to the immunosuppressive role of granulomas; by inhibiting indoleamine 2,3-dioxygenase, it is possible to alter granuloma architecture and enhance immune control of M. tuberculosis in NHPs |
10.1038/s41586-019-1817-8 | 20,601,686 | Abstract Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide 1 . The only available vaccine, BCG (Bacillus Calmette–Guérin), is given intradermally and has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission 1,2 . Here we show that ... | 10.1038/s41579-022-00763-4 | This study explores the association between BCG vaccine efficacy and the route of administration, finding that intravenous BCG administration elicits unprecedented protection against M. tuberculosis infection |
10.1126/science.1162228 | 41,536,477 | RNA polymerases are highly regulated molecular machines. We present a method (global run-on sequencing, GRO-seq) that maps the position, amount, and orientation of transcriptionally engaged RNA polymerases genome-wide. In this method, nuclear run-on RNA molecules are subjected to large-scale parallel sequencing and map... | 10.1038/s41580-018-0028-8 | References 33–35 report widespread antisense transcription from gene promoters giving rise to short unstable upstream antisense RNAs. |
10.1101/gad.308619.117 | 123,634,009 | Gene expression is regulated by promoters, which initiate transcription, and enhancers, which control their temporal and spatial activity. However, the discovery that mammalian enhancers also initiate transcription questions the inherent differences between enhancers and promoters. Here, we investigate the transcriptio... | 10.1038/s41580-018-0028-8 | This work introduces a functional assay to simultaneously measure enhancer and promoter activity of candidate fragments and shows that core-promoter motifs confer promoter functionality to enhancers. |
10.1101/gad.245662.114 | 41,369,175 | The TCT core promoter element is present in most ribosomal protein (RP) genes in Drosophila and humans. Here we show that TBP (TATA box-binding protein)-related factor TRF2, but not TBP, is required for transcription of the TCT-dependent RP genes. In cells, TCT-dependent transcription, but not TATA-dependent transcript... | 10.1038/s41580-018-0028-8 | References 133 and 134 reveal that TRF2 replaces TBP within the PIC to drive transcription of a specific subset of genes. |
10.7554/elife.29736 | 62,625,684 | Gene transcription can be activated by decreasing the duration of RNA polymerase II pausing in the promoter-proximal region, but how this is achieved remains unclear. Here we use a ‘multi-omics’ approach to demonstrate that the duration of polymerase pausing generally limits the productive frequency of transcription in... | 10.1038/s41580-018-0028-8 | References 151–153 report a wide-range of paused Pol II half-lives at promoters genome-wide. |
10.1126/science.aan3269 | 103,309,131 | Multitalented enhancers Productive transcription from DNA demands initiation, elongation, and termination. Enhancers are DNA sequences that loop with promoters to initiate transcription. Chen et al. show that enhancers also regulate gene expression by modulating transcription elongation. PAF1, a RNA polymerase II–assoc... | 10.1038/s41580-018-0028-8 | References 159 and 160 report widespread pausing of Pol II at enhancers. |
10.1126/science.aao2793 | 20,623,426 | Profiling transcription—a SLAM dunk Identification of the direct target genes of transcription factors could shed light on how healthy cells become malignant. Muhar et al. applied a modified version of a transcript-mapping method called SLAM-seq to identify the target genes of two transcriptional regulators of major in... | 10.1038/s41580-018-0028-8 | References 187 and 188 demonstrate that BRD proteins, in particular BRD4, are globally required for transition into productive elongation in a manner that is independent of CDK9 recruitment. |
10.1101/gad.924301 | 19,698,088 | To investigate the basis for enhancer–promoter specificity, we compared the ability of enhancers to activate transcription in vivo from core promoters containing either downstream promoter element (DPE) or TATA box motifs. To eliminate position effects, we generated and analyzed pairs of sister Drosophila lines that co... | 10.1038/s41580-018-0028-8 | This work demonstrates that TATA-box-containing and DPE-containing core promoters can be differentially activated when integrated into the same genomic locus. |
10.7554/elife.28447 | 123,574,070 | The Mediator complex has been described as a general transcription factor, but it is unclear if it is essential for Pol II transcription and/or is a required component of the preinitiation complex (PIC) in vivo. Here, we show that depletion of individual subunits, even those essential for cell growth, causes a general ... | 10.1038/s41580-018-0028-8 | This work demonstrates that the depletion of different Mediator subunits affects transcription of a specific subset of genes more strongly than others. |
10.1126/science.1232542 | 104,266,701 | The Regulatory Genome Multicellular organisms contain a variety of cell types that are morphologically and functionally distinct even though they typically contain the same genomic DNA. Differences stem from differential gene expression. Gene regulatory genomic regions (enhancers) are well studied, yet despite major ef... | 10.1038/s41580-018-0028-8 | This work functionally maps enhancer activity across an entire genome. |
10.1126/science.aat7554 | 125,142,286 | The innate immune cell compartment is highly diverse in the healthy central nervous system (CNS), including parenchymal and non-parenchymal macrophages. However, this complexity is increased in inflammatory settings by the recruitment of circulating myeloid cells. It is unclear which disease-specific myeloid subsets ex... | 10.1038/s41583-019-0201-x | This research identifies disease-associated CAM subsets during CNS autoimmunity in mice |
10.1126/science.aaa1934 | 41,678,442 | Cellular diversity in the brain revealed The mammalian brain has an extraordinarily large number of cells. Although there are quite a few different cell types, many cells in any one category tend to look alike. Zeisel et al. analyzed the transcriptomes of mouse brain cells to reveal more than meets the eye. Interneuron... | 10.1038/s41583-019-0201-x | This is the first scRNA-seq study on the rodent CNS, describing the distinct profiles of CAMs versus microglia |
10.1073/pnas.0805453106 | 62,127,474 | Cerebral amyloid angiopathy (CAA), the deposition of β-amyloid (Aβ) peptides in leptomeningeal and cortical blood vessels, affects the majority of patients with Alzheimer's disease (AD). Evidence suggests that vascular amyloid deposits may result from impaired clearance of neuronal Aβ along perivascular spaces. We inve... | 10.1038/s41583-019-0201-x | Hawkes and McLaurin describe evidence of a functional role of CAMs in an Alzheimer disease model |
10.1126/scitranslmed.aaa5447 | 104,211,232 | Nanoparticle-functionalized T cells actively transport a cytotoxic drug to systemic sites of lymphoma dissemination, enhancing the efficacy of antitumor chemotherapy. | 10.1038/s41578-019-0110-7 | In this paper, chemotherapy-loaded nanocapsules with sustained release over 3 days are backpacked onto T cell surfaces capable of lymph node homing, achieving improved drug delivery to the lymph node-resident tumour. |
10.1038/s41467-017-01830-8 | 123,922,897 | Abstract Targeted delivery of compounds to particular cell subsets can enhance therapeutic index by concentrating their action on the cells of interest. Because attempts to target tumors directly have yielded limited benefit, we instead target endogenous immune cell subsets in the circulation that can migrate actively ... | 10.1038/s41578-019-0110-7 | This paper highlights the concept that cells that are the target of a drug can also be its carrier to enable targeted drug delivery |
10.1126/science.1127592 | 84,469,739 | The contribution of bone marrow–derived circulating endothelial progenitor cells (CEPs) to tumor angiogenesis has been controversial, primarily because of their low numbers in blood vessels of untreated tumors. We show that treatment of tumor-bearing mice with vascular disrupting agents (VDAs) leads to an acute mobiliz... | 10.1038/s41568-019-0209-6 | This study is perhaps one of the first demonstrating how therapy induces a systemic angiogenic response that, in turn, contributes to tumour regrowth. In response to VDAs, endothelial precursor cells rapidly home to the treated tumour site, supporting angiogenesis and subsequent tumour regrowth |
10.1158/0008-5472.can-12-2233 | 20,847,456 | Abstract Tumor metastasis is a highly complex, dynamic, and inefficient process involving multiple steps, yet it accounts for more than 90% of cancer-related deaths. Although it has long been known that fibrotic signals enhance tumor progression and metastasis, the underlying molecular mechanisms are still unclear. Ide... | 10.1038/s41568-019-0209-6 | This paper is one of a few published studies that demonstrates the link between LOX and ECM remodelling leading to fibrosis and metastasis. LOX-induced lung fibrosis accounts for metastatic spread |
10.1073/pnas.0708148104 | 79,403,780 | Cancer patients treated with antiangiogenic multitargeted receptor tyrosine kinase (RTK) inhibitors show increased levels of plasma VEGF and placental growth factor and decreased levels of soluble VEGF receptor-2, thus implicating these overall changes as a possible class effect of such drugs and raising the possibilit... | 10.1038/s41568-019-0209-6 | This paper is one of the first to demonstrate a host systemic effect in response to the anti-angiogenic receptor tyrosine kinase inhibitor sunitinib. Circulating factors whose levels change in response to treatment are suggested as biomarkers for drug activity |
10.1158/0008-5472.can-11-0627 | 104,134,611 | Abstract Recent studies suggest that chemotherapy, in addition to its cytotoxic effects on tumor cells, can induce a cascade of host events to support tumor growth and spread. Here, we used an experimental pulmonary metastasis model to investigate the role of this host response in metastasis formation. Mice were pretre... | 10.1038/s41568-019-0209-6 | Along with reference 119, this paper is one of the first studies describing a true systemic host response phenomenon following treatment with chemotherapeutic drugs |
10.1101/gad.180331.111 | 83,244,351 | The microenvironment is known to critically modulate tumor progression, yet its role in regulating treatment response is poorly understood. Here we found increased macrophage infiltration and cathepsin protease levels in mammary tumors following paclitaxel (Taxol) chemotherapy. Cathepsin-expressing macrophages protecte... | 10.1038/s41568-019-0209-6 | This important paper demonstrates how macrophages contribute to tumour resistance, showing that, in response to several cytotoxic agents, macrophages express various cathepsins, which in turn protect tumour cells from the cytotoxic effect of the drug |
10.1126/scitranslmed.aan3464 | 41,543,328 | Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others h... | 10.1038/s41568-019-0209-6 | This mechanistic study describes how surgery-induced immune modulation contributes to the outgrowth of dormant tumours at metastatic sites |
10.1084/jem.20151665 | 62,057,418 | Although traditional chemotherapy kills a fraction of tumor cells, it also activates the stroma and can promote the growth and survival of residual cancer cells to foster tumor recurrence and metastasis. Accordingly, overcoming the host response induced by chemotherapy could substantially improve therapeutic outcome an... | 10.1038/s41568-019-0209-6 | This paper provides an explanation for tumour resistance following MTD chemotherapy in desmoplastic tumours |
10.1073/pnas.1822001116 | 83,366,522 | PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti–PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we... | 10.1038/s41568-019-0209-6 | This study is one of the first that provides a mechanism explaining hyperprogression during treatment with ICIs. The authors demonstrate that hyperprogressive gastric carcinomas from patients treated with anti-PD1 therapy are infiltrated with proliferating T reg cells that suppress immune activity |
10.1038/s41586-020-1969-6 | 20,697,450 | Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-... | 10.1038/s41576-021-00431-y | This is the flagship paper for an international effort to analyse WGS data from 2,658 primary tumours, describing the consortium’s variant calling steps as well as reporting the landscape of somatic mutation especially for structural variation |
10.1038/s41586-019-1689-y | 20,697,788 | Abstract Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer... | 10.1038/s41576-021-00431-y | This paper reports the mutational landscape of >2,500 metastatic tumours, finding genetic variants that may be used to stratify patients towards therapies for >60% of the cases |
10.1038/s41586-019-1913-9 | 125,292,520 | Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analys... | 10.1038/s41576-021-00431-y | This study describes comprehensive identification and classification of SVs based on WGS data from >2,600 tumours, and reports 16 structural variation signatures and their characteristics |
10.1038/s41586-019-1907-7 | 41,705,507 | Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as ... | 10.1038/s41576-021-00431-y | This paper reports a large-scale analysis of the timing of point mutations and CNAs, and describes the common trajectories of tumour development across multiple tumour types |
10.1126/scitranslmed.aar1916 | 107,290,410 | Prolonged perioperative delivery of immunotherapy prevents local tumor recurrence and eliminates established spontaneous metastases. | 10.1038/s41578-019-0106-3 | Alginate gels placed in tumour beds during resection surgery provided long-term delivery of immunotherapies, and prevented relapse and metastases in breast cancer models by promoting local innate immunity and systemic adaptive responses. |
10.1126/science.aad9272 | 62,511,999 | Engineering a healing immune response Infections, surgeries, and trauma can all cause major tissue damage. Biomaterial scaffolds, which help to guide regenerating tissue, are an exciting emerging therapeutic strategy to promote tissue repair. Sadtler et al. tested how biomaterial scaffolds interact with the immune syst... | 10.1038/s41578-019-0106-3 | This study demonstrates that tissue-derived ECM scaffolds can reshape adoptive immune responses through modulating T H 2-mediated responses, and improve skeletal muscle regeneration after volumetric loss. |
10.1126/scitranslmed.aai9044 | 125,263,048 | Glycosaminoglycan-based hydrogels scavenge proinflammatory chemokines, reduce the influx of immune cells, and improve the healing of chronic wounds. | 10.1038/s41578-019-0106-3 | A hydrogel based on star-shaped polyethylene glycol (starPEG) functionalized with glycosaminoglycan (GAG) heparin scavenges pro-inflammatory factors from the cutaneous wound bed, improving wound healing by resolving inflammation. |
10.1126/science.1256815 | 20,877,653 | Quantum spin Hall (QSH) effect materials feature edge states that are topologically protected from backscattering. However, the small band gap in materials that have been identified as QSH insulators limits applications. We use first-principles calculations to predict a class of large-gap QSH insulators in two-dimensio... | 10.1038/s41578-021-00304-0 | This paper predicts that several group 6 transition-metal dichalcogenide monolayers in 1T phase are quantum spin Hall insulators competing with the trivial semiconducting 1H phase and metallic 1T phase |
10.1126/science.aad8609 | 20,526,951 | Thinning a ferroelectric makes it better As a ferroelectric material becomes thinner, the temperature below which it develops its permanent electrical polarization usually decreases. Chang et al. fabricated high-quality thin films of SnTe that, in contrast to this conventional wisdom, had a considerably higher transiti... | 10.1038/s41578-021-00304-0 | The first experimental report of in-plane ferroelectricity in an atomically thin material |
10.1038/ncomms14956 | 20,425,819 | Abstract Interest in two-dimensional (2D) van der Waals materials has grown rapidly across multiple scientific and engineering disciplines in recent years. However, ferroelectricity, the presence of a spontaneous electric polarization, which is important in many practical applications, has rarely been reported in such ... | 10.1038/s41578-021-00304-0 | The first theoretical prediction of simultaneous out-of-plane and in-plane ferroelectricity in monolayer α-In 2 Se 3 |
10.1038/ncomms10843 | 82,980,619 | Abstract Monolayers of transition metal dichalcogenides can exist in several structural polymorphs, including 2H, 1T and 1T′. The low-symmetry 1T′ phase has three orientation variants, resulting from the three equivalent directions of Peierls distortion in the parental 1T phase. Using first-principles calculations, we ... | 10.1038/s41578-021-00304-0 | One of the earliest studies of ferroelasticity and ferroelastic transitions in 2D materials |
10.1073/pnas.1108174108 | 20,811,717 | A moiré pattern is formed when two copies of a periodic pattern are overlaid with a relative twist. We address the electronic structure of a twisted two-layer graphene system, showing that in its continuum Dirac model the moiré pattern periodicity leads to moiré Bloch bands. The two layers become more strongly coupled ... | 10.1038/s41578-021-00304-0 | This paper predicts the existence of strong-correlation physics in magic-angle twisted bilayer graphene |
10.1186/s10194-022-01402-2 | 135,315,575 | Abstract Background According to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimate... | 10.1038/s41582-022-00763-1 | A review updating Stovner et al. (2007) 41 , also aiming to understand the methodological factors that influence estimates of the prevalence of headache disorders |
10.1111/j.1468-2982.2009.01941.x | 124,590,381 | The aim of this review was to summarize population-based studies reporting prevalence and/or incidence of chronic migraine (CM) and to explore variation across studies. A systematic literature search was conducted. Relevant data were abstracted and estimates were subdivided based on the criteria used in each study. Six... | 10.1038/s41582-022-00763-1 | The first attempt to review the prevalence of chronic migraine |
10.1111/j.1468-2982.2007.01288.x | 83,490,873 | This study, which is a part of the initiative 'Lifting The Burden: The Global Campaign to Reduce the Burden of Headache Worldwide', assesses and presents all existing evidence of the world prevalence and burden of headache disorders. Population-based studies applying International Headache Society criteria for migraine... | 10.1038/s41582-022-00763-1 | The first review of data on headache prevalence conducted by Lifting The Burden |
10.1152/ajpendo.1997.272.5.e864 | 59,006,055 | The effects of exercise training on cell surface GLUT-4 in skeletal muscle of the obese (fa/fa) Zucker rat were investigated using the impermeant glucose transporter photoaffinity reagent 2-N-4-(1-azi-2,2,2-trifluoroethyl)-benzoyl-1,3-bis- (D-mannos-4-yloxy)-2-propylamine (ATB-BMPA). In the absence of insulin, 3-O-meth... | 10.1038/s41580-021-00390-6 | Study presenting evidence that the defect in glucose transport in IR is specific to insulin action and does not apply to exercise or contraction |
10.1083/jcb.142.6.1429 | 41,728,567 | The effects of insulin stimulation and muscle contractions on the subcellular distribution of GLUT4 in skeletal muscle have been studied on a preparation of single whole fibers from the rat soleus. The fibers were labeled for GLUT4 by a preembedding technique and observed as whole mounts by immunofluorescence microscop... | 10.1038/s41580-021-00390-6 | Study demonstrating that insulin and contraction stimulate recruitment of GLUT4 from distinct intracellular pools |
10.1038/ncomms15446 | 80,418,634 | Nature Communications 8 Article: 14700 (2017); Published 13 March 2017; Updated 14 August 2017 The financial support for this Article was not properly acknowledged. The acknowledgements should include a reference to support, ‘by the ONR under award number N00014-16-1-3169 (Designing a Dynamic Platform that Provides Mul... | 10.1038/s41578-018-0050-7 | This study describes the development of an advanced nanostructured material that offers a new methodology to mechanically perturb cells |
10.1038/ncomms12002 | 41,038,203 | Abstract Arrangements of nanostructures in well-defined patterns are the basis of photonic crystals, metamaterials and holograms. Furthermore, rewritable optical materials can be achieved by dynamically manipulating nanoassemblies. Here we demonstrate a mechanism to configure plasmonic nanoparticles (NPs) in polymer me... | 10.1038/s41578-018-0050-7 | This paper describes a relatively simple and fast process to record holographic images in the 3D position of Ag nanoparticles in polymer films through the interference light reflected off an object |
10.1126/science.aax3528 | 62,454,602 | Ice loss from the world’s glaciers and ice sheets contributes to sea level rise, influences ocean circulation, and affects ecosystem productivity. Ongoing changes in glaciers and ice sheets are driven by submarine melting and iceberg calving from tidewater glacier margins. However, predictions of glacier change largely... | 10.1038/s41561-022-01036-8 | This paper reports the only direct measurements to date of submarine melting at a marine-terminating glacier. |
10.5194/tc-14-3071-2020 | 83,127,218 | Abstract. The Greenland ice sheet is one of the largest contributors to global mean sea-level rise today and is expected to continue to lose mass as the Arctic continues to warm. The two predominant mass loss mechanisms are increased surface meltwater run-off and mass loss associated with the retreat of marine-terminat... | 10.1038/s41561-022-01036-8 | A paper presenting the results of a huge community effort that aimed to project future changes in the Greenland ice sheet in response to atmospheric and oceanic warming. |
10.1126/science.aar5078 | 83,540,309 | Endolysosomes can be damaged by diverse materials. Terminally damaged compartments are degraded by lysophagy, but pathways that repair salvageable organelles are poorly understood. Here we found that the endosomal sorting complex required for transport (ESCRT) machinery, known to mediate budding and fission on endolyso... | 10.1038/s41580-019-0185-4 | This study elegantly shows that the ESCRT machinery is recruited to injured endolysosomes to allow their recovery from damage. |
10.1126/science.1204592 | 125,284,360 | Starvation activates a transcriptional program controlling autophagosome formation, lysosome fusion, and substrate degradation. | 10.1038/s41580-019-0185-4 | Sardiello et al. (2009) and Settembre et al. (2011) describe the discovery of a lysosomal–autophagic gene network and its master regulator TFEB, the first example of global transcriptional control of lysosomal function. |
10.1083/jcb.201807019 | 41,577,246 | Mutations in the human VPS13 genes are responsible for neurodevelopmental and neurodegenerative disorders including chorea acanthocytosis (VPS13A) and Parkinson’s disease (VPS13C). The mechanisms of these diseases are unknown. Genetic studies in yeast hinted that Vps13 may have a role in lipid exchange between organell... | 10.1038/s41580-019-0185-4 | This article reports that the protein VPS13C, which is mutated in some forms of Parkinson disease, is a lipid transport protein that tethers late endosomes/lysosomes to the ER. |
10.1083/jcb.201703094 | 79,872,064 | Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/th... | 10.1038/s41580-019-0185-4 | Filipek et al. (2017) and Pu et al. (2017) show that the Ragulator complex engages in a negative regulatory interaction with BORC, mediating perinuclear clustering of lysosomes in response to nutrient deprivation and lysosome dispersal towards the cell periphery in response to epidermal growth factor stimulation. |
10.1126/science.aaa2628 | 62,273,155 | Too hungry to eat, too hungry not to eat Pancreatic beta cells, the source of insulin in response to food, employ an unusual mechanism to adapt to nutrient depletion. Goginashvili et al. found that starvation of beta cells induced selective degradation of newly formed insulin granules through their fusion with lysosome... | 10.1038/s41580-019-0185-4 | Starvation of pancreatic β-cells is shown to induce direct fusion of lysosomes with nascent secretory insulin granules by a process that is distinct from conventional autophagy and is controlled by protein kinase D. |
10.1083/jcb.201507112 | 18,476,396 | We examined the luminal pH of individual lysosomes using quantitative ratiometric fluorescence microscopy and report an unappreciated heterogeneity: peripheral lysosomes are less acidic than juxtanuclear ones despite their comparable buffering capacity. An increased passive (leak) permeability to protons, together with... | 10.1038/s41580-019-0185-4 | This study highlights the heterogeneity of lysosomes by demonstrating that peripherally localized lysosomes have higher pH and lower proteolytic activity than their perinuclearly localized counterparts. |
10.1111/epi.13709 | 104,431,235 | Summary The International League Against Epilepsy ( ILAE ) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical ... | 10.1038/s41582-020-0409-4 | This position paper from the International League Against Epilepsy describes changes to the classification of epilepsy, which were implemented in 2017, and defines major concepts such as epileptic syndrome, epileptic and developmental encephalopathy, and genetic generalized epilepsies |
10.1111/epi.13913 | 29,279,155 | Summary Objective The study provides updated information about the distribution of seizures, epilepsies, and etiologies of epilepsy in the general child population, and compares the old and new classification systems from the International League Against Epilepsy ( ILAE ). Methods The study platform was the Norwegian M... | 10.1038/s41582-020-0409-4 | This article classified a cohort of patients using the International League Against Epilepsy classification of epilsepsy and illustrated the number of patients that can be classified by aetiology and those with unknown aetiology |
10.1111/epi.14454 | 24,672,189 | Abstract Childhood absence epilepsy ( CAE ) is one of the most frequent epilepsies in infancy. The first‐line recommended therapy for CAE is based on the prescription of the narrow‐spectrum ethosuximide and the broad‐spectrum valproic acid, which have similar efficacy in the first 12 months. Nevertheless, some antiepil... | 10.1038/s41582-020-0409-4 | This article highlights the negative impact on the long-term outcome of receiving an inappropriate first anti-epileptic medication, even if this medication is administered on a temporary basis |
10.2217/pme.13.57 | 62,356,055 | Ten years ago, the proposition that healthcare is evolving from reactive disease care to care that is predictive, preventive, personalized and participatory was regarded as highly speculative. Today, the core elements of that vision are widely accepted and have been articulated in a series of recent reports by the US I... | 10.1038/s41582-020-0409-4 | This article discusses the concept of personalized, preventive, predictive and participatory, or ‘P4’, medicine |
10.1038/ismej.2013.172 | 38,450,543 | Abstract It is well established that host-associated microbial communities can interfere with the colonization and establishment of microbes of foreign origins, a phenomenon often referred to as bacterial interference or colonization resistance. However, due to the complexity of the indigenous microbiota, it has been e... | 10.1038/s41575-022-00610-0 | This paper offers insights into several parts gut microorganisms might play to create colonization resistance using Escherichia coli as a model organism |
10.1038/s41467-018-06103-6 | 104,269,369 | Abstract Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infection (CDI). Bacterial colonization in recipients after FMT has been studied, but little is known about the role of the gut fungal community, or mycobiota. Here, we show evidence of gut fungal dysbiosis in CDI, ... | 10.1038/s41575-022-00610-0 | This study demonstrates a correlation between gut fungi and CDI, which is an area of research that merits further study |
10.1038/s41522-019-0087-4 | 42,640,690 | Abstract Clostridium difficile is a major cause of nosocomial infections. Bacterial persistence in the gut is responsible for infection relapse; sporulation and other unidentified mechanisms contribute to this process. Intestinal bile salts cholate and deoxycholate stimulate spore germination, while deoxycholate kills ... | 10.1038/s41575-022-00610-0 | This study is one of the first papers to characterize biofilm formation by C. difficile |
10.1146/annurev-micro-090816-093458 | 20,713,313 | Clostridium difficile is the cause of antibiotics-associated diarrhea and pseudomembranous colitis. The pathogen produces three protein toxins: C. difficile toxins A (TcdA) and B (TcdB), and C. difficile transferase toxin (CDT). The single-chain toxins TcdA and TcdB are the main virulence factors. They bind to cell mem... | 10.1038/s41575-022-00610-0 | This is an excellent Review of C. difficile toxins and their effects on the host |
10.1038/s41467-020-20746-4 | 38,821,478 | Abstract Clostridioides difficile is a bacterial pathogen that causes a range of clinical disease from mild to moderate diarrhea, pseudomembranous colitis, and toxic megacolon. Typically, C. difficile infections (CDIs) occur after antibiotic treatment, which alters the gut microbiota, decreasing colonization resistance... | 10.1038/s41575-022-00610-0 | This study is the first to show that C. difficile uses its toxins to make the gut a more hospitable space |
10.1073/pnas.1916965117 | 103,085,989 | Intestinal bile acids are known to modulate the germination and growth of Clostridioides difficile . Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant of C. difficile disease. We show that individual primary and secondary bile acids reversibly bin... | 10.1038/s41575-022-00610-0 | This study is the first to show that bile acids interact directly with C. difficile toxins to affect disease |
10.1038/s41467-021-21355-5 | 81,875,429 | Abstract Clostridioides difficile spores produced during infection are important for the recurrence of the disease. Here, we show that C. difficile spores gain entry into the intestinal mucosa via pathways dependent on host fibronectin-α 5 β 1 and vitronectin-α v β 1 . The exosporium protein BclA3, on the spore surface... | 10.1038/s41575-022-00610-0 | This study is the first to demonstrate that C. difficile spores are internalized in the mouse intestine, which contributes to spore persistence and recurrent disease |
10.3389/fimmu.2021.702378 | 132,600,742 | The field of microbiome research has developed rapidly over the past decades and has become a topic of major interest to basic, preclinical, and clinical research, the pharmaceutical industry as well as the general public. The microbiome is a complex and diverse ecosystem and defined as the collection of all host-assoc... | 10.1038/s41575-022-00610-0 | This Review offers a view of the inter-kingdom interactions taking place within the human organism and how coevolution shapes local and systemic immunity |
10.1073/pnas.141230798 | 125,178,091 | The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF c... | 10.1038/s41594-020-0438-0 | This paper shows the first example of using chimeric molecules to redirect the specificity of a ubiquitin ligase toward a target protein of interest |
10.1126/science.1244851 | 125,069,684 | Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecula... | 10.1038/s41594-020-0438-0 | This study and the concurrent study by Lu et al. (ref. 28 ) demonstrate how thalidomide promotes degradation of IKZF1/3 transcription factors |
10.1126/science.1244917 | 83,452,688 | Drug With a (Re)Purpose Thalidomide, once infamous for its deleterious effects on fetal development, has re-emerged as a drug of great interest because of its beneficial immunomodulatory effects. A derivative drug called lenalidomide significantly extends the survival of patients with multiple myeloma, but the molecula... | 10.1038/s41594-020-0438-0 | This study and the concurrent study by Krönke et al. (ref. 27 ) demonstrate how thalidomide promotes degradation of IKZF1/3 transcription factors |
10.1126/science.aal3755 | 62,136,418 | An old cancer drug's degrading new look Typically, cancer drugs that help only a small number of patients in clinical trials are not pursued. This might change in a future world of precision medicine, where biomarkers will match specific drugs to the patients most likely to respond. Han et al. identified the mechanism ... | 10.1038/s41594-020-0438-0 | This paper and the concurrent study by Uehara et al. (ref. 57 ) demonstrate how aryl-sulfonamides promote degradation of RBM39 |
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