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10.1158/0008-5472.can-04-4058 | 122,222,081 | Abstract Individuals with the tumor predisposition syndrome, neurofibromatosis 1 (NF1), are prone to development of nervous system tumors, including neurofibromas and pilocytic astrocytomas. Based on the ability of the NF1 gene product (neurofibromin) to function as a GTPase activating protein for RAS, initial biologic... | 10.1038/nrdp.2017.4 | This is the first report to demonstrate that neurofibromin negatively regulates mTOR signalling, which is relevant to neurofibromatosis type 1-associated tumour growth. |
10.1002/ana.23793 | 82,995,397 | Children with neurofibromatosis type 1 (NF1) are prone to learning and behavioral abnormalities, including problems with spatial learning and attention. The molecular etiology for these deficits is unclear, as previous studies have implicated defective dopamine, cyclic adenosine monophosphate (cAMP), and Ras homeostasi... | 10.1038/nrdp.2017.4 | This study demonstrates that neurofibromin controls mouse learning by increasing the levels of dopamine in the brain. |
10.1126/science.286.5447.2172 | 107,237,376 | Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome resulting from germ line mutations in the NF1 tumor suppressor gene. Hallmark features of the disease are the development of benign peripheral nerve sheath tumors (neurofibromas), which can progress to malignancy. Unlike humans, mice that are hetero... | 10.1038/nrdp.2017.4 | This important study is the first to report the generation of mouse MPNSTs. |
10.1002/ana.24093 | 61,556,436 | Objective Children with neurofibromatosis‐1 (NF1) are at risk for developing numerous nervous system abnormalities, including cognitive problems and brain tumors (optic pathway glioma). Currently, there are few prognostic factors that predict clinical manifestations or outcomes in patients, even in families with an ide... | 10.1038/nrdp.2017.4 | This report is the first to demonstrate that sex is a major determinant of vision loss in children and mice with neurofibromatosis type 1-associated optic pathway glioma. |
10.1200/jco.2005.03.8349 | 20,550,588 | Purpose Optic pathway gliomas (OPGs) are the most common CNS tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second tumors in NF1-related OPGs after radiotherapy. Patients and Methods We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subseq... | 10.1038/nrdp.2017.4 | This is the first study to demonstrate that radiation is associated with secondary malignancies in patients with neurofibromatosis type 1. |
10.1155/2012/975364 | 78,510,449 | Objective . To examine physical, cognitive, and social-emotional predictors of quality of life (HRQOL) and functional disability (FD) in adolescents diagnosed with Neurofibromatosis-1. Methods . Participants were twenty-seven adolescents with a diagnosis of NF-1 who were recruited through an NF-1 specialty clinic at a ... | 10.1038/nrdp.2017.4 | This important study describes the predictors of QOL and functional disability in adolescents with neurofibromatosis type 1. |
10.1111/j.1349-7006.2006.00165.x | 103,034,665 | Mutations of DNA double‐strand breaks (DSB) repair genes, ATM , MRE11 , RAD50 , NBS1 and ATR , are postulated to play a role in the development of gastrointestinal malignancies with an impaired mismatch repair (MMR) function. In the present study, mutations of these genes together with the presence of microsatellite in... | 10.1038/nrc3399 | Demonstration of the impact of MMR defects on the function of HRR pathways. |
10.1126/science.1140321 | 41,481,827 | Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We pe... | 10.1038/nrc3399 | Proteomic analysis of phosphorylation networks downstream of DNA damage-activated ATM and ATR that identifies >700 proteins, which confirmed many targets of the DDR pathway and several new ones. |
10.1126/science.278.5340.1064 | 125,132,824 | The discovery of anticancer drugs is now driven by the numerous molecular alterations identified in tumor cells over the past decade. To exploit these alterations, it is necessary to understand how they define a molecular context that allows increased sensitivity to particular compounds. Traditional genetic approaches ... | 10.1038/nrc3399 | The first paper to identify the potential use of synthetic lethality in cancer. |
10.1093/jnci/dji141 | 38,382,928 | Abstract Background: Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain. Me... | 10.1038/nrc3399 | An epidemiological study of the cancer incidence and mortality of >1,000 individuals with heterozygous ATM mutations, identifying an increased risk of breast cancer and some other cancer types. |
10.1073/pnas.0506758102 | 20,885,623 | The development of efficient and inexpensive genome sequencing methods has revolutionized the study of human bacterial pathogens and improved vaccine design. Unfortunately, the sequence of a single genome does not reflect how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide... | 10.1038/nrmicro1552 | A comparative genome analysis of GBS strains that explores genetic variability and its implications for microbial pathogenesis. |
10.1126/science.1109869 | 62,619,452 | Group B Streptococcus (GBS) is a multiserotype bacterial pathogen representing a major cause of life-threatening infections in newborns. To develop a broadly protective vaccine, we analyzed the genome sequences of eight GBS isolates and cloned and tested 312 surface proteins as vaccines. Four proteins elicited protecti... | 10.1038/nrmicro1552 | The first report using multiple genome screening as a strategy to identify GBS vaccine candidates. This article also shows the potential of this approach for other microorganisms with considerable genetic variability. |
10.1073/pnas.88.24.11460 | 83,333,825 | The results obtained in this study establish that liposome formulations incorporating a synthetic polyethylene glycol-derivatized phospholipid have a pronounced effect on liposome tissue distribution and can produce a large increase in the pharmacological efficacy of encapsulated antitumor drugs. This effect is substan... | 10.1038/nrd725 | This classical study shows that the conjugation of PEG to the surface of liposomes greatly prolongs the blood residence time and optimizes the pharmacokinetics. |
10.1073/pnas.88.19.8661 | 83,302,667 | The biological functions of the BCL2 gene were investigated in transgenic mice harboring human BCL2 cDNA under the control of an immunoglobulin heavy chain enhancer (E mu). Mice of a representative transgenic strain, E mu-bcl-2-22, had a great excess of B lymphocytes, immunoglobulin-secreting cells, and serum immunoglo... | 10.1038/nrm3722 | This study provided the first evidence that increased lymphocyte survival elicited by changes in regulation of the BCL-2 family could contribute to autoimmune disease. |
10.1101/gad.1304105 | 20,751,956 | Commitment of cells to apoptosis is governed largely by the interaction between members of the Bcl-2 protein family. Its three subfamilies have distinct roles: The BH3-only proteins trigger apoptosis by binding via their BH3 domain to prosurvival relatives, while the proapoptotic Bax and Bak have an essential downstrea... | 10.1038/nrm3722 | This study showed that activation of BAK is restrained predominantly by MCL1 and BCL-X L |
10.1126/science.275.5302.983 | 39,332,100 | Heterodimerization between members of the Bcl-2 family of proteins is a key event in the regulation of programmed cell death. The molecular basis for heterodimer formation was investigated by determination of the solution structure of a complex between the survival protein Bcl-x L and the death-promoting region of the ... | 10.1038/nrm3722 | Building on the structure of BCL-X L (shown in reference 31), this study showed that a BAK BH3 peptide binds in the surface groove of BCL-X L , revealing a principal mode of regulation of apoptosis by this family. |
10.1126/science.286.5445.1735 | 107,243,398 | Apoptosis can be triggered by members of the Bcl-2 protein family, such as Bim, that share only the BH3 domain with this family. Gene targeting in mice revealed important physiological roles for Bim. Lymphoid and myeloid cells accumulated, T cell development was perturbed, and most older mice accumulated plasma cells a... | 10.1038/nrm3722 | The BH3-only protein BIM was shown to be essential for specific cytotoxic responses and to maintain lymphoid homeostasis, thereby preventing autoimmunity. |
10.1126/science.1090072 | 82,810,149 | Apoptosis provoked by DNA damage requires the p53 tumor suppressor, but which of the many p53-regulated genes are required has remained unknown. Two genes induced by this transcription factor, noxa and puma ( bbc3 ), stand out, because they encode BH3-only proteins, proapoptotic members of the Bcl-2 family required to ... | 10.1038/nrm3722 | The BH3-only proteins PUMA and to a lesser extent NOXA, which are induced by the tumour suppressor protein p53, were shown to be crucial mediators of the apoptosis elicited by genotoxic damage and certain drugs. |
10.1126/science.1059108 | 125,115,620 | Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a “BH3-domain–only” BCL-2 family member, triggers the homooligomerization of “multidomain” conserved proapoptotic family members B... | 10.1038/nrm3722 | Together with the physiological results showing that apoptosis requires BAX or BAK (see reference 151), this study and reference 153 showed that BH3-only proteins must function upstream of and through BAX and BAK. |
10.1158/0008-5472.can-07-5836 | 125,269,125 | Abstract Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it i... | 10.1038/nrm3722 | The orally bioavailable derivative of ABT-737, ABT-263 (now called navitoclax), has shown promise in early clinical trials. |
10.1093/bioinformatics/bth496 | 109,115,222 | Abstract Motivation: With more and more scientific literature published online, the effective management and reuse of this knowledge has become problematic. Natural language processing (NLP) may be a potential solution by extracting, structuring and organizing biomedical information in online literature in a timely man... | 10.1038/nrg1768 | These authors provide a quantitative overview of the causes of gene-name ambiguity, and suggest how researchers and publishers can help to minimize this problem. |
10.1073/pnas.0404315101 | 46,034,548 | A major challenge in human genetics is identifying the molecular basis of common heritable disorders. In contrast to rare single-gene diseases, multifactorial disorders are thought to arise from the combined effect of multiple gene variants, such that any single variant may have only a modest effect on disease suscepti... | 10.1038/nrg1768 | The study shows how literature-based molecular networks and genetic linkage mapping can be integrated to find candidate disease genes. |
10.1186/1471-2156-6-45 | 59,803,827 | Abstract Background Human inherited diseases can be associated by genetic linkage with one or more genomic regions. The availability of the complete sequence of the human genome allows examining those locations for an associated gene. We previously developed an algorithm to prioritize genes on a chromosomal region acco... | 10.1038/nrg1768 | Reference 103 integrates genetic linkage-mapping data with data from the literature to suggest candidate genes for inherited diseases. Reference 104 shows later improvements of the method. |
10.1126/science.282.5393.1484 | 41,569,490 | Tankyrase, a protein with homology to ankyrins and to the catalytic domain of poly(adenosine diphosphate–ribose) polymerase (PARP), was identified and localized to human telomeres. Tankyrase binds to the telomeric protein TRF1 (telomeric repeat binding factor–1), a negative regulator of telomere length maintenance. Lik... | 10.1038/nrd3868 | Tankyrase is first identified in this study as a PARP that functions at mammalian telomeres. |
10.1126/science.1094754 | 104,103,664 | Cohesins keep sister chromatids associated from the time of their replication in S phase until the onset of anaphase. In vertebrate cells, two distinct pathways dissociate cohesins, one acts on chromosome arms and the other on centromeres. Here, we describe a third pathway that acts on telomeres. Knockdown of tankyrase... | 10.1038/nrd3868 | This study defines the essential role of tankyrase in resolving cohesion of sister chromatids between replication and mitosis. |
10.1073/pnas.1100959108 | 103,726,813 | The bacterial pathogen Helicobacter pylori chronically infects the human gastric mucosa and is the leading risk factor for the development of gastric cancer. The molecular mechanisms of H. pylori -associated gastric carcinogenesis remain ill defined. In this study, we examined the possibility that H. pylori directly co... | 10.1038/nrm.2016.100 | This paper finds that direct cell contact is sufficient for the induction of DSBs in H. pylori -infected cells and that prolonged infection leads to persistent unrepaired breaks. |
10.1126/science.1127059 | 62,634,224 | Transient infection of eukaryotic cells with commensal and extraintestinal pathogenic Escherichia coli of phylogenetic group B2 blocks mitosis and induces megalocytosis. This trait is linked to a widely spread genomic island that encodes giant modular nonribosomal peptide and polyketide synthases. Contact with E. coli ... | 10.1038/nrm.2016.100 | This study identified the genotoxic activity of the colibactin biosynthetic pathway encoded by the pks genomic island of E. coli |
10.1073/pnas.1001261107 | 125,175,815 | Escherichia coli is a normal inhabitant of the human gut. However, E. coli strains of phylogenetic group B2 harbor a genomic island called “ pks ” that codes for the production of a polyketide-peptide genotoxin, Colibactin. Here we report that in vivo infection with E. coli harboring the pks island, but not with a pks ... | 10.1038/nrm.2016.100 | This paper reports that infection of enterocytes with low doses of colibactin-positive E. coli leads to DSBs that are not completely repaired, leading to chromosomal instability and the emergence of anchorage-independent growth. |
10.1083/jcb.200703099 | 18,025,212 | The idea that conversion of glucose to ATP is an attractive target for cancer therapy has been supported in part by the observation that glucose deprivation induces apoptosis in rodent cells transduced with the proto-oncogene MYC, but not in the parental line. Here, we found that depletion of glucose killed normal huma... | 10.1038/nrc.2016.71 | This paper connects MYC transformation to the dependence on glutamine to prevent apoptosis. |
10.1073/pnas.0709747104 | 104,382,239 | Tumor cell proliferation requires rapid synthesis of macromolecules including lipids, proteins, and nucleotides. Many tumor cells exhibit rapid glucose consumption, with most of the glucose-derived carbon being secreted as lactate despite abundant oxygen availability (the Warburg effect). Here, we used 13 C NMR spectro... | 10.1038/nrc.2016.71 | This study shows that MYC-mediated transformation drives glutamine into biosynthetic pathways. |
10.1073/pnas.1117773108 | 41,700,160 | Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is ma... | 10.1038/nrc.2016.71 | This study describes the reverse flux of glutamine through IDH to citrate in a HIF-dependent manner. |
10.1073/pnas.0810199105 | 41,442,195 | Mammalian cells fuel their growth and proliferation through the catabolism of two main substrates: glucose and glutamine. Most of the remaining metabolites taken up by proliferating cells are not catabolized, but instead are used as building blocks during anabolic macromolecular synthesis. Investigations of phosphoinos... | 10.1038/nrc.2016.71 | This study finds that MYC regulates key glutamine metabolism genes. |
10.1126/scitranslmed.aaa1009 | 103,766,256 | Glutamine-based PET imaging takes advantage of gliomas’ glutamine addiction and can be used to assess metabolic nutrient uptake in gliomas. | 10.1038/nrc.2016.71 | This paper validates the use of labelled glutamine in the imaging of human gliomas. |
10.1073/pnas.0401496101 | 103,468,346 | Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet produc... | 10.1038/nrc2439 | With Reference 19, this paper identified hypomorphic point mutations in Myb that effect platelet generation and other haematopoietic parameters in adult mice. |
10.1073/pnas.0610055104 | 16,718,506 | The colonic crypt is the functional unit of the colon mucosa with a central role in ion and water reabsorption. Under steady-state conditions, the distal colonic crypt harbors a single stem cell at its base that gives rise to highly proliferative progenitor cells that differentiate into columnar, goblet, and endocrine ... | 10.1038/nrc2439 | Showed that Myb is essential to normal colonic crypt homeostasis through its effects on differentiation and proliferation. |
10.1634/stemcells.2007-0293 | 109,070,372 | Abstract Ongoing production of neurons in adult brain is restricted to specialized neurogenic niches. Deregulated expression of genes controlling homeostasis of neural progenitor cell division and/or their microenvironment underpins a spectrum of brain pathologies. Using conditional gene deletion, we show that the prot... | 10.1038/nrc2439 | The role of MYB in adult brain neurogenesis was revealed in this study as well as effects on the ependymal cell layer that supports the neurogenic stem cell niche. |
10.1002/gcc.20378 | 102,934,852 | Abstract Although MYB overexpression in colorectal cancer (CRC) is known to be a prognostic indicator for poor survival, the basis for this overexpression is unclear. Among multiple levels of MYB regulation, the most dynamic is the control of transcriptional elongation by sequences within intron 1. The authors have pro... | 10.1038/nrc2439 | Showed the importance of sequence in the first intron of MYB — which might encode an RNA stem-loop and polyT motifs — in regulating MYB transcriptional attenuation, and that this region in the first intron is commonly mutated in colon carcinoma. |
10.1073/pnas.0700104104 | 38,488,084 | MYB (the human ortholog of c- myb ) is expressed in a high proportion of human breast tumors, and that expression correlates strongly with estrogen receptor (ER) positivity. This may reflect the fact that MYB is a target of estrogen/ER signaling. Because in many cases MYB expression appears to be regulated by transcrip... | 10.1038/nrc2439 | Demonstrated that MYB is required for the proliferation of breast cancer cells and that oestrogen and its receptor regulate attenuation of MYB transcription. |
10.1182/blood-2006-12-064683 | 62,341,874 | Abstract The C-Myb transcription factor is essential for hematopoiesis, including in the T-cell lineage. The C-Myb locus is a common site of retroviral insertional mutagenesis, however no recurrent genomic involvement has been reported in human malignancies. Here, we identified 2 types of genomic alterations involving ... | 10.1038/nrc2439 | With Reference 119, this paper reported a significant frequency of genomic alterations in MYB in human T-cell leukaemia. |
10.1126/science.3498214 | 81,425,350 | Expression of c- myb proto-oncogene messenger RNA (mRNA) and protein has been detected principally in tumors and in normal tissue of hematopoietic origin. In each hematopoietic lineage examined, expression of the c- myb gene is markedly downregulated during hematopoietic maturation. However, the mechanism by which diff... | 10.1038/nrc2439 | One of the first reports showing that Myb expression is regulated at the level of transcriptional elongation. |
10.1073/pnas.88.6.2351 | 56,558,805 | The c-myb protooncogene is preferentially expressed in hematopoietic cells, and its encoded protein, Myb, is required for hematopoietic cell proliferation. To analyze the relative Myb dependence of normal and leukemic human hematopoietic progenitor cells, normal bone marrow cells, several types of leukemic blast cells,... | 10.1038/nrc2439 | References 115 and 116 showed that MYB is required for the proliferation of human leukaemia cells and that normal haematopoietic cells might be less sensitive to MYB inhibition, suggesting that there could be a therapeutic window for agents that target MYB. |
10.1126/science.288.5470.1432 | 104,383,657 | A paramyxovirus virus termed Nipah virus has been identified as the etiologic agent of an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore. The outbreak was first noted in late September 1998 and by mid-June 1999, more than 265 encephalitis cases, including 105 dea... | 10.1038/nrmicro1323 | Describes the isolation of NiV and provides the first information on the preliminary characterization of the virus from work done in six laboratories in four countries: Malaysia, USA, Singapore and Australia. |
10.1126/science.7701348 | 102,782,583 | A morbillivirus has been isolated and added to an increasing list of emerging viral diseases. This virus caused an outbreak of fatal respiratory disease in horses and humans. Genetic analyses show it to be only distantly related to the classic morbilliviruses rinderpest, measles, and canine distemper. When seen by elec... | 10.1038/nrmicro1323 | Describes the outbreak of severe respiratory disease in a Brisbane stable and isolation of the causative agent, at the time called equine morbillivirus, a name later changed to HeV when the genetic distinction between HeV and morbilliviruses became more obvious. |
10.1073/pnas.0504887102 | 107,342,671 | Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus of the family Paramyxoviridae and are unique in that they exhibit a broad species tropism and cause fatal disease in both animals and humans. They infect cells through a pH-independent membrane fusion process mediated by their fusion and attachmen... | 10.1038/nrmicro1323 | References 51 and 52 show by different means that ephrin B2 is a functional cell receptor for both HeV and NiV, therefore providing an explanation for the observed tissue and organ tropism of these viruses. |
10.1128/jvi.79.20.12714-12720.2005 | 19,389,829 | ABSTRACT Proteolytic processing of paramyxovirus fusion (F) proteins is essential for the generation of a mature and fusogenic form of the F protein. Although many paramyxovirus F proteins are proteolytically processed by the cellular protease furin at a multibasic cleavage motif, cleavage of the newly emerged Hendra v... | 10.1038/nrmicro1323 | References 77–81 reveal the mechanism used by henipaviruses to proteolytically activate their F proteins, a process not used by any other known viral protein. |
10.1128/jvi.79.10.6078-6088.2005 | 38,788,098 | ABSTRACT The Nipah virus V and W proteins, which are encoded by the P gene via RNA editing, have a common N-terminal domain but unique C-terminal domains. They localize to the cytoplasm and nucleus, respectively, and have both been shown to function as inhibitors of JAK/STAT signaling. Here we report that V and W prote... | 10.1038/nrmicro1323 | This paper reveals that NiV W protein inhibits both TLR3-induced and intracellular dsRNA-induced signalling pathways, unlike the V protein, which remains in the cytoplasm and targets the dsRNA-signalling pathway. |
10.1128/jvi.78.11.5633-5641.2004 | 125,275,861 | ABSTRACT In previous reports it was demonstrated that the Nipah virus V and W proteins have interferon (IFN) antagonist activity due to their ability to block signaling from the IFN-α/β receptor (J. J. Rodriguez, J. P. Parisien, and C. M. Horvath, J. Virol. 76: 11476-11483, 2002; M. S. Park et al., J. Virol. 77: 1501-1... | 10.1038/nrmicro1323 | The influence of the C-terminal domains of the V and W proteins of NiV is elegantly shown by demonstrating their ability to inhibit STAT1 activation from the cytoplasmic and nuclear compartments, respectively. |
10.1073/pnas.91.19.9014 | 41,635,248 | Liver injury in PiZZ alpha 1-antitrypsin (alpha 1-AT) deficiency probably results from toxic effects of the abnormal alpha 1-AT molecule accumulating within the ER of liver cells. However, only 12-15% of individuals with this same genotype develops liver disease. Therefore, we predicted that other genetic traits that d... | 10.1038/nrg907 | Individuals with Z -α 1 -antitrypsin-related liver disease (as opposed to those with plasma deficiency) have a lag in degrading the retained protein, which indicates that the handling of the polymers is likely to be important in determining which patients develop juvenile cirrhosis. |
10.1126/science.1118948 | 83,459,694 | Subclasses of immunoglobulin G (IgG) display substantial differences in their ability to mediate effector responses, contributing to variable activity of antibodies against microbes and tumors. We demonstrate that the mechanism underlying this long-standing observation of subclass dominance in function is provided by t... | 10.1038/nri.2017.106 | The authors show that significant differences in the ratios of activating to inhibitory receptor binding predict in vivo activity of antitumour monoclonal antibodies, forming a model of Fc domain effector function regulation through the simultaneous engagement of multiple receptors that collectively contribute to the i... |
10.1084/jem.20100995 | 102,581,427 | One important function of humoral immunity is toxin neutralization. The current view posits that neutralization results from antibody-mediated interference with the binding of toxins to their targets, a phenomenon viewed as dependent only on antibody specificity. To investigate the role of antibody constant region func... | 10.1038/nri.2017.106 | The authors show here that neutralization of anthrax toxin by passive immunization of monoclonal antibodies, up to this point thought to be dependent primarily on antigen specificity and thus direct blockade of the toxin, requires the presence of FcγR and specific isotypes. |
10.4049/jimmunol.1200501 | 19,850,524 | Abstract IgG molecules are widely used as therapeutic agents either in the form of intact Abs or as Fc fusion proteins. Although efficient binding of the IgG Fc fragment to cellular FcγRs may be essential to achieve a high cytolytic activity, it may be advantageous for other applications to limit or abolish this intera... | 10.1038/nri.2017.106 | This study provides evidence that immune complex size significantly impacts binding to FcR and thus potentially impacts effector functions. |
10.4049/jimmunol.170.7.3621 | 60,823,164 | Abstract Despite a century of study, the relationship between Ag-specific Ig concentration and protection remains poorly understood for the majority of pathogens. In certain conditions, administration of high Ab doses before challenge with an infectious agent can be less effective than smaller Ab doses, a phenomenon wh... | 10.1038/nri.2017.106 | In a mouse model of Cryptococcus neoformans infection, the authors demonstrate the challenges of passive immune therapy against a microorganism, as the overall impact of a monoclonal antibody is protective, non-protective or disease-enhancing depending on the pathogen inoculum. |
10.4049/jimmunol.169.3.1379 | 68,474,635 | Abstract Ab specificity is determined by V region sequence. The murine Mab 18B7 (IgG1) binds to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan and produces annular immunofluorescence (IF) on yeast cells. The heavy and light V regions of 18B7 were expressed with the human C regions μ, γ1, γ2, γ3... | 10.1038/nri.2017.106 | The impact of the antibody Fc domain on the Fab domain is shown in this study, with isotype changes that alter antibody specificity to the Cryptococcus polysaccharide capsule. |
10.1073/pnas.0700999104 | 119,727,214 | Dendritic cells (DCs) are capable of initiating adaptive immune responses against infectious agents by presenting pathogen-derived antigens on MHC molecules to naïve T cells. Because of their key role in priming adaptive immunity, it is expected that interfering with DC function would be advantageous to the pathogen. W... | 10.1038/nri.2017.106 | References 169 and 170 provide evidence of antibody-controlled trafficking of bacteria within a cell, directing opsonized microorganisms to lysosomes for direct destruction and further antigen processing and presentation to induce innate and adaptive immune responses. |
10.1073/pnas.172229899 | 60,319,921 | The botulinum neurotoxins (BoNTs) cause the paralytic human disease botulism and are one of the highest-risk threat agents for bioterrorism. To generate a pharmaceutical to prevent or treat botulism, monoclonal antibodies (mAbs) were generated by phage display and evaluated for neutralization of BoNT serotype A (BoNT/A... | 10.1038/nri.2017.106 | Multiple non-overlapping monoclonal antibodies are used in this paper to demonstrate synergism. Here, the combination of three antibodies drives more effective neutralization against botulinum toxin compared with the lack of any protection seen when used individually. |
10.1182/blood-2009-10-248609 | 61,262,418 | Abstract The anti-CD20 monoclonal antibody (mAb) rituximab has been used successfully for lymphoma therapy for more than 10 years. Although several direct mechanisms by which anti-CD20 mAbs act have been characterized in vitro, their specific role in clinical efficacy is still debated. Little is known about the possibl... | 10.1038/nri.2017.106 | Using antitumour monoclonal antibodies, references 194 and 195 show that in addition to the short-term FcR-mediated ADCC observed upon passive immunization in human FcR-transgenic mice, antibodies can drive adaptive cellular immunity to the tumour, resulting in long-term antitumour activity. |
10.1073/pnas.92.5.1347 | 17,822,338 | Ceramide, a lipid mediator, has been most closely associated with antiproliferative activities. In this study, we examine the mechanism by which ceramide induces growth suppression and the role of the retinoblastoma gene product (Rb) in this process. Withdrawal of serum from the serum-dependent MOLT-4 cells resulted in... | 10.1038/nrc1411 | Defines an RB-dependent mechanism by which ceramide induces growth arrest. |
10.4049/jimmunol.1401109 | 17,876,166 | Abstract Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immun... | 10.1038/nri3845 | This paper shows that the therapeutic activity of high-dose intratumoural IFNβ relies on IFNAR signalling in endothelial cells and the consequent ablation of the tumour vasculature. |
10.1126/science.1068768 | 29,201,609 | Immunoglobulin (Ig) loci are selectively activated for transcription and rearrangement during B lymphocyte development. Using fluorescence in situ hybridization, we show that Ig heavy (H) and Igκ loci are preferentially positioned at the nuclear periphery in hematopoietic progenitors and pro-T cells but are centrally c... | 10.1038/nri1458 | This paper was the first to show that the immunoglobulin-gene loci change their spatial position in the nucleus as a function of B-cell differentiation. Subnuclear positioning might regulate transcription, as well as V(D)J recombination. |
10.1101/gad.291504 | 83,000,454 | The subnuclear location and chromatin state of the immunoglobulin heavy-chain ( IgH ) locus have been implicated in the control of V(D)J recombination. V H -to- DJ H rearrangement of distal, but not proximal V H genes, furthermore, depends on the B-lineage commitment factor Pax5 (BSAP). Here we demonstrate that ectopic... | 10.1038/nri1458 | This report showed that PAX5 activates locus contraction and distal V H -to-DJ H rearrangements in pro-B cells. An unknown factor that is present in pro-B cells collaborates with PAX5 in these processes. |
10.1101/gad.12.12.1801 | 123,861,953 | Allelic exclusion in κ light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional κ light chain on the surface of the B cell leads to an intracellular signal that down-regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a fee... | 10.1038/nri1458 | This paper showed that the κ-chain gene is fully methylated on both alleles early in lymphoid development, but it undergoes monoallelic demethylation in pre-B cells before rearrangement. This was the first report that epigenetic modifications underlie the process of allelic exclusion. |
10.1002/art.38098 | 62,272,311 | Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new ... | 10.1038/nrdp.2015.2 | This paper describes the revised classification criteria for systemic sclerosis. |
10.1002/art.38288 | 40,750,359 | Objective Systemic sclerosis (SSc)–related interstitial lung disease (ILD) is one of the leading causes of mortality. We undertook this study to analyze the gene expression of lung tissue in a prospective cohort of patients with SSc‐related ILD and to compare it with that in control lungs and with 2 prospective clinica... | 10.1038/nrdp.2015.2 | This paper highlights the role of innate immunity and macrophages in systemic sclerosis-associated interstitial lung disease. |
10.1126/scisignal.2004592 | 122,199,175 | DNA damage not only promotes a mitotic checkpoint response but also activates a pathway that can produce fibrotic disease. | 10.1038/nrdp.2015.2 | This study implicates oxidative stress and WNT signalling as key drivers in tissue damage and fibrosis. |
10.1002/art.24038 | 40,740,882 | Abstract Objective To identify in patients with Raynaud's phenomenon (RP) independent markers that predict progression to definite systemic sclerosis (SSc) and to determine in patients with progression to SSc the type and sequence of microvascular damage and its relationship to SSc‐specific autoantibodies. Methods Cons... | 10.1038/nrdp.2015.2 | This paper reinforces that Raynaud phenomenon precedes and can predict development of systemic sclerosis in some cases. |
10.3899/jrheum.090375 | 103,821,182 | Objective. We studied a large clinical practice and multicenter database to estimate the minimally important difference (MID) in systemic sclerosis (SSc) using global rating of change anchors for the Health Assessment Questionnaire-Disability Index (HAQ-DI) and visual analog scale (VAS) in pain, fatigue, sleep, global ... | 10.1038/nrdp.2015.2 | This study defines the minimally important differences in patient-reported outcomes. |
10.1002/art.27549 | 124,556,755 | Abstract Objective This study was undertaken to examine the temporal relationship between scleroderma development and malignancy, and to evaluate whether this differs by autoantibody status among affected patients. Methods Study participants had a diagnosis of scleroderma, a diagnosis of cancer, cancer, an available se... | 10.1038/nrdp.2015.2 | This seminal study provides potential mechanistic links between cancer and systemic sclerosis. Its clinical and biological relevance might provide future insights into aetiopathogenesis of dsSSc. |
10.1126/science.1177486 | 83,540,122 | Growing on You The human gut and skin harbor diverse microbial communities that are known to vary strikingly among individuals. Here, Costello et al. (p. 1694 , published online 5 November) analyzed microbial diversity among several distinct body habitats (including the gut, mouth, inside the ears and nose, and skin) o... | 10.1038/nrg3129 | This paper was the first to establish that the microbial communities harboured across the human body are personalized but vary substantially across body sites and over time. |
10.1073/pnas.0904489106 | 41,758,151 | We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary... | 10.1038/nrg3129 | The authors of this paper suggest a link between a person's microbiome and their ability to metabolize a common drug, paracetamol (acetaminophen). |
10.1073/pnas.1000081107 | 125,323,192 | The colonization process of the infant gut microbiome has been called chaotic, but this view could reflect insufficient documentation of the factors affecting the microbiome. We performed a 2.5-y case study of the assembly of the human infant gut microbiome, to relate life events to microbiome composition and function.... | 10.1038/nrg3129 | This paper describes a two-year longitudinal study of the development of the gut microbiota in an infant. This work provides a detailed analysis of the relationship between life events and changes in microbiome composition and function. |
10.1128/aem.71.12.8228-8235.2005 | 41,655,395 | ABSTRACT We introduce here a new method for computing differences between microbial communities based on phylogenetic information. This method, UniFrac, measures the phylogenetic distance between sets of taxa in a phylogenetic tree as the fraction of the branch length of the tree that leads to descendants from either o... | 10.1038/nrg3129 | This study introduces UniFrac, a phylogenetically aware measure of similarity, and one of the most widely used methods to establish the extent to which different microbial communities resemble each other. |
10.1073/pnas.1102938108 | 20,833,498 | The proportion of the human gut bacterial community that is recalcitrant to culture remains poorly defined. In this report, we combine high-throughput anaerobic culturing techniques with gnotobiotic animal husbandry and metagenomics to show that the human fecal microbiota consists largely of taxa and predicted function... | 10.1038/nrg3129 | This paper showed that a substantial proportion of an individual's gut microbiota can be recaptured using anaerobic culturing conditions, both in vitro and in vivo |
10.1073/pnas.192568299 | 123,358,799 | Most models of the primitive atmosphere around the time life originated suggest that the atmosphere was dominated by carbon dioxide, largely based on the notion that the atmosphere was derived via volcanic outgassing, and that those gases were similar to those found in modern volcanic effluent. These models tend to dow... | 10.1038/nrmicro1595 | References 1–3 provide insights into the possible roles of CO in primordial organic syntheses. |
10.1073/pnas.97.4.1851 | 103,637,633 | Nitric oxide (NO) and carbon monoxide (CO) seem to be neurotransmitters in the brain. The colocalization of their respective biosynthetic enzymes, neuronal NO synthase (nNOS) and heme oxygenase-2 (HO2), in enteric neurons and altered intestinal function in mice with genomic deletion of the enzymes ( nNOS Δ/Δ and HO2 Δ/... | 10.1038/nrmicro1595 | References 10–15 document the importance of CO production by haem oxygenase-1 and CO-based signalling in animals, and summarize a potential application for reducing rejection of transplanted organs. |
10.1128/mr.60.4.609-640.1996 | 41,771,950 | Production and consumption processes in soils contribute to the global cycles of many trace gases (CH4, CO, OCS, H2, N2O, and NO) that are relevant for atmospheric chemistry and climate. Soil microbial processes contribute substantially to the budgets of atmospheric trace gases. The flux of trace gases between soil and... | 10.1038/nrmicro1595 | This reference provides a thorough review of CO and other gases produced and consumed in soils. |
10.1046/j.1365-2486.2002.00545.x | 79,811,639 | Abstract Carbon monoxide (CO) plays a major role in tropospheric chemical dynamics. Accordingly, global CO budgets have been reasonably well documented. Atmospheric CO consumption by soils contributes significantly to these budgets, with the magnitude of the sink generally considered to reflect a balance between microb... | 10.1038/nrmicro1595 | This study documents the production of CO by plant roots and associated oxidation by rhizosphere bacteria. |
10.1128/aem.56.12.3727-3734.1990 | 42,627,317 | The novel thermophilic CO- and H 2 -oxidizing bacterium UBT1 has been isolated from the covering soil of a burning charcoal pile. The isolate is gram positive and obligately chemolithoautotrophic and has been named Streptomyces thermoautotrophicus on the basis of G+C content (70.6 ± 0.19 mol%), a phospholipid pattern o... | 10.1038/nrmicro1595 | This paper describes the only known obligate CO oxidizer, a thermophilic streptomycete isolated from a smouldering coal pile. |
10.1128/aem.59.12.4161-4165.1993 | 27,958,968 | Strains of Rhizobium forming nitrogen-fixing symbioses with common bean were systematically examined for the presence of the uptake hydrogenase ( hup ) structural genes and expression of uptake hydrogenase (Hup) activity. DNA with homology to the hup structural genes of Bradyrhizobium japonicum was present in 100 of 24... | 10.1038/nrmicro1595 | References 119–127 show parallels between hydrogen and CO dynamics and significance in rhizobia–legume symbioses. |
10.1073/pnas.0900653106 | 101,005,140 | The tyrosine kinase Bcr-Abl causes chronic myeloid leukemia and is the cognate target of tyrosine kinase inhibitors like imatinib. We have charted the protein–protein interaction network of Bcr-Abl by a 2-pronged approach. Using a monoclonal antibody we have first purified endogenous Bcr-Abl protein complexes from the ... | 10.1038/nrc2900 | This paper uses interaction proteomics to map the core protein network involved in signalling by the BCR–ABL1 oncogene and also examines the effects of the BCR–ABL1 kinase inhibitor imatinib on the network |
10.1158/0008-5472.can-08-2515 | 16,838,436 | Abstract Integrins interact with extracellular matrix (ECM) and deliver intracellular signaling for cell proliferation, survival, and motility. During tumor metastasis, integrin-mediated cell adhesion to and migration on the ECM proteins are required for cancer cell survival and adaptation to the new microenvironment. ... | 10.1038/nrc2900 | This study uses a combination of quantitative proteomics and functional siRNA experiments to identify proteins that mediate integrin-regulated cell adhesion and migration |
10.1126/scisignal.2000526 | 81,562,373 | Protein O-GlcNAcylation regulates cell division. | 10.1038/nrc2900 | This paper shows that O-GlcNAcylation competes with phosphorylation and plays a major part in the regulation of mitotic spindle assembly and cytokinesis |
10.1126/scisignal.2000316 | 109,107,522 | Comparing the human phosphoproteome to that of flies, worms, and yeast reveals insight into evolution and disease. | 10.1038/nrc2900 | Here, the reconstruction of kinase–substrate networks based on phosphoproteomics data and evolutionary conservation of the phoshorylation sites revealed that several diseases, including cancer, affect conserved parts of the phosphorylation networks |
10.1126/science.1225437 | 19,560,243 | DNA Repair in Vitro Accurate replication of the genome is critical to an organism's continued survival. Damaged DNA not repaired before the commencement of replication can cause the DNA replication fork to stall or collapse, which can result in mutation or recombination, with potentially serious consequences for cell a... | 10.1038/nrm3935 | The direct visualization of fork reversal and restart in the bacteriophage T4 system illustrated the dynamics of strand exchange and protein turnover at the replication fork. |
10.1126/science.1074023 | 81,088,080 | Checkpoint-mediated control of replicating chromosomes is essential for preventing cancer. In yeast, Rad53 kinase protects stalled replication forks from pathological rearrangements. To characterize the mechanisms controlling fork integrity, we analyzed replication intermediates formed in response to replication blocks... | 10.1038/nrm3935 | This is the first visualization of reversed replication forks in S. cerevisiae , linking fork reversal with checkpoint defects. |
10.1083/jcb.201406099 | 125,251,182 | Replication fork reversal protects forks from breakage after poisoning of Topoisomerase 1. We here investigated fork progression and chromosomal breakage in human cells in response to a panel of sublethal genotoxic treatments, using other topoisomerase poisons, DNA synthesis inhibitors, interstrand cross-linking induce... | 10.1038/nrm3935 | This paper shows that RAD51-dependent replication fork reversal is a global response to a wide variety of replication perturbations. |
10.1083/jcb.201212058 | 82,081,113 | Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slo... | 10.1038/nrm3935 | This paper shows that oncogenes that deregulate DNA replication cause fork reversal, and that the cleavage of reversed forks contributes to oncogene-induced genome instability. |
10.1073/pnas.1415025111 | 19,511,236 | Significance All phases of DNA replication are tightly regulated to ensure that daughter cells inherit a precise copy of the genomic DNA. Although the mechanisms regulating initiation and elongation have been well characterized, the process of how cells recognize replicated regions and complete replication at the preci... | 10.1038/nrm3935 | This study shows that replication termination in E. coli depends on DSB-processing factors and RecG, and involves over-replication of the termination sequence. |
10.1126/science.287.5452.501 | 104,325,817 | Although ubiquitinated histones are present in substantial levels in vertebrate cells, the roles they play in specific biological processes and the cellular factors that regulate this modification are not well characterized. Ubiquitinated H2B (uH2B) has been identified in the yeast Saccharomyces cerevisiae , and mutati... | 10.1038/nrm1049 | Identified Rad6 as a Ub-conjugating enzyme for histone H2B in budding yeast and opened the way for genetic analysis of histone ubiquitylation. |
10.1126/science.1069490 | 58,552,095 | The 19 S proteasome regulatory particle plays a critical role in cellular proteolysis. However, recent reports have demonstrated that 19 S proteins play a nonproteolytic role in nucleotide excision repair and transcription elongation. We show by chromatin immunoprecipitation assays that proteins comprising the 19 S com... | 10.1038/nrm1049 | Showed that components of the 19S proteasome are recruited to a transcriptionally-active gene in yeast. |
10.1073/pnas.072068399 | 101,610,145 | Transcription-coupled repair (TCR) is essential for the rapid, preferential removal of DNA damage in active genes. The large subunit of RNA polymerase (Pol) II is ubiquitinated in cells after UV-irradiation or cisplatin treatment, which induces DNA damage preferentially repaired by TCR. Several human mutations, such as... | 10.1038/nrm1049 | Provided biochemical evidence that DNA-damage-dependent ubiquitylation of RNA polymerase II is coupled to transcription. |
10.1101/gad.944801 | 123,926,206 | The Wnt-responsive transcription factor LEF1 can activate transcription in association with β-catenin and repress transcription in association with Groucho. In search of additional regulatory mechanisms of LEF1 function, we identified the protein inhibitor of activated STAT, PIASy, as a novel interaction partner of LEF... | 10.1038/nrm1049 | Established a solid connection between SUMO-modification of a transcription factor, transcriptional regulation and PML-body formation. |
10.1073/pnas.162424199 | 17,718,746 | The heterodimeric Elongin BC complex has been shown to interact in vitro and in cells with a conserved BC-box motif found in an increasing number of proteins including RNA polymerase II elongation factor Elongin A, suppressor of cytokine signaling (SOCS)-box proteins, and the von Hippel–Lindau tumor suppressor protein.... | 10.1038/nrm1049 | Established that Ub-ligase activity is directly associated with the RNA polymerase II holoenzyme. |
10.1101/gad.867501 | 16,748,159 | The budding yeast transcriptional activator Gcn4 is rapidly degraded in an SCF Cdc4 -dependent manner in vivo. Upon fractionation of yeast extracts to identify factors that mediate Gcn4 ubiquitination, we found that Srb10 phosphorylates Gcn4 and thereby marks it for recognition by SCF Cdc4 ubiquitin ligase. Srb10 is a ... | 10.1038/nrm1049 | Showed that the yeast transcription factor GCN4 is marked for destruction by a kinase that is present in the RNA polymerase II holoenzyme. |
10.1126/science.1062079 | 19,616,876 | The ability of transcriptional activation domains (TADs) to signal ubiquitin-mediated proteolysis suggests an involvement of the ubiquitin-proteasome pathway in transcription. To probe this involvement, we asked how ubiquitylation regulates the activity of a transcription factor containing the VP16 TAD. We show that th... | 10.1038/nrm1049 | Showed that ubiquitylation of a transcription factor bearing the prototypical VP16 activation domain can be required for transcriptional activation. |
10.4049/jimmunol.1000679 | 80,125,784 | Abstract T cell development is marked by the loss of alternative lineage choices accompanying specification and commitment to the T cell lineage. Commitment occurs between the CD4 and CD8 double-negative (DN) 2 and DN3 stages in mouse early T cells. To determine the gene regulatory changes that accompany commitment, we... | 10.1038/nri3702 | References 27 and 28 reveal the timing of T cell lineage commitment, showing its clear separation from TCR-dependent events and defining its basis in terms of changes in regulatory gene expression. |
10.1126/science.1182378 | 39,470,613 | It's All About Self-Renewal The Lmo2 oncogene was identified as a contributing factor in human T cell acute lymphoblastic leukemia (T-ALL) nearly two decades ago, but the gene rose to prominence in 2003 when its inadvertent activation by a retroviral vector was shown to cause leukemia in two patients in a gene therapy ... | 10.1038/nri3702 | In this paper, the authors use fate mapping to demonstrate the role of Lmo2 in inducing self-renewal in early T cells, which can lead to leukaemia initiation. This role of Lmo2 is a prototype for linking natural thymocyte proliferative expansion with oncogenesis. |
10.1182/blood-2012-06-440065 | 81,130,036 | Key Points Gata3 is critical for the transition of “double-negative” (DN) thymocyte DN1 to DN2. Gata3 represses a latent B-cell potential in DN thymocytes. | 10.1038/nri3702 | This paper identifies GATA3 as the crucial intrinsic regulatory factor in the earliest T cell lineage precursor cells that is responsible for excluding access to the B cell lineage. |
10.1182/blood-2012-08-449447 | 67,240,305 | Key Points GATA3 is elevated in E2A−/− DN2 cells. GATA3 contributes to arrested T-cell development from E2A−/− DN2 cells. | 10.1038/nri3702 | This paper reveals that GATA3 activity must be kept under inhibitory restraint by the same bHLH E proteins that also collaborate with it to drive T cell specification. This is shown to be one important way in which E2A promotes successful T cell commitment. |
10.1126/science.278.5341.1291 | 29,285,435 | In evaluating current combination drug regimens for treatment of human immunodeficiency virus (HIV) disease, it is important to determine the existence of viral reservoirs. After depletion of CD8 cells from the peripheral blood mononuclear cells (PBMCs) of both patients and normal donors, activation of patient CD4 lymp... | 10.1038/nrmicro1580 | Refs 4, 5 and 6 demonstrate that latently infected cells persist in patients in whom HAART has suppressed viraemia to undetectable levels. |
10.1073/pnas.0736332100 | 19,076,992 | Viral replication and latently infected cellular reservoirs persist in HIV-infected patients achieving undetectable plasma virus levels with potent antiretroviral therapy. We exploited a predictable drug resistance mutation in the HIV reverse transcriptase to label and track cells infected during defined intervals of t... | 10.1038/nrmicro1580 | An elegant study that follows the decay of infected cells carrying viruses with a particular drug-resistance mutation. This study also provides evidence for the lifetime persistence of HIV-1. |
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