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10.1073/pnas.0509249103
63,086,713
Naturally occurring CD4 + CD25 + T regulatory (Treg) cells have been shown to inhibit adaptive responses by T cells. Natural killer (NK) cells represent an important component of innate immunity in both cancer and infectious disease states. We investigated whether CD4 + CD25 + Treg cells could affect NK cell function i...
10.1038/nri1863
References 62 and 63 provide novel evidence that T Reg cells can inhibit the function of NK cells, raising the possibility that such T cells might have a role in NK-cell self-tolerance.
10.1146/annurev.med.57.110104.115650
123,205,208
Following the demonstration of the nature of the enzymatic defects in the sphingolipid storage disorders in the mid-1960s, consideration was directed to the development of therapy for patients with these conditions. High on the list of possibilities was enzyme supplementation or replacement. Many years of arduous inves...
10.1038/nrd.2017.214
This is a review by the pioneer Brady describing the development of ERT for LSDs.
10.1146/annurev.biochem.031209.093756
58,485,084
My postdoctoral training in the biosynthesis of plant polysaccharides at the University of California, Berkeley, led me, rather improbably, to study mucopolysaccharide storage disorders in the intramural program of the National Institutes of Health (NIH). I have traced the path from studies of mucopolysaccharide turnov...
10.1038/nrd.2017.214
This is a definitive review by the pioneer Neufeld on the discovery of cross-correction and its application to LSD therapies.
10.1126/science.276.5311.428
59,248,883
The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesis N -butyldeoxynojirimycin, was evaluated in a mouse m...
10.1038/nrd.2017.214
This study provides in vivo evidence that SRT could reduce storage in peripheral organs and the CNS, paving the way for the approval of miglustat for the treatment of Gaucher disease and Niemann–Pick type C disease.
10.1126/scitranslmed.aad9823
81,965,220
Increasing Hsp70 expression in lysosomes using the small-molecule arimoclomol ameliorates pathology in several animal models of sphingolipidoses.
10.1038/nrd.2017.214
This study provides in vivo evidence in animal models that the HSP70 inducer arimoclomol has therapeutic benefit in multiple LSDs.
10.1073/pnas.97.20.10954
61,144,297
Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of G M2 ganglioside and related glycolipids in the central nervous system. The glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. In symptomatic Sandhoff diseas...
10.1038/nrd.2017.214
This study reports the discovery that neuroinflammation actively contributes to disease progression, underscoring the potential of anti-inflammatory therapies for LSDs.
10.1111/jpc.12632
41,566,121
Abstract Internationally, T ay‐ S achs disease ( TSD ) preconception screening of A shkenazi J ewish ( AJ ) individuals and couples has led to effective primary prevention of TSD . In A ustralia, adolescent preconception genetic screening programs operate mainly in J ewish community high schools. These existing program...
10.1038/nrd.2017.214
This is a study describing the benefits of carrier screening for the prevention of Tay–Sachs disease in the Ashkenazi Jewish community.
10.1073/pnas.91.10.4234
16,765,115
We report on the isolation of mouse cDNA clones which encode a collagenous sequence designated here as the alpha 1 chain of type XVIII collagen. The overlapping clones cover 2.8 kilobases and encode an open reading frame of 928 amino acid residues comprising a putative signal peptide of 25 residues, an amino-terminal n...
10.1038/nrm1702
References 3 and 4 provide the first reports on collagen XVIII.
10.1073/pnas.97.12.6722
82,433,635
Perlecan, a heparan sulfate proteoglycan, has been suggested to be critical for regulation of vascular repair. We generated clones of endothelial cells expressing an antisense vector targeting domain III of perlecan. Transfected cells produced significantly less perlecan than parent cells and showed a reduced ability t...
10.1038/nrm1702
Presents compelling evidence for a role of perlecan in vascular injury.
10.1093/oso/9780198566311.003.0009
149,265,415
Abstract Conventional cancer chemotherapeutic agents lack selectivity and in the past effort has mainly been focused on high-dose systemic chemotherapy, which tried to balance minimal adverse effects to normal tissues with maximal antitumour activity. To achieve selectivity, the focus since the 1960s has been to search...
10.1038/nrd2468
This review summarizes the recent progress of ADEPT for cancer treatment.
10.1126/science.1228984
18,636,811
Powering LPS Export The surface of Gram-negative bacteria such as Escherichia coli is covered in lipopolysaccharide (LPS), which must be synthesized within the cytoplasm and then exported across the periplasm to the outer leaflet of the outer membrane. Okuda et al. (p. 1214 , published online 8 November) describe the d...
10.1038/nrmicro.2016.25
This study describes the first observation of intermediate LPS transport states in living cells.
10.1073/pnas.1323516111
104,077,049
Significance Gram-negative bacteria contain an unusual outer membrane that prevents the entry of most currently available antibiotics. This membrane contains a complex glycolipid, LPS, on the exterior. It is not understood how such a large molecule, which can contain hundreds of sugars and six fatty acyl chains, is tra...
10.1038/nrmicro.2016.25
This paper provides the first biochemical and genetic evidence that LPS transport is powered by ATP hydrolysis by LptB.
10.1016/j.febslet.2009.05.051
62,531,773
MINT‐7137160: lptb (uniprotkb:P0A9V1) physically interacts (MI:0914) with lptf (uniprotkb:P0AF98) and lptg (uniprotkb:P0ADC6) by pull down (MI:0096)
10.1038/nrmicro.2016.25
This study describes the purification of the LptBFGC complex at the IM.
10.1073/pnas.1015617108
36,507,166
The cell surfaces of Gram-negative bacteria are composed of lipopolysaccharide (LPS). This glycolipid is found exclusively in the outer leaflet of the asymmetric outer membrane (OM), where it forms a barrier to the entry of toxic hydrophobic molecules into the cell. LPS typically contains six fatty acyl chains and up t...
10.1038/nrmicro.2016.25
This paper establishes that LptD and LptE form a plug-and-barrel structure and suggests that membrane insertion proceeds through a lateral gate in a proline-rich region of the β-barrel of LptD.
10.1101/gad.209901
41,560,565
Chromatin remodeling is an important step in promoter activation during cellular lineage commitment and differentiation. We show that the ability of the C/EBPα transcription factor to direct adipocyte differentiation of uncommitted fibroblast precursors and to activate SWI/SNF-dependent myeloid-specific genes depends o...
10.1038/nrg1882
These authors demonstrated that SWI/SNF enzymes facilitated adipogenic differentiation through interaction with an adipogenic activator.
10.1101/gad.10.17.2117
103,681,545
The SWI/SNF complex in yeast facilitates the function of transcriptional activators by opposing chromatin-dependent repression of transcription. We demonstrate that in mammals SWI/SNF complexes are present in multiple forms made up of 9-12 proteins that we refer to as BRG1-associated factors (BAFs) ranging from 47 to 2...
10.1038/nrg1882
Cloning of the genes encoding subunits of SWI/SNF complexes revealed gene families and tissue-specific expression of some genes, advancing the concept that chromatin-remodelling enzymes could be modified for specific functions by the inclusion or exclusion of individual enzyme subunits.
10.1101/gad.1319105
100,786,070
Precise control of cell proliferation and differentiation is critical for organogenesis. Geminin (Gem) has been proposed to link cell cycle exit and differentiation as a prodifferentiation factor and plays a role in neural cell fate acquisition. Here, we identified the SWI/SNF chromatin-remodeling protein Brg1 as an in...
10.1038/nrg1882
The cell-cycle regulator geminin, which was previously implicated in neural-cell-fate acquisition, was shown to function in maintaining the undifferentiated state by antagonizing the pro-differentiation function of the BRG1 subunit of SWI/SNF enzymes during neurogenesis.
10.1093/genetics/160.1.333
123,141,912
Abstract How new discrete states of morphological traits evolve is poorly understood. One possibility is that single-gene changes underlie the evolution of new discrete character states and that evolution is dependent on the occurrence of new single-gene mutations. Another possibility is that multiple-gene changes are ...
10.1038/nrg1426
An empirical study of cryptic genetic variation in which quantitative trait locus mapping was used to identify modifiers of traits that emerge in the cross between teosinte and maize, but that are invariant in teosinte.
10.1126/science.271.5246.200
61,175,332
Development is buffered against unpredictable environmental and genetic effects. Here, a molecular genetic analysis of one type of developmental homeostasis, the establishment of thoracic segmental identity under the control of the Ultrabithorax ( Ubx ) gene in Drosophila melanogaster , is presented. Flies were artific...
10.1038/nrg1426
This reconstitution of a classic experiment involving artificial selection on phenocopy induction by ether vapour was the first to pinpoint an actual gene that is responsible for cryptic genetic variation.
10.1126/science.1065810
82,755,186
In Saccharomyces cerevisiae , more than 80% of the ∼6200 predicted genes are nonessential, implying that the genome is buffered from the phenotypic consequences of genetic perturbation. To evaluate function, we developed a method for systematic construction of double mutants, termed synthetic genetic array (SGA) analys...
10.1038/nrg1426
The first systematic, synthetic lethal screen, demonstrating the enormous potential for two-locus interactions to produce novel phenotypes.
10.1126/science.1194637
20,828,539
Primitive Origins for Microglia Microglia are the resident macrophages of the central nervous system and are associated with neurodegeneration and brain inflammatory diseases. Although the developmental origins of other tissue macrophage populations are well established, the origins of microglia remain controversial. G...
10.1038/nri2971
This study demonstrated that microglial cells are derived from primitive myeloid precursors rather than haematopoietic cells.
10.1126/science.1110647
104,394,772
Microglial cells represent the immune system of the mammalian brain and therefore are critically involved in various injuries and diseases. Little is known about their role in the healthy brain and their immediate reaction to brain damage. By using in vivo two-photon imaging in neocortex, we found that microglial cells...
10.1038/nri2971
This study used TPLSM to show that microglial processes are highly dynamic and continually scan the naive brain parenchyma.
10.1126/science.1164164
26,881,953
Reactivation of herpes simplex virus type 1 (HSV-1) from neuronal latency is a common and potentially devastating cause of disease worldwide. CD8 + T cells can completely inhibit HSV reactivation in mice, with interferon-γ affording a portion of this protection. We found that CD8 + T cell lytic granules are also requir...
10.1038/nri2971
This study revealed an interesting mechanism by which CTLs use lytic granules to non-cytopathically control HSV-1 in latently infected neurons.
10.1126/science.1075901
29,295,833
COP9 signalosome (CSN) cleaves the ubiquitin-like protein Nedd8 from the Cul1 subunit of SCF ubiquitin ligases. The Jab1/MPN domain metalloenzyme (JAMM) motif in the Jab1/Csn5 subunit was found to underlie CSN's Nedd8 isopeptidase activity. JAMM is found in proteins from archaea, bacteria, and eukaryotes, including the...
10.1038/nrm1908
Discovery of a novel metalloprotease domain in CSN complex that is responsible for deubiquitylation and/or deneddylation activities.
10.1126/science.1120615
80,126,628
Translesion synthesis (TLS) is the major pathway by which mammalian cells replicate across DNA lesions. Upon DNA damage, ubiquitination of proliferating cell nuclear antigen (PCNA) induces bypass of the lesion by directing the replication machinery into the TLS pathway. Yet, how this modification is recognized and inte...
10.1038/nrm1908
Describes two novel ubiquitin binding domains, UBM and UBZ, that allow Y-family TLS polymerases to interact with monoubiquitylated PCNA.
10.1126/science.1254257
104,261,992
Cancer at single-cell resolution Single-cell sequencing can illuminate the genetic properties of brain cancers and reveal heterogeneity within a tumor. Patel et al. examined the genome sequence of single cells isolated from brain glioblastomas. The findings revealed shared chromosomal changes but also extensive transcr...
10.1038/nrg3833
This paper provides an example in which sequencing the transcriptomes of a large number of single cells provided important insights into intra- and inter-tumour heterogeneity.
10.1126/science.1076194
38,570,742
Apoptosis-inducing factor (AIF), a mitochondrial oxidoreductase, is released into the cytoplasm to induce cell death in response to apoptotic signals. However, the mechanisms underlying this process have not been resolved. We report that inactivation of the Caenorhabditis elegans AIF homolog wah-1 by RNA interference d...
10.1038/nrm1836
References 23?26 present interesting evidence that engulfment or DNA degradation of apoptotic cells also contribute to cell killing.
10.1242/dev.00597
58,530,442
The NSM cells of the nematode Caenorhabditis elegans differentiate into serotonergic neurons, while their sisters, the NSM sister cells, undergo programmed cell death during embryogenesis. The programmed death of the NSM sister cells is dependent on the cell-death activator EGL-1, a BH3-only protein required for progra...
10.1038/nrm1836
Convincing genetic and biochemical work that describes a transcriptional pathway that regulates apoptosis in the two sister cells of the NSM neurons in C. elegans
10.4049/jimmunol.164.7.3855
39,051,232
Abstract Immunization of BALB/c mice with alum-adsorbed OVA, followed by three bronchoprovocations with aerosolized OVA, resulted in the development of airway hyperresponsiveness (AHR) and allergic inflammation in the lung accompanied by severe infiltration of eosinophils into airways. In this murine asthma model, admi...
10.1038/nri914
References 13 and 14 identify crucial roles for mast cells in the airway hyperresponsiveness (references 13 and 14 ) and airway inflammation (reference 13 ) that is induced by relatively 'weak' immunological stimulation.
10.1073/pnas.92.20.9201
45,532,183
Detergent-resistant plasma membrane structures, such as caveolae, have been implicated in signalling, transport, and vesicle trafficking functions. Using sucrose gradient ultracentrifugation, we have isolated low-density, Triton X-100-insoluble membrane domains from RBL-2H3 mucosal mast cells that contain several marke...
10.1038/nri914
This study, and other papers by this group, initiated the current series of studies on the role of lipid rafts in mast-cell activation and other examples of immunoreceptor-triggered cell activation.
10.1083/jcb.149.5.1131
58,554,681
We have determined the membrane topography of the high-affinity IgE receptor, FcεRI, and its associated tyrosine kinases, Lyn and Syk, by immunogold labeling and transmission electron microscopic (TEM) analysis of membrane sheets prepared from RBL-2H3 mast cells. The method of Sanan and Anderson (Sanan, D.A., and R.G.W...
10.1038/nri914
This paper analyses the localization of FcɛRI and signalling molecules on the mast-cell plasma membrane using electron microscopy.
10.3390/cells10071697
135,355,823
The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type o...
10.1038/nri914
References 66–68 describe IgE-dependent enhancement of FcɛRI cell-surface expression and its functional relevance to antigen-dependent mast-cell activation. An IgE-initiated positive-feedback mechanism ( Fig. 3 ) is also proposed (references 67 and 68
10.1084/jem.194.11.1561
100,820,830
Mast cells reside in tissues, where upon activation through the high-affinity-IgE-receptor (FcϵRI) they degranulate and orchestrate the allergic reaction. Mast cells survive this activation and can thus be reactivated. In this study we demonstrate that this process depends on the pro-survival gene A1. Activation of mas...
10.1038/nri914
References 87 and 88 identify the ability of FcɛRI aggregation to enhance mast-cell survival.
10.1101/gr.133728.111
62,408,061
Cross-talk between DNA methylation and histone modifications drives the establishment of composite epigenetic signatures and is traditionally studied using correlative rather than direct approaches. Here, we present sequential ChIP-bisulfite-sequencing (ChIP-BS-seq) as an approach to quantitatively assess DNA methylati...
10.1038/nrg.2017.57
In this study, the authors show that DNA methylation and H3K27me3 are mutually exclusive at CpG islands and that loss of DNA methylation leads to reduced H3K27me3 at bivalent promoters.
10.1126/science.1262088
62,216,304
Keeping repressed genes repressed Hox genes confer positional identity to cells and tissues. Maintaining precise spatial patterns of Hox gene expression is vital during metazoan development. The transcriptional repressor CTCF is involved in the regulation of chromatin architecture. Narendra et al. show that a CTCF prot...
10.1038/nrg.2017.57
In this paper, the authors delete the CTCF-binding site within the HOX cluster to show that CTCF insulates TADs and prevents the spreading of epigenetic marks to neighbouring TADs.
10.1084/jem.194.6.769
103,843,520
Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a ...
10.1038/nri2173
References 17 and 18 show that targeting antigen to DCs without providing a maturation stimulus induces tolerance.
10.4049/jimmunol.177.4.2276
101,081,471
Abstract Targeting of Ags and therapeutics to dendritic cells (DCs) has immense potential for immunotherapy and vaccination. Because DCs are heterogeneous, optimal targeting strategies will require knowledge about functional specialization among DC subpopulations and identification of molecules for targeting appropriat...
10.1038/nri2173
Together with references 34 and 39 , this study demonstrates that the targeting of receptors preferentially expressed on two different DC subsets can result in disparate immune responses.
10.1084/jem.20052442
123,366,183
T cells recognize protein antigens as short peptides processed and displayed by antigen-presenting cells. However, the mechanism of peptide selection is incompletely understood, and, consequently, the differences in the immunogenicity of protein antigens remain largely unpredictable and difficult to manipulate. In this...
10.1038/nri2173
This report indicates that the immunogenicity of antigens can be enhanced by preventing rapid degradation.
10.1084/jem.20051106
83,436,200
The presentation of exogenous protein antigens in a major histocompatibility complex class I–restricted fashion to CD8+ T cells is called cross-presentation. We demonstrate that cross-presentation of soluble viral antigens (derived from hepatitis C virus [HCV], hepatitis B virus [HBV], or human immunodeficiency virus) ...
10.1038/nri2173
This study shows that the cross-presentation of antigens is enhanced by a relatively simple trick: preventing endosomal acidification by co-administering the antimalarial drug chloroquine.
10.1158/0008-5472.can-05-4310
81,724,239
Abstract Dendritic cells are unique in their capacity to process antigens and prime naive CD8+ T cells. Contrary to most cells, which express the standard proteasomes, dendritic cells express immunoproteasomes constitutively. The melanoma-associated protein Melan-AMART1 contains an HLA-A2-restricted peptide that is poo...
10.1038/nri2173
An elegant example of how T cells recognizing peptide epitopes that are not generated by the immunoproteasome can be primed by DCs expressing the peptide, but not the protein, antigen.
10.1084/jem.20120822
40,782,240
Foxp3+ CD4+ T helper cells called regulatory T (T reg) cells play a key role in controlling reactivity to self-antigens and onset of autoimmunity. T reg cells either arise in thymus and are called natural T reg (nT reg) cells or are generated in the periphery through induction of Foxp3 and are called inducible T reg (i...
10.1038/nri3545
References 8 and 9 show that NRP1 is a marker of thymus-derived but not of peripherally derived T Reg cells and that it is involved in T Reg cell functions.
10.1073/pnas.1105937108
58,440,576
Spatiotemporal changes in gene expression underlie many evolutionary novelties in nature. However, the evolutionary origins of novel expression patterns, and the transcriptional control elements (“enhancers”) that govern them, remain unclear. Here, we sought to explore the molecular genetic mechanisms by which new enha...
10.1038/nrg3095
This study screened tissue-specific gene expression across multiple developmental stages among closely related species of Drosophila to identify novel expression patterns. Genetic changes responsible for these putatively novel enhancer activities were then identified.
10.1126/science.1186176
38,279,478
Subtle Variation Despite vast phenotypic differences, vertebrates have many readily recognizable specific cell types, like liver hepatocytes. The gene expression that defines specific cells depends on evolutionarily conserved orthologous transcription factors. Schmidt et al. (p. 1036 , published online 8 April) studied...
10.1038/nrg3095
This study uses ChIP coupled with next-generation sequencing to quantify the binding of two TFs in liver cells from five vertebrate species.
10.1084/jem.183.5.2283
20,453,413
Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chro...
10.1038/nrc1880
This is the first documentation of the oncogenic potential of human TAN1 in the haematopoietic system of a murine model.
10.1126/science.1102160
38,225,070
Very rare cases of human T cell acute lymphoblastic leukemia (T-ALL) harbor chromosomal translocations that involve NOTCH1 , a gene encoding a transmembrane receptor that regulates normal T cell development. Here, we report that more than 50% of human T-ALLs, including tumors from all major molecular oncogenic subtypes...
10.1038/nrc1880
Demonstrates the causative role of somatic activating mutations in NOTCH1 in the development of human T-ALL.
10.1073/pnas.260497597
65,353,107
General immunostimulants (adjuvants) are essential for generating immunity to many antigens. In bacterial infections, adjuvants are provided by components of the microorganism, e.g., lipopolysaccharide. However, it is unclear what provides the adjuvant effect for immune responses that are generated to tumors and many v...
10.1038/nri2215
References 10 and 11 identified the existence of endogenous molecules (danger signals) that function as adjuvants to promote acquired immunity.
10.1084/jem.20050390
108,246,014
Reperfusion injury (RI), a potential life-threatening disorder, represents an acute inflammatory response after periods of ischemia resulting from myocardial infarction, stroke, surgery, or trauma. The recent identification of a monoclonal natural IgM that initiates RI led to the identification of nonmuscle myosin heav...
10.1038/nri2215
This paper shows that natural IgM antibodies bind myosin released from necrotic cells in ischaemia–reperfusion injury and stimulate inflammation by activating complement.
10.1126/science.1086907
125,119,084
During B lymphocyte development, antibodies are assembled by random gene segment reassortment to produce a vast number of specificities. A potential disadvantage of this process is that some of the antibodies produced are self-reactive. We determined the prevalence of self-reactive antibody formation and its regulation...
10.1038/nri2133
This paper shows that a high frequency of early immature B cells generated during human B-cell development are self-reactive.
10.1084/jem.179.1.125
87,018,351
The life span of anergic self-reactive B cells was determined by 5-bromo-2'-deoxyuridine (BrdU) loading of tolerant double-transgenic (Dbl-Tg) mice produced by mating hen egg lysozyme (HEL)-transgenic mice with the corresponding immunoglobulin-transgenic (Ig-Tg) mice, the B cells of which express anti-HEL IgM and IgD. ...
10.1038/nri2133
This paper is one of several key studies that identify the short half-life of self-reactive B cells.
10.1084/jem.191.8.1443
45,025,282
Signal transduction through the B cell antigen receptor (BCR) is altered in B cells that express a receptor that recognizes self-antigen. To understand the molecular basis for the change in signaling in autoreactive B cells, a transgenic model was used to isolate a homogeneous population of tolerant B lymphocytes. Thes...
10.1038/nri2133
This paper highlights defective B-cell signalling by anergic B cells.
10.1002/anie.200701979
124,130,828
Abstract I would like to thank the Nobel Assembly of the Karolinska Institute for the opportunity to describe some recent work on RNA‐triggered gene silencing. First a few disclaimers, however. Telling the full story of gene silencing would be a mammoth enterprise that would take me many years to write and would take y...
10.1038/nrd4685
This paper provides a brief history and background on RNAi.
10.1158/2159-8290.cd-13-0900
102,937,134
Abstract RNAi is a powerful tool for target identification and can lead to novel therapies for pharmacologically intractable targets such as KRAS. RNAi therapy must combine potent siRNA payloads with reliable in vivo delivery for efficient target inhibition. We used a functional “Sensor” assay to establish a library of...
10.1038/nrd4685
This paper nicely demonstrates the in vivo use of multiple different siRNAs within the same nanoparticle and the enhanced efficacy that can be obtained from such an approach.
10.1073/pnas.1411393111
100,348,390
Significance CALAA-01 is a targeted nanoparticle containing siRNA that is a first-in-class experimental therapeutic for cancer. To our knowledge, it is the first targeted, polymer-based nanoparticle-carrying siRNA to be systemically administered to humans. Results from a human phase Ia/Ib clinical trial are presented a...
10.1038/nrd4685
This paper summarizes all the clinical and preclinical results with CALAA 01.
10.1158/2159-8290.cd-12-0429
107,231,962
Abstract RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effecti...
10.1038/nrd4685
This study reports the first human results with ALN-VSP, a lipid-based formulation of two siRNAs. It is also the first example of two siRNAs used in the clinic.
10.1200/jco.2013.55.0376
104,297,634
Purpose Atu027 is a novel liposomal RNA interference therapeutic that includes a short-interfering RNA (siRNA), which silences expression of protein kinase N3 in the vascular endothelium. Atu027 has previously been shown to inhibit local tumor invasion as well as lymph node and pulmonary metastasis in mouse cancer mode...
10.1038/nrd4685
This paper presents the first human data with Atu027, a lipid-based formulation of siRNA.
10.1073/pnas.1309566110
123,224,402
Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on an...
10.1038/nrd4685
This paper reports correlations between preclinical and clinical data for the polymer-based, drug-containing nanoparticle denoted CRLX101.
10.1073/pnas.0600479103
20,520,495
Mosquitoes ( Aedes aegypti ) were genetically modified to exhibit impaired vector competence for dengue type 2 viruses (DENV-2). We exploited the natural antiviral RNA interference (RNAi) pathway in the mosquito midgut by constructing an effector gene that expresses an inverted-repeat (IR) RNA derived from the premembr...
10.1038/nrg1870
Demonstrates the reduced ability of Aedes aegypti to function as a vector for dengue following midgut expression of an inverted-repeat RNA that is based on a viral gene.
10.1111/j.1365-2583.2005.00580.x
125,113,474
Abstract Some vector‐borne disease control strategies using transgenic mosquitoes require transgene spread to high frequency in populations. Transposable elements (TEs) are DNA sequences that replicate and transpose within the genomes of other organisms and may therefore be represented in the next generation in higher ...
10.1038/nrg1870
Examines the spread of TEs when the initial insertion sites and reinsertion sites are not always on different chromosomes, and when there are fitness costs associated with TE insertions.
10.1146/annurev.ento.49.061802.123344
27,026,544
▪ Abstract The concept that an insect species' genome could be altered in a manner that would result in the control of that species (i.e., autocidal control) or in the replacement of a pestiferous strain of the species with a more benign genotype was first proposed in the mid-twentieth century. A major research effort ...
10.1038/nrg1870
Contrasts the population genetic properties of several classical and molecular methods of gene drive and genetic suppression of populations.
10.1126/science.1117607
62,139,805
A proposed strategy to aid in controlling the growing burden of vector-borne disease is population replacement, in which a natural vector population is replaced by a population with a reduced capacity for disease transmission. An important component of such a strategy is the drive system, which serves to spread a desir...
10.1038/nrg1870
A demonstration that Wolbachia is able to show high rates of maternal transmission and cytoplasmic incompatibility after transfer into the naturally uninfected dengue vector, the mosquito Aedes aegypti
10.1126/science.1137509
61,056,278
Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we...
10.1038/nrc3002
This is the original report identifying WTX as a Wilms' tumour gene. It presents a nice story of going from observing a gene copy number change over a very short genomic region to identifying a new cancer-related gene.
10.1002/gcc.20553
60,106,498
Abstract Wilms tumor is genetically heterogeneous, and until recently only one Wilms tumor gene was known, WT1 at 11p13. However, WT1 is altered in only ∼20% of Wilms tumors. Recently a novel gene, WTX at Xq11.1, was reported to be mutated in Wilms tumors. No overlap between tumors with mutations in WTX and WT1 was not...
10.1038/nrc3002
This paper presents data from more than 100 Wilms' tumours regarding the type, frequency and co-occurrence of WT1 WTX and CTNNB1 mutations.
10.1182/blood-2002-06-1656
85,634,862
The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal he...
10.1038/nrc3002
This was the first study to examine the role of Wt1 in haematopoiesis in vivo . Creating chimaeras of Wt1 -wild-type and Wt1 -null cells, this work established that Wt1 is not required for normal haematopoiesis, but is important for robust haematopoiesis.
10.1182/blood-2008-09-177949
67,344,119
Abstract Wilms tumor 1 (WT1) mutations have recently been identified in approximately 10% of adult acute myeloid leukemia (AML) with normal cytogenetics (CN-AML) and are associated with poor outcome. Using array-based comparative genome hybridization in pediatric CN-AML samples, we detected a WT1 deletion in one sample...
10.1038/nrc3002
This study of a large panel of paediatric AMLs not only confirmed earlier reports of WT1 mutations being an independent indicator of poor prognosis, but it also provided novel data regarding the association of WT1 mutations with other genetic alterations and an assessment of WT1 mutation status in paired samples taken ...
10.1073/pnas.1117592109
41,744,226
In anaerobic biota, reducing equivalents (electrons) are transferred between different species of microbes [interspecies electron transfer (IET)], establishing the basis of cooperative behaviors and community functions. IET mechanisms described so far are based on diffusion of redox chemical species and/or direct conta...
10.1038/nrmicro.2016.93
This article demonstrates that semiconductive minerals facilitate electron transfer between microbial cells of different species.
10.1126/science.aaa4834
20,356,017
Building a biogeochemical battery Iron acts as both a source and sink of electrons for microorganisms in the environment. Some anaerobic bacteria use oxidized Fe(III) as an electron acceptor, whereas phototrophic bacteria can use reduced Fe(II) as an electron donor. Byrne et al. show that the iron-bearing mineral magne...
10.1038/nrmicro.2016.93
This article shows an emerging function of mixed-valance minerals for acting as environmental batteries to support microbial metabolisms.
10.1111/1758-2229.12204
4,855,883
Summary The multi‐heme, outer membrane c ‐type cytochrome ( c ‐ C yt) OmcB of G eobacter sulfurreducens was previously proposed to mediate electron transfer across the outer membrane. However, the underlying mechanism has remained uncharacterized. In G . sulfurreducens , the omcB gene is part of two tandem four‐gene cl...
10.1038/nrmicro.2016.93
This article describes a new class of trans-outer membrane protein complexes for electron transfer during extracellular reduction of minerals.
10.1126/science.1196526
20,531,711
Wired for Life Syntrophic bacteria live on the metabolic by-products of a partner species. The exchange of the by-products accompanies a flow of electrons in the opposite direction that helps some species grow in conditions that would otherwise be unfavorable. In mixed anaerobic cultures of two related Geobacter specie...
10.1038/nrmicro.2016.93
This article shows the direct involvement of microbial nanowires and multihaem c -type cytochromes in interspecies electron transfer.
10.1073/pnas.0900086106
83,006,227
A number of species of Gram-negative bacteria can use insoluble minerals of Fe(III) and Mn(IV) as extracellular respiratory electron acceptors. In some species of Shewanella , deca -heme electron transfer proteins lie at the extracellular face of the outer membrane (OM), where they can interact with insoluble substrate...
10.1038/nrmicro.2016.93
This is the first report of a porin–cytochrome protein complex that transfers electrons across the microbial outer membrane, which is an electrical and physical barrier, during extracellular reduction of minerals.
10.1073/pnas.1017200108
80,700,948
Some bacterial species are able to utilize extracellular mineral forms of iron and manganese as respiratory electron acceptors. In Shewanella oneidensis this involves decaheme cytochromes that are located on the bacterial cell surface at the termini of trans-outer-membrane electron transfer conduits. The cell surface c...
10.1038/nrmicro.2016.93
This article shows for the first time the structure at atomic resolution of the microbial terminal reductases that transfer electrons to mineral surfaces.
10.1073/pnas.1316156111
122,247,693
Significance Certain bacteria use complex assemblies of multiheme proteins to shuttle electrons from the inside of the cell over distances exceeding 100 Å to extracellular substrates. Recently, the first crystal structure of a representative deca-heme protein was solved, but the mechanism of electron conduction remains...
10.1038/nrmicro.2016.93
This paper describes a design principle that enables rapid electron transfer by multihaem c -type cytochromes that are key components of microbial extracellular electron transfer pathways and nanowires.
10.1073/pnas.1220823110
62,100,864
Extracellular redox-active compounds, flavins and other quinones, have been hypothesized to play a major role in the delivery of electrons from cellular metabolic systems to extracellular insoluble substrates by a diffusion-based shuttling two-electron-transfer mechanism. Here we show that flavin molecules secreted by ...
10.1038/nrmicro.2016.93
This paper provides the first evidence that secreted flavins function as cofactors of microbial terminal metal reductases, which represents an alternative to the proposed electron shuttle function of flavins.
10.1128/jb.00776-06
83,117,509
ABSTRACT Phototrophic Fe(II)-oxidizing bacteria couple the oxidation of ferrous iron [Fe(II)] to reductive CO 2 fixation by using light energy, but until recently, little has been understood about the molecular basis for this process. Here we report the discovery, with Rhodopseudomonas palustris TIE-1 as a model organi...
10.1038/nrmicro.2016.93
This paper shows that the homologues of microbial proteins that are used for extracellular Fe(III) reduction are also directly involved in extracellular Fe(II) oxidation.
10.1128/mbio.00084-15
122,554,107
ABSTRACT Direct measurement of multiple physical properties of Geobacter sulfurreducens pili have demonstrated that they possess metallic-like conductivity, but several studies have suggested that metallic-like conductivity is unlikely based on the structures of the G. sulfurreducens pilus predicted from homology model...
10.1038/nrmicro.2016.93
This publication proposes the molecular structural basis for metallic-like electron transfer by Geobacter spp. nanowires.
10.1039/c5cp03432a
19,300,044
Geobacter sulfurreducens (GS) electronically connects with extracellular electron acceptors using such as Fe( iii ) oxides and U( vi ) conductive protein filaments or pili.
10.1038/nrmicro.2016.93
This publication proposes the molecular structural basis of electron hopping by Geobacter spp. nanowire, which is an alternative to the metallic-like electron transfer mechanism.
10.1126/science.1169984
123,175,113
Electrons Accepted Here Methane is produced in large quantities in marine sediments during the breakdown of organic matter. Methane is a powerful greenhouse gas that plays a large role in the regulation of climate. Methane is also an energy source for the abundant anaerobic methanotrophs that consume most of it before ...
10.1038/nrmicro.2016.93
The first report to show that intracellular oxidation of methane is coupled to extracellular reduction of Mn( IV )-bearing and Fe(III)-bearing minerals by archaea.
10.1152/physrev.00011.2002
41,767,478
Chronic pain can occur after peripheral nerve injury, infection, or inflammation. Under such neuropathic pain conditions, sensory processing in the affected body region becomes grossly abnormal. Despite decades of research, currently available drugs largely fail to control such pain. This review explores the possibilit...
10.1038/nrd1251
This article reviews the immunology of peripheral nerves, dorsal root ganglia and spinal nerves; the evidence from animal models of immune involvement in pathological pain; and the evidence that diverse human clinical pain syndromes involve an immune component.
10.1126/science.288.5472.1765
62,424,475
We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity—the capacity of neu...
10.1038/nrd1251
An excellent review of neuronal changes implicated in creation and maintenance of exaggerated pain states.
10.1523/jneurosci.21-08-02808.2001
102,389,788
Perispinal (intrathecal) injection of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein gp120 creates exaggerated pain states. Decreases in response thresholds to both heat stimuli (thermal hyperalgesia) and light tactile stimuli (mechanical allodynia) are rapidly induced after gp120 administration. gp12...
10.1038/nrd1251
The first demonstration that activation of spinal cord glia, in their role as immune cells; (i) is sufficient to induce thermal hyperalgesia and mechanical allodynia, (ii) induces the production and release of pro-inflammatory cytokines, and (iii) this pro-inflammatory cytokine release is causal to the resultant pain e...
10.4049/jimmunol.1003968
67,476,591
Abstract Naive T cells receive stimulation from the positive selecting ligand in the periphery for their survival. This stimulation does not normally lead to overt activation of T cells, as the T cells remain largely quiescent until they receive either antigenic or lymphopenic stimuli. The underlying mechanism responsi...
10.1038/nri3198
References 7 and 8 show that the maintenance of T cell quiescence requires TSC1.
10.1084/jem.20020307
109,136,739
The T cell costimulatory molecule CD28 is important for T cell survival, yet both the signaling pathways downstream of CD28 and the apoptotic pathways they antagonize remain poorly understood. Here we demonstrate that CD4+ T cells from CD28-deficient mice show increased susceptibility to Fas-mediated apoptosis via a ph...
10.1038/nri1131
This study shows that active protein kinase B (PKB) can alter the composition of the CD95-associated death-inducing signalling complex (DISC). T cells that express active PKB have reduced acitvation of caspase-8, pro-apoptotic BID (BH3-interacting domain death agonist) and caspase-3, owing to the impaired recruitment o...
10.1084/jem.191.12.2031
21,545,903
Lymphocytes deficient in the T cell costimulatory molecule CD28 exhibit defects in cell survival, clonal expansion, and differentiation into effector cells. It is known that CD28-mediated signaling results in the upregulation of the Bcl family member Bcl-XL. To investigate the role that Bcl-XL plays in the various func...
10.1038/nri1131
This study shows that despite the importance of apoptosis, it alone cannot account for the phenotype of CD28-deficient mice. Overexpression of BCL-X L does not re-constitute a normal phenotype in the CD28-deficient mice.
10.1126/science.283.5402.680
45,532,108
Although dispensable, costimulation through CD28 facilitates activation of naı̈ve T lymphocytes. CD28 engagement led to the redistribution and clustering of membrane and intracellular kinase-rich raft microdomains at the site of T cell receptor (TCR) engagements. Although not affecting TCR down-regulation, this process...
10.1038/nri1131
This study was the first to show that CD28 can potentiate the appearance and clustering of lipid rafts on the surface of T cells, thereby providing an alternate mechanism to account for the ability of CD28 to potentiate TCR signalling. It is, however, unlikely to account for the unique aspects of CD28 signalling in T c...
10.1084/jem.194.11.1675
79,454,359
Coreceptors CD28 and cytotoxic T lymphocyte antigen (CTLA)-4 have opposing effects on TcR/CD3 activation of T cells. While CD28 enhances and CTLA-4 inhibits activation, the underlying molecular basis of these effects has yet to be established. In this context, ganglioside and cholesterol enriched membrane microdomains ...
10.1038/nri1131
The study shows that cytotoxic T lymphocyte antigen 4 (CTLA4) can potently inhibit the appearance of lipid rafts on the surface of primary T cells in response to both CD3 and CD3–CD28 stimulation. Furthermore, the effect of CD28 was found to induce raft expression mainly of peripheral T cells that otherwise would not e...
10.1084/jem.20021646
66,425,612
Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) is an essential negative regulator of T cell activation. Recent evidence suggests that CTLA-4 association with the immunological synapse during contact with antigen-presenting cells is important for its inhibitory function. In the present study, we observed a direct ...
10.1038/nri1131
This study provides evidence that CTLA4 might also interfere with the entry of the TCR into rafts on the surface of cells. This underlines the close proximity of CTLA4 with the TCR complex.
10.1083/jcb.132.6.1011
122,378,408
We have followed the transfer of EGF-EGF receptor (EGFR) complexes from endosomal vacuoles that contain transferrin receptors (TfR) to lysosome vacuoles identified by their content of HRP loaded as a 15-min pulse 4 h previously. We show that the HRP-loaded lysosomes are lysosomal-associated membrane protein-1 (LAMP-1) ...
10.1038/nrm2217
Electron-microscopic study that supports the concept of direct fusion between late endosomes and lysosomes and also demonstrates tethers between the organelles.
10.1126/science.1103966
41,644,611
We found that the autophagic machinery could effectively eliminate pathogenic group A Streptococcus (GAS) within nonphagocytic cells. After escaping from endosomes into the cytoplasm, GAS became enveloped by autophagosome-like compartments and were killed upon fusion of these compartments with lysosomes. In autophagy-d...
10.1038/nrm2217
A clear demonstration that the autophagic machinery can act as an innate defence system against invading pathogens.
10.1126/science.1098188
20,561,721
Salmonella enterica , the cause of food poisoning and typhoid fever, induces actin cytoskeleton rearrangements and membrane ruffling to gain access into nonphagocytic cells, where it can replicate and avoid innate immune defenses. Here, we found that SopB, a phosphoinositide phosphatase that is delivered into host cell...
10.1038/nrm2217
Phagocytosed Salmonella secretes a phosphoinositide phosphatase that maintains high levels of phosphatidylinositol-3-phosphate in the phagosome membrane and delays formation of the phagolysosome.
10.1002/mrm.10367
103,663,452
Abstract Proton spectroscopy can noninvasively provide useful information on brain tumor type and grade. Short‐ (30 ms) and long‐ (136 ms) echo time (TE) 1 H spectra were acquired from normal white matter (NWM), meningiomas, grade II astrocytomas, anaplastic astrocytomas, glioblastomas, and metastases. Very low myo‐Ino...
10.1038/nrc1390
An informative paper on the use of in vivo MRS as a tool for generating metabolic profiles of human brain tumours. In this study the authors distinguish meningiomas, grade II astrocytomas, anaplastic astrocytomas and glioblastomas using the relative ratios of lactate, alanine, saturated lipid, myo -inositol and choline...
10.1111/j.1749-6632.2002.tb04888.x
4,803,265
A bstract : Recent development of technologies (e.g., microarray technology) that are capable of producing massive amounts of genetic data has highlighted the need for new pattern recognition techniques that can mine and discover biologically meaningful knowledge in large data sets. Many researchers have begun an endea...
10.1038/nrc1390
An excellent and unbiased review of the current pattern-recognition techniques available to researchers. Although written from a DNA-microarray perspective, the information is still of relevance to those engaged in metabolomics.
10.1126/science.286.5444.1571
62,518,466
The complete genome sequence of the radiation-resistant bacterium Deinococcus radiodurans R1 is composed of two chromosomes (2,648,638 and 412,348 base pairs), a megaplasmid (177,466 base pairs), and a small plasmid (45,704 base pairs), yielding a total genome of 3,284,156 base pairs. Multiple components distributed on...
10.1038/nrmicro1264
The description of the D. radiodurans R1 genome sequence; it has served as a reference for almost all research on the species since 1999.
10.1126/science.1103185
100,592,339
Deinococcus radiodurans is extremely resistant to ionizing radiation. How this bacterium can grow under chronic γ radiation [50 grays (Gy) per hour] or recover from acute doses greater than 10 kGy is unknown. We show that D. radiodurans accumulates very high intracellular manganese and low iron levels compared with rad...
10.1038/nrmicro1264
The authors show that Mn(II) is necessary for the ionizing-radiation resistance of D. radiodurans and provide evidence that elevated intracellular Mn might also protect other species.
10.1126/science.1077865
60,375,251
The bacterium Deinococcus radiodurans survives ionizing irradiation and other DNA-damaging assaults at doses that are lethal to all other organisms. How D . radiodurans accurately reconstructs its genome from hundreds of radiation-generated fragments in the absence of an intact template is unknown. Here we show that th...
10.1038/nrmicro1264
The first formal discussion of the unusual nucleoid architecture associated with this species. Some of the conclusions have been controversial, stimulating several subsequent studies.
10.1534/genetics.104.029249
29,342,297
Abstract During the first hour after a sublethal dose of ionizing radiation, 72 genes were upregulated threefold or higher in D. radiodurans R1. Thirty-three of these loci were also among a set of 73 genes expressed in R1 cultures recovering from desiccation. The five transcripts most highly induced in response to each...
10.1038/nrmicro1264
This manuscript identifies five 'hypothetical proteins' that contribute significantly to D. radiodurans radioresistance in RecA-dependent and RecA-independent processes, indicating that this species uses novel mechanisms to facilitate DNA repair.
10.1111/j.1365-2958.2004.04272.x
82,463,352
Summary The extraordinary radiation resistance of Deinococcus radiodurans results from the efficient capacity of the bacterium to repair DNA double‐strand breaks. By analysing the DNA damage repair‐deficient mutant, KH311, a unique radiation‐inducible gene (designated pprA ) responsible for loss of radiation resistance...
10.1038/nrmicro1264
PprA is a protein of unknown function that is necessary for radioresistance in D. radiodurans . The protein will bind to the ends of double-stranded DNA and stimulate DNA ligation. The authors suggest that PprA helps mediate NHEJ in this species.
10.1002/ajmg.1320470514
40,796,410
Abstract I report 2 unusual cases of Proteus syndrome that support the concept of somatic mosaicism. In one patient, a huge connective tissue nevus covered the chest and abdomen and hyperostoses of the calvaria were observed. In the other patient, linear verrucous epidermal nevi, epibulbar dermoids, and hyperostoses we...
10.1038/nrg906
An excellent synthesis of observations from clinical genetics that relate to germinal and somatic mosaicism.
10.1073/pnas.81.11.3511
102,667,269
The cytotoxic reactivity of lymphocytes for autologous melanoma cells was studied in a group of 13 melanoma patients. No cytotoxicity was observed with lymphocytes freshly isolated from peripheral blood or with lymphocytes cocultured for 7 days with autologous melanoma cells. Growth of lymphocytes previously sensitized...
10.1038/nrc1669
First application of autologous typing methodology for the identification of patients with CD8 + T cells with specificity for human cancer cells
10.1126/science.1840703
20,882,788
Many human melanoma tumors express antigens that are recognized in vitro by cytolytic T lymphocytes (CTLs) derived from the tumor-bearing patient. A gene was identified that directed the expression of antigen MZ2-E on a human melanoma cell line. This gene shows no similarity to known sequences and belongs to a family o...
10.1038/nrc1669
A landmark paper in cancer immunology in which the first CD8 + T-cell target in human cancer is identified. This molecule, MAGEA1, was also the first CT antigen to be discovered
10.1073/pnas.92.25.11810
18,927,585
Expression of cDNA libraries from human melanoma, renal cancer, astrocytoma, and Hodgkin disease in Escherichia coli and screening for clones reactive with high-titer IgG antibodies in autologous patient serum lead to the discovery of at least four antigens with a restricted expression pattern in each tumor. Besides an...
10.1038/nrc1669
The introduction of SEREX technology for analysing the humoral immune response to cancer — another landmark paper in cancer immunology
10.1002/ijc.10276
19,777,331
Abstract Cancer/testis (CT) antigens are immunogenic proteins expressed predominantly in gametogenic tissue and cancer; they are considered promising target molecules for cancer vaccines. The identification of new CT genes is essential to the development of polyvalent cancer vaccines designed to overcome tumor heteroge...
10.1038/nrc1669
First use of publicly available transcriptome data for the identification of CT antigens