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10.1073/pnas.0700460104
104,292,001
Hematopoietic stem cells (HSCs) execute self-renewal divisions throughout fetal and adult life, although some of their properties do alter. Here we analyzed the magnitude and timing of changes in the self-renewal properties and differentiated cell outputs of transplanted HSCs obtained from different sources during deve...
10.1038/nature07038
The paper found that the self-renewal capacity of fetal HSCs differs from that of adult bone-marrow-derived stem cells.
10.1182/blood-2007-07-099754
100,977,406
Hematopietic stem cells (HSCs) maintain life-long hematopoiesis in the bone marrow via their ability to self-renew and to differentiate into all blood lineages. Although a central role for the canonical wnt signaling pathway has been suggested in HSC self-renewal as well as in the development of B and T cells, conditio...
10.1038/nature07038
This study shows that the WNT-mediated signalling pathway is not required for HSC homeostasis in adulthood, even though WNT proteins are sufficient for the proliferation of HSCs.
10.1126/science.1117637
20,085,370
Epimorphic regeneration requires the presence or creation of pluripotent cells capable of reproducing lost organs. Zebrafish fin regeneration is mediated by the creation of blastema cells. Here, we characterize the devoid of blastema ( dob ) mutant that fails fin regeneration during initial steps, forms abnormal regene...
10.1038/nature07038
This study shows that Fgf20 is a dedicated growth factor for tail-fin regeneration in zebrafish, suggesting that each tissue might have its own set of growth conditions for regeneration.
10.1126/stke.3552006pe38
101,142,220
Shockingly few transcription factors and cell signaling pathways are utilized to pattern organs and to specify the fate of a seemingly endless variety of unique cell types during animal development. This dichotomy led to the hypothesis that each factor is used in multiple tissues and that a combinatorial code of factor...
10.1038/nature07038
References 35 and 36 show that constitutive activation of β-catenin leads to a block in differentiation and indicates that repeated activation of pathways that increase HSC number can lead to stem-cell exhaustion.
10.1101/gad.1299305
109,116,750
The Polycomb group (PcG) gene Bmi1 promotes cell proliferation and stem cell self-renewal by repressing the Ink4a/Arf locus. We used a genetic approach to investigate whether Ink4a or Arf is more critical for relaying Bmi1 function in lymphoid cells, neural progenitors, and neural stem cells. We show that Arf is a gene...
10.1038/nature07038
References 47 and 48 show that the chromatin-associated factor BMI1 controls the cell cycle of stem cells by altering expression of INK4A and ARF.
10.1101/gad.12.15.2403
62,289,667
Little is known about the transcription factors that mediate lineage commitment of multipotent hematopoietic precursors. One candidate is the Ets family transcription factor PU.1, which is expressed in myeloid and B cells and is required for the development of both these lineages. We show here that the factor specifica...
10.1038/nature07038
This paper reports that the overexpression of transcription factors can lead to an altered cell-fate programme.
10.1098/rspb.2011.0599
38,754,148
Hemichordate worms possess ciliated gills on their trunk, and the homology of these structures with the pharyngeal gill slits of chordates has long been a topic of debate in the fields of evolutionary biology and comparative anatomy. Here, we show conservation of transcription factor expression between the developing p...
10.1038/nature14434
This report shows extensive patterning similarities between the development of chordate and enteropneust gills, further supporting morphological homology.
10.1073/pnas.97.9.4469
58,561,134
The deuterostome phyla include Echinodermata, Hemichordata, and Chordata. Chordata is composed of three subphyla, Vertebrata, Cephalochordata ( Branchiostoma ), and Urochordata (Tunicata). Careful analysis of a new 18S rDNA data set indicates that deuterostomes are composed of two major clades: chordates and echinoderm...
10.1038/nature14434
This manuscript proposes that the extant enteropneust, rather than pterobranch, adult body plan may best represent ancestral deuterostome characters.
10.1126/science.1132195
62,116,325
Carbon supercapacitors, which are energy storage devices that use ion adsorption on the surface of highly porous materials to store charge, have numerous advantages over other power-source technologies, but could realize further gains if their electrodes were properly optimized. Studying the effect of the pore size on ...
10.1038/nenergy.2016.70
This paper demonstrates that microporous carbons can be used to maximize the capacitance, owing to the desolvation of the ions in subnanometre pores.
10.1126/science.1073774
61,475,990
Specific short oligonucleotide sequences that enhance pre-mRNA splicing when present in exons, termed exonic splicing enhancers (ESEs), play important roles in constitutive and alternative splicing. A computational method, RESCUE-ESE, was developed that predicts which sequences have ESE activity by statistical analysis...
10.1038/nature08909
This paper describes one of the first genome-wide predictions of splicing regulatory sequences
10.1073/pnas.1308253110
125,079,269
Significance Inflammation is a crucial host defense response but can cause chronic disease if unregulated. Several endogenous anti-inflammatory and proresolving circuits balance and modulate inflammation, including a mechanism centered on the formyl peptide receptor (FPR) family. One receptor, ALX/FPR2, recognizes both...
10.1038/nature13479
This article reports exciting results indicating that heterodimers and homodimers of ALX/FPR2 signal different responses by activation of distinct intracellular signalling mechanisms.
10.1084/jem.20121887
4,805,400
Resolution of inflammation is an active process that is mediated in part by antiinflammatory lipid mediators. Although phospholipase A2 (PLA2) enzymes have been implicated in the promotion of inflammation through mobilizing lipid mediators, the molecular entity of PLA2 subtypes acting upstream of antiinflammatory lipid...
10.1038/nature13479
This article reports the identification of a secretory phospholipase A2 activated during contact hypersensitive reactions that is specifically involved in the generation of resolvin D1 and protectin D1.
10.4049/jimmunol.1003456
83,119,560
Abstract Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by HSV-1 infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents ...
10.1038/nature13479
This is an exciting first report demonstrating that resolvin E1 protects the eye from Herpes simplex virus infection and stimulates clearance of the virus.
10.2337/db12-0684
41,687,278
Obesity and type 2 diabetes are emerging global epidemics associated with chronic, low-grade inflammation. A characteristic feature of type 2 diabetes is delayed wound healing, which increases the risk of recurrent infections, tissue necrosis, and limb amputation. In health, inflammation is actively resolved by endogen...
10.1038/nature13479
In this article, the authors demonstrate that pro-resolving mediators such as RvD1 can expedite healing of wounds encountered in diabetes.
10.1152/ajpregu.00128.2013
103,361,250
Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistan...
10.1038/nature13479
This article reports exciting new results indicating that strenuous exercise activates acute inflammation and pro-inflammatory eicosanoids, which then transition in humans to pro-resolving mediators present in peripheral blood following a time course consistent with lipid-mediator class switching and resolution of exer...
10.1146/annurev.physchem.53.082301.113146
20,861,918
▪ Abstract This article reviews the concepts and methods of transition path sampling. These methods allow computational studies of rare events without requiring prior knowledge of mechanisms, reaction coordinates, and transition states. Based upon a statistical mechanics of trajectory space, they provide a perspective ...
10.1038/nchembio.202
Transition path sampling is described as a way to probe, in an unbiased fashion, the nature of barrier crossing in condensed-phase reactions
10.1126/science.1129333
62,023,371
In the Drosophila germline, repeat-associated small interfering RNAs (rasiRNAs) ensure genomic stability by silencing endogenous selfish genetic elements such as retrotransposons and repetitive sequences. Whereas small interfering RNAs (siRNAs) derive from both the sense and antisense strands of their double-stranded R...
10.1038/nature07754
This paper was the first to describe a Dicer-independent pathway for the biogenesis of the guide strand of small RNAs.
10.1126/science.1140494
103,805,933
In Drosophila , repeat-associated small interfering RNAs (rasiRNAs) are produced in the germ line by a Dicer-independent pathway and function through the PIWI subfamily of Argonautes to ensure silencing of retrotransposons. We sequenced small RNAs associated with the PIWI subfamily member AGO3. Although other members o...
10.1038/nature07754
References 43 and 44 were the first to describe slicer-mediated small RNA production.
10.1126/science.1621094
103,554,086
A family of highly polymorphic neuronal cell surface proteins, the neurexins, has been identified. At least two genes for neurexins exist. Each gene uses alternative promoters and multiple variably spliced exons to potentially generate more than a 100 different neurexin transcripts. The neurexins were discovered by the...
10.1038/nature07456
This paper reports the discovery of NRXNs as presynaptic α-latrotoxin receptors.
10.1126/science.277.5331.1511
45,483,916
PSD-95 is a component of postsynaptic densities in central synapses. It contains three PDZ domains that localize N -methyl- d -aspartate receptor subunit 2 (NMDA2 receptor) and K + channels to synapses. In mouse forebrain, PSD-95 bound to the cytoplasmic COOH-termini of neuroligins, which are neuronal cell adhesion mol...
10.1038/nature07456
Together with the finding that NRXNs bind to the MAGUK CASK (ref. 48 ), this paper reveals a quasi-symmetrical design of the NRXN–NLGN junction that contains PSD95 bound to NLGNs postsynaptically.
10.1126/science.1146221
107,159,644
Autism spectrum disorders (ASDs) are characterized by impairments in social behaviors that are sometimes coupled to specialized cognitive abilities. A small percentage of ASD patients carry mutations in genes encoding neuroligins, which are postsynaptic cell-adhesion molecules. We introduced one of these mutations into...
10.1038/nature07456
This paper describes a mouse model of ASD in which a point mutation found in two brothers with ASD (Arg451Cys in NLGN3) was introduced into mice by homologous recombination.
10.1126/science.1185383
41,670,484
Continuing population and consumption growth will mean that the global demand for food will increase for at least another 40 years. Growing competition for land, water, and energy, in addition to the overexploitation of fisheries, will affect our ability to produce food, as will the urgent requirement to reduce the imp...
10.1038/nature10452
This article reviews a recent effort by the UK-based Foresight Project, which assessed global conditions and trends in agriculture and food security, and set the benchmark for the world’s discussions on this important topic.
10.1126/science.1111772
125,304,167
Land use has generally been considered a local environmental issue, but it is becoming a force of global importance. Worldwide changes to forests, farmlands, waterways, and air are being driven by the need to provide food, fiber, water, and shelter to more than six billion people. Global croplands, pastures, plantation...
10.1038/nature10452
This paper reviews the global extent of land use practices, especially agriculture, and how it has become a transformative force in the global environment—through changes in climate, water resources, biogeochemical cycles and biodiversity.
10.1073/pnas.1011078107
83,446,529
Expanding croplands to meet the needs of a growing population, changing diets, and biofuel production comes at the cost of reduced carbon stocks in natural vegetation and soils. Here, we present a spatially explicit global analysis of tradeoffs between carbon stocks and current crop yields. The difference among regions...
10.1038/nature10452
This paper explores how future expansion of agriculture would lead to increasing greenhouse gas emissions (from deforestation) and increasing food production (by adding more farmland), and assesses the geographic patterns of the tradeoffs between the two.
10.1111/j.1466-8238.2010.00563.x
125,327,282
ABSTRACT Aim As the demands for food, feed and fuel increase in coming decades, society will be pressed to increase agricultural production – whether by increasing yields on already cultivated lands or by cultivating currently natural areas – or to change current crop consumption patterns. In this analysis, we consider...
10.1038/nature10452
These authors present a new technique for estimating global patterns of yield and ‘yield gaps’, highlighting opportunities for improving food production around the world.
10.1063/1.324527
106,703,289
Chromium chrysoberyl undergoes a phase transformation from a paramagnetic state to a complex antiferromagnetic state at 28 K. The spiral spin structure of the antiferromagnetic state violates all the crystallographic symmetry elements, making Cr2BeO4 potentially ferroelectric. Chynoweth experiments conducted at low tem...
10.1038/natrevmats.2016.46
First report of magnetically induced ferroelectricity, which is well ahead of its time.
10.1126/science.1133306
125,327,337
Biofuels derived from low-input high-diversity (LIHD) mixtures of native grassland perennials can provide more usable energy, greater greenhouse gas reductions, and less agrichemical pollution per hectare than can corn grain ethanol or soybean biodiesel. High-diversity grasslands had increasingly higher bioenergy yield...
10.1038/nature07190
A demonstration of why grassland perennials, such as switchgrass, are superior for biofuel production when compared to crops that presently serve as food crops, such as soya bean or maize.
10.1128/aem.57.4.893-900.1991
81,443,248
Zymomonas mobilis genes for pyruvate decarboxylase (pdc) and alcohol dehydrogenase II (adhB) were integrated into the Escherichia coli chromosome within or near the pyruvate formate-lyase gene (pfl). Integration improved the stability of the Z. mobilis genes in E. coli, but further selection was required to increase ex...
10.1038/nature07190
A description of the genetic modification of E. coli , yielding a strain capable of fermenting pentose and hexose sugars—which are present in lignocellulose—into ethanol.
10.1126/science.1163174
104,037,380
During synaptic vesicle fusion, the soluble N -ethylmaleimide-sensitive factor–attachment protein receptor (SNARE) protein syntaxin-1 exhibits two conformations that both bind to Munc18-1: a “closed” conformation outside the SNARE complex and an “open” conformation in the SNARE complex. Although SNARE complexes contain...
10.1038/nature11320
This paper and ref. 49 describe the complex phenotype of the LE mutant of syntaxin on docking and fusion of synaptic vesicles.
10.1126/science.1193134
59,408,208
Three's the Charm The molecular machinery mediating membrane fusion during secretion from a cell requires a complex of so-called SNARE protein that forms a coiled bundle of four parallel α-helices. Mohrmann et al. (p. 502 , published online 16 September) developed an elegant approach to find out how many SNARE complexe...
10.1038/nature11320
Using a titration approach this study and ref. 89 reveal that neurotransmitter release requires only few SNARE complexes.
10.1002/cbic.201100020
124,173,957
Abstract Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. SNAREs are the core constituents of the protein machinery responsible for this membrane fusion, but the actual fusion mechanism remains unclear. Here, we have simulated neuronal SNARE‐mediated mem...
10.1038/nature11320
Using coarse-grain simulations, the transition states involved in SNARE-mediated membrane fusion are described on the basis of first principles.
10.1073/pnas.70.10.2837
16,765,559
The P i ⇄ HOH exchange reaction of oxidative phosphorylation is considerably less sensitive to uncouplers than the P i ⇄ ATP and ATP ⇄ HOH exchanges. The uncoupler-insensitive P i ⇄ HOH exchange is inhibited by oligomycin. These results and other considerations suggest that the relatively rapid and uncoupler-insensitiv...
10.1038/nature08145
This is the first article in a series in which Paul Boyer emphasizes the cooperation of at least two equivalent reaction sites in the F 1 -ATPase, paving the way to the present view of a rotary 'binding change mechanism'
10.1073/pnas.0807683105
109,027,858
The 2 nanomotors of rotary ATP synthase, ionmotive F O and chemically active F 1 , are mechanically coupled by a central rotor and an eccentric bearing. Both motors rotate, with 3 steps in F 1 and 10–15 in F O . Simulation by statistical mechanics has revealed that an elastic power transmission is required for a high r...
10.1038/nature08145
This is the latest article in a series in which the necessary elastic power transmission between the stepping motors F O and F 1 is correlated with the elastic compliance of specific domains
10.1063/1.437095
20,413,883
Greatly enhanced Raman scattering from monolayers of pyridine adsorbed on silver has been reported by several authors. I propose that the anomalous intensity arises from preresonant or resonant excitations of conduction electron resonances in adsorbate covered metal bumps on the surface. The bumps form a two-dimensiona...
10.1038/natrevmats.2016.21
Giant Raman intensity demonstrated from a roughened Ag electrode was shown to originate from the excitation of surface plasmons.
10.1146/annurev-physchem-032511-143807
41,550,166
Tip-enhanced Raman spectroscopy (TERS) is a very powerful variant of surface-enhanced Raman spectroscopy (SERS). In a sense, TERS overcomes most of the drawbacks of SERS but keeps its advantages, such as its high sensitivity. TERS offers the additional advantages of high spatial resolution, much beyond the Abbe limit, ...
10.1038/natrevmats.2016.21
An excellent review on TERS from its history and principles to applications.
10.1126/science.1159499
62,496,665
On nanotextured noble-metal surfaces, surface-enhanced Raman scattering (SERS) is observed, where Raman scattering is enhanced by a factor, Ḡ , that is frequently about one million, but underlying the factor Ḡ is a broad distribution of local enhancement factors, η. We have measured this distribution for benzenethiol...
10.1038/natrevmats.2016.21
First experimental evidence for the contribution to the overall Raman signal from various sites on SERS substrates.
10.1073/pnas.0507853103
122,699,789
The iron-molybdenum cofactor (FeMoco) of the nitrogenase MoFe protein is a highly complex metallocluster that provides the catalytically essential site for biological nitrogen fixation. FeMoco is assembled outside the MoFe protein in a stepwise process requiring several components, including NifB-co, an iron- and sulfu...
10.1038/nature08302
This paper is the first X-ray absorption spectroscopy/extended X-ray absorption fine structure (XAS/EXAFS)-based structural analysis of the FeMo-co precursor on NifEN.
10.1073/pnas.0510711103
27,992,309
The first step in molybdenum cofactor biosynthesis, the conversion of 5′-GTP to precursor Z, an oxygen-sensitive tetrahydropyranopterin is catalyzed by the S -adenosylmethionine (SAM)-dependent enzyme MoaA and the accessory protein MoaC. This reaction involves the radical-initiated intramolecular rearrangement of the g...
10.1038/nature08302
This paper describes the structural basis of radical SAM-based conversion of GTP into cPMP.
10.1002/wcc.62
40,012,271
Abstract Policymakers, scientists, and social scientists have debated a wide array of responses to the realities and prospects of anthropogenic climate change. The focus of this review is on the 2 ° C temperature target, described as the maximum allowable warming to avoid dangerous anthropogenic interference in the cli...
10.1038/nature18307
An introduction to the roots of the 2 °C climate target and its development over the past decades
10.1017/cbo9781107415416
62,593,213
This latest Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC) will again form the standard reference for all those concerned with climate change and its consequences, including students, researchers and policy makers in environmental science, meteorology, climatology, biology, ecology, atm...
10.1038/nature18307
The most recent intergovernmental report synthesizing our current understanding of the physical science and impacts of, and possible solutions to avoid, climate change.
10.5194/essd-7-349-2015
125,089,112
Abstract. Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon cycle, support the development of climate policies, and project future climate change. Here we describe data s...
10.1038/nature18307
A yearly authoritative update of global anthropogenic carbon emissions, and natural and anthropogenic sinks
10.1002/chem.201002273
59,947,906
Abstract Enol and phenol functionalities are very common in organic molecules. Utilization of these materials is very appealing in organic synthesis because they are important alternatives to organohalides in cross‐coupling reactions. In this review, we summarize the transition‐metal‐catalyzed cross‐coupling of enol‐ a...
10.1038/nature13274
A detailed account of cross-coupling reactions of phenol derivatives of all types, including those catalysed by metals other than nickel.
10.1002/ejoc.201200914
40,075,361
Abstract Nickel catalysis for biaryl coupling reactions has received significant attention as a less expensive and less toxic alternative to “standard” palladium catalysis. Here we describe recent developments in nickel‐catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particula...
10.1038/nature13274
A concise overview of the state of biaryl synthesis by a variety of nickel-catalysed methods.
10.1126/science.1138659
83,017,798
We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic reg...
10.1038/nature07458
This important study found a higher proportion of de novo CNVs in simplex autism families than in multiplex autism families, suggesting that the underlying genetic mechanisms of disease may be distinct in these cases.
10.1073/pnas.0903103106
20,848,288
We have developed an online catalog of SNP-trait associations from published genome-wide association studies for use in investigating genomic characteristics of trait/disease-associated SNPs (TASs). Reported TASs were common [median risk allele frequency 36%, interquartile range (IQR) 21%−53%] and were associated with ...
10.1038/nature08494
Comprehensive analysis of genomic annotations for disease-associated SNPs defined by GWAS, showing great majority of associated loci in intronic or intergenic regions of unknown function.
10.1126/science.1167728
20,492,843
Genome-wide association studies (GWASs) are regularly used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of 10 candidate genes in ...
10.1038/nature08494
Four rare variants in IFIH1 independently lowering risk of type 1 diabetes were identified by sequencing exons and splice sites of 10 genes under GWA-defined peaks, demonstrating the power of intensive sequencing to identify potentially causative variants in follow-up of GWAS.
10.1073/pnas.92.11.4798
40,664,684
We consider a model of the photosystem II (PS II) reaction center in which its spectral properties result from weak (approximately 100 cm-1) excitonic interactions between the majority of reaction center chlorins. Such a model is consistent with a structure similar to that of the reaction center of purple bacteria but ...
10.1038/nature22012
This paper proposes the original multimer model for the PSII reaction centre.
10.1063/1.4764100
103,682,290
The influence of fast vibrations on energy transfer and conversion in natural molecular aggregates is an issue of central interest. This article shows the important role of high-energy quantized vibrations and their non-equilibrium dynamics for energy transfer in photosynthetic systems with highly localized excitonic s...
10.1038/nature22012
This article demonstrates the role of discrete and quantized vibrations in photosynthetic light harvesting.
10.26421/qic4.2-5
104,236,082
We present evidence that there exist quantum computations that can be carried out in constant depth, using 2-qubit gates, that cannot be simulated classically with high accuracy. We prove that if one can simulate these circuits classically efficiently then ${\rm BQP} \subseteq {\rm AM}$.
10.1038/nature23458
This paper gave the first complexity-theoretic argument that a simple class of quantum circuits should be hard to simulate classically
10.1098/rspa.2010.0301
82,800,185
We consider quantum computations comprising only commuting gates, known as IQP computations, and provide compelling evidence that the task of sampling their output probability distributions is unlikely to be achievable by any efficient classical means. More specifically, we introduce the class post-IQP of languages dec...
10.1038/nature23458
This paper gave evidence that instantaneous quantum polynomial-time (IQP) circuits are hard to simulate classically
10.1084/jem.20040590
102,580,943
Using mice in which the eGfp gene replaced the first exon of the Il4 gene (G4 mice), we examined production of interleukin (IL)-4 during infection by the intestinal nematode Nippostrongylus brasiliensis (Nb). Nb infection induced green fluorescent protein (GFP)pos cells that were FcεRIpos, CD49bbright, c-kitneg, and Gr...
10.1038/ni.f.217
The first study that identified mouse basophils as the main IL-4-producing cells during parasite infection.
10.1034/j.1600-065x.2001.790113.x
45,005,655
Summary: Enhanced serum IgE levels in adults and children with HIV‐1 infection could be a marker of poor prognosis. HIV‐1 infection is believed to involve a switch toward a “T H 2‐like” cytokine pattern. HIV‐1 gp120 from different clades is a potent stimulus for histamine release from human basophils and mast cells. Gp...
10.1038/ni.f.217
An excellent review proposing a new function for basophils during HIV-1 infection in human.
10.1017/s0016672301005055
84,370,035
Gene expression microarrays are an innovative technology with enormous promise to help geneticists explore and understand the genome. Although the potential of this technology has been clearly demonstrated, many important and interesting statistical questions persist. We relate certain features of microarrays to other ...
10.1038/nrg863
The authors apply classical statistical experimental design to cDNA microarray experiments and keep Cy3 and Cy5 spot intensities separate in the analysis. The study assumes global normalization is adequate.
10.1093/bioinformatics/18.12.1609
86,154,029
Abstract Motivation: We present statistical methods for determining the number of per gene replicate spots required in microarray experiments. The purpose of these methods is to obtain an estimate of the sampling variability present in microarray data, and to determine the number of replicate spots required to achieve ...
10.1038/nrg863
The authors limit their discussions to replicate spots within a slide.
10.1126/science.1100035
20,674,845
Large, living biological specimens present challenges to existing optical imaging techniques because of their absorptive and scattering properties. We developed selective plane illumination microscopy (SPIM) to generate multidimensional images of samples up to a few millimeters in size. The system combines two-dimensio...
10.1038/nmeth.1709
The first paper to highlight the advantages of planar illumination for developmental imaging, essentially launching the renaissance of PIM.
10.1128/aem.63.8.3246-3253.1997
19,480,813
A comparative study of 30 phages of Streptococcus thermophilus was performed based on DNA restriction profiles, DNA homology, structural proteins, packaging mechanisms, and host range data. All phages exhibited distinct DNA restriction profiles, with some phages displaying similarly sized restriction fragments. DNA hom...
10.1038/nrmicro1393
Differentiates S. thermophilus phages into two distinct evolutionary lineages and describes a PCR-based diagnostic method for their classification in vitro
10.1128/jb.179.21.6741-6748.1997
19,311,687
A novel bacteriophage protection system for Lactococcus lactis based on a genetic trap, in which a strictly phage-inducible promoter isolated from the lytic phage phi31 is used to activate a bacterial suicide system after infection, was developed. The lethal gene of the suicide system consists of the three-gene restric...
10.1038/nrmicro1393
Demonstrates the successful implementation of phage-triggered suicide systems as a method for phage defence.
10.1083/jcb.200712029
104,440,855
Solid tumors can be highly aneuploid and many display high rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). In principle, aneuploidy is the consequence of CIN, but the relationship between CIN and aneuploidy has not been clearly defined. In this study, we use live cell imaging an...
10.1038/nrm2718
The first demonstration that chromosome missegregation in CIN cells is driven by kinetochore malorientations.
10.1126/science.1160058
29,235,140
Aneuploidy, an incorrect number of chromosomes, is the leading cause of miscarriages and mental retardation in humans and is a hallmark of cancer. We examined the effects of aneuploidy on primary mouse cells by generating a series of cell lines that carry an extra copy of one of four mouse chromosomes. In all four tris...
10.1038/nrm2718
This elegant study demonstrates aneuploid mouse embryonic fibroblasts that are stably trisomic for one of four mouse chromosomes exhibit altered metabolism and impaired proliferation.
10.1101/gad.1700908
20,879,058
Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer ce...
10.1038/nrm2718
A genome-wide RNA interference screen was used to identify novel mechanisms by which cells suppress multipolar mitotic divisions.
10.1083/jcb.77.3.853
83,280,609
An epithelial cell line (MDCK) was used to prepare monolayers which, in vitro, develop properties of transporting epithelia. Monolayers were formed by plating cells at high densities (10(6) cells/cm2) on collagen-coated nylon cloth disks to saturate the area available for attachment, thus avoiding the need for cell div...
10.1038/nrm1593
A landmark paper that characterized the formation of an epithelium in vitro
10.1073/pnas.75.10.5071
45,519,659
Infection of two different lines of polarized epithelial cells grown as monolayers with several types of enveloped viruses results, for each virus type, in a characteristic asymmetric budding of virions. Influenza virus (WSN strain), simian virus 5, and Sendai virus bud exclusively from the free (apical) surface of the...
10.1038/nrm1593
Showed that enveloped viruses can be used as tools to study the generation and maintenance of epithelial polarity.
10.1073/pnas.85.24.9557
18,819,075
Polarized epithelial cell monolayers contain two distinct plasma membrane domains as delineated by the presence of tight junctions--i.e., an apical surface that faces the external environment and a basolateral surface that functions both in cell-cell contact and cell-substrate attachment. Central to the understanding o...
10.1038/nrm1593
First indication that a lipid (GPI) contributes to apical targeting.
10.1083/jcb.139.4.929
38,558,182
Delivery of newly synthesized membrane-spanning proteins to the apical plasma membrane domain of polarized MDCK epithelial cells is dependent on yet unidentified sorting signals present in the luminal domains of these proteins. In this report we show that structural information for apical sorting of transmembrane neuro...
10.1038/nrm1593
First indication that O -glycans function as an apical targeting mechanism.
10.1083/jcb.200407094
38,337,355
An essential but insufficient step for apical sorting of glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) in epithelial cells is their association with detergent-resistant microdomains (DRMs) or rafts. In this paper, we show that in MDCK cells both apical and basolateral GPI-APs associate with DRMs during...
10.1038/nrm1593
An exciting observation that throws light on the role of protein oligomerization in promoting apical targeting.
10.1083/jcb.120.2.353
61,236,238
Glycosyl-phosphatidylinositol (GPI)-anchored proteins are sorted to the apical surface of many epithelial cell types. To better understand the mechanism for apical segregation of these proteins, we analyzed the lateral mobility and molecular associations of a model GPI-anchored protein, herpes simplex virus gD1 fused t...
10.1038/nrm1593
Initial proposal that a clustering event might be involved in apical targeting of GPI-anchored proteins.
10.1083/jcb.114.3.413
45,519,677
In the polarized kidney cell line MDCK, the influenza virus hemagglutinin (HA) has been well characterized as a model for apically sorted membrane glycoproteins. Previous work from our laboratory has shown that a single amino acid change in the cytoplasmic sequence of HA converts it from a protein that is excluded from...
10.1038/nrm1593
Showed dual importance of tyrosine signals in endocytosis and basolateral targeting.
10.1083/jcb.108.3.821
105,398,552
Biochemical changes in the influenza virus hemagglutinin during intracellular transport to the apical plasma membrane of epithelial cells were investigated in Madin-Darby canine kidney (MDCK) cells and in LLC-PK1 cells stably transfected with a hemagglutinin gene. After pulse-labeling a substantial fraction of hemagglu...
10.1038/nrm1593
First demonstration that an apical transmembrane protein might be associated with lipid rafts.
10.1083/jcb.200308104
19,416,867
Epithelial differentiation involves the generation of luminal surfaces and of a noncentrosomal microtubule (MT) network aligned along the polarity axis. Columnar epithelia (e.g., kidney, intestine, and Madin-Darby canine kidney [MDCK] cells) generate apical lumina and orient MT vertically, whereas liver epithelial cell...
10.1038/nrm1593
A kinase for microtubule-associated proteins is a key organizer of microtubules and lumen polarity in epithelial cells.
10.1083/jcb.105.3.1241
40,518,432
We have used pulse-chase metabolic radiolabeling with L-[35S]methionine in conjunction with subcellular fractionation and specific protein immunoprecipitation techniques to compare the posttranslational transport pathways taken by endogenous domain-specific integral proteins of the rat hepatocyte plasma membrane in viv...
10.1038/nrm1593
Identifies transcytosis as a primary mode of delivery of apical proteins in liver cells.
10.1083/jcb.200308142
61,192,287
Lipid rafts play important roles in cellular functions through concentrating or sequestering membrane proteins. This requires proteins to differ in the stability of their interactions with lipid rafts. However, knowledge of the dynamics of membrane protein–raft interactions is lacking. We employed FRAP to measure in li...
10.1038/nrm1593
Reports the biophysical characterization of different types of lipid rafts and their possible role in apical targeting.
10.1073/pnas.95.17.10078
103,691,599
Innate nonself recognition must rely on common structures of invading microbes. In a differential display screen for up-regulated immune genes in the moth Trichoplusia ni we have found mechanisms for recognition of bacterial cell wall fragments. One bacteria-induced gene encodes a protein that, after expression in the ...
10.1038/nri3089
This was the first description of cloning of insect and mammalian PGRP genes, showing that PGRPs are conserved in evolution.
10.1126/science.1149357
62,289,691
Although commensalism with gut microbiota exists in all metazoans, the host factors that maintain this homeostatic relationship remain largely unknown. We show that the intestinal homeobox gene Caudal regulates the commensal-gut mutualism by repressing nuclear factor kappa B–dependent antimicrobial peptide genes. Inhib...
10.1038/nri3089
A demonstration of immune tolerance in the D. melanogaster gut and the participation of Caudal in this process.
10.1126/science.1117311
41,629,693
Because the mucosal epithelia are in constant contact with large numbers of microorganisms, these surfaces must be armed with efficient microbial control systems. Here, we show that the Drosophila nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme, dual oxidase (dDuox), is indispensable for gut antimicr...
10.1038/nri3089
A demonstration that ROS production has an essential role in the gut immune response in D. melanogaster
10.1073/pnas.0901226106
125,141,761
Tsetse flies, the sole vectors of African trypanosomes, have coevolved with mutualistic endosymbiont Wigglesworthia glossinidiae . Elimination of Wigglesworthia renders tsetse sterile and increases their trypanosome infection susceptibility. We show that a tsetse peptidoglycan recognition protein (PGRP-LB) is crucial f...
10.1038/nri3089
A demonstration of the role of PGRP-LB in tolerance towards symbiotic bacteria and in trypanosome transmission in tsetse flies.
10.1111/j.1462-2920.2009.02121.x
125,168,113
Summary In horizontally transmitted mutualisms between marine animals and their bacterial partners, the host environment promotes the initial colonization by specific symbionts that it harvests from the surrounding bacterioplankton. Subsequently, the host must develop long‐term tolerance to immunogenic bacterial molecu...
10.1038/nri3089
This study identified the role of PGRP2 in Euprymna scolopes – Vibrio fischeri symbiosis.
10.1126/science.1070238
62,169,148
Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY...
10.1038/nrd3248
This study identified S1P receptors as the targets of fingolimod and showed that the drug causes the accumulation of lymphocytes at lymphatic endothelial barriers.
10.4049/jimmunol.164.11.5761
79,939,427
Abstract FTY720 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride) prolongs survival of solid organ allografts in animal models. Mechanisms of FTY720 immunomodulation were studied in mice infected with lymphocytic choriomeningitis virus (LCMV) to assess T cell responses or with vesicular stomatitis viru...
10.1038/nrd3248
This paper reports that fingolimod does not impair the induction, expansion or memory of T cells.
10.1084/jem.20091619
104,102,525
Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lym...
10.1038/nrd3248
This study identified lymphatic endothelial cells as the source of S1P required for egress of T cells from lymph nodes.
10.1126/science.1139221
83,013,204
Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origi...
10.1038/nrd3248
This study demonstrates the key role of S1P in the egress of T cells from lymph nodes.
10.1146/annurev.immunol.22.012703.104702
20,761,136
The memory T cell pool functions as a dynamic repository of antigen-experienced T lymphocytes that accumulate over the lifetime of the individual. Recent studies indicate that memory T lymphocytes contain distinct populations of central memory (T CM ) and effector memory (T EM ) cells characterized by distinct homing c...
10.1038/nrd3248
A comprehensive review of T CM and T EM cell functions and their role in immunological memory.
10.1002/ana.20049
125,058,125
Abstract It is unclear how immune cells traffic between the lymphoid compartment and the central nervous system (CNS), which lacks lymphatic vessels and is shielded by the blood–brain barrier. We studied the expression of CCR7, a chemokine receptor required for migration of T cells and dendritic cells (DCs) to lymphoid...
10.1038/nrd3248
This study demonstrated that most T cells found in the CNS of patients with MS express T CM and not T EM phenotypes.
10.1242/jcs.02637
29,142,954
The phosphorylated sphingolipid metabolites sphingosine 1-phosphate (S1P) and ceramide 1-phosphate (C1P) have emerged as potent bioactive agents. Recent studies have begun to define new biological functions for these lipids. Generated by sphingosine kinases and ceramide kinase, they control numerous aspects of cell phy...
10.1038/nrd3248
A comprehensive review of the role of S1P in inflammation.
10.1177/1352458509357065
45,494,204
In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety resu...
10.1038/nrd3248
A Phase II extension study of fingolimod in relapsing MS.
10.1073/pnas.89.23.11219
20,075,537
In the human genome, the erythroid-specific hypersensitive site HS2 enhancer regulates the transcription of the downstream beta-like globin genes 10-50 kilobases away. The mechanism of HS2 enhancer function is not known. The present study employs RNA protection assays to analyze the transcriptional status of the HS2 en...
10.1038/nrg.2016.4
This study first identified the presence of enhancer transcription in mammalian cells.
10.1101/gad.1.3.307
104,225,131
We present a detailed analysis of the transcriptional products of the bithoraxoid (bxd) region of the Ultrabithorax domain in the bithorax complex of Drosophila melanogaster. This region is transcribed twice during development: between 3 and 6 hr of embryogenesis, a set of early transcripts, 1.1 to 1.3 kb in size, is s...
10.1038/nrg.2016.4
This study identified the first intergenic non-coding transcripts in Drosophila melanogaster
10.1126/science.1259418
103,779,158
Uncaging promoter and enhancer dynamics In order to understand cellular differentiation, it is important to understand the timing of the regulation of gene expression. Arner et al. used cap analysis of gene expression (CAGE) to analyze gene enhancer and promoter activities in a number of human and mouse cell types. The...
10.1038/nrg.2016.4
This study provides evidence that a subset of enhancers is temporally the 'leading' transcription units, representing the earliest activation events in response to stimulus.
10.1073/pnas.1317023110
107,228,482
Significance Using high-throughput experiments, we determined the functional epigenomic landscape in pancreatic islet cells. Computational integration of these data along with similar data from the ENCODE project revealed the presence of large gene control elements across diverse cell types that we refer to as “stretch...
10.1038/nrg.2016.4
References 55 and 56 first coined the concept of super and stretch enhancers, respectively, to denote the widespread phenomenon of clustered enhancers in mammalian cells.
10.1126/science.aad3346
62,216,497
Noncoding RNA helps protein binding Besides reading the coding regions of genes, RNA polymerase generates RNA at promoter-proximal and -distal DNA elements, but the function of these molecules is largely unknown. Sigova et al. show that these RNAs facilitate interactions between gene regulators and the regulatory eleme...
10.1038/nrg.2016.4
This paper supports a hypothesis that a general role of ncRNAs, including eRNAs, is to assist the binding of transcription factors, such as YY1, to the regulatory elements.
10.1126/science.1160809
20,879,499
Fuel Economy for Growing Cells Sophisticated 21st-century analyses of the signaling pathways that control cell growth have led researchers back to the seminal work of Otto Warburg, who discovered in the 1920s that tumor cells generate their energy in an unusual way—by switching from mitochondrial respiration to glycoly...
10.1038/nrc3803
This excellent review summarizes the role of the Warburg effect on cell proliferation.
10.1073/pnas.95.20.11715
41,685,744
Transcriptional activation of erythropoietin, glycolytic enzymes, and vascular endothelial growth factor occurs during hypoxia or in response to cobalt chloride (CoCl 2 ) in Hep3B cells. However, neither the mechanism of cellular O 2 sensing nor that of cobalt is fully understood. We tested whether mitochondria act as ...
10.1038/nrc3803
This study was the first to demonstrate that mitochondria-derived ROS can regulate transcription through their control of HIF1α stability.
10.1073/pnas.1003428107
38,443,445
Otto Warburg's theory on the origins of cancer postulates that tumor cells have defects in mitochondrial oxidative phosphorylation and therefore rely on high levels of aerobic glycolysis as the major source of ATP to fuel cellular proliferation (the Warburg effect). This is in contrast to normal cells, which primarily ...
10.1038/nrc3803
This study examines the role of mitochondrial ROS signalling in the tumorigenic behaviour induced by KRAS activation.
10.1126/science.1156906
107,139,954
Mutations in mitochondrial DNA (mtDNA) occur at high frequency in human tumors, but whether these mutations alter tumor cell behavior has been unclear. We used cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA in a mouse tumor cell line that was poorly metastatic with mtDNA from a cell line that wa...
10.1038/nrc3803
This study demonstrates that mtDNA mutations can amplify tumour progression by increasing cellular ROS generation.
10.1073/pnas.0408894102
45,488,813
Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11–12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation inde...
10.1038/nrc3803
This study used cellular cybrids to examine the role of mtDNA mutations on ROS generation and tumorigenicity in prostate cancer cells.
10.1073/pnas.95.14.7987
26,860,865
Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer compos...
10.1038/nrc3803
This is a classic paper describing the regions of the HIF1α protein that confer sensitivity to hypoxia.
10.1101/gad.1360106
101,679,259
Pdx1 ( IPF-1 in humans, which is altered in MODY-4 ) is essential for pancreas development and mature β-cell function. Pdx1 is expressed dynamically within the developing foregut, but how its expression characteristics are linked to the various steps of organ specification, differentiation, and function is unknown. Del...
10.1038/nrg2318
This careful and elegant genetic study shows that different upstream cis sequences control the levels of the Pdx1 gene in different tissues, and that subtle changes in the levels of expression of Pdx1 give rise to dramatic morphological embryonic phenotypes.
10.1073/pnas.0405776102
80,814,432
Heterozygous mutations in the human POU-homeobox TCF2 ( vHNF1, HNF1 β) gene are associated with maturity-onset diabetes of the young, type 5, and abnormal urogenital tract development. Recently, pancreas atrophies have been reported in several maturity-onset diabetes of the young type 5 patients, suggesting that TCF2 i...
10.1038/nrg2318
This paper provides a careful, comparative analysis of the effect of Hnf1b mutation on the expression of other transcription factors involved in early pancreatic development, thus unveiling part of the relevant regulatory network.
10.1186/1471-213x-7-37
38,215,360
Abstract Background In the mouse, the parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm. GATA4, a zinc finger transcription factor, is strongly expressed in these endodermal domains and molecular analyses have implicated GATA4 in potentiating liver gene...
10.1038/nrg2318
The authors generated tetraploid chimeric embryos that were embryonic null for Gata4 , to bypass the requirement for Gata4 in extra-embryonic tissues. The results showed that Gata4 is necessary for liver-bud development, possibly in a cell non-autonomous fashion, as well as for the development of the ventral pancreatic...
10.1242/dev.01570
125,334,418
Cell fate and morphogenesis within the embryo is dependent upon secreted molecules that transduce signals between neighboring tissues. Reciprocal mesenchymal-epithelial interactions have proven essential during branching morphogenesis and cell differentiation within the lung; however, the interactions that result in lu...
10.1038/nrg2318
The authors of this paper discovered that simply treating foregut endoderm explants with different concentrations of FGF could induce pancreas, liver or lung progenitors. The results correlated with different levels of endogenous FGF signalling in embryos in the spatial context of the emergence of each tissue.
10.1242/dev.01643
38,542,873
Early growth and differentiation of the pancreatic endoderm is regulated by soluble factors from the pancreatic mesenchyme. Previously, we demonstrated that N-cadherin-deficient mice lack a dorsal pancreas, due to a critical role of N-cadherin in dorsal pancreatic mesenchymal cell survival. Here, we show that restoring...
10.1038/nrg2318
These authors made the unexpected discovery that cardiac N-cadherin expression could restore a pancreatic developmental defect in an N-cadherin-null mouse model. Further studies revealed a role for sphingosine-1-phosphate: when it is secreted into the bloodstream it promotes early pancreatic development.