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10.1126/science.278.5342.1467
102,392,021
The bacterial Sec and signal recognition particle ( ffh -dependent) protein translocation mechanisms are conserved between prokaryotes and higher plant chloroplasts. A third translocation mechanism in chloroplasts [the proton concentration difference (ΔpH) pathway] was previously thought to be unique. The hcf106 mutati...
10.1038/35073038
This was the first report of the hcf106 sequence and the first indication that the system might be present in bacteria.
10.1046/j.1365-2958.1996.00114.x
101,174,795
The precursor polypeptides of periplasmic proteins binding seven types of redox cofactor have unusually long signal sequences bearing a consensus (S/T)‐R‐R‐x‐F‐L‐K motif immediately before the hydrophobic region. Such ‘double‐arginine’ signal sequences are not, in general, found on the precursors of other periplasmic p...
10.1038/35073038
This is a comprehensive description of the rationale for the existence of the Tat pathway and a listing of predicted substrates.
10.1146/annurev.micro.54.1.641
41,661,218
▪ Abstract Virulence factors of pathogenic bacteria (adhesins, toxins, invasins, protein secretion systems, iron uptake systems, and others) may be encoded by particular regions of the prokaryotic genome termed pathogenicity islands. Pathogenicity islands were first described in human pathogens of the species Escherich...
10.1038/35080089
Comprehensive coverage of the origin, functions and evolutionary significance of pathogenicity islands and horizontal gene transfer.
10.1083/jcb.2.4.193
83,525,405
A number of different synapses have been described in the medulla, cerebellar cortex, and cerebral cortex of the rat. All of these possess the same fundamental fine structure as follows: 1. Close apposition of the limiting membranes of presynaptic and postsynaptic cells without any protoplasmic continuity across the sy...
10.1038/35104069
One of the first characterizations of membrane structures in dendrites using electron microscopy. Palay proposed that structures of the protein-synthetic pathway are present in dendrites at long distances from the cell body.
10.1523/jneurosci.19-01-00168.1999
42,606,187
There is a growing body of evidence that local protein synthesis beneath synapses may provide a novel mechanism underlying plastic phenomena. In vivo and in vitro biochemical data show that dendrites can perform translation and glycosylation. Using antibodies directed against the eukaryotic protein synthetic machinery,...
10.1038/35104069
Triller's group identified BiP, TGN38 and Rab1 on membrane structures near postsynaptic sites in dendrites, confirming that dendrites contain endoplasmic reticulum and Golgi apparatus.
10.1073/pnas.91.23.10800
100,841,919
Neurons are highly polarized cells with a mosaic of cytoplasmic and membrane proteins differentially distributed in axons, dendrites, and somata. In Drosophila and Xenopus, mRNA localization coupled with local translation is a powerful mechanism by which regionalized domains of surface or cytoplasmic proteins are gener...
10.1038/35104069
Used RNA amplification to measure many mRNA species within individual dendrites. Different levels of glutamate receptor subunit mRNAs were present in different dendrites of a common cell body.
10.1523/jneurosci.16-24-07812.1996
81,798,683
Sorting of RNAs to specific subcellular loci occurs in diverse settings from fly oocytes to mammalian neurons. Using the membrane-permeable nucleic acid stain SYTO 14, we directly visualized the translocation of endogenous RNA in living cells. Labeled RNA was distributed nonrandomly as discrete granules in neuronal pro...
10.1038/35104069
Showed that translocation of mRNA along dendrites of cortical neurons occurs in 'granules' of ribosomes.
10.1073/pnas.93.23.13250
19,083,992
Neuronal signaling requires that synaptic proteins be appropriately localized within the cell and regulated there. In mammalian neurons, polyribosomes are found not just in the cell body, but also in dendrites where they are concentrated within or beneath the dendritic spine. The α subunit of Ca 2+ -calmodulin-dependen...
10.1038/35104069
Identified the 3′-UTR region of α-CaMKII mRNA as important for mRNA translocation along dendrites.
10.1073/pnas.231485698
38,578,171
Neuronal processes contain mRNAs and membrane structures, and some forms of synaptic plasticity seem to require protein synthesis in dendrites of hippocampal neurons. To quantitate dendritic protein synthesis, we used multiphoton microscopy of green fluorescent protein synthesized in living isolated dendrites. Transfec...
10.1038/35104069
Measured rates of dendritic translation and showed that sites of translation were heterogeneous and exponential in dendrites on agonist stimulation of metabotropic glutamate receptors, whereas translation in cell bodies was linear.
10.1126/science.273.5280.1402
83,020,706
Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus. Unlike other forms of plasticity, neurotrophin-induced plasticity exhibited an immediate requirement for protein synthesis. Plasticity...
10.1038/35104069
Proposed that protein synthesis in dendrites of hippocampal slices is important for some forms of synaptic plasticity.
10.1073/pnas.92.16.7376
122,574,659
Chromosome rearrangements, such as large deletions, inversions, or translocations, mediate migration of large DNA segments within or between chromosomes, which can have major effects on cellular genetic control. A method for chromosome manipulation would be very useful for studying the consequences of large-scale DNA r...
10.1038/35093564
References 38 and 39 introduce the use of targeted Cre/ loxP strategies for generating chromosomal translocations in mouse embryonic stem cells.
10.1126/science.7777856
82,991,984
Analysis of data collected on 131 species of primates, bats, and insectivores showed that the sizes of brain components, from medulla to forebrain, are highly predictable from absolute brain size by a nonlinear function. The order of neurogenesis was found to be highly conserved across a wide range of mammals and to co...
10.1038/35072555
Data on the size of brain components and the order of neurogenesis was compiled from over 130 species to generate a nonlinear function that can be used to predict the outcome of changes in the rate or duration of neurogenesis on brain structure.
10.1523/jneurosci.21-12-04259.2001
38,871,468
In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. Cyclin kinase inhibitors have been implicated as important regulators of proliferation during development by blocking the activity of cyclin–cyclin-dependent kinase comple...
10.1038/35072555
The first evidence that retinal progenitor cells might use different mechanisms to exit the cell cycle during development.
10.1126/science.254.5029.282
82,984,284
The neocortex is patterned in layers of neurons that are generated in an orderly sequence during development. This correlation between cell birthday and laminar fate prompted an examination of how neuronal phenotypes are determined in the developing cortex. At various times after labeling with [3H]thymidine, embryonic ...
10.1038/35072555
A series of transplantation experiments are described in the developing neocortex that demonstrate a correlation between cell-cycle phase and the ability to respond to developmental cues.
10.1242/dev.126.3.555
38,274,163
The seven major classes of cells of the vertebrate neural retina are generated from a pool of multipotent progenitor cells. Recent studies suggest a model of retinal development in which both the progenitor cells and the environment change over time (Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. and Ezzeddine, D...
10.1038/35072555
Shows that the competence of retinal progenitor cells to respond to the extrinsic cues that regulate amacrine-cell fate specification might be cell-cycle-phase restricted.
10.1101/gad.14.7.783
130,285,496
Fission yeast ( Schizosaccharomyces pombe ) centromeres are composed of large (40–100 kb) inverted repeats that display heterochromatic features, thus providing a good model for higher eukaryotic centromeres. The association of three proteins that mediate region-specific silencing across centromere 1 has been mapped by...
10.1038/35084512
By analysing chromatin content, this study showed that the Schizosaccharomyces pombe centromere is composed of spatially and functionally separate protein domains.
10.1093/genetics/158.4.1615
103,748,763
Abstract The centromere is essential for proper segregation and inheritance of genetic information. Centromeres are generally regulated to occur exactly once per chromosome; failure to do so leads to chromosome loss or damage and loss of linked genetic material. The mechanism for faithful regulation of centromere activ...
10.1038/35084512
First study of the mechanism of neocentromere formation, which shows that neocentromere formation in Drosophila requires proximity to a functional centromere and probably occurs by spreading of centromeric proteins onto non-centromeric DNA.
10.1073/pnas.88.9.3734
81,169,469
CENP-A, a centromere-specific 17-kDa protein, has histone-like properties. However, in contrast to the common somatic histones, CENP-A is quantitatively retained in bull spermatozoa, and we have exploited this fact to purify CENP-A to apparent homogeneity. Partial sequence analysis of the purified protein indicates tha...
10.1038/35084512
This paper and reference 65 describe the ground-breaking biochemical characterization of CENPA and the demonstration that it is a centromere-specific core histone.
10.1126/science.288.5474.2215
4,723,133
Mammalian kinetochores contain the centromere-specific histone H3 variant CENP-A, whose incorporation into limited chromosomal regions may be important for centromere function and chromosome segregation during mitosis. However, regulation of CENP-A localization and its role have not been clear. Here we report that the ...
10.1038/35084512
The initial characterization of the Schizosaccharomyces pombe homologue of CENPA and the first demonstration of a protein required for CENPA localization, Mis6.
10.1083/jcb.153.6.1209
100,668,978
In all eukaryotes, segregation of mitotic chromosomes requires their interaction with spindle microtubules. To dissect this interaction, we use live and fixed assays in the one-cell stage Caenorhabditis elegans embryo. We compare the consequences of depleting homologues of the centromeric histone CENP-A, the kinetochor...
10.1038/35084512
References 73 and 74 describe, for the first time, the organization and functional interactions between kinetochore proteins on holocentric chromosomes.
10.1083/jcb.151.5.1113
61,651,131
The specification of metazoan centromeres does not depend strictly on centromeric DNA sequences, but also requires epigenetic factors. The mechanistic basis for establishing a centromeric “state” on the DNA remains unclear. In this work, we have directly examined replication timing of the prekinetochore domain of human...
10.1038/35084512
Excellent study showing that human centromeres are replicated asynchronously in mid- to late S phase and that CENPA assembly into centromeric nucleosomes is not dependent on DNA replication.
10.1083/jcb.113.5.1091
18,686,128
The three-dimensional structure of the kinetochore and the DNA/protein composition of the centromere-kinetochore region was investigated using two novel techniques, caffeine-induced detachment of unreplicated kinetochores and stretching of kinetochores by hypotonic and/or shear forces generated in a cytocentrifuge. Kin...
10.1038/35084512
A classic paper on centromere structure that proposes that the centromere/kinetochore is composed of repeating subunits.
10.1073/pnas.90.7.3103
40,525,398
We have tested the hypothesis that guanine-nucleotide-binding-protein-coupled receptors may be able to interact with each other at a molecular level. To address this question, we have initially created two chimeric receptors, alpha 2/m3 and m3/alpha 2, in which the C-terminal receptor portions (containing transmembrane...
10.1038/35067575
Using α 2 -adrenergic/M3 muscarinic chimeric proteins, this study documented the occurrence of intermolecular functional complementation indicating that G-protein-coupled receptors can function as dimeric entities.
10.1146/annurev.bi.65.070196.004101
17,599,347
The proteasome is an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells and is responsible for the degradation of most cellular proteins. The 20S (700-kDa) proteasome contains multiple peptidase activities that function through a new type of proteolytic mechanism involving a threonine acti...
10.1038/35056572
This review gives a good basic introduction to the proteasome system, its components and its different functions.
10.1084/jem.191.3.503
1,353,153
Interferon (IFN)-γ–induced cells express the proteasome subunits low molecular weight protein (LMP)2, LMP7, and MECL-1 (multicatalytic endopeptidase complex–like 1), leading to the formation of immunoproteasomes. Although these subunits are thought to optimize MHC class I antigen processing, the extent of their role an...
10.1038/35056572
Experimental evidence is presented that the β5i (LMP7) subunit influences the structure of the immunoproteasomes and affects the activity of the two other immunosubunits.
10.4049/jimmunol.164.9.4500
83,484,289
Abstract Proteasomes are the major source for the generation of peptides bound by MHC class I molecules. To study the functional relevance of the IFN-γ-inducible proteasome subunits low molecular mass protein 2 (LMP2), LMP7, and mouse embryonal cell (MEC) ligand 1 in Ag processing and concomitantly that of immunoprotea...
10.1038/35056572
This paper describes the establishment of tetracycline-regulated immunosubunit expression and presents evidence that only minor amounts of immunoproteasomes are required for efficient antigen presentation.
10.1126/science.8128231
81,444,071
The γ chain of the interleukin-2 (IL-2) receptor is shared with the functional IL-4 receptor and is causatively related to X-linked severe combined immunodeficiency (XSCID), which is ascribed to a profound T cell defect. Studies with monoclonal antibodies specific for the IL-2 receptor γ chain showed that the γ chain p...
10.1038/35105066
References 15–18 were the first to show that IL-2R is shared by the IL-4 and IL-7 receptors, leading it to be renamed as the common cytokine receptor
10.1126/science.270.5237.797
29,104,832
Males with X-linked severe combined immunodeficiency (XSCID) have defects in the common cytokine receptor γ chain (γ c ) gene that encodes a shared, essential component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15. The Janus family tyrosine kinase Jak3 is the only signaling molecule known to b...
10.1038/35105066
References 40 and 41 showed that mutations in Jak3 cause SCID.
10.1126/science.1061154
59,405,228
Interferons (IFN) α/β and γ induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss ...
10.1038/35105066
Impairment of mycobacterial infections associated with mutations in the STAT1 gene.
10.1084/jem.188.11.2067
59,720,908
We have analyzed the immune system in Stat5-deficient mice. Although Stat5a−/− splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b−/− splenocytes cannot be corrected by this treatment. Interes...
10.1038/35105066
References 77 and 78 show impaired immunological phenotype in Stat5a and 5b knockout mice, respectively.
10.1126/science.288.5472.1796
103,279,231
Experiments with vesicles containing N -methyl- d -aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites. Selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of mLin-10 (Mi...
10.1038/35039075
Identifies a novel, neuron-specific microtubule motor protein (KIF17) that is found in a complex with Mint, CASK and NR2B. This protein complex is localized to vesicles, and is proposed to transport NMDA receptors within dendrites. Interestingly, PSD-95 is not associated with this complex, indicating a specific postsyn...
10.1126/science.287.5461.2262
38,401,141
To elucidate mechanisms that control and execute activity-dependent synaptic plasticity, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) with an electrophysiological tag were expressed in rat hippocampal neurons. Long-term potentiation (LTP) or increased activity of the calcium/calmodulin-dependen...
10.1038/35039075
Expression of LTP or increasing the activity of CaMKII results in the delivery of tagged GluR1 AMPA receptors to the synapse surface. Delivery is dependent on a PDZ domain-mediated interaction, as mutating the PDZ domain at the GluR1 carboxyl terminus abolishes efficient delivery.
10.1093/genetics/157.1.103
125,293,520
Abstract The Saccharomyces cerevisiae Sgs1 protein is a member of the RecQ family of DNA helicases and is required for genome stability, but not cell viability. To identify proteins that function in the absence of Sgs1, a synthetic-lethal screen was performed. We obtained mutations in six complementation groups that we...
10.1038/35088500
An excellent example of a synthetic lethal screen and plasmid shuffle analysis.
10.1126/science.2889267
80,564,698
The clonal composition of human colorectal tumors was studied by means of restriction fragment length polymorphisms (RFLPs). First, X-linked RFLPs were used to examine the pattern of X chromosome inactivation in colorectal tumors of females. All 50 tumors examined showed monoclonal patterns of X chromosome inactivation...
10.1038/35094067
Analysis of the clonal composition of human colorectal tumours by means of X–linked restriction-fragment length polymorphisms. The results support a monoclonal origin for colorectal neoplasms, and indicate that a gene on the short arm of chromosome 17 might be associated with progression from the benign to the malignan...
10.1126/science.1651562
62,220,332
Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers, particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus, a portion of the region that is tightly linked to FAP was cloned. ...
10.1038/35094067
References 48 and 49 are the first reports showing the molecular cloning of the APC gene.
10.1126/science.8259518
41,710,872
Mutations in the human APC gene are linked to familial adenomatous polyposis and to the progression of sporadic colorectal and gastric tumors. To gain insight into APC function, APC-associated proteins were identified by immunoprecipitation experiments. Antibodies to APC precipitated a 95-kilodalton protein that was pu...
10.1038/35094067
References 51 and 52 show how two cellular proteins were found to associate with APC, and that these were identified as the E-cadherin-associated proteins α- and β-catenin. A 15-amino-acid motif that is repeated three times in APC was shown to be sufficient for interaction with the catenins.
10.1126/science.275.5307.1784
20,662,493
The adenomatous polyposis coli (APC) tumor suppressor protein binds to β-catenin, a protein recently shown to interact with Tcf and Lef transcription factors. The gene encoding hTcf-4, a Tcf family member that is expressed in colonic epithelium, was cloned and characterized. hTcf-4 transactivates transcription only whe...
10.1038/35094067
TCF4 transactivates transcription only when associated with β-catenin. Nuclei of APC −/− colon carcinoma cells were found to contain a stable and constitutively active β-catenin–TCF4 complex. Reintroduction of APC removed β-catenin from TCF4 and abrogated the transcriptional transactivation.
10.1126/science.275.5307.1787
62,240,106
Inactivation of the adenomatous polyposis coli ( APC ) tumor suppressor gene initiates colorectal neoplasia. One of the biochemical activities associated with the APC protein is down-regulation of transcriptional activation mediated by β-catenin and T cell transcription factor 4 (Tcf-4). The protein products of mutant ...
10.1038/35094067
Colorectal tumours with intact APC were found to contain activating β-catenin mutations that alter functionally significant phosphorylation sites. These results indicate that regulation of β-catenin is crucial to APC's tumour-suppressing function and that loss of this function can be achieved by mutations in either APC...
10.1073/pnas.96.10.5522
104,190,736
β-Catenin plays a dual role in the cell: one in linking the cytoplasmic side of cadherin-mediated cell–cell contacts to the actin cytoskeleton and an additional role in signaling that involves transactivation in complex with transcription factors of the lymphoid enhancing factor (LEF-1) family. Elevated β-catenin level...
10.1038/35094067
References 92–94 are the first reports on the identification of downstream targets of the APC/β-catenin pathway. MYC was shown to be repressed by wild-type APC and activated by β-catenin, and through TCF4 binding sites in its promoter. β-catenin also activates cyclin D1 transcription through promoter sequences to the c...
10.1146/annurev.neuro.22.1.389
102,293,990
▪ Abstract We describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components—nerve terminal, muscle fiber, and Schwa...
10.1038/35097557
A comprehensive review of NMJ development, covering topics not included here, such as presynaptic development, synapse elimination, regeneration and comparison with neuron–neuron synapses.
10.1083/jcb.83.1.143
109,185,848
The development of clusters of acetylcholine (ACh) receptors at newly formed synapses between embryonic chick spinal cord and muscle cells grown in vitro has been studied by iontophoretic mapping with ACh. A semi-automated technique using on-line computer analysis of ACh responses and a photographic system to record th...
10.1038/35097557
References 16 and 17 are the classic papers showing that motor axons organize postsynaptic differentiation.
10.1098/rstb.1981.0078
15,727,217
The number and distribution of acetylcholine (ACh) receptors on muscle cells was studied during development of normal, paralysed and aneural embryonic rat diaphragm muscles. (i) ACh receptors initially are dispersed over the surface of rat embryo myotubes. At day 15| of gestation junctional receptor clusters (‘J-cluste...
10.1038/35097557
A classic and long-maligned demonstration that AChR clusters form, and are arranged in an end-plate band, even in aneural muscle.
10.1126/science.286.5439.503
59,687,888
Quantitative fluorescence imaging was used to study the regulation of acetylcholine receptor (AChR) number and density at neuromuscular junctions in living adult mice. At fully functional synapses, AChRs have a half-life of about 14 days. However, 2 hours after neurotransmission was blocked, the half-life of the AChRs ...
10.1038/35097557
A new method used to show rapid and marked effects of electrical activity on AChR stability in the postsynaptic membrane, indicating mechanisms for linking activity to synaptic architecture.
10.1046/j.1432-1327.2001.02093.x
86,237,062
Acetylcholine receptor (AChR) γ and ε subunits were tagged by green fluorescent protein (GFP) to analyse assembly and targeting in live muscle fibers at the neuromuscular junction. N‐ or C‐terminal fusion polypeptides showed no fluorescence upon transfection of HEK cells. When GFP was inserted into the cytoplasmic loop...
10.1038/35097557
Example of a new reagent that will allow the imaging of postsynaptic development in vivo
10.1126/science.1439819
103,666,857
Single DNA molecules were chemically attached by one end to a glass surface and by their other end to a magnetic bead. Equilibrium positions of the beads were observed in an optical microscope while the beads were acted on by known magnetic and hydrodynamic forces. Extension versus force curves were obtained for indivi...
10.1038/35040072
This first single-molecule study of DNA elasticity demonstrates the combined use of magnetic and flow fields.
10.1126/science.288.5463.143
62,577,968
Atomic force microscopy and single-molecule force spectroscopy were combined to image and manipulate purple membrane patches from Halobacterium salinarum . Individual bacteriorhodopsin molecules were first localized and then extracted from the membrane; the remaining vacancies were imaged again. Anchoring forces betwee...
10.1038/35040072
In this study of a membrane protein, the authors present an elegant example of combining force and imaging SFM.
10.1126/science.7701345
81,393,025
The stretching of single, tethered DNA molecules by a flow was directly visualized with fluorescence microscopy. Molecules ranging in length ( L ) from 22 to 84 micrometers were held stationary against the flow by the optical trapping of a latex microsphere attached to one end. The fractional extension x / L is a unive...
10.1038/35040072
This paper describes how flow fields can be used to stretch DNA and reveal new facets of single-molecule polymer rheology.
10.1126/science.3547653
123,121,850
Optical trapping and manipulation of viruses and bacteria by laser radiation pressure were demonstrated with single-beam gradient traps. Individual tobacco mosaic viruses and dense oriented arrays of viruses were trapped in aqueous solution with no apparent damage using ∼120 milliwatts of argon laser power. Trapping an...
10.1038/35040072
This landmark paper demonstrates the power of optical traps to manipulate microscopic objects.
10.1126/science.282.5390.902
39,977,695
RNA polymerase (RNAP) moves along DNA while carrying out transcription, acting as a molecular motor. Transcriptional velocities for single molecules of Escherichia coli RNAP were measured as progressively larger forces were applied by a feedback-controlled optical trap. The shapes of RNAP force-velocity curves are dist...
10.1038/35040072
By using an optical trap, the authors reveal aspects of transcription on a single molecule level.
10.1177/026988119801200103
38,424,361
There is a good deal of clinical evidence suggesting that compulsion to resume drug taking is an important part of the addiction syndrome. The symptoms comprising motivation to resume drug use, namely craving and compulsion, have been studied experimentally in human subjects. While much work remains to be done, there i...
10.1038/35094560
A clear summary of the clinical correlates of classical conditioning in addiction.
10.1146/annurev.pa.36.040196.002043
79,482,860
Research on drug abuse has recently focused on understanding the vulnerability to develop addiction that is present in certain individuals. These investigations suggest that addiction results from an interaction between drugs and specific individual substrates. Differences in the propensity to develop drug intake can b...
10.1038/35094560
An exposition of the role of stress and stress hormones in drug abuse; complementary to the content of this review.
10.1126/science.285.5435.1870
62,065,416
Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model th...
10.1038/35094560
An up-to-date review of current thinking about LTP in the hippocampus.
10.1146/annurev.neuro.23.1.185
17,590,649
The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the stria...
10.1038/35094560
Reviews the actions of dopamine on neuronal excitability and synaptic transmission in the striatum.
10.1046/j.1460-9568.1999.00576.x
41,755,974
Abstract Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug‐induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addict...
10.1038/35094560
These two papers show that the chronic in vivo administration of psychostimulants changes the morphology of dendritic spines in the nucleus accumbens and prefrontal cortex.
10.1073/pnas.91.23.11217
101,038,857
Neurogenesis and neuronal replacement in a population of wild free-ranging animals are described. Our subjects were adult black-capped chickadees (Parus atricapillus). Neuronal birth dates were determined by a single systemic injection of [3H]thymidine, followed by release of the bird and its recapture 6 or more weeks ...
10.1038/35044558
Suggests a correlation between neurogenesis and the formation of new memories in birds. Subsequent work in mammals has supported this hypothesis.
10.1200/jco.2001.19.6.1779
39,042,692
PURPOSE: Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect t...
10.1038/35101056
This study shows that a variable number of tandem repeats in the thymidylate synthase promoter is associated with response to 5-fluorouracil. It provides evidence for further incorporation of pharmacogenetics studies in cancer clinical trials.
10.1200/jco.2001.19.5.1279
89,407,003
PURPOSE: Glutathione S-transferase theta (GSTT1) and mu (GSTM1) genes are polymorphic, the genes being absent in approximately 15% and 50% of the population, respectively. Because glutathione S-transferases may be involved in the metabolism of chemotherapy drugs, we hypothesized that presence or absence of the genes ma...
10.1038/35101056
A randomized trial showed that intensive chemotherapy was more effective than conventionally administered chemotherapy. However, this study demonstrates that the benefit of the intensive schedule depends on polymorphisms in genes that encode glutathione transferase.
10.1073/pnas.93.23.13206
61,216,519
The comparison of malaria indicators among populations that have different genetic backgrounds and are uniformly exposed to the same parasite strains is one approach to the study of human heterogeneities in the response to the infection. We report the results of comparative surveys on three sympatric West African ethni...
10.1038/35103577
Study of three West African ethnic groups with similar exposure to malaria. It provides evidence that one group, the Fulani, might have genetic factors that enhance their immunity to malaria.
10.1126/science.279.5354.1173
61,297,965
Host-parasite coevolution has been likened to a molecular arms race, with particular parasite genes evolving to evade specific host defenses. Study of the variants of an antigenic epitope of Plasmodium falciparum that induces a cytotoxic T cell response supports this view. In African children with malaria, the variants...
10.1038/35103577
Demonstration of the complex interaction between variation in the human immune system and parasite variation in malaria.
10.1073/pnas.160037097
102,409,467
Electrical coupling by gap junctions is an important form of cell-to-cell communication in early brain development. Whereas glial cells remain electrically coupled at postnatal stages, adult vertebrate neurons were thought to communicate mainly via chemical synapses. There is now accumulating evidence that in certain n...
10.1038/35077566
Single-cell PCR showed that Cx36 is expressed in two types of cortical interneuron as well as in putative excitatory spiny stellate cells. In general, electrical synapses were specifically found between neurons of the same class, but a few cell pairs consisting of fusiform interneurons and spiny stellate (putative exci...
10.1046/j.1460-9568.1998.00163.x
79,452,764
Abstract The connexins are the protein subunits of the gap junction intercellular channels. In the present study a new rat connexin was cloned by degenerate reverse transcription‐polymerase chain reaction and its gene isolated from a mouse genomic library. The nucleotide sequence encodes a protein of 321 amino acids (c...
10.1038/35077566
The first publication of a neuronal specific connexin (Cx36) in mammals. Using microdissected inferior olive, a new connexin cDNA sequence was identified. The general pattern of cellular expression of Cx36 suggested that this connexin is neuron-specific.
10.1126/science.286.5439.531
82,952,752
Although cancer classification has improved over the past 30 years, there has been no general approach for identifying new cancer classes (class discovery) or for assigning tumors to known classes (class prediction). Here, a generic approach to cancer classification based on gene expression monitoring by DNA microarray...
10.1038/35049567
A generic approach to cancer classification is proposed on the basis of gene expression monitoring using DNA arrays. Transcript profiling is used to distinguish acute myeloid leukaemia from acute lymphoblastic leukaemia.
10.1126/science.274.5289.998
41,743,401
Laser capture microdissection (LCM) under direct microscopic visualization permits rapid one-step procurement of selected human cell populations from a section of complex, heterogeneous tissue. In this technique, a transparent thermoplastic film (ethylene vinyl acetate polymer) is applied to the surface of the tissue s...
10.1038/35049567
Technology is described for sampling the macromolecules of tissue cells under microscopic visualization. The extracted DNA, RNA or protein of pure tissue cells can be applied to DNA, RNA or protein profiling arrays.
10.1083/jcb.150.1.105
123,244,592
Is membrane fusion an essentially passive or an active process? It could be that fusion proteins simply need to pin two bilayers together long enough, and the bilayers could do the rest spontaneously. Or, it could be that the fusion proteins play an active role after pinning two bilayers, exerting force in the bilayer ...
10.1038/35052017
Taking advantage of the liposome fusion system (first described in reference 58 ), the authors delved deep into the mechanisms by which the SNAREs fuse two lipid bilayers.
10.1002/gene.1014
124,371,997
Abstract Summary: We describe here an approach for monitoring regulated gene expression by noninvasive imaging in living mice. We have utilized the tetracycline inducible system to simultaneously coregulate the expression of two genes encoding the firefly luciferase and the Cre recombinase, respectively. Results from o...
10.1038/35093537
This study provides a model for the non-invasive imaging of conditional gene expression in mice, in which the TetR system was used to simultaneously regulate two transgenes, which encode Cre and luciferase, from a bidirectional promoter. A photon-imaging system was then used to follow the expression of luciferase in li...
10.1073/pnas.130192197
104,209,822
Regulatory elements that control tetracycline resistance in Escherichia coli were previously converted into highly specific transcription regulation systems that function in a wide variety of eukaryotic cells. One tetracycline repressor (TetR) mutant gave rise to rtTA, a tetracycline-controlled transactivator that requ...
10.1038/35093537
Investigators considering a TetR-based approach should review the improved rtTA variants described here, as well as in reference 26
10.1073/pnas.96.15.8483
62,623,968
Previous attempts to establish transgenic mouse models to study the functions of transforming growth factor β1 (TGFβ1) in the skin revealed controversial roles for TGFβ1 in epidermal growth (inhibition vs. stimulation) and resulted in neonatal lethality in one instance. To establish a viable transgenic model for studyi...
10.1038/35093537
In this paper, topical application of a synthetic steroid was used to control Tgfb1 expression in mouse skin through the transactivator GLVPc, showing that Tgf-β1 inhibits epidermal cell growth.
10.1126/science.8016642
28,264,651
Deletion of the promoter and the first exon of the DNA polymerase β gene (pol β) in the mouse germ line results in a lethal phenotype. With the use of the bacteriophage-derived, site-specific recombinase Cre in a transgenic approach, the same mutation can be selectively introduced into a particular cellular compartment...
10.1038/35093537
This paper describes the first tissue-specific gene inactivation and provides a model for using three loxP sites to remove the selection cassette from the conditional allele in vitro . See references 59 and 60 for variations on this strategy.
10.1073/pnas.89.14.6232
20,713,470
An efficient and accurate method for controlled in vivo transgene modulation by site-directed recombination is described. Seven transgenic mouse founder lines were produced carrying the murine lens-specific alpha A-crystallin promoter and the simian virus 40 large tumor-antigen gene sequence, separated by a 1.3-kilobas...
10.1038/35093537
This first demonstration of Cre-mediated transgene activation provides a model for the general strategy. For an elaboration of this model, see reference 88 , and for an alternative model, see reference 83
10.1101/gad.892001
18,789,945
We report the successful transfer of a fully functional lac operator-repressor gene regulatory system to the mouse. The key component is a lac repressor transgene that resembles a typical mammalian gene both in codon usage and structure and expresses functional levels of repressor protein in the animal. We used the rep...
10.1038/35093537
This paper reports a modified lac operator–repressor system that functions in the mouse and was used to regulate a coat-colour transgene, such that its expression is IPTG responsive.
10.1126/science.275.5306.1640
27,976,103
Axonal pathfinding in the nervous system is mediated in part by cell-to-cell signaling events involving members of the Eph receptor tyrosine kinase (RTK) family and their membrane-bound ligands. Genetic evidence suggests that transmembrane ligands may transduce signals in the developing embryo. The cytoplasmic domain o...
10.1038/35058515
References 6 and 7 provided the first biochemical evidence for signalling via ephrin-B proteins, by showing that tyrosine phosphorylation of the cytoplasmic region of the ephrin occurs following clustering by Eph receptor.
10.1126/science.289.5483.1360
40,526,561
Contact-mediated axon repulsion by ephrins raises an unresolved question: these cell surface ligands form a high-affinity multivalent complex with their receptors present on axons, yet rather than being bound, axons can be rapidly repelled. We show here that ephrin-A2 forms a stable complex with the metalloprotease Kuz...
10.1038/35058515
An important paper that reveals a mechanism required in order that Eph–ephrin interactions lead to repulsion. After Eph–ephrin-A binding, there is a slow local proteolytic cleavage of the ephrin by Kuzbanian that allows cells to disengage.
10.1126/science.273.5280.1402
83,020,706
Two neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), are able to produce a long-lasting enhancement of synaptic transmission in the hippocampus. Unlike other forms of plasticity, neurotrophin-induced plasticity exhibited an immediate requirement for protein synthesis. Plasticity...
10.1038/35049004
Indirect evidence that strongly argues for a role for neurotrophin-induced local protein synthesis in the dendrites of CA1 pyramidal neurons of the hippocampus.
10.1111/j.1460-9568.1995.tb01112.x
107,344,083
Abstract We investigated the mechanism of neuronal nerve growth factor (NGF) release with regard to the potential function of NGF as a mediator of neuronal plasticity in the CNS. The analysis was performed in hippocampal slices and in primary cultures of hippocampal neurons, transiently transfected with an NGF cDNA con...
10.1038/35049004
The first evidence that neurotrophin secretion from neurons can be triggered by membrane depolarization.
10.1073/pnas.93.22.12547
100,819,387
Long-term potentiation (LTP) has been shown to be impaired in mice deficient in the brain-derived neurotrophic factor (BDNF) gene, as well as in a number of other knockout animals. Despite its power the gene-targeting approach is always fraught with the danger of looking at the cumulative direct and indirect effects of...
10.1038/35049004
This report provided the critical evidence for the requirement of BDNF in the induction of long-term potentiation in the CA1 region of the hippocampus.
10.1073/pnas.95.22.13085
38,573,450
Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A–H). Two FA genes, corresponding to complementation groups A and C, have been cloned, but the function of the FAA and FAC proteins remains unknown. We have recently shown that the FAA and FAC protei...
10.1038/35076590
This study showed that FANCA needs to be phosphorylated to function; this happens in all complementation groups except FA-B.
10.1073/pnas.97.26.14748
124,116,898
Perception and cortical responses are not only driven “bottom-up” by the external stimulus but are altered by internal constraints such as expectancy or the current behavioral goal. To investigate neurophysiological mechanisms of such top-down effects, we analyzed the temporal interactions of neurons on different level...
10.1038/35067550
This paper highlights the top-down influences of behavioural expectation at various levels of the visual stream, and examines the differences in synchronization at long distances. The role of multifrequency interaction is also examined.
10.1126/science.1055465
123,192,102
In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons activated by the attended stimulus showed increased gamma-frequency (35 t...
10.1038/35067550
A study of synchronized neuronal activity in attentional selection, showing increased oscillatory synchronized activity in the high frequency range (35–90 Hz) and decreased activity in the low-frequency range (<17 Hz). This phenomenon might serve a fundamental role in enhancing behaviorally relevant signals in the cort...
10.1073/pnas.97.4.1867
38,270,566
Experimental and modeling efforts suggest that rhythms in the CA1 region of the hippocampus that are in the beta range (12–29 Hz) have a different dynamical structure than that of gamma (30–70 Hz). We use a simplified model to show that the different rhythms employ different dynamical mechanisms to synchronize, based o...
10.1038/35067550
The different rhythms are based on different firing properties of neurons, in turn depending on the various ion channels used. Using Hodgkin–Huxley equation modelling, this study reproduces the role and interaction of the synchrony over short and long distances, thus illuminating the process of synchrony at the cellula...
10.1073/pnas.95.24.14529
38,405,834
A minimal hypothesis is proposed concerning the brain processes underlying effortful tasks. It distinguishes two main computational spaces: a unique global workspace composed of distributed and heavily interconnected neurons with long-range axons, and a set of specialized and modular perceptual, motor, memory, evaluati...
10.1038/35067550
A detailed analysis of how a cognitive task can be modelled by means of the large-scale integration ('global workspace') of various relevant brain regions starting from local coherence and constituting a global dynamic pattern. A comparison with experimental results is provided.
10.1073/pnas.93.2.589
62,436,923
In the vertebrate central nervous system, the retina has been a useful model for studies of cell fate determination. Recent results from studies conducted in vitro and in vivo suggest a model of retinal development in which both the progenitor cells and the environment change over time. The model is based upon the noti...
10.1038/35053522
The first proposal of the competence model for retinal development.
10.1002/cne.901880205
100,358,813
Abstract The period of cell genesis of rod and cone photoreceptor cells has been determined in the retinas of C57BL/6J mice. Embryonic mice were exposed to a single dose of 3 H‐thymidine at embryonic day (E) 10‐18 by injecting pregnant mice intraperitoneally. Animals at postnatal ages were injected subcutaneously once ...
10.1038/35053522
References 4 – 7 are classic studies that describe the birthdates of the main classes of retinal cells in several species.
10.1242/dev.126.3.555
38,274,163
The seven major classes of cells of the vertebrate neural retina are generated from a pool of multipotent progenitor cells. Recent studies suggest a model of retinal development in which both the progenitor cells and the environment change over time (Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. and Ezzeddine, D...
10.1038/35053522
Shows a number of key features of retinal cell-fate determination, including limitations in the competence of retinal progenitors at different times and the ability of extrinsic signals to alter the relative proportions of cell types generated within a given competence state.
10.1242/dev.124.6.1119
104,211,469
Cell fate determination in the developing vertebrate retina is characterized by the sequential generation of seven classes of cells by multipotent progenitor cells. Despite this order of genesis, more than one cell type is generated at any time; for example, in the rat, several cell types are born during the prenatal p...
10.1038/35053522
Shows heterogeneity in retinal progenitors and an intrinsic bias in one subset of progenitors to produce distinct cell types.
10.1242/dev.125.6.1059
19,196,115
The different retinal cell types arise during vertebrate development from a common pool of progenitor cells. The mechanisms responsible for determining the fate of individual retinal cells are, as yet, poorly understood. Ganglion cells are one of the first cell types to be produced in the developing vertebrate retina a...
10.1038/35053522
Clearly shows feedback inhibition of ganglion cell genesis by postmitotic ganglion cells, and also shows that this action is distinct from the Delta-Notch signalling pathway.
10.1083/jcb.87.2.509
79,815,508
A newly discovered method (Heidemann and McIntosh, 1980, Nature [Lond.] 286:517) for displaying the molecular polarity of microtubules (MTs) has been slightly modified and applied to the midbodies of cultured mammalian cells and the phragmoplasts of Haemanthus endosperm. The method involves the decoration of preexistin...
10.1038/35048005
Classic paper showing that opposing sets of phragmoplast microtubules meet at their fast-growing plus ends.
10.1242/jcs.105.4.891
103,738,604
Microtubules in plant cells, as in animal cells, are dynamic structures. However, our lack of knowledge about the constituents of microtubules in plant cells has prevented us from understanding the mechanisms that control microtubule dynamics. To characterize some of these constituents, a cytoplasmic extract was prepar...
10.1038/35048005
Isolation of a group of approximately 65-kDa tobacco proteins that bundle microtubules in vitro
10.1073/pnas.96.26.14931
17,595,932
In plants, cortical microtubules (MTs) occur in characteristically parallel groups maintained up to one microtubule diameter apart by fine filamentous cross-bridges. However, none of the plant microtubule-associated proteins (MAPs) so far purified accounts for the observed separation between MTs in cells. We previously...
10.1038/35048005
MAP65 forms inter-microtubule bridges in vitro of the length observed in plant cells.
10.1242/jcs.110.2.179
123,030,037
Analysis of a cDNA for a 125 kDa polypeptide, previously isolated from phragmoplasts of tobacco BY-2 cells as a candidate for a plus end-directed microtubule motor, revealed this polypeptide to be a novel member of the kinesin superfamily. We named this protein TKRP125 (tobacco kinesin-related polypeptide of 125 kDa). ...
10.1038/35048005
Cloning of a BimC-type kinesin found in the phragmoplast shows that these mitotic motors also function in cytokinesis in plants.
10.1083/jcb.139.6.1485
82,646,994
In higher plant cytokinesis, plasma membrane and cell wall originate by vesicle fusion in the plane of cell division. The Arabidopsis KNOLLE gene, which is required for cytokinesis, encodes a protein related to vesicle-docking syntaxins. We have raised specific rabbit antiserum against purified recombinant KNOLLE prote...
10.1038/35048005
The direction and timing of membrane flow are key elements in plant cytokinesis. This and the following references 52 – 58 describe a range of non-MAP proteins likely to be important in regulating the formation of the cell plate.
10.1126/science.7652556
123,235,408
Vulval induction during Caenorhabditis elegans development is mediated by LET-23, a homolog of the mammalian epidermal growth factor receptor tyrosine kinase. The sli-1 gene is a negative regulator of LET-23 and is shown here to encode a protein similar to c-Cbl, a mammalian proto-oncoprotein. SLI-1 and c-Cbl share app...
10.1038/35067100
A seminal publication that identified Cbl as a negative regulator of receptor tyrosine kinases.
10.1126/science.286.5438.309
122,354,302
Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates signaling by marking active receptors for degradation. c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-protein ligases (or E3s...
10.1038/35067100
This paper, along with references 18 and 19 , was the first to define Cbl as an E3 ubiquitin protein ligase.
10.1101/gad.12.23.3663
28,256,861
Ligand-induced down-regulation of two growth factor receptors, EGF receptor (ErbB-1) and ErbB-3, correlates with differential ability to recruit c-Cbl, whose invertebrate orthologs are negative regulators of ErbB. We report that ligand-induced degradation of internalized ErbB-1, but not ErbB-3, is mediated by transient...
10.1038/35067100
References 44 and 45 were the first to show that c-Cbl can function as a negative regulator of receptor tyrosine kinase signalling by directing the multi-ubiquitylation of activated receptors.
10.1126/science.276.5311.418
80,662,031
Engagement of antigen and immunoglobulin receptors on hematopoietic cells is directly coupled to activation of nonreceptor protein tyrosine kinases (PTKs) that then phosphorylate critical intracellular substrates. In mast cells stimulated through the FcɛRI receptor, activation of several PTKs including Syk leads to deg...
10.1038/35067100
First paper to show a negative regulatory role for Cbl towards a protein tyrosine kinase in mammalian cells.
10.1073/pnas.95.26.15547
38,573,458
Cbl is the product of the protooncogene c- cbl and is involved in T cell antigen receptor (TCR)-mediated signaling. To understand the role of Cbl for immune system development and function, we generated a Cbl-deficient mouse strain. In Cbl-deficient mice, positive selection of the thymocytes expressing major histocompa...
10.1038/35067100
References 70 and 71 provided evidence that c-Cbl functions as a negative regulator of ZAP-70 and that ZAP-70 in c-Cbl −/− thymocytes can be activated in the absence of CD4 co-receptor stimulation.
10.1083/jcb.150.2.377
81,573,786
Cell transformation by Rous sarcoma virus results in a dramatic change of adhesion structures with the substratum. Adhesion plaques are replaced by dot-like attachment sites called podosomes. Podosomes are also found constitutively in motile nontransformed cells such as leukocytes, macrophages, and osteoclasts. They ar...
10.1038/35099066
An interesting discovery of dynamin localization at the tubular invaginations of the plasma membrane in podosomes and characterization of its involvement in podosome formation.
10.1126/science.7846531
80,661,967
Integrin receptors mediate cell adhesion, signal transduction, and cytoskeletal organization. How a single transmembrane receptor can fulfill multiple functions was clarified by comparing roles of receptor occupancy and aggregation. Integrin occupancy by monovalent ligand induced receptor redistribution, but minimal ty...
10.1038/35099066
The local reaction that is induced by interactions of integrins with matrix proteins was analysed by application of micron-sized beads that were covered with a protein of interest to the cell surface. Both the clustering of integrin molecules and their direct interaction with matrix proteins through the RGD motif (occu...
10.1083/jcb.133.6.1403
104,233,568
Activated rhoA, a ras-related GTP-binding protein, stimulates the appearance of stress fibers, focal adhesions, and tyrosine phosphorylation in quiescent cells (Ridley, A.J., and A. Hall, 1992. Cell. 70:389-399). The pathway by which rho triggers these events has not been elucidated. Many of the agents that activate rh...
10.1038/35099066
This study first showed the role of myosin II downstream of Rho in the formation of focal adhesions.
10.1083/jcb.153.4.881
83,540,383
Fibroblast migration involves complex mechanical interactions with the underlying substrate. Although tight substrate contact at focal adhesions has been studied for decades, the role of focal adhesions in force transduction remains unclear. To address this question, we have mapped traction stress generated by fibrobla...
10.1038/35099066
This study showed that locomoting cells apply the strongest forces to small zyxin-containing focal complexes at the leading edge.
10.1126/science.6987736
20,376,312
When tissue cells are cultured on very thin sheets of cross-linked silicone fluid, the traction forces the cells exert are made visible as elastic distortion and wrinkling of this substratum. Around explants this pattern of wrinkling closely resembles the "center effects" long observed in plasma clots and traditionally...
10.1038/35099066
This study showed for the first time that the cell applies mechanical force to the substrate to which it adheres.