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10.1002/gcc.10000
102,949,962
Abstract The common fragile site, FRA3B, has been shown to be a site of frequent homozygous deletions in some cancers, resulting in loss of expression of the associated FHIT gene. It has been proposed that FHIT is a tumor suppressor gene that is inactivated as a result of the instability of FRA3B in tumorigenesis. More...
10.1038/35106058
Identification and sequencing of the FRAXB region, and characterization of deletions in FRAXB in oesophageal cancer cells.
10.1073/pnas.091095898
79,590,496
It has been suggested that delayed DNA replication underlies fragility at common human fragile sites, but specific sequences responsible for expression of these inducible fragile sites have not been identified. One approach to identify such cis-acting sequences within the large nonexonic regions of fragile sites would ...
10.1038/35106058
The first comparison of orthologous fragile-site sequences of two species, mouse and human.
10.1073/pnas.080063497
81,680,192
To investigate the role of the Fhit gene in carcinogen induction of neoplasia, we have inactivated one Fhit allele in mouse embryonic stem cells and produced (129/SvJ × C57BL/6J) F 1 mice with a Fhit allele inactivated (+/−). Fhit +/+ and +/− mice were treated intragastrically with nitrosomethylbenzylamine and observed...
10.1038/35106058
Reports the development of Fhit knockout mice, their exquisite carcinogen susceptibility and development of a carcinogen-induced Muir–Torre-like syndrome.
10.1073/pnas.191345898
19,976,744
Mice carrying one inactivated Fhit allele ( Fhit +/− mice) are highly susceptible to tumor induction by N- nitrosomethylbenzylamine, with 100% of Fhit +/− mice exhibiting tumors of the forestomach/squamocolumnar junction vs. 25% of Fhit +/+ controls. In the current study a single N- nitrosomethylbenzylamine dose was ad...
10.1038/35106058
Provides evidence that Fhit might be a one-hit tumour suppressor, at least in some mouse tissues.
10.1073/pnas.061020098
65,345,259
The tumor suppressor gene FHIT spans a common fragile site and is highly susceptible to environmental carcinogens. FHIT inactivation and loss of expression is found in a large fraction of premaligant and malignant lesions. In this study, we were able to inhibit tumor development by oral gene transfer, using adenoviral ...
10.1038/35106058
Reports prevention of in vivo carcinogen-induced cancers in mice by infection with Fhit -encoding adenoviruses.
10.1126/science.289.5487.2137
80,842,954
The Drosophila retina is patterned by a morphogenetic wave driven by the Hedgehog signaling protein. Hedgehog, secreted by the first neurons, induces neuronal differentiation and hedgehog expression in nearby uncommitted cells, thereby propagating the wave. Evidence is presented here that the zebrafish Hedgehog homolog...
10.1038/35098564
Indicates that Hedgehog signalling might be used in patterning the vertebrate retina.
10.1073/pnas.040556497
38,253,002
The Notch signaling pathway defines an evolutionarily conserved cell–cell interaction mechanism that throughout development controls the ability of precursor cells to respond to developmental signals. Here we show that Notch signaling regulates the expression of the master control genes eyeless , vestigial , and Distal...
10.1038/35098564
Indicates that Notch might have a role in signalling during appendage specification.
10.1126/science.7892602
104,361,412
The Drosophila gene eyeless ( ey ) encodes a transcription factor with both a paired domain and a homeodomain. It is homologous to the mouse Small eye ( Pax-6 ) gene and to the Aniridia gene in humans. These genes share extensive sequence identity, the position of three intron splice sites is conserved, and these genes...
10.1038/35098564
Shows that eyeless can direct ectopic eye development in Drosophila
10.1242/dev.126.19.4213
41,611,106
We report here that misexpression of the transcription factor Pax6 in the vertebrate Xenopus laevis leads to the formation of differentiated ectopic eyes. Multiple molecular markers indicated the presence of mature lens fiber cells, ganglion cells, Muller cells, photoreceptors and retinal pigment epithelial cells in a ...
10.1038/35098564
Shows that ectopic eye development can also occur in vertebrates as a result of ectopic Pax6 expression.
10.1101/gad.3.8.1099
45,476,684
Mutations in the Notch locus affect a variety of developmental decisions in Drosophila. In this paper, we examine the role of Notch in the developing retina. We reduced Notch activity at successive intervals during development of the retina, and then examined the effect on individual cells. When Notch activity was redu...
10.1038/35098564
Shows that Notch functions at many stages in Drosophila eye development and indicates a 'permissive' role for its function.
10.1242/dev.128.13.2497
104,311,068
The vertebrate retina contains seven major neuronal and glial cell types in an interconnected network that collects, processes and sends visual signals through the optic nerve to the brain. Retinal neuron differentiation is thought to require both intrinsic and extrinsic factors, yet few intrinsic gene products have be...
10.1038/35098564
Describes the role that the mouse homologue of atonal has in retinal ganglion cell formation.
10.1162/08989290051137594
101,895,155
A still photograph of an object in motion may convey dynamic information about the position of the object immediately before and after the photograph was taken (implied motion). Medial temporal/medial superior temporal cortex (MT/MST) is one of the main brain regions engaged in the perceptual analysis of visual motion....
10.1038/35086023
This fMRI study found greater activation in area MT/MST when viewing static photographs with implied motion than when viewing photographs without implied motion. It is one of the first neurophysiological demonstrations that dynamic information can be extracted from still photographs.
10.1111/j.1467-9280.1993.tb00585.x
56,841,098
In demonstrations of apparent motion, observers typically report seeing motion along the shortest possible path between two sequentially presented objects. Recent work has demonstrated that violations of this shortest path rule occur with realistic photographs of a human body displayed for sufficiently long temporal in...
10.1038/35086023
An excellent demonstration of the cognitive mechanisms involved in human motion perception.
10.1126/science.286.5445.1692
62,213,101
The ability to “mentalize,” that is to understand and manipulate other people's behavior in terms of their mental states, is a major ingredient in successful social interactions. A rudimentary form of this ability may be seen in great apes, but in humans it is developed to a high level. Specific impairments of mentaliz...
10.1038/35086023
An elegant article that reviews developmental and neuroscientific studies on 'mentalizing,' and proposes that the detection of biological motion may have evolved to enable us to infer other people's mental states.
10.1152/jn.1995.73.6.2608
83,017,967
1. We stimulated the motor cortex of normal subjects (transcranial magnetic stimulation) while they 1) observed an experimenter grasping 3D-objects, 2) looked at the same 3D-objects, 3) observed an experimenter tracing geometrical figures in the air with his arm, and 4) detected the dimming of a light. Motor evoked pot...
10.1038/35086023
An important demonstration using TMS of increased activity in the motor system during the observation of actions.
10.1101/gad.11.14.1827
58,468,182
We isolated a novel bHLH protein gene Mesp2 (for mesoderm posterior 2) that cross-hybridizes with Mesp1 expressed in the early mouse mesoderm. Mesp2 is expressed in the rostral presomitic mesoderm, but down-regulated immediately after the formation of the segmented somites. To determine the function of MesP2 protein (M...
10.1038/35098552
Shows that the transcription factor Mesp2 is involved in establishing the rostrocaudal polarity of somites.
10.1242/dev.128.23.4873
41,660,933
The temporal and spatial regulation of somitogenesis requires a molecular oscillator, the segmentation clock. Through Notch signalling, the oscillation in cells is coordinated and translated into a cyclic wave of expression of hairy-related and other genes. The wave sweeps caudorostrally through the presomitic mesoderm...
10.1038/35098552
Indicates that Fgf functions to keep PSM cells in an immature state in zebrafish.
10.1242/dev.103.1.69
62,158,049
The somitic involvement in the formation of the vertebral column was examined using the chick-quail chimaera model. Single cervical somites from quail donor embryos were transplanted into similarly staged chick host embryos. Following further incubation, serial sections of variously staged embryos were stained with the...
10.1038/35098552
The first demonstration of resegmenation in which half-somites are implicated.
10.1073/pnas.95.1.334
20,407,358
We used reverse transcription–coupled PCR to produce a high-resolution temporal map of fluctuations in mRNA expression of 112 genes during rat central nervous system development, focusing on the cervical spinal cord. The data provide a temporal gene expression “fingerprint” of spinal cord development based on major fam...
10.1038/35076576
This is one of the first analyses of large-scale gene expression — in this case, RT–PCR data — using clustering and data-mining techniques. It elegantly shows how integrating the results derived using various distance metrics can reveal different but meaningful patterns in the data.
10.1073/pnas.95.25.14863
104,393,952
A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data s...
10.1038/35076576
This is an excellent demonstration of the power of hierarchical clustering to the analysis of microarray data. The authors also provide software — Cluster and Treeview — which became the standard for analysing microarray data.
10.1126/science.275.5298.343
101,797,635
Since 1990, the National Cancer Institute (NCI) has screened more than 60,000 compounds against a panel of 60 human cancer cell lines. The 50-percent growth-inhibitory concentration (GI 50 ) for any single cell line is simply an index of cytotoxicity or cytostasis, but the patterns of 60 such GI 50 values encode unexpe...
10.1038/35076576
Weinstein and colleagues present one of the first and most elegant applications of hierarchical clustering and other data-mining and visualization techniques to the analysis of large-scale data in molecular biology.
10.1073/pnas.96.6.2907
40,779,263
Array technologies have made it straightforward to monitor simultaneously the expression pattern of thousands of genes. The challenge now is to interpret such massive data sets. The first step is to extract the fundamental patterns of gene expression inherent in the data. This paper describes the application of self-or...
10.1038/35076576
Tamayo and colleagues use self-organizing maps (SOMs) to explore patterns of gene expression generated using Affymetrix arrays, and provide the GENECLUSTER implementation of SOMs.
10.1073/pnas.97.1.262
61,453,195
We introduce a method of functionally classifying genes by using gene expression data from DNA microarray hybridization experiments. The method is based on the theory of support vector machines (SVMs). SVMs are considered a supervised computer learning method because they exploit prior knowledge of gene function to ide...
10.1038/35076576
This paper shows the power of supervised techniques, in this case support vector machines, to provide additional insight into gene expression and function.
10.1073/pnas.90.10.4528
61,095,132
We describe a system to evaluate the function of lymphocyte-specific and generally expressed genes in the differentiation and/or function of lymphocytes. RAG-2 (recombination-activating gene 2)-deficient mice have no mature B and T lymphocytes due to the inability to initiate VDJ recombination. Blastocysts from RAG-2-d...
10.1038/3509551
This paper contained the first description of the RAG complementation assay.
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...
10.1038/3509551
This report describes the first use of the Cre/ loxP system for tissue-specific deletion in lymphocytes.
10.1083/jcb.138.6.1193
61,007,549
The mechanisms of localization and retention of membrane proteins in the inner nuclear membrane and the fate of this membrane system during mitosis were studied in living cells using the inner nuclear membrane protein, lamin B receptor, fused to green fluorescent protein (LBR–GFP). Photobleaching techniques revealed th...
10.1038/35073068
Shows the connectivity of the endoplasmic reticulum (ER) and nuclear envelope in vivo and provides a visual example of how a protein can be mobile in one domain of the cell and immobile in another domain.
10.1126/science.273.5276.797
16,716,568
The mechanism by which Golgi membrane proteins are retained within the Golgi complex in the midst of a continuous flow of protein and lipid is not yet understood. The diffusional mobilities of mammalian Golgi membrane proteins fused with green fluorescent protein from Aequorea victoria were measured in living HeLa cell...
10.1038/35073068
First paper to use FRAP to measure the diffusion rate of a GFP chimaera in a cellular organelle, the Golgi. In addition, this paper introduces the FLIP method of photobleaching.
10.1083/jcb.142.1.69
100,820,770
Membrane microdomains (“lipid rafts”) enriched in glycosylphosphatidylinositol (GPI)-anchored proteins, glycosphingolipids, and cholesterol have been implicated in events ranging from membrane trafficking to signal transduction. Although there is biochemical evidence for such membrane microdomains, they have not been v...
10.1038/35073068
Uses acceptor photobleaching FRET to assess the organization of lipid rafts at the cell surface. Contains a detailed discussion of the theory for interpreting FRET from donors and acceptors constrained to membranes.
10.1242/jcs.108.3.1051
123,737,704
Quantitative microscopic imaging of resonance energy transfer (RET) was applied for immunological high resolution proximity mapping of several cytoskeletal components of cell adhesions. To conduct this analysis, a microscopic system was developed, consisting of a highly stable field illuminator, computer-controlled fil...
10.1038/35073068
An elegant FRET microscopy study using immunofluorescence labelling to probe the distribution of proteins in adherens junctions.
10.1073/pnas.96.18.10123
58,555,924
Fluorescence correlation microscopy (FCM) was applied to characterize fusion proteins of the green fluorescent protein (GFP) on the cellular as well as molecular level within seconds in an integrated instrument. FCM combines the inherent sensitivity and high spatial resolution of fluorescence correlation spectroscopy w...
10.1038/35073068
Provides a concise overview of how FCS and confocal microscopy can be linked to study the diffusional mobility of GFP-tagged proteins in cells.
10.1126/science.7792600
18,981,767
A gene, ATM , that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities....
10.1038/35043058
The report of the cloning of the ATM gene after a two-decade search.
10.1126/science.281.5383.1674
82,624,813
The ATM protein, encoded by the gene responsible for the human genetic disorder ataxia telangiectasia (A-T), regulates several cellular responses to DNA breaks. ATM shares a phosphoinositide 3-kinase–related domain with several proteins, some of them protein kinases. A wortmannin-sensitive protein kinase activity was a...
10.1038/35043058
References 6 and 7 reported that ATM directly phosphorylates p53 and is activated by DNA damage.
10.1126/science.287.5459.1824
26,930,737
Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2 −/− embryonic stem cells failed to maintain γ-irradiation–induced arrest in the G 2 phase of the cell cycle. Chk2 −/− thymocytes were resistant to DNA ...
10.1038/35043058
Development of Chk2-knockout mouse cells and linkage of Chk2 to p53 and the G1-checkpoint pathway.
10.1101/gad.14.3.289
133,917,805
Upon DNA damage, the amino terminus of p53 is phosphorylated at a number of serine residues including S20, a site that is particularly important in regulating stability and function of the protein. Because no known kinase has been identified that can modify this site, HeLa nuclear extracts were fractionated and S20 pho...
10.1038/35043058
References 40 and 41 show that CHK2 phosphorylates p53 on serine 20 and contributes to its stabilization in an ATM-dependent manner.
10.1126/science.277.5331.1501
60,710,767
Human Cdc25C is a dual-specificity protein phosphatase that controls entry into mitosis by dephosphorylating the protein kinase Cdc2. Throughout interphase, but not in mitosis, Cdc25C was phosphorylated on serine-216 and bound to members of the highly conserved and ubiquitously expressed family of 14-3-3 proteins. A mu...
10.1038/35043058
Demonstration of a G2-checkpoint control mechanism involving 14-3-3 protein binding regulated by phosphorylation of CDC25C.
10.1126/science.2000496
88,225,283
The primary motor cortex (MI) contains a map organized so that contralateral limb or facial movements are elicited by electrical stimulation within separate medial to lateral MI regions. Within hours of a peripheral nerve transection in adult rats, movements represented in neighboring MI areas are evoked from the corti...
10.1038/35067570
Identifies intracortical inhibitory circuits as a substrate for fast and accurate modulation of cortical motor representations.
10.1152/jn.2000.83.5.3147
81,662,875
It has been hypothesized that the magnocellular red nucleus (RNm) contributes to compensation for motor impairments associated with lesions of the pyramidal tract. To test this hypothesis, we used stimulus triggered averaging (StTA) of electromyographic (EMG) activity to characterize changes in motor output from the re...
10.1038/35067570
Detailed electrophysiological study showing a spontaneous reorganization of red nucleus output following corticospinal tract lesion in monkey. This study introduces nicely the concept of the subcortical motor centre reorganization and suggests its contribution to functional recovery.
10.1146/annurev.physiol.62.1.723
26,945,363
▪ Abstract Motor systems can adapt rapidly to changes in external conditions and to switching of internal goals. They can also adapt slowly in response to training, alterations in the mechanics of the system, and any changes in the system resulting from injury. This article reviews the mechanisms underlying short- and ...
10.1038/35067570
Extensive and comprehensive review of the adaptive capabilities of the spinal motor circuits.
10.1152/jn.1998.79.3.1329
20,799,404
de Leon, R. D., J. A. Hodgson, R. R. Roy, and V. R. Edgerton. Locomotor capacity attributable to step training versus spontaneous recovery after spinalization in adult cats. J. Neurophysiol. 79: 1329–1340, 1998. Locomotor performance, hindlimb muscle activity and gait patterns during stepping were studied in step-train...
10.1038/35067570
This paper investigates in qualitative and quantitative details the influence of treadmill training on locomotion of cats that have received a complete spinal cord transection. They show that spinal cord circuits disconnected from their supraspinal inputs are able to 'learn' a motor task.
10.1152/jn.1999.81.1.85
81,063,501
de Leon, R. D., J. A. Hodgson, R. R. Roy, and V. R. Edgerton. Retention of hindlimb stepping ability in adult spinal cats after the cessation of step training. J. Neurophysiol. 81: 85–94, 1999. Adult spinal cats were trained to perform bipedal hindlimb locomotion on a treadmill for 6–12 wk. After each animal acquired t...
10.1038/35067570
Treadmill stepping recovery observable after training in spinal cats persists for weeks after cessation of the training period. The training effect then declines progressively but can be quickly re-induced by shorter training sessions.
10.1002/cne.901580103
40,247,402
Abstract The hypothesis that collateral sprouting might be correlated with recovery of function was tested by a combination of behavioral and anatomical studies. Partial hemisections, sparing the dorsal columns, were made between T 12 and L 1 of cat spinal cord. Initially, all reflex and locomotor hindlimb activity was...
10.1038/35067570
One of the first studies to introduce the concept of collateral sprouting in the spinal cord as a mechanism of functional recovery.
10.1523/jneurosci.17-07-02499.1997
123,584,284
To investigate the molecular mechanisms of cholinergic sprouting in the hippocampus after removal of entorhinal cortical inputs, we evaluated trophic factor gene expression in the denervated hippocampus. Despite the proposed role for nerve growth factor (NGF) in this sprouting, we observed no change in NGF mRNA or prot...
10.1038/35067570
Demonstrates the role of lesion-induced, secreted factors in the induction of fibre sprouting into a denervated central nervous system region.
10.1128/mcb.15.4.1942
19,253,623
The Ras-related protein Cdc42 plays a role in yeast cell budding and polarity. Two related proteins, Rac1 and RhoA, promote formation in mammalian cells of membrane ruffles and stress fibers, respectively, which contain actin microfilaments. We now show that microinjection of the related human Cdc42Hs into Swiss 3T3 fi...
10.1038/35044547
References 5 – 9 describe the original studies of Rho, Rac and Cdc42 in mammalian fibroblasts, establishing these proteins as key regulators of actin structures in response to extracellular stimuli.
10.1083/jcb.111.1.143
40,766,335
The Saccharomyces cerevisiae CDC42 gene product is involved in the morphogenetic events of the cell division cycle; temperature-sensitive cdc42 mutants are unable to form buds and display delocalized cell-surface deposition at the restrictive temperature (Adams, A. E. M., D. I. Johnson, R. M. Longnecker, B. F. Sloat, a...
10.1038/35044547
References 10 – 11 describe the original identification of Cdc42 as a key regulator of cell polarity in yeast.
10.1101/gad.8.15.1787
84,360,298
The small GTPases of the Rac/Rho/Cdc42 subfamily are implicated in actin cytoskeleton-membrane interaction in mammalian cells and budding yeast. The in vivo functions of these GTPases in multicellular organisms are not known. We have cloned Drosophila homologs of rac and CDC42, Drac1, and Dcdc42. They share 70% amino a...
10.1038/35044547
The first paper investigating the function of Rac and Cdc42 in neurons. In Drosophila embryonic sensory neurons, perturbation of Rac activity affects primarily axon growth, whereas perturbation of Cdc42 activity affects both axon and dendrite outgrowth.
10.1083/jcb.126.3.801
61,234,349
Addition of the bioactive phospholipid lysophosphatidic acid (LPA) or a thrombin receptor-activating peptide (TRP) to serum-starved N1E-115 or NG108-15 neuronal cells causes rapid growth cone collapse, neurite retraction, and transient rounding of the cell body. These shape changes appear to be driven by receptor-media...
10.1038/35044547
The first paper investigating the function of Rho in neuronal cell lines. Rho activation causes neuronal process retraction.
10.1083/jcb.149.2.263
104,266,064
The ephrins, ligands of Eph receptor tyrosine kinases, have been shown to act as repulsive guidance molecules and to induce collapse of neuronal growth cones. For the first time, we show that the ephrin-A5 collapse is mediated by activation of the small GTPase Rho and its downstream effector Rho kinase. In ephrin-A5–tr...
10.1038/35044547
Provides biochemical evidence that Rho mediates the effect of ephrin-A5 axon guidance cue.
10.1126/science.281.5375.416
58,564,402
The leukocyte-specific adapter molecule SLP-76 (Src homology 2 domain–containing leukocyte protein of 76 kilodaltons) is rapidly phosphorylated on tyrosine residues after receptor ligation in several hematopoietically derived cell types. Mice made deficient for SLP-76 expression contained no peripheral T cells as a res...
10.1038/35100523
References 10 and 11 describe mice with targeted disruption of the Slp76 gene. These mice have a complete block in thymocyte development, presumably due to impaired signalling through the pre-TCR, emphasizing the vital role played by SLP76 as a positive regulator of T-cell function.
10.1126/science.1057176
16,748,705
GADS is an adaptor protein implicated in CD3 signaling because of its ability to link SLP-76 to LAT. A GADS-deficient mouse was generated by gene targeting, and the function of GADS in T cell development and activation was examined. GADS – CD4 – CD8 – thymocytes exhibited a severe block in proliferation but still diffe...
10.1038/35100523
Describes mice made deficient in Gads. Unlike Slp76 −/− or Lat −/− mice, thymocyte development is normal in Gads-deficient animals and mature T cells populate the periphery, but severe defects in thymocyte selection and function of the mature T cells which develop.
10.1126/science.290.5490.333
123,919,353
Signaling proteins are thought to be tightly regulated spatially and temporally in order to generate specific and localized effects. For Rac and other small guanosine triphosphatases, binding to guanosine triphosphate leads to interaction with downstream targets and regulates subcellular localization. A method called F...
10.1038/35100523
Highlights the use of a method based on FRET modified to examine the spatio-temporal pattern of RAC1 activation in living cells.
10.1084/jem.191.9.1591
122,856,688
According to a recently proposed hypothesis, initiation of signal transduction via immunoreceptors depends on interactions of the engaged immunoreceptor with glycosphingolipid-enriched membrane microdomains (GEMs). In this study, we describe a novel GEM-associated transmembrane adaptor protein, termed phosphoprotein as...
10.1038/35100523
References 53 and 54 describe the initial characterization of PAG/CBP, indicating its localization in lipid rafts and its association with CSK. These papers provide evidence for how an adaptor protein might regulate an enzyme by directing its subcellular localization.
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...
10.1038/35100523
This study shows a function for c-Cbl as an E3 ubiquitin-protein ligase with direct in vitro evidence of a role for the TKB and RING domains.
10.1073/pnas.97.15.8629
20,419,061
Astrocytes can release glutamate in a calcium-dependent manner and consequently signal to adjacent neurons. Whether this glutamate release pathway is used during physiological signaling or is recruited only under pathophysiological conditions is not well defined. One reason for this lack of understanding is the limited...
10.1038/35058528
By using quantitative imaging and photorelease of Ca 2+ , this study showed that physiological levels of Ca 2+ evoke sufficient release of glutamate from astrocytes to modulate neurons.
10.1126/science.1967852
104,169,881
The finding that astrocytes possess glutamate-sensitive ion channels hinted at a previously unrecognized signaling role for these cells. Now it is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluore...
10.1038/35058528
Original cell-culture study showing transmitter-induced Ca 2+ signalling in astrocytes and the potential for long-range signal transmission between these cells. The results of this study opened the field to the possibility that astrocytes could form a pathway for information transfer.
10.1073/pnas.93.23.13268
122,098,534
Focally evoked calcium waves in astrocyte cultures have been thought to propagate by gap-junction-mediated intercellular passage of chemical signal(s). In contrast to this mechanism we observed isolated astrocytes, which had no physical contact with other astrocytes in the culture, participating in a calcium wave. This...
10.1038/35058528
The presence of an extracellular signal, which was later shown to be ATP, mediating astrocyte–astrocyte signalling was clearly shown in this study, which provided evidence that Ca 2+ waves could 'jump' over cell-free regions.
10.1073/pnas.97.1.325
102,653,461
Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we mea...
10.1038/35072566
References 45 and 46 report increased activity of sympathetic systems in depression.
10.1073/pnas.94.1.227
38,480,728
The pathophysiology of systemic inflammation and sepsis involves peripheral organs, causing gastrointestinal, renal, and cardiovascular alterations, as well as the central nervous system (CNS), affecting sleep, temperature regulation, behavior, and neuroendocrine function. The molecular basis of the CNS effects of syst...
10.1038/35072566
Shows that central and peripheral cytokine compartments are integrated but differentially regulated: central cytokines are counter-regulated to a smaller extent than peripherally secreted ones.
10.1126/science.274.5292.1527
103,816,661
Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in...
10.1038/35072566
Discovery of a polymorphism in the regulatory region of the serotonin transporter gene that reduces transcriptional efficiency and might be correlated with anxiety traits.
10.1126/science.284.5411.167
28,000,881
Visual imagery is used in a wide range of mental activities, ranging from memory to reasoning, and also plays a role in perception proper. The contribution of early visual cortex, specifically Area 17, to visual mental imagery was examined by the use of two convergent techniques. In one, subjects closed their eyes duri...
10.1038/35090055
This study demonstrates that area 17 is activated during imagery, and that impairing the functioning of this area, in turn, impairs the performance of an imagery task, providing evidence that this area has a causal role in such processing.
10.1162/jocn.1996.8.1.29
41,341,109
Neuropsychological studies have suggested that imagery processes may be mediated by neuronal mechanisms similar to those used in perception. To test this hypothesis, and to explore the neural basis for song imagery, 12 normal subjects were scanned using the water bolus method to measure cerebral blood flow (CBF) during...
10.1038/35090055
Auditory imagery is in many ways analogous to visual imagery, but activates only 'higher level' brain areas, not early auditory cortex. The similarities and differences between the different modalities illuminate key facets of the underlying mechanisms of imagery.
10.1126/science.171.3972.701
107,244,890
The time required to recognize that two perspective drawings portray objects of the same three-dimensional shape is found to be (i) a linearly increasing function of the angular difference in the portrayed orientations of the two objects and (ii) no shorter for differences corresponding simply to a rigid rotation of on...
10.1038/35090055
This is the classic — and in many ways still the best — study of mental rotation. It is methodologically tight and reveals that rotation in the picture plane and in depth are equally easy, even though the stimuli are only pictures of three-dimensional objects.
10.1126/science.7754376
20,592,306
The borders of human visual areas V1, V2, VP, V3, and V4 were precisely and noninvasively determined. Functional magnetic resonance images were recorded during phase-encoded retinal stimulation. This volume data set was then sampled with a cortical surface reconstruction, making it possible to calculate the local visua...
10.1038/35090055
This paper is a landmark in the development of techniques to delineate topographically organized areas in the human brain; such techniques will no doubt prove to be increasingly important in the study of mental imagery.
10.1073/pnas.95.17.9755
102,658,199
Damage-induced SOS mutagenesis requiring the UmuD′C proteins occurs as part of the cells’ global response to DNA damage. In vitro studies on the biochemical basis of SOS mutagenesis have been hampered by difficulties in obtaining biologically active UmuC protein, which, when overproduced, is insoluble in aqueous soluti...
10.1038/35040051
The first evidence for the intrinsic polymerase activity in UmuD′ 2 C (now pol V).
10.1073/pnas.96.16.8919
20,489,191
The damage-inducible UmuD′ and UmuC proteins are required for most SOS mutagenesis in Escherichia coli . Our recent assay to reconstitute this process in vitro , using a native UmuD′ 2 C complex, revealed that the highly purified preparation contained DNA polymerase activity. Here we eliminate the possibility that this...
10.1038/35040051
Purified UmuD′ 2 C from a temperature-sensitive DNA polymerase III mutant possesses intrinsic polymerase activity and can do translesion synthesis, demonstrating that UmuD′ 2 C is a bona fide DNA polymerase.
10.1101/gad.14.13.1642
133,917,614
The Saccharomyces cerevisiae RAD30 gene encodes DNA polymerase η. Humans possess two Rad30 homologs. One ( RAD30A/POLH ) has previously been characterized and shown to be defective in humans with the Xeroderma pigmentosum variant phenotype. Here, we report experiments demonstrating that the second human homolog ( RAD30...
10.1038/35040051
Demonstration that human Rad30B/pol ι prefers to make the wobble G?T base pair over the correct A?T base pair, and overall has extremely poor fidelity.
10.1126/science.289.5480.774
38,582,112
Establishment of cohesion between sister chromatids is coupled to replication fork passage through an unknown mechanism. Here we report that TRF4 , an evolutionarily conserved gene necessary for chromosome segregation, encodes a DNA polymerase with β-polymerase–like properties. A double mutant in the redundant homologs...
10.1038/35040051
Discovery that the yeast Trf4 protein is a polymerase essential for sister-chromatid cohesion, indicating that possible polymerase exchange mechanisms may be needed to replicate chromosomes fully.
10.1101/gad.859201
18,000,382
Telomere shortening is the mechanism underlying replicative aging in fibroblasts. A variety of reports now claim that inactivation of the p16 INK4a /pRB pathway is required in addition to telomere maintenance for the immortalization of cells such as skin keratinocytes and breast epithelial cells. We here show that the ...
10.1038/35106045
References 18 19 and 21 show that culture conditions, rather than an intrinsic clock, limit the proliferative lifespan of many cell types.
10.1073/pnas.97.9.4493
104,361,049
The conservation of developmental functions exerted by Antp-class homeoproteins in protostomes and deuterostomes suggested that homologs with related functions are present in diploblastic animals. Our phylogenetic analyses showed that Antp-class homeodomains belong either to non-Hox or to Hox/paraHox families. Among th...
10.1038/35047605
Provides a thorough phylogenetic analysis of the cnidarian Hox-like genes relative to bilaterian homeobox sequences.
10.1126/science.290.5490.344
41,518,119
Vernalization, the acceleration of flowering by a long period of cold temperature, ensures that many plants overwinter vegetatively and flower in spring. In Arabidopsis , allelic variation at the FRIGIDA ( FRI ) locus is a major determinant of natural variation in flowering time. Dominant alleles of FRI confer late flo...
10.1038/35084556
A pioneer paper that shows the molecular basis of naturally occurring, putatively adaptive variation — in this case, flowering time. The authors show how populations with a different flowering time result from a deletion at the FRIGIDA locus.
10.1046/j.1469-8137.2001.00076.x
17,595,361
Summary Structural and phylogenetic studies of KNOX genes identified in the bryophyte Physcomitrella patens are reported here, to provide insights into the evolution of class 1 and class 2 KNOX genes. Three KNOTTED1 ‐like homeobox ( KNOX ) genomic clones were isolated and sequenced from P. patens . Corresponding cDNAs ...
10.1038/35084556
Shows that the fundamental duplication of KNOX (knotted homeobox) genes into two classes is characteristic of all land plants but not of an alga, indicating that this duplication might have been a key step in the evolution of land flora.
10.1046/j.1365-2141.1998.00519.x
125,080,114
Eighty‐seven patients with β thalassaemia of intermediate severity were investigated in our Unit to determine whether it is possible to consistently predict phenotypic severity from genotypic factors. The subjects were from the following ethnic backgrounds: Asian Indian (35.1%), Middle Eastern (24.3%), Mediterranean (2...
10.1038/35066048
The most complete analysis so far of the molecular mechanisms for the milder forms of β-thalassaemia.
10.1182/blood.v95.1.342.001k33_342_346
73,968,620
To assess the relative contribution of genetic factors in the variation of F cells (FC) and other hematologic variables, we conducted a classical twin study in unselected twins. The sample included 264 identical (monozygotic [MZ]) twin pairs and 511 nonidentical (dizygotic [DZ]) same-sex twin pairs (aged 20 to 80 years...
10.1038/35066048
The most extensive study so far on the genetic factors that modify the small amounts of fetal haemaglobin that are produced in normal adults.
10.1098/rstb.1999.0539
100,830,886
The completion of the human genome project will provide a vast amount of information about human genetic diversity. One of the major challenges for the medical sciences will be to relate genotype to phenotype. Over recent years considerable progress has been made in relating the molecular pathology of monogenic disease...
10.1038/35066048
An extensive review of phenotype–genotype relationships in monogenic disease, including those other than the haemoglobin disorders.
10.1091/mbc.11.5.1555
41,092,489
The ordered activation of the ubiquitin protein ligase anaphase-promoting complex (APC) or cyclosome by CDC20 in metaphase and by CDH1 in telophase is essential for anaphase and for exit from mitosis, respectively. Here, we show that CDC20 can only bind to and activate the mitotically phosphorylated form of theXenopus ...
10.1038/35048096
A careful biochemical study on the role of phosphorylation in controlling the activities of the Cdc20 and Cdh1 forms of APC/C.
10.1126/science.273.5280.1377
123,528,668
Cdc2, the cyclin-dependent kinase that controls mitosis, is negatively regulated by phosphorylation on its threonine-14 and tyrosine-15 residues. Cdc25, the phosphatase that dephosphorylates both of these residues, undergoes activation and phosphorylation by multiple kinases at mitosis. Plx1, a kinase that associates w...
10.1038/35048096
This paper identifies the Cdc25 phosphatase as a likely physiological substrate of Plx1 and thereby implicates Plks in controlling Cdk1 activity.
10.1126/science.282.5394.1701
16,751,691
The Xenopus polo-like kinase 1 (Plx1) is essential during mitosis for the activation of Cdc25C, for spindle assembly, and for cyclin B degradation. Polo-like kinases from various organisms are activated by phosphorylation by an unidentified protein kinase. A protein kinase, polo-like kinase kinase 1 or xPlkk1, that pho...
10.1038/35048096
An impressive biochemical study that identifies the first candidate upstream regulator of a Plk.
10.1101/gad.11.24.3401
39,185,808
The centromere–kinetochore complex is a specialized chromatin structure that mediates bipolar attachment of replicated chromosomes to the mitotic spindle, thereby ensuring proper sister chromatid separation during anaphase. The manner in which this important multimeric structure is specified and assembled within chroma...
10.1038/35089568
Pioneered the techniques of crosslinking and chromatin immunoprecipitation for analysing the binding of centromere proteins in vivo in budding yeast.
10.1126/science.2928784
59,312,898
Ornithine decarboxylase (ODC) was converted from a protein with a short intracellular half-life in mammalian cells to a stable protein by truncating 37 residues at its carboxyl terminus. Cells expressing wild-type protein lost ODC activity with a half-life of approximately 1 hour. Cells expressing the truncated protein...
10.1038/35056508
Showed that a region of vertebrate ODC that is redundant for enzymatic activity is necessary for degradation.
10.1158/1538-7445.am2011-248
96,275,148
Abstract The endogenous antizyme inhibitor (AZI) is best characterized for its role in regulating polyamine homeostasis. Polyamines are organic cations synthesized by the enzyme ornithine decarboxylase (ODC), a protein which is negatively regulated and targeted for proteasomal degradation by antizyme (AZ). AZI is a pot...
10.1038/35056508
Indicated a possible function for antizyme in the regulation of prostate cell growth.
10.1073/pnas.070055897
100,816,314
Previous studies with mice overproducing ornithine decarboxylase have demonstrated the importance of polyamine homeostasis for normal mammalian spermatogenesis. The present study introduces a likely key player in the maintenance of proper polyamine homeostasis during spermatogenesis. Antizyme 3 is a paralog of mammalia...
10.1038/35056508
Described a novel form of antizyme with a very restricted tissue distribution.
10.1126/science.7569926
41,363,358
Conformational changes, including local protein folding, play important roles in protein-DNA interactions. Here, studies of the transcription factor Ets-1 provided evidence that local protein unfolding also can accompany DNA binding. Circular dichroism and partial proteolysis showed that the secondary structure of the ...
10.1038/35099076
This shows that conformational changes in an inhibitory module of Ets-1 result in loss of DNA-binding autoinhibition.
10.1128/mcb.21.8.2802-2814.2001
84,501,059
ABSTRACT The transcriptional status of eukaryotic genes is determined by a balance between activation and repression mechanisms. The nuclear hormone receptors represent classical examples of transcription factors that can regulate this balance by recruiting corepressor and coactivator complexes in a ligand-dependent ma...
10.1038/35099076
This shows that Elk-1 can act as both an activator and repressor protein, with the ETS-domain showing repressive activity.
10.1126/science.288.5470.1439
17,805,305
The ets family transcription factor PU.1 is required for the development of multiple lineages of the immune system. Using retroviral transduction of PU.1 complementary DNA into mutant hematopoietic progenitors, we demonstrate that differing concentrations of the protein regulate the development of B lymphocytes as comp...
10.1038/35099076
This shows how different concentrations of an ETS-domain protein (PU.1) result in the differentiation of two haematopoietic lineages.
10.1083/jcb.101.2.597
19,707,024
Previous observations indicated that the lamellipodium ("leading edge") of fibroblasts contains a dense meshwork, as well as numerous bundles (microspikes) of actin filaments. Most, if not all, of the filaments have a uniform polarity, with the "barbed" end associated with the membrane. I investigated whether and how a...
10.1038/35040061
These photobleaching studies show that actin monomers are added at the leading edge and that the actin meshwork translocates backward towards the centre of the cell in a stationary lamellipodium.
10.1083/jcb.109.4.1597
18,584,334
Listeria monocytogenes was used as a model intracellular parasite to study stages in the entry, growth, movement, and spread of bacteria in a macrophage cell line. The first step in infection is phagocytosis of the Listeria, followed by the dissolution of the membrane surrounding the phagosome presumably mediated by he...
10.1038/35040061
This is the initial publication showing that the bacterial pathogen, Listeria monocytogenes , associates with host cytoplasmic actin, suggesting that these bacteria move within and between cells in some manner involving the actin cytoskeleton.
10.1128/iai.60.9.3609-3619.1992
61,056,822
Listeria monocytogenes is able to escape from the phagolysosome and grow within the host cell cytoplasm. By 3 h after initiation of infection, actin filaments begin to concentrate at one end of the bacterium. Polarization of F-actin is associated with intracellular bacterial movement, long projections of actin filament...
10.1038/35040061
Shows that actin monomers add to the tail only at the bacterial surface whereas α–actinin and tropomyosin are found throughout the tail, and suggests that actin polymerization may provide the force for motility.
10.1073/pnas.95.11.6181
83,491,863
The Arp2/3 complex is a stable assembly of seven protein subunits including two actin-related proteins (Arp2 and Arp3) and five novel proteins. Previous work showed that this complex binds to the sides of actin filaments and is concentrated at the leading edges of motile cells. Here, we show that Arp2/3 complex purifie...
10.1038/35040061
Shows that Arp2/3 has a high affinity for the pointed end of actin filaments in addition to side binding, and leads to a model for actin filament network branching that is the current model for actin assembly at the leading edge.
10.1083/jcb.145.5.1009
82,334,409
The leading edge (∼1 μm) of lamellipodia in Xenopus laevis keratocytes and fibroblasts was shown to have an extensively branched organization of actin filaments, which we term the dendritic brush. Pointed ends of individual filaments were located at Y-junctions, where the Arp2/3 complex was also localized, suggesting a...
10.1038/35040061
This is a beautiful study using correlative light and electron microscopy to compare protein localization and structure of the actin network in the lamellipodia of fast moving keratocytes and slower moving fibroblasts.
10.1083/jcb.136.6.1307
40,896,547
Actin-binding proteins of the actin depolymerizing factor (ADF)/cofilin family are thought to control actin-based motile processes. ADF1 from Arabidopsis thaliana appears to be a good model that is functionally similar to other members of the family. The function of ADF in actin dynamics has been examined using a combi...
10.1038/35040061
Shows that the actin depolymerization rate in vitro is directly affected by ADF/cofilin in a concentration-dependent fashion and that addition of ADF to cell extracts increases turnover rate in L. monocytogenes actin tails.
10.1083/jcb.153.5.999
109,195,892
Death receptors can trigger cell demise dependent or independent of caspases. In WEHI-S fibrosarcoma cells, tumor necrosis factor (TNF) induced an increase in cytosolic cathepsin B activity followed by death with apoptotic features. Surprisingly, this process was enhanced by low, but effectively inhibiting, concentrati...
10.1038/35085008
The first identification of a protease (cathepsin B) that mediates death-receptor-induced caspase-independent apoptosis-like PCD. The requirement of cathepsin B for phosphatidylserine exposure, blebbing and final execution in TNF-induced caspase-dependent death is also shown. Provides a table of specificity profiles fo...
10.1073/pnas.97.14.7871
81,147,468
Heat shock protein 70 is an antiapoptotic chaperone protein highly expressed in human breast tumors and tumor cell lines. Here, we demonstrate that the mere inhibition of its synthesis by adenoviral transfer or classical transfection of antisense Hsp70 cDNA (asHsp70) results in massive death of human breast cancer cell...
10.1038/35085008
The first demonstration of an endogenous protein (Hsp70) that is specifically required for the survival of tumorigenic cells. The transformation-associated death programme inhibited by Hsp70 is shown to be caspase independent.
10.1084/jem.185.8.1481
81,730,193
Apoptosis and necrosis are considered conceptually and morphologically distinct forms of cell death. Here, we report that demise of human T cells caused by two classic apoptotic triggers (staurosporin and CD95 stimulation) changed from apoptosis to necrosis, when cells were preemptied of adenosine triphosphate (ATP). N...
10.1038/35085008
Initial demonstration that initially similar cell-death signals are switched between apoptosis and programmed necrosis by metabolic conditions in the cell.
10.1084/jem.188.5.919
103,529,130
Murine L929 fibrosarcoma cells were transfected with the human Fas (APO-1/CD95) receptor, and the role of various caspases in Fas-mediated cell death was assessed. Proteolytic activation of procaspase-3 and -7 was shown by Western analysis. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone and benzyloxycarbonyl-Asp(OMe)-Glu(OM...
10.1038/35085008
Demonstrates the ability of tumour necrosis factor receptor 1 and Fas to trigger caspase-independent programmed necrosis, mediated by the production of mitochondrial reactive oxygen species.
10.4049/jimmunol.164.12.6520
120,878,444
Abstract Caspase activation, exposure of phosphatidylserine (PS) on the outer surface of the plasma membrane, and rapid phagocytic removal of dying cells are key features of apoptosis. Nonapoptotic/necrotic modes of death occur independent of caspase activation, but the role of phagocytosis is largely unknown. To addre...
10.1038/35085008
Shows that cells dying by different caspase-independent mechanisms can be recognized by phagocytes in various ways and can be efficiently ingested.
10.1083/jcb.136.1.215
102,729,532
There is increasing evidence for a central role in mammalian apoptosis of the interleukin-1β– converting enzyme (ICE) family of cysteine proteases, homologues of the product of the nematode “death” gene, ced-3. Ced-3 is thought to act as an executor rather than a regulator of programmed cell death in the nematode. Howe...
10.1038/35085008
Shows that caspase activation functions as a general switch between necrosis and apoptosis, but is not required for death itself.
10.1073/pnas.93.25.14559
81,494,942
Expression of BAX, without another death stimulus, proved sufficient to induce a common pathway of apoptosis. This included the activation of interleukin 1β-converting enzyme (ICE)-like proteases with cleavage of the endogenous substrates poly(ADP ribose) polymerase and D4-GDI (GDP dissociation inhibitor for the rho fa...
10.1038/35085008
The first demonstration of caspase-independent programmed cell death induced by Bax-like molecules.
10.1073/pnas.97.26.14376
19,014,889
The term apoptosis often has been used interchangeably with the term programmed cell death. Here we describe a form of programmed cell death that is distinct from apoptosis by the criteria of morphology, biochemistry, and response to apoptosis inhibitors. Morphologically, this alternative form of programmed cell death ...
10.1038/35085008
Definition of paraptosis as a mode of neuronal death that is independent of caspase activity. Contains numerous references on alternative death modes.
10.1162/jocn.1997.9.2.266
20,549,443
Language comprises a lexicon for storing words and a grammar for generating rule-governed forms. Evidence is presented that the lexicon is part of a temporal-parietalhnedial-temporal “declarative memory” system and that granlmatical rules are processed by a frontamasal-ganglia “procedural” system. Patients produced pas...
10.1038/35094573
Based on evidence from anterior and posterior aphasia, and from Alzheimer', Parkinson's and Huntington's diseases, it is argued that grammatical rules depend on a frontal/basal ganglia procedural system, whereas lexical items are stored in a temporal lobe declarative memory system.
10.1073/pnas.96.13.7592
39,930,938
The formation of the past tense of verbs in English has been the focus of the debate concerning connectionist vs. symbolic accounts of language. Brain-injured patients differ with respect to whether they are more impaired in generating irregular past tenses ( take–took ) or past tenses for nonce verbs ( wug–wugged ). S...
10.1038/35094573
A connectionist model that attempts to simulate previous empirically-demonstrated neurological double dissociations between regular and irregular past tense forms.
10.1126/science.1566060
122,903,761
A previously unknown class of dominant, maternal-effect lethal M factors was found to be widespread in natural populations of the flour beetle, Tribolium castaneum, collected on several continents. Such factors are integrated into the host chromosomes at variable locations and show the remarkable property of self-selec...
10.1038/35084545
An empirical paper detailing the discovery of Medea , a new type of selfish genetic element.