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10.1126/science.278.5338.675
39,474,152
A systematic search of the nonrecombining region of the human Y chromosome (NRY) identified 12 novel genes or families, 10 with full-length complementary DNA sequences. All 12 genes, and six of eight NRY genes or families previously isolated by less systematic means, fell into two classes. Genes in the first group were...
10.1038/35056058
Genes in the non-recombining region of the human Y chromosome conform to a small number of functional themes.
10.1073/pnas.88.24.11256
3,742,594
To investigate the evolution of the mammalian sex chromosomes, we have compared the gene content of the X chromosomes in the mammalian groups most distantly related to man (marsupials and monotremes). Previous work established that genes on the long arm of the human X chromosome are conserved on the X chromosomes in al...
10.1038/35056058
This paper shows that there was a large translocation from autosome to sex chromosome in an ancestor of placental mammals, resulting in great enlargement of the placental sex chromosomes.
10.1083/jcb.153.1.159
58,551,558
The spindle position checkpoint in Saccharomyces cerevisiae delays mitotic exit until the spindle has moved into the mother–bud neck, ensuring that each daughter cell inherits a nucleus. The small G protein Tem1p is critical in promoting mitotic exit and is concentrated at the spindle pole destined for the bud. The pre...
10.1038/35099020
This paper indicates that the presence of cytoplasmic microtubules in the bud neck might provide an inhibitory signal for the MEN by regulating the activity of Bub2–Bfa1. The authors correlate the loss of cytoplasmic microtubules from the bud neck with exit from mitosis. In mutants defective in cytoplasmic microtubule ...
10.1242/jcs.114.14.2649
123,075,918
In Saccharomyces cerevisiae, the phosphoprotein phosphatase Cdc14p plays a central role in exit from mitosis, by promoting B-type cyclin degradation and allowing accumulation of the cyclin-dependent kinase inhibitor Sic1p. Cdc14p is sequestered in the nucleolus during interphase, from where it is released at the end of...
10.1038/35099020
S. pombe orthologue of S. cerevisiae CDC14 , called flp1 + , was identified and proposed to have a reduced role in cell-cycle regulation. Localization of flp1 is similar to that of Cdc14 in S. cerevisiae : it is in the nucleolus and on the SPB during interphase, and becomes re-localized to the mitotic spindles, the nuc...
10.1242/jcs.113.10.1695
83,419,482
We have isolated the Schizosaccharomyces pombe orthologue of the Saccharomyces cerevisiae MOB1 gene in a screen designed to enrich for septation mutants. The gene is essential, and cells lacking it display a phenotype typical of septation signalling network mutants. mob1p is located on both spindle pole bodies througho...
10.1038/35099020
A homologue of S. cerevisiae MOB1 was cloned from S. pombe and found to be a member of the SIN pathway. mob1 localizes to the SPB as well as to the medial ring late in the cell cycle. mob1 can form a complex with sid2. The authors propose that the mob1–sid2 complex is involved in carrying the septation signal from the ...
10.1242/jcs.113.7.1223
62,067,200
Cell division in Schizosaccharomyces pombe is achieved through the use of a medially positioned actomyosin ring. A division septum is formed centripetally, concomitant with actomyosin ring constriction. Genetic screens have identified mutations in a number of genes that affect actomyosin ring or septum assembly. These ...
10.1038/35099020
The authors characterize the cytokinesis checkpoint, which halts cell cycle progression when a septum fails to form. A mutation in the drc1 + cps1 + gene prevents the cells from forming a septum. Cells lacking drc1 + cps1 + arrest with two nuclei with a 2n DNA content. The authors show that this arrest is mediated by w...
10.1126/science.1057330
109,156,801
As an organelle coupling nuclear and cytoplasmic divisions, the centrosome is essential to mitotic fidelity, and its inheritance could be critical to understanding cell transformation. Investigating the behavior of the centrosome in living mitotic cells, we documented a transient and remarkable postanaphase repositioni...
10.1038/35099020
This paper shows that the mammalian centrosome has an important role in cytokinesis. The behaviour of GFP-tagged centrioles shows a post-anaphase repositioning of the old centriole to the midbody that is essential for cytokinesis, as ablation of the centriole causes defects in cytokinesis.
10.1083/jcb.153.1.237
101,173,535
When centrosomes are destroyed during prophase by laser microsurgery, vertebrate somatic cells form bipolar acentrosomal mitotic spindles (Khodjakov, A., R.W. Cole, B.R. Oakley, and C.L. Rieder. 2000. Curr. Biol. 10:59–67), but the fate of these cells is unknown. Here, we show that, although these cells lack the radial...
10.1038/35099020
This study investigates the effects of destroying centrosomes after prophase. The authors find that although anaphase occurs normally and can produce two acentrosomal daugher cells, cytokinesis is markedly affected with 30–50% of cells failing to execute cytokinesis properly.
10.1126/science.285.5424.113
125,294,056
Lymphocyte development is critically influenced by self-antigens. T cells are subject to both positive and negative selection, depending on their degree of self-reactivity. Although B cells are subject to negative selection, it has been difficult to test whether self-antigen plays any positive role in B cell developmen...
10.1038/35105052
The first demonstration that self-antigen drives the selection of innate lymphocytes.
10.1084/jem.153.3.694
41,151,638
The antiphosphocholine (PC) antibody in normal mouse sera (NMS) provides protection against intravenous infection with encapsulated strain WU2 of type 3 Streptococcus pneumoniae. Mice unable to make anti-PC antibody, as a result of suppression with anti-T-15 idiotype or inheritance of the xid gene of CAB/N mice, are hi...
10.1038/35105052
The first demonstration that innate lymphocytes confer natural protection against infection.
10.1084/jem.193.8.893
18,633,189
To define the phenotype and T cell receptor (TCR) repertoire of CD1d-dependent T cells, we compared the populations of T cells that persisted in major histocompatibility complex (MHC)-deficient mice, which lack mainstream T cells, with those from MHC/CD1d doubly deficient mice, which lack both mainstream and CD1d-depen...
10.1038/35105052
The intriguing demonstration that most of the mouse CD1d-restricted T-cell receptor repertoire is innate rather than adaptive.
10.1126/science.7973709
104,301,637
The role played in immune surveillance by γδ T cells residing in various epithelia has not been clear. It is shown here that activated γδ T cells obtained from skin and intestine express the epithelial cell mitogen keratinocyte growth factor (KGF). In contrast, intraepithelial αβ T cells, as well as all lymphoid αβ and...
10.1038/35105052
A demonstration of the crosstalk between tissues and their resident lymphocytes.
10.1152/jn.1995.73.1.1
42,503,747
1. On the basis of its anatomic connections and single-unit properties, the superior temporal polysensory area (STP) would seem to be primarily involved in visuospatial functions. We have examined the effects of lesions of STP on saccadic eye movements, visual fixation, and smooth pursuit eye movements to directly test...
10.1038/35086057
The first study to investigate the behavioural effects of lesions confined to the STP in monkeys. Saccade latency was found to be increased for orienting to contralesional targets, whereas responses towards ipsilesional targets were unaffected.
10.1152/jn.1996.76.1.109
41,441,699
1. Processing of visual information in primates is believed to occur in at least two separate cortical pathways, commonly labeled the "form" and "motion" pathways. This division lies in marked contrast to our everyday visual experience, in which we have a unified percept of both the form and motion of objects, implying...
10.1038/35086057
Functional evidence is reported that information from the dorsal and ventral systems converge in the superior temporal polysensory area at the single-unit level, providing a conjoint representation of object identity and direction of motion.
10.1093/oso/9780198524533.001.0001
149,178,222
Abstract As we move around in our environment, and interact with it, many of the most important problems we face involve the processing of spatial information. We have to be able to navigate by perceiving and remembering the locations and orientations of the objects around us relative to ourself; we have to sense and a...
10.1038/35086057
A review and analysis of 'object-centred' and egocentric effects in patients with spatial neglect. It is suggested that the pathological egocentric bias produced by the lesion that leads to neglect can be superimposed on relatively preserved visual object-segmentation processes.
10.1126/science.7701330
104,003,151
Neurons in the superior temporal gyrus of anesthetized rhesus monkeys were exposed to complex acoustic stimuli. Bandpassed noise bursts with defined center frequencies evoked responses that were greatly enhanced over those evoked by pure tones. This finding led to the discovery of at least one new cochleotopic area in ...
10.1038/35086057
Single-unit recordings in the superior temporal gyrus of the rhesus monkey revealed neurons showing preferences for vocalizations from the monkeys' own repertoire (species-specific communication calls).
10.1034/j.1399-0004.2000.580112.x
35,883,641
Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by a CAG repeat expansion in the CACNA1A gene. The neurodegeneration that occurs in CAG repeat diseases is considered to share a common mechanism that may result in the gain of a toxic function related to the expanded polyglutamine tracts. Howev...
10.1038/35039051
Whereas onset of neurological symptoms in two sisters homozygous for SCA6 mutant alleles was identical, disease progression and symptoms varied significantly, supporting a role for genetic, environmental or stochastic modifiers.
10.1073/pnas.94.8.3872
20,022,738
Huntington disease (HD) is associated with abnormal expansions of a CAG repeat close to the 5′ end of the IT15 gene. We have assembled a set of 293 HD subjects whose ages of onset were known and sized their HD CAG repeats. These repeats accounted for 69% of the variance of age of onset when we used the most parsimoniou...
10.1038/35039051
This paper identifies the first genetic factor other than the disease gene that modifies the onset of a polyglutamine disorder, confirmed in a different population by MacDonald and colleagues 78
10.1083/jcb.152.4.809
104,410,971
Melanosomes and premelanosomes are lysosome-related organelles with a unique structure and cohort of resident proteins. We have positioned these organelles relative to endosomes and lysosomes in pigmented melanoma cells and melanocytes. Melanosome resident proteins Pmel17 and TRP1 localized to separate vesicular struct...
10.1038/35096009
Describes the model for melanosome biogenesis discussed in this review and is the first paper to demonstrate a distinction between melanosomes and lysosomes.
10.1083/jcb.141.5.1121
58,551,668
The Chediak-Higashi syndrome (CHS) is a human recessive autosomal disease caused by mutations in a single gene encoding a protein of unknown function, called lysosomal-trafficking regulator. All cells in CHS patients bear enlarged lysosomes. In addition, T- and natural killer cell cytotoxicity is defective in these pat...
10.1038/35096009
This paper describes the late endosomal/ lysosomal protein sorting defects observed in Chediak Higashi syndrome, using B lymphocytes as a model.
10.1083/jcb.130.4.807
16,725,327
The structural and functional integrity of cytoplasmic organelles is maintained by intracellular mechanisms that sort and target newly synthesized proteins to their appropriate cellular locations. In melanocytic cells, melanin pigment is synthesized in specialized organelles, melanosomes. A family of melanocyte-specifi...
10.1038/35096009
The first paper to show that targeting signals for integral membrane transport to melanosomes and to lysosomes are similar.
10.1083/jcb.143.7.1899
59,302,826
Unlike wild-type mouse melanocytes, where melanosomes are concentrated in dendrites and dendritic tips, melanosomes in dilute (myosin Va−) melanocytes are concentrated in the cell center. Here we sought to define the role that myosin Va plays in melanosome transport and distribution. Actin filaments that comprise a cor...
10.1038/35096009
This paper was the first tp propose the current model for melanosome transport in melanocytes.
10.1083/jcb.152.4.795
40,524,185
Rab GTPases are regulators of intracellular membrane traffic. We report a possible function of Rab27a, a protein implicated in several diseases, including Griscelli syndrome, choroideremia, and the Hermansky-Pudlak syndrome mouse model, gunmetal. We studied endogenous Rab27a and overexpressed enhanced GFP-Rab27a fusion...
10.1038/35096009
Together with references 89 and 101 , this paper provides mechanistic insights into the role of Rab27a and myosin Va in melanosome transport.
10.1083/jcb.152.4.825
100,813,025
Rab27a activity is affected in several mouse models of human disease including Griscelli (ashen mice) and Hermansky-Pudlak (gunmetal mice) syndromes. A loss of function mutation occurs in the Rab27a gene in ashen (ash), whereas in gunmetal (gm) Rab27a dysfunction is secondary to a mutation in the α subunit of Rab geran...
10.1038/35096009
Together with reference 103 , this paper shows the requirement for Rab27a in lysosome-like organelle secretion, using cytotoxic T cells as a model system.
10.1126/science.8009217
83,408,569
Malaria is a disease caused by repeated cycles of growth of the parasite Plasmodium in the erythrocyte. Various cellular and molecular strategies allow the parasite to evade the human immune response for many cycles of parasite multiplication. Under certain circumstances Plasmodium infection causes severe anemia or cer...
10.1038/35100540
This paper provides a concise overview of the pathogenesis of malaria.
10.1126/science.2417315
41,624,245
Red blood cells that are infected with the malaria parasite Plasmodium falciparum express new antigens on their surface. In a study of these antigens in the erythrocytes of naturally infected children in the Gambia, an antibody-mediated agglutination assay revealed an extreme degree of antigenic diversity. Serum sample...
10.1038/35100540
This paper provides some of the best early insights into the nature of natural immunity to malaria and provides an explanation for why prolonged exposure to the parasite is required for this to develop.
10.1126/science.8100366
123,801,339
CD4 + T cells play a major role in protective immunity against the blood stage of malaria, but the mechanism of protection is unclear. By adoptive transfer of cloned T cell lines, direct evidence is provided that both T H 1 and T H 2 subsets of CD4 + T cells can protect mice against Plasmodium chabaudi chabaudi infecti...
10.1038/35100540
Indicates that T H 1- and T H 2-type T cells can control malaria infections through different mechanisms.
10.1073/pnas.95.4.1715
38,573,535
The immune response to malaria parasites includes T cell responses that reduce parasites by effector T cell responses and by providing help for antibody responses. Some parasites are more sensitive to antibody and others are more sensitive to cell-mediated immunity. We demonstrate that cultured CD4 + T cells that produ...
10.1038/35100540
Indicates that malaria infection can cause deletion of parasite-specific CD4 + T cells. This might prove to be a useful parasite-defence mechanism.
10.1126/science.286.5441.950
84,427,523
Posttranscriptional gene silencing (PTGS) is a nucleotide sequence–specific defense mechanism that can target both cellular and viral mRNAs. Here, three types of transgene-induced PTGS and one example of virus-induced PTGS were analyzed in plants. In each case, antisense RNA complementary to the targeted mRNA was detec...
10.1038/35052556
A potential mediator of post-transcriptional gene silencing (PTGS) was identified for the first time. This small ∼ 25-nucleotide RNA has become a hallmark of silencing processes that are mediated by double-stranded (ds) RNA molecules
10.1073/pnas.96.24.14147
82,988,841
In transgenic and nontransgenic plants, viruses are both initiators and targets of a defense mechanism that is similar to posttranscriptional gene silencing (PTGS). Recently, it was found that potyviruses and cucumoviruses encode pathogenicity determinants that suppress this defense mechanism. Here, we test diverse vir...
10.1038/35052556
This is one of several papers that establishes a second biological function for RNAi by linking dsRNA-induced silencing to virus resistance in plants
10.1126/science.285.5429.901
104,265,497
The functions of many open reading frames (ORFs) identified in genome-sequencing projects are unknown. New, whole-genome approaches are required to systematically determine their function. A total of 6925 Saccharomyces cerevisiae strains were constructed, by a high-throughput strategy, each with a precise deletion of o...
10.1038/35066084
A report on the progress of an international consortium that disrupted each annotated open reading frame in the yeast genome using a targeted PCR-based gene-deletion strategy.
10.1126/science.290.5500.2306
59,323,339
Understanding how DNA binding proteins control global gene expression and chromosomal maintenance requires knowledge of the chromosomal locations at which these proteins function in vivo. We developed a microarray method that reveals the genome-wide location of DNA-bound proteins and used this method to monitor binding...
10.1038/35066084
References 42 and 43 describe a new genomic approach that combines chromatin immunoprecipitation and microarray hybridization to map the binding sites of chromosomal proteins in vivo.
10.1126/science.272.5262.735
125,208,521
The P 2Z receptor is responsible for adenosine triphosphate (ATP)-dependent lysis of macrophages through the formation of membrane pores permeable to large molecules. Other ATP-gated channels, the P 2X receptors, are permeable only to small cations. Here, an ATP receptor, the P2X 7 receptor, was cloned from rat brain a...
10.1038/35058521
Cloning and expression of the P2X 7 subunit, and the demonstration of its ability to change its permeability.
10.1085/jgp.113.5.695
121,938,134
The single channel properties of cloned P2X2 purinoceptors expressed in human embryonic kidney (HEK) 293 cells and Xenopus oocytes were studied in outside-out patches. The mean single channel current–voltage relationship exhibited inward rectification in symmetric solutions with a chord conductance of ∼30 pS at −100 mV...
10.1038/35058521
The first detailed study of the single-channel behaviour of P2X 2 receptors.
10.1523/jneurosci.20-20-07517.2000
10,339,048
Within the Caenorhabditis elegans genome there exist at least 42 genes encoding TWK (two-P domain K + ) channels, potassium channel subunits that contain two pore regions and four transmembrane domains. We now report the first functional characterization of a TWK channel from C. elegans . Although potassium channels ha...
10.1038/35058574
Describes the identification of TWK-18, the first functional two-P/four-transmembrane domain clone of at least 42 potential variants in C. elegans
10.1126/science.283.5398.94
81,877,078
CmPP16 from Cucurbita maxima was cloned and the protein was shown to possess properties similar to those of viral movement proteins. CmPP16 messenger RNA (mRNA) is present in phloem tissue, whereas protein appears confined to sieve elements (SE). Microinjection and grafting studies revealed that CmPP16 moves from cell ...
10.1038/35067016
First evidence for an endogenous protein in pumpkin that mediates long-distance translocation of mRNAs through the plant's vascular system.
10.1126/science.276.5315.1128
124,089,832
In many organisms, pattern formation in the embryo develops from the polarized distributions of messenger RNAs (mRNAs) in the egg. In Xenopus , the mRNA encoding Vg1, a growth factor involved in mesoderm induction, is localized to the vegetal cortex of oocytes. A protein named Vera was shown to be involved in Vg1 mRNA ...
10.1038/35067016
First evidence for an association of a zip-code-binding protein (Vera) with the endoplasmic reticulum (ER) of Xenopus oocytes. This work suggests co-transport of the localized Vg1 mRNA with the ER.
10.1101/gad.12.11.1593
58,400,618
Vg1 mRNA translocation to the vegetal cortex of Xenopus oocytes requires intact microtubules, and a 3′ UTR cis -acting element (termed VLE), which also mediates sequence-specific binding of several proteins. One protein, the 69-kD Vg1 RBP, associates Vg1 RNA to microtubules in vitro. Here we show that Vg1 RBP-binding s...
10.1038/35067016
Reference 59 60 and 22 led to the surprising finding that the zip-code-binding proteins (ZBPs) involved in chicken β-actin mRNA or Xenopus Vg1 mRNA localization are homologous, although the localization mechanisms seemed to be different. This led to the idea that ZBPs might be mRNA-binding modules that can associate wi...
10.1083/jcb.148.3.427
79,454,612
Localization of bicoid (bcd) mRNA to the anterior and oskar (osk) mRNA to the posterior of the Drosophila oocyte is critical for embryonic patterning. Previous genetic studies implicated exuperantia (exu) in bcd mRNA localization, but its role in this process is not understood. We have biochemically isolated Exu and sh...
10.1038/35067016
The first example of a biochemical approach to purify localized RNP complexes from Drosophila
10.1126/science.289.5487.2120
59,365,103
The asymmetric localization of messenger RNA (mRNA) and protein determinants plays an important role in the establishment of complex body plans. In Drosophila oocytes, the anterior localization of bicoid mRNA and the posterior localization of oskar mRNA are key events in establishing the anterior-posterior axis. Althou...
10.1038/35067016
The identification of the long-sought microtubule motor required for localization of oskar mRNA and Staufen protein to the posterior end of Drosophila oocytes.
10.1073/pnas.96.21.11820
41,281,361
Direct-force measurements of the interactions between recombinant C-cadherin from Xenopus demonstrated that the ectodomain of cadherin exhibits multiple adhesive contacts that involve successive domains along the extracellular region of the protein. Contacts between the fully interdigitated antiparallel proteins form t...
10.1038/35040042
A recent paper that suggests a new model of cadherin trans -dimer formation.
10.1083/jcb.145.3.539
41,711,001
We have isolated a novel actin filament–binding protein, named afadin, localized at cadherin-based cell–cell adherens junctions (AJs) in various tissues and cell lines. Afadin has one PDZ domain, three proline-rich regions, and one actin filament–binding domain. We found here that afadin directly interacted with a fami...
10.1038/35040042
One of a series of papers (refs 40 44 ) that describe a new protein complex that localizes to adherens junctions, and that might interact with the cadherin?catenin complex functionally.
10.1242/dev.126.23.5421
104,398,700
The tissue polarity genes control the polarity of hairs, bristles and ommatidia in the adult epidermis of Drosophila. We report here the identification of a new tissue polarity gene named starry night (stan). Mutations in this essential gene alter the polarity of cuticular structures in all regions of the adult body. T...
10.1038/35040042
References 55 and 56 show a role for the Flamingo/Starry Night cadherin in planar epithelial polarity. Reference 55 also shows that the subcellular distribution of Flamingo/Starry Night depends on the direction of Wnt/Frizzled signalling.
10.1242/dev.125.23.4681
41,623,964
Paraxial Protocadherin (PAPC) encodes a transmembrane protein expressed initially in Spemann's organizer and then in paraxial mesoderm. Together with another member of the protocadherin family, Axial Protocadherin (AXPC), it subdivides gastrulating mesoderm into paraxial and axial domains. PAPC has potent homotypic cel...
10.1038/35040042
Experiments in this paper indicate an important role for a protocadherin in the convergent extension movements during frog gastrulation.
10.1083/jcb.135.3.767
45,365,849
Molecular mechanisms linking pre- and postsynaptic membranes at the interneuronal synapses are little known. We tested the cadherin adhesion system for its localization in synapses of mouse and chick brains. We found that two classes of cadherin-associated proteins, alpha N- and beta-catenin, are broadly distributed in...
10.1038/35040042
References 82 and 83 show that classic cadherins are components of synaptic adherens junctions.
10.1111/j.1442-2026.1997.tb00387.x
18,894,772
Abstract Objective To analyse the significance of commonly used symptoms, signs and radiography in predicting skull fractures, intracranial injuries and the need for neurosurgical intervention in paediatric head injuries. Setting A paediatric tertiary referral hospital in central Sydney. Method A 10 year retrospective ...
10.1038/35040009
Provides a historical overview of the morphological and biochemical features of apoptosis.
10.1073/pnas.96.7.4125
44,855,400
Although an excitotoxic mechanism of neuronal injury has been proposed to play a role in chronic neurodegenerative disorders such as Alzheimer’s disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the preseni...
10.1038/35040009
Uses knock-in mice to identify the gain-of-function action of mutant presenilin-1 as a pro-apoptotic activity that results from perturbed cellular calcium homeostasis and can be suppressed by neurotrophic factors.
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...
10.1038/35036191
References 6 and 7 are two classic summaries of the state of research on E-LTP.
10.1126/science.167.3926.1740
123,454,860
A behavioral reflex mediated by identified motor neurons in the abdominal ganglion of Aplysia undergoes two simple forms of short-term modification. When the gill-withdrawal reflex was repeatedly evoked by a tactile stimulus to the siphon or mantle shelf, the amplitude of the response showed marked decrement (habituati...
10.1038/35036191
References 11 and 12 were the first systematic attempts to address the questions of behavioural relevance and time course of synaptic plasticity related to memory storage at the level of single identified nerve cells.
10.1126/science.287.5451.248
38,447,845
The memory consolidation hypothesis proposed 100 years ago by Müller and Pilzecker continues to guide memory research. The hypothesis that new memories consolidate slowly over time has stimulated studies revealing the hormonal and neural influences regulating memory consolidation, as well as molecular and cellular mec...
10.1038/35036191
Reviews the importance of modulatory transmitters for attentional and motivational significance of long-term memory storage.
10.1084/jem.187.1.129
29,131,174
T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. T...
10.1038/35100503
References 21 and 22 are the initial studies that identified the preferential expression of specific chemokine receptors on polarized T lymphocytes. They outline the basic principle of preferential expression on the basis of a specific cytokine environment.
10.1084/jem.179.3.881
101,582,940
Eosinophil accumulation is a prominent feature of allergic inflammatory reactions, such as those occurring in the lung of the allergic asthmatic, but the endogenous chemoattractants involved have not been identified. We have investigated this in an established model of allergic inflammation, using in vivo systems both ...
10.1038/35100503
A protein mediator that preferentially induced eosinophil accumulation in the airway was first discovered in guinea-pig airways, but the importance for human disease was quickly realized. Much of the early therapy in the chemokine field has been geared towards inhibiting the action of eotaxin with its specific receptor...
10.1084/jem.185.4.785
28,073,833
The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C–C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosino...
10.1038/35100503
The finding that eotaxin-deficient mice showed virtually normal allergic airway responses allowed investigators to realize that targeting the receptor, CCR3, might be more efficacious than an individual chemokine ligand.
10.1084/jem.188.1.157
18,503,791
The complex pathophysiology of lung allergic inflammation and bronchial hyperresponsiveness (BHR) that characterize asthma is achieved by the regulated accumulation and activation of different leukocyte subsets in the lung. The development and maintenance of these processes correlate with the coordinated production of ...
10.1038/35100503
One of the earliest studies showing that chemokines were not just a family of cytokines with overlapping functions, but rather induced factors that participated in a response in a coordinated manner. Multiple chemokines have a significant role in different aspects of the allergen-induced responses in the lung.
10.4049/jimmunol.165.1.10
5,828,335
Abstract The in vivo function of Th cell subsets is largely dependent on the ability of differentiated CD4+ T cells to be recruited to specific sites and secrete restricted sets of cytokines. In this paper we demonstrate that Th1 and Th2 cells secrete discrete patterns of chemokines, small m.w. cytokines that function ...
10.1038/35100503
Identifies a primary role for T H 2 cytokine-induced STAT6 regulation of chemokines and their receptors on T lymphocytes, indicating that their expression might be dependent on gene regulation and not on differentiation state.
10.1084/jem.191.2.265
106,921,717
Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the liga...
10.1038/35100503
The first study to show that different chemokine receptors are used at distinct phases of disease progression to promote T-lymphocyte accumulation. Complements the earlier studies by this group that show coordinated chemokine production.
10.4049/jimmunol.166.3.1457
60,537,418
Abstract Chemokine-induced eosinophil chemotaxis is mediated primarily through the C-C chemokine receptor, CCR3. We have now detected CCR3 immunoreactivity on epithelial cells in biopsies of patients with asthma and other respiratory diseases. CCR3 mRNA was detected by Northern blot analysis after TNF-α stimulation of ...
10.1038/35100503
One of the first studies to show that the chemokine receptor CCR3 can be expressed on airway epithelial cells during asthmatic responses. Interestingly, these same cells produce an abundant amount of CCR3-specific ligands during asthmatic responses. The consequences and mechanisms associated with this finding will prob...
10.1084/jem.193.5.573
28,258,190
Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (−/−) mice. ...
10.1038/35100503
The first study to indicate that chemokine receptors can be targeted for therapy to alter the T H 2-specific asthmatic responses. The preferential expression of CCR8 on T H 2 cells and reduced T H 2 cytokine phenotype within the lung of CCR8-deficient mice is a vital clue for therapeutic targeting of a specific recepto...
10.1083/jcb.135.6.1685
62,477,012
We report a new method for in situ localization of DNA sequences that allows excellent preservation of nuclear and chromosomal ultrastructure and direct, in vivo observations. 256 direct repeats of the lac operator were added to vector constructs used for transfection and served as a tag for labeling by lac repressor. ...
10.1038/35103000
The first description of an experimental system to study a chromatin region in living cells.
10.1083/jcb.147.5.929
79,454,512
Inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals represent an important mechanism for transmitting external stimuli to the cell. However, information about intracellular spatial patterns of InsP3 itself is not generally available. In particular, it has not been determined how the interplay of InsP3 generat...
10.1038/35103000
A clear and compelling examination of the importance of partial differential equation models when studying large cells or cells with long processes in which one must account for simultaneous diffusion and spatially distributed chemical reactions.
10.1083/jcb.143.6.1485
59,310,840
Quantitative time-lapse imaging data of single cells expressing the transmembrane protein, vesicular stomatitis virus ts045 G protein fused to green fluorescent protein (VSVG–GFP), were used for kinetic modeling of protein traffic through the various compartments of the secretory pathway. A series of first order rate l...
10.1038/35103000
This was among the first studies to combine the power of green fluorescent protein chimaeras, photobleaching techniques and kinetic analysis to answer questions about protein transport in living cells.
10.1126/science.277.5322.55
125,327,431
Angiogenesis is thought to depend on a precise balance of positive and negative regulation. Angiopoietin-1 (Ang1) is an angiogenic factor that signals through the endothelial cell–specific Tie2 receptor tyrosine kinase. Like vascular endothelial growth factor, Ang1 is essential for normal vascular development in the mo...
10.1038/35067005
Shows that Ang2 is an antagonist of Tie2, providing the first evidence that related growth factors might have opposing actions towards receptor tyrosine kinases in vertebrates.
10.1101/gad.8.16.1897
122,856,231
The receptor tyrosine kinases (RTKs) expressed on the surface of endothelial cells are likely to play key roles in initiating the program of endothelial cell growth during development and subsequent vascularization during wound healing and tumorigenesis. Expression of the Tek RTK during mouse development is restricted ...
10.1038/35067005
Description of the importance of Tie2 in regulating the survival and integrity of the endothelium during development.
10.1242/dev.126.20.4569
62,574,744
TEK (TIE2) and TIE (TIE1) are structurally related receptor tyrosine kinases expressed in endothelial cells and their precursors. Genetic studies in the mouse have revealed essential functions of both receptors in angiogenic expansion of the vasculature during development. As previously shown, mouse embryos homozygous ...
10.1038/35067005
Shows that the functions mediated by the Tie1 and Tie2 receptors are not redundant through analysis of chimeric embryos. An interesting endocardial developmental phenotype is also revealed.
10.1126/science.286.5449.2511
83,130,753
Angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF) are endothelial cell–specific growth factors. Direct comparison of transgenic mice overexpressing these factors in the skin revealed that the VEGF-induced blood vessels were leaky, whereas those induced by Ang1 were nonleaky. Moreover, vessels in Ang1-...
10.1038/35067005
Shows that Ang1 can block vascular permeability induced by VEGF.
10.1126/science.284.5422.1994
81,976,899
In contrast with the prevailing view that most tumors and metastases begin as avascular masses, evidence is presented here that a subset of tumors instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumor but instead regresses...
10.1038/35067005
Shows that Ang2 is associated with tumour angiogenesis in a model where the tumour co-opts existing host vessels.
10.1073/pnas.220418097
79,468,883
Epifluorescence microscopy studies of mixtures of phospholipids and cholesterol at the air–water interface often exhibit coexisting liquid phases. The properties of these liquids point to the formation of “condensed complexes” between cholesterol and certain phospholipids, such as sphingomyelin. It is found that monola...
10.1038/35080071
This paper, and several other papers from the same group in 1999/2000, bridge a gap between physical chemistry and cell biology by showing liquid–liquid phase separations in lipid mixtures of biological relevance. McConnell first demonstrated such phase separations 20 years ago.
10.1177/42.2.8288861
123,762,744
The ultrastructural distribution of the ganglioside GM1 was investigated in A431 cells. After fixation, the cells were frozen in liquid nitrogen, freeze-substituted, and then embedded in Lowicryl resin at -45 degrees C. By use of the cholera toxin-binding subunit adsorbed to gold as a specific probe to label on the sec...
10.1038/35080071
This paper provides solid morphological evidence for the concentration of a glycolipid in caveolae.
10.1126/science.283.5407.1530
38,424,185
Long interspersed nuclear elements (LINE-1s or L1s) are the most abundant retrotransposons in the human genome, and they serve as major sources of reverse transcriptase activity. Engineered L1s retrotranspose at high frequency in cultured human cells. Here it is shown that L1s insert into transcribed genes and retrotra...
10.1038/35038572
Use of a cultured-cell assay to show that L1s insert into transcribed genes and can retrotranspose sequences derived from their 3′ flanks to new genomic locations.
10.1126/science.280.5361.301
65,233,555
Assembly of immunoglobulin and T cell receptor genes from separate gene segments [V(D)J recombination] begins with DNA double-strand breakage by the RAG1 and RAG2 proteins, acting at a pair of recombination signal sequences (RSSs). Here, the RAG proteins are shown to reverse the cleavage reaction by joining an RSS to a...
10.1038/35038572
Reference 82 and 83 show that the RAG1 and RAG2 proteins, together, form a DNA transposase which can excise a piece of DNA flanked by recombination signal sequences and move it to another DNA molecule.
10.1126/science.1064252
4,579,897
A classic model proposes that the mammalian neocortex is divided into areas early in neurogenesis, but the molecular mechanisms that generate the area map have been elusive. Here we provide evidence that FGF8 regulates development of the map from a source in the anterior telencephalon. Using electroporation-mediated ge...
10.1038/35104078
This study shows that the anteroposterior positioning of areal boundaries in mammalian neocortex can be regulated by a diffusible signalling molecule, FGF8, secreted from a 'signal centre' in the anterior telencephalon.
10.1126/science.287.5454.864
62,191,077
Brain function requires precisely orchestrated connectivity between neurons. Establishment of these connections is believed to require signals secreted from outgrowing axons, followed by synapse formation between selected neurons. Deletion of a single protein, Munc18-1, in mice leads to a complete loss of neurotransmit...
10.1038/35104078
By deleting a molecule required for synaptic vesicle fusion, this work shows that activity is not essential for many general aspects of neural development, including the formation of morphological synapses, but is required for the maintenance of connectivity.
10.1126/science.2497519
81,369,235
A strategy was devised for identifying regions of the mouse genome that are transcriptionally active in a temporally and spatially restricted manner during development. The approach is based on the introduction into embryonic stem cells of two types of lacZ reporter constructs that can be activated by flanking mouse ge...
10.1038/35093548
The first example of enhancer-trap and gene-trap mutagenesis in mouse ES cells, and of ES-cell-derived mice. It was published the same year as the first targeted mutagenesis of non-selectable genes.
10.1101/gad.5.9.1513
38,450,621
A general strategy for selecting insertion mutations in mice has been devised. Constructs lacking a promoter and including a beta-galactosidase gene, or a reporter gene encoding a protein with both beta-galactosidase and neomycin phosphotransferase activity, were designed so that activation of the reporter gene depends...
10.1038/35093548
The development of the ROSA β-geo vectors and the first application of gene trapping to isolate lethal mutations.
10.1101/gad.6.6.919
60,544,332
Two retrovirus promoter trap vectors (U3His and U3Neo) have been used to disrupt genes expressed in totipotent murine embryonal stem (ES) cells. Selection in L-histidinol or G418 produced clones in which the coding sequences for histidinol-dehydrogenase or neomycin-phosphotransferase were fused to sequences in or near ...
10.1038/35093548
This paper provided the foundation for the current promoter-trapping efforts.
10.1073/pnas.92.14.6592
18,799,109
A strategy based on the gene trap was developed to prescreen mouse embryonic stem cells for insertional mutations in genes encoding secreted and membrane-spanning proteins. The "secretory trap" relies on capturing the N-terminal signal sequence of an endogenous gene to generate an active beta-galactosidase fusion prote...
10.1038/35093548
An elegant method to trap a specific class of gene. This project has evolved into one of the gene-trap resource centres.
10.1093/genetics/139.2.889
83,486,014
Abstract We have used a gene-trap vector and mouse embryonic stem (ES) cells to screen for insertional mutations in genes developmentally regulated at 8.5 days of embryogenesis (dpc). From 38,730 cell lines with vector insertions, 393 clonal integrations had disrupted active transcription units, as assayed by beta-gala...
10.1038/35093548
This work served as proof of principle for high-throughput gene-trap screens.
10.1073/pnas.93.26.15279
65,352,696
A strategy employing gene-trap mutagenesis and site-specific recombination (Cre/ loxP ) has been developed to isolate genes that are transcriptionally activated during programmed cell death. Interleukin-3 (IL-3)-dependent hematopoietic precursor cells (FDCP1) expressing a reporter plasmid that codes for herpes simplex ...
10.1038/35093548
This paper shows a use of gene trapping other than for mutagenesis.
10.1126/science.2274784
38,518,077
Metaphase chromosomes are dynamically modified in interphase. This review focuses on how these structures can be modified, and explores the functional mechanisms and significance of these changes. Current analyses of genes often focus on relatively short stretches of DNA and consider chromatin conformations that incorp...
10.1038/35066075
An excellent attempt to integrate a multitude of experimental findings in the framework of a functional higher-order chromatin architecture. This paper is still a 'must read'.
10.1177/21.8.715
98,795,174
In many immunohistochemical studies horseradish peroxidase (HRP) is used as the marker enzyme. An in situ and indirect quantitation of antigen or antibody would be possible by determination of the HRP activity. For this reason quantitative aspects of histochemical reaction procedures to localize HRP activity have been ...
10.1038/35066075
A thorough historical account of in situ hybridization from its beginnings to present-day technologies.
10.1242/jcs.113.9.1565
104,368,901
The large-scale chromatin organization of the major histocompatibility complex and other regions of chromosome 6 was studied by three-dimensional image analysis in human cell types with major differences in transcriptional activity. Entire gene clusters were visualized by fluorescence in situ hybridization with multipl...
10.1038/35066075
Activation of specific genes from the major histocompatibility locus correlates with an expansion of the gene-harbouring chromatin loops from the surface of chromosome-6 territories.
10.1083/jcb.144.5.813
59,313,388
Individual chromosomes are not directly visible within the interphase nuclei of most somatic cells; they can only be seen during mitosis. We have developed a method that allows DNA strands to be observed directly in living cells, and we use it to analyze how mitotic chromosomes form. A fluorescent analogue (e.g., Cy5-d...
10.1038/35066075
This in vivo study relates the gross structure of a chromosome territory to that of a prophase chromosome.
10.1083/jcb.146.6.1211
20,690,944
We investigated the nuclear higher order compartmentalization of chromatin according to its replication timing (Ferreira et al. 1997) and the relations of this compartmentalization to chromosome structure and the spatial organization of transcription. Our aim was to provide a comprehensive and integrated view on the re...
10.1038/35066075
Describes evidence that chromosome territories contribute to gene-rich and gene-poor higher-order chromatin compartments.
10.1126/science.291.5505.843
41,155,778
Studies of nuclear architecture reveal that the dynamic properties of proteins in the nucleus are critical for their function. The high mobility of proteins ensures their availability throughout the nucleus; their dynamic interplay generates an ever-changing, but overall stable, architectural framework, within which nu...
10.1038/35066075
A summary of the evidence that movement of proteins in the nucleus to their site of action occurs by simple diffusion.
10.1091/mbc.10.1.211
103,496,831
In this study we demonstrate, at an ultrastructural level, the in situ distribution of heterogeneous nuclear RNA transcription sites after microinjection of 5-bromo-UTP (BrUTP) into the cytoplasm of living cells and subsequent postembedding immunoelectron microscopic visualization after different labeling periods. More...
10.1038/35066075
Electron-microscopic evidence that nascent RNA is synthesized at chromatin-domain surfaces.
10.1073/pnas.92.7.2710
61,890,064
Fluorescence in situ hybridization data on distances between defined genomic sequences are used to construct a quantitative model for the overall geometric structure of a human chromosome. We suggest that the large-scale geometry during the G0/G1 part of the cell cycle may consist of flexible chromatin loops, averaging...
10.1038/35066075
First quantitative modelling of gene distances in distinct chromosome territories.
10.1073/pnas.95.11.6043
18,898,851
Fluorescein-labeled oligodeoxynucleotides (oligos) were introduced into cultured rat myoblasts, and their molecular movements inside the nucleus were studied by fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP). FCS revealed that a large fraction of both intranuclear olig...
10.1038/35066075
Using in vivo fluorescence correlation spectroscopy, the authors show that nuclear poly(A) RNA moves by a diffusion-like process.
10.1126/science.292.5522.1728
20,371,838
Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein...
10.1038/35096067
First PKB/Akt knockout paper, demonstrating the unexpected finding of a specific role for PKBβ/Akt2 in glucose homeostasis.
10.1101/gad.12.16.2488
38,401,288
A neurosecretory pathway regulates a reversible developmental arrest and metabolic shift at the Caenorhabditis elegans dauer larval stage. Defects in an insulin-like signaling pathway cause arrest at the dauer stage. We show here that two C. elegans Akt/PKB homologs, akt-1 and akt-2, transduce insulin receptor-like sig...
10.1038/35096067
The first genetically identified PKB/AKT target, DAF-16, is a forkhead-like transcription factor ? a prelude to the identification of mammalian homologues of PKB/AKT substrates.
10.1126/science.283.5402.689
19,282,235
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive human disease associated with multiple deletions of skeletal muscle mitochondrial DNA (mtDNA), which have been ascribed to a defect in communication between the nuclear and mitochondrial genomes. Examination of 12 MNGIE probands rev...
10.1038/35072063
The first description of a mutation in a gene involved in nuclear–mitochondrial DNA communication.
10.1159/000134066
102,703,436
Humamrodent somatic cell hybrids carrying a single, intact, selectable human chromosome are valuable both for functional somatic cell genetic analysis and genome mapping procedures. Here, we describe the construction and detailed molecular cytogenetic characterization of a panel of 23 stable hybrids, representing all 2...
10.1038/35072063
Important new technology in the characterization of the chromosome localization responsible for disease.
10.1126/science.280.5369.1564
20,505,608
The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLO...
10.1038/35036078
A key paper about a basic device, the feedback loop: the positive elements of the loop were finally uncovered.
10.1126/science.284.5413.502
123,022,837
Circadian rhythms of mammals are entrained by light to follow the daily solar cycle (photoentrainment). To determine whether retinal rods and cones are required for this response, the effects of light on the regulation of circadian wheel-running behavior were examined in mice lacking these photoreceptors. Mice without ...
10.1038/35036078
Along with reference 76, this represented a big leap forward in the search for the mammalian circadian photoreceptor: it is neither the cones nor the rods, and so lies elsewhere in the retina.
10.1126/science.278.5343.1632
104,123,661
Transgenic Drosophila that expressed either luciferase or green fluorescent protein driven from the promoter of the clock gene period were used to monitor the circadian clock in explanted head, thorax, and abdominal tissues. The tissues (including sensory bristles in the leg and wing) showed rhythmic bioluminescence, a...
10.1038/35036078
This paper presents the first description of independent non-neural peripheral clocks in animals.
10.1084/jem.187.12.2081
100,943,218
Immunoglobulin (Ig) heavy chain (HC) class switch recombination (CSR) is a late B cell process that involves intrachromosomal DNA rearrangement. Ku70 and Ku80 form a DNA end-binding complex required for DNA double strand break repair and V(D)J recombination. Ku70−/− (K70T) mice, like recombination activating gene (RAG)...
10.1038/35080033
References 22–24 showed that class-switch recombination depends on non-homologous end joining.
10.1084/jem.192.10.1509
109,159,494
Somatic hypermutation and isotype switch recombination occur in germinal center B cells, are linked to transcription, and are similarly affected by deficiency in MutS homologue (MSH)2. Class-switch recombination is abrogated by disruption of genes encoding components of the catalytic subunit of DNA-dependent protein ki...
10.1038/35080033
Unlike class-switch recombination, somatic hypermutation does not require the catalytic subunit of the DNA-dependent protein kinase (DNA-PK cs ), indicating that different mechanisms of DNA repair might occur between class-switch recombination and somatic hypermutation.
10.1126/science.1059852
59,706,053
Listeria monocytogenes is responsible for severe food-borne infections, but the mechanisms by which bacteria cross the intestinal barrier are unknown. Listeria monocytogenes expresses a surface protein, internalin, that interacts with a host receptor, E-cadherin, to promote entry into human epithelial cells. Murine E-c...
10.1038/35085062
This paper is the culmination of many in vitro studies on Listeria interaction with host cells. It shows that the internalin–E-cadherin interaction is crucial for the establishment of infection in vivo
10.1128/mmbr.62.2.379-433.1998
83,397,687
SUMMARY Various gram-negative animal and plant pathogens use a novel, sec-independent protein secretion system as a basic virulence mechanism. It is becoming increasingly clear that these so-called type III secretion systems inject (translocate) proteins into the cytosol of eukaryotic cells, where the translocated prot...
10.1038/35085062
An excellent overview of type III secretion systems and their secreted proteins.
10.1083/jcb.119.2.301
103,823,462
For determination of the physiological role and mechanism of vacuolar proteolysis in the yeast Saccharomyces cerevisiae, mutant cells lacking proteinase A, B, and carboxypeptidase Y were transferred from a nutrient medium to a synthetic medium devoid of various nutrients and morphological changes of their vacuoles were...
10.1038/35056522
This is the first report that yeast induces autophagy that is quite similar to that in mammals under various starvation conditions.
10.1083/jcb.151.2.263
80,133,073
Autophagy and the Cvt pathway are examples of nonclassical vesicular transport from the cytoplasm to the vacuole via double-membrane vesicles. Apg8/Aut7, which plays an important role in the formation of such vesicles, tends to bind to membranes in spite of its hydrophilic nature. We show here that the nature of the as...
10.1038/35056522
This showed that Apg8 associates with the intermediate membranes of the autophagosome by serial modification reactions.