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  • Articles  (11)
  • Inaugural Articles  (11)
  • National Academy of Sciences  (11)
  • Springer
  • 2020-2023
  • 2010-2014  (11)
  • 1970-1974
  • 1965-1969
  • 1945-1949
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  • 2011  (11)
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  • Articles  (11)
Publisher
  • National Academy of Sciences  (11)
  • Springer
Years
  • 2020-2023
  • 2010-2014  (11)
  • 1970-1974
  • 1965-1969
  • 1945-1949
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  • 1
    Publication Date: 2011-08-18
    Description: Aberrations in epigenetic processes, such as histone methylation, can cause cancer. Retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) can demethylate tri- and dimethylated lysine 4 in histone H3, which are epigenetic marks for transcriptionally active chromatin, whereas the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor promotes H3K4 methylation. Previous studies suggested that inhibition of RBP2 contributed to tumor suppression by the retinoblastoma protein (pRB). Here, we show that genetic ablation of Rbp2 decreases tumor formation and prolongs survival in Rb1+/− mice and Men1-defective mice. These studies link RBP2 histone demethylase activity to tumorigenesis and nominate RBP2 as a potential target for cancer therapy.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 2011-01-04
    Description: Is there a Muslim disadvantage in economic integration for second-generation immigrants to Europe? Previous research has failed to isolate the effect that religion may have on an immigrant family's labor market opportunities because other factors, such as country of origin or race, confound the result. This paper uses a correspondence test in the French labor market to identify and measure this religious effect. The results confirm that in the French labor market, anti-Muslim discrimination exists: a Muslim candidate is 2.5 times less likely to receive a job interview callback than is his or her Christian counterpart. A high-n survey reveals, consistent with expectations from the correspondence test, that second-generation Muslim households in France have lower income compared with matched Christian households. The paper thereby contributes to both substantive debates on the Muslim experience in Europe and methodological debates on how to measure discrimination. Following the National Academy of Sciences’ 2001 recommendations on combining a variety of methodologies and applying them to real-world situations, this research identifies, measures, and infers consequences of discrimination based on religious affiliation, controlling for potentially confounding factors, such as race and country of origin.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 3
    Publication Date: 2011-01-19
    Description: Argonaute and Piwi proteins are key players in the RNA silencing pathway, with the former interacting with micro-RNAs (miRNAs) and siRNAs, whereas the latter targets piwi-interacting RNAs (piRNAs) that are 2′-O-methylated (2′-OCH3) at their 3′ ends. Germline-specific piRNAs and Piwi proteins play a critical role in genome defense against transposable elements, thereby protecting the genome against transposon-induced defects in gametogenesis and fertility. Humans contain four Piwi family proteins designated Hiwi1, Hiwi2, Hiwi3, and Hili. We report on the structures of Hili-PAZ (Piwi/Argonaute/Zwille) domain in the free state and Hiwi1 PAZ domain bound to self-complementary 14-mer RNAs (12-bp + 2-nt overhang) containing 2′-OCH3 and 2′-OH at their 3′ ends. These structures explain the molecular basis underlying accommodation of the 2′-OCH3 group within a preformed Hiwi1 PAZ domain binding pocket, whose hydrophobic characteristics account for the preferential binding of 2′-OCH3 over 2′-OH 3′ ends. These results contrast with the more restricted binding pocket for the human Ago1 PAZ domain, which exhibits a reverse order, with preferential binding of 2′-OH over 2′-OCH3 3′ ends.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 4
    Publication Date: 2011-06-15
    Description: The ability to derive meaning from complex sensory input requires the integration of information over space and time, as well as cognitive mechanisms to shape that integration. We studied these processes in the primary visual cortex (V1), where neurons are thought to integrate visual inputs along contours defined by an association field (AF). We recorded extracellularly from single cells in macaque V1 to map the AF, by using an optimization algorithm to find the contours that maximally activated individual cells. We combined the algorithm with a delayed-match-to-sample task, to test how the optimal contours might be molded by the monkey's expectation for particular cue shapes. We found that V1 neurons were selective for complex shapes, a property previously ascribed to higher cortical areas. Furthermore, the shape selectivity was reprogrammed by perceptual task: Over the whole network, the optimal modes of geometric selectivity shifted between distinct subsets of the AF, alternately representing different stimulus features known to predominate in natural scenes. Our results suggest a general model of cortical function, whereby horizontal connections provide a broad domain of potential associations, and top–down inputs dynamically gate these linkages to task switch the function of a network.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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  • 5
    Publication Date: 2011-12-07
    Description: The exceptionally high temperature sensitivity of certain transient receptor potential (TRP) family ion channels is the molecular basis of hot and cold sensation in sensory neurons. The laws of thermodynamics dictate that opening of these specialized TRP channels must involve an unusually large conformational standard-state enthalpy, ΔHo: positive ΔHo for heat-activated and negative ΔHo for cold-activated TRPs. However, the molecular source of such high-enthalpy changes has eluded neurobiologists and biophysicists. Here we offer a general, unifying mechanism for both hot and cold activation that recalls long-appreciated principles of protein folding. We suggest that TRP channel gating is accompanied by large changes in molar heat capacity, ΔCP. This postulate, along with the laws of thermodynamics and independent of mechanistic detail, leads to the conclusion that hot- and cold-sensing TRPs operate by identical conformational changes.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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  • 6
    Publication Date: 2011-11-02
    Description: What are the physical limits to cell behavior? Often, the physical limitations can be dominated by the proteome, the cell’s complement of proteins. We combine known protein sizes, stabilities, and rates of folding and diffusion, with the known protein-length distributions P(N) of proteomes (Escherichia coli, yeast, and worm), to formulate distributions and scaling relationships in order to address questions of cell physics. Why do mesophilic cells die around 50 °C? How can the maximal growth-rate temperature (around 37 °C) occur so close to the cell-death temperature? The model shows that the cell’s death temperature coincides with a denaturation catastrophe of its proteome. The reason cells can function so well just a few degrees below their death temperature is because proteome denaturation is so cooperative. Why are cells so dense-packed with protein molecules (about 20% by volume)? Cells are packed at a density that maximizes biochemical reaction rates. At lower densities, proteins collide too rarely. At higher densities, proteins diffuse too slowly through the crowded cell. What limits cell sizes and growth rates? Cell growth is limited by rates of protein synthesis, by the folding rates of its slowest proteins, and—for large cells—by the rates of its protein diffusion. Useful insights into cell physics may be obtainable from scaling laws that encapsulate information from protein knowledge bases.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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  • 7
    Publication Date: 2011-03-30
    Description: It is widely believed that functional mammalian microRNA (miRNA) recognition sequences are located preferentially in the 3' untranslated region (3'UTR) of target mRNAs. Nonetheless, putative miRNA target sites within coding regions have been found at lower frequency in genome-wide studies, and several have been genetically validated. To account for these findings, it has been proposed that translation may inhibit miRNA access to target sites. Here we identify a naturally occurring viral miRNA target that, owing to the compact nature of the viral transcriptome, is situated naturally in the coding region of one transcript and in the 3′UTR of an overlapping mRNA. Examination of the expression of these mRNAs reveals that the cognate miRNA can inhibit expression in both contexts, but inhibition is more potent when the target site is in the UTR. Similarly, forced translation of the target site in the UTR diminished, but did not abolish, its down-regulation by the miRNA. These data affirm that miRNAs can exert regulatory effects on targets within coding regions; however, the dampening of these effects by translation likely accounts for the observed selection for target sites in the 3′UTRs.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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  • 8
    Publication Date: 2011-02-02
    Description: Imprinted genes are expressed primarily or exclusively from either the maternal or paternal allele, a phenomenon that occurs in flowering plants and mammals. Flowering plant imprinted gene expression has been described primarily in endosperm, a terminal nutritive tissue consumed by the embryo during seed development or after germination. Imprinted expression in Arabidopsis thaliana endosperm is orchestrated by differences in cytosine DNA methylation between the paternal and maternal genomes as well as by Polycomb group proteins. Currently, only 11 imprinted A. thaliana genes are known. Here, we use extensive sequencing of cDNA libraries to identify 9 paternally expressed and 34 maternally expressed imprinted genes in A. thaliana endosperm that are regulated by the DNA-demethylating glycosylase DEMETER, the DNA methyltransferase MET1, and/or the core Polycomb group protein FIE. These genes encode transcription factors, proteins involved in hormone signaling, components of the ubiquitin protein degradation pathway, regulators of histone and DNA methylation, and small RNA pathway proteins. We also identify maternally expressed genes that may be regulated by unknown mechanisms or deposited from maternal tissues. We did not detect any imprinted genes in the embryo. Our results show that imprinted gene expression is an extensive mechanistically complex phenomenon that likely affects multiple aspects of seed development.
    Keywords: Inaugural Articles
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    Electronic ISSN: 1091-6490
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  • 9
    Publication Date: 2011-07-27
    Description: Cohesin is a member of the Smc family of protein complexes that mediates higher-order chromosome structure by tethering different regions of chromatin. We present a new in vitro system that assembles cohesin-DNA complexes with in vivo properties. The assembly of these physiological salt-resistant complexes requires the cohesin holo-complex, its ability to bind ATP, the cohesin loader Scc2p and a closed DNA topology. Both the number of cohesin molecules bound to the DNA substrate and their distribution on the DNA substrate are limited. Cohesin and Scc2p bind preferentially to cohesin associated regions (CARs), DNA sequences with enriched cohesin binding in vivo. A subsequence of CARC1 promotes cohesin binding to neighboring sequences within CARC1. The enhancer-like function of this sequence is validated by in vivo deletion analysis. By demonstrating the physiological relevance of these in vitro assembled cohesin-DNA complexes, we establish our in vitro system as a powerful tool to elucidate the mechanism of cohesin and other Smc complexes.
    Keywords: Inaugural Articles
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  • 10
    Publication Date: 2011-09-07
    Description: Legionella pneumophila is a bacterial pathogen of amoebae and humans. Intracellular growth requires a type IVB secretion system that translocates at least 200 different proteins into host cells. To distinguish between proteins necessary for growth in culture and those specifically required for intracellular replication, a screen was performed to identify genes necessary for optimal growth in nutrient-rich medium. Mapping of these genes revealed that the L. pneumophila chromosome has a modular architecture consisting of several large genomic islands that are dispensable for growth in bacteriological culture. Strains lacking six of these regions, and thus 18.5% of the genome, were viable but required secondary point mutations for optimal growth. The simultaneous deletion of five of these genomic loci had no adverse effect on growth of the bacterium in nutrient-rich media. Remarkably, this minimal genome strain, which lacked 31% of the known substrates of the type IVB system, caused only marginal defects in intracellular growth within mouse macrophages. In contrast, deletion of single regions reduced growth within amoebae. The importance of individual islands, however, differed among amoebal species. The host-specific requirements of these genomic islands support a model in which the acquisition of foreign DNA has broadened the L. pneumophila host range.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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