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  • 1
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    Evolutionary origin of a novel gene expression pattern through co-option of the latent activities of existing regulatory sequences [Evolution] (2011)
    National Academy of Sciences
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    Publication Date: 2011-06-22
    Description: Spatiotemporal changes in gene expression underlie many evolutionary novelties in nature. However, the evolutionary origins of novel expression patterns, and the transcriptional control elements (“enhancers”) that govern them, remain unclear. Here, we sought to explore the molecular genetic mechanisms by which new enhancers arise. We undertook a survey of closely related Drosophila species to identify recently evolved novel gene expression patterns and traced their evolutionary history. Analyses of gene expression in a variety of developing tissues of the Drosophila melanogaster species subgroup revealed high rates of expression pattern divergence, including numerous evolutionary losses, heterochronic shifts, and expansions or contractions of expression domains. However, gains of novel expression patterns were much less frequent. One gain was observed for the Neprilysin-1 (Nep1) gene, which has evolved a unique expression pattern in optic lobe neuroblasts of Drosophila santomea. Dissection of the Nep1 cis-regulatory region localized a newly derived optic lobe enhancer activity to a region of an intron that has accumulated a small number of mutations. The Nep1 optic lobe enhancer overlaps with other enhancer activities, from which the novel activity was co-opted. We suggest that the novel optic lobe enhancer evolved by exploiting the cryptic activity of extant regulatory sequences, and this may reflect a general mechanism whereby new enhancers evolve.
    Keywords: Inaugural Articles
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  • 2
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    QnAs with Leroy E. Hood [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-06-08
    Description: Molecular biologist Leroy Hood says a transformation in medicine is gingerly afoot. The change, which he calls P4 medicine (predictive, preventive, personalized, and participatory), could turn today’s reactive approach to medicine into a proactive one in the future. Hood, president of the Institute for Systems Biology in Seattle, Washington, is no stranger to scientific revolutions. In the 1980s Hood helped invent automated DNA and protein synthesizers and sequencers, which made the Human Genome Project possible. Those technological feats snagged Hood many laurels, including the Kyoto Prize and the Lemelson-MIT Prize for Invention and Innovation. Hood tells PNAS how systems biology—the...
    Keywords: QnAs
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  • 3
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    Adaptive shape processing in primary visual cortex [Neuroscience] (2011)
    National Academy of Sciences
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    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
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  • 4
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    QnAs with May R. Berenbaum [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-08-03
    Description: Insects and plants often share a complicated relationship, and University of Illinois, Urbana–Champaign entomologist May Berenbaum has a fine understanding of its chemistry. Berenbaum, a member of the National Academy of Sciences, has long studied how insects and plants evolve chemical arsenals to survive together, pitting cunning defense against toxic offense. Author of a number of popular science books on coevolution, Berenbaum won the 2011 Tyler Prize for Environmental Achievement for her contributions to entomology. Among her many pursuits is an exploration of the likely cause of honey bee die-offs across the United States, an affliction called colony collapse disorder....
    Keywords: QnAs
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  • 5
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    Lte1 promotes mitotic exit by controlling the localization of the spindle position checkpoint kinase Kin4 [Cell Biology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-08-03
    Description: For a daughter cell to receive a complete genomic complement, it is essential that the mitotic spindle be positioned accurately within the cell. In budding yeast, a signaling system known as the spindle position checkpoint (SPOC) monitors spindle position and regulates the activity of the mitotic exit network (MEN), a GTPase signaling pathway that promotes exit from mitosis. The protein kinase Kin4 is a central component of the spindle position checkpoint. Kin4 primarily localizes to the mother cell and associates with spindle pole bodies (SPBs) located in the mother cell to inhibit MEN signaling. In contrast, the kinase does not associate with the SPB in the bud. Thus, only when a MEN bearing SPB leaves the mother cell and the spindle is accurately positioned along the mother–bud axis can MEN signaling occur and cell division proceed. Here, we describe a mechanism ensuring that Kin4 only associates with mother cell-located SPBs. The bud-localized MEN regulator Lte1, whose molecular function has long been unclear, prevents Kin4 that escapes into the bud from associating with SPBs in the daughter cell.
    Keywords: Inaugural Articles
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  • 6
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    The neurexin ligands, neuroligins and leucine-rich repeat transmembrane proteins, perform convergent and divergent synaptic functions in vivo [Neuroscience] (2011)
    National Academy of Sciences
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    Publication Date: 2011-10-05
    Description: Synaptic cell adhesion molecules, including the neurexin ligands, neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs), are thought to organize synapse assembly and specify synapse function. To test the synaptic role of these molecules in vivo, we performed lentivirally mediated knockdown of NL3, LRRTM1, and LRRTM2 in CA1 pyramidal cells of WT and NL1 KO mice at postnatal day (P)0 (when synapses are forming) and P21 (when synapses are largely mature). P0 knockdown of NL3 in WT or NL1 KO neurons did not affect excitatory synaptic transmission, whereas P0 knockdown of LRRTM1 and LRRTM2 selectively reduced AMPA receptor-mediated synaptic currents. P0 triple knockdown of NL3 and both LRRTMs in NL1 KO mice yielded greater reductions in AMPA and NMDA receptor-mediated currents, suggesting functional redundancy between NLs and LRRTMs during early synapse development. In contrast, P21 knockdown of LRRTMs did not alter excitatory transmission, whereas NL manipulations supported a role for NL1 in maintaining NMDA receptor-mediated transmission. These results show that neurexin ligands in vivo form a dynamic synaptic cell adhesion network, with compensation between NLs and LRRTMs during early synapse development and functional divergence upon synapse maturation.
    Keywords: Inaugural Articles
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  • 7
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    A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels [Neuroscience] (2011)
    National Academy of Sciences
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    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
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  • 8
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    Illuminating the landscape of host-pathogen interactions with the bacterium Listeria monocytogenes [Microbiology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-12-07
    Description: Listeria monocytogenes has, in 25 y, become a model in infection biology. Through the analysis of both its saprophytic life and infectious process, new concepts in microbiology, cell biology, and pathogenesis have been discovered. This review will update our knowledge on this intracellular pathogen and highlight the most recent breakthroughs. Promising areas of investigation such as the increasingly recognized relevance for the infectious process, of RNA-mediated regulations in the bacterium, and the role of bacterially controlled posttranslational and epigenetic modifications in the host will also be discussed.
    Keywords: Inaugural Articles
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  • 9
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    Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time [Medical Sciences] (2011)
    National Academy of Sciences
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    Publication Date: 2011-11-23
    Description: In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17β-estradiol (E2) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E2 paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E2-induced apoptosis by analysis of gene expression across time (2–96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E2-induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E2 in 5C cells compared with both WS8 and 2A cells and hence, were associated with E2-induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E2 inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E2-induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E2-inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E2 interacted to superadditively induce apoptosis. Therefore, these data indicate that E2 induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.
    Keywords: Inaugural Articles
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  • 10
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    QnAs with Bruce M. Spiegelman [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-11-30
    Description: Like good and bad cholesterol, human body fat comes in two varieties: white fat cells, which store excess calories, and brown fat cells, which burn energy to generate body heat. Less well known outside the scientific community, brown fat cells have long been a fascination for National Academy of Sciences member Bruce Spiegelman, a professor of cell biology at Dana–Farber Cancer Institute and Harvard Medical School. Spiegelman’s work on fat metabolism is far-reaching: From finding ways to stimulate brown fat development in the body to unraveling the activity of drugs against diabetes, he has shown how understanding the genetics of...
    Keywords: QnAs
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  • 11
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    Physical limits of cells and proteomes [Biophysics and Computational Biology] (2011)
    National Academy of Sciences
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    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
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  • 12
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    QnAs with John P. Grotzinger [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-09-21
    Description: In late November 2011, the National Aeronautics and Space Administration (NASA) plans to launch its robotic explorer to scour Mars for signs of the planet’s ability to support life. The Mars Science Laboratory (MSL) spacecraft is scheduled to lift off from Cape Canaveral Air Force Station in Florida, shuttling Curiosity, an SUV-sized rover with a hefty scientific payload, to the red planet’s surface. John Grotzinger, a member of the National Academy of Sciences and professor of geology at the California Institute of Technology, helps oversee the mission. He became involved in the quest after studying how changes in the Earth’s...
    Keywords: QnAs
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  • 13
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    QnAs with Vern L. Schramm [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-09
    Description: At Albert Einstein College of Medicine of Yeshiva University in New York City, Vern Schramm, a professor of biochemistry, devises ways to block cellular enzymes. Those enzymes, which catalyze a range of reactions at the heart of normal physiology, might hold keys to treating psoriasis, autoimmune disease, and some forms of cancer. Schramm’s studies on the mechanism of enzyme-catalyzed reactions have led to a handful of drugs now being tested in clinical trials. In 2009, he developed a test for ricin, a deadly toxin found in castor beans, which has the potential to be used by bioterrorists. Schramm tells PNAS...
    Keywords: QnAs
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  • 14
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    QnAs with Gary King [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-30
    Description: Gary King, a professor of social science at Harvard University and a member of the National Academy of Sciences, fashions tools that harness the power of statistics, machine learning, and informatics to make sense of the numbers that matter to society. From evaluating the efficacy of a Mexican health policy reform to predicting the fate of the US Social Security trust fund, King’s sophisticated number crunching has important practical implications for disciplines as diverse as social, political, and health sciences. King tells PNAS how quantitative social science research can extend from academic journals into real-world scenarios.PNAS:You designed a health policy...
    Keywords: QnAs
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  • 15
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    Symmetry, asymmetry, and kinetics of silencing establishment in Saccharomyces cerevisiae revealed by single-cell optical assays [Genetics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-01-26
    Description: In Saccharomyces cerevisiae, silent chromatin inhibits the expression of genes at the HML, HMR, and telomeric loci. When silent chromatin forms de novo, the rate of its establishment is influenced by different chromatin states. In particular, loss of the enzyme Dot1, an H3 K79 methyltransferase, leads to rapid silencing establishment. We tested whether silencing establishment was antagonized by H3 K79 methylation or by the Dot1 protein itself competing with Sir3 for binding sites on nucleosomes. To do so, we monitored fluorescence activity in cells containing a GFP gene within the HML locus during silencing establishment in a series of dot1 and histone mutant backgrounds. Silencing establishment rate was correlated with Dot1’s enzymatic function rather than with the Dot1 protein itself. In addition, histone mutants that mimicked the conformation of unmethylated H3 K79 increased the rate of silencing establishment, indicating that the H3 K79 residue affected silencing independently of Dot1 abundance. Using fluorophore-based reporters, we confirmed that mother and daughter cells often silence in concert, but in instances where asymmetric silencing occurs, daughter cells established silencing earlier than their mothers. This noninvasive technique enabled us to demonstrate an asymmetry in silencing establishment of a key regulatory locus controlling cell fate.
    Keywords: Inaugural Articles
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  • 16
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    Development of an artificial cell, from self-organization to computation and self-reproduction [Biophysics and Computational Biology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-02
    Description: This article describes the state and the development of an artificial cell project. We discuss the experimental constraints to synthesize the most elementary cell-sized compartment that can self-reproduce using synthetic genetic information. The original idea was to program a phospholipid vesicle with DNA. Based on this idea, it was shown that in vitro gene expression could be carried out inside cell-sized synthetic vesicles. It was also shown that a couple of genes could be expressed for a few days inside the vesicles once the exchanges of nutrients with the outside environment were adequately introduced. The development of a cell-free transcription/translation toolbox allows the expression of a large number of genes with multiple transcription factors. As a result, the development of a synthetic DNA program is becoming one of the main hurdles. We discuss the various possibilities to enrich and to replicate this program. Defining a program for self-reproduction remains a difficult question as nongenetic processes, such as molecular self-organization, play an essential and complementary role. The synthesis of a stable compartment with an active interface, one of the critical bottlenecks in the synthesis of artificial cell, depends on the properties of phospholipid membranes. The problem of a self-replicating artificial cell is a long-lasting goal that might imply evolution experiments.
    Keywords: Inaugural Articles
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  • 17
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    Viral microRNA target allows insight into the role of translation in governing microRNA target accessibility [Biochemistry] (2011)
    National Academy of Sciences
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    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
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  • 18
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    QnAs with Gilbert Strang [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-16
    Description: Of the world’s mathematicians, Gilbert Strang is possibly the most visible—or at least among the most frequently viewed. Millions of students from the Americas, Africa, China, Europe, India, and Singapore have watched Strang’s lectures on linear algebra courtesy of Massachusetts Institute of Technology (MIT)’s OpenCourseWare Web site (1), and many have e-mailed him to ask for one-on-one help. A former president of the Society for Industrial and Applied Mathematics (SIAM), author of several textbooks (2–9), and 2009 electee to the National Academy of Sciences, Strang wrote the book on linear algebra—and his text has changed how the material is taught....
    Keywords: QnAs
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  • 19
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    Regulation of imprinted gene expression in Arabidopsis endosperm [Plant Biology] (2011)
    National Academy of Sciences
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    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.
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  • 20
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    General purpose computer-assisted clustering and conceptualization [Computer Sciences] (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-16
    Description: We develop a computer-assisted method for the discovery of insightful conceptualizations, in the form of clusterings (i.e., partitions) of input objects. Each of the numerous fully automated methods of cluster analysis proposed in statistics, computer science, and biology optimize a different objective function. Almost all are well defined, but how to determine before the fact which one, if any, will partition a given set of objects in an “insightful” or “useful” way for a given user is unknown and difficult, if not logically impossible. We develop a metric space of partitions from all existing cluster analysis methods applied to a given dataset (along with millions of other solutions we add based on combinations of existing clusterings) and enable a user to explore and interact with it and quickly reveal or prompt useful or insightful conceptualizations. In addition, although it is uncommon to do so in unsupervised learning problems, we offer and implement evaluation designs that make our computer-assisted approach vulnerable to being proven suboptimal in specific data types. We demonstrate that our approach facilitates more efficient and insightful discovery of useful information than expert human coders or many existing fully automated methods.
    Keywords: Inaugural Articles
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  • 21
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    mut-16 and other mutator class genes modulate 22G and 26G siRNA pathways in Caenorhabditis elegans [Genetics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-01-26
    Description: Argonaute-associated siRNAs and Piwi-associated piRNAs have overlapping roles in silencing mobile genetic elements in animals. In Caenorhabditis elegans, mutator (mut) class genes mediate siRNA-guided repression of transposons as well as exogenous RNAi, but their roles in endogenous RNA silencing pathways are not well-understood. To characterize the endogenous small RNAs dependent on mut class genes, small RNA populations from a null allele of mut-16 as well as a regulatory mut-16(mg461) allele that disables only somatic RNAi were subjected to deep sequencing. Additionally, each of the mut class genes was tested for a requirement in 26G siRNA pathways. The results indicate that mut-16 is an essential factor in multiple endogenous germline and somatic siRNA pathways involving several distinct Argonautes and RNA-dependent RNA polymerases. The results also reveal essential roles for mut-2 and mut-7 in the ERGO-1 class 26G siRNA pathway and less critical roles for mut-8, mut-14, and mut-15. We show that transposons are hypersusceptible to mut-16–dependent silencing and identify a requirement for the siRNA machinery in piRNA biogenesis from Tc1 transposons. We also show that the soma-specific mut-16(mg461) mutant allele is present in multiple C. elegans laboratory strains.
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  • 22
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    Spatial control of cell fate using synthetic surfaces to potentiate TGF-{beta} signaling [Biochemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-07-20
    Description: In organisms, cell-fate decisions result from external cues presented by the extracellular microenvironment or the niche. In principle, synthetic niches can be engineered to give rise to patterned cell signaling, an advance that would transform the fields of tissue engineering and regenerative medicine. Biomaterials that display adhesive motifs are critical steps in this direction, but promoting localized signaling remains a major obstacle. We sought to exert precise spatial control over activation of TGF-β signaling. TGF-β signaling, which plays fundamental roles in development, tissue homeostasis, and cancer, is initiated by receptor oligomerization. We therefore hypothesized that preorganizing the transmembrane receptors would potentiate local TGF-β signaling. To generate surfaces that would nucleate the signaling complex, we employed defined self-assembled monolayers that present peptide ligands to TGF-β receptors. These displays of nondiffusible ligands do not compete with the growth factor but rather sensitize bound cells to subpicomolar concentrations of endogenous TGF-β. Cells adhering to the surfaces undergo TGF-β-mediated growth arrest and the epithelial to mesenchymal transition. Gene expression profiles reveal that the surfaces selectively regulate TGF-β responsive genes. This strategy provides access to tailored surfaces that can deliver signals with spatial control.
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    In vitro assembly of physiological cohesin/DNA complexes [Biochemistry] (2011)
    National Academy of Sciences
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    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.
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    Metabolic principles of river basin organization [Environmental Sciences] (2011)
    National Academy of Sciences
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    Publication Date: 2011-07-20
    Description: The metabolism of a river basin is defined as the set of processes through which the basin maintains its structure and responds to its environment. Green (or biotic) metabolism is measured via transpiration and blue (or abiotic) metabolism through runoff. A principle of equal metabolic rate per unit area throughout the basin structure is developed and tested in a river basin characterized by large heterogeneities in precipitation, vegetation, soil, and geomorphology. This principle is suggested to have profound implications for the spatial organization of river basin hydrologic dynamics, including the minimization of energy expenditure known to control the scale-invariant characteristics of river networks over several orders of magnitude. Empirically derived, remarkably constant rates of average transpiration per unit area through the basin structure lead to a power law for the probability distribution of transpiration from a randomly chosen subbasin. The average runoff per unit area, evaluated for subbasins of a wide range of topological magnitudes, is also shown to be remarkably constant independently of size. A similar result is found for the rainfall after accounting for canopy interception. Allometric scaling of metabolic rates with size, variously addressed in the biological literature and network theory under the label of Kleiber’s law, is similarly derived. The empirical evidence suggests that river basin metabolic activity is linked with the spatial organization that takes place around the drainage network and therefore with the mechanisms responsible for the fractal geometry of the network, suggesting a new coevolutionary framework for biological, geomorphological, and hydrologic dynamics.
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    p53 binding to nucleosomes within the p21 promoter in vivo leads to nucleosome loss and transcriptional activation [Biochemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-06-30
    Description: It is well established that p53 contacts DNA in a sequence-dependent manner in order to transactivate its myriad target genes. Yet little is known about how p53 interacts with its binding site/response element (RE) within such genes in vivo in the context of nucleosomal DNA. In this study we demonstrate that both distal (5′) and proximal (3′) p53 REs within the promoter of the p21 gene in unstressed HCT116 colon carcinoma cells are localized within a region of relatively high nucleosome occupancy. In the absence of cellular stress, p53 is prebound to both p21 REs within nucleosomal DNA in these cells. Treatment of cells with the DNA-damaging drug doxorubicin or the p53 stabilizing agent Nutlin-3, however, is accompanied by p53-dependent subsequent loss of nucleosomes associated with such p53 REs. We show that in vitro p53 can bind to mononucleosomal DNA containing the distal p21 RE, provided the binding site is not close to the diad center of the nucleosome. In line with this, our data indicate that the p53 distal RE within the p21 gene is located close to the end of the nucleosome. Thus, low- and high-resolution mapping of nucleosome boundaries around p53 REs within the p21 promoter have provided insight into the mechanism of p53 binding to its sites in cells and the consequent changes in nucleosome occupancy at such sites.
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    Atomic-scale insight and design principles for turbine engine thermal barrier coatings from theory [Chemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-04-06
    Description: To maximize energy efficiency, gas turbine engines used in airplanes and for power generation operate at very high temperatures, even above the melting point of the metal alloys from which they are comprised. This feat is accomplished in part via the deposition of a multilayer, multicomponent thermal barrier coating (TBC), which lasts up to approximately 40,000 h before failing. Understanding failure mechanisms can aid in designing circumvention strategies. We review results of quantum mechanics calculations used to test hypotheses about impurities that harm TBCs and transition metal (TM) additives that render TBCs more robust. In particular, we discovered a number of roles that Pt and early TMs such as Hf and Y additives play in extending the lifetime of TBCs. Fundamental insight into the nature of the bonding created by such additives and its effect on high-temperature evolution of the TBCs led to design principles that can be used to create materials for even more efficient engines.
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    QnAs with James E. Haber [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-04-06
    Description: As the director of the Rosenstiel Basic Medical Sciences Research Center at Brandeis University in Waltham, MA, James Haber seeks to understand how cells repair damaged DNA—and what happens when the process goes awry, triggering the onset of cancer and other devastating diseases. Haber’s work on yeast genetics has earned him some of the highest honors in science, including the Thomas Hunt Morgan Medal for lifetime contributions in genetics and election to the National Academy of Sciences in 2010. Haber recently spoke with PNAS about the technologies his laboratory has used to explore a form of DNA damage known as...
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    Real-time analysis of double-strand DNA break repair by homologous recombination [Genetics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-02-23
    Description: The ability to induce synchronously a single site-specific double-strand break (DSB) in a budding yeast chromosome has made it possible to monitor the kinetics and genetic requirements of many molecular steps during DSB repair. Special attention has been paid to the switching of mating-type genes in Saccharomyces cerevisiae, a process initiated by the HO endonuclease by cleaving the MAT locus. A DSB in MATa is repaired by homologous recombination—specifically, by gene conversion—using a heterochromatic donor, HMLα. Repair results in the replacement of the a-specific sequences (Ya) by Yα and switching from MATa to MATα. We report that MAT switching requires the DNA replication factor Dpb11, although it does not require the Cdc7-Dbf4 kinase or the Mcm and Cdc45 helicase components. Using Southern blot, PCR, and ChIP analysis of samples collected every 10 min, we extend previous studies of this process to identify the times for the loading of Rad51 recombinase protein onto the DSB ends at MAT, the subsequent strand invasion by the Rad51 nucleoprotein filament into the donor sequences, the initiation of new DNA synthesis, and the removal of the nonhomologous Y sequences. In addition we report evidence for the transient displacement of well-positioned nucleosomes in the HML donor locus during strand invasion.
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    Identifying barriers to Muslim integration in France [Political Sciences] (2011)
    National Academy of Sciences
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    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.
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    microRNA miR-275 is indispensable for blood digestion and egg development in the mosquito Aedes aegypti [Developmental Biology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-01-04
    Description: The mosquito Aedes aegypti is the major vector of arboviral diseases, particularly of Dengue fever, of which there are more than 100 million cases annually. Mosquitoes, such as A. aegypti, serve as vectors for disease pathogens because they require vertebrate blood for their egg production. Pathogen transmission is tightly linked to repeated cycles of obligatory blood feeding and egg maturation. Thus, the understanding of mechanisms governing egg production is necessary to develop approaches that limit the spread of mosquito-borne diseases. Previous studies have identified critical roles of hormonal- and nutrition-based target of rapamycin (TOR) pathways in controlling blood-meal–mediated egg maturation in mosquitoes. In this work, we uncovered another essential regulator of blood-meal–activated processes, the microRNA miR-275. The depletion of this microRNA in A. aegypti females after injection of its specific antagomir resulted in severe defects in blood digestion, fluid excretion, and egg development, clearly demonstrating that miR-275 is indispensable for these physiological processes. miR-275 exhibits an expression profile that suggests its regulation by a steroid hormone, 20-hydroxyecdysone (20E). In vitro organ culture experiments demonstrated that miR-275 is induced by this hormone in the presence of amino acids, indicative of a dual regulation by 20E and TOR. This report has uncovered the critical importance of microRNAs in controlling blood-meal–activated physiological events required for completion of egg development in mosquito disease vectors.
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    Completely phased genome sequencing through chromosome sorting [Statistics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-01-05
    Description: The two haploid genome sequences that a person inherits from the two parents represent the most fundamentally useful type of genetic information for the study of heritable diseases and the development of personalized medicine. Because of the difficulty in obtaining long-range phase information, current sequencing methods are unable to provide this information. Here, we introduce and show feasibility of a scalable approach capable of generating genomic sequences completely phased across the entire chromosome.
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    Structural basis for piRNA 2'-O-methylated 3'-end recognition by Piwi PAZ (Piwi/Argonaute/Zwille) domains [Biochemistry] (2011)
    National Academy of Sciences
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    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.
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    On the unreasonable effectiveness of the post-Newtonian approximation in gravitational physics [Physics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-04-13
    Description: The post-Newtonian approximation is a method for solving Einstein’s field equations for physical systems in which motions are slow compared to the speed of light and where gravitational fields are weak. Yet it has proven to be remarkably effective in describing certain strong-field, fast-motion systems, including binary pulsars containing dense neutron stars and binary black hole systems inspiraling toward a final merger. The reasons for this effectiveness are largely unknown. When carried to high orders in the post-Newtonian sequence, predictions for the gravitational-wave signal from inspiraling compact binaries will play a key role in gravitational-wave detection by laser-interferometric observatories.
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    Roles of two protein phosphatases, Reg1-Glc7 and Sit4, and glycogen synthesis in regulation of SNF1 protein kinase [Genetics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-04-20
    Description: The SNF1 protein kinase of Saccharomyces cerevisiae is a member of the SNF1/AMP-activated protein kinase family, which is essential for metabolic control, energy homeostasis, and stress responses in eukaryotes. SNF1 is activated in response to glucose limitation by phosphorylation of Thr210 on the activation loop of the catalytic subunit Snf1. The SNF1 β-subunit contains a glycogen-binding domain that has been implicated in glucose inhibition of Snf1 Thr210 phosphorylation. To assess the role of glycogen, we examined Snf1 phosphorylation in strains with altered glycogen metabolism. A reg1Δ mutant, lacking Reg1-Glc7 protein phosphatase 1, exhibits elevated glycogen accumulation and phosphorylation of Snf1 during growth on high levels of glucose. Unexpectedly, mutations that abolished glycogen synthesis also restored Thr210 dephosphorylation in glucose-grown reg1Δ cells, indicating that elevated glycogen synthesis contributes to activation of SNF1 and that another phosphatase acts on Snf1. We present evidence that Sit4, a type 2A-like protein phosphatase, contributes to dephosphorylation of Snf1 Thr210. Finally, evidence that the effects of glycogen are not mediated by binding to the β-subunit raises the possibility that elevated glycogen synthesis alters glucose metabolism and thereby reduces glucose signaling to the SNF1 pathway.
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    Electrostatic influences of charged inner pore residues on the conductance and gating of small conductance Ca2+ activated K+ channels [Biophysics and Computational Biology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-04-13
    Description: SK channels underlie important physiological functions by linking calcium signaling with neuronal excitability. Potassium currents through SK channels demonstrate inward rectification, which further reduces their small outward conductance. Although it has been generally attributed to block of outward current by intracellular divalent ions, we find that inward rectification is in fact an intrinsic property of SK channels independent of intracellular blockers. We identified three charged residues in the S6 transmembrane domain of SK channels near the inner mouth of the pore that collectively control the conductance and rectification through an electrostatic mechanism. Additionally, electrostatic contributions from these residues also play an important role in determining the intrinsic open probability of SK channels in the absence of Ca2+, affecting the apparent Ca2+ affinity for activation.
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    Efficiency of the CO2-concentrating mechanism of diatoms [Environmental Sciences] (2011)
    National Academy of Sciences
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    Publication Date: 2011-03-09
    Description: Diatoms are responsible for a large fraction of CO2 export to deep seawater, a process responsible for low modern-day CO2 concentrations in surface seawater and the atmosphere. Like other photosynthetic organisms, diatoms have adapted to these low ambient concentrations by operating a CO2 concentrating mechanism (CCM) to elevate the concentration of CO2 at the site of fixation. We used mass spectrometric measurements of passive and active cellular carbon fluxes and model simulations of these fluxes to better understand the stoichiometric and energetic efficiency and the physiological architecture of the diatom CCM. The membranes of diatoms are highly permeable to CO2, resulting in a large diffusive exchange of CO2 between the cell and external milieu. An active transport of carbon from the cytoplasm into the chloroplast is the main driver of the diatom CCM. Only one-third of this carbon flux is fixed photosynthetically, and the rest is lost by CO2 diffusion back to the cytoplasm. Both the passive influx of CO2 from the external medium and the recycling of the CO2 leaking out of the chloroplast are achieved by the activity of a carbonic anhydrase enzyme combined with the maintenance of a low concentration of HCO3− in the cytoplasm. To achieve the CO2 concentration necessary to saturate carbon fixation, the CO2 is most likely concentrated within the pyrenoid, an organelle within the chloroplast where the CO2-fixating enzyme is located.
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    QnAs with Peter H. Gleick [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-07-06
    Description: National Academy of Sciences member Peter Gleick is cofounder and president of the Pacific Institute for Studies in Development, Environment, and Security in Oakland, California, where he explores new ways of thinking about water issues. His creative insights have resulted in the biennial book series The World’s Water, a MacArthur Fellowship award in 2003, multiple appearances as an expert witness before Congress and the courts, and the 2010 book Bottled and Sold: The Story Behind Our Obsession with Bottled Water. Peak water, the concept introduced in his PNAS Inaugural Article (1), became one of the New York Times’ “Words of...
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    QnAs with Eric S. Lander [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-07-13
    Description: This year marks the 10th anniversary of the sequencing of the human genome. More than two decades after the launch of the Human Genome Project, researchers have made remarkable inroads into unraveling human biology, evolution, and disease. As the tools of genome sequencing and analysis grow more sophisticated, insights into the human genome will slowly shift the terrain in the treatment of disease. To be sure, the shift has already begun. Eric Lander, founding director of the Broad Institute of Harvard and Massachusetts Institute of Technology and a member of the National Academy of Sciences, offers PNAS readers his perspectives...
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    Minimization of the Legionella pneumophila genome reveals chromosomal regions involved in host range expansion [Microbiology] (2011)
    National Academy of Sciences
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    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.
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    Chemical genetic strategy for targeting protein kinases based on covalent complementarity [Biochemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-09-14
    Description: The conserved nature of the ATP-binding site of the 〉 500 human kinases renders the development of specific inhibitors a challenging task. A widely used chemical genetic strategy to overcome the specificity challenge exploits a large-to-small mutation of the gatekeeper residue (a conserved hydrophobic amino acid) and the use of a bulky inhibitor to achieve specificity via shape complementarity. However, in a number of cases, introduction of a glycine or alanine gatekeeper results in diminished kinase activity and ATP affinity. A new chemical genetic approach based on covalent complementarity between an engineered gatekeeper cysteine and an electrophilic inhibitor was developed to address these challenges. This strategy was evaluated with Src, a proto-oncogenic tyrosine kinase known to lose some enzymatic activity using the shape complementarity chemical genetic strategy. We found that Src with a cysteine gatekeeper recapitulates wild type activity and can be irreversibly inhibited both in vitro and in cells. A cocrystal structure of T338C c-Src with a vinylsulfonamide-derivatized pyrazolopyrimidine inhibitor was solved to elucidate the inhibitor binding mode. A panel of electrophilic inhibitors was analyzed against 307 kinases and MOK (MAPK/MAK/MRK overlapping kinase), one of only two human kinases known to have an endogenous cysteine gatekeeper. This analysis revealed remarkably few off-targets, making these compounds the most selective chemical genetic inhibitors reported to date. Protein engineering studies demonstrated that it is possible to increase inhibitor potency through secondary-site mutations. These results suggest that chemical genetic strategies based on covalent complementarity should be widely applicable to the study of protein kinases.
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    Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection [Immunology] (2011)
    National Academy of Sciences
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    Publication Date: 2011-09-07
    Description: During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94–NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56dimCD16+ NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94–NKG2C receptor and CD57 in CMV+ donors. These CD57+NKG2Chi NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57+NKG2Chi NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57+NKG2Chi NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C+ NK cells proliferated, became NKG2Chi, and finally acquired CD57. Thus, we propose that CD57 might provide a marker of “memory” NK cells that have been expanded in response to infection.
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    Randomized approximate nearest neighbors algorithm [Applied Mathematics] (2011)
    National Academy of Sciences
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    Publication Date: 2011-09-21
    Description: We present a randomized algorithm for the approximate nearest neighbor problem in d-dimensional Euclidean space. Given N points {xj} in , the algorithm attempts to find k nearest neighbors for each of xj, where k is a user-specified integer parameter. The algorithm is iterative, and its running time requirements are proportional to T·N·(d·(log d) + k·(d + log k)·(log N)) + N·k2·(d + log k), with T the number of iterations performed. The memory requirements of the procedure are of the order N·(d + k). A by-product of the scheme is a data structure, permitting a rapid search for the k nearest neighbors among {xj} for an arbitrary point . The cost of each such query is proportional to T·(d·(log d) + log(N/k)·k·(d + log k)), and the memory requirements for the requisite data structure are of the order N·(d + k) + T·(d + N). The algorithm utilizes random rotations and a basic divide-and-conquer scheme, followed by a local graph search. We analyze the scheme’s behavior for certain types of distributions of {xj} and illustrate its performance via several numerical examples.
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    QnAs with Susan L. Lindquist [QnAs] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-12-14
    Description: Prions defy molecular biology’s central dogma. Misfolded proteins that self-perpetuate, prions were first isolated in the early 1980s as the cause of a fatal sheep disease called scrapie. Since then, prions have been implicated in human neurodegenerative diseases, composing a rogue’s gallery of deadly disease agents. Susan Lindquist, a member of the National Academy of Sciences and a professor of biology at the Massachusetts Institute of Technology’s Whitehead Institute for Biomedical Research, has found that prions may have a little-appreciated positive side. Lindquist casts these seeming biochemical misfits in a surprising evolutionary role: Her studies have revealed that prions might...
    Keywords: QnAs
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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    QnAs with David Baltimore [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-12-21
    Description: At the age of 37, David Baltimore accomplished what many researchers dream of but few achieve: reversing an entrenched dogma, eventually leading to a new view of life. In the early 1970s, Baltimore, a member of the National Academy of Sciences and a professor of biology at the California Institute of Technology, discovered reverse transcriptase—an enzyme found in some tumor viruses whose genetic code is written in the RNA alphabet. He found that reverse transcriptase can copy RNA into DNA, indicating that some viruses replicate via a DNA intermediate. The finding, which won Baltimore and others the 1975 Nobel Prize...
    Keywords: QnAs
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    QnAs with Inder M. Verma [QnAs] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-12-21
    Description: On November 1, 2011, Inder Verma, a professor of molecular biology at the Salk Institute for Biological Studies in La Jolla, California and a member of the National Academy of Sciences since 1997, took the reins of PNAS as Editor-in-Chief. Verma succeeds University of California, Berkeley cell biologist Randy Schekman as leader of the journal. Verma received a PhD from the Weizmann Institute of Science in Israel and performed postdoctoral research in the laboratory of Nobel Laureate David Baltimore. Long recognized in the scientific community for his work in cancer genetics and gene therapy, Verma was most recently honored with...
    Keywords: QnAs
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    mTOR links incretin signaling to HIF induction in pancreatic beta cells [Biochemistry] (2011)
    National Academy of Sciences
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    Publication Date: 2011-10-12
    Description: Under feeding conditions, the incretin hormone GLP-1 promotes pancreatic islet viability by triggering the cAMP pathway in beta cells. Increases in PKA activity stimulate the phosphorylation of CREB, which in turn enhances beta cell survival by upregulating IRS2 expression. Although sustained GLP-1 action appears important for its salutary effects on islet function, the transient nature of CREB activation has pointed to the involvement of additional nuclear factors in this process. Following the acute induction of CREB-regulated genes, cAMP triggers a second delayed phase of gene expression that proceeds via the HIF transcription factor. Increases in cAMP promote the accumulation of HIF1α in beta cells by activating the mTOR pathway. As exposure to rapamycin disrupts GLP-1 effects on beta cell viability, these results demonstrate how a pathway associated with tumor growth also mediates salutary effects of an incretin hormone on pancreatic islet function.
    Keywords: Inaugural Articles
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    QnAs with Cynthia Kenyon [QnAs] (2011)
    National Academy of Sciences
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    Publication Date: 2011-10-12
    Description: For more than a decade, developmental biologist Cynthia Kenyon has sought the essence of youth in the soil-dwelling roundworm Caenorhabditis elegans. Through her studies on genes that control aging in the worm, Kenyon, a member of the National Academy of Sciences and a professor of biochemistry at the University of California, San Francisco, joined the quest for immortality that has tickled the imagination of thinkers since time immemorial. Kenyon’s work has uncovered aging-related genes that affect physiological processes like metabolism, respiration, and reproduction. Contradictory reports of experimental compounds purported to extend life or delay aging in animals have often roiled...
    Keywords: QnAs
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    Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1 [Genetics] (2011)
    National Academy of Sciences
    Details
    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
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    War and early state formation in the northern Titicaca Basin, Peru [Anthropology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-08-24
    Description: Excavations at the site of Taraco in the northern Titicaca Basin of southern Peru indicate a 2,600-y sequence of human occupation beginning ca. 1100 B.C.E. Previous research has identified several political centers in the region in the latter part of the first millennium B.C.E. The two largest centers were Taraco, located near the northern lake edge, and Pukara, located 50 km to the northwest in the grassland pampas. Our data reveal that a high-status residential section of Taraco was burned in the first century A.D., after which economic activity in the area dramatically declined. Coincident with this massive fire at Taraco, Pukara adopted many of the characteristics of state societies and emerged as an expanding regional polity. We conclude that organized conflict, beginning approximately 500 B.C.E., is a significant factor in the evolution of the archaic state in the northern Titicaca Basin.
    Keywords: Inaugural Articles
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    QnAs with Robert C. Malenka [QnAs] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-10-05
    Description: Experiences bridge brain circuitry with behavior, affecting our ability to learn and remember. By influencing the nature of neurotransmission across synapses—junctions between nerve cells—experiences can physically shape the mind. Those influences, collectively termed synaptic plasticity, have been a focus of study for neuroscientist Robert Malenka for more than two decades. Malenka, a member of the National Academy of Sciences, has uncovered molecular mechanisms underlying synaptic plasticity. Along the way, he has pinpointed changes in a raft of synaptic proteins that can alter the efficacy of neurotransmission across synapses. An offshoot of his studies on synaptic plasticity, Malenka’s work on how...
    Keywords: QnAs
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    Eco-evolutionary spatial dynamics in the Glanville fritillary butterfly [Population Biology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-08-31
    Description: Demographic population dynamics, gene flow, and local adaptation may influence each other and lead to coupling of ecological and evolutionary dynamics, especially in species inhabiting fragmented heterogeneous environments. Here, I review long-term research on eco-evolutionary spatial dynamics in the Glanville fritillary butterfly inhabiting a large network of approximately 4,000 meadows in Finland. The metapopulation persists in a balance between frequent local extinctions and recolonizations. The genetic spatial structure as defined by neutral markers is much more coarse-grained than the demographic spatial structure determined by the fragmented habitat, yet small-scale spatial structure has important consequences for the dynamics. I discuss three examples of eco-evolutionary spatial dynamics. (i) Extinction-colonization metapopulation dynamics influence allele frequency changes in the phosphoglucose isomerase (Pgi) gene, which leads to strong associations between genetic variation in Pgi and dispersal, recolonization, and local population dynamics. (ii) Inbreeding in local populations increases their risk for extinction, whereas reciprocal effects between inbreeding, population size, and emigration represent likely eco-evolutionary feedbacks. (iii) Genetically determined female oviposition preference for two host plant species exhibits a cline paralleling a gradient in host plant relative abundances, and host plant preference of dispersing females in relation to the host plant composition of habitat patches influences immigration (gene flow) and recolonization (founder events). Eco-evolutionary spatial dynamics in heterogeneous environments may not lead to directional evolutionary changes unless the environment itself changes, but eco-evolutionary dynamics may contribute to the maintenance of genetic variation attributable to fluctuating selection in space and time.
    Keywords: Inaugural Articles
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
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