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  • The origin and evolution of cell-intrinsic antibacterial defenses in eukaryotes
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-11-12
    Daniel J Richter, Tera C Levin

    To survive in a world dominated by bacteria, eukaryotes have evolved numerous self-defense strategies. While some defenses are recent evolutionary innovations, others are ancient, with roots early in eukaryotic history. With a focus on antibacterial immunity, we highlight the evolution of pattern recognition receptors that detect bacteria, where diverse functional classes have been formed from the repeated use and reuse of a small set of protein domains. Next, we discuss core microbicidal strategies shared across eukaryotes, and how these systems may have been co-opted from ancient cellular mechanisms. We propose that studying antibacterial responses across diverse eukaryotes can reveal novel modes of defense, while highlighting the critical innovations that occurred early in the evolution of our own immune systems.

  • Editorial overview: Investigating phenotype evolution in the post-genomic era.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-10-23
    Jeremy G Wideman,Thomas A Richards

  • Evolutionary dynamics of membrane transporters and channels: enhancing function through fusion.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-09-29
    Benjamin J Willson,Liam Nm Chapman,Gavin H Thomas

    The formation of complex multidomain proteins has occurred many times during evolution. For enzymes, this often confers the addition of new functions or new routes to regulate function. Herein we review how this same process has impacted on the function of membrane transporters and channels, proteins that, due to their integral membrane location, are potentially more constrained in the fusions they can accommodate. Using examples primarily from bacterial systems, we illustrate diverse instances of functional fusions and find evidence for promiscuous fusion partners that have fused to many different classes of membrane protein. We consider the evidence that topology and stoichiometry issues might limit the range of fusions that are selected in nature and attempt to find examples where a functional benefit of direct fusion over split proteins has been demonstrated. Finally, we consider whether the reverse process of gene fission has been important in membrane transporter evolution.

  • Chromatin folding and nuclear architecture: PRC1 function in 3D.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-07-20
    Robert S Illingworth

    Embryonic development requires the intricate balance between the expansion and specialisation of defined cell types in time and space. The gene expression programmes that underpin this balance are regulated, in part, by modulating the chemical and structural state of chromatin. Polycomb repressive complexes (PRCs), a family of essential developmental regulators, operate at this level to stabilise or perpetuate a repressed but transcriptionally poised chromatin configuration. This dynamic state is required to control the timely initiation of productive gene transcription during embryonic development. The two major PRCs cooperate to target the genome, but it is PRC1 that appears to be the primary effector that controls gene expression. In this review I will discuss recent findings relating to how PRC1 alters chromatin accessibility, folding and global 3D nuclear organisation to control gene transcription.

  • Congenital heart disease: emerging themes linking genetics and development.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-06-25
    Shiaulou Yuan,Samir Zaidi,Martina Brueckner

    Although congenital heart disease (CHD) is the most common survivable birth defect, the etiology of most CHD remains unclear. Several lines of evidence from humans and vertebrate models have supported a genetic component for CHD, yet the extreme locus heterogeneity and lack of a distinct genotype-phenotype correlation have limited causative gene discovery. However, recent advances in genomic technologies are permitting detailed evaluation of the genetic abnormalities in large cohorts of CHD patients. This has led to the identification of copy-number variation and de novo mutations together accounting for up to 15% of CHD. Further, new strategies coupling human genetics with model organisms have provided mechanistic insights into the molecular and developmental pathways underlying CHD pathogenesis, notably chromatin remodeling and ciliary signaling.

  • Shining light on Drosophila oogenesis: live imaging of egg development.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-09-21
    Li He,Xiaobo Wang,Denise J Montell

    Drosophila oogenesis is a powerful model for the study of numerous questions in cell and developmental biology. In addition to its longstanding value as a genetically tractable model of organogenesis, recently it has emerged as an excellent system in which to combine genetics and live imaging. Rapidly improving ex vivo culture conditions, new fluorescent biosensors and photo-manipulation tools, and advances in microscopy have allowed direct observation in real time of processes such as stem cell self-renewal, collective cell migration, and polarized mRNA and protein transport. In addition, entirely new phenomena have been discovered, including revolution of the follicle within the basement membrane and oscillating assembly and disassembly of myosin on a polarized actin network, both of which contribute to elongating this tissue. This review focuses on recent advances in live-cell imaging techniques and the biological insights gleaned from live imaging of egg chamber development.

  • The evolution of the human genome.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2015-09-05
    Corinne N Simonti,John A Capra

    Human genomes hold a record of the evolutionary forces that have shaped our species. Advances in DNA sequencing, functional genomics, and population genetic modeling have deepened our understanding of human demographic history, natural selection, and many other long-studied topics. These advances have also revealed many previously underappreciated factors that influence the evolution of the human genome, including functional modifications to DNA and histones, conserved 3D topological chromatin domains, structural variation, and heterogeneous mutation patterns along the genome. Using evolutionary theory as a lens to study these phenomena will lead to significant breakthroughs in understanding what makes us human and why we get sick.

  • Physical control of tissue morphogenesis across scales.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2018-11-06
    Georgina A Stooke-Vaughan,Otger Campàs

    During embryogenesis, tissues and organs are progressively shaped into their functional morphologies. While the information about tissue and organ shape is encoded genetically, the sculpting of embryonic structures in the 3D space is ultimately a physical process. The control of physical quantities involved in tissue morphogenesis originates at cellular and subcellular scales, but it is their emergent behavior at supracellular scales that guides morphogenetic events. In this review, we highlight the physical quantities that can be spatiotemporally tuned at supracellular scales to sculpt tissues and organs during embryonic development of animal species, and connect them to the cellular and molecular mechanisms controlling them.

  • Mechanotransduction in cardiovascular morphogenesis and tissue engineering.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-10-07
    Anne-Laure Duchemin,Helene Vignes,Julien Vermot,Renee Chow

    Cardiovascular morphogenesis involves cell behavior and cell identity changes that are activated by mechanical forces associated with heart function. Recently, advances in in vivo imaging, methods to alter blood flow, and computational modelling have greatly advanced our understanding of how forces produced by heart contraction and blood flow impact different morphogenetic processes. Meanwhile, traditional genetic approaches have helped to elucidate how endothelial cells respond to forces at the cellular and molecular level. Here we discuss the principles of endothelial mechanosensitity and their interplay with cellular processes during cardiovascular morphogenesis. We then discuss their implications in the field of cardiovascular tissue engineering.

  • The multifaceted role of nerves in animal regeneration.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-09-25
    Chiara Sinigaglia,Michalis Averof

    The discovery that the nervous system plays a critical role in salamander limb regeneration, in 1823, provided the first mechanistic insights into regenerative phenomena and stimulated a long quest for molecular regulators. A role for nerves in the context of regeneration has been suggested for most vertebrate and invertebrate groups, thus offering a possible shared mechanism for the regulation of regenerative processes among animals. Methodological differences and technical limitations, especially in invertebrate groups, have so far hampered broad comparisons and the search for common principles on the role of nerves. This review considers both old and recent work in this topic and provides a broad perspective on the roles of nerves during regeneration. Nerves are found consistently to have important roles in regeneration, but their mode of action varies across species. The ongoing technological developments in a broad range of invertebrate models are now paving the way for the discovery of the shared and unique roles of nerves in animal regeneration.

  • Produce, carry/position, and connect: morphogenesis using rigid materials.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-09-24
    Noriko Funayama

    Animal morphogenesis can be summarized as a reconfiguration of a mass of cells. Although extracellular matrices that include rigid skeletal elements, such as cartilage/bones and exoskeletons, have important roles in morphogenesis, they are also secreted in situ by accumulated cells or epithelial cells. In contrast, recent studies of the skeleton construction of sponges (Porifera) illuminate a conceptually different mechanism of morphogenesis in which cells manipulate rather fine rigid materials (spicules) to form larger structures. Here, two different types of sponge skeleton formation using calcareous spicules or siliceous spicules are compared with regard to the concept of the production of rigid materials and their use in skeletons. The comparison highlights the advantages of their different strategies of forming sponge skeletons.

  • Editorial overview: Tissue-level dynamics in development and evolution.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-09-24
    Gáspár Jékely,Maria Ina Arnone

  • Acquisition of multipotent and migratory neural crest cells in vertebrate evolution.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-08-31
    Martin Cheung,Andrew Tai,Peter Jianning Lu,Kathryn Se Cheah

    The emergence of multipotent and migratory neural crest (NC) cells defines a key evolutionary transition from invertebrates to vertebrates. Studies in vertebrates have identified a complex gene regulatory network that governs sequential stages of NC ontogeny. Comparative analysis has revealed extensive conservation of the overall architecture of the NC gene regulatory network between jawless and jawed vertebrates. Among invertebrates, urochordates express putative NC gene homologs in the neural plate border region, but these NC-like cells do not have migratory capacity, whereas cephalochordates contain no NC cells but its genome contains most homologs of vertebrate NC genes. Whether the absence of migratory NC cells in invertebrates is due to differences in enhancer elements or an intrinsic limitation in potency remains unclear. We provide a brief overview of mechanisms that might explain how ancestral NC-like cells acquired the multipotency and migratory capacity seen in vertebrates.

  • Cell polarity oscillations in mitotic epithelia.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-08-30
    Sophia Doerr,Katerina Ragkousi

    Epithelial organization and function depend on coordinated cell polarity. In developing tissues, proliferative epithelia maintain whole tissue polarity as individual cells undergo symmetric divisions. However, recent work has shown that cells in diverse epithelia remodel their polarity in a cell cycle-dependent manner. Here, we discuss the different mechanisms that drive mitotic polarity oscillations and their implications for tissue morphogenesis.

  • 更新日期:2019-11-01
  • Mapping the protein-protein and genetic interactions of cancer to guide precision medicine.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-07-10
    Mehdi Bouhaddou,Manon Eckhardt,Zun Zar Chi Naing,Minkyu Kim,Trey Ideker,Nevan J Krogan

    Massive efforts to sequence cancer genomes have compiled an impressive catalogue of cancer mutations, revealing the recurrent exploitation of a handful of 'hallmark cancer pathways'. However, unraveling how sets of mutated proteins in these and other pathways hijack pro-proliferative signaling networks and dictate therapeutic responsiveness remains challenging. Here, we show that cancer driver protein-protein interactions are enriched for additional cancer drivers, highlighting the power of physical interaction maps to explain known, as well as uncover new, disease-promoting pathway interrelationships. We hypothesize that by systematically mapping the protein-protein and genetic interactions in cancer-thereby creating Cancer Cell Maps-we will create resources against which to contextualize a patient's mutations into perturbed pathways/complexes and thereby specify a matching targeted therapeutic cocktail.

  • Large-scale datasets uncovering cell signalling networks in cancer: context matters.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-06-15
    Sumana Sharma,Evangelia Petsalaki

    Cell signaling pathways control the responses of cells to external perturbations. Depending on the cell's internal state, genetic background and environmental context, signaling pathways rewire to elicit the appropriate response. Such rewiring also can lead to cancer development and progression or cause resistance to therapies. While there exist static maps of annotated pathways, they do not capture these rewired networks. As large-scale datasets across multiple contexts and patients are becoming available the doors to infer and study context-specific signaling network have also opened. In this review, we will highlight the most recent approaches to study context-specific signaling networks using large-scale omics and genetic perturbation datasets, with a focus on studies of cancer and cancer-related pathways.

  • Functional screens identify coordinators of RNA molecule birth, life, and death as targetable cancer vulnerabilities.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-05-24
    Christian J Braun,Michael T Hemann

    RNA molecules are subject to a complex co-transcriptional and post-transcriptional life cycle, controlled at all stages by RNA binding proteins (RBPs) and non-coding RNAs that influence mRNA stability, splicing, localization, and decay. Together with mechanisms regulating the process of transcription itself, non-coding RNAs and RBPs contribute to a model of para-transcriptional coordination of gene expression, which is utilized during normal tissue physiology and cancer development in order to execute complex gene expression programs. Several key regulators of RNA biology, such as certain splice factors, represent bona fide cancer vulnerabilities, but our understanding of these processes is still far away from being comprehensive. Genetic forward screens utilizing technologies such as transposons, RNAi and CRISPR aid the field in rapidly establishing functional phenotypes and genetic cancer cell addictions. This review focuses on four individual regulatory gene expression processes governed by regulators of the RNA life cycle, the impact of functional genomics on streamlining the discovery process and the role of such mechanisms in tumor biology.

  • The social lives of migrating cells in Drosophila.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2006-06-27
    Denise J Montell

    Studies of cell migration in Drosophila are yielding insights into the complex interactions migrating cells have with each other and with the cells in their environment. Intriguing links between factors that promote cell migration and those that control cell survival have been reported recently. For example, migrating germ cells compete with the surrounding somatic tissue for the substrate of the lipid phosphate phosphatases encoded by the genes Wunen and Wunen2. Germ cells take up the dephosphorylated lipid and require it for their survival. In addition, the secreted growth factors called PVFs, previously thought to guide the migrations of hemocytes in the embryo, were found to function instead predominantly as survival factors. And in border cells, DIAP1 and Dronc, two proteins known mainly for their ability to regulate cell death, were found to control cell migration.

  • Genes that drive invasion and migration in Drosophila.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2004-04-28
    Michelle Starz-Gaiano,Denise J Montell

    Successful cell migration depends on the careful regulation of the timing of movement, the guidance of motile cells, and cytoskeletal and adhesive changes within the cells. This review focuses on genes that act cell-autonomously to promote these aspects of cell migration in Drosophila. We discuss recent advances in understanding the migration of the ovarian border cells, embryonic blood cells, primordial germ cells, somatic gonadal precursors, and tracheal cells. Comparison of genes that regulate these processes to those that promote tumorigenesis and metastasis in mammals demonstrates that studies in fruit flies are uncovering new genes highly relevant to cancer biology.

  • Epigenetic gene regulation, chromatin structure, and force-induced chromatin remodelling in epidermal development and homeostasis.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2019-05-22
    Yekaterina A Miroshnikova,Idan Cohen,Elena Ezhkova,Sara A Wickström

    The skin epidermis is a constantly renewing stratified epithelium that provides essential protective barrier functions throughout life. Epidermal stratification is governed by a step-wise differentiation program that requires precise spatiotemporal control of gene expression. How epidermal self-renewal and differentiation are regulated remains a fundamental open question. Cell-intrinsic and cell-extrinsic mechanisms that modify chromatin structure and interactions have been identified as key regulators of epidermal differentiation and stratification. Here, we will review the recent advances in our understanding of how chromatin modifiers, tissue-specific transcription factors, and force-induced nuclear remodeling processes function to shape chromatin and to control epidermal tissue development and homeostasis.

  • The ageing genome, clonal mosaicism and chronic disease.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2017-01-10
    Mitchell J Machiela,Stephen J Chanock

    Clonal mosaicism arises when a postzygotic mutational event is detectable in subpopulations of cells as an alternative genotype while not present in the germline genome. Although described in a subset of pediatric disorders, new genomic technologies have detected higher than anticipated frequencies of clonal mosaicism in adult population studies, stimulating investigation as to how clonal mosaicism could contribute to chronic human diseases, such as cancer, diabetes and neurodegenerative disorders. It has also been postulated to be an important mechanism for functional cellular diversity, including the brain. Early studies have characterized the spectrum of detectable mosaic alterations and have begun to investigate whether detectable mosaicism could be important as an overall biomarker for risk or in the case of hematologic cancers, identification of preleukemic clones.

  • The African diaspora: history, adaptation and health.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-09-20
    Charles N Rotimi,Fasil Tekola-Ayele,Jennifer L Baker,Daniel Shriner

    The trans-Atlantic slave trade brought millions of Africans to the New World. Advances in genomics are providing novel insights into the history and health of Africans and the diasporan populations. Recent examples reviewed here include the unraveling of substantial hunter-gatherer and 'Eurasian' admixtures across sub-Saharan Africa, expanding our understanding of ancestral African genetics; the global ubiquity of mixed ancestry; the revealing of African ancestry in Latin Americans that likely derived from the slave trade; and understanding of the ancestral backgrounds of APOL1 and LPL found to influence kidney disease and lipid levels, respectively, providing specific insights into disease etiology and health disparities.

  • Human mitochondrial DNA replication machinery and disease.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-04-12
    Matthew J Young,William C Copeland

    The human mitochondrial genome is replicated by DNA polymerase γ in concert with key components of the mitochondrial DNA (mtDNA) replication machinery. Defects in mtDNA replication or nucleotide metabolism cause deletions, point mutations, or depletion of mtDNA. The resulting loss of cellular respiration ultimately induces mitochondrial genetic diseases, including mtDNA depletion syndromes (MDS) such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders such as progressive external ophthalmoplegia, ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy. Here we review the current literature regarding human mtDNA replication and heritable disorders caused by genetic changes of the POLG, POLG2, Twinkle, RNASEH1, DNA2, and MGME1 genes.

  • Mitochondrial iron overload: causes and consequences.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-03-31
    Tracey A Rouault

    Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified.

  • TP53 mutation, mitochondria and cancer.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-03-24
    William M Kamp,Ping-Yuan Wang,Paul M Hwang

    Under normal conditions, basal levels of wild-type p53 promote mitochondrial function through multiple mechanisms. Remarkably, some missense mutations of p53, in contrast to the null state, can result in the retention of its metabolic activities. These effects are particularly prominent in the mitochondria and demonstrate a functional role for mutant p53 in cancer metabolism. This review summarizes accumulating data on the mechanisms by which p53 missense mutations can regulate mitochondrial metabolism and promote the viability and survival of both normal and cancer cells, thus acting as a double edged sword for the host. Greater understanding of these mechanisms may provide insights for developing new treatment or preventive strategies against cancer.

  • Replication origins: determinants or consequences of nuclear organization?
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-02-05
    Anna B Marks,Owen K Smith,Mirit I Aladjem

    Chromosome replication, gene expression and chromatin assembly all occur on the same template, necessitating a tight spatial and temporal coordination to maintain genomic stability. The distribution of replication initiation events is responsive to local and global changes in chromatin structure and is affected by transcriptional activity. Concomitantly, replication origin sequences, which determine the locations of replication initiation events, can affect chromatin structure and modulate transcriptional efficiency. The flexibility observed in the replication initiation landscape might help achieve complete and accurate genome duplication while coordinating the DNA replication program with transcription and other nuclear processes in a cell-type specific manner. This review discusses the relationships among replication origin distribution, local and global chromatin structures and concomitant nuclear metabolic processes.

  • Hide and seek: how chromatin-based pathways silence retroelements in the mammalian germline.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2016-01-29
    Antoine Molaro,Harmit S Malik

    Retroelements comprise a major fraction of most mammalian genomes. To protect their fitness and stability, hosts must keep retroelements in check in their germline. In most tissues mobile element insertions are decorated with chromatin modifications suggestive of transcriptional silencing. However, germline cells undergo massive chromatin reprogramming events, which erase repressive chromatin marks and necessitate de novo re-establishment of silencing. How do host genomes achieve the discrimination necessary for this de novo silencing? A series of recent studies have revealed aspects of the multi-pronged strategy that mammalian genomes use to identify and silence retroelements. These strategies include the use of small RNA-guides, of specialized DNA-binding protein adaptors and of proteins that repair chromatin discontinuities caused by retroelement insertions. Genetic analyses reveal the importance of these mechanisms of protection, each of which specializes in silencing retroelements of different evolutionary ages. Together, these strategies allow mammalian genomes to withstand the high burden of their parasites.

  • Genomic changes during evolution of animal parasitism in eukaryotes.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2015-12-08
    Amber Leckenby,Neil Hall

    Understanding how pathogens have evolved to survive in close association with their hosts is an important step in unraveling the biology of host-pathogen interactions. Comparative genomics is a powerful tool to approach this problem as an increasing number of genomes of multiple pathogen species and strains become available. The ever-growing catalog of genome sequences makes comparison of organisms easier, but it also allows us to reconstitute the evolutionary processes occurring at the genomic level that may have led to the acquisition of pathogenic or parasitic mechanisms.

  • The mutational landscape of endometrial cancer.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2015-01-27
    Bo Hong,Matthieu Le Gallo,Daphne W Bell

    Globally, endometrial carcinoma causes about 74000 deaths annually. Endometrial carcinomas can be classified into several histological subtypes including endometrioid and serous histologies. Over the course of the past two years, a number of studies have decoded the exomes of endometrioid and serous endometrial carcinomas revealing novel somatically mutated genes that are likely to drive their development. Moreover, an integrated genomic analysis of these two histological subtypes by The Cancer Genome Atlas has led to their molecular reclassification into four discrete molecular subgroups. Collectively, these genomic advances set the stage for future biological and clinical studies to determine their relevance for patient care.

  • Intergenic lncRNAs and the evolution of gene expression.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2014-05-24
    Ana C Marques,Chris P Ponting

    Eukaryote genomes encode a surprisingly large number of noncoding transcripts. Around two-thirds of human transcribed loci do not encode protein, and many are intergenic and produce long (>200 nucleotides) noncoding RNAs (lncRNAs). Extensive analyses using comparative genomics and transcriptomics approaches have established that lncRNA sequence and transcription tend to turn over rapidly during evolution. Our appreciation of the biological roles of lncRNAs, based only on a handful of transcripts with well-characterized functions, is that lncRNAs have diverse roles in regulating gene expression. These proposed roles together with their rapid rates of evolution suggest that lncRNAs could contribute to the divergent expression patterns observed among species and potentially to the origin of new traits.

  • Existence and consequences of G-quadruplex structures in DNA.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2014-03-04
    Pierre Murat,Shankar Balasubramanian

    While the discovery of B-form DNA 60 years ago has defined our molecular view of the genetic code, other postulated DNA secondary structures, such as A-DNA, Z-DNA, H-DNA, cruciform and slipped structures have provoked consideration of DNA as a more dynamic structure. Four-stranded G-quadruplex DNA does not use Watson-Crick base pairing and has been subject of considerable speculation and investigation during the past decade, particularly with regard to its potential relevance to genome integrity and gene expression. Here, we discuss recent data that collectively support the formation of G-quadruplexes in genomic DNA and the consequences of formation of this structural motif in biological processes.

  • Supercoiling in DNA and chromatin.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2014-03-04
    Nick Gilbert,James Allan

    Supercoiling is a fundamental property of DNA and chromatin. It is modulated by polymerase and topoisomerase activities and, through regulated constraint, by DNA/chromatin binding proteins. As a non-covalent and elusive topological modification, supercoiling has proved intractable to research despite being a crucial regulator of nuclear structure and function. Recent studies have improved our understanding of the formation, regulation and organisation of supercoiling domains in vivo, and reinforce the prospect that the propagation of supercoiling can influence local and global chromatin structure. However, to further our understanding the development of new experimental tools and models are required to better dissect the mechanics of this key topological regulator.

  • Modulation of chromatin modifying complexes by noncoding RNAs in trans.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2014-02-19
    Ezequiel Názer,Elissa P Lei

    Increasing evidence supports a central role for ncRNA in numerous aspects of chromatin function. For instance, ncRNAs can act as a scaffold for the recruitment of certain chromatin modifying complexes to specific sites within the genome. It is easily imaginable how this can occur in cis, but examples also exist whereby targeting of complexes by ncRNA occurs in trans to the site of transcription. Moreover, association of an ncRNA with a particular locus can trigger localization of the gene to a subnuclear structure harboring a specialized transcriptional environment. In this review, we discuss new insights into the mechanisms by which ncRNAs function in trans with respect to Polycomb Group, chromatin insulator, and dosage compensation complexes in mammals and/or Drosophila.

  • Histone variants: the tricksters of the chromatin world.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2014-01-28
    Catherine Volle,Yamini Dalal

    The eukaryotic genome exists in vivo at an equimolar ratio with histones, thus forming a polymer composed of DNA and histone proteins. Each nucleosomal unit in this polymer provides versatile capabilities and dynamic range. Substitutions of the individual components of the histone core with structurally distinct histone variants and covalent modifications alter the local fabric of the chromatin fiber, resulting in epigenetic changes that can be regulated by the cell. In this review, we highlight recent advances in the study of histone variant structure, assembly, and inheritance, their influence on nucleosome positioning, and their cumulative effect upon gene expression, DNA repair and the progression of disease. We also highlight fundamental questions that remain unanswered regarding the behavior of histone variants and their influence on cellular function in the normal and diseased states.

  • The role of pluripotency gene regulatory network components in mediating transitions between pluripotent cell states.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-08-13
    Nicola Festuccia,Rodrigo Osorno,Valerie Wilson,Ian Chambers

    Pluripotency is a property that early embryonic cells possess over a considerable developmental time span. Accordingly, pluripotent cell lines can be established from the pre-implantation or post-implantation mouse embryo as embryonic stem (ES) or epiblast stem (EpiSC) cell lines, respectively. Maintenance of the pluripotent phenotype depends on the function of specific transcription factors (TFs) operating within a pluripotency gene regulatory network (PGRN). As cells move from an ES cell to an EpiSC state, the PGRN changes with expression of some TFs reduced (e.g. Nanog) or eliminated (e.g. Esrrb). Re-expressing such TFs can move cells back to an earlier developmental identity and is being applied to attempt establishment of human cell lines with the properties of mouse ES cells.

  • ECM-modulated cellular dynamics as a driving force for tissue morphogenesis.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-07-16
    William P Daley,Kenneth M Yamada

    The extracellular matrix (ECM) plays diverse regulatory roles throughout development. Coordinate interactions between cells within a tissue and the ECM result in the dynamic remodeling of ECM structure. Both chemical signals and physical forces that result from such microenvironmental remodeling regulate cell behavior that sculpts tissue structure. Here, we review recent discoveries illustrating different ways in which ECM remodeling promotes dynamic cell behavior during tissue morphogenesis. We focus first on new insights that identify localized ECM signaling as a regulator of cell migration, shape, and adhesion during branching morphogenesis. We also review mechanisms by which the ECM and basement membrane can both sculpt and stabilize epithelial tissue structure, using as examples Drosophila egg chamber development and cleft formation in epithelial organs. Finally, we end with an overview of the dynamic mechanisms by which the ECM can regulate stem cell differentiation to contribute to proper tissue morphogenesis.

  • Planar cell polarity in vertebrate limb morphogenesis.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-06-12
    Bo Gao,Yingzi Yang

    Studies of the vertebrate limb development have contributed significantly to understanding the fundamental mechanisms underlying growth, patterning, and morphogenesis of a complex multicellular organism. In the limb, well-defined signaling centers interact to coordinate limb growth and patterning along the three axes. Recent analyses of live imaging and mathematical modeling have provided evidence that polarized cell behaviors governed by morphogen gradients play an important role in shaping the limb bud. Furthermore, the Wnt/planar cell polarity (PCP) pathway that controls uniformly polarized cell behaviors in a field of cells has emerged to be critical for directional morphogenesis in the developing limb. Directional information coded in the morphogen gradient may be interpreted by responding cells through regulating the activities of PCP components in a Wnt morphogen dose-dependent manner.

  • Fine-tuned shuttles for bone morphogenetic proteins.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-06-06
    Kristi A Wharton,Mihaela Serpe

    Bone morphogenetic proteins (BMPs) are potent secreted signaling factors that trigger phosphorylation of Smad transcriptional regulators through receptor complex binding at the cell-surface. Resulting changes in target gene expression impact critical cellular responses during development and tissue homeostasis. BMP activity is tightly regulated in time and space by secreted modulators that control BMP extracellular distribution and availability for receptor binding. Such extracellular regulation is key for BMPs to function as morphogens and/or in the formation of morphogen activity gradients. Here, we review shuttling systems utilized to control the distribution of BMP ligands in tissue of various geometries, developing under different temporal constraints. We discuss the biological advantages for employing specific strategies for BMP shuttling and roles of varied ligand forms.

  • Genetics of prion diseases.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-03-23
    Sarah E Lloyd,Simon Mead,John Collinge

    Prion diseases are transmissible, fatal neurodegenerative diseases that include scrapie and bovine spongiform encephalopathy (BSE) in animals and Creutzfeldt-Jakob disease (CJD) in human. The prion protein gene (PRNP) is the major genetic determinant of susceptibility, however, several studies now suggest that other genes are also important. Two recent genome wide association studies in human have identified four new loci of interest: ZBTB38-RASA2 in UK CJD cases and MTMR7 and NPAS2 in variant CJD. Complementary studies in mouse have used complex crosses to identify new modifiers such as Cpne8 and provided supporting evidence for previously implicated genes (Rarb and Stmn2). Expression profiling has identified new candidates, including Hspa13, which reduces incubation time in a transgenic model.

  • ATRX and the replication of structured DNA.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-03-05
    David Clynes,Richard J Gibbons

    Understanding the underlying molecular basis for disease can often be a prolonged and tortuous process with many false leads and blind alleys. Relating the cause of ATR-X syndrome to the function of the protein ATRX is a case in point. In this review we attempt to bring together the diverse biological phenomena associated with ATRX dysfunction with what has recently been discovered concerning the chromatin remodelling activity of this protein. This potentially casts light on how defective DNA replication/histone replacement can impact on transcription, telomere maintenance and also possibly chromosome segregation.

  • Non-coding transcription and large-scale nuclear organisation of immunoglobulin recombination.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2013-02-26
    Michael J T Stubbington,Anne E Corcoran

    The enormous antigen receptor loci in lymphocytes are a paradigm of dynamic nuclear organisation, which is integral to their need to move extensively in 3D space to achieve distal gene synapse for V(D)J recombination and allelic exclusion. The loci undergo extensive 3D looping to bring distal genes together, controlled by several tissue-specific and ubiquitous factors, but how these factors achieve looping, synapsis and V(D)J recombination has been a mystery. Now several studies provide evidence that non-coding transcription, often proposed to play a role, is indeed an important driver, and furthermore has a specific nuclear destination for recombination. Both local transcription-independent looping and longer range factor-mediated transcription-dependent looping play separate roles in altering AgR architecture to enable V(D)J recombination.

  • Reprogramming and development in nuclear transfer embryos and in interspecific systems.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-10-16
    Patrick Narbonne,Kei Miyamoto,J B Gurdon

    Nuclear transfer (NT) remains the most effective method to reprogram somatic cells to totipotency. Somatic cell nuclear transfer (SCNT) efficiency however remains low, but recurrent problems occurring in partially reprogrammed cloned embryos have recently been identified and some remedied. In particular, the trophectoderm has been identified as a lineage whose reprogramming success has a large influence on SCNT embryo development. Several interspecific hybrid and cybrid reprogramming systems have been developed as they offer various technical advantages and potential applications, and together with SCNT, they have led to the identification of a series of reprogramming events and responsible reprogramming factors. Interspecific incompatibilities hinder full exploitation of cross-species reprogramming systems, yet recent findings suggest that these may not constitute insurmountable obstacles.

  • Reprogramming somatic cells towards pluripotency by cellular fusion.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-08-08
    Jorge Soza-Ried,Amanda G Fisher

    Pluripotent cells arise within the inner cell mass (ICM) of mammals and have the potential to generate all cell types of the adult organism through a process of commitment and ordered differentiation. Despite many decades of investigation, the mechanisms that guide and stabilise cell fate choice as well as those that can be engineered to promote its reversal, remain only partially resolved. Reprogramming of somatic cells towards a pluripotent-like state can be achieved by several different experimental routes including nuclear transfer, the supply of a defined cocktail of transcription factors, or by fusing somatic cells with a pluripotent stem cell partner. These approaches have been used to demonstrate the remarkable intrinsic epigenetic plasticity of many terminally differentiated cell types, as well as to define the factors that are required for pluripotent conversion. In this review we summarise some recent advances using cell fusion-based studies to better understand the basis of pluripotency and the epigenetic mechanisms that promote cell type inter-conversion.

  • A Fox stops the Wnt: implications for forebrain development and diseases.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-06-30
    Catherine Danesin,Corinne Houart

    In recent years, much progress has been made in understanding the process by which the brain is organised into specific regions. Much less is known about the way neuronal subtypes are defined inside these areas and how the temporal control of connectivity between neurons is achieved. Our thought processes and behaviours depend upon the development of neuronal circuits located in the most anterior brain area: the telencephalon (forming our cerebral cortex). The transcription factor Foxg1 is crucial to the development of specific neuronal fates inside this region and recent findings in zebrafish and mouse unveiled its impact as an integrator of telencephalic signalling centres. This essential regulatory activity may be key to understand Foxg1-dependent human disorders.

  • Development of the sensory nervous system in the vertebrate head: the importance of being on time.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-06-26
    Laura Lleras-Forero,Andrea Streit

    Sense organs and cranial sensory ganglia are functionally diverse, yet share a common developmental origin. They arise from a pool of multipotent progenitors and local signals gradually restrict their development potential to specify the inner ear, olfactory epithelium, lens and sensory neurons. This process requires the temporal integration of multiple signalling pathways, cross-repressive transcription factor interactions and tight coordination of cell fate specification and morphogenesis.

  • Notch signaling and neural connectivity.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-05-23
    Edward Giniger

    The cell surface receptor Notch contributes to the development of nearly every tissue in most metazoans by controlling the fates and differentiation of cells. Recent results have now established that Notch also regulates the connectivity of the nervous system, and does so at a variety of levels, including specification of neuronal identity, division, survival and migration, as well as axon guidance, morphogenesis of dendritic arbors and weighting of synapse strength. To these ends, Notch engages at least two signal transduction pathways, one that controls nuclear gene expression and another that directly targets the cytoskeleton. Coordinating the many functions of Notch to produce neural structure is thus a pivotal aspect of building and maintaining the nervous system.

  • Transcription factories: genetic programming in three dimensions.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-03-01
    Lucas Brandon Edelman,Peter Fraser

    Among the most intensively studied systems in molecular biology is the eukaryotic transcriptional apparatus, which expresses genes in a regulated manner across hundreds of different cell types. Several studies over the past few years have added weight to the concept that transcription takes place within discrete 'transcription factories' assembled inside the cell nucleus. These studies apply innovative technical approaches to gain insights into the molecular constituents, dynamical behaviour and organizational regulators of transcription factories, providing exciting insights into the spatial dimension of transcriptional control.

  • Different means, same end-heterochromatin formation by RNAi and RNAi-independent RNA processing factors in fission yeast.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2012-01-17
    Francisca E Reyes-Turcu,Shiv Is Grewal

    The assembly of heterochromatin in eukaryotic genomes is critical for diverse chromosomal events including regulation of gene expression, silencing of repetitive DNA elements, proper segregation of chromosomes and maintenance of genomic integrity. Previous studies have shown that noncoding RNAs and the RNA interference (RNAi) machinery promote the assembly of heterochromatin that serves as a multipurpose platform for targeting effectors involved in various chromosomal processes. Recent work has revealed that RNAi-independent mechanisms, involving RNA processing activities that utilize both noncoding and coding RNAs, operate in the assembly of heterochromatin. These findings have established that, in addition to coding for proteins, mRNAs also function as signaling molecules that modify chromatin structure by targeting heterochromatin assembly factors.

  • Enhancer and promoter interactions-long distance calls.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-12-16
    Ivan Krivega,Ann Dean

    In metazoans, enhancers of gene transcription must often exert their effects over tens of kilobases of DNA. Over the past decade it has become clear that to do this, enhancers come into close proximity with target promoters with the looping away of intervening sequences. In a few cases proteins that are involved in the establishment or maintenance of these loops have been revealed but how the proper gene target is selected remains mysterious. Chromatin insulators had been appreciated as elements that play a role in enhancer fidelity through their enhancer blocking or barrier activity. However, recent work suggests more direct participation of insulators in enhancer-gene interactions. The emerging view begins to incorporate transcription activation by distant enhancers with large scale nuclear architecture and subnuclear movement.

  • What do expression dynamics tell us about the mechanism of transcription?
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-08-25
    Daniel R Larson

    Single-cell microscopy studies have the potential to provide an unprecedented view of gene expression with exquisite spatial and temporal sensitivity. However, there is a challenge to connect the holistic cellular view with a reductionist biochemical view. In particular, experimental efforts to characterize the in vivo regulation of transcription have focused primarily on measurements of the dynamics of transcription factors and chromatin modifying factors. Such measurements have elucidated the transient nature of many nuclear interactions. In the past few years, experimental approaches have emerged that allow for interrogation of the output of transcription at the single-molecule, single-cell level. Here, I summarize the experimental results and models that aim to provide an integrated view of transcriptional regulation.

  • More than a splicing code: integrating the role of RNA, chromatin and non-coding RNA in alternative splicing regulation.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-04-19
    Reini F Luco,Tom Misteli

    Large portions of the genome undergo alternative pre-mRNA splicing in often intricate patterns. Alternative splicing regulation requires extensive control mechanisms since errors can have deleterious consequences and may lead to developmental defects and disease. Recent work has identified a complex network of regulatory RNA elements which guide splicing decisions. In addition, the discovery that transcription and splicing are intimately coupled has opened up new directions into alternative splicing regulation. Work at the interface of chromatin and RNA biology has revealed unexpected molecular links between histone modifications, the transcription machinery, and non-coding RNAs (ncRNAs) in the determination of alternative splicing patterns.

  • Intermediate phenotypes in psychiatric disorders.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-03-08
    Roberta Rasetti,Daniel R Weinberger

    The small effect size of most individual risk factors for psychiatric disorders likely reflects biological heterogeneity and diagnostic imprecision, which has encouraged genetic studies of intermediate biological phenotypes that are closer to the molecular effects of risk genes than are the clinical symptoms. Neuroimaging-based intermediate phenotypes have emerged as particularly promising because they map risk associated gene effects onto physiological processes in brain that are altered in patients and in their healthy relatives. Recent evidence using this approach has elucidated discrete, dissociable biological mechanisms of risk genes at the level of neural circuitries, and their related cognitive functions. This approach may greatly contribute to our understanding of the genetics and pathophysiology of psychiatric disorders.

  • Chromatin states in pluripotent, differentiated, and reprogrammed cells.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2011-02-15
    Cynthia L Fisher,Amanda G Fisher

    The pluripotent state of embryonic stem cells is maintained by a core network of transcription factors, and by chromatin remodelling factors that support an environment permissive for transcription. Polycomb and trithorax Group proteins enable 'bivalent' chromatin to be established at lineage-specific genes within pluripotent cells that is thought to poise genes for rapid activation upon induction of differentiation. As differentiation proceeds, chromatin condenses and there is a genome-wide increase in the abundance of repressive histone modifications, alterations in the subnuclear organisation of particular genomic regions, and changes in DNA methylation profiles within genes. Reprogramming of somatic cells provides a platform to investigate the role of chromatin-based factors in establishing and maintaining pluripotency.

  • Developmental control of the early mammalian embryo: competition among heterogeneous cells that biases cell fate.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-06-18
    Alexander W Bruce,Magdalena Zernicka-Goetz

    The temporal and spatial segregation of the two extra-embryonic cell lineages, trophectoderm and primitive endoderm (TE and PE respectively), from the pluripotent epiblast (EPI) during mammalian pre-implantation development are prerequisites for the successful implantation of the blastocyst. The mechanisms underlying these earliest stages of development remain a fertile topic for research and informed debate. In recent years novel roles for various transcription factors, polarity factors and signalling cascades have been uncovered. This mini-review seeks to summarise some of this work and to put it into the context of the regulative nature of early mammalian development and to highlight how the increasing evidence of naturally occurring asymmetries and heterogeneity in the embryo can bias specification of the distinct cell types of the blastocyst.

  • Cohesin: a global player in chromosome biology with local ties to gene regulation.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-06-15
    Matthias Merkenschlager

    Cohesin complexes hold sister chromatids together, which is essential for proper chromosome segregation during cell division and for post-replicative DNA repair. Recent studies suggest that, in addition to this global role in chromosome biology, cohesin is recruited to specific chromosomal locations by CTCF, and perhaps by other sequence-specific DNA binding factors. Once in position, cohesin controls chromosome conformation at the local level. Could this be key to understanding cohesin's role in gene expression?

  • Genome-wide association studies in common cancers--what have we learnt?
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-04-27
    Jajini Susan Varghese,Douglas F Easton

    Genome-wide association studies (GWAS) have led to the identification of more than 100 common, low-penetrance loci for cancer. At these loci, common genetic variants are associated with moderate increases in risk, typically <1.5-fold. Almost all loci lie in genomic regions not previously suspected to be involved in cancer. A plausible functional basis for a few loci, such as FGFR2 for breast cancer and MSMB for prostate cancer, has been elucidated, but the majority are not understood and suggest new mechanisms of carcinogenesis. Most loci are specific to a single cancer type, and are often subtype specific (e.g. ER-positive breast cancer). There are notable differences in the genetic architecture for different cancer types, with a greater contribution of common variants for prostate cancer. The clinical utility of variants to predict individual disease risk of disease is currently limited, but this may change as more variants are identified.

  • Genetic predisposition to gastro-oesophageal cancer.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-03-30
    Pierre Lao-Sirieix,Carlos Caldas,Rebecca C Fitzgerald

    Gastro-oesophageal cancers were ranked as the second cause of death from cancer worldwide despite a steady decrease in incidence for squamous cell carcinoma (SCC) of the oesophagus and distal gastric cancers. Adenocarcinoma of the oesophagus (OAC) is the tumour whose incidence has seen the highest increase in the past 30 years. Most of these cancers are strongly associated with environmental and life style risk factors such as smoking and alcohol for SCC, gastro-oesophageal reflux for OAC and Helicobacter pylori for distal gastric cancer. It may therefore be unsurprising that SCC is associated with polymorphisms in ALDH2 and ADH1B1, enzyme involved in alcohol metabolism, and with CYP1A1, involved in xenobiotics detoxification. OAC, whose incidence in absolute terms remains low, has been much less studied and at best the associations identified with risk are weak. Diffuse type gastric cancers while relatively uncommon have a strong genetic association with mutation of the CDH1 gene and prostate specific cancer antigen (PSCA) was demonstrated in a GWAS to be associated with an increased risk of diffuse gastric cancer but not intestinal type gastric cancer. This family of cancer is more associated with polymorphisms at the IL-1beta, IL-1RN loci and MHTFR loci. Specific strains of H pylori containing the virulence factors VacA s1, VacA m1 and cag A together with polymorphism at the IL-1beta and IL-1RN loci have up to a 87-fold increase in risk for developing intestinal type gastric cancer. While progress has been made to identify genetic variants associated with upper-gastrointestinal cancers, the relative small prevalence for some subtypes underlies the need for consortia, especially in view of the large variations in the prevalence of polymorphisms between different populations.

  • The transcriptional interactome: gene expression in 3D.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-03-10
    Stefan Schoenfelder,Ieuan Clay,Peter Fraser

    Transcription in the eukaryotic nucleus has long been thought of as conforming to a model in which RNA polymerase complexes are recruited to and track along isolated templates. However, a more dynamic role for chromatin in transcriptional regulation is materializing: enhancer elements interact with promoters forming loops that often bridge considerable distances and genomic loci, even located on different chromosomes, undergo chromosomal associations. These associations amass to form an extensive 'transcriptional interactome', enacted at functional subnuclear compartments, to which genes dynamically relocate. The emerging view is that long-range chromosomal associations between genomic regions, and their repositioning in the three-dimensional space of the nucleus, are key contributors to the regulation of gene expression.

  • RNAi-dependent formation of heterochromatin and its diverse functions.
    Curr. Opin. Genet. Dev. (IF 5.288) Pub Date : 2010-03-09
    Shiv Is Grewal

    Expression profiling of eukaryotic genomes has revealed widespread transcription outside the confines of protein-coding genes, leading to production of antisense and non-coding RNAs (ncRNAs). Studies in Schizosaccharomyces pombe and multicellular organisms suggest that transcription and ncRNAs provide a framework for the assembly of heterochromatin, which has been linked to various chromosomal processes. In addition to gene regulation, heterochromatin is crucial for centromere function, cell fate determination as well as transcriptional and posttranscriptional silencing of repetitive DNA elements. Recently, heterochromatin factors have been shown to suppress antisense RNAs at euchromatic loci. These findings define conserved pathways that probably have major impact on the epigenetic regulation of eukaryotic genomes.

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